NYNP26 • New York Advanced Practice Nurses 2026 (Includes 25 Pharmacology Hours)

Table of Contents

NYNP26 • New York Advanced Practice Nurses 2026 (Includes 25 Pharmacology Hours)

How to Receive Credit

NetCE 3 Hour Course #95152 • Responsible and Effective Opioid Prescribing

95152 • Responsible and Effective Opioid Prescribing

1. INTRODUCTION

2. SCOPE OF THE PROBLEM

3. PAIN MANAGEMENT APPROACHES

4. CREATING A TREATMENT PLAN AND ASSESSMENT OF ADDICTION RISK

5. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

6. INTERVENTIONS FOR SUSPECTED OR KNOWN ADDICTION OR DRUG DIVERSION

7. COMPLIANCE WITH STATE AND FEDERAL LAWS

8. MANAGEMENT OF OPIOID USE DISORDER

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 7 Hour Course #95310 • Anticoagulation and Antiplatelet Therapy: Clinical Use Guidelines

95310 • Anticoagulation and Antiplatelet Therapy: Clinical Use Guidelines

1. INTRODUCTION

2. BACKGROUND AND INTRODUCTION

3. PATHOPHYSIOLOGY OF DISEASE

4. ANTIPLATELETS

5. ANTICOAGULANTS

6. INDICATIONS FOR ANTIPLATELETS AND ANTICOAGULANTS

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #94674 • Pneumonia

94674 • Pneumonia

1. HISTORICAL BACKGROUND

2. DEFINITIONS

3. EPIDEMIOLOGY AND SCOPE

4. GUIDELINE-DIRECTED MANAGEMENT AND PREVENTION OF PNEUMONIA

5. PATHOGENESIS AND CLASSIFICATION OF PNEUMONIA

6. COMMUNITY-ACQUIRED PNEUMONIA

7. PREVENTION OF PNEUMONIA

8. PNEUMONIA ASSOCIATED WITH HEALTHCARE FACILITIES

9. SUMMARY

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #95231 • Psychopharmacology

95231 • Psychopharmacology

1. INTRODUCTION

2. A BRIEF HISTORY OF PSYCHIATRY AND PSYCHOPHARMACOLOGY

3. ANTIPSYCHOTIC MEDICATIONS

4. ANTIDEPRESSANT MEDICATIONS

5. MOOD STABILIZERS AND BIPOLAR DISORDER

6. ANTIANXIETY MEDICATIONS

7. PHARMACOTHERAPY FOR SUBSTANCE USE DISORDERS

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NYNP26 • New York Advanced Practice Nurses 2026 (Includes 25 Pharmacology Hours)

Mark Rose, BS, MA, LP

Justin Delic, PharmD, BCCCP

Carol Whelan, APRN

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

NYNP26 • New York Advanced Practice Nurses 2026 (Includes 25 Pharmacology Hours)

Expiration Date: 05/31/2027

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

95152 • Responsible and Effective Opioid Prescribing

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat pain patients with opioids. By implementing these tools, clinicians can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

Table of Contents

95152 • Responsible and Effective Opioid Prescribing

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. SCOPE OF THE PROBLEM

3. PAIN MANAGEMENT APPROACHES

ACUTE PAIN

CHRONIC PAIN

PALLIATIVE CARE AND PAIN AT THE END OF LIFE

4. CREATING A TREATMENT PLAN AND ASSESSMENT OF ADDICTION RISK

RISK ASSESSMENT TOOLS

INFORMED CONSENT AND TREATMENT AGREEMENTS

PERIODIC REVIEW AND MONITORING

CONCURRENT USE OF BENZODIAZEPINES

CONSULTATION AND REFERRAL

MEDICAL RECORDS

PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

DISCONTINUING OPIOID THERAPY

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

5. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

6. INTERVENTIONS FOR SUSPECTED OR KNOWN ADDICTION OR DRUG DIVERSION

7. COMPLIANCE WITH STATE AND FEDERAL LAWS

CONTROLLED SUBSTANCES LAWS/RULES

STATE-SPECIFIC LAWS AND RULES

8. MANAGEMENT OF OPIOID USE DISORDER

CRISIS INTERVENTION

HARM REDUCTION

DETOXIFICATION AND WITHDRAWAL

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

STIGMA OF ADDICTION

PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

95152 • Responsible and Effective Opioid Prescribing

Education Category. Pharmacology

Release Date. 05/01/2024

Expiration Date. 04/30/2027

Course Overview

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat pain patients with opioids. By implementing these tools, clinicians can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

Audience

This course is designed for all physicians, osteopaths, physician assistants, pharmacy professionals, and nurses who may alter prescribing practices or intervene to prevent drug diversion and inappropriate opioid use.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 3 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 3 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 3 ANCC contact hour(s). NetCE designates this continuing education activity for 3 pharmacology hour(s) for physician assistants. NetCE designates this continuing education activity for 3 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 3.6 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 3 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. NetCE designates this activity for 3 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-24-015-H05-P. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the activity with individual assessments of the participant and feedback to the participant, enables the participant to earn 3 MOC points in the American Board of Pediatrics' (ABP) Maintenance of Certification (MOC) program. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABP MOC credit. This activity has been designated for 3 Lifelong Learning (Part II) credits for the American Board of Pathology Continuing Certification Program. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. NetCE is authorized by IACET to offer 0.3 CEU(s) for this program. AACN Synergy CERP Category A.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353 (valid through July 30, 2029); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2027; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This course is designed to meet the Vermont requirement for 2 hours of education in the prescribing of controlled substances. This course is designed to meet the New York requirement for 3 hours of education in pain management, palliative care, and addiction every three years for those who are authorized to prescribe controlled substances. This course is designed to meet the Arkansas requirement for 3 hours of education in the prescribing of controlled substances. This course is designed to meet 3 hours of the New Mexico requirement for education in the prescribing of controlled substances. This course is approved by the Wisconsin Medical Examining Board to meet the requirement for 2 hours of education in responsible opioid prescribing. This course has been approved by the Kentucky Board of Medical Licensure to meet the requirement for continuing medical education relating to pain management and addiction disorders, as required by HB 1 of the Kentucky General Assembly. Course approval #0617-H3-NET1a. This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to provide clinicians who prescribe or distribute opioids with an appreciation for the complexities of opioid prescribing and the dual risks of litigation due to inadequate pain control and drug diversion or misuse in order to provide the best possible patient care and to prevent a growing social problem.

Learning Objectives

Upon completion of this course, you should be able to:

1. Apply epidemiologic trends in opioid use and misuse to current practice so at-risk patient populations can be more easily identified, assessed, and treated.

2. Create comprehensive treatment plans for patients with pain that address patient needs as well as drug diversion prevention.

3. Evaluate behaviors that may indicate drug seeking or diverting as well as approaches for patients suspected of misusing opioids.

4. Identify state and federal laws governing the proper prescription and monitoring of controlled substances.

5. Describe the available treatment modalities for opioid use disorder.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Mary Franks, MSN, APRN, FNP-C

Randall L. Allen, PharmD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Pain is the leading reason for seeking medical care, and pain management is a large part of many healthcare professionals' practice. Opioid analgesics are approved by the U.S. Food and Drug Administration (FDA) for moderate and severe pain and are broadly accepted in acute pain, cancer pain, and end-of-life care, but are controversial in chronic noncancer pain. In response to the long-standing neglect of severe pain, indications for opioid analgesic prescribing were expanded in the 1990s, followed by inappropriate prescribing and increasing abuse, addiction, diversion, and overdose through the 2000s. In tandem with the continued under-treatment of pain, these practice patterns led to needless suffering from uncontrolled pain, opioid analgesic addiction, and overdose. Opioid analgesic prescribing and associated overdose peaked in 2011 with both now in multi-year decline.

Patients show substantial opioid response variations in analgesia and tolerability and may exhibit a range of psychologic, emotional, and behavioral responses that reflect inadequate pain control, an emerging opioid use problem, or both. Clinician delivery of best possible care to patients with pain requires appreciation of the complexities of opioid prescribing and the dual risks of inadequate pain control and inappropriate use, drug diversion, or overdose. A foundation for appropriate opioid prescribing is the understanding of factual data that clarify the prevalence, causality, and prevention of serious safety concerns with opioid prescribing.

2. SCOPE OF THE PROBLEM

Inappropriate opioid analgesic prescribing for pain is defined as the non-prescribing, inadequate prescribing, excessive prescribing, or continued prescribing despite evidence of ineffectiveness of opioids[1]. Appropriate opioid prescribing is essential to achieve pain control; to minimize patient risk of abuse, addiction, and fatal toxicity; and to minimize societal harms from diversion. The foundation of appropriate opioid prescribing is thorough patient assessment, treatment planning, and follow-up and monitoring. Essential for proper patient assessment and treatment planning is comprehension of the clinical concepts of opioid abuse and addiction, their behavioral manifestations in patients with pain, and how these potentially problematic behavioral responses to opioids both resemble and differ from physical dependence and pseudo-dependence. Prescriber knowledge deficit has been identified as a key obstacle to appropriate opioid prescribing and, along with gaps in policy, treatment, attitudes, and research, contributes to widespread inadequate treatment of pain [2].

The extent of opioid analgesic use in the United States in the 2000s was unprecedented in the country's history and unparalleled anywhere in the world. Before 1990, physicians in the United States were skeptical of prescribing opioids for chronic noncancer pain. In 2019, 22.1% of adults used a prescription opioid such as oxycodone and hydrocodone for chronic pain, and sales of opioid analgesics totaled approximately $7 billion in 2016 [3,4].

Worldwide consumption of opioid analgesics has increased dramatically in the past few decades, with the United States driving a substantial proportion of this increase. For example, the 1990 global consumption of hydrocodone was 4 tons (3,628 kg), compared with the 2009 consumption of 39 tons (35,380 kg); 99% of this was consumed in the United States. Similarly, 3 tons (2,722 kg) of oxycodone were consumed globally in 1990, versus 77 tons (69,853 kg) in 2009, of which 62 tons (56,245 kg or 81%) were consumed in the United States [5]. With only 4.23% of the world's population, the United States annually consumes more than 80% of all opioid supplies, including [6,7]:

- 99% of all hydrocodone

- 68% of all oxycodone

- 52% of all methadone

- 40% of all hydromorphone

- 19% of all fentanyl

This disproportionate rate of opioid consumption reflects sociocultural and economic factors and standards of clinical medicine.

Between 1992 and 2003, the U.S. population increased 14%, while persons abusing opioid analgesics increased 94% and first-time non-medical opioid analgesic users 12 to 17 years of age increased 542% [8]. It is interesting to note that while opioid prescribing has increased precipitously among adults in the United States, the rate remained low and steady for children between 1996 and 2012 [9]. A study using data from 2005 to 2015 showed opioid prescribing in 57 million visits from adolescents and young adults, representing a prescribing rate of nearly 15% in emergency departments and nearly 3% in outpatient clinical settings [10]. During the course of the study, emergency department prescribing decreased slightly while outpatient clinical setting prescribing remained the same [10]. To assist in monitoring the public health problem associated with prescribed opioids, numerous governmental, non-profit, and private sector agencies and organizations are involved in collecting, reporting, and analyzing data on the abuse, addiction, fatal overdose, and treatment admissions related to opioid analgesics.

Before it was halted in 2011, the Drug Abuse Warning Network (DAWN) provided estimates of the health consequences of nonmedical use of individual drugs, including opioid medications [11]. DAWN indicates that opioid abuse is a growing problem in the United States. In 2005 and 2011, hydrocodone and its combinations accounted for 51,225 and 97,183 emergency department visits, respectively. Oxycodone and its combinations resulted in 42,810 visits to the emergency department in 2005; this number increased to 175,229 visits in 2011 [12,13]. Visits for nonmedical use of all opioids increased from 217,594 to 420,040 during the six-year period. In 2016–2017, there were 127,101 nonmedical opioid emergency department visits [14]. While this number is an improvement from previous years, nonmedical use accounts for 47.6% of all emergency department visits related to opioids [14].

3. PAIN MANAGEMENT APPROACHES

Healthcare professionals should know the best clinical practices in opioid prescribing, including the associated risks of opioids, approaches to the assessment of pain and function, and pain management modalities. Pharmacologic and nonpharmacologic approaches should be used on the basis of current knowledge in the evidence base or best clinical practices. Patients with moderate-to-severe chronic pain who have been assessed and treated, over a period of time, with non-opioid therapy or nonpharmacologic pain therapy without adequate pain relief, are considered to be candidates for a trial of opioid therapy [3,15]. Initial treatment should always be considered individually determined and as a trial of therapy, not a definitive course of treatment [16].

In 2016, the CDC issued updated guidance on the prescription of opioids for chronic pain [3]. The guideline addresses when to initiate or continue opioids for chronic pain; opioid selection, dosage, duration, follow-up, and discontinuation; and assessing risk and addressing harms of opioid use. In addition, the CDC further updated guidance against the misapplication of this guideline in 2019, noting that some policies and practices attributed to the guideline were inconsistent with the recommendations [17].

While these guidelines were based on the best available evidence at the time, there was some criticism that they were too focused on limiting opioid prescriptions—to the point of patients and prescribers complaining of stigma and reduced access to needed opioid analgesics. In response to this and to the availability of new evidence, the CDC published an updated guideline in 2022 [18]. The updated clinical practice guideline is intended to achieve improved communication between clinicians and patients about the risks and benefits of pain treatment, including opioid therapy for pain; improved safety and effectiveness for pain treatment, resulting in improved function and quality of life for patients experiencing pain; and a reduction in the risks associated with long-term opioid therapy, including opioid use disorder, overdose, and death [18]. It is important to remember that inappropriately limiting necessary opioid medications to address patients' pain can be damaging and should be avoided. A central tenet of the updated 2022 guideline is that acute, subacute, and chronic pain needs to be appropriately and effectively treated regardless of whether opioids are part of a treatment regimen [18].

ACUTE PAIN

Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids in a quantity no greater than that needed for the expected duration of severe pain. In most cases, three days or less will be sufficient; more than seven days will rarely be needed [3]. Payers and health systems should not use the 2022 guideline to set rigid standards related to dosage or duration of opioid therapy. The guideline is not a replacement for clinical judgment or individualized, patient-centered care [19].

With postoperative, acute, or intermittent pain, analgesia often requires frequent titration, and the two- to four-hour analgesic duration with short-acting hydrocodone, morphine, and oxycodone is more effective than extended-release formulations. Short-acting opioids are also recommended in patients who are medically unstable or with highly variable pain intensity [20,21,22].

CHRONIC PAIN

Nonpharmacologic therapy and non-opioid pharmacologic therapy are the preferred first-line therapies for chronic pain [18]. Several nonpharmacologic approaches are therapeutic complements to pain-relieving medication, lessening the need for higher doses and perhaps minimizing side effects. These interventions can help decrease pain or distress that may be contributing to the pain sensation. Approaches include palliative radiotherapy, complementary/alternative methods, manipulative and body-based methods, and cognitive/behavioral techniques. The choice of a specific nonpharmacologic intervention is based on the patient's preference, which, in turn, is usually based on a successful experience in the past.

Implantable intrathecal opioid infusion and/or spinal cord stimulation may be options for severe, intractable pain. Both options require that devices or ports be implanted, with associated risks. With intrathecal opioid infusion, the ability to deliver the drug directly into the spine provides pain relief with significantly smaller opioid doses, which can help to minimize side effects (e.g., drowsiness, dizziness, dry mouth, nausea, vomiting, and constipation) that can accompany systemic pain medications that might be delivered orally, transdermally, or through an IV [23]. However, use of opioid infusion has traditionally been limited to cancer pain. With spinal cord stimulation therapy, the most challenging aspect is patient selection. In order for patients to be considered for spinal cord stimulation, other options should have been ineffective or be contraindicated. Spinal cord stimulation is indicated for severe neuropathic pain persisting at least six months.

If opioids are used, they should be combined with nonpharmacologic therapy and non-opioid pharmacologic therapy, as appropriate. Clinicians should consider opioid therapy only if expected benefits for pain and function are anticipated to outweigh risks to the patient [18].

Opioid therapy for chronic pain should be presented as a trial for a pre-defined period (e.g., ≤30 days). The goals of treatment should be established with all patients prior to the initiation of opioid therapy, including reasonable improvements in pain, function, depression, anxiety, and avoidance of unnecessary or excessive medication use [1,18]. The treatment plan should describe therapy selection, measures of progress, and other diagnostic evaluations, consultations, referrals, and therapies. Opioid therapy should not be initiated without consideration by the clinician and patient of an exit strategy to be used if opioid therapy is unsuccessful [18].

In patients who are opioid-naïve, start at the lowest possible dose and titrate to effect. Dosages for patients who are opioid-tolerant should always be individualized and titrated by efficacy and tolerability [1,18]. When starting opioid therapy for chronic pain, clinicians should prescribe short-acting instead of extended-release/long-acting opioid formulations [18].

Evidence Based Practice Recommendation

The CDC recommends that clinicians should evaluate benefits and risks with patients within one to four weeks of starting opioid therapy for subacute or chronic pain or of dosage escalation. Clinicians should regularly re-evaluate benefits and risks of continued opioid therapy with patients.

https://www.cdc.gov/mmwr/volumes/71/rr/rr7103a1.htm

Last Accessed: April 19, 2024

Strength of Recommendation/Level of Evidence: A4 (Most patients should receive based on clinical experience and observations, observational studies with important limitations, or randomized clinical trials with several major limitations)

The need for frequent progress and benefit/risk assessments during the trial should be included in patient education. Patients should also have full knowledge of the warning signs and symptoms of respiratory depression. Prescribers should carefully reassess evidence of benefits and risks when increasing the dosage to ≥50 mg morphine equivalent dose (MED) per day. Decisions to titrate dose to ≥90 mg MED/day should be avoided or carefully justified [17,18].

Prescribers should be knowledgeable of federal and state opioid prescribing regulations. Issues of equianalgesic dosing, close patient monitoring during all dose changes, and cross-tolerance with opioid conversion should be considered. If necessary, treatment may be augmented, with preference for nonopioids and immediate-release opioids over long-acting/extended-release opioids. Taper opioid dose when no longer needed [18,24].

PALLIATIVE CARE AND PAIN AT THE END OF LIFE

Unrelieved pain is the greatest fear among people with a life-limiting disease, and the need for an increased understanding of effective pain management is well-documented [25]. Although experts have noted that 75% to 90% of end-of-life pain can be managed effectively, rates of pain are high, even among people receiving palliative care [25,26,27,28].

The inadequate management of pain is the result of several factors related to both patients and clinicians. In a survey of oncologists, patient reluctance to take opioids or to report pain were two of the most important barriers to effective pain relief [29]. This reluctance is related to a variety of attitudes and beliefs [25,29]:

- Fear of addiction to opioids

- Worry that if pain is treated early, there will be no options for treatment of future pain

- Anxiety about unpleasant side effects from pain medications

- Fear that increasing pain means that the disease is getting worse

- Desire to be a "good" patient

- Concern about the high cost of medications

Education and open communication are the keys to overcoming these barriers. Every member of the healthcare team should reinforce accurate information about pain management with patients and families. The clinician should initiate conversations about pain management, especially regarding the use of opioids, as few patients will raise the issue themselves or even express their concerns unless they are specifically asked [30]. It is important to acknowledge patients' fears individually and provide information to help them differentiate fact from fiction [26]. For example, when discussing opioids with a patient who fears addiction, the clinician should explain that the risk of addiction is low [25]. It is also helpful to note the difference between addiction and physical dependence.

There are several other ways clinicians can allay patients' fears about pain medication:

- Assure patients that the availability of pain relievers cannot be exhausted; there will always be medications if pain becomes more severe.

- Acknowledge that side effects may occur but emphasize that they can be managed promptly and safely and that some side effects will abate over time.

- Explain that pain and severity of disease are not necessarily related.

Encouraging patients to be honest about pain and other symptoms is also vital. Clinicians should ensure that patients understand that pain is multidimensional and emphasize the importance of talking to a member of the healthcare team about possible causes of pain, such as emotional or spiritual distress. The healthcare team and patient should explore psychosocial and cultural factors that may affect self-reporting of pain, such as concern about the cost of medication.

Clinicians' attitudes, beliefs, and experiences also influence pain management, with addiction, tolerance, side effects, and regulations being the most important concerns [25,27,29,31]. A lack of appropriate education and training in the assessment and management of pain has been noted to be a substantial contributor to ineffective pain management [29,31]. As a result, many clinicians, especially primary care physicians, do not feel confident about their ability to manage pain in their patients [29,31].

Clinicians require a clear understanding of available medications to relieve pain, including appropriate dosing, safety profiles, and side effects. If necessary, clinicians should consult with pain specialists to develop an effective approach.

Strong opioids are used for severe pain at the end of life [26,27]. Morphine, buprenorphine, oxycodone, hydromorphone, fentanyl, and methadone are the most widely used in the United States [32]. Unlike nonopioids, opioids do not have a ceiling effect, and the dose can be titrated until pain is relieved or side effects become unmanageable. For patients who are opioid-naïve or who have been receiving low doses of a weak opioid, the initial dose should be low, and, if pain persists, the dose may be titrated up daily until pain is controlled.

More than one route of opioid administration will be needed by many patients during end-of-life care, but in general, opioids should be given orally, as this route is the most convenient and least expensive. The transdermal route is preferred to the parenteral route, although dosing with a transdermal patch is less flexible and so may not be appropriate for patients with unstable pain [27]. Intramuscular injections should be avoided because injections are painful, drug absorption is unreliable, and the time to peak concentration is long [27].

4. CREATING A TREATMENT PLAN AND ASSESSMENT OF ADDICTION RISK

Information obtained by patient history, physical examination, and interview, from family members, a spouse, or state prescription drug monitoring program (PDMP), and from the use of screening and assessment tools can help the clinician to stratify the patient according to level of risk for developing problematic opioid behavioral responses (Table 1) [33,34]. Low-risk patients receive the standard level of monitoring, vigilance, and care. Moderate-risk patients should be considered for an additional level of monitoring and provider contact, and high-risk patients are likely to require intensive and structured monitoring and follow-up contact, additional consultation with psychiatric and addiction medicine specialists, and limited supplies of short-acting opioid formulations [18,35].

Table 1: RISK STRATIFICATION FOR PATIENTS PRESCRIBED OPIOIDS

Low Risk

Definable physical pathology with objective signs and reliable symptoms

Clinical correlation with diagnostic testing, including MRI, physical examination, and interventional diagnostic techniques

With or without mild psychologic comorbidity

With or without minor medical comorbidity

No or well-defined and controlled personal or family history of alcoholism or substance abuse

Age 45 years or older

High levels of pain acceptance and active coping strategies

High motivation and willingness to participate in multimodal therapy and attempting to function at normal levels

Medium Risk

Significant pain problems with objective signs and symptoms confirmed by radiologic evaluation, physical examination, or diagnostic interventions

Moderate psychologic problems, well controlled by therapy

Moderate coexisting medical disorders that are well controlled by medical therapy and are not affected by chronic opioid therapy (e.g., central sleep apnea)

Develops mild tolerance but not hyperalgesia without physical dependence or addiction

History of personal or family history of alcoholism or substance abuse

Pain involving more than three regions of the body

Defined pathology with moderate levels of pain acceptance and coping strategies

Willing to participate in multimodal therapy, attempting to function in normal daily life

High Risk

Widespread pain without objective signs and symptoms

Pain involving more than three regions of the body

Aberrant drug-related behavior

History of alcoholism or drug misuse, abuse, addiction, diversion, dependency, tolerance, or hyperalgesia

Major psychologic disorders

Age younger than 45 years

HIV-related pain

High levels of pain exacerbation and low levels of coping strategies

Unwilling to participate in multimodal therapy, not functioning close to a near normal lifestyle

HIV = human immunodeficiency syndrome, MRI = magnetic resonance imaging.

Source: [33,34]

Before deciding to prescribe an opioid analgesic, clinicians should perform and document a detailed patient assessment that includes [1]:

- Pain indications for opioid therapy

- Nature and intensity of pain

- Past and current pain treatments and patient response

- Comorbid conditions

- Pain impact on physical and psychologic function

- Social support, housing, and employment

- Home environment (i.e., stressful or supportive)

- Pain impact on sleep, mood, work, relationships, leisure, and substance use

- Patient history of physical, emotional, or sexual abuse

If substance abuse is active, in remission, or in the patient's history, consult an addiction specialist before starting opioids [1]. In active substance abuse, do not prescribe opioids until the patient is engaged in treatment/recovery program or other arrangement made, such as addiction professional co-management and additional monitoring. When considering an opioid analgesic (particularly those that are extended-release or long-acting), one must always weigh the benefits against the risks of overdose, abuse, addiction, physical dependence and tolerance, adverse drug interactions, and accidental exposure by children [18,24].

Screening and assessment tools can help guide patient stratification according to risk level and inform the appropriate degree of structure and monitoring in the treatment plan. It should be noted that despite widespread endorsement of screening tools used to help determine patient risk level, most tools have not been extensively evaluated, validated, or compared to each other, and evidence of their reliability is poor [33,34].

RISK ASSESSMENT TOOLS

Opioid Risk Tool (ORT)

The Opioid Risk Tool (ORT) is a five-item, patient-administered assessment to help predict aberrant drug-related behavior. The ORT is also used to establish patient risk level through categorization into low, medium, or high levels of risk for aberrant drug-related behaviors based on responses to questions of previous alcohol/drug abuse, psychologic disorders, and other risk factors [36].

Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R)

The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) is a patient-administered, 24-item screen with questions addressing history of alcohol/substance use, psychologic status, mood, cravings, and stress. Like the ORT, the SOAPP-R helps assess risk level of aberrant drug-related behaviors and the appropriate extent of monitoring [36,37].

Screening Instrument or Substance Abuse Potential (SISAP)

The Screening Instrument or Substance Abuse Potential (SISAP) tool is a self-administered, five-item questionnaire addressing history developed used to predict the risk of opioid misuse. The SISAP is used to identify patients with a history of alcohol/substance abuse and improve pain management by facilitating focus on the appropriate use of opioid analgesics and therapeutic outcomes in the majority of patients who are not at risk of opioid abuse, while carefully monitoring those who may be at greater risk [36].

CAGE and CAGE-AID

The original CAGE (Cut down, Annoyed, Guilty, and Eye-opener) Questionnaire consisted of four questions designed to help clinicians determine the likelihood that a patient was misusing or abusing alcohol. These same four questions were modified to create the CAGE-AID (adapted to include drugs), revised to assess the likelihood of current substance abuse [38].

Diagnosis, Intractability, Risk, and Efficacy (DIRE) Score

The Diagnosis, Intractability, Risk, and Efficacy (DIRE) risk assessment score is a clinician-rated questionnaire that is used to predict patient compliance with long-term opioid therapy [36,39]. Patients scoring lower on the DIRE tool are poor candidates for long-term opioid analgesia.

INFORMED CONSENT AND TREATMENT AGREEMENTS

The initial opioid prescription is preceded by a written informed consent or "treatment agreement" [1]. This agreement should address potential side effects, tolerance and/or physical dependence, drug interactions, motor skill impairment, limited evidence of long-term benefit, misuse, dependence, addiction, and overdose. Informed consent documents should include information regarding the risk/benefit profile for the drug(s) being prescribed. The prescribing policies should be clearly delineated, including the number/frequency of refills, early refills, and procedures for lost or stolen medications.

The treatment agreement also outlines joint physician and patient responsibilities. The patient agrees to using medications safely, refraining from "doctor shopping," and consenting to routine urine drug testing (UDT). The prescriber's responsibility is to address unforeseen problems and prescribe scheduled refills. Reasons for opioid therapy change or discontinuation should be listed. Agreements can also include sections related to follow-up visits, monitoring, and safe storage and disposal of unused drugs.

PERIODIC REVIEW AND MONITORING

When implementing a chronic pain treatment plan that involves the use of opioids, the patient should be frequently reassessed for changes in pain origin, health, and function [1]. This can include input from family members and/or the state PDMP. During the initiation phase and during any changes to the dosage or agent used, patient contact should be increased. At every visit, chronic opioid response may be monitored according to the "5 A's" [1,40]:

- Analgesia

- Activities of daily living

- Adverse or side effects

- Aberrant drug-related behaviors

- Affect (i.e., patient mood)

Signs and symptoms that, if present, may suggest a problematic response to the opioid and interference with the goal of functional improvement include [41,42]:

- Excessive sleeping or days and nights turned around

- Diminished appetite

- Short attention span or inability to concentrate

- Mood volatility, especially irritability

- Lack of involvement with others

- Impaired functioning due to drug effects

- Use of the opioid to regress instead of re-engaging in life

- Lack of attention to hygiene and appearance

The decision to continue, change, or terminate opioid therapy is based on progress toward treatment objectives and absence of adverse effects and risks of overdose or diversion [1]. Satisfactory therapy is indicated by improvements in pain, function, and quality of life. Brief assessment tools to assess pain and function may be useful, as may UDTs. Treatment plans may include periodic pill counts to confirm adherence and minimize diversion.

Involvement of Family

Family members of the patient can provide the clinician with valuable information that better informs decision making regarding continuing opioid therapy. Family members can observe whether a patient is losing control of his or her life or becoming less functional or more depressed during the course of opioid therapy. They can also provide input regarding positive or negative changes in patient function, attitude, and level of comfort. The following questions can be asked of family members or a spouse to help clarify whether the patient's response to opioid therapy is favorable or unfavorable [41,42]:

- Is the person's day centered around taking the opioid medication? Response can help clarify long-term risks and benefits of the medication and identify other treatment options.

- Does the person take pain medication only on occasion, perhaps three or four times per week? If yes, the likelihood of addiction is low.

- Have there been any other substance (alcohol or drug) abuse problems in the person's life? An affirmative response should be taken into consideration when prescribing.

- Does the person in pain spend most of the day resting, avoiding activity, or feeling depressed? If so, this suggests the pain medication is failing to promote rehabilitation. Daily activity is essential, and the patient may be considered for enrollment in a graduated exercise program

- Is the person in pain able to function (e.g., work, do household chores, play) with pain medication in a way that is clearly better than without? If yes, this suggests the pain medication is contributing to wellness.

Assessment Tools

VIGIL

VIGIL is the acronym for a five-step risk management strategy designed to empower clinicians to appropriately prescribe opioids for pain by reducing regulatory concerns and to give pharmacists a framework for resolving ambiguous opioid analgesic prescriptions in a manner that preserves legitimate patient need while potentially deterring diverters. The components of VIGIL are:

- Verification: Is this a responsible opioid user?

- Identification: Is the identity of this patient verifiable?

- Generalization: Do we agree on mutual responsibilities and expectations?

- Interpretation: Do I feel comfortable allowing this person to have controlled substances?

- Legalization: Am I acting legally and responsibly?

- The foundation of VIGIL is a collaborative physician/pharmacist relationship [43].

Current Opioid Misuse Measure (COMM)

The Current Opioid Misuse Measure (COMM) is a 17-item patient self-report assessment designed to help clinicians identify misuse or abuse in patients being treated for chronic pain. Unlike the ORT and the SOAPP-R, the COMM identifies aberrant behaviors associated with opioid misuse in patients already receiving long-term opioid therapy [35]. Sample questions include: In the past 30 days, how often have you had to take more of your medication than prescribed? In the past 30 days, how much of your time was spent thinking about opioid medications (e.g., having enough, taking them, dosing schedule)?

Pain Assessment and Documentation Tool (PADT)

Guidelines by the CDC, the Federation of State Medical Boards (FSMB), and the Joint Commission stress the importance of documentation from both a healthcare quality and medicolegal perspective. Research has found widespread deficits in chart notes and progress documentation with patients with chronic pain receiving opioid therapy, and the Pain Assessment and Documentation Tool (PADT) was designed to address these shortcomings [44]. The PADT is a clinician-directed interview, with most sections (e.g., analgesia, activities of daily living, adverse events) consisting of questions asked of the patient. However, the potential aberrant drug-related behavior section must be completed by the physician based on his or her observations of the patient.

The Brief Intervention Tool

The Brief Intervention Tool is a 26-item, "yes-no," patient-administered questionnaire used to identify early signs of opioid abuse or addiction. The items assess the extent of problems related to drug use in several areas, including drug use-related functional impairment [45].

Urine Drug Tests

UDTs may be used to monitor adherence to the prescribed treatment plan and to detect unsanctioned drug use. They should be used more often in patients receiving addiction therapy, but clinical judgment is the ultimate guide to testing frequency (Table 2) [46]. The CDC 2016 guideline recommends clinicians should use UDT before starting opioid therapy and consider UDT at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs [3]. However, this recommendation was based on low-quality evidence that indicates little confidence in the effect estimate, and it is not included in the 2022 updated guideline [18].

Table 2: PATIENT RISK LEVEL AND FREQUENCY OF MONITORING

Monitoring Tool

Patient Risk Level

Low

Medium

High

Urine drug test

Every 1 to 2 years

Every 6 to 12 months

Every 3 to 6 months

State prescription drug monitoring program

Twice per year

Three times per year

Four times per year

Source: [46]

Initially, testing involves the use of class-specific immunoassay drug panels [1]. If necessary, this may be followed with gas chromatography/mass spectrometry for specific drug or metabolite detection. It is important that testing identifies the specific drug rather than the drug class, and the prescribed opioid should be included in the screen. Any abnormalities should be confirmed with a laboratory toxicologist or clinical pathologist. Immunoassay may be used point-of-care for "on-the-spot" therapy changes, but the high error rate prevents its use in major clinical decisions except with liquid chromatography coupled to tandem mass spectrometry confirmation.

Urine test results suggesting opioid misuse should be discussed with the patient using a positive, supportive approach. The test results and the patient discussion should be documented.

CONCURRENT USE OF BENZODIAZEPINES

In 2021, nearly 14% of persons who died of an opioid overdose also tested positive for benzodiazepines, a class of sedative medication commonly prescribed for anxiety, insomnia, panic attack, and muscle spasm [47]. Benzodiazepines work by raising the level of the neurotransmitter gamma-aminobutyric acid (GABA) in the brain. Common formulations include diazepam, alprazolam, and clonazepam. Combining benzodiazepines with opioids is unsafe because both classes of drug cause central nervous system depression and sedation and can decrease respiratory drive—the usual cause of overdose fatality. Both classes have the potential for drug dependence and addiction.

The CDC recommends that healthcare providers use caution when prescribing benzodiazepines concurrently with opioids whenever possible [18]. If a benzodiazepine is to be discontinued, the clinician should taper the medication gradually, because abrupt withdrawal can lead to rebound anxiety and complications such as hallucinations, seizures, delirium tremens, and, in rare instances, death. The rate of tapering should be individualized [18].

CONSULTATION AND REFERRAL

It is important to seek consultation or patient referral when input or care from a pain, psychiatry, addiction, or mental health specialist is necessary. Clinicians who prescribe opioids should become familiar with opioid addiction treatment options (including licensed opioid treatment programs for methadone and office-based opioid treatment for buprenorphine) if referral is needed [1].

Ideally, providers should be able to refer patients with active substance abuse who require pain treatment to an addiction professional or specialized program. In reality, these specialized resources are scarce or non-existent in many areas [1]. Therefore, each provider will need to decide whether the risks of continuing opioid treatment while a patient is using illicit drugs outweigh the benefits to the patient in terms of pain control and improved function [48].

MEDICAL RECORDS

As noted, documentation is a necessary aspect of all patient care, but it is of particular importance when opioid prescribing is involved. All clinicians should maintain accurate, complete, and up-to-date medical records, including all written or telephoned prescription orders for opioid analgesics and other controlled substances, all written instructions to the patient for medication use, and the name, telephone number, and address of the patient's pharmacy [1]. Good medical records demonstrate that a service was provided to the patient and that the service was medically necessary. Regardless of the treatment outcome, thorough medical records protect the prescriber.

PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

Patients and caregivers should be counseled regarding the safe use and disposal of opioids. As part of its mandatory Risk Evaluation and Mitigation Strategy (REMS) for extended-release/long-acting opioids, the U.S. Food and Drug Administration (FDA) has developed a patient counseling guide with information on the patient's specific medications, instructions for emergency situations and incomplete pain control, and warnings not to share medications or take them unprescribed [49,50].

When prescribing opioids, clinicians should provide patients with the following information [49]:

- Product-specific information

- Taking the opioid as prescribed

- Importance of dosing regimen adherence, managing missed doses, and prescriber contact if pain is not controlled

- Warning and rationale to never break or chew/crush tablets or cut or tear patches prior to use

- Warning and rationale to avoid other central nervous system depressants, such as sedative-hypnotics, anxiolytics, alcohol, or illicit drugs

- Warning not to abruptly halt or reduce the opioid without physician oversight of safe tapering when discontinuing

- The potential of serious side effects or death

- Risk factors, signs, and symptoms of overdose and opioid-induced respiratory depression, gastrointestinal obstruction, and allergic reactions

- The risks of falls, using heavy machinery, and driving

- Warning and rationale to never share an opioid analgesic

- Rationale for secure opioid storage

- Warning to protect opioids from theft

- Instructions for disposal of unneeded opioids, based on product-specific disposal information

There are no universal recommendations for the proper disposal of unused opioids, and patients are rarely advised of what to do with unused or expired medications [51]. According to the FDA, most medications that are no longer necessary or have expired should be removed from their containers, mixed with undesirable substances (e.g., cat litter, used coffee grounds), and put into an impermeable, nondescript container (e.g., disposable container with a lid or a sealed bag) before throwing in the trash [52]. Any personal information should be obscured or destroyed. The FDA recommends that certain medications, including oxycodone/acetaminophen (Percocet), oxycodone (OxyContin tablets), and transdermal fentanyl (Duragesic Transdermal System), be flushed down the toilet instead of thrown in the trash [52,53]. The FDA provides a free toolkit of materials (e.g., social media images, fact sheets, posters) to raise awareness of the serious dangers of keeping unused opioid pain medicines in the home and with information about safe disposal of these medicines. The Remove the Risk Outreach toolkit is updated regularly and can be found at https://www.fda.gov/drugs/ensuring-safe-use-medicine/safe-opioid-disposal-remove-risk-outreach-toolkit [53]. Patients should be advised to flush prescription drugs down the toilet only if the label or accompanying patient information specifically instructs doing so. In April 2023, the FDA issued a letter requiring all manufacturers of opioid analgesics dispensed in outpatient settings to submit a proposed modification to the Opioid Analgesic REMS. The modification requires manufacturers to make available prepaid mail-back envelopes to outpatient pharmacies and other opioid dispensers as an opioid analgesic disposal option for patients. The FDA expects to take action on this modification in 2024 [50].

The American College of Preventive Medicine has established best practices to avoid diversion of unused drugs and educate patients regarding drug disposal [51]:

- Consider writing prescriptions in smaller amounts.

- Educate patients about safe storing and disposal practices.

- Give drug-specific information to patients about the temperature at which they should store their medications. Generally, the bathroom is not the best storage place. It is damp and moist, potentially resulting in potency decrements, and accessible to many people, including children and teens, resulting in potential theft or safety issues.

- Ask patients not to advertise that they are taking these types of medications and to keep their medications secure.

- Refer patients to community "take back" services overseen by law enforcement that collect controlled substances, seal them in plastic bags, and store them in a secure location until they can be incinerated. Contact your state law enforcement agency or visit https://www.dea.gov to determine if a program is available in your area.

DISCONTINUING OPIOID THERAPY

The decision to continue or end opioid prescribing should be based on a physician-patient discussion of the anticipated benefits and risks. An opioid should be discontinued with resolution of the pain condition, intolerable side effects, inadequate analgesia, lack of improvement in quality of life despite dose titration, deteriorating function, or significant aberrant medication use [1,18].

Clinicians should provide patients physically dependent on opioids with a safely structured tapering protocol. Withdrawal is managed by the prescribing physician or referral to an addiction specialist. Patients should be reassured that opioid discontinuation is not the end of treatment; continuation of pain management will be undertaken with other modalities through direct care or referral.

As a side note, cannabis use by patients with chronic pain receiving opioid therapy has traditionally been viewed as a treatment agreement violation that is grounds for termination of opioid therapy. However, some now argue against cannabis use as a rationale for termination or substantial treatment and monitoring changes, especially considering the increasing legalization of medical use at the state level [48].

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

For patients who are not proficient in English, it is important that information regarding the risks associated with the use of opioids and available resources be provided in their native language, if possible. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Interpreters can be a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers who ultimately enhance the clinical encounter. In any case in which information regarding treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered. Print materials are also available in many languages, and these should be offered whenever necessary.

5. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

Research has more closely defined the location of prescribed opioid diversion into illicit use in the supply chain from the manufacturer to the distributor, retailer, and the end user (the pain patient). This information carries with it substantial public policy and regulatory implications. The 2021 National Survey on Drug Use and Health asked non-medical users of prescription opioids how they obtained their most recently used drugs [54]. Among persons 12 years of age or older, 33.9% obtained their prescription opioids from a friend or relative for free, 39.3% got them through a prescription from one doctor (vs. 34.7% in 2019), 7.3% bought them from a friend or relative, and 3.7% took them from a friend or relative without asking [54]. Other sources included a drug dealer or other stranger (7.9%); multiple doctors (3.2%); and theft from a doctor's office, clinic, hospital, or pharmacy (0.7%) (vs. 0.9% in 2019) [54].

As discussed, UDTs can give insight into patients who are misusing opioids. A random sample of UDT results from 800 patients treated for pain at a Veterans Affairs facility found that 25.2% were negative for the prescribed opioid while 19.5% were positive for an illicit drug/unreported opioid [55]. Negative UDT results for the prescribed opioid do not necessarily indicate diversion but may indicate the patient halted his/her use due to side effects, lack of efficacy, or pain remission. The concern arises over the increasingly stringent climate surrounding clinical decision-making regarding aberrant UDT results and that a negative result for the prescribed opioid or a positive UDT may serve as the pretense to terminate a patient rather than guide him/her into addiction treatment or an alternative pain management program [56].

In addition to aberrant urine screens, there are certain behaviors that are suggestive of an emerging opioid use disorder. The most suggestive behaviors are [48,57,58]:

- Selling medications

- Prescription forgery or alteration

- Injecting medications meant for oral use

- Obtaining medications from nonmedical sources

- Resisting medication change despite worsening function or significant negative effects

- Loss of control over alcohol use

- Using illegal drugs or non-prescribed controlled substances

- Recurrent episodes of:

- Prescription loss or theft

- Obtaining opioids from other providers in violation of a treatment agreement

- Unsanctioned dose escalation

- Running out of medication and requesting early refills

Behaviors with a lower level of evidence for their association with opioid misuse include [48,57,58]:

- Aggressive demands for more drug

- Asking for specific medications

- Stockpiling medications during times when pain is less severe

- Using pain medications to treat other symptoms

- Reluctance to decrease opioid dosing once stable

- In the earlier stages of treatment:

- Increasing medication dosing without provider permission

- Obtaining prescriptions from sources other than the pain provider

- Sharing or borrowing similar medications from friends/family

6. INTERVENTIONS FOR SUSPECTED OR KNOWN ADDICTION OR DRUG DIVERSION

There are a number of actions that prescribers and dispensers can take to prevent or intervene in cases of drug diversion. These actions can be generally categorized based on the various mechanisms of drug diversion.

Prevention is the best approach to addressing drug diversion. As noted, a common source of nonmedical use of prescribed opioids is from a family member or friend, through sharing, buying, or stealing. To avoid drug sharing among patients, healthcare professionals should educate patients on the dangers of sharing opioids and stress that "doing prescription drugs" is the same as "using street drugs" [51]. In addition, patients should be aware of the many options available to treat chronic pain aside from opioids. To prevent theft, patients should be advised to keep medications in a private place and to refrain from telling others about the medications being used.

Communication among providers and pharmacies can help to avoid inappropriate attainment of prescription drugs through "doctor shopping." Prescribers should keep complete and up-to-date records for all controlled substance prescribing. When possible, electronic medical records should be integrated between pharmacies, hospitals, and managed care organizations [51]. If available, it is also best practice to periodically request a report from the state's prescription reporting program to evaluate the prescribing of opioids to your patients by other providers [51].

When dealing with patients suspected of drug seeking/diversion, first inquire about prescription, over-the-counter, and illicit drug use and perform a thorough examination [51]. Pill counting and/or UDT may be necessary to investigate possible drug misuse. Photo identification or other form of identification and social security number may be required prior to dispensing the drug, with proof of identity documented fully. If a patient is displaying suspicious behaviors, consider prescribing for limited quantities [59].

If a patient is found to be abusing prescribed opioids, this is considered a violation of the treatment agreement and the clinician must make the decision whether or not to continue the therapeutic relationship. If the relationship is terminated, it must be done ethically and legally. The most significant issue is the risk of patient abandonment, which is defined as ending a relationship with a patient without consideration of continuity of care and without providing notice to the patient. The American Medical Association Code of Ethics states that physicians have an obligation to support continuity of care for their patients. While physicians have the option of withdrawing from a case, they should notify the patient (or authorized decision maker) long enough in advance to permit the patient to secure another physician and facilitate transfer of care when appropriate [60]. Patients may also be given resources and/or recommendations to help them locate a new clinician.

Patients with chronic pain found to have an ongoing substance abuse problem or addiction should be referred to a pain specialist for continued treatment. Theft or loss of controlled substances is reported to the DEA. If drug diversion has occurred, the activity should be documented and a report to law enforcement should be made [59].

7. COMPLIANCE WITH STATE AND FEDERAL LAWS

In response to the rising incidence in prescription opioid abuse, addiction, diversion, and overdose since the late 1990s, the FDA has mandated opioid-specific REMS to reduce the potential negative patient and societal effects of prescribed opioids [50]. Other elements of opioid risk mitigation include FDA partnering with other governmental agencies, state professional licensing boards, and societies of healthcare professionals to help improve prescriber knowledge of appropriate and safe opioid prescribing and safe home storage and disposal of unused medication [41].

Several regulations and programs at the state level have been enacted in an effort to reduce prescription opioid abuse, diversion, and overdose, including [61]:

- Physical examination required prior to prescribing

- Tamper-resistant prescription forms

- Pain clinic regulatory oversight

- Prescription limits

- Prohibition from obtaining controlled substance prescriptions from multiple providers

- Patient identification required before dispensing

- Immunity from prosecution or mitigation at sentencing for individuals seeking assistance during an overdose

CONTROLLED SUBSTANCES LAWS/RULES

The U.S. Drug Enforcement Administration (DEA) is responsible for formulating federal standards for the handling of controlled substances. In 2011, the DEA began requiring every state to implement electronic databases that track prescribing habits, referred to as PDMPs. Specific policies regarding controlled substances are administered at the state level [62].

According to the DEA, drugs, substances, and certain chemicals used to make drugs are classified into five distinct categories or schedules depending upon the drug's acceptable medical use and the drug's abuse or dependency potential [63]. The abuse rate is a determinate factor in the scheduling of the drug; for example, Schedule I drugs are considered the most dangerous class of drugs with a high potential for abuse and potentially severe psychologic and/or physical dependence.

STATE-SPECIFIC LAWS AND RULES

Most states have established laws and rules governing the prescribing and dispensing of opioid analgesics. It is each prescriber's responsibility to have knowledge of and adhere to the laws and rules of the state in which he or she prescribes.

Arkansas Laws and Rules

An excerpt from the Arkansas Code rules and regulations relating to the regulation of controlled substances is available by clicking here.

Colorado Laws and Rules

An excerpt from the Colorado Revised Statutes relating to the electronic prescription drug monitoring program and the full Guidelines for the Safe Prescribing and Dispensing of Opioids are available by clicking here.

Michigan Laws and Rules

A summary of legislation enacted in Michigan to curb substance abuse and drug diversion is available by clicking here.

Nebraska Laws and Rules

An excerpt reprinted from the Nebraska Revised Statutes 71-2454 and 71-2455 is available by clicking here.

New Jersey Laws and Rules

An excerpt from the New Jersey Administrative Code Title 13, Chapter 45A, Prescription Monitoring Program is available by clicking here.

New Mexico Laws and Rules

An excerpt from the New Mexico Administrative Code Title 16, Chapter 10, Part 14: Management of Pain and Other Conditions with Controlled Substances is available by clicking here.

New York Laws and Rules

An excerpt from the New York Code, Rules, and Regulations relating to the regulation of controlled substances is available by clicking here.

Vermont Laws and Rules

Information on use of the Vermont Prescription Monitoring System (VPMS) is available by clicking here.

Washington Laws and Rules

Laws governing the prescribing of opioids in the state of Washington are available by clicking here.

Wisconsin Laws and Rules

The Wisconsin Medical Examining Board Opioid Prescribing Guideline is available by clicking here.

8. MANAGEMENT OF OPIOID USE DISORDER

Management of opioid dependence entails different methods to achieve different goals, depending on the health situation and treatment history of the patient. These treatment approaches include [64]:

- Crisis intervention: Directed at immediate survival by reversing the potentially lethal effects of overdose with an opioid antagonist.

- Harm reduction: Intended to reduce morbidity and mortality associated with use of dirty needles and overdose.

- Detoxification/withdrawal: Aims to remove the opioid of abuse from the patient's body, either through gradual taper and substitution of a long-acting opioid or through ultra-rapid opioid detoxification.

- Maintenance treatment or opioid (agonist) replacement therapy: Aimed at reduction/elimination of illicit opioid use and lifestyle stabilization. Maintenance follows detoxification/withdrawal, whereby the patient is tapered from short-acting opioids and introduced to a long-acting opioid agonist, such as methadone or buprenorphine. Patients remain on agonist therapy short-term, long-term, or indefinitely depending on individual needs.

- Abstinence-oriented therapy: Treatment directed at cure. The patient is tapered off of short-acting opioids during the detoxification/withdrawal process and may be placed on an opioid antagonist with the goal of minimizing relapse.

All treatment approaches share the common goal of improving health outcomes and reducing drug-related criminality and public nuisance [64].

CRISIS INTERVENTION

In response to acute overdose, the short-acting opioid antagonist naloxone is considered the criterion standard. Naloxone is effective in reversing respiratory depression and coma in patients who have overdosed. There is no evidence that subcutaneous or intramuscular use is inferior to intravenous naloxone. This prompted discussion of making naloxone available to the general public for administration outside the healthcare setting to treat acute opioid overdose, and in 2014, the FDA approved naloxone as an autoinjector dosage form for home use by family members or caregivers [65]. The autoinjector delivers 0.4 mg naloxone intramuscularly or subcutaneously. The autoinjector comes with visual and voice instruction, including directs to seek emergency medical care after use [65]. In 2015, the FDA approved intranasal naloxone after a fast-track designation and priority review. Intranasal naloxone is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. It is available in a ready-to-use 2-mg, 4-mg, or 8-mg single-dose sprayer [66,67,68]. In 2023, the FDA approved Narcan, the first over-the-counter naloxone nasal spray [69]. Narcan is available as a 3-, 4-, or 8-mg single dose, administered in one nostril [70].

HARM REDUCTION

Harm reduction measures are primarily employed to minimize the morbidity and mortality from opioid abuse and to reduce public nuisance [38,71]. As a part of this effort, measures to prevent and minimize the frequency and severity of overdoses have been identified. Enrollment in opioid substitution therapy, with agents such as methadone and buprenorphine, substantially reduces the risk of overdose as well as the risk for infection and other sequelae of illicit opioid use [38,71].

DETOXIFICATION AND WITHDRAWAL

The process of tapering patients with opioid dependence from agonist therapy is often referred to as detoxification, or more accurately, medically supervised withdrawal [72,73]. Its purpose is to eliminate physical dependence on opioid medications. It can be considered the medically supported transition to a medication-free state or to antagonist therapy. A careful and thorough review of the risks and benefits of detoxification should be provided, and informed consent obtained from patients prior to choosing this option [73,74]. Detoxification alone should not be considered a treatment and should only be promoted in the context of a well-planned relapse-prevention program [64,73]. Studies have shown that most patients with opioid use disorder who undergo medically supervised withdrawal will start using opioids again and will not continue in recommended care [75,76,77,78,79].

Discontinuation of opioid use must be implemented slowly and cautiously to avoid a marked abstinence syndrome. Withdrawal symptoms may not begin for days after abrupt discontinuation of methadone or buprenorphine given their longer half-lives. Protracted abstinence, or post-acute withdrawal, may last for several months and is characterized by asthenia, depression, and hypotension. Post-acute withdrawal is more likely to occur with methadone than other opioids [72].

The three primary treatment modalities used for detoxification are opioid agonists, non-opioid medications, and rapid and ultra-rapid opioid detoxification [72]. The most frequently employed method of opioid withdrawal is a slow, supervised detoxification during which an opioid agonist, usually methadone, is substituted for the abused opioid [80]. Methadone is the most frequently used opioid agonist due to the convenience of its once-a-day dosing [72]. Methadone is highly bound to plasma proteins and accumulates more readily than heroin in all body tissues. Methadone also has a longer half-life, approximately 22 hours, which makes withdrawal more difficult than from heroin. Substitution therapy with methadone has a high initial dropout rate (30% to 90%) and an early relapse rate. Alternative pharmacologic detoxification choices include clonidine (with or without methadone), midazolam, trazodone, or buprenorphine [80]. Naltrexone is used following medically supervised withdrawal to help prevent relapse to opioid misuse [81].

Many opioid withdrawal symptoms, such as restlessness, rhinorrhea, lacrimation, diaphoresis, myosis, piloerection, and cardiovascular changes, are mediated through increased sympathetic activation, the result of increased neuron activity in the locus coeruleus. Non-opioid agents (such as clonidine), which inhibit hyperactivation of noradrenergic pathways stemming from the locus coeruleus nucleus, have been used to manage acute withdrawal [80,82]. The first non-opioid treatment approved for the management of opioid withdrawal symptoms is lofexidine [83]. In studies, lofexidine resulted in less severe withdrawal symptoms and greater treatment retention than placebo.

However, some withdrawal symptoms, including anxiety and myalgias, are resistant to clonidine; benzodiazepines and nonsteroidal anti-inflammatory agents may be necessary to treat these symptoms. To mitigate withdrawal symptoms and assist in detoxification, alpha2-agonists, opioid agonist-antagonists, benzodiazepines, and antidepressants have been used [80].

Following detoxification, patients may feel exhausted and weak. Other complications, such as slight variations in hemodynamic status and gastrointestinal tract symptoms, follow quickly and may take several days to resolve. Muscle cramps and low back pain can be treated with nonsteroidal anti-inflammatory drugs. However, the newer cyclooxygenase-2 (COX-2) inhibitors may be advantageous because they produce fewer gastrointestinal side effects [80]. Insomnia is a frequent aspect of acute and protracted withdrawal, as opioids disrupt the normal sleep-wake cycle and many addicts require narcotics to sleep. Although long-term disruption of the normal sleep-wake cycle cannot be corrected rapidly, melatonin (3 mg), benzodiazepines, or antihistamines can be used with beneficial effects. Hypnosis and relaxation techniques are nonpharmacologic methods that may also be used [80]. Psychosocial treatments offered in addition to pharmacologic detoxification treatments positively impact treatment retention and completion, results at follow-up, and compliance [84,85].

Ultra-Rapid Opioid Detoxification

Ultra-rapid opioid detoxification (UROD) has been developed as a means of avoiding the physical symptoms of withdrawal from opioids through the use of general anesthesia. UROD consists of naltrexone-assisted detoxification under heavy sedation or full anesthesia. UROD is also referred to as rapid or anesthesia-assisted detoxification. Other novel names for the process include [86]:

- UROD: General anesthesia; duration <6 hours

- Rapid opioid detoxification (ROD): Deep sedation; duration 6 to 72 hours

- Compressed opioid detoxification (COD) and naltrexone-compressed opioid detoxification (NCOD): Duration three to six days; preceded by a period of abstinence from opioids under sedation prior to introduction of naltrexone

The common underlying themes in all UROD techniques are a desire to condense the detoxification process into a shorter period to blunt the awareness of physical discomfort and to shorten the time lag between a patient's last dose of opioid and transfer to naltrexone maintenance [86]. This is accomplished by precipitating withdrawal following the administration of opioid antagonists under deep sedation or anesthesia.

Detoxification and withdrawal are rarely complete following UROD, and residual withdrawal symptoms can include drug craving, sympathetic hyperactivity, muscle pain, bone pain, nausea, vomiting, diarrhea, and insomnia. UROD does little to prevent protracted abstinence syndrome, which can last 3 to 10 weeks. Naltrexone may reduce opioid craving during the post-UROD period, with 50 mg per day recommended for relapse prevention. However, patients undergoing long-term naltrexone therapy can become sensitized to opioid drugs, heightening the risk of fatal overdose if opioid use is resumed [80].

A major shortcoming of UROD is the lack of evidence that an opioid antagonist can accelerate the restoration of neurobiologic homeostasis following opioid withdrawal [86]. Although significant drawbacks and questionable long-term efficacy exist with UROD, popular demand has proven difficult to restrain, in part due to the marketing of the procedure as a painless cure for opioid dependence. Marketing and the media have also blurred the fact that the original purpose of the procedure was to induce patients as rapidly as possible onto naltrexone and not to immediately permanently terminate years of opioid dependence [87].

Serious adverse events related to the anesthetic procedure also have been reported. A randomized, controlled trial directly comparing naltrexone-assisted detoxification with and without full anesthesia clearly stated that heavy sedation or full anesthesia should not be used because it does not confer any advantages in withdrawal symptom severity or increased rates of initiation or maintenance and it increases the potential for life-threatening adverse events [64]. A trial comparing naltrexone-induced, anesthesia-assisted detoxification with buprenorphine- or clonidine-assisted detoxification found no difference in withdrawal severity and rates of completion. However, potentially life-threatening adverse events associated with the UROD anesthesia were observed [88]. The risk for adverse events, the high monetary cost, and use of scarce intensive care resources suggest that this form of treatment should not be pursued [89,90]. Additionally, UROD has not undergone the processes of therapeutic protocols, which are recognized as essential in scientific medicine, and no animal studies have been conducted with the procedure [87].

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

Two principle treatment modalities are offered for patients with opioid dependence: agonist maintenance or detoxification followed by outpatient or residential drug-free treatment. Both can be effective, with no clear indication for each, although agonist maintenance leads to greater treatment retention [91]. A reasonable approach is initial outpatient or residential treatment referral for patients relatively new to treatment, with agonist maintenance appropriate for patients with history of treatment failures, greater disease severity, or a history of drug overdoses. Naltrexone is best reserved for patients with strong legal incentives to abstain, family involvement to monitor treatment, or concurrent enrollment and involvement in a psychosocial intervention [92].

At present, there are no direct interventions that are capable of reversing the effects of drugs of dependence on learning and motivation systems [93]. Instead, the management of opioid dependence often consists of pharmacotherapy with methadone and buprenorphine, which do not eliminate physical dependence on opioids. These medications instead reduce the use of illicit opioids and produce very strong positive health outcomes as measured by decreased mortality, improved mental and physical health, and reduced risk of disease transmission [93]. Considering the high rate of relapse after detoxification, maintenance therapy with methadone or buprenorphine is currently considered to be the first-line treatment for patients with opioid dependence [64]. Both agents are superior to withdrawal management alone and both significantly reduce illicit opioid use [94].

Any treatment for opioid dependence must take into consideration the chronic relapsing nature of opioid dependence, characterized by a variable course of relapse and remission in many patients. Treatments should emphasize patient motivation, psychoeducation, continuity of care, integration of pharmacotherapy and psychosocial support, and improved liaison between the treatment staff and the judicial system. Pharmacotherapy must be offered in a comprehensive healthcare context that also addresses the psychosocial aspects of dependence [64]. Patients who are dependent on opioids frequently suffer from physical and psychiatric disorders, and targeted interventions of psychiatric comorbidity are essential in improving treatment outcome for these patients [64]. Polysubstance abuse is the rule rather than the exception in opioid dependence, and concurrent use of other substances should be carefully monitored and treated when necessary [64]. Concurrent use of other drugs or active engagement in other addictive behaviors should lead to consideration of other treatment plan components for the patient. The presence of co-occurring substance use disorders should provoke a re-evaluation of the level of care in which the patient is treated [94]. Incarceration should never automatically result in discontinuation of an existing treatment; imprisonment offers a window of opportunity to initiate or restart treatment with a necessary continuation after release [64].

Agonist Replacement Therapy

The goal of opioid replacement therapy is to reduce illicit drug use and associated health risks, with secondary goals of reducing unsafe sexual practices, improving vocational and psychosocial functioning, and enhancing quality of life [72]. The theoretical basis of opioid replacement stems from the finding that chronic opioid use results in an endogenous opioid deficiency as a result of the down-regulation of opioid production. This creates overwhelming cravings and necessitates interventions that shift the patient's attention and drive from obsessive preoccupation with the next use of opioids to more adaptive areas of focus, such as work, relationships, and non-drug leisure activities [72].

The neurobiologic changes resulting from prolonged opioid exposure provide a rationale for specific pharmacotherapies, such as long-acting opioid agonists, that are aimed at stabilizing these complex systems [95]. Opioid agonist maintenance treatment stabilizes brain neurochemistry by replacing short-acting opioids, which can create rapid changes in opioid levels in the serum and brain, with a long-acting opioid that has relative steady-state pharmacokinetics. Opioid agonist maintenance treatment is designed to have minimal euphoric effect, block the euphoria associated with administration of exogenous opioids (competitive antagonism), eliminate the risk of infectious disease and health consequences associated with injection drug use, and prevent opioid withdrawal [95].

Successful maintenance treatment entails stabilization of opioid dependence through opioid receptor occupation. Positron emission tomography studies have revealed that only 25% to 35% of brain opioid receptors are occupied during steady-state methadone maintenance, suggesting that unoccupied opioid receptors disrupted during cycles of opioid abuse could normalize during methadone maintenance [72]. Additionally, opioid replacement therapy blocks much of the euphoria from illicit heroin use. Long-term opioid agonist treatment also has a positive impact on public health, through significantly reducing overdose deaths, criminal activity, and the spread of infectious disease [72].

As of 2020, there were 1,754 treatment programs including opioid replacement therapy in the United States [96]. However, this represents less than 20% of all patients with opioid use disorder. Although some have criticized the practice of methadone and buprenorphine therapy on the grounds that one opioid is merely being substituted for another, the clinical benefits strongly support this treatment modality [72]. When compared to active street heroin users, these benefits include a four-times lower HIV seroprevalence rates, 70% fewer crime-days per year, and a one-year mortality rate of 1% (versus 8%) [97].

Abstinence-Oriented Therapies

The primary goal of abstinence-oriented interventions is cure, which is defined as long-term, stable abstinence from all opioids. Abstinence is achieved in two phases: detoxification and relapse prevention. Outcomes in abstinence-oriented programs are generally poor [64].

The primary goal of pharmacotherapy during detoxification is to alleviate opioid withdrawal severity and associated distress/medical complications and to enhance patient motivation to continue treatment. Withdrawal can also be reduced by psychosocial measures, such as contingency management or counseling, and as discussed, the addition of psychosocial therapy to pharmacologic treatment increases efficacy. Buprenorphine and clonidine are both used to manage withdrawal symptoms, but buprenorphine's advantages, compared with clonidine, are related to its favorable side effect profile and positive effects on well-being and psychosocial variables [64].

12-Step/Self-Help Programs

Twelve-step programs for opioid abuse and dependence include Narcotics Anonymous (NA), Heroin Anonymous (HA), and Methadone Anonymous (MA) and are modeled after Alcoholics Anonymous (AA), an abstinence-based support and self-improvement program that is based on the 12-step model of recovery. AA has helped hundreds of thousands of alcoholics achieve sobriety [98]. The 12-step model emphasizes acceptance of dependence as a chronic, progressive disease that can be arrested through abstinence but not cured. Additional elements include spiritual growth, personal responsibility, and helping other addicted persons. By inducing a shift in the consciousness of the addict, 12-step programs offer a holistic solution and are a resource for emotional support [98]. Although research on efficacy and patient outcomes in NA and MA is very limited, many prominent researchers emphasize the important role ongoing involvement in 12-step programs plays in recovery from substance abuse [99].

The understanding of drug dependence as a chronic and relapsing disorder has helped professionals gain a better comprehension of the vital role played by 12-step programs. Every patient attempting to recover from a substance use disorder will encounter a time when he or she faces urges to use without the resources or assistance of healthcare professionals. Twelve-step programs are not considered treatment, nor are they intended as substitutes for treatment. Instead, they are organizations that provide ongoing and indefinite support in the achievement and maintenance of abstinence and in personal growth and character development [99].

Part of the effectiveness of NA, HA, and MA is related to their ability to provide a competing and alternative reinforcer to drug use. Involvement in 12-step programs can enhance the quality of social support and the social network of the member, a potentially highly reinforcing aspect the person stands to forfeit if they resume drug using. Other reinforcing elements of 12-step involvement include recognition for increasingly durable periods of abstinence and frequent awareness of the consequences of drug and alcohol use through attendance of meetings [100]. Research shows that establishing a pattern of 12-step program attendance early in treatment predicts the level of ongoing involvement. Emphasis and facilitation of early engagement in a 12-step program involvement are key [101].

STIGMA OF ADDICTION

Many terms used in discussions of opioid use and misuse may have ambiguous meanings, and the absence of consensus in the terminology and definitions of substance use, substance use disorders, and addiction has led to considerable confusion and misconceptions. These misconceptions may be harbored by clinicians, patients, family members, and the public and can negatively impact patient interaction, assessment, treatment, and outcomes. This, coupled with pervasive stereotypes about what an opioid addict "looks" like, can negatively impact willingness to receive treatment or seek help and impair the patient's self-worth and mental health. Correction of these erroneous beliefs and attitudes is important, as is the use of nonpejorative and nonstigmatizing language when describing opioid analgesics, the patients who need them, and patients who develop aberrant behaviors or addiction involving opioids [31,102]. It is important for all healthcare professionals to remember that addiction can affect any patients, regardless of age, sex, socioeconomic status, education, ability, or race.

PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

The relapse rate among patients receiving treatment for opioid dependence and other substance abuse is high (25% to 97%), comparable to that of other patients with chronic relapsing conditions, including hypertension and asthma [103]. Many cases of relapse are attributable to treatment noncompliance and lack of lifestyle modification [104].

Duration of agonist replacement therapy is usually recommended as a minimum of one year, and some patients will receive agonist replacement therapy indefinitely. Longer durations of treatment are associated with higher rates of abstinence from illicit opioids [93].

Much remains unknown about patient outcomes following termination of long-term opioid replacement therapy. Some patients aim to achieve total abstinence from all opioids, but little is known about patient characteristics and strategies used among those who remain abstinent. It is likely that at least some of the patients who remain abstinent from all opioids do so with the help of a 12-step support program, such as NA [93].

9. CONCLUSION

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat patients with opioids. By implementing these tools, the clinician can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

Works Cited

1. Federation of State Medical Boards. Guidelines for the Chronic Use of Opioid Analgesics. Washington, DC: The Federation of State Medical Boards; 2017.

2. Institute of Medicine, Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press; 2011.

3. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR. 2016;65(1):1-49.

4. U.S. Food and Drug Administration. FDA Analysis of Long-Term Trends in Prescription Opioid Analgesic Products: Quantity, Sales, and Price Trends. Available at https://www.fda.gov/media/111695/download. Last accessed March 20, 2024.

5. Kenen K, Mack K, Paulozzi L. Trends in prescriptions for oxycodone and other commonly used opioids in the United States, 2000–2010. Open Medicine. 2012;6(2)e41.

6. Worldometer. United States Population (Live). Available at https://www.worldometers.info/world-population/us-population/. Last accessed March 20, 2024.

7. International Narcotics Control Board. Narcotic Drugs: Estimated World Requirements for 2023. Available at https://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2022/Narcotic_Drugs_Technical_Publication_2022.pdf. Last accessed March 20, 2024.

8. Zacny JP, Gutierrez S, Bolbolan SA. Profiling the subjective, psychomotor, and physiological effects of a hydrocodone/acetaminophen product in recreational drug users. Drug Alcohol Depend. 2005;78(3):243-252.

9. Groenewald CB, Rabbitts JA, Gebert JT, Palermo TM. Trends in opioid prescriptions among children and adolescents in the United States: a nationally representative study from 1996 to 2012. Pain. 2016;157(5):1021-1027.

10. Hudgins JD, Porter JJ, Monuteaux MC, Bourgeois FT. Trends in opioid prescribing for adolescents and young adults in ambulatory care settings. Pediatrics. 2019;143(6):e20181578.

11. Miller NS, Greenfeld A. Patient characteristics and risks factors for development of dependence on hydrocodone and oxycodone.Am J Ther. 2004;11:26-32.

12. Substance Abuse and Mental Health Services Administration. Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits. Rockville, MD: U.S. Department of Health and Human Services; 2007.

13. Substance Abuse and Mental Health Services Administration. Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2014.

14. Lovegrove MC, Dowell D, Geller AI, et al. US emergency department visits for acute harms from prescription opioid use, 2016–2017. Am J Pub Health. 2019;109:784-791.

15. Management of Opioid Therapy for Chronic Pain Working Group. VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain. Washington, DC: Department of Veterans Affairs, Department of Defense; 2017.

16. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113-130.

17. Centers for Disease Control and Prevention. [CDC Archive]. CDC Advises Against Misapplication of the Guideline for Prescribing Opioids for Chronic Pain. Available at https://archive.cdc.gov/#/details?url=https://www.cdc.gov/media/releases/2019/s0424-advises-misapplication-guideline-prescribing-opioids.html. Last accessed March 20, 2024.

18. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC clinical practice guideline for prescribing opioids for pain—United States, 2022. MMWR. 2022;71(3):1-95.

19. Centers for Disease Control and Prevention. Healthcare Administrators: Applying the 2022 CDC Clinical Practice Guideline for Prescribing Opioids for Pain. Available at https://www.cdc.gov/opioids/healthcare-professionals/prescribing/guideline/healthcare-administrators.html. Last accessed March 20, 2024.

20. Argoff CE, Silvershein DI. A comparison of long- and short-acting opioids for the treatment of chronic noncancer pain: tailoring therapy to meet patient needs. Mayo Clin Proc. 2009;84(7):602-612.

21. McCarberg BH, Barkin RL. Long-acting opioids for chronic pain: pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia. Am J Ther. 2001;8(3):181-186.

22. National Comprehensive Cancer Network. Adult Cancer Pain, 2024. Available at https://www.nccn.org/professionals/physician_gls/pdf/pain.pdf. Last accessed March 20, 2024.

23. Mailis A, Taenzer P. Evidence-based guideline for neuropathic pain interventional treatments: spinal cord stimulation, intravenous infusions, epidural injections and nerve blocks. Pain Res Manage. 2012;17(3):150-158.

24. U.S. Food and Drug Administration. Medication Guides: Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS). Available at https://www.fda.gov/media/79776/download. Last accessed March 20, 2024.

25. American Pain Foundation. Breakthrough cancer pain: mending the break in the continuum of care. J Pain Palliat Care Pharmacother. 2011;25(3):252-264.

26. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Palliative Care Version 1.2024. Available at https://www.nccn.org/professionals/physician_gls/pdf/palliative.pdf. Last accessed March 20, 2024.

27. Dalal S, Bruera E. Assessment and management of pain in the terminally ill. Prim Care Clin Office Pract. 2011;38:195-223.

28. Gao W, Gulliford M, Higginson IJ. Prescription patterns of analgesics in the last 3 months of life: a retrospective analysis of 10,202 lung cancer patients. Br J Cancer. 2011;104(11):1704-1710.

29. Breuer B, Fleishman SB, Cruciani RA, Portenoy RK. Medical oncologists' attitudes and practice in cancer pain management: a national survey. J Clin Oncol. 2011;29(36):4769-4775.

30. Abrahm JL. A Physician's Guide to Pain and Symptom Management in Cancer Patients. 3rd ed. Baltimore, MD: Johns Hopkins University Press; 2014.

31. The Public Notice. EBBRAC Recommendations and New York State Department of Health's Coverage Determinations. Implantable Infusion Pumps for Non-Cancer Pain. Available at https://www.health.ny.gov/health_care/medicaid/ebbrac/docs/2016-12-15_publicnotice.pdf. Last accessed March 20, 2024.

32. Pergolizzi JV Jr, Mercadante S, Echaburu AV, et al. The role of transdermal buprenorphine in the treatment of cancer pain: an expert panel consensus. Curr Med Res Opin. 2009;25(6):1517-1528.

33. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: part 2—guidance. Pain Physician. 2012;15(3 Suppl):S67-S116.

34. Kaye AD, Jones MR, Kaye AM, et al. Prescription opioid abuse in chronic pain: an updated review of opioid abuse predictors and strategies to curb opioid abuse (part 2). Pain Physician. 2017;20(Supp 2):S111-S133.

35. Miner J, Babitz M, Dunn A, Fondario A, Smith M. Utah Clinical Guidelines on Prescribing Opioids for Treatment of Pain. Salt Lake City, UT: Utah Department of Health; 2018.

36. Cheattle MD. Risk Assessment: Safe Opioid Prescribing Tools. Available at https://www.medcentral.com/pain/chronic/risk-assessment-safe-opioid-prescribing-tools. Last accessed March 20, 2024.

37. Butler SF, Budman SH, Fernandez KC, Fanciullo GJ, Jamison RN. Cross-validation of a Screener to Predict Opioid Misuse in Chronic Pain Patients (SOAPP-R). J Addict Med. 2009;3(2):66-73.

38. Singer JA. Harm Reduction: Shifting from a War on Drugs to a War on Drug-Related Deaths. Available at https://www.cato.org/policy-analysis/harm-reduction-shifting-war-drugs-war-drug-related-deaths. Last accessed March 20, 2024.

39. Fine PG, Finnegan T, Portenoy RK. Protect your patients, protect your practice: practical risk assessment in the structuring of opioid therapy in chronic pain. J Fam Pract. 2010;59(9 Suppl 2):S1-S16.

40. American Chronic Pain Association. ACPA– Stanford Resource Guide to Chronic Pain Management: 2021 Edition. Available at https://med.stanford.edu/content/dam/sm/pain/documents/ACPA-Stanford-Resource-Guide-to-Chronic-Pain-Management-2021-Edition-4-18-21-.pdf. Last accessed March 20, 2024.

41. Strickland JM, Huskey A, Brushwood DB. Pharmacist-physician collaboration in pain management practice. J Opioid Manag. 2007;3:295-301.

42. American Society of Anesthesiologists. Opioid Abuse. Available at https://www.asahq.org/madeforthismoment/pain-management/opioid-treatment/opioid-abuse. Last accessed March 20, 2024.

43. Opioid Dispensing Guidelines for Pennsylvania. Available at https://www.dos.pa.gov/ProfessionalLicensing/BoardsCommissions/Documents/PA%20Guidelines%20on%20the%20Dispensing%20of%20Opioids%20(2).pdf. Last accessed March 20, 2024.

44. Passik SD, Kirsh KL, Whitcomb L, et al. A new tool to assess and document pain outcomes in chronic pain patients receiving opioid therapy. Clin Ther. 2004;26:552-561.

45. Katz NP. Opioid Prescribing Toolkit: A Workbook for Clinicians. New York, NY: Oxford University Press; 2010.

46. Atluri SL, Akbik H, Sudarshan G. Prevention of opioid abuse in chronic non-cancer pain: an algorithmic, evidence-based approach. Pain Physician. 2012;15:ES177-ES189.

47. National Institute on Drug Abuse. Benzodiazepines and Opioids. Available at https://www.drugabuse.gov/drugs-abuse/opioids/benzodiazepines-opioids. Last accessed March 20, 2024.

48. Baxter J. National Institute on Drug Abuse. Minimizing the Misuse of Prescription Opioids in Patients with Chronic Nonmalignant Pain. Available at https://nida.nih.gov/sites/default/files/minimizingmisuse_part1.pdf. Last accessed March 20, 2024.

49. Opioid Analgesic REMS: Patient Counseling Guide. Available at https://www.accessdata.fda.gov/drugsatfda_docs/rems/Opioid_Analgesic_2021_04_09_Patient_Counseling_Guide.pdf. Last accessed March 20, 2024.

50. U.S. Food and Drug Administration. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS). Available at https://www.fda.gov/drugs/information-drug-class/opioid-analgesic-risk-evaluation-and-mitigation-strategy-rems. Last accessed March 20, 2024.

51. American College of Preventive Medicine. Use, Abuse, Misuse and Disposal of Prescription Pain Medication Patient Guide. Available at https://cdn.ymaws.com/acpm.site-ym.com/resource/resmgr/timetools-files/painmedsclinicalreference.pdf. Last accessed March 20, 2024.

52. U.S. Food and Drug Administration. Disposal of Unused Medicines: What You Should Know. Available at https://www.fda.gov/drugs/safe-disposal-medicines/disposal-unused-medicines-what-you-should-know. Last accessed March 20, 2024.

53. Federal Drug Administration. Safe Opioid Disposal: Remove the Risk Outreach Toolkit. Available at https://www.fda.gov/drugs/ensuring-safe-use-medicine/safe-opioid-disposal-remove-risk-outreach-toolkit. Last accessed March 20, 2024.

54. Substance Abuse and Mental Health Services Administration. 2021 National Survey on Drug Use and Health Releases: Detailed Tables. Available at https://www.samhsa.gov/data/release/2021-national-survey-drug-use-and-health-nsduh-releases#detailed-tables. Last accessed March 20, 2024.

55. Sekhon R, Aminjavahery N, Davis CN Jr, et al. Compliance with opioid treatment guidelines for chronic non-cancer pain (CNCP) in primary care at a Veterans Affairs Medical Center (VAMC). Pain Med. 2013;14(10):1548-1556.

56. Meier B. Increase in Urine Testing Raises Ethical Questions. Available at https://www.nytimes.com/2013/08/02/business/increase-in-urine-testing-raises-ethical-questions.html?_r=0. Last accessed March 20, 2024.

57. Passik SD. Issues in long-term opioid therapy: unmet needs, risks, and solutions. Mayo Clin Proc. 2009;84:593-601.

58. Holliday S, Hayes C, Dunlop A. Opioid use in chronic non-cancer pain. Part 2: prescribing issues and alternatives. Australian Fam Physician. 2013;42:104-111.

59. U.S. Department of Health and Human Services Drug Diversion: What Is a Prescriber's Role in Preventing the Diversion of Prescription Drugs? Available at https://www.hhs.gov/guidance/document/drug-diversion-what-prescribers-role-preventing-diversion-prescription-drugs. Last accessed March 20, 2024.

60. American Medical Association. Chapter 1: Patient-Physician Relationships: Opinion 1.1.5 Terminating the Patient-Physician Relationship. Available at https://code-medical-ethics.ama-assn.org/chapters/patient-physician-relationships. Last accessed March 20, 2024.

61. Centers for Disease Control and Prevention. Prevent Opioid Use Disorder. Available at https://www.cdc.gov/opioids/overdoseprevention/opioid-use-disorder.html. Last accessed March 20, 2024.

62. Hannon K. Prescription Drug Abuse Crisis in New York State: Comprehensive Approach – New. Available at https://www.scribd.com/doc/82474334/Prescription-Drug-Abuse-Crisis-in-NYS-Comprehensive-Approach-New. Last accessed March 20, 2024.

63. U.S. Drug Enforcement Administration. Drug Scheduling. Available at https://www.dea.gov/drug-scheduling. Last accessed March 20, 2024.

64. van den Brink W, Haasen C. Evidence-based treatment of opioid-dependent patients. Can J Psychiatry. 2006;51(10):635-646.

65. Cassels C. FDA Okays Handheld Autoinjector for Opioid Overdose. Available at https://www.medscape.com/viewarticle/823039. Last accessed March 20, 2024.

66. Narcan Nasal Spray (naloxone intranasal) [package insert]. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208411lbl.pdf. Last accessed March 20, 2024.

67. U.S. Food and Drug Administration. [Archive]. FDA Moves Quickly to Approve Easy-To-Use Nasal Spray to Treat Opioid Overdose. Available at https://wayback.archive-it.org/7993/20180125101447/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm473505.htm. Last accessed March 20, 2024.

68. U.S. Food and Drug Administration. FDA Approves Higher Dosage of Naloxone Nasal Spray to Treat Opioid Overdose. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-higher-dosage-naloxone-nasal-spray-treat-opioid-overdose. Last accessed March 20, 2024.

69. U.S. Food and Drug Administration. FDA News Release: FDA Approves First Over-the-Counter Naloxone Nasal Spray. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-over-counter-naloxone-nasal-spray. Last accessed March 20, 2024.

70. LexiComp Online. Available at https://online.lexi.com. Last accessed March 20, 2024.

71. Darke S, Hall W. Heroin overdose: research and evidence-based intervention. J Urban Health. 2003;80(2):189-200.

72. Krantz MJ, Mehler PS. Treating opioid dependence: growing implications for primary care. Arch Intern Med. 2004;164(3):277-288.

73. Substance Abuse and Mental Health Services Administration. Federal Guidelines for Opioid Treatment Programs. HSS Publication No. (SMA) PEP15-FEDGUIDEOTP. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2015.

74. Substance Abuse and Mental Health Services Administration. SAMHSA Overdose Prevention and Response Toolkit. Available at https://store.samhsa.gov/sites/default/files/overdose-prevention-response-kit-pep23-03-00-001.pdf. Last accessed March 20, 2024.

75. Strang J, McCambridge J, Best D, et al. Loss of tolerance and overdose mortality after inpatient opiate detoxifcation: follow-up study. BMJ. 2003;326(7396):959–960.

76. Weiss RD, Potter JS, Fiellin DA, et al. Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Arch Gen Psychiatry. 2011;68(12):1238–1246.

77. Fiellin D, Schottenfeld R, Cutter C, Moore A, Barry D, O'Connor P. (2014). Primary care based buprenorphine taper vs maintenance therapy for prescription opioid dependence: a randomized clinical trial. JAMA Int Med. 2014;174(12):1947–1954.

78. Gruber V, Delucchi K, Kielstein A, Batki S. A randomized trial of six-month methadone maintenance with standard or minimal counseling versus 21-day methadone detoxifcation. Drug Alcohol Dependence. 2008;94:199.

79. Smyth BP, Barry J, Keenan E, Ducray K. (2010). Lapse and relapse following inpatient treatment of opiate dependence. Irish Med J. 2010;103(6):176–179.

80. Kaye AD, Gevirtz C, Bosscher HA, et al. Ultrarapid opiate detoxification: a review. Can J Anaesth. 2003;50(7):663-671.

81. Substance Abuse and Mental Health Services Administration. Treatment Improvement Protocol 63: Medications for Opioid Use Disorder, Updated 2021. Available at https://store.samhsa.gov/sites/default/files/pep21-02-01-002.pdf. Last accessed March 20, 2024.

82. American Society of Addiction Medicine. National practice guideline for the use of medications in the treatment of addiction involving opioid use. Available at https://www.asam.org/quality-care/clinical-guidelines/national-practice-guideline. Last accessed March 20, 2024.

83. U.S. Food and Drug Administration. FDA Approves the First Non-Opioid Treatment for Management of Opioid Withdrawal Symptoms in Adults. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-non-opioid-treatment-management-opioid-withdrawal-symptoms-adults. Last accessed March 20, 2024.

84. Amato L, Minozzi S, Davoli M, Vecchi S, Ferri M, Mayet S. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst Rev. 2008;(4):CD005031.

85. Amato L, Minozzi S, Davoli M, Vecchi S. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst Rev. 2011;9:CD005031.

86. Singh J, Basu D. Ultra-rapid opioid detoxification: current status and controversies. J Postgrad Med. 2004;50(3):227-232.

87. Streel E, Verbanck P. Ultra-rapid opiate detoxification: from clinical applications to basic science. Addict Biol. 2003;8(2):141-146.

88. Collins ED, Kleber HD, Whittington RA, Heitler NE. Anesthesia-assisted vs. buprenorphine- or clonidine-assisted heroin detoxification and naltrexone induction: a randomized trial. JAMA. 2005;294(8):903-913.

89. Gowing L, Ali R, White J. Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal. Cochrane Database Syst Rev. 2006;2:CD002022.

90. Gowing L, Ali R, White JM. Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal. Cochrane Database Syst Rev. 2010;1:CD002022.

91. Fiellin DA, O'Connor PG. Office-based treatment of opioid-dependent patients. N Engl J Med. 2002;347(11):817-823.

92. Nunes EV, Sullivan MA, Levin FR. Treatment of depression in patients with opiate dependence. Biol Psychiatry. 2004;56(1):793-802.

93. Wasan AD, Correll DJ, Kissin I, O'Shea S, Jamison RN. Iatrogenic addiction in patients treated for acute or subacute pain: a systematic review. J Opioid Manag. 2006;2(1):16-22.

94. American Society of Addiction Medicine. The ASAM National Practice Guideline for the Treatment of Opioid Use Disorder: 2020 Focused Update. Available at https://sitefinitystorage.blob.core.windows.net/sitefinity-production-blobs/docs/default-source/guidelines/npg-jam-supplement.pdf?sfvrsn=a00a52c2_2. Last accessed March 20, 2024.

95. Fiellin DA, Friedland GH, Gourevitch MN. Opioid dependence: rationale for and efficacy of existing and new treatments. Clin Infect Dis. 2006;43(Suppl 4):S173-S177.

96. Substance Abuse and Mental Health Services Administration. National Survey of Substance Abuse Treatment Services (N-SSATS): 2020, Data on Substance Abuse Treatment Facilities. Available at https://www.samhsa.gov/data/report/national-survey-substance-abuse-treatment-services-n-ssats-2020-data-substance-abuse. Last accessed March 20, 2024.

97. Kleber HD. Methadone maintenance 4 decades later: thousands of lives saved but still controversial. JAMA. 2008;300(19):2303-2305.

98. Humphreys K, Wing S, McCarty D, et al. Self-help organizations for alcohol and drug problems: toward evidence-based practice and policy. J Substance Abuse Treat. 2004;26(3):151-165.

99. Ronel N, Gueta K, Abramsohn Y, Caspi N, Adelson M. Can a 12-step program work in methadone maintenance treatment? Int J Offender Ther Comp Criminol. 2011;55(7):1135-1153.

100. Stoops WW, Lile JA, Glaser PE, Hays LR, Rush CR. Alternative reinforcer response cost impacts cocaine choice in humans. Prog Neuropsychopharmacol Biol Psychiatry. 2012;36(1):189-193.

101. Donovan DM, Ingalsbe MH, Benbow J, Daley DC. 12-step interventions and mutual support programs for substance use disorders: an overview. Soc Work Public Health. 2013;28(3-4):313-332.

102. Oliver J, Coggins C, Compton P, et al. American Society for Pain Management Nursing position statement: pain management in patients with substance use disorders. Pain Manage Nurs. 2012;13(3):169-183.

103. Dixon DW. Opioid Abuse Follow-Up. Prognosis. Available at https://emedicine.medscape.com/article/287790-followup#e4. Last accessed March 20, 2024.

104. Vukmir RB. Drug seeking behavior. Am J Drug Alcohol Abuse. 2004;30:551-575.

Evidence-Based Practice Recommendations Citations

1. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC Clinical practice guideline for prescribing opioids for pain—United States, 2022. MMWR. 2022;71(3):1-95. Available at https://www.cdc.gov/mmwr/volumes/71/rr/rr7103a1.htm. Last accessed April 19, 2024.

95310 • Anticoagulation and Antiplatelet Therapy: Clinical Use Guidelines

Justin Delic, PharmD, BCCCP

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

This comprehensive course explores the appropriate use of antithrombotic agents for improved patient outcomes. Key topics include pharmacology of common antiplatelet and anticoagulant drugs, evidence-based indications for mono- and combination therapy, monitoring parameters for safe and effective use, and management of potential complications. Upon completion, you'll be equipped with essential knowledge and clinical pearls for delivering high-quality antithrombotic care.

Table of Contents

95310 • Anticoagulation and Antiplatelet Therapy: Clinical Use Guidelines

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. BACKGROUND AND INTRODUCTION

3. PATHOPHYSIOLOGY OF DISEASE

4. ANTIPLATELETS

ASPIRIN

P2Y12 INHIBITORS

5. ANTICOAGULANTS

UNFRACTIONATED HEPARIN

LOW-MOLECULAR-WEIGHT HEPARINS

WARFARIN

DIRECT THROMBIN INHIBITORS

FACTOR XA INHIBITORS

6. INDICATIONS FOR ANTIPLATELETS AND ANTICOAGULANTS

PRIMARY PREVENTION OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

CHRONIC CORONARY DISEASE

ACUTE CORONARY SYNDROME

ATRIAL FIBRILLATION

ACUTE ISCHEMIC STROKE/TRANSIENT ISCHEMIC ATTACK

VALVULAR HEART DISEASE

VENOUS THROMBOEMBOLISM

PERIPHERAL ARTERIAL DISEASE

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

95310 • Anticoagulation and Antiplatelet Therapy: Clinical Use Guidelines

Education Category. Pharmacology

Release Date. 07/01/2024

Expiration Date. 06/30/2027

Course Overview

This comprehensive course explores the appropriate use of antithrombotic agents for improved patient outcomes. Key topics include pharmacology of common antiplatelet and anticoagulant drugs, evidence-based indications for mono- and combination therapy, monitoring parameters for safe and effective use, and management of potential complications. Upon completion, you'll be equipped with essential knowledge and clinical pearls for delivering high-quality antithrombotic care.

Audience

This course is designed for physicians, nurses, and pharmacists whose patients benefit from anticoagulation and/or antiplatelet therapy.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 7 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 7 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 7 ANCC contact hour(s). NetCE designates this continuing education activity for 7 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 8.4 hours for Alabama nurses. NetCE designates this activity for 7 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-24-018-H01-P. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 7 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 0.7 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353 (valid through July 30, 2029); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2027; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to provide clinicians with clinical guidance on the appropriate use of antithrombotic agents in order to improve patient outcomes.

Learning Objectives

Upon completion of this course, you should be able to:

1. Compare and contrast the mechanisms of action of commonly used anticoagulant and antiplatelet agents, including unfractionated heparin, low molecular weight heparins, vitamin K antagonists, direct thrombin inhibitors, factor Xa inhibitors, aspirin, and P2Y12 inhibitors.

2. Identify best practice and evidence-based recommendations for initiating anticoagulant therapy for various conditions, including atrial fibrillation, acute coronary syndrome, prosthetic heart valves, and venous thromboembolism using risk stratification frameworks.

3. Recognize clinical situations warranting antiplatelet therapy, either alone or in combination with anticoagulants, based on updated treatment guidelines for relevant vascular conditions, including acute coronary syndrome, coronary artery disease, acute ischemic stroke, and peripheral arterial disease.

4. Select the most appropriate medication monitoring strategy based on specific anticoagulant or antiplatelet agent and therapeutic indication.

5. Indicate safe strategies for transitioning between anticoagulant and antiplatelet agents to avoid therapy gaps or excessive overlap that can precipitate thrombotic complications or bleeding, based on indication timeframe, procedure guidance, and antithrombotic agent properties.

6. Recognize special populations who may require additional monitoring of anticoagulant or antiplatelet therapies due to altered pharmacokinetics and pharmacodynamic parameters.

Faculty

Justin Delic, PharmD, BCCCP, is a critical care clinical pharmacy specialist at Cooper University Hospital in Camden, New Jersey. He completed his first year of pharmacy residency at UPMC Mercy Hospital in Pittsburgh, Pennsylvania, followed by a second year of residency specializing in critical care medicine at University Hospitals Cleveland Medical Center in Cleveland, Ohio. Following residency, he went on to practice as an assistant professor of clinical pharmacy at the Philadelphia College of Pharmacy in Philadelphia, Pennsylvania, prior to transitioning into his current role as a clinical pharmacy specialist at Cooper University Hospital. His areas of expertise include pharmacology, neurocritical care, simulation education, and anticoagulation.

Faculty Disclosure

Contributing faculty, Justin Delic, PharmD, BCCCP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Candace Pierce, DNP, RN, CNE, COI

Randall L. Allen, PharmD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Despite the wide availability of effective anticoagulant and antiplatelet medications, confusion on proper role, duration, transitions, monitoring, and real-world translation of evolving clinical practice guidelines drives the persistent over-, under-, and misuse of these agents. This gap between knowledge and appropriate evidence-based practice leads directly to worsened patient outcomes and increased health system costs. This course looks to provide consolidated, practical guidance tools that build provider competence and confidence in navigating nuanced prescribing decisions surrounding antithrombotic therapies to significantly narrow this gap tied to preventable patient harm.

2. BACKGROUND AND INTRODUCTION

The development of antithrombotics, including both anticoagulants and antiplatelets, has been one of the most significant advancements in the treatment and prevention of cardiovascular and thromboembolic disease states in history. Many of these agents have been around for decades, with the use of aspirin being traced back to 1897, and the oral anticoagulant warfarin first being used in humans in 1954 [1,2]. These discoveries provided groundbreaking treatment options for patients and prescribers alike; however, they also brought along with them concerns for an increased risk of bleeding. Over the past two decades, this landscape has continued to change with the approval of the direct oral anticoagulants (DOACs) and other antiplatelet agents within this therapeutic category. Although many of these newer agents provide an improved safety profile, they are still associated with significant morbidity and mortality related to bleeding events worldwide. Today, aspirin remains one of the most commonly used medications in the United States despite a slight decline in use over the past decade, and the DOACs have rapidly been adopted since their approvals, replacing warfarin as the oral anticoagulants of choice in most patients [3,4,5,6].

Although these agents continue to be prescribed often and provide significant benefit in many patients, experts indicate a need for improved use and monitoring of these medications. Recent studies have found that on one end of the spectrum, many older adults with disorders such as atrial fibrillation (AF) are undertreated with anticoagulants, while on the other end of the spectrum, many emergency department visits and hospitalizations are due to adverse reactions from these medications [7,8,9,10,11]. In a cross–sectional study by Dreijer et al., authors evaluated nearly 43,000 reported medical errors from 2012 to 2015 in both hospitals and primary care, and they found that anticoagulants were involved in over 8% of reported errors [12]. This recognition of the continued impact that antithrombotics (or the lack thereof) have on patient outcomes has sparked efforts to improve the use of these agents and has even prompted some hospitals to direct time and resources into developing multidisciplinary anticoagulation stewardship programs that specifically focus on appropriate antithrombotic use within their institutions [13,14]. With this in mind, it is obvious that despite the advancements in the overall safety of newer antithrombotic agents, improvement in the appropriate prescribing and monitoring of these agents should remain a top priority for prescribers and other healthcare professionals alike.

3. PATHOPHYSIOLOGY OF DISEASE

In order to identify the role of antithrombotics in the management of atherosclerotic and thromboembolic disease, it is first important to understand the pathophysiology related to hemostasis and thrombosis within the body. Hemostasis is the body's natural process of stopping blood from leaving a vessel after vascular injury by sealing the injured vessel and preventing further blood loss [15]. For hemostasis to occur, the body vasoconstricts the injured blood vessel in order to minimize blood loss and forms a platelet plug (a process known as primary hemostasis) that is further stabilized by a dense fibrin mesh (a process known as secondary hemostasis). Although it is common to think of these three phases in sequence, they actually occur simultaneously and potentiate one another during this process [16]. The formation of the platelet plug (primary hemostasis) involves three main steps, including platelet adhesion to the vessel wall, platelet activation, and platelet aggregation. Each of these three steps is initiated with the activation of various receptors on the platelet and can be a target for antiplatelet medications. The formation of a fibrin mesh (secondary hemostasis), on the other hand, involves activation of the coagulation cascade.

As opposed to hemostasis, thrombosis is the creation of a blood clot within a vessel through the activation of the coagulation cascade and is generally an unwanted result of coagulation within the body. When thrombosis occurs, a blood clot containing fibrin, platelet aggregates, and trapped red blood cells is created within a vessel, potentially resulting in partial or complete blockage of the vessel and preventing distal areas of the body from receiving oxygen and nutrients necessary for survival [16]. This can further lead to significant cell damage and death, making it an important focus for prevention in patients at greatest risk [15]. Although thrombosis may develop for a number of causes, thrombosis related to atherosclerotic disease is of particular relevance for this course, as it is a significant contributor to the development of disease states such as acute coronary syndrome (ACS) and acute ischemic stroke. In atherosclerosis, plaque made up of cholesterol, fatty substances, cellular waste products, calcium, and fibrin builds up in arteries, leading to a thickening of the blood vessel wall and a narrowing of the vessel opening. As the plaque continues to grow, it can partially or completely block blood flow through a vessel, or it can become unstable and rupture, sending pieces of this dislodged plaque buildup through the bloodstream until it becomes stuck within a narrowed vessel later in its path. Unstable plaques, which are at the greatest risk of rupture, typically have thin fibrous caps with large lipid cores, and, when ruptured, release thrombogenic material from within the plaque that leads to platelet adhesion, activation of additional platelets, and aggregation at the site until a thrombus is formed [17]. Since this platelet activation and aggregation can lead to a thrombus that blocks blood flow or embolizes to distal parts of the body, a primary goal of medical therapy for ACS, stroke, and other atherosclerotic diseases is to prevent the formation of these thrombi and the resultant death and disability that they may cause.

In order for either hemostasis or thrombosis to occur, the coagulation cascade must be activated by one of two separate pathways called the tissue factor pathway (also known as the "extrinsic" pathway) or the contact pathway (also known as the "intrinsic" pathway). Although the tissue factor (extrinsic) pathway is classically known as the pathway that is implicated in hemostasis, it likely also plays a role in many types of thrombosis as well. Alternatively, the contact (intrinsic) pathway does not affect normal hemostasis but rather is thought to contribute to thrombosis only [15]. The tissue factor (extrinsic) pathway becomes activated once blood is exposed to cells that express an extrinsic substance (i.e., tissue factor), leading to a complex of tissue factor and factor VIIa that further triggers coagulant activation. On the other hand, the contact (intrinsic) pathway is typically activated when blood comes into contact with exogenous material, resulting in an initial activation of factor XII to factor XIIa that leads to further activation of the cascade. Once either of these pathways are initiated, a series of proteolytic reactions occur that further activate various coagulation factors and substances within the body. Eventually, both pathways converge into the last few steps where factor X is converted to factor Xa by factor VIIIa, factor II (prothrombin) is converted to factor IIa (thrombin) by factor Va, and factor IIa (thrombin) converts factor I (fibrinogen) to factor Ia (fibrin) and activates platelets, leading to a clot [15,18]. Since both extrinsic and intrinsic pathways share the same final steps, this portion of the cascade is known as the "common pathway." As will be discussed in the next section, anticoagulant agents inhibit the activation of many of these coagulation factors (e.g., factor Xa inhibitors or direct thrombin inhibitors), preventing the development of thrombosis. A simplified version of the coagulation cascade can be seen in Figure 1.

Figure 1: COAGULATION CASCADE

Source: Author

4. ANTIPLATELETS

ASPIRIN

Aspirin (also known as acetylsalicylic acid or ASA) has been used for well over a century and remains one of the most commonly prescribed medications to this day. It is currently approved for the prevention and treatment of many vascular diseases, including acute myocardial infarction (MI), unstable angina, stable ischemic heart disease, transient ischemic attack (TIA), and cerebral infarction as well as for prophylaxis of venous thromboembolism following total hip replacement and reduction of platelet adhesion following revascularization procedures such as carotid endarterectomy or coronary artery bypass grafting (CABG). Unrelated to its antiplatelet effects, aspirin is also approved for the treatment of pain, fever, and inflammation [19,20]. Aspirin works via irreversible inhibition of cyclooxygenase-1 and 2 (COX-1 and 2), which ultimately decreases the formation of prostaglandin precursors, leading to its therapeutic effects. Aspirin's antiplatelet effect, in particular, is due to its inhibition of the formation of thromboxane A2, a prostaglandin derivative, within the platelet. Thromboxane A2 is known to be responsible for the platelet aggregation step of clot formation, which can therefore be reduced with the use of aspirin [19,20]. Aspirin is currently available in both immediate and extended-release oral formulations as well as in the form of a rectal suppository, and no intravenous formulation is currently available. Aspirin doses vary by indication but are typically 81–325 mg orally daily for indications that require aspirin use for its antiplatelet effects, while doses for analgesia and anti-inflammatory effects are often much higher and given more frequently [19]. As with any antithrombotic, precautions should be used due to an increased risk of bleeding with this agent, and aspirin should be used with particular caution in patients at high risk of bleeding from gastrointestinal ulcers, in severe hepatic or renal failure, with heavy alcohol use, and in patients within their last trimester of pregnancy (except when being utilized at low doses for pregnancy-related conditions). Although no routine monitoring of aspirin levels or antiplatelet response are required, patients should be monitored for signs or symptoms of bleeding during use.

P2Y12 INHIBITORS

The P2Y12 inhibitors are a group of agents that provide their antiplatelet effects through a mechanism different from that of aspirin. These agents work by inhibiting the P2Y12 component of adenosine diphosphate (ADP) receptors on the platelet surface, resultantly preventing activation of the glycoprotein IIb/IIIA receptor complex and reducing platelet aggregation [21]. Currently, the P2Y12 inhibitors that are available in the United States include clopidogrel, prasugrel, ticagrelor, and the most recently approved intravenous agent, cangrelor. Although ticlopidine was historically included in this group, this agent is no longer available in the United States. Despite all of these medications having the same overall mechanism for platelet inhibition, important differences exist that must be recognized between agents in order to ensure safe and effective use.

Clopidogrel (Plavix) is a second generation thienopyridine that was first approved in the United States in 1997, making it the oldest of the currently available oral P2Y12 inhibitors. Similar to prasugrel, clopidogrel is a prodrug that requires activation by the cytochrome P450 system (primarily CYP2C19) to be converted into an active metabolite that provides its antiplatelet effect. In patients with normal metabolism, about 85% of the prodrug is hydrolyzed into an inactive metabolite, while only the remaining 15% is metabolized into the active form of the drug [21]. Patients who are poor metabolizers (clopidogrel nonresponders) or those concomitantly taking medications that inhibit CYP2C19, such as omeprazole, can experience reduced effectiveness of clopidogrel due to an inability to convert the parent drug into its active metabolite. These patients have been shown to have worse outcomes following ACS and percutaneous coronary intervention (PCI). In practice, patients may be tested to identify their CYP2C19 genotype or can receive platelet function testing to evaluate their response to clopidogrel in order to aid in treatment decisions. It is also important to note that clopidogrel provides irreversible platelet inhibition for the lifespan of the platelet, which can be for 7 to 10 days. If clopidogrel needs to be held prior to elective surgery, this should be done at least 5 days prior to the procedure due to clopidogrel's irreversible platelet inhibition and prolonged duration of effect [22]. Clopidogrel is currently indicated for prevention and treatment of ACS, acute ischemic stroke, TIA, and established peripheral artery disease (PAD). The most common adverse reaction associated with clopidogrel use includes bleeding, though other rare events such as thrombotic thrombocytopenic purpura (TTP) have been reported in the literature. Clopidogrel is only available as an oral tablet at this time and is typically dosed at 75–150 mg daily alone or in combination with aspirin or an anticoagulant [22]. A loading dose of 300–600 mg of clopidogrel may be used when it is imperative to achieve therapeutic concentrations rapidly, such as directly after an ischemic event or in patients who are receiving revascularization or stenting; however, the benefits of this are typically weighed against the risk of bleeding for each individual patient.

Prasugrel (Effient) is a third generation thienopyridine that was approved in the United States in 2009. Similar to clopidogrel, prasugrel is a prodrug that requires rapid metabolism in order to be converted into an active metabolite that provides its irreversible platelet inhibition; however, the formation of this active metabolite is much more efficient compared to clopidogrel [21]. Although the active metabolites of clopidogrel and prasugrel are approximately equipotent, the metabolism of prasugrel results in higher plasma concentrations of active drug compared to clopidogrel, leading to effects that are more potent, immediate, and predictable [21]. Currently, it is only approved in the management of ACS. Due to the risk of fatal and intracranial bleeding seen in initial studies, prasugrel is generally not recommended in patients 75 years of age and older, unless benefit is felt to exceed the risk in select scenarios. In addition, bleeding from prasugrel is noted to be increased in patients of low body weight (<60 kg), those who are already at an increased bleeding risk for other reasons, and those who are concomitantly taking medications that may also increase the risk of bleeding. It is also contraindicated in patients with a history of prior TIA or stroke. If temporary discontinuation is required due to surgery or invasive procedure, it is recommended that prasugrel be discontinued at least 7 days prior the procedure, and it is also recommended that prasugrel not be started in patients who are likely to undergo CABG [23,24]. The most common adverse reaction associated with prasugrel is bleeding, though other rare events such as TTP have been reported in the literature as well. Prasugrel is only available as an oral tablet at this time and is typically dosed as an initial 60-mg loading dose followed by 10 mg daily in combination with aspirin. A reduced dose of 5 mg daily may be utilized in patients at higher risk of bleeding to prasugrel, particularly those who weigh less than 60 kg [23,24]. Compared to other P2Y12 inhibitors, prasugrel's use has been limited in some populations due to safety concerns related to an increased risk of bleed and adverse effects.

Ticagrelor (Brilinta) is the most recently approved oral P2Y12 inhibitor with an initial United States approval in 2011. Unlike clopidogrel and prasugrel, ticagrelor is a direct-acting, reversible platelet inhibitor that does not require metabolism from prodrug to active metabolite in order to provide its antiplatelet effect. Ticagrelor and its metabolite both work in the inhibition of P2Y12 and are approximately equipotent [21,25]. Unlike other P2Y12 inhibitors, ticagrelor requires twice daily dosing, due to its reversible platelet binding and half-life of 6 to 12 hours. Currently, it is approved in the management of ACS, select patients with stable coronary artery disease (CAD), and minor stroke, and it has been shown to be superior to clopidogrel in the first 12 months following ACS [25,26]. Similar to other P2Y12 inhibitors, ticagrelor is a potent antiplatelet that can cause significant bleeding, and it is contraindicated in patients with a history of intracranial hemorrhage. In addition to this risk of bleeding, ticagrelor is also noted to cause dyspnea in approximately 14% of patients, and it has been reported to be associated with bradyarrhythmias, including atrioventricular block, as well [26,27]. Ticagrelor is only available as an oral tablet at this time and is typically dosed as an initial 180 mg loading dose followed by 90 mg twice daily for the first year following ACS in combination with aspirin 75–100 mg. Despite some conflicting reports, aspirin doses greater than 100 mg are currently thought to reduce the effectiveness of ticagrelor and should be avoided, based on a subgroup analysis of the PLATO trial [26,28]. If prolonged use beyond one year is required, ticagrelor dose should be reduced to 60 mg orally twice daily. If temporary interruption in therapy is required prior to surgery due to the risk of bleeding, ticagrelor should be held five days prior to the procedure when possible [25].

Cangrelor (Kengreal) is currently the only available intravenous P2Y12 inhibitor in the United States and was first approved in 2015. Similar to ticagrelor, cangrelor is a direct-acting P2Y12 platelet inhibitor that binds selectively and reversibly to the platelet receptor in order to prevent platelet activation in a dose-dependent manner [21]. It is currently approved as an adjunct to PCI for reducing peri-procedural MI, repeat revascularization, and stent thrombosis in patients not yet treated with another P2Y12 inhibitor or glycoprotein IIb/IIIa inhibitor (e.g., eptifibatide), and it is also used off-label as bridging therapy prior to cardiac surgery in patients at high risk of thrombotic complications when oral antiplatelet therapy is held. Cangrelor's main advantages include its quick onset of action (approximately 2 minutes) and extremely short half-life of 3 to 6 minutes. These properties, paired with its reversible platelet inhibition, allow for platelet function to return to normal within one hour of cangrelor discontinuation [21]. Cangrelor is typically dosed as a 30-mcg/kg intravenous bolus followed by a 4-mcg/kg/min infusion and continued for at least two hours or the duration of the procedure, whichever is longer, when used for its labeled indication. Off-label use of cangrelor as bridging therapy requires a lower dosing regimen, most commonly cited as 0.75 mcg/kg/min, based on the BRIDGE trial [29]. Reported adverse effects related to cangrelor are limited and are primarily related to its increased risk of bleeding.

Monitoring of P2Y12 inhibitors can be done through the use of platelet function testing, such as with the VerifyNow assay. VerifyNow is a P2Y12 point-of-care, optical aggregometry assay that evaluates the level of platelet inhibition in terms of platelet reactivity units or P2Y12 reaction units (PRU) based on the rate and extent of platelet aggregation in a blood sample [30,31]. Although not routinely performed in all patients, this test can be particularly useful in select clinical scenarios, such as when evaluating a patient's ability to metabolize clopidogrel into its active metabolite and receive its therapeutic effect. By assessing PRU in a patient taking clopidogrel, this test can assist in determining if the patient is a poor metabolizer (clopidogrel nonresponder) that may be at an increased risk of ischemic events. In patients without appropriate response, providers can then assess if another agent, such as one of the newer P2Y12 inhibitors, may be more appropriate for treatment. When evaluating the results of the VerifyNow assay, certain cutoffs have been associated with ischemic events (PRU >208) as well as with bleeding events (PRU <85) [31]. Although this test has certain limitations and may not be as accurate in select populations, such as patients from East Asia, it provides additional information to make informed decisions regarding antithrombotic therapy.

Healthcare Consideration

In patients who receive monitoring for P2Y12 inhibitors with the VerifyNow assay, interpretation of results can be tricky. Since the assay evaluates platelet reactivity, lower PRU values indicate more platelet inhibition (i.e., an increased risk of bleeding), whereas higher PRU values indicate less platelet inhibition (i.e., less risk of bleeding and possible risk of thrombotic events). As always, it is important to be mindful of how to interpret results whenever monitoring patients for safety and efficacy of their antithrombotic therapies.

With the widespread use of P2Y12 inhibitors, it may be common to encounter the clinical scenario of switching between agents during therapy. Although this change may be necessary, it also presents potential concerns regarding the safety of making this switch appropriately. When switching agents, patients may be at risk for inadequate platelet inhibition (and an increased risk of thrombotic complications related to gaps in therapy) as well as at risk of excessing platelet inhibition (and an increased risk of bleeding related to overlapping therapy). By being mindful of drug-specific pharmacological properties such as half-life, site of action, and speed of onset, these risks can be mitigated. Due to these concerns, Angiolillo et al. published a white paper detailing the international expert consensus on switching platelet P2Y12 receptor-inhibiting therapies [21]. This document reviews the relevant pharmacology and timing considerations when switching between oral P2Y12 inhibitors and between an intravenous P2Y12 inhibitor (i.e., cangrelor) and oral P2Y12 inhibitors. A brief summary of these recommendations, based on time from the index event, is provided inTable 1 and Table 2. Although these general consensus recommendations provide a starting point, they may not be applicable in all clinical scenarios and should be evaluated in the context of personalized patient care.

Table 1: SWITCHING ORAL P2Y12 INHIBITORS DURING ACUTE/EARLY PHASE (WITHIN 30 DAYS OF INDEX EVENT)

Clopidogrel Transitioned to:

Prasugrel

Begin prasugrel 60-mg loading dose, regardless of timing and dosing of clopidogrel

Ticagrelor

Begin ticagrelor 180-mg loading dose, regardless of timing and dosing of clopidogrel

Prasugrel Transitioned to:

Clopidogrel

Begin clopidogrel 600-mg loading dose, administered 24 hours after last prasugrel dosea

Ticagrelor

Begin ticagrelor 180-mg loading dose, administered 24 hours after last prasugrel dose

Ticagrelor Transitioned to:

Clopidogrel

Begin clopidogrel 600-mg loading dose, administered 24 hours after last ticagrelor dosea

Prasugrel

Begin prasugrel 60-mg loading dose, administered 24 hours after last ticagrelor dose

aIf a patient is being de-escalated to clopidogrel for bleeding concerns, consider omitting loading dose and initiating clopidogrel 75-mg maintenance dose 24 hours after last prasugrel or ticagrelor dose.

Source: Author

Table 2: SWITCHING ORAL P2Y12 INHIBITORS DURING LATE/VERY LATE PHASE (GREATER THAN 30 DAYS AFTER INDEX EVENT)

Clopidogrel Transitioned to:

Prasugrel

Begin prasugrel 10-mg maintenance dose, beginning 24 hours after last clopidogrel dose

Ticagrelor

Begin ticagrelor 90-mg BID maintenance dose, beginning 24 hours after last clopidogrel dose

Prasugrel Transitioned to:

Clopidogrel

Begin clopidogrel 75-mg maintenance dose, beginning 24 hours after last prasugrel dose

Ticagrelor

Begin ticagrelor 90-mg BID maintenance dose, beginning 24 hours after last prasugrel dose

Ticagrelor Transitioned to:

Clopidogrel

Begin clopidogrel 600-mg loading dose, administered 24 hours after last ticagrelor dosea

Prasugrel

Begin prasugrel 60-mg loading dose, administered 24 hours after last ticagrelor dose

aIf a patient is being de-escalated to clopidogrel for bleeding concerns, consider omitting loading dose and initiating clopidogrel 75-mg maintenance dose 24 hours after last prasugrel or ticagrelor dose.

Source: Author

When transitioning from oral P2Y12 inhibitors to intravenous P2Y12 inhibitors in the setting of bridging for surgery, clopidogrel and ticagrelor should typically be discontinued 5 days before the procedure, while prasugrel is recommended to be discontinued for 7 days prior to procedure. Following this, it is reasonable to begin cangrelor up to 3 to 4 days after prasugrel discontinuation and 2 to 3 days of clopidogrel and ticagrelor discontinuation. When transitioning patients from intravenous P2Y12 inhibitor to an oral P2Y12 inhibitor, it is important to note that the loading doses of clopidogrel or prasugrel should not be administered until immediately after discontinuation of cangrelor. Ticagrelor, on the other hand, may be administered anytime during or immediately following cangrelor infusion [21].

Healthcare Consideration

Although many medications require an overlapping period to ensure a smooth transition, this is not the case when transitioning from cangrelor to clopidogrel or prasugrel. Due to the properties of these different medications, the activity of clopidogrel or prasugrel will actually be blocked if administered during cangrelor infusion, and the patient will not receive the effect of the drug until the next dose is given. It is important to ensure that loading doses of clopidogrel and prasugrel are not given until immediately after the cangrelor infusion is stopped in order to have the most benefit.

5. ANTICOAGULANTS

UNFRACTIONATED HEPARIN

Unfractionated heparin (UFH) is another antithrombotic with a long-standing, rich history in the field of medicine. Heparin was initially approved in the United States in 1939 and remains one of the most commonly used injectable anticoagulants to this day. Heparin provides its anticoagulant effect by binding to antithrombin III (ATIII) in order to create a complex that inhibits the activation of factor IIa (thrombin) as well as factors IXa, Xa, XIa, and XIIa, in addition to other mechanisms [32]. Heparin also helps prevent the formation of a fibrin clot by inhibiting activation of the fibrin stabilizing factor. Contrary to some belief, heparin does not break down an existing clot like thrombolytics, but rather, solely acts to prevent the continued propagation and further stabilization of an active clot. Heparin is typically administered as a continuous intravenous infusion or as a subcutaneous injection, depending on indication and availability of intravenous access. Due to its extensive history and favorable pharmacokinetic profile, heparin remains a drug of choice in numerous disease states and clinical scenarios. It is currently approved for prophylaxis and treatment of venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE), peripheral arterial embolism, AF with embolization, acute and chronic consumptive coagulopathies (e.g., disseminated intravascular coagulation), prevention of clotting in arterial and cardiac surgery, and as an anticoagulant for use in blood transfusions, extracorporeal circulation, and dialysis procedures [33,34]. The dosing of heparin can vary significantly by indication. A few of the most common dosing regimens that may be seen in practice are listed in Table 3; however, this list is not all inclusive and may also vary slightly by institution.

Table 3: COMMON HEPARIN DOSING REGIMENS

Indication

Heparin Dosing Regimena

VTE prophylaxis

5,000 units subcutaneously every 8 or 12 hoursb

VTE treatment

Initial: 80 units/kg IV bolus followed by 18 units/kg/hour IV infusion

AF

Initial: 60–80 units/kg (maximum 5,000 units) IV bolus followed by 12–18 units/kg/hour (maximum 1,000 units/hour) IV infusion

ACS, NSTEMI (off-label)

Initial: 60 units/kg (maximum 5,000 units) IV bolus followed by 12 units/kg/hour (maximum 1,000 units/hour) IV infusion

aActual body weight should be used for weight-based dosing of heparin in most patients. In patients with a BMI ≥40 kg/m^2, use adjusted body weight or consider using a reduced dosing rate with appropriate monitoring.

bDoses up to 7,500 units every 8 hours may be used in patients with obesity and should especially be considered in a BMI 50 kg/m^2

Source: [34]

In terms of cautions and contraindications, heparin is known to increase the risk of bleeding, and it is also known to cause thrombocytopenia, elevations in serum aminotransferases, and heparin-induced thrombocytopenia (HIT) with or without thrombosis in some patients. Of note, not all patients who experience heparin-related thrombocytopenia have HIT, and appropriate assessment of thrombocytopenia using risk scores (e.g., 4T score) and confirmatory testing (e.g., heparin antibody and serotonin release assay) should be performed if HIT is suspected. Heparin is contraindicated in patients with HIT as well as those with hypersensitivity to heparin or pork since it is derived from animal tissue [33]. In patients who require temporary interruption of a heparin infusion due to surgery, the heparin infusion should be held at least 4 to 6 hours before the procedure due to its variable half-life of 0.5–2 hours [35].

After a heparin infusion has been initiated, monitoring of its response and titration to a therapeutic goal is imperative in order to ensure both safety and efficacy. For decades, the standard method of monitoring heparin infusions in hospitalized patients had been through assessment of the aPTT, with a target range of 1.5 to 2.5 times the control. Due to the high degree of variability in aPTT readings between laboratories and reagents, guiding organizations made recommendations in the 1990s that institution-specific therapeutic goal ranges should be determined according to a corresponding heparin level, with heparin concentrations of 0.2–0.4 unit/mL by protamine titration or 0.3–0.7 unit/mL by antifactor Xa assay being used for reference of therapeutic range [36]. Monitoring of heparin by anti-factor Xa assay has been shown to have certain benefits over traditional aPTT monitoring, including a faster time to therapeutic levels of heparin, a longer time in goal range, and fewer adjustments in dosing and repeated testing [37,38]. This has prompted some institutions to change from using aPTT to antifactor Xa assay as the standard for heparin monitoring and titration. Regardless of institution-specific monitoring strategy, heparin should be monitored at standard intervals (e.g., every 6 hours) until consistently resulting in the therapeutic range before further extending monitoring frequency. In patients with subtherapeutic heparin monitoring despite receiving more than 35,000 units of heparin per day after titration, heparin resistance should be suspected [39]. Heparin resistance may occur in patients due to various causes, including deficiency of endogenous ATIII, the necessary cofactor required for heparin's anticoagulant effect. Although current practice varies in the management of patients with suspected heparin resistance, potential mitigation strategies that have been employed include continuing to increase the dose of heparin until reaching response, providing supplementation of exogenous ATIII if available, and changing to a different anticoagulant that does not require ATIII for activity, such as argatroban or bivalirudin [39].

Transitioning from heparin to other anticoagulants is a clinical scenario that occurs often in the hospital setting and can be associated with a significant risk of medication errors and adverse effects if not handled appropriately. Based on the pharmacokinetic properties of each anticoagulant, currently recommended transitioning strategies are provided in Table 4 [40].

Table 4: HEPARIN (INTRAVENOUS INFUSION) TRANSITION TO OTHER ANTICOAGULANTS

Transitioned to

Transition Strategy

Enoxaparin (SUBQ)

Begin enoxaparin within one hour of stopping heparin infusion.

Warfarin (oral)

Begin warfarin and continue heparin until INR is within therapeutic range (based on indication) for at least 2 measurements about 24 hours apart.

DOAC (oral)a

Begin DOAC when the heparin infusion is stopped.

aIncluding apixaban, dabigatran, rivaroxaban, and edoxaban

Source: [40]

LOW-MOLECULAR-WEIGHT HEPARINS

The low-molecular-weight heparins (LMWHs) are a group of anticoagulants that provide anticoagulant effects with a similar mechanism to heparin except with an increased inhibition of factor Xa over factor IIa (thrombin) [32]. Multiple agents are included within this class including enoxaparin, dalteparin, nadroparin, and tinzaparin; however, enoxaparin is currently the most widely used agent within the United States and will be the focus of this section.

Enoxaparin (Lovenox) was first approved in the United States in 1993 and remains one of the most commonly used subcutaneous anticoagulants to this day. Enoxaparin is currently approved for prophylaxis and treatment of VTE in a variety of patient populations, prophylaxis of ischemic complications of unstable angina and non-Q-wave MI, and treatment of ST-segment elevation MI. Since enoxaparin is similar in composition to heparin, it is also contraindicated in patients with a history of HIT within the past 100 days (or with circulating antibodies) as well as in patients with a hypersensitivity to heparin or pork products. Enoxaparin is currently available as a subcutaneous injection, though it can also be administered intravenously in the management of ACS, and dosing varies based on indication. Of note, enoxaparin exposure is significantly increased in those with renal impairment and dosage or frequency adjustments are required, particularly in those with a creatinine clearance <30 mL/min [41,42]. Although not all inclusive, a list of common enoxaparin dosing regimens are provided in Table 5.

Table 5: COMMON ENOXAPARIN DOSING REGIMENS

Indication

Enoxaparin Dosing Regimen

VTE prophylaxis

40 mg subcutaneously every 24 hours (Select patient populations may require alternate dosing or frequencya)

VTE treatment

1 mg/kg subcutaneously every 12 hours or 1.5 mg/kg every 24 hours

ACS (NSTEMI) or AF (periprocedural management)

1 mg/kg subcutaneously every 12 hours

aTrauma, morbid obesity, low body weight, or reduced renal function

Source: Author

Adverse effects associated with enoxaparin include bleeding, thrombocytopenia, increases in serum aminotransferases, and injection site pain. Additionally, enoxaparin has been associated with epidural and spinal hematomas in patients undergoing neuraxial anesthesia or spinal puncture, resulting in significant long-term or even permanent paralysis. Factors increasing the risk of bleeding and the timing of the last enoxaparin dose should be closely evaluated in patients receiving these procedures [41]. In patients undergoing surgery, the last dose of therapeutic enoxaparin should be given no closer than 24 hours prior to surgery [35].

Therapeutic drug monitoring is not routinely performed in most patients receiving enoxaparin; however, antifactor Xa monitoring can be useful in the management of special populations or those with a high risk of altered pharmacokinetics (e.g., morbid obesity, low body weight, pregnancy, or those with reduced kidney function in whom other anticoagulants are not appropriate) [32]. Due to enoxaparin's greater impact on factor Xa than factor IIa (thrombin), antifactor Xa monitoring is preferred over other monitoring parameters, such as aPTT. Peak antifactor Xa activity is generally measured 4-6 hours after enoxaparin dosing once steady state is reached after the third or fourth dose of enoxaparin. Although slight differences may exist between institutions, an antifactor Xa goal range of 0.2-0.5 units/mL is generally acceptable for VTE prophylaxis, and a range of 0.6-1 unit/mL is acceptable for therapeutic dosing when enoxaparin is administered twice daily. If therapeutic enoxaparin is being dosed once daily (e.g., 1.5 mg/kg every 24 hours), an antifactor Xa range of 1-2 units/mL is typically used [32]. When transitioning from enoxaparin to a different anticoagulant, particular care should be utilized to ensure efficacy and safety. Current recommendations for transitioning between agents are provided in Table 6 [40].

Table 6: ENOXAPARIN (SUBCUTANEOUS) TRANSITION TO OTHER AGENTS

Transitioned to

Transition Strategy

Heparin (intravenous)

Begin intravenous heparin without a loading dose (rate based on indication) 1 to 2 hours before the next dose of enoxaparin would be due.

Warfarin (oral)

Begin warfarin and continue enoxaparin until INR is within therapeutic range (based on indication) for at least 2 measurements about 24 hours apart.

DOAC (oral)a

Begin DOAC within 2 hours prior to when the next scheduled dose of enoxaparin would be due.

aIncluding apixaban, dabigatran, rivaroxaban, and edoxaban

Source: [40]

Healthcare Consideration

Special populations, such as patients who are pregnant, morbidly obese, severely malnourished or underweight, and those with organ failure (e.g., acute or chronic kidney or liver disease) may respond differently to medications than those from the normal population and often are excluded from initial trials. Differences in pharmacokinetic parameters such as absorption, distribution, metabolism, and excretion can vary significantly in these patients, and medications should be used cautiously and based on best evidence. When possible, it is useful to use therapeutic drug monitoring to ensure both efficacy and safety of high-risk medications.

WARFARIN

Warfarin (Coumadin) is an oral vitamin K antagonist that was initially approved in the United States in 1954. Until recently, warfarin had been the most widely prescribed oral anticoagulant in the management of a variety of thromboembolic and cardiovascular disease states, only to be replaced with the DOACs over the past decade. Warfarin provides its anticoagulant effect by inhibiting the synthesis of activated vitamin K-dependent clotting factors, including factors II, VII, IX, and X, and also the production of the body's natural anticoagulants, proteins C and S [43]. Warfarin is indicated in the prophylaxis and treatment of VTE, prophylaxis and treatment of thromboembolic complications from AF and cardiac valve replacement, and reduction in the risk of death, recurrent MI, or thromboembolic events after MI. Initial dosing of warfarin should be individualized based on patient factors including age, weight, and any relevant drug-drug interactions and adjusted based on INR response. Although variation exists based on patient factors, an initial starting warfarin dose in most patients is 5 mg once daily. Adverse reactions related to warfarin include the risk of bleeding, necrosis of skin and other tissues due to its effect on proteins C and S, and atheroemboli and cholesterol microemboli, among others. A few of the most relevant contraindications to warfarin include pregnancy (except in women with mechanical heart valves), recent surgery in critical areas, underlying bleeding tendencies or blood dyscrasias, and unsupervised use in patients with high potential for noncompliance [44,45]. In patients requiring treatment interruption before surgery, warfarin should be held at least 5 days prior to the procedure in order to allow time for the INR to normalize. In select patients at high risk of thromboembolic events, a shorter-acting anticoagulant such as heparin infusion may be utilized as a bridge during the perioperative period once INR becomes subtherapeutic and held closer to surgery, if required [35,44].

Monitoring and titration of warfarin dosing is achieved with the use of the INR. Target INR varies by indication, with the most common therapeutic range being 2–3 for indications such as the treatment of VTE and prevention of stroke in AF; however, some patients may require other target ranges based on risk of bleeding or indication (e.g., target range of 2.5–3.5 for management of mechanical mitral valve). Although some anticoagulant effect occurs within 24 hours of initiating warfarin, it is important to recognize that peak effect of warfarin may not be reached for 72 to 96 hours following administration, due to the variation in duration of half-lives of the inhibited coagulation factors. This complicates dosing of warfarin as a change in warfarin dose may not be fully reflected in the INR for multiple days [43,44].

In addition to warfarin's effect on INR, dosing titration can further be complicated by the impact of other endogenous and exogenous factors on INR as well as significant drug-drug interactions between warfarin and many other medications. Since INR reflects vitamin K-dependent clotting factors, patients with poor nutritional intake, hepatic disorders, or other reasons for vitamin K deficiency may have an increased INR, regardless of warfarin. It is, therefore, important to educate patients to have a consistent intake of foods that are rich in vitamin K, such as leafy greens. Additionally, drug-drug interactions can have a significant impact on warfarin's effect on INR and should be accounted for when initiating or adjusting warfarin doses. Warfarin can be impacted by both inhibitors and inducers of CYP2C9, CYP1A2, and CYP3A4 as well as antibiotics, antifungals, and herbal products. A few of the most notable CYP450 inhibitors that may increase warfarin concentrations include amiodarone, fluconazole, cotrimoxazole, ciprofloxacin, oral contraceptives, and voriconazole. Notable CYP450 inducers that may reduce concentrations of warfarin include carbamazepine, phenobarbital, rifampin, and phenytoin [43,44]. It is recommended to evaluate drug-drug interactions whenever medications are being changed in patients receiving warfarin. When transitioning from warfarin to a different anticoagulant, particular care should be utilized to ensure efficacy and safety. Current recommendations for transitioning between agents are provided in Table 7 [40].

Table 7: WARFARIN (ORAL) TRANSITION TO OTHER AGENTS

Transitioned to

Transition Strategy

Heparin (intravenous)

Discontinue warfarin and begin heparin once INR is ≤2 or lower INR limit of therapeutic range

Enoxaparin (subcutaneous)

Discontinue warfarin and begin enoxaparin once INR is ≤2 or lower INR limit of therapeutic range

DOAC (oral)a

Discontinue warfarin and begin DOAC once INR is <2 or lower INR limit of therapeutic range

aIncluding apixaban, dabigatran, rivaroxaban, or edoxaban

Source: [40]

DIRECT THROMBIN INHIBITORS

The direct thrombin inhibitors (DTIs) are a group of anticoagulants that provide their effects through direct inhibition of factor IIa (thrombin), as their name suggests. Through their reduction of thrombin generation, these agents ultimately prevent the conversion of fibrinogen into fibrin and the formation of a fibrin-bound clot. Currently, the only available oral DTI is dabigatran; however, intravenous agents, such as argatroban and bivalirudin, are also available for use as continuous infusions. Although argatroban and bivalirudin are important agents in the management of HIT and cardiac intervention as an alternative to heparin, this review will focus on the use of dabigatran.

Dabigatran etexilate (Pradaxa) was the first of the currently available direct oral anticoagulants to come to market with an original approval date in the United States in 2010. Currently, it is approved for reducing the risk of stroke and systemic embolism in patients with non-valvular AF, prevention and treatment of VTE, and VTE prophylaxis in total hip arthroplasty. Dabigatran is only available in oral formulations at this time, and dosing for common indications is listed below in Table 8. Due to dabigatran's renal elimination, use should be avoided in patients on hemodialysis or with a creatinine clearance < 30 mL/min, with the exception of a recommended renal dosage adjustment in patients with severe renal impairment (CrCl 15–30 mL/min) during the management of nonvalvular AF, specifically [46].

Table 8: COMMON DABIGATRAN DOSING REGIMENS

Indication

Dabigatran Dosing Regimen

AF (nonvalvular)

150 mg orally every 12 hours

VTE treatment

150 mg orally every 12 hours, after at least 5 days of initial therapy with a parenteral anticoagulant

VTE prophylaxis in total hip arthroplasty

220 mg orally daily, after an initial dose of 110 mg or 220 mg based on timing from surgery and hemostasis

Source: [40]

Adverse reactions and precautions related to the use of dabigatran include an increased risk of bleeding as well as gastritis-like symptoms reported in greater than 15% of patients. Since dabigatran is known to be influenced by P-glycoprotein (P-gp), caution should be used when dabigatran is concomitantly administered with P-gp inducers, such as rifampin, or P-gp inhibitors, such as dronedarone. If dabigatran therapy interruption is required for surgery, it should be held 1 to 2 days prior to the procedure in patients without renal dysfunction (CrCl ≥50 mL/min) and for 3 to 5 days in patients with renal dysfunction (CrCl <50 mL/min). Although routine monitoring of dabigatran is not recommended, bleeding risk with dabigatran in select scenarios can best be assessed with use of the ecarin clotting time (ECT), if available, or aPTT if not [43,46]. When transitioning from dabigatran to a different anticoagulant, particular care should be utilized to ensure efficacy and safety. Current recommendations for transitioning between agents are provided in Table 9 [40].

Table 9: DABIGATRAN (ORAL) TRANSITION TO OTHER AGENTS

Transitioned to

Transition Strategy

Heparin (intravenous)

CrCl >30 mL/min: Begin heparin 12 hours after last dose of dabigatran.

CrCl <30 mL/min: Begin heparin 24 hours after last dose of dabigatran.

Enoxaparin (subcutaneous)

CrCl >30 mL/min: Begin enoxaparin 12 hours after last dose of dabigatran.

CrCl <30 mL/min: Begin enoxaparin 24 hours after last dose of dabigatran.

Warfarin (oral)

Dabigatran can elevate the INR and complicate warfarin dosing. Consider stopping dabigatran, beginning warfarin the same day, and bridging with a parenteral anticoagulant until INR is within therapeutic range.

Another DOAC (oral)a

Begin the new DOAC when the next dose of dabigatran would be due.

aIncluding apixaban, rivaroxaban, or edoxaban

Source: [40]

FACTOR XA INHIBITORS

The factor Xa inhibitors are a group of anticoagulants that provide their effects through direct inhibition of factor Xa, as their name suggests. Through factor Xa inhibition, these agents ultimately decrease thrombin generation and prevent the formation of a fibrin-bound clot. Currently, the available oral factor Xa inhibitors include apixaban, rivaroxaban, and edoxaban, while fondaparinux is the only available agent for injection. Although betrixaban had previously been included within this class as well, it was removed from the market in the United States over the past few years. Despite these agents having the same mechanism for providing anticoagulation, important differences exist between these medications that must be recognized.

Rivaroxaban (Xarelto) was the second of the currently approved direct oral anticoagulants to be approved for use in the United States and was originally approved in 2011. Rivaroxaban currently has an extensive list of approved indications including nonvalvular AF, stable CAD, treatment and prevention of VTE, stable peripheral artery disease (PAD), and VTE prophylaxis following total hip or knee arthroplasty. Of note, rivaroxaban should not be used in the setting of prosthetic heart valves and valvular AF or in the setting of patients with triple positive antiphospholipid syndrome [47]. Most common adverse effects related to rivaroxaban include the risk of bleeding. Similar to enoxaparin, rivaroxaban carries a warning for the occurrence of epidural or spinal hematomas in patients treated with the drug and receiving neuraxial anesthesia or a spinal procedure. In patients requiring temporary discontinuation of therapy due to surgery or an invasive procedure, rivaroxaban should be held at least 24 hours prior to the procedure to reduce the risk of bleeding. Rivaroxaban dosing varies by indication, and due to some renal elimination of rivaroxaban, dosing alterations are often required in patients with renal dysfunction. Rivaroxaban should typically be avoided in patients on hemodialysis and those with CrCl <15 mL/min. Examples of common rivaroxaban dosing regimens are provided inTable 10 [47,48].

Table 10: COMMON RIVAROXABAN DOSING REGIMENS

Indication

Rivaroxaban Dosing Regimen

AF (nonvalvular)

20 mg orally once daily with evening meal

VTE treatment

15 mg orally twice daily with food for 21 days, followed by 20 mg once daily with food

CAD or stable PAD

2.5 mg orally twice daily, in combination with low dose aspirin

Source: [47,48]

As with the other DOACs, routine coagulation monitoring of rivaroxaban is not required or recommended. In clinical situations where assessment of the anticoagulant effect is useful, prothrombin time (PT) may be useful to determine presence of rivaroxaban, though normal values cannot rule out use. In select institutions, antifactor Xa calibrated for rivaroxaban may be used if available, or antifactor Xa calibrated for LMWH can detect presence of drug concentrations but not accurately quantify the level of anticoagulation. Although drug interactions are not as common as with other agents such as warfarin, use with combined CYP3A4 and P-gp inducers or inhibitors should be avoided [43,47]. When transitioning from rivaroxaban to a different anticoagulant, particular care should be utilized to ensure efficacy and safety. Current recommendations for transitioning between agents are provided in Table 11 [40].

Table 11: RIVAROXABAN (ORAL) TRANSITION TO OTHER AGENTS

Transitioned to

Transition Strategy

Heparin (intravenous)

Begin heparin when the next dose of rivaroxaban would be due.

Enoxaparin (subcutaneous)

Begin enoxaparin when the next dose of rivaroxaban would be due.

Warfarin (oral)

Rivaroxaban can elevate the INR and complicate warfarin dosing. Consider stopping rivaroxaban, beginning warfarin the same day, and bridging with a parenteral anticoagulant until INR is within therapeutic range.

Another DOAC (oral)a

Begin new DOAC when the next dose of rivaroxaban would be due.

aIncluding apixaban, dabigatran, or edoxaban

Source: [40]

Apixaban (Eliquis) is another direct oral anticoagulant that was initially approved for use in the United States in 2012. As of 2021, it is the most prescribed oral anticoagulant in the United States and has surpassed the use of other direct oral anticoagulants and warfarin, due to its enhanced safety profile [4]. Apixaban is currently approved for use in the management of AF, VTE, and postoperative VTE prophylaxis following hip or knee replacement surgery. Of note, apixaban is not currently approved for use in the management of prosthetic heart valves or valvular AF. The most common adverse reactions to apixaban are related to minor or major bleeding, though it has shown to be comparable, if not superior, to other agents in terms of bleeding risk. In patients requiring elective surgery or invasive procedures, apixaban should be discontinued at least 48 hours prior to procedures with a high-risk of bleeding and at least 24 hours prior to procedures with a low risk of bleeding or with procedures in a non-critical location where bleeding can be easily controlled [49]. Like other agents, apixaban carries a warning for the occurrence of epidural or spinal hematomas in patients treated with the drug and receiving neuraxial anesthesia or a spinal procedure. Apixaban is most often dosed at 5 mg orally twice daily; however, certain dosing nuances exist based on indication and patient factors [49]. Example dosing regimens for some of the most common indications are listed in Table12.

Similar to the other direct oral anticoagulants, routine coagulation monitoring of apixaban is not required or recommended. If assessment of apixaban's anticoagulant effect is required in select scenarios, PT or anti-factor Xa calibrated for LMWH can be used to determine the presence of relevant apixaban drug concentrations; however, this method does not provide accurate quantification of how much anticoagulant effect is present. Although drug interactions are not as common as with other agents such as warfarin, dose reduction or avoidance of use may be required in patients concomitantly receiving inhibitors or inducers of both CYP3A4 and P-gp [49,50]. When transitioning from apixaban to a different anticoagulant, particular care should be utilized to ensure efficacy and safety. Current recommendations for transitioning between agents are provided in Table 13 [40].

Table 12: APIXABAN (ORAL) TRANSITION TO OTHER AGENTS

Transitioned to

Transition Strategy

Heparin (intravenous)

Begin heparin when the next dose of apixaban would be due.

Enoxaparin (subcutaneous)

Begin enoxaparin when the next dose of apixaban would be due.

Warfarin (oral)

Apixaban can elevate the INR and complicate warfarin dosing. Consider stopping apixaban, beginning warfarin the same day, and bridging with a parenteral anticoagulant until INR is within therapeutic range.

Another DOAC (oral)a

Begin new DOAC when the next dose of apixaban would be due.

aIncluding rivaroxaban, dabigatran, or edoxaban

Source: [40]

Edoxaban (Savaysa) was the next of the currently approved DOACs approved for use in the United States with an initial approval in 2015. Although this agent has some potential advantages over warfarin in select scenarios, edoxaban use has fallen out of favor, particularly due to its reduced efficacy in the treatment of nonvalvular AF in patients with creatinine clearance greater than 95 mL/min. Currently, edoxaban is approved for use in the management of nonvalvular AF and treatment of VTE, though certain limitations to its use exist. In addition to reduced efficacy in patients with nonvalvular AF with CrCl >95 mL/min, edoxaban is currently only approved for treatment of VTE following 5 to 10 days of initial parenteral anticoagulation, further limiting its use as an initial treatment option. Edoxaban should not be utilized in patients with mechanical heart valves, moderate-to-severe mitral stenosis, or those with triple positive antiphospholipid syndrome [51]. The most common adverse effects reported with edoxaban use include bleeding, as well as anemia, rash, and abnormal liver function tests. Edoxaban also carries the same warning for spinal and epidural hematoma in patients receiving neuraxial anesthesia or spinal puncture as other DOACs and enoxaparin. Concomitant use of rifampin or other agents that also increase risk of bleeding should be avoided, and dose reduction is required in patients who use certain P-gp inhibitors. The most common dosing regimen for edoxaban is 60 mg once daily in patients with a CrCl 51–95 mL/min, and a dosage reduction to 30 mg once daily is required for patients with a CrCl 15–50 mL/min or in patients with low body weight (≤60 kg) when being treated for VTE, specifically. In patients requiring temporary discontinuation of therapy due to surgery or an invasive procedure, edoxaban should be held at least 24 hours prior to the procedure to reduce the risk of bleeding [51].

Similar to the other DOACs, routine coagulation monitoring of edoxaban is not required or recommended in patients receiving this medication. In clinical situations where assessment of the anticoagulant effect is useful, PT may be useful to determine presence of edoxaban, though normal values cannot rule out use. In select institutions, antifactor Xa calibrated for edoxaban may be used if available, or antifactor Xa calibrated for LMWH can detect presence of drug concentrations but not accurately quantify the level of anticoagulation [52]. When transitioning from edoxaban to a different anticoagulant, particular care should be utilized to ensure efficacy and safety. Current recommendations for transitioning between agents are provided in Table 14.

Table 13: EDOXABAN (ORAL) TRANSITION TO OTHER AGENTS

Transitioned to

Transition Strategy

Heparin (intravenous)

Begin heparin when the next dose of edoxaban would be due.

Enoxaparin (subcutaneous)

Begin enoxaparin when the next dose of edoxaban would be due.

Warfarin (oral)

Edoxaban can elevate the INR and complicate warfarin dosing. Consider stopping edoxaban, beginning warfarin the same day, and bridging with a parenteral anticoagulant until INR is within therapeutic range.

Another DOAC (oral)a

Begin new DOAC when the next dose of edoxaban would be due.

aIncluding apixaban, dabigatran, or rivaroxaban

Source: [40]

Healthcare Consideration

Classes of antithrombotics each work in distinct ways to prevent thrombosis. When utilizing combination therapy, ensure that medications from different classes are being used together synergistically, instead of using multiple agents from the same class that work in the same way. Additionally, the more agents that are being used simultaneously (e.g., triple therapy), the more the risk of bleeding. It is important to minimize the duration of using more than two agents to reduce the risk of bleeding, whenever possible.

6. INDICATIONS FOR ANTIPLATELETS AND ANTICOAGULANTS

PRIMARY PREVENTION OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

As a whole, atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality worldwide [53]. ASCVD-related conditions are caused by the buildup of plaque in arterial walls, which can then lead to a variety of disease processes including acute coronary syndromes, ischemic stroke and TIA, PAD, and coronary or carotid arterial stenosis. Although each disease process has its own unique management, the use of antithrombotics remains a standard of practice in the prevention and treatment of each of these ASCVD-related disease states. One of the most significant changes in the management of ASCVD-related disease states over the past few years has been the change in recommendations for providing aspirin as primary prevention of ASCVD. Historically, aspirin has been widely administered for ASCVD prevention in many patient populations. As of the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease, aspirin is no longer recommended for widespread use but rather limited to patients who may receive the greatest benefit with the least risk of harm. The guideline provides a Class 2b recommendation to consider utilizing low-dose aspirin (75–100 mg orally daily) for primary prevention of ASCVD in patients aged 40 to 70 years who are at a higher risk of ASCVD but no increased risk of bleeding [53]. Additionally, these guidelines go on to recommend against the use of low-dose aspirin routinely for primary prevention of ASCVD in patients older than 70 years of age (Class 3, potential harm) or in patients of any age who are at an increased risk of bleeding (Class 3, potential harm). Examples of increased bleeding risk include those patients with a history of peptic ulcer disease or gastrointestinal bleeding, patients with thrombocytopenia or coagulopathy, or patients concomitantly taking other medications that also increase the risk of bleeding such as nonsteroidal anti-inflammatory drugs, steroids, and other anticoagulants. In patients being considered for primary prevention of ASCVD, the guidelines recommend utilizing ASCVD risk estimators such as the pooled cohort equations or evaluating patient-specific ASCVD risk factors to assess which patients may benefit from the use of aspirin in appropriate age ranges.

CHRONIC CORONARY DISEASE

Chronic coronary disease (CCD) is an encompassing term that includes obstructive and nonobstructive CAD, ischemic heart disease, and chronic angina symptoms. Within the United States, approximately 20.1 million people live with CCD, and despite significant advancements in management, it remains the leading cause of death both in the United States and worldwide [54]. In patients with CAD, an atherosclerotic narrowing of the coronary arteries occurs, potentially limiting the flow of blood to vital areas of the heart. Although many patients with CAD may remain asymptomatic, this disease can progress to the point of causing symptoms or complications that must be managed via medications or intervention. Antiplatelets and anticoagulants can be used in the management of CCD to prevent atherosclerotic plaque from forming blockages within the coronary vasculature or other cardiovascular complications leading to comorbidity or death. For simplicity, antithrombotic recommendations will be discussed in the context of stable CCD not requiring revascularization and CCD requiring revascularization (e.g., PCI or CABG), while acute coronary syndrome will be discussed separately.

As per the 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guidelines for patients with CCD, low-dose aspirin 81 mg monotherapy is recommended in order to reduce atherosclerotic events in patients with stable CCD and no indication for anticoagulant therapy (Class 1). In patients with CCD requiring revascularization, guideline recommendations become a bit more nuanced, based on intervention. In patients with CCD treated with PCI, dual antiplatelet therapy (DAPT) with aspirin and clopidogrel for 6 months post-PCI followed by single antiplatelet therapy (SAPT) is recommended (Class 1). In patients with CCD treated with PCI and drug-eluting stent (DES) who completed 1-3 months of DAPT, monotherapy with a P2Y12 inhibitor for at least 12 months is reasonable for management (Class 2a). Additional recommendations of a lower class include that it may be reasonable for patients with CCD and history of MI to have their duration of DAPT be extended from 12 months to up to 3 years (Class 2b) and that the use of DAPT after CABG may be useful to reduce the incidence of saphenous vein graft occlusion (Class 2b) [54].

In patients with CCD who have electively been treated with PCI and require a DOAC for another indication, DAPT should be administered for 1 to 4 weeks followed by SAPT with clopidogrel for 6 months in addition to the DOAC (Class 1). If it is determined that a patient in this category has a high thrombotic risk and low bleeding risk, DAPT with aspirin and clopidogrel can be extended for up to 1 month in addition to the DOAC (Class 2a). In patients with CCD who require a DOAC and receive PCI, discontinuation of aspirin therapy may be considered after one year from PCI with continuation of DOAC alone, if low atherothrombotic risk exists (Class 2b). Additionally, DOAC monotherapy may be considered over aspirin in patients with CCD who already require DOAC use and have no acute indication for concomitant antiplatelet therapy (Class 2b). Lastly, a select population may benefit from low-dose aspirin 81 mg daily plus low-dose rivaroxaban 2.5 mg twice daily in patients with CCD who do not have an indication for therapeutic DOAC or DAPT, are high risk of recurrent ischemic events, and have a low-to-moderate bleeding risk (Class 2a) [54].

ACUTE CORONARY SYNDROME

Acute coronary syndrome (ACS) is a common yet devastating event that occurs in nearly 1 million patients each year in the United States, with a mortality rate of up to 14% of these events [17]. ACS is an encompassing term that includes STEMI, NSTEMI, and unstable angina. Most commonly, ACS occurs due to atherosclerotic plaque rupture leading to thrombus formation and coronary artery occlusion; however, additional mechanisms such as coronary dissection, vasospasm, embolism, or arteritis may lead to this event as well. In the occurrence of disrupted plaques, exposure of thrombogenic material within the plaque leads to platelet adhesion, further platelet activation via P2Y12 receptors and glycoprotein IIb/IIIa receptors, and ultimately platelet aggregation and thrombus formation. With this progression in mind, it's easy to see the rationale for utilizing antiplatelet medications to prevent thrombus formation in ACS, and the importance of these medications is even greater in patients requiring emergent PCI, where stretching of the arterial wall can further disrupt the epithelium and cause additional platelet activation, potentially leading to stent thrombosis and in-stent restenosis in select patients [17].

Evidence Based Practice Recommendation

It may be reasonable to administer intravenous glycoprotein IIb/IIIa receptor antagonist in the precatheterization laboratory setting (e.g., ambulance, emergency department) to patients with STEMI for whom primary PCI is intended.

https://www.ahajournals.org/doi/10.1161/CIR.0b013e3182742c84

Last Accessed: June 24, 2024

Strength of Recommendation/Level of Evidence: IB (Procedure/treatment should be performed based on data derived from a single randomized clinical trial or nonrandomized studies evaluating limited populations.)

In the initial treatment for ACS, current guidelines recommend combination of DAPT and anticoagulant therapy regardless of the choice of invasive (e.g. PCI) or conservative (e.g. medical) management strategies. As soon as ACS is suspected, aspirin 162–325 mg should be administered (chewed) and continued indefinitely unless contraindications exist. Parenteral anticoagulants including unfractionated heparin, enoxaparin, bivalirudin, or fondaparinux should be utilized in the initial period for up to 48 hours or until PCI is performed in patients with NSTEMI (Class 1), and parenteral anticoagulation using unfractionated heparin (with or without an intravenous glycoprotein IIb/IIIa inhibitor) or bivalirudin should be used to assist in emergent revascularization (e.g., PCI) in patients with STEMI (Class 1) [55,56,57]. Generally speaking, anticoagulation does not need to be continued long-term in these patients unless a patient has an additional indication for anticoagulation, such as AF, or in the select use of low-dose anticoagulation plus antiplatelet agent(s).

From an antiplatelet standpoint, DAPT is currently the cornerstone of management and typically includes aspirin (begun as soon as possible when ACS is suspected) plus a P2Y12 inhibitor such as clopidogrel, prasugrel, or ticagrelor (begun as soon as possible if conservative management is chosen or at the time of intervention with PCI, in applicable patients). DAPT has been proven to reduce the risk of recurrent ischemic events in those with ACS. Despite current guidelines favoring the use of the newer, more potent P2Y12 inhibitors such as prasugrel or ticagrelor, clopidogrel remains one of the most commonly used agents in the United States [58]. In the 2014 ACC/AHA guidelines for the management of NSTEMI, clopidogrel or ticagrelor is recommended, with a preference for ticagrelor; however, prasugrel is also recommended in patients undergoing PCI who do not have a high risk for bleeding. Since the release of the guidelines, additional studies have continued to evaluate the use of these newer P2Y12 inhibitors in patients with ACS. Results from comparisons of these medications have led to changes in the most recent European guidelines for ACS, which now recommend considering prasugrel over ticagrelor in patients with ACS who are proceeding to PCI (Class 2a) [59]. Caution should still be utilized when using prasugrel in patients 75 years of age or older due to potential increase in bleeding, and this agent remains contraindicated in patients with a history of stroke.

Healthcare Consideration

In the ISAR-REACT 5 trial published in 2019, authors evaluated the use of ticagrelor versus prasugrel in patients with ACS who were planned to receive invasive evaluation. Despite limitations to the study, the authors concluded that in patients with ACS with or without ST-segment elevation, prasugrel was superior to ticagrelor in this population of approximately 4,000 patients. This was supported by a lower incidence of death, MI, or stroke in the prasugrel group with a similar incidence of bleeding [60].

Evidence Based Practice Recommendation

After PCI for STEMI, aspirin should be continued indefinitely.

https://www.ahajournals.org/doi/10.1161/CIR.0b013e3182742c84

Last Accessed: June 24, 2024

Strength of Recommendation/Level of Evidence: IA (Procedure/treatment should be performed based on data derived from multiple randomized clinical trials or meta-analyses evaluating multiple populations.)

An important decision in the management of ACS includes the duration of antiplatelet therapy following the event. Within the first 30 days after ACS, the risk of thrombosis tends to be greater than the risk of bleeding, making this a time frame when patients are particularly vulnerable to recurrent events; however, the risk of thrombosis significantly declines after those initial 30 days and the risk of bleeding may be held in higher regard. For these reasons, a balanced risk-assessment that includes both the risk of thrombosis and the risk of bleeding should be incorporated. According to the 2016 ACC/AHA guidelines, both aspirin and a P2Y12 inhibitor should be given for at least 12 months in patients with ACS requiring DAPT (Class 1). In select patients who do not have a high risk of bleeding, DAPT may be continued beyond 12 months if deemed beneficial (Class 2b); alternatively, in select patients requiring DAPT who develop significant bleeding or have a high risk of bleeding, aspirin monotherapy can be considered after 6 months of DAPT, with discontinuation of P2Y12 inhibitor therapy (Class 2b) [58]. In patients with ACS undergoing CABG, the P2Y12 inhibitor may be held or discontinued prior to surgery; however, it should be resumed following CABG and continued as part of DAPT to complete one year of treatment (Class 1) [58].

ATRIAL FIBRILLATION

Atrial fibrillation (AF) is the most common arrhythmia in the world and is associated with significant morbidity and mortality. AF was estimated to be present in 5.2 million people in the United States in 2010, and due to an aging population, increased detection, and other factors, it is expected to rise to over 12 million people by 2030. AF is associated with a 1.5- to 2-fold increased risk of death and carries a significant burden of cost and resource utilization in the healthcare system [61]. AF is commonly described as an "irregularly irregular" rhythm, in which chaotic rapid atrial beating leads to the potential for complications and poor outcomes in patients. Management of AF is multifaceted and includes lifestyle and risk factor modification, AF burden mitigation with rate or rhythm control, and reduction in the risk of stroke and systemic embolism with the use of anticoagulants. All patients with AF should be evaluated for their thromboembolic risk using validated clinical risk scores such as the CHA2DS2-VASc score, which can provide an annual risk assessment of thromboembolic events. In patients with an intermediate annual risk of thromboembolic events (e.g., CHA2DS2-VASc score of 1 in men or 2 in women), anticoagulation should be considered along with an overall assessment of potential risks and benefits (Class 2a), and in patients with AF and an estimated annual thromboembolic risk of ≥2% (e.g., CHA2DS2-VASc score ≥2 in men or ≥3 in women), anticoagulation is recommended, in order to prevent stroke and systemic embolism (Class 1) [61].

In terms of anticoagulant choice for AF, current guidelines recommend the use of DOACs over warfarin, except in the setting of mitral stenosis or mechanical heart valve (Class 1) and recommend against the use of aspirin either alone or in combination with clopidogrel for the management of AF (Class 3, harm/no benefit). The superiority of DOACs over warfarin in patients with AF has been consistent in the DOAC trials, including Re-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48. In patients who are required to receive warfarin, a target INR range 2–3 is recommended, along with routine INR monitoring, a diet with consistent vitamin K intake, and regular drug-drug interaction evaluations (Class 1). In patients with AF who require temporary interruption of oral anticoagulation therapy for an invasive procedure or surgery, bridging with an intravenous anticoagulant (e.g., heparin) is generally not required, except in the setting of patients with high thromboembolic risk, such as those with mechanical heart valve [61].

Although guidelines for patients with isolated AF are relatively straightforward, AF often complicates other disease states that also require antithrombotic therapy, posing new risks and considerations. In patients with AF complicated by ACS or those undergoing PCI, indications for DAPT plus anticoagulation therapy (i.e., triple therapy) may exist; however, triple therapy has been shown to significantly increase the risk of bleeding and should be minimized whenever possible. In the current AF guidelines, it is recommended in patients with AF who undergo PCI; DOACs along with antiplatelet therapy are preferred over warfarin and antiplatelet therapy. In most of these patients, triple therapy with DAPT and a DOAC may be required initially; however, early discontinuation of aspirin after 1-4 weeks and continuation of a P2Y12 inhibitor plus DOAC is preferred over continued use of triple therapy, in order to reduce the risk of bleeding (Class 1). Additionally, patients with CCD may also have AF, and although patients with CCD typically require aspirin, current guidelines recommend that patients with both CCD and AF utilize monotherapy with an oral anticoagulant alone in order to decrease the risk of major bleeding (Class 1). Although a lower class of recommendation, a similar recommendation exists for patients with stable PAD and concomitant AF. In this patient population, monotherapy with an oral anticoagulant is deemed reasonable over therapy with an anticoagulant plus an antiplatelet agent (Class 2a) [61].

Case Study: JP

JP is a 76-year-old male with a past medical history significant for coronary artery disease, asthma, hypertension, and hyperlipidemia who presents to the hospital due to complaints of feeling extremely fatigued and having a very fast pounding feeling in his chest. After initial assessment and electrocardiogram, JP is diagnosed with new onset atrial fibrillation and initiated on metoprolol 25 mg orally BID for rate control. After calculating his CHA2DS2-VASc score, the primary team determines that JP is at greater than 2% annual risk of ischemic stroke and requires anticoagulation as well. Prior to admission, JP was taking aspirin 81 mg orally daily, lisinopril 20 mg orally daily, atorvastatin 20 mg orally daily, and an albuterol inhaler as needed.

Study Questions

- Based on current guidelines, what anticoagulant(s) should JP be started on?

- What other components of his antithrombotic regimen may need to change?

- Does JP require any anticoagulant-specific monitoring based on his new medication regimen?

Discussion

According to the 2023 ACC/AHA/ACCP/HRS guidelines for the diagnosis and management of atrial fibrillation, it is recommended that JP be initiated on anticoagulation for prevention of stroke and systemic embolism from atrial fibrillation based on his CHA2DS2-VASc score. As this is nonvalvular atrial fibrillation, first-line therapy includes any of the DOACs (e.g., apixaban, rivaroxaban, dabigatran, or edoxaban), based on their enhanced safety profile over vitamin K antagonists (e.g., warfarin). When selecting a specific agent, edoxaban should be avoided if JP's CrCl is greater than 95 mL/min; however, the remainder of the decision may be based on insurance coverage, patient preference (e.g., once-daily dosing versus twice-daily dosing), drug-interactions, or availability.

Since JP was taking an aspirin for his CAD prior to admission, this must also be addressed. According to the same AF guidelines, monotherapy with an oral anticoagulant alone should be used in patients with CCD and AF in order to decrease the risk of major bleeding. For this reason, JP's aspirin may be discontinued now that he is being started on an oral anticoagulant.

As for specific monitoring, JP will not require routine monitoring with any of the DOACs, another benefit of utilizing these agents over older agents such as warfarin.

ACUTE ISCHEMIC STROKE/TRANSIENT ISCHEMIC ATTACK

Acute ischemic stroke (AIS) and transient ischemic attack (TIA) are related neurologic events with significant disability but common occurrence worldwide. Acute ischemic stroke and TIA can both be described as a blockage that prevents blood flow from reaching various areas of the brain, though in TIA this blockage is brief and does not cause permanent damage. In the United States alone, nearly 700,000 people experience an ischemic stroke, while 240,000 people experience a TIA each year [62,63]. The risk of recurrent stroke or TIA is high, with estimates of approximately 1 in 25 people having a recurrent event within 30 days; however, this risk can be mitigated with appropriate secondary prevention. In the initial acute management of stroke or TIA, the focus is to ensure that cerebrovascular blood flow is restored to all affected areas if possible. This is typically done through the use of thrombolytics (e.g., alteplase or tenecteplase) that break down the clot as well as the use of endovascular therapies in select patient populations. Following initial management, secondary prevention should be initiated after 24 hours in patients who received thrombolytic therapy or immediately if no thrombolytic therapy was administered. The choice of antithrombotic regimen and duration can be impacted significantly by the etiology as well as severity. In patients with stroke or TIA caused by non-valvular AF, anticoagulation with a DOAC is recommended over warfarin (except in the setting of severe mitral stenosis or mechanical heart valve) or antiplatelet therapy (Class 1). In patients with stroke or TIA and valvular AF, warfarin is recommended to reduce the risk of recurrent stroke or TIA (Class 1). In patients with stroke or TIA caused by significant (50% to 99%) stenosis of a major intracranial artery, aspirin 325 mg daily is recommended (Class 1), though the addition of clopidogrel 75 mg per day may be considered for up to 90 days in patients with severe stenosis (70% to 99%) of a major intracranial artery (Class 2a). Patients with stroke or TIA and left ventricular thrombus (LV) thrombus should receive anticoagulation with warfarin for at least 3 months (Class 1), though other guidance documents have discussed the potential use of DOACs in select patients based on more recent data [64]. In patients with a noncardioembolic ischemic stroke or TIA, antiplatelet therapy is preferred over anticoagulant therapy and should be dependent on the severity of disease. In patients with noncardioembolic minor stroke (NIHSS score ≤3) or high-risk TIA (ABCD2 score ≥4), DAPT with aspirin plus clopidogrel should be initiated and continued for 21 to 90 days, followed by single antiplatelet therapy (Class 1). In patients with non-cardioembolic stroke or TIA who do not meet the aforementioned criteria, single antiplatelet therapy should be used [63].

Healthcare Consideration

The CHANCE and POINT trials were two independent multicenter randomized controlled trials that showed the benefit of short-term dual antiplatelet therapy to prevent recurrent ischemic stroke in patients with minor stroke or high-risk TIA. The CHANCE trial evaluated patients who received aspirin plus clopidogrel for 21 days (followed by aspirin monotherapy) versus aspirin monotherapy for minor stroke or TIA in China. The POINT trial evaluated patients who received aspirin plus clopidogrel for 90 days versus aspirin monotherapy for minor stroke or TIA in North America, Europe, Australia, and New Zealand. In both trials, DAPT resulted in fewer ischemic events and overall benefit, though bleeding rates were higher [65,66].

Healthcare Consideration

In order to meet the Joint Commission standardized performance measures for comprehensive stroke centers, all patients with acute ischemic stroke must receive antithrombotic therapy by the end of hospital day two. For this reason, it is imperative that patients receive their antithrombotic (most often aspirin) as early as possible, once cleared to do so, in order to meet metrics and ensure good patient outcomes. This will typically be 24 hours after thrombolytics (e.g., alteplase or tenecteplase) or sooner in patients who are treated more conservatively.

VALVULAR HEART DISEASE

Valvular heart disease (VHD) occurs when any valve in the heart is damaged or diseased, and it is a term that includes conditions such as regurgitation or stenosis of various valves. VHD can have numerous etiologies including congenital conditions (e.g., malformations of the valves), infection (e.g., infective endocarditis), rheumatic disease, or conditions linked to other types of heart disease (e.g., heart failure, atherosclerosis, aortic aneurysm, or MI). In the United States, approximately 2.5% of people have VHD, with higher representation in older adults, and almost 30,000 deaths can be traced back to the disease annually [67]. Although many patients may be managed conservatively, intervention with valve repair or replacement is often required in more severe disease. Following prosthetic valve implantation with either a bioprosthetic or mechanical heart valve, antithrombotic therapy is a cornerstone of management in order to prevent valve or leaflet thrombosis and reduce the incidence of thromboembolic complications.

When considering the most appropriate antithrombotic regimen for patients with valve replacement, the most important point to evaluate is the type of prosthetic valve that was placed (e.g., mechanical or bioprosthetic). In patients with a mechanical prosthetic valve, current guidelines recommend therapeutic anticoagulation with a vitamin K antagonist, such as warfarin (Class 1). Of note, DOACs are contraindicated in patients with a mechanical valve prosthesis and should be avoided (Class 3, harm). Target INR goal for patients with a mechanical valve varies based on location of the valve and the presence of other risk factors for thromboembolism, such as AF, previous thromboembolism, LV dysfunction, hypercoagulable state, or older generation of prosthesis such as ball-in-cage valve. In patients with a mechanical aortic valve replacement (AVR) and no other risk factors for thromboembolism, a vitamin K antagonist with a target INR range of 2–3 is recommended (Class 1). In patients with a mechanical mitral valve alone or those with a mechanical AVR and risk factors for thromboembolism, a vitamin K antagonist with a target INR range of 2.5–3.5 is recommended (Class 1). In any patient with a mechanical valve receiving warfarin, the addition of aspirin 75–100 mg daily may be considered if additional antiplatelet therapy is indicated and risk of bleeding is low (Class 2b) [68].

In patients who receive a bioprosthetic valve, the risk of thromboembolism is comparatively lower than those with a mechanical valve and can often be managed by antiplatelets alone or after a short course of anticoagulation following valve replacement in those who are at a low risk of bleeding. In all patients with a bioprosthetic AVR or MVR, aspirin 75–100 mg daily as lifelong therapy is reasonable in the absence of other indications for anticoagulation, including surgical AVR or MVR and transcatheter aortic valve implantation (TAVI) (Class 2a). In patients with a surgical bioprosthetic AVR or MVR who are at a low risk of bleeding, anticoagulation with a vitamin K antagonist is reasonable for the first 3 to 6 months with a goal INR range of 2–3 (Class 2a). In patients receiving TAVI who are at a low risk of bleeding, anticoagulation with a vitamin K antagonist with a goal INR range of 2–3 or DAPT with aspirin 75–100 mg orally daily plus clopidogrel 75 mg orally daily (Class 2b) are reasonable options for the first three to six months (Class 2b) [68].

The selection of antithrombotic therapy in patients with VHD may also be further complicated by the presence of AF when determining whether to use a vitamin K antagonist or DOAC. In general, patients who have established AF plus rheumatic mitral stenosis, mechanical AVR, or mechanical MVR should receive long-term anticoagulation with a vitamin K antagonist (Class 1), and in those with new onset AF within three months of bioprosthetic valve implantation, anticoagulation with a vitamin K antagonist is reasonable (Class 2a). In patients with AF and VHD who have not received a prosthetic valve replacement (native valve disease that is not rheumatic mitral stenosis) or in those with a bioprosthetic valve who have AF occurring greater than three months after replacement may receive DOAC, if anticoagulation is indicated based on CHA2DS2-VASc score (Class 1) [68].

VENOUS THROMBOEMBOLISM

Venous thromboembolism (VTE) is the overarching term that includes both DVT and PE. In the United States, approximately 300,000 to 600,000 VTE events occur annually, causing significant morbidity for patients and increased resource utilization in healthcare settings [69]. The occurrence of VTE is often multicausal and is likely triggered by interactions between multiple risk factors. VTE development is often traced back to Virchow's triad, which is the combination of stasis, vascular wall damage or dysfunction, and hypercoagulability [70]. Blood stasis in valve pockets of large vessels is thought to predispose the formation of venous thrombi, especially during times of immobilization. Vascular damage or dysfunction in the area further leads to an increased expression of surface adhesion molecules and ultimately platelet activation and adhesion. Through the increased inflammation and activation of leukocytes, the extrinsic pathway of the coagulation cascade is thought to be activated, resulting in the formation of a fibrin-bound clot. Once this thrombus forms, it may lead to blockages within the vessel or embolize to other areas of the body, such as in the case of PE [70].

Evidence Based Practice Recommendation

For patients with DVT and/or PE, the ASH guideline panel suggests using direct oral anticoagulants (DOACs) over vitamin K antagonists.

https://ashpublications.org//bloodadvances/article/4/19/4693/463998

Last Accessed: February 17, 2026

Strength of Recommendation/Level of Evidence: Conditional recommendation based on moderate certainty in the evidence of effects

The cornerstone of therapy for VTE centers around anticoagulation. Currently, guidelines from both the American Society of Hematology and the American College of Chest Physicians recommend DOACs over vitamin K antagonists for the treatment of DVT and PE, due to their enhanced safety and efficacy profiles, and any of the DOACs can be used (strong recommendation) [71]. In terms of duration of therapy, anticoagulation with an oral anticoagulant should be continued for at least three months, followed by an assessment for the need to continue therapy (strong recommendation). In patients with VTE who are unable to receive a DOAC or those who have antiphospholipid syndrome, vitamin K antagonists with a target INR range of 2–3 may be used (weak recommendation). In select patients with a chronic risk factor or unprovoked VTE, extended duration of therapy beyond three to six months may be required. One such population includes patients who develop acute VTE in the setting of cancer, where anticoagulation may be continued beyond standard therapy and often indefinitely. Although LMWH had previously been the anticoagulant of choice in patients with cancer-associated thrombosis, guidelines now recommend that DOACs, including apixaban, edoxaban, or rivaroxaban, be used over LMWH for the initiation and treatment of VTE in these patients, with the exception of patients with luminal gastrointestinal malignancies (strong recommendation) [71]. In these patients, apixaban or LMWH is preferred, due to increased risk of gastrointestinal bleeding with edoxaban and rivaroxaban.

PERIPHERAL ARTERIAL DISEASE

Peripheral arterial disease (PAD) of the lower extremity refers to the atherosclerotic obstruction of vessels within the region from the aortoiliac segments to the pedal arteries. Recent estimates report that PAD is the third leading cause of atherosclerotic morbidity after coronary heart disease and stroke and is present in approximately 7% of adults 40 years of age or older in the United States [72]. PAD can range in severity from asymptomatic disease to critical limb ischemia and require significant intervention if left untreated. Despite strong recommendations with high levels of evidence in most recent guidelines, patients with PAD remain undertreated and adherence to antiplatelet use in symptomatic patients at hospital discharge is reported to be as low as 57.7% to 67.3% in the literature [72].

In most recent guidelines, antiplatelet therapy is recommended in symptomatic patients in order to reduce the risk of MI, stroke, or vascular death (Class 1) and should be considered in asymptomatic patients as well (Class 2a). Currently, this can include monotherapy with aspirin 75–325 mg orally daily or clopidogrel 75 mg orally daily (Class 1). DAPT may also be beneficial in select patients with PAD, including those with symptomatic PAD after lower extremity revascularization (Class 2b). In patients progressing to acute limb ischemia, systemic anticoagulation with heparin should be provided to all patients unless contraindicated (Class 1) and revascularization with either surgery or intra-arterial thrombolysis should be performed [73,74].

7. CONCLUSION

The use of antithrombotics, including both antiplatelets and anticoagulants, can be complex; however, healthcare providers can improve the use of these agents in various healthcare settings by understanding the underlying mechanisms, drug properties, monitoring strategies, and indications for use of these agents. By applying this knowledge, healthcare providers are able to improve patient outcomes and avoid adverse effects that lead to patient harm. As with all areas of medicine, the indications for antiplatelets and anticoagulants continue to change, and it is important to be mindful of updates and advancements as treatment options change in the future.

Works Cited

1. Montinari MR, Minelli S, De Caterina R. The first 3500 years of aspirin history from its roots—a concise summary. Vascul Pharmacol. 2019;113:1-8.

2. Pirmohamed M. Warfarin: almost 60 years old and still causing problems. Br J Clin Pharmacol. 2006;62(5):509-511.

3. Boakye E, Uddin SMI, Obisesan OH, et al. Aspirin for cardiovascular disease prevention among adults in the United States: trends, prevalence, and participant characteristics associated with use. Am J Prev Cardiol. 2021;8:100256.

4. ClinCalc.com. ClinCalc DrugStats Database: The Top 200 Drugs of 2021. Available at https://clincalc.com/DrugStats/. Last accessed June 10, 2024.

5. Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128(12):1300-1305.e2.

6. Navar AM, Kolkailah AA, Overton R, et al. Trends in oral anticoagulant use among 436 864 patients with atrial fibrillation in community practice, 2011 to 2020. J Am Heart Assoc. 2022;11(22):e026723.

7. Budnitz DS, Shehab N, Lovegrove MC, Geller AI, Lind JN, Pollock DA. US emergency department visits attributed to medication harms, 2017–2019. JAMA. 2021;326(13):1299-1309.

8. Davies EC, Green CF, Taylor S, Williamson PR, Mottram DR, Pirmohamed M. Adverse drug reactions in hospital in-patients: a prospective analysis of 3695 patient-episodes. PLoS One. 2009;4(2):e4439.

9. Geller AI, Shehab N, Lovegrove MC, et al. Emergency visits for oral anticoagulant bleeding. J Gen Int Med. 2020;35(1):371-373.

10. Geller AI, Shehab N, Lovegrove MC, Weidle NJ, Budnitz DS. Bleeding related to oral anticoagulants: trends in US emergency department visits, 2016–2020. Thromb Res. 2023;225:110-115.

11. Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 2004;329:15-19.

12. Dreijer AR, Diepstraten J, Bukkems VE, et al. Anticoagulant medication errors in hospitals and primary care: a cross-sectional study. Int J Qual Health Care. 2019;31(5):346-352.

13. Burnett AE, Barnes GD. A call to action for anticoagulation stewardship. Res Pract Thromb Haemost. 2022;6(5):e12757.

14. Koolian M, Wiseman D, Mantzanis H, Kampouris N, Kerzner RS, Kahn SR. Anticoagulation stewardship: descriptive analysis of a novel approach to appropriate anticoagulant prescription. Res Pract Thromb Haemost. 2022;6(6):e12758.

15. Smith SA, Travers RJ, Morrissey JH. How it all starts: initiation of the clotting cascade. Crit Rev Biochem Mol Biol. 2015;50(4):326-336.

16. Scridon A. Platelets and their role in hemostasis and thrombosis—from physiology to pathophysiology and therapeutic implications.Int J Mol Sci. 2022;23(21):12772.

17. Kamran H, Jneid H, Kayani WT, et al. Oral antiplatelet therapy after acute coronary syndrome: a review. JAMA. 2021;325(15):1545-1555.

18. Hoffman M, Monroe DM III. A cell-based model of hemostasis. Thromb Haemost. 2001;85(6):958-965.

19. Bayer Inc. Aspirin. [package insert].

20. LexiDrug. Aspirin. Available at http://online.lexi.com. Last accessed June 10, 2024.

21. Angiolillo DJ, Rollini F, Storey RF, et al. International expert consensus on switching platelet p2y12 receptor-inhibiting therapies. Circulation. 2017;136(20):1955-1975.

22. Sanofi-Aventis. Clopidogrel. [package insert].

23. Eli Lilly and Company. Prasugrel. [package insert].

24. LexiDrug. Prasugrel. Available at http://online.lexi.com. Last accessed June 10, 2024.

25. AstraZeneca Inc. Ticagrelor. [package insert].

26. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.

27. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372(19):1791-1800.

28. Mahaffey KW, Wojdyla DM, Carroll K, et al. Ticagrelor compared with clopidogrel by geographic region in the platelet inhibition and patient outcomes (PLATO) trial. Circulation. 2011;124(5):544-554.

29. Angiolillo DJ, Firstenberg MS, Price MJ, et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA. 2012;307(3):265-274.

30. Angiolillo DJ, Been L, Rubinstein M, Martin M, Rollini F, Franchi F. Use of the VerifyNow point of care assay to assess the pharmacodynamic effects of loading and maintenance dose regimens of prasugrel and ticagrelor. J Thromb Thrombolysis. 2021;51(3):741-747.

31. Mason GA, Rabbolini DJ. The current role of platelet function testing in clinical practice. Semin Thromb Hemost. 2021;47(07):843-854.

32. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e24S-e43S.

33. Hospira Inc. Heparin. [package insert].

34. LexiDrug. Heparin. Available at http://online.lexi.com. Last accessed June 10, 2024.

35. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e326S-e350S.

36. Vandiver JW, Vondracek TG. Antifactor Xa levels versus activated partial thromboplastin time for monitoring unfractionated heparin. Pharmacother: J Human Pharmacol Drug Ther. 2012;32(6):546-558.

37. Rosborough TK. Monitoring unfractionated heparin therapy with antifactor Xa activity results in fewer monitoring tests and dosage changes than monitoring with the activated partial thromboplastin time. Pharmacother: J Human Pharmacol Drug Ther. 1999;19(6):760-766.

38. Guervil DJ, Rosenberg AF, Winterstein AG, Harris NS, Johns TE, Zumberg MS. Activated partial thromboplastin time versus antifactor Xa heparin assay in monitoring unfractionated heparin by continuous intravenous infusion. Ann Pharmacother. 2011;45 (7-8):861-868.

39. Levy JH, Sniecinski RM, Rocca B, et al. Defining heparin resistance: communication from the ISTH SSC subcommittee of perioperative and critical care thrombosis and hemostasis. J Thromb Haemost. 2023;21(12):P3649-P3657.

40. Chen A, Stecker E, Warden BA. Direct oral anticoagulant use: a practical guide to common clinical challenges. J Am Heart Assoc. 2020;9(13):e017559.

41. Sanofi-Aventis. Enoxaparin. [package insert].

42. LexiDrug. Enoxaparin. Available at http://online.lexi.com. Last accessed June 10, 2024.

43. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy. Chest. 2012;141(2 Suppl):e44S-e88S.

44. Bristol-Myers Squibb. Warfarin. [package insert].

45. LexiDrug. Warfarin. Available at http://online.lexi.com. Last accessed June 10, 2024.

46. Boehringer Ingelheim Pharmaceuticals, Inc. 2023. Dabigatran etexilate. [package insert].

47. Janssen Pharmaceuticals, Inc. 2023. Rivaroxaban. [package insert].

48. LexiDrug. Rivaroxaban. Available at http://online.lexi.com. Last accessed June 10, 2024.

49. Bristol-Myers Squibb. Apixaban. [package insert].

50. LexiDrug. Apixaban. Available at http://online.lexi.com. Last accessed June 10, 2024.

51. Daiichi Sankyo Co. Edoxaban. [package insert].

52. LexiDrug. Edoxaban. Available at http://online.lexi.com. Last accessed June 10, 2024.

53. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140(11):e596-e646.

54. Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2023;148(9):e9-e119.

55. Rodriguez F, Harrington RA. Management of antithrombotic therapy after acute coronary syndromes. N Engl J Med. 2021;384(5):452-460.

56. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(25):2354-2394.

57. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e362-e425.

58. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2016;68(10):1082-1115.

59. Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC guidelines for the management of acute coronary syndromes. Eur Heart J. 2023;44(38):3720-3826.

60. Schüpke S, Neumann FJ, Menichelli M, et al. Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med. 2019;381(16):1524-1534.

61. Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149(1):e1-e156.

62. Mendelson SJ, Prabhakaran S. Diagnosis and management of transient ischemic attack and acute ischemic stroke: a review. JAMA. 2021;325(11):1088-1098.

63. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 guideline for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association. Stroke. 2021;52(7):e364-e467.

64. Levine GN, McEvoy JW, Fang JC, et al. Management of patients at risk for and with left ventricular thrombus: a scientific statement from the American Heart Association. Circulation. 2022;146(15):e205-e223.

65. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11-19.

66. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379(3):215-225.

67. Centers for Disease Control and Prevention. About Valvular Heart Disease. Available at https://www.cdc.gov/heartdisease/valvular_disease.htm. Last accessed June 10, 2024.

68. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021;143(5):e72-e227.

69. Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4(19):4693-4738.

70. Khan F, Tritschler T, Kahn SR, Rodger MA. Venous thromboembolism. Lancet. 2021;398(10294):P64-P77.

71. Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report. Chest. 2021;160(6):e545-e608.

72. Criqui MH, Matsushita K, Aboyans V, et al. Lower extremity peripheral artery disease: contemporary epidemiology, management gaps, and future directions: a scientific statement from the American Heart Association. Circulation. 2021;144(9):e171-e191.

73. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2017;135(12):e726-e779.

74. Conte MS, Pomposelli FB, Clair DG, et al. Society for Vascular Surgery practice guidelines for atherosclerotic occlusive disease of the lower extremities: management of asymptomatic disease and claudication. J Vasc Surg. 2015;61(3 Suppl):2S-41S.e1.

Evidence-Based Practice Recommendations Citations

1. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78-e140. Available at https://www.ahajournals.org/doi/10.1161/CIR.0b013e3182742c84. Last accessed February 17, 2026.

2. Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4(19):4693-4738. Available at https://ashpublications.org//bloodadvances/article/4/19/4693/463998. Last accessed February 17, 2026.

94674 • Pneumonia

John M. Leonard, MD

Carol Whelan, APRN

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

Pneumonia is a substantial healthcare concern, ranking among the most common reasons for emergency department and outpatient visits, hospitalizations, and deaths among both adults and children. Decreasing the incidence of pneumonia and its associated morbidity and mortality requires a multifaceted approach and a strategy that includes: a concerted effort to improve rates of pneumococcal and influenza vaccinations, especially among high-risk populations; better adherence to guideline-recommended treatment; systems-level approaches to improve the appropriate use of antibiotics; and performance improvement initiatives to reduce healthcare-associated infections.

Table of Contents

94674 • Pneumonia

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. HISTORICAL BACKGROUND

2. DEFINITIONS

3. EPIDEMIOLOGY AND SCOPE

4. GUIDELINE-DIRECTED MANAGEMENT AND PREVENTION OF PNEUMONIA

5. PATHOGENESIS AND CLASSIFICATION OF PNEUMONIA

6. COMMUNITY-ACQUIRED PNEUMONIA

EPIDEMIOLOGY

RISK FACTORS

ETIOLOGY

CLINICAL PRESENTATION IN ADULTS

DIAGNOSIS AND MANAGEMENT OF COMMUNITY-ACQUIRED PNEUMONIA IN ADULTS

ILLUSTRATIVE CASE

PNEUMONIA IN THE PEDIATRIC PATIENT

7. PREVENTION OF PNEUMONIA

IMMUNIZATION

8. PNEUMONIA ASSOCIATED WITH HEALTHCARE FACILITIES

EPIDEMIOLOGY

RISK FACTORS

ETIOLOGY

DIAGNOSIS

TREATMENT

PREVENTION

ILLUSTRATIVE CASE

9. SUMMARY

Works Cited

Evidence-Based Practice Recommendations Citations

94674 • Pneumonia

Education Category. Infection Control / Internal Medicine

Release Date. 09/01/2024

Expiration Date. 08/31/2027

Course Overview

Pneumonia is a substantial healthcare concern, ranking among the most common reasons for emergency department and outpatient visits, hospitalizations, and deaths among both adults and children. Decreasing the incidence of pneumonia and its associated morbidity and mortality requires a multifaceted approach and a strategy that includes: a concerted effort to improve rates of pneumococcal and influenza vaccinations, especially among high-risk populations; better adherence to guideline-recommended treatment; systems-level approaches to improve the appropriate use of antibiotics; and performance improvement initiatives to reduce healthcare-associated infections.

Audience

This course is designed for all physicians, physician assistants, and nurses, especially those working in the emergency department, outpatient settings, pediatrics, nursing homes, and intensive care units.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is approved to offer continuing education through the Florida Board of Nursing Home Administrators, Provider #50-2405. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU. NetCE is approved as a provider of online continuing education for certified nursing assistants through the California Department of Public Health Licensing and Certification Division. Nurse Aide Certification (NAC) Provider #7005.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 10 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 10 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 10 ANCC contact hour(s). NetCE designates this continuing education activity for 5 pharmacology hour(s) for physician assistants. NetCE designates this continuing education activity for 5 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 12 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 10 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. NetCE designates this activity for 10 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-24-034-H01-P. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the activity with individual assessments of the participant and feedback to the participant, enables the participant to earn 10 MOC points in the American Board of Pediatrics' (ABP) Maintenance of Certification (MOC) program. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABP MOC credit. This activity has been designated for 10 Lifelong Learning (Part II) credits for the American Board of Pathology Continuing Certification Program. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. This home study course is approved by the Florida Board of Nursing Home Administrators for 10 credit hour(s). NetCE is authorized by IACET to offer 1 CEU(s) for this program. AACN Synergy CERP Category A.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353 (valid through July 30, 2029); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2027; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to provide physicians, nurses, and other healthcare professionals who manage the care of patients with pneumonia a foundation for effective management strategies in order to improve outcomes and foster an interprofessional collaborative practice consistent with published guidelines.

Learning Objectives

Upon completion of this course, you should be able to:

1. Discuss the epidemiology, scope, and classification of pneumonias.

2. Predict the likely etiology (pathogens) in a given case of pneumonia, based on epidemiologic features, clinical setting, and risk factor assessment.

3. Assess the diagnostic probability of pneumonia in a given patient, using careful history and clinical examination findings.

4. Determine, by clinical criteria and severity of illness score, which patients with pneumonia require hospitalization or admission to an intensive care unit.

5. Develop a management plan for community-acquired pneumonia, including selection of initial antibiotic therapy appropriate to clinical context and site of care, in accordance with established guidelines.

6. Outline the diagnosis and management of community-acquired pneumonia in pediatric patients.

7. Devise a strategy for prevention of community-acquired pneumonia, including risk factor reduction and recommended immunization protocols.

8. Identify the epidemiology and risk factors of hospital-acquired, ventilator-associated, and nursing home-acquired pneumonia.

9. Anticipate the likely pathogens and antibiotic-sensitivity patterns associated with pneumonia that arises in healthcare facilities.

10. Initiate the management of patients with hospital-acquired or ventilator-associated pneumonia, including guideline-adherent selection of empiric antibiotic therapy.

11. Develop a strategy to reduce the risk of pneumonia for patients in healthcare facilities.

Faculty

Carol Whelan, APRN, has been working in nursing education since 2000. She received her Master's degree in psychiatric/mental health nursing from St. Joseph College in West Hartford, Connecticut, and completed post-graduate nurse practitioner training at Yale University. Ms. Whelan is an Associate Clinical Professor and Lecturer at Yale University and works as an APRN at the Department of Veterans' Affairs in Connecticut, where she also serves as the Vice President of Medical Staff. She has authored many articles, textbook chapters, and books.

John M. Leonard, MD, Professor of Medicine Emeritus, Vanderbilt University School of Medicine, completed his post-graduate clinical training at the Yale and Vanderbilt University Medical Centers before joining the Vanderbilt faculty in 1974. He is a clinician-educator and for many years served as director of residency training and student educational programs for the Vanderbilt University Department of Medicine. Over a career span of 40 years, Dr. Leonard conducted an active practice of general internal medicine and an inpatient consulting practice of infectious diseases.

Faculty Disclosure

Contributing faculty, Carol Whelan, APRN, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Contributing faculty, John M. Leonard, MD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John V. Jurica, MD, MPH

Mary Franks, MSN, APRN, FNP-C

Randall L. Allen, PharmD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

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Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. HISTORICAL BACKGROUND

Hippocrates first described the clinical picture of pneumonia in 400 B.C.E., including the presence of fever, chest pain, productive cough, rales, and dyspnea[1]. However, the disease was recognized even before Hippocrates' time. The disease has resulted in a serious public health and mortality burden over the years, with Osler referring to pneumonia as the "captain of the men of death" in the early 1900s. During this same period, pneumonia surpassed tuberculosis as a leading cause of death.

In the past century, dramatic advances in health care have greatly improved outcomes for patients with pneumonia. These advances include the introduction of effective antibiotics and immunization practices, improved clinical care, and safer surgical technique. Although morbidity and mortality from pneumonia has declined in developed countries, pneumonia remains a major health concern, and the emergence of multidrug-resistant organisms has led to renewed interest and research on this ancient disease.

2. DEFINITIONS

Pneumonia is defined as a lower respiratory tract, parenchymal infection of the lung. The usual clinical presentation is that of acute- or subacute-onset fever, productive cough, pleuritic chest pain, localized rales and signs of consolidation, accompanied by pulmonary opacification(s) on chest radiograph. For clinical purposes, pneumonia in a nonhospitalized patient is designated as either community-acquired (CAP) or healthcare-associated (HCAP) depending on whether there has been significant exposure to a healthcare environment (e.g., hospital, nursing home, dialysis clinic) within the previous 90 days. Pneumonias that develop as a complication of hospitalization are termed "nosocomial" and are further divided into hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). These are important distinctions, as HCAP and nosocomial pneumonias carry a greater risk for less common, multidrug-resistant bacterial infection.

The term "pneumonia" is sometimes used in reference to other inflammatory conditions of the lung when a component of infection is known or suspected. An example is "aspiration pneumonia," whereby a focal chemical pneumonitis (lung injury) is followed rapidly by bacterial overgrowth and incipient infection (pneumonia).

3. EPIDEMIOLOGY AND SCOPE

Pneumonia is a substantial healthcare concern, ranking among the most common reasons for emergency department and outpatient visits, hospitalizations, and deaths among both adults and children [2,3,4,5,6]. The World Health Organization (WHO) lists pneumonia as the world's fourth leading cause of death, accounting for an estimated 2.5 million lives lost to lower respiratory infection in 2021 [228]. Collected data consistently demonstrate a bimodal distribution of mortality, with peaks in children younger than 5 years of age and adults older than 75 years of age. Worldwide, pneumonia was responsible for an estimated 808,000 deaths in children younger than 5 years of age in 2017, mainly in developing countries [228]. In the United States, pneumonia is the leading cause of death from infectious disease and the eighth most common cause of death overall. According to data from the National Center for Health Statistics, there were 41,108 deaths from bacterial and viral pneumonias in 2022, a rate of 12.3 per 100,000 population [234]. There is seasonal variation in the incidence of pneumonia, with most cases occurring in the winter months.

U.S. hospital discharge statistics show that the rate of hospitalization for pneumonia varies with age, being highest among adults 75 to 84 years of age. In recent decades, the rate of hospitalization for pneumonia has been relatively stable for adults younger than 65 years of age and has declined somewhat for adults older than 65 years (Table 1) [6]. In 2021, there were 1.4 million U.S. hospital visits with pneumonia due to infectious organism as the primary diagnosis [2].

Table 1: DISCHARGES FROM HOSPITAL WITH A FIRST-LISTED DIAGNOSIS OF PNEUMONIA, BY AGE

Age

Rate (per 10,000)

1990

2000

2009–2010

18 to 44 years

12.5

10.9

9.5

45 to 64 years

33.5

35.3

32.6

65 to 74 years

98.1

121.3

83.8

75 to 84 years

224.6

263.5

179.3

85 years and older

501.0

514.9

355.3

Source: [6]

The mortality rate for pneumonia and influenza combined has decreased substantially in the United States over the past 20 years, falling from 23.7 per 100,000 in 2000 to 12.3 per 100,000 in 2022 [234]. Two important public health factors, which may account for this trend, are the increased utilization of pneumococcal and influenza vaccines among adults and children and the decline in cigarette smoking [220,221].

Despite advances made in prevention, treatment, and clinical outcomes, the impact on healthcare delivery systems and the aggregate cost of caring for patients with pneumonia are expected to increase in years to come. This is because of an aging U.S. population, the very group in whom the rate of pneumonia is highest. Using a decision analytic model that assumes no targeted intervention, a population medicine study group projected the incidence of pneumococcal pneumonia in the United States will increase by 38% between 2014 and 2040, with hospitalizations for pneumococcal pneumonia increasing by 96% (from 401,000 to 790,000) in that same period. As a result, healthcare costs associated with pneumonia are expected to increase by $2.5 billion and demand for healthcare services for pneumonia is expected to double [14].

4. GUIDELINE-DIRECTED MANAGEMENT AND PREVENTION OF PNEUMONIA

In the past two decades, clinical guidelines for the management of pneumonia have been developed by infectious disease and pulmonary medicine societies to improve outcomes and decrease the cost of care. Unfortunately, adherence to guideline-directed management protocols has been low, despite studies demonstrating that lack of adherence is associated with higher rates of adverse outcomes and inappropriate use of antimicrobials [15,16,17,18,20,21]. Attention to guidelines varies across hospitals, clinical settings, and specialty practices. Adherence rates tend to be lower among non-pulmonologists and in relation to patient variables such as presence or absence of comorbidities and recent use of antibiotics [20,22,23]. Several barriers to guideline adherence have been identified, including lack of familiarity, concern over the practicality and perceived cost of recommended antibiotics, limited documentation of improved outcomes, and potential conflict with other guidelines [23]. The time spent on continuing education activities appears to have a direct correlation with a positive attitude toward, and propensity to follow, published clinical guidelines.

Success in reducing the incidence of pneumonia relies on effective strategies to prevent disease. The primary strategy for prevention of CAP is immunization with influenza and pneumococcal vaccines, targeting high-risk groups (i.e., young children, older individuals, and people with compromised immune systems). Targeted immunization has been shown to decrease the rate of hospitalization for pneumonia and influenza and to decrease the risk of long-term morbidity and mortality [7,9,10,218]. However, vaccine utilization rates are low, especially the rate of pneumococcal vaccination among high-risk groups and influenza vaccination among children [6,11]. Only about one-quarter of adults have ever had a pneumococcal vaccine.

Prevention of HCAP focuses on care measures to preserve healthy pulmonary defense mechanisms and reduce transmission of healthcare-associated, often multidrug-resistant, bacterial pathogens. Adherence to guidelines for the prevention of pneumonia that arises in the hospital setting has been low, with approximately 39% to 66% of hospitals reporting full compliance and up to one-half of nurses reporting that they do not routinely adhere to recommended prevention practices [12,13].

Decreasing the incidence of pneumonia and its associated morbidity and mortality requires a multifaceted approach and a strategy that includes a concerted effort to improve rates of pneumococcal and influenza vaccinations, especially among high-risk populations; better adherence to guideline-recommended treatment; systems-level approaches to improve the appropriate use of antibiotics; and performance improvement initiatives to reduce healthcare-associated infections. This course is designed to assist healthcare professionals provide better care to their patients by highlighting guideline-recommended diagnosis, treatment, and prevention of pneumonia.

5. PATHOGENESIS AND CLASSIFICATION OF PNEUMONIA

Pneumonia is an acute inflammatory condition within the parenchyma of the lung caused by infection that reaches the lower respiratory tract. In most cases, pneumonia develops as a consequence of bacterial colonization/infection of the upper respiratory tract, followed by microaspiration of infected secretions at a time of impaired host pulmonary defense mechanisms [217]. The prime host defenses against foreign particulate matter that reaches the lower respiratory tract are the cough reflex, tracheobronchial (mucociliary) clearance, and alveolar macrophage phagocytosis. Activation of the humeral (antibody) immune response provides augmentation of phagocytosis and the acute cellular response. One or more of these defense mechanisms may be impaired by a variety of factors, including underlying cardiopulmonary and neurologic disease, sedative medication, bronchial obstruction, concurrent active viral and mycoplasma bronchitis, and toxic/metabolic conditions such as alcohol excess, acidosis, and hypoxia. Individuals with an impaired immune system, such as occurs from immunosuppressive drugs, human immunodeficiency virus (HIV), chronic disease, or old age, are more susceptible to infection [4].

Clinically, pneumonia is often described in reference to suspected or established causative pathogens (i.e., viral, bacterial, fungal, or parasitic); however, the precise etiology cannot be identified in more than half the cases in which testing is done [9,24,25]. Classifying pneumonia according to setting in which it develops is more useful for clinical purposes because the most common pathogens, as well as clinical outcomes, are similar within distinct clinical settings [26,27]. Pneumonia was once broadly classified as either community-acquired (developing outside of a hospital or other healthcare facility) or nosocomial (developing 48 hours or more after hospital admission, usually postoperatively). In its 2016 guideline, the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) noted three distinct categories within the broader classification of pneumonia associated with healthcare facilities: HAP, VAP, and HCAP (Table 2) [3,28]. These three categories of pneumonia are similar in that they often result from colonization, then infection, by resistant gram-negative bacilli and methicillin-resistant Staphylococcus aureus (MRSA), necessitating broader empiric antibiotic therapy than that commonly used for CAP [27].

Table 2: TYPES OF PNEUMONIA

Type

Definition

Community-acquired

New infection in a patient residing in the community, with no recent exposure to a healthcare setting or antibiotics

Hospital-acquired

New infection occurring more than 48 hours after hospital admission

Ventilator-associated

New infection occurring more than 48 to 72 hours after endotracheal intubation

Healthcare-associated

Infection developing within 90 days after hospitalization in an acute care facility for 2 days or more

Infection in a resident of a nursing home or long-term care facility

Infection after receiving care in an outpatient setting (e.g., hemodialysis or intravenous therapy clinic)

Infection occurring with 30 days after home care (e.g., intravenous antibiotic therapy, chemotherapy, or wound care)

Source: [28]

As noted, the cause of pneumonia varies according to setting and patient age. Viruses are the most common cause in young children, whereas bacteria are the more frequent cause among older children and adults [29,30,31]. Studies have shown that respiratory viral pathogens play a greater role in the pathogenesis of pneumonia than once thought; many cases of pneumonia, both pediatric and adult, involve a combination of bacterial and viral pathogens or two or more viral pathogens [9,24,30,32]. The increase in the number of viral infections is thought to be related, in part, to better diagnostic testing methods, most notably, polymerase chain reaction (PCR)-based techniques [24,33,34].

Pyogenic bacterial infection is the cause of nearly all cases of HAP and VAP, and the distribution of pathogens varies among institutions [26,28,29]. Mixed infection appears to be common, as more than one pathogen is frequently isolated from sputum cultures in these cases [28]. Bacteria isolated from cases of early-onset HAP (within four days after admission) are usually sensitive to available drugs [28]. In contrast, late-onset HAP (i.e., more than five days after admission) is likely to be caused by multidrug-resistant pathogens, such as Pseudomonas spp., MRSA, and Acinetobacter spp. [26,35]. Viral and fungal pathogens rarely cause HAP or VAP [28].

6. COMMUNITY-ACQUIRED PNEUMONIA

EPIDEMIOLOGY

Determining accurate incidence rates for CAP is challenging because "pneumonia" is not a reportable disease; moreover, case definition varies across studies and national databases often link pneumonia with influenza. Epidemiology of pneumonia relies primarily on data derived from community-based cohort studies and surveillance networks. Approximately 5 to 6 million cases of pneumonia are diagnosed annually, with about 1 million occurring in older adults [36]. Approximately 4.2 million adult outpatient visits are related to CAP every year, and the mortality rate is less than 1% for adults treated on an outpatient basis [37].

The burden of disease is considerably greater for patients hospitalized with pneumonia. A prospective cohort study of adult residents living in Louisville, Kentucky (population 587,000 adults), recorded 7,449 unique patients hospitalized with CAP between June 2014 and June 2016 [232]. The annual age-adjusted incidence was 649 patients hospitalized with CAP per 100,000 adults, which extrapolates to nearly 1.6 million annual adult CAP hospitalizations in the United States. The observed mortality during hospitalization was 6.5%. An earlier report placed the average overall mortality rate for hospitalized adults at 12%, but the rate is higher—about 30% to 40%—for adults who require admission to an intensive care unit (ICU) [37]. The estimated direct and indirect financial costs are $3.7 billion and $1.8 billion, respectively [38].

The burden of pneumonia is greatest among the elderly (65 years of age and older). In one study of 46,237 people 65 years of age and older, the overall rate of CAP was 18.2 cases per 1,000 person-years for people 65 to 69 years of age, increasing to 52.3 cases per 1,000 person-years for those 85 years of age or older [39].

The mortality rate for adults with pneumonia has decreased substantially over the past two decades. In a review of more than 2.6 million Medicare claims for pneumonia between 1987 and 2005, the age- and sex-adjusted mortality rate dropped from 13.5% to 9.7% [40].

The rate of pediatric outpatient visits for CAP has been reported to be 35 to 52 per 1,000 children 3 to 6 years of age and 74 to 92 per 1,000 children 2 years of age and younger [10]. The hospitalization rate for children up to 18 years of age is 201.1 per 100,000; the highest rate is for infants younger than 1 year of age (912.9 per 100,000) and lowest for teenagers (62.8 per 100,000) [4]. According to data from the Centers for Disease Control and Prevention (CDC), 343 infants (younger than 1 year of age) and 502 children (1 to 17 years of age) in the United States died as a result of pneumonia (or another lower respiratory tract infection) in 2021 [234].

RISK FACTORS

The primary risk factors for CAP are age, smoking history, and chronic lung disease (e.g., chronic obstructive pulmonary disease [COPD]) and other comorbidities. Occupational dust exposure and history of childhood pneumonia have also been associated with an increased risk, as has male gender, unemployment, and single marital status [39,41]. As noted earlier, the risk for pneumonia is higher for individuals 65 years or older compared with younger adults, with the risk further increasing for those 85 years and older [39]. Alcoholism and chronic diseases, such as respiratory disease, cardiovascular disease, or kidney disease, also increase the risk for pneumonia, especially in the older population [3,42,43]. Conditions of frailty, dementia, alcohol use, and sedative medication all lead to diminished or ineffectual cough and the propensity for aspiration, thereby increasing the risk for pneumonia. Diseases or medications that suppress the immune system increase the risk among all ages [39,42]. In the pediatric population, very young children are at increased risk because their immune systems have not fully developed. Secondhand smoke exposure, particularly with two or more smokers in the home, is a significant risk factor for pneumonia in children [241].

Although molecular diagnostic techniques have identified a diverse pulmonary alveolar microbiota coexisting within the healthy lung, the pulmonary airways may be considered "sterile" in regard to pathogens associated with incident pneumonic infection. Respiratory tract microbiota may work in concert with pulmonary defense mechanisms, including mucociliary clearance and alveolar macrophage phagocytosis, to keep the lower respiratory tract free from bacterial colonization/infection [238]. Cigarette smoking and other chronic respiratory conditions eventually cause bronchial inflammation and disrupt host defense mechanisms to such an extent that "colonization" of the airways by microbial pathogens is established early in the course of many persons with COPD [44]. The pathogens most commonly implicated are adenovirus, Chlamydophila pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Bacterial colonization in this setting represents low-grade chronic infection, which, in combination with clinical exacerbations, augments airway inflammation, and contributes to pathogenesis and disease progression.

The use of proton pump inhibitors (PPIs) may increase the risk of developing pneumonia, but data are somewhat unclear. One study found that only treatment with PPIs within the past 30 days (and not long-term use) was associated with increased risk, but a later meta-analysis showed that the risk was increased among people taking PPIs or histamine2 receptor antagonists [44,45].

Among nursing home patients, older age and male sex are risk factors for pneumonia. Other risk factors for this population include swallowing difficulty, inability to take oral medications, profound disability, bedridden state, and urinary incontinence [42].

ETIOLOGY

Given the right conditions, a great many micro-organisms are capable of infecting the lung. In general, however, the number of viruses and bacteria implicated in most cases of CAP in adults and children is relatively small. For a given case, the clinical setting and the patient's age, comorbidity, and risk factors are useful predictors of causation. Viral pneumonia (e.g., influenza) is most commonly linked to community outbreaks.

The most common cause of CAP is S. pneumoniae, identified in approximately one-third of all cases and 40% to 50% of all culture-confirmed bacterial pneumonia cases that require hospitalization [9,29,30,46]. The most common causative pathogen varies in relation to the patient's age, illness severity, and clinical context (Table 3) [29,30,47].

Table 3: MOST LIKELY ETIOLOGIES OF COMMUNITY-ACQUIRED PNEUMONIA ACCORDING TO PATIENT AGE AND SETTING

Age and/or Setting

Most Likely Pathogens

Adults

Outpatient

Streptococcus pneumoniae

Mycoplasma pneumoniae

Chlamydophila pneumoniae

Haemophilus influenzae

Respiratory viruses

Legionella spp.

Inpatient, not intensive care unit

S. pneumoniae

M. pneumoniae

C. pneumoniae

H. influenzae

Legionella spp.

Respiratory viruses

Intensive care unit

S. pneumoniae

Staphylococcus aureus

Legionella spp.

Gram-negative bacilli

H. influenzae

Children

Birth to 3 weeks

Group B streptococci

Listeria monocytogenes

Gram-negative bacilli

Cytomegalovirus

3 weeks to 3 months

S. pneumoniae

Respiratory viruses

Bordetella pertussis

S. aureus

Chlamydia trachomatis (transnatal exposure)

4 months to 4 years

S. pneumoniae

Respiratory viruses

M. pneumoniae (in older children)

Group A streptococci

5 to 15 years

S. pneumoniae

M. pneumoniae

C. pneumoniae

Source: [29,47]

Clues to the etiology of the pneumonia can often be found in the patient's past medical history (Table 4). Persons with chronic bronchitis/COPD frequently have tracheobronchial colonization with S. pneumoniae, H. influenzae, or M. catarrhalis, and when pneumonia supervenes, it is usually with one of these pathogens. Heavy alcohol use carries the risk for anaerobic pleuropulmonary infection (e.g., lung abscess, empyema) and pneumococcal or gram-negative bacillary (e.g., Klebsiella pneumoniae, Proteus spp.) pneumonia.

Table 4: COMORBIDITY AND EXPOSURE IN RELATION TO AT-RISK PATHOGENS

Patient Characteristic

Suspect Pathogen(s)

Alcoholism

Oral anaerobes

Streptococcus pneumoniae

Gram-negative bacilli

COPD, tobacco use

Haemophilus influenzae

S. pneumoniae

Moraxella catarrhalis

Nursing home resident

S. pneumoniae

Gram-negative bacilli

H. influenzae

Staphylococcus aureus

Poor dental hygiene

Oral anaerobes

Recent exposure to contaminated plumbing or water

Legionella organisms

Exposure to exotic birds and/or decaying bird nesting sites

Chlamydia psittaci

Histoplasma capsulatum (histoplasmosis)

HIV infection

Pneumocystis carinii

S. pneumoniae

H. influenzae

Mycobacterium tuberculosis

Exposure to excreta of wild rodents

Sin nombre virus (hantavirus pulmonary syndrome)

COPD = chronic obstructive pulmonary disease.

Source: Adapted with permission from File TM, Tan JS, Plouffe JF. Community-acquired pneumonia: what's needed for accurate diagnosis. Postgrad Med. 1996;99(1):102. ©1996 McGraw-Hill.

Other epidemiologic clues to the etiology of pneumonias include seasonal and geographic considerations. Influenza outbreaks are associated with a seasonal increase in secondary S. pneumoniae, S. aureus, and H. influenzae pneumonias. Legionellosis is acquired through inhalation of an aerosol arising from contaminated water; cases present sporadically or as cluster outbreaks related to a point source exposure such as a reservoir, water tower, or air conditioning system [229].

Bacterial Pathogens

Bacterial causes of CAP predominate, accounting for at least half of all adult cases, including older individuals [9,42]. S. pneumoniae is the leading cause of CAP in any adult age-group, with or without comorbid conditions [6,7,10]. It is estimated that pneumococcal infection accounts for 20% to 60% of all hospitalized patients with pneumonia [6]. Common bacterial pathogens other than S. pneumoniae include H. influenzae type b, S. aureus, and gram-negative bacilli [25,26,29,48]. H. influenzae type b is a small, pleomorphic gram-negative rod known for causing pneumonia in older adults and patients with underlying lung disease.

Atypical pneumonia (and the pathogens associated with this syndrome) is so labeled because the onset of illness tends to be subacute and the clinical exam and radiographic features lack the classical findings seen with typical cases of pneumonia. The most common atypical pathogens are Mycoplasma pneumoniae and C. pneumoniae, followed by Legionella spp. [9]. M. pneumoniae is a tiny bacterium that lacks a rigid cell wall. It is spread by droplet nuclei, and transmission within a community proceeds slowly over many weeks. Mycoplasma infection is a disease of adolescence and young adulthood, and it is the most common cause of atypical pneumonia in those younger than 40 years of age [66]. Small cluster outbreaks of pneumonia have been observed in large families, schools, nursing homes, and other closed population. There are about 60 different species of Legionella, but most disease is caused by Legionella pneumophila, a gram-negative rod usually transmitted via inhalation of aerosolized water contaminated with the bacteria [229].

The distribution of etiologic agents varies in relation to illness severity and management setting. In cases of relatively mild illness that permit outpatient treatment, blood cultures are rarely positive and the diagnosis relies on sputum culture and/or serial serology. In a Canadian study of CAP in the ambulatory setting, designed to determine the frequency of usual and atypical bacterial pathogens, an etiologic diagnosis was established in 48% of patients examined [222]. Of the 419 patients who had blood cultures, 7 (1.4%) were positive, all for S. pneumoniae. The atypical pathogen group (M. pneumoniae or C. pneumoniae) accounted for 29% of cases, S. pneumoniae for 6%, and Haemophilus spp. for 5%. The etiologic role of viruses was not studied [222].

A similar distribution and frequency was observed in a well-studied series from Spain, comparing pneumonia microbial etiology in three clinical management settings: outpatient, inpatient on the general care ward, and inpatient admissions to the ICU [29]. Among outpatients with CAP, the most frequently identified etiology was the atypical pathogen group (36%), followed by S. pneumoniae (35%), viruses (9%), and mixed etiologies (9%). As the severity of illness increased, marked by admission to the hospital general ward and ICU, the likelihood of mycoplasma or chlamydia etiology decreased substantially (14%) and the frequency of S. pneumoniae (43%), mixed bacterial pathogens (22%), S. aureus, Pseudomonas, and other gram-negative bacteria infection increased.

S. aureus is an uncommon cause of CAP but should be suspected during influenza outbreaks and in any patient with sepsis syndrome and multifocal pulmonary infiltrates. The role of S. aureus, and MRSA specifically, was examined in an observational study of 627 CAP cases admitted to 12 university-affiliated hospitals during the winter months (influenza season) of 2006–2007 [49]. Of the 595 patients from whom blood and sputum cultures were collected, a bacterial pathogen was identified in 107 (17%). The most common pathogen identified was S. pneumoniae (57 cases), followed by S. aureus (23 cases, 14 of which were MRSA). Thus, S. aureus accounted for 5% of the total and 22% of the cases in which the etiology was identified. Of the 23 patients with staphylococcal pneumonia, blood cultures were positive in 39% and sputum culture in 89%. Clinical features observed to be highly associated with S. aureus infection were multiple pulmonary infiltrates, altered mental status, illness severity requiring ICU admission, and intubation [49].

Viral Pathogens

Studies have indicated that 5% to 20% of adult CAP may be caused by a viral pathogen [50]. However, as noted earlier, the role of respiratory tract viral infection in pneumonia is complex and perhaps underestimated. Studies utilizing newer diagnostic methods such as PCR have demonstrated rates of viral infection as high as 39% in patients presenting with pneumonia [9,34]. Because these studies rely on specimens and washings taken from the nasopharynx, rather than directly from the lung, it is not clear to what extent viral isolates in this setting represent primary pneumonia pathogens or concomitant viral upper respiratory infection that may impair pulmonary defense mechanisms and thus predispose to bacterial pneumonia.

Clinical and pathologic studies of pneumonia during influenza seasons have demonstrated clearly that influenza virus (types A and B) is an important cause of primary viral CAP [25,47]. Seasonal respiratory syncytial virus (RSV), rhinovirus, adenovirus, and parainfluenza virus are also commonly associated with pneumonia in adults [31,34,47]. Since the advent of coronavirus disease 2019 (COVID-19) pandemic, SARS-CoV-2 has superseded the usual viral respiratory pathogens. RSV and rhinovirus are especially common among older adults and nursing home residents [31]. Clinical studies that utilize viral culture for case definition have found that RSV can be recovered from 3% to 10% of older adults with pneumonia [30]. The paramyxovirus hMPV, first isolated in 2001 from children hospitalized with acute respiratory infection, has now been reported in all age groups and stages of disease, from asymptomatic carrier state to severe bronchitis and pneumonia [30].

Mixed Pathogens

Mixed viral-bacterial infection has been documented in 30% of adult cases of CAP in some studies [9,31,34]. S. pneumoniae in combination with rhinovirus, influenza A, or RSV is found most commonly [34]. On rare occasions fungal and parasitic pathogens are isolated in association with CAP syndrome.

CLINICAL PRESENTATION IN ADULTS

Clinical Features

The clinical recognition of CAP in adults is challenging because its presentation is similar to other acute respiratory illnesses such as pulmonary embolism/infarction and congestive heart failure [3,51,52]. Diagnosis relies on clinical features combined with radiographic findings; however, both the clinical presentation and chest x-ray abnormalities are variable and in part nonspecific, particularly in the elderly [3,29]. Common presenting symptoms and signs are:

- Productive cough, purulent sputum

- Fever with rigors (shaking chills)

- Dyspnea

- Pleuritic chest pain

- Tachypnea

- Tachycardia

- Hypoxemia

- Signs of consolidation (e.g., crackles, bronchial breath sounds, egophony)

- Signs of pleural effusion (e.g., absent fremitus, dullness to percussion, decreased breath sounds)

Pneumonia in the elderly may present without a history of chills or fever, little cough, and a paucity of findings on exam and chest x-ray. Often in such cases, some combination of tachypnea, tachycardia, and altered mental status is the only sign [31,42].

Physical examination should focus on the chest, with auscultation to detect localized crackles (rales), bronchial breath sounds, and other signs of consolidation or pleural effusion [47]. Pulse oximetry should also be done. The most clinically significant individual findings are (in descending order) egophony, bronchial breath sounds, and dullness on percussion [53].

Chest Radiography

When pneumonia is suspected on the basis of these clinical features, chest radiography is the standard for confirming the diagnosis, and posteroanterior and lateral radiographs are recommended [3,29]. Some degree of infiltrate is almost always demonstrated on chest radiographs of patients who have been ill longer than 24 to 48 hours, although the appearance may be subtle or absent on initial presentation [29,47]. Pneumonia is described according to its anatomic distribution on chest radiographs as either lobar, multifocal/lobar, bronchopneumonic, or interstitial. Chest radiography also provides clues to alternative diagnoses having similar signs and symptoms. Computed tomography (CT), which is more sensitive than chest radiographs, may be useful in selected patients where diagnostic considerations are complex and initial radiographic studies are negative or inconclusive.

The characteristic symptoms and signs, combined with radiographic findings of an infiltrate, establish the clinical diagnosis of pneumonia. One validated prediction tool commonly used assigns 1 point for each of five clinical features present in conjunction with an infiltrate on chest radiography [54]:

- Temperature >37.8°C (100.04°F)

- Heart rate >100 beats per minute

- Crackles on auscultation

- Decreased breath sounds

- Absence of asthma

A score of 4 or 5 indicates a 25% to 50% probability of pneumonia; a score of 2 or 3 indicates a probability of 3% to 10%; and a score of 0 or 1 represents a probability of l% or less [29,54]. Neither clinical nor radiographic features can reliably differentiate primary viral from bacterial or combined viral-bacterial pneumonia [9,31,32]. There are some features that, if present, aid in making the distinction. The presence of a viral epidemic in the community, such as influenza or RSV, increases the likelihood of a viral etiology [32]. The patient's age can also help identify the most probable cause; as noted previously, viral infections have been found more often in young children and adults older than 60 years of age compared with younger adults [9,24]. Chest pain is significantly more frequent in adults with bacterial pneumonia than in those with viral pneumonia [9]. Radiographic findings are generally not useful in identifying a specific pathogen, although multilobar infiltrates suggest infection with S. pneumoniae, S. aureus, or L. pneumophila, and patchy, interstitial infiltrates suggest a viral or mycoplasmal etiology [47,49].

Atypical Pneumonia

The first use of the term atypical pneumonia was in 1938 to describe a series of seven patients who had developed an unusual form of tracheobronchitis [65]. There had also been descriptions of outbreaks of pneumonia that behaved atypically in Europe in the 1920s. In general, these outbreaks were milder and had higher recovery rates than expected for the typical case of pneumonia.

At the present time, atypical pneumonia is encountered, and managed, primarily in the outpatient setting. The causative pathogen most commonly identified in such cases is M. pneumoniae. According to CDC estimates, Mycoplasma infections occur at the rate of 2 million cases each year and are responsible for between 1 and 10 of every 50 cases of CAP [66].

Atypical pneumonia syndrome, best represented by mycoplasma infection, presents with a subacute prodrome of malaise, low-grade fever, headache, myalgia, and non-productive cough. Symptoms progress slowly over days to weeks; often patients are thought to have an upper respiratory infection or bronchitis and appear less ill than those with typical bacterial pneumonia [65,66]. The physical examination usually reveals fine rales but no signs of lung consolidation. In the early stage, there may be maculopapular skin eruptions and, on examination of the ear canal, bullous myringitis of the tympanic membrane. Chest x-ray reveals patchy alveolar densities or inhomogeneous segmental infiltrates, often bilateral involving the middle lobe and lingual. The white blood cell count may be normal or only slightly elevated. Full recovery is expected with no residual effects in a previously healthy individual. However, the disease can be severe in those with sickle cell anemia, older adults, and those with immunosuppression [65].

In younger patients, C. pneumoniae (TWAR strain) infection may present as atypical pneumonia. Outbreaks tend to occur in communal settings such as military units and college dormitories [231]. The illness is similar to that seen with mycoplasma infection, except that laryngitis is a prominent feature and nonexudative pharyngitis is common [26]. Chest x-ray may show patchy consolidation, interstitial infiltrates, or funnel-shaped lesions. The white blood cell count is usually normal.

Legionellosis

The first recorded outbreak of legionellosis occurred in 1976 at an annual convention of the American Legion in Philadelphia. A total of 182 of the delegates (many of whom were elderly) became ill, and 146 were hospitalized. The mortality rate was 16%. Because the conference ended prior to the development of significant symptoms in many patients, hospitals all over the United States admitted one or more of the patients who had attended the convention. Despite an outpouring of resources, it took six months to isolate the organism, later named L. pneumophila. The pneumonia caused by the organism is commonly known as Legionnaires' disease [65].

L. pneumophila is a small gram-negative bacillus, atypical in its clinical presentation and for its lack of susceptibility to ß-lactam antibiotics. There are about 60 identified species of Legionella, although L. pneumophila is the primary pulmonary pathogen [230]. Legionella accounts for an estimated 8,000 to 18,000 cases of pneumonia requiring hospitalization in the United States each year [229,230]. Suspicion for infection with Legionella organisms should be high in older adults, in those with chronic underlying disease, and in all patients with pneumonia severe enough to require hospitalization.

Legionella bacteria are found in common sources of freshwater but not usually in sufficient numbers to cause disease. However, in commercial water systems such as those found in large buildings, storage tanks, cooling towers, decorative fountains, or hot tubs, Legionella growth exceeds the threshold required for transmission to susceptible hosts via aerosolization [229]. Because hotels, resorts, and cruise ships often use large, complex water systems and other aerosol-generating devices, travel is a risk factor for disease. This is also true for hospitals and long-term care facilities.

The onset of infection is marked by dry cough, fever of 38.3°C–38.8°C (101°F–102°F), then progressive symptoms and signs of pneumonia accompanied by multi-organ involvement—vomiting, diarrhea, headache, and altered mental status. Chest x-ray reveals rapidly progressive, asymmetric infiltrates without signs of consolidation. Prompt diagnosis relies on clinical suspicion, urine antigen assay, and specialized culture techniques.

DIAGNOSIS AND MANAGEMENT OF COMMUNITY-ACQUIRED PNEUMONIA IN ADULTS

Recommendations for the laboratory diagnosis and treatment of pneumonia in adults were first developed independently by the ATS and the IDSA, and guidelines were published in the 1990s and early 2000s [36,63,64]. Although each guideline differed somewhat, the principles of care were the same [36]. In order to avoid confusion associated with separate guidance, the IDSA and ATS jointly developed the current guideline for CAP, published in 2007 and updated in 2019 [47,235]. The IDSA/ATS guideline focuses on decision making about site of care, laboratory testing, empirical selection of antibiotics, and issues in the delivery of antibiotics (e.g., timing of the first dose, transition from parenteral to oral antibiotics, duration of therapy). Treatment of symptoms associated with CAP is not addressed in the guideline. A systematic review published in 2012 found insufficient evidence to determine if there is benefit to over-the-counter medications (e.g., mucolytics, cough suppressants) for cough associated with acute pneumonia [67].

Laboratory Diagnosis

The challenge of diagnosis is complicated by the lack of cost-effective, reliable, and rapidly available tests to discriminate between viral and bacterial pneumonia [37]. The IDSA/ATS guideline notes that routine cultures of sputum and blood are not recommended for patients treated in the ambulatory setting, as results rarely impact management decisions [47]. The primary reason for cultures and serologic testing is to identify specific pathogens suspected on the basis of clinical and epidemiologic findings or cases in which the results of testing will substantially alter the empirical treatment of the patient [47]. Testing is recommended when there are symptoms or signs of severe CAP (e.g., multilobar infiltrates, respiratory insufficiency, sepsis, leukopenia), when drug-resistant or unusual pathogens are suspected (e.g., MRSA, Pseudomonas, Legionella), and when patients do not show clinical improvement within 72 hours after starting empiric treatment [235].

Blood Culture

Blood cultures are optional and not recommended as a routine diagnostic test for CAP managed in the ambulatory setting. The principle reason is that the yield is low, and studies show that a positive culture leading to a change in antimicrobial therapy occurs in about 3% or fewer cases [55,56,222]. The IDSA/ATS guideline recommends pretreatment blood cultures in patients managed in the hospital who are classified as severe CAP, or being empirically treated for MRSA or gram-negative bacilli, or have a history of hospitalization and antimicrobial therapy within the previous 90 days [235]. Blood and sputum cultures should also be obtained in patients hospitalized with CAP and any one of the following conditions:

- Cavitary infiltrates

- Leukopenia

- Active alcohol abuse

- Chronic liver disease

- Asplenia

- COPD

- Pleural effusion

- Illness severity requiring admission to the ICU

Blood cultures are indicated for patients who have severe CAP, as they are more likely to have infection with a pathogen other than S. pneumoniae [235].

The ATS and the American College of Emergency Physicians (ACEP) also note that blood cultures need not be obtained routinely in all patients admitted with CAP [57]. Similarly to IDSA/ATS, ACEP adds that blood cultures should be considered for patients at higher risk, such as persons who have compromised immune systems, significant comorbidities, severe disease, or another risk factor for infection with resistant organisms [57].

Sputum Culture and Gram Stain

Sputum Gram stain and culture are also considered optional and are not recommended for routine management of adult CAP in the ambulatory setting. Pretreatment Gram stain and culture of respiratory secretions are recommended in adults hospitalized with CAP, in accordance with the same decision criteria outlined above for obtaining blood cultures [235]. Examination and culture of respiratory secretions should be performed only on specimens that meet quality performance measures for collection, transport, and processing of sputum samples.

The diagnostic utility of sputum Gram stain and culture has been demonstrated in patients hospitalized with pneumococcal pneumonia confirmed by positive blood culture. In a series of 58 patients from whom good quality sputum specimens (>10 inflammatory cells per epithelial cell) were submitted before or within six hours after initiation of antibiotic therapy, pneumococci were identified by Gram stain in 63% and by culture in 89% of cases [224].

Newer Diagnostic Techniques

Assays for the detection of antigen and other components of bacterial and viral pathogens have become a useful adjunct for establishing the etiology of pneumonia. Among these is the detection of bacterial antigen in the urine of patients with CAP. In a clinical series report, an assay for S. pneumoniae cell wall polysaccharide in urine was positive in 64% of patients with pneumococcal pneumonia; the sensitivity increased to 88% in patients who were bacteremic [225].

In a meta-analysis of published studies, the assay for detection of Legionella antigen in the urine of patients with pneumonia has been shown to have excellent specificity (99%) but only modest sensitivity (74%) [226]. Thus, a urine Legionella antigen assay is very useful to "rule in" the diagnosis but does not rule it out—a negative result should be interpreted with caution. The ATS/IDSA guideline recommends against routinely testing urine for Legionella antigen in adults with CAP, except when indicated by epidemiologic factors, such as association with a Legionella outbreak or recent travel or in adults with severe CAP [235]. Isolation of Legionella from sputum can be accomplished on selective media. Serologic diagnosis requires acute and convalescent serum; it is useful to confirm a case, but of little value in early diagnosis.

Testing for Viruses

Viral culture remains the criterion standard for diagnosis of viral pneumonia, but because of limitations such as the need for prompt transportation, time needed for viral detection, and the lack of sensitivity for all viruses, rapid antigen testing is often done. In adults, rapid testing has a sensitivity of 50% to 60% and a specificity of at least 90% [31]. Testing of nasal swab specimens is slightly less sensitive than testing of wash specimens, but wash specimens can be difficult to obtain in frail or cognitively impaired adults. Rapid RSV tests are usually not useful for adults, as the level of virus titers shed is low [31]. Diagnostic testing (PCR) for SARS-CoV-2 by nasopharyngeal swab may be performed on patients presenting with CAP in areas experiencing COVID-19 epidemic activity, although lower respiratory symptoms typically begin as upper respiratory symptoms are resolving or have already resolved.

Molecular diagnostic testing of sputum holds promise for providing a rapid and accurate etiologic diagnosis. Studies show that real-time PCR is significantly more sensitive and specific for the detection of the common respiratory viruses that cause CAP, as well as M. pneumoniae and C. pneumoniae [24,33]. However, molecular assays are expensive and not currently widely available [31].

Biomarkers

Over the past several years, researchers have been evaluating biomarkers for their utility in diagnosis and for determining duration of empirical therapy for presumed bacterial pneumonia. Procalcitonin has been shown to be superior to other commonly used markers for its specificity for bacterial infection and its ability to distinguish CAP from asthma and COPD [58,59]. This marker has predictive value; however, no biomarker should be used on its own and, if used, should be considered within the context of clinical and laboratory findings [59]. The 2019 IDSA/ATS guidelines do not recommend the use of procalcitonin to determine need for initial antimicrobial therapy [235].

Site of Care

One of the most important decisions in the management of CAP is determining the site of care—that is, outpatient or inpatient and, if the latter, a general care floor or an ICU [68]. Many physicians admit patients to the hospital when they could be managed effectively on an outpatient basis [47]. This decision requires a careful evaluation of the severity of illness in the context of the personal and social well-being of the patient. Objective severity-of-illness scores and prognostic models can aid in identifying patients who may require hospitalization or admission to an ICU. The most widely used scales are the CRB-65 (confusion, respiratory rate, blood pressure, age 65 years or older) (Figure 1), the CURB-65 severity score (which adds urea level to the CRB-65 criteria), and the Pneumonia Severity Index (PSI) (Table 5). These assessment tools are recommended by the IDSA/ATS as an aid to clinical judgment in determining the site of care [47,69,70]. The scales have been compared, and they do not differ significantly in overall performance [71]. However, each scale has advantages and disadvantages, and none factor in all clinical considerations (such as comorbidities or social factors) [68]. CURB-65 and CRB-65 are easier to score as they have fewer variables and are more likely to correctly classify high-risk patients (i.e., high positive-predictive value) [72]. In contrast, the PSI is more sensitive and is better at determining which patients do not require hospitalization (i.e., low false-negative rate). About 30% to 60% of patients at low risk are unnecessarily admitted to the hospital according to the PSI score [68].

Figure 1: CLINICAL SEVERITY ASSESSMENT IN THE COMMUNITY SETTING: THE CRB-65 SCORE

aDefined as a Mental Test Score of 8 or less or new disorientation in person, place, or time.

Source: Reprinted with Permission from Lim W, van der Eerden MM, Laing R, et al. Defining community-acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 2003;58:377-382.

Table 5: PNEUMONIA SEVERITY INDEX: POINT SCORING SYSTEM FOR STEP 2 OF THE PREDICTION RULE FOR ASSIGNMENT TO RISK CLASSES II, III, IV, AND V

Characteristic

Points Assigneda

Nursing home resident

+10

Demographic factor (age)

Men

Age (yr)

Women

Age (yr)-10

Coexisting illnessesb

Neoplastic disease

+30

Liver disease

+20

Congestive heart failure

+10

Cerebrovascular disease

+10

Renal disease

+10

Physical-examination findings

Altered mental statusc

+20

Respiratory rate ≥30 breaths/min

+20

Systolic blood pressure <90 mm Hg

+20

Temperature <35°C or ≥40°C

+15

Pulse ≥125 beats/min

+10

Laboratory and radiographic findings

Arterial pH <7.35

+30

Blood urea nitrogen ≥30 mg/dL

+20

Sodium <130 mmol/L

+20

Glucose ≥250 mg/dL

+10

Hematocrit <30%

+10

Partial pressure of arterial oxygen <60 mm Hgd

+10

Pleural effusion

+10

aA total point score for a given patient is obtained by summing the patient's age in years (age minus 10 for women) and the points for each applicable characteristic. The points assigned to each predictor variable were based on coefficients obtained from the logistic-regression model used in step 2 of the prediction rule. A score <70 is risk class II, 71–90 is risk class III, 91–130 is risk class IV, and >130 is risk class V. Higher risk classes are associated with increased mortality.

bNeoplastic disease is defined as any cancer except basal or squamous cell cancer of the skin that was active at the time of presentation or diagnosed within one year of presentation. Liver disease is defined as a clinical or histologic diagnosis of cirrhosis or another form of chronic liver disease, such as chronic active hepatitis. Congestive heart failure is defined as systolic or diastolic ventricular dysfunction documented by history, physical examination, and chest radiograph, echocardiogram, multiple gated acquisition scan, or left ventriculogram. Cerebrovascular disease is defined as a clinical diagnosis of stroke or transient ischemic attack or stroke documented by magnetic resonance imaging or computed tomography. Renal disease is defined as a history of chronic renal disease or abnormal blood urea nitrogen and creatinine concentrations documented in the medical record.

cAltered mental status is defined as disorientation with respect to person, place, or time that is not known to be chronic, stupor, or coma.

dIn the Pneumonia PORT cohort study, an oxygen saturation of less than 90% on pulse oximetry or intubation before admission was also considered abnormal.

Source: Reprinted with permission from Fine M, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336:243-250.

The PSI, CURB-65, and CRB-65 were developed to predict the risk of death. Because this risk does not always equate to the need for hospitalization and/or ICU admission, other scales have been developed. For example, SMART-COP provides a score based on a composite of systolic blood pressure, multilobar involvement on chest radiograph, albumin level, respiratory rate, tachycardia, confusion, oxygenation, and arterial pH [73]. SMART-COP was found to accurately predict the need for intensive respiratory or vasopressor support. Another tool, the Severe Community-Acquired Pneumonia (SCAP) score, includes points assigned to eight variables: arterial pH, systolic pressure, confusion, blood urea nitrogen level, respiratory rate, chest radiograph findings, pulmonary arterial oxygen tension (PaO_2), and age (older than 80 years) [74]. SCAP has identified a larger proportion of patients as low risk compared with the PSI, CURB-65, and CRB-65, and is better than or as accurate as those scores at predicting adverse outcomes in hospitalized patients [74,75]. The IDSA/ATS guideline notes that the results of these objective criteria should always be accompanied by clinical judgment, including consideration of subjective factors, such as the availability of outpatient support resources and the patient's ability to safely and reliably take oral medication [47].

It is estimated that admission to an ICU is needed for 10% to 20% of patients hospitalized with CAP [76]. The IDSA/ATS guideline recommends two major and nine minor criteria to define severe pneumonia requiring ICU admission. [47]. The major criteria are septic shock requiring vasopressors or acute respiratory failure requiring intubation and mechanical ventilation. The presence of at least three of the following minor criteria suggests the need for ICU admission [47]:

- Increased respiratory rate (≥30 breaths per minute)

- Low PaO_2/fraction of inspired oxygen ratio (≤250)

- Multilobar infiltrates

- Confusion/disorientation

- Uremia (blood urea nitrogen level ≥20 mg/dL)

- Leukopenia (white blood cell [WBC] count <4,000 cells/mm^3)

- Thrombocytopenia (platelet count <100,000 cells/mm^3)

- Hypothermia (core temperature <36°C [96.8°F])

- Hypotension requiring aggressive fluid resuscitation

These criteria are based on empirical evidence from published studies and validated in pneumonia cohorts from different countries [235,77,78].

Selection of Antibiotics

The goal of antibiotic treatment of pneumonia is to eradicate the infection or to reduce the bacterial load so the patient's own immune response is able to limit spread and speed recovery. The choice of regimen is based on consideration of known or suspected etiology, patient's age and severity of illness, comorbidities, and knowledge of resistance patterns in the community. When culture results are known, one should tailor therapy in accordance with antibiotic sensitivities and avoid unnecessarily prolonged treatment so as to minimize the potential for the development of resistance [37].

Pending results of cultures and serologic testing, an initial empiric treatment regimen is selected according to patient variables and clinical setting (Table 6) [47]. Patients with mild illness and no serious coexisting disease may be managed as outpatients. The 2019 ATS/IDSA guideline recommends amoxicillin 1 g three times daily, doxycycline 100 mg twice daily, or a macrolide (e.g., azithromycin 500 mg on first day then 250 mg daily or clarithromycin 500 mg twice daily) [235]. The macrolide monotherapy recommendation is conditional based on prevalence of local pneumococcal resistance (<25%) and provided the patient has not received antimicrobials within the previous three months [47]. S. pneumoniae resistance to macrolides is four times more likely in adult patients who have received this class of drug within the previous three months, in which case a fluoroquinolone or ß-lactam plus macrolide combination should be selected. Patients with comorbidities should receive broader spectrum treatment as they are more likely to harbor resistant pathogens and to be more vulnerable to poor outcomes if the initial regimen is inadequate. For outpatient adults with comorbidities, the ATS/IDSA guideline recommends one of the following options (in no order of preference) [235]:

- Monotherapy: Respiratory fluoroquinolone (levofloxacin 750 mg daily, moxifloxacin 400 mg daily, or gemifloxacin 320 mg daily)

- Combination therapy: Amoxicillin/clavulanate 500 mg/125 mg three times daily or a cephalosporin (cefpodoxime 200 mg twice daily or cefuroxime 500 mg twice daily) and doxycycline or a macrolide

Table 6: RECOMMENDED EMPIRICAL ANTIMICROBIAL THERAPY ACCORDING TO 2019 IDSA/ATS GUIDELINE FOR THE MANAGEMENT OF COMMUNITY-ACQUIRED PNEUMONIA

Site of Care and Patient Characteristics

Recommended Drug Class

Specific Drug Options

Level of Evidence

Previously healthy outpatient, no exposure to antibiotics within past three months

Amoxicillin

—

Strong recommendation, moderate quality of evidence

Tetracycline or macrolide

Doxycycline, azithromycin, or clarithromycin

Conditional recommendation, low-to-moderate quality of evidence

Outpatients with comorbiditiesa or exposure to antibiotics within the previous three monthsb

Monotherapy with a respiratory fluoroquinolone

Moxifloxacin, gemifloxacin, or levofloxacin

Strong recommendation, moderate quality of evidence

Combination therapy with a ß-lactam + macrolide or doxycycline

Amoxicillin-clavulanate or cephalosporin (cefpodoxime or cefuroxime) + azithromycin or clarithromycin or doxycycline

Conditional recommendation, low quality of evidence

Inpatient (not ICU)

Respiratory fluoroquinolone

—

Strong recommendation, high quality of evidence

ß-lactam + macrolide

—

Strong recommendation, high quality of evidence

Inpatient (ICU)

ß-lactam + azithromycin

OR

ß-lactam + respiratory fluoroquinolone

Alternative for penicillin allergy: respiratory fluoroquinolone and aztreonam

Cefotaxime, ceftriaxone, or ampicillin-sulbactam

Strong recommendation, high quality of evidence

aComorbidities include chronic heart, lung, liver, or renal disease; diabetes mellitus; alcoholism; malignant disease; or asplenia or use of immunosuppressant drugs.

bIf patient has been exposed to antibiotics within previous three months, a different drug from a different class should be used.

Source: [235]

Evidence Based Practice Recommendation

The American College of Radiology asserts chest x-ray is the imaging modality of choice for complicated pneumonia.

https://acsearch.acr.org/docs/69446/Narrative

Last Accessed: August 29, 2024

Strength of Recommendation: 9

The choice of treatment option requires consideration of clinical and epidemiologic factors unique to patient and locale. As a rule, patients with recent exposure to one class of antibiotics should receive treatment with antibiotics from a different class to avoid possible bacterial resistance to the initial regimen. Fluoroquinolones should not be used routinely, as widespread use increases the possibility that resistance will develop.

The selection of a respiratory fluoroquinolone or a ß-lactam plus macrolide combination is recommended also for patients with CAP who are hospitalized on a general floor [235]. Patients with recent hospitalization and parenteral antibiotic treatment, as well as those with severe pneumonia usually requiring admission to an ICU, need empiric treatment for usual pathogens and consideration of coverage for S. aureus and gram-negative bacteria infection pending sputum and blood culture results. This is achieved with a regimen that combines a broad-spectrum ß-lactam (e.g., piperacillin/tazobactam) or a carbapenem with either azithromycin or a respiratory fluoroquinolone, adding vancomycin or linezolid to cover MRSA if there is clinical suspicion of S. aureus infection. Antibiotic selection for treatment of CAP in reference to specific pathogens is summarized in Table 7 [47].

Table 7: ANTIBIOTIC SELECTION FOR SPECIFIC PATHOGENS ACCORDING TO IDSA/ATS GUIDELINE FOR THE MANAGEMENT OF COMMUNITY-ACQUIRED PNEUMONIA

Pathogen

Preferred Antibiotic

Alternative Options

Streptococcus pneumoniae, not penicillin resistant

Penicillin G, amoxicillin

Macrolide, cephalosporins, clindamycin, doxycycline, respiratory fluoroquinolone

Streptococcus pneumoniae, penicillin resistant

Based on susceptibility (cefotaxime, ceftriaxone, fluoroquinolone)

Vancomycin, linezolid, high-dose amoxicillin

Haemophilus influenzae, non-ß-lactamase producing

Amoxicillin

Fluoroquinolone, doxycycline, azithromycin, clarithromycin

Haemophilus influenzae, ß-lactamase producing

Second- or third-generation cephalosporin, amoxicillin-clavulanate

Fluoroquinolone, doxycycline, azithromycin, clarithromycin

Mycoplasma pneumoniae/Chlamydophila pneumoniae

Macrolide, a tetracycline

Fluoroquinolone

Legionella spp.

Fluoroquinolone, azithromycin

Doxycycline

Pseudomonas aeruginosa

Antipseudomonalß-lactam plus ciprofloxacin or levofloxacin or aminoglycoside

Aminoglycoside plus ciprofloxacin or levofloxacin

Acinetobacter spp.

Carbapenem

Cephalosporin-aminoglycoside, ampicillin-sulbactam, colistin

Staphylococcus aureus, methicillin susceptible

Antistaphylococcal penicillin

Cefazolin, clindamycin

Staphylococcus aureus, methicillin resistant

Vancomycin or linezolid

Trimethoprim/sulfamethoxazole

Source: [47,235]

Evidence Based Practice Recommendation

The Infectious Diseases Society of America recommends empirical therapy for MRSA pending sputum and/or blood culture results for hospitalized patients with severe community-acquired pneumonia defined by any one of the following: a requirement for ICU admission, necrotizing or cavitary infiltrates, or empyema.

https://academic.oup.com/cid/article/52/3/e18/306145

Last Accessed: August 27, 2024

Level of Evidence: A-III (Good supporting evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees)

For adults who present with presumed viral CAP, it is unclear whether antibiotic treatment is beneficial. However, when the patient with CAP has epidemiologic, clinical, or laboratory evidence of active influenza, a neuraminidase inhibitor should be included in the treatment regimen [32,235]. During the COVID-19 pandemic, patients with upper respiratory tract infection progressing to clinical and/or radiographic signs suspicious for viral pneumonia should immediately receive SARS-CoV-2 diagnostic testing and consideration for COVID-19 treatment protocol. Updated guidance for managing patients with COVID-19 pneumonia is available at the IDSA website [94].

Timing of Initial Antibiotic Therapy

The time to the first dose of antibiotics for adults with CAP has engendered debate. A 2003 guideline developed by the IDSA recommended initiation of antibiotic therapy within four hours after hospitalization. Quality measures linked to this timeframe were developed by the Joint Commission and the Centers for Medicare and Medicaid Services [2,66,79,80]. Experts have criticized the timeframe requirement, with some noting that it has the potential to result in less-than-optimal care and others adding that diagnosis of pneumonia in the emergency department is challenging, especially in older patients who have an atypical presentation [51,52,79,80]. In a survey of 121 emergency physicians, 55% of the respondents said they had prescribed antibiotics to patients they did not believe had pneumonia in an effort to comply with the Centers for Medicare and Medicaid Services quality measure; 42% of these respondents said they had prescribed as such more than three times a month [80]. Sixty percent of the respondents said they did not believe that the guideline improves patient care. The results of a systematic review and a large-scale study have shown no decrease in mortality with a first dose administered within four hours [57,81,82].

As emphasized by the IDSA/ATS guideline committee, the recommendation at present is to begin antibiotic treatment promptly, without delay, administering the initial dose at the site of care (e.g., emergency department, clinic, office) where the diagnosis is first made [235].

Duration of Therapy

With the availability of well-absorbed, effective oral antibiotics, hospitalized adults do not require intravenous antibiotics for the duration of treatment. Intravenous therapy can be changed to an oral regimen when the patient is hemodynamically stable, improving clinically, and able to take oral medications safely [235]. For patients on a general ward floor, this transition can often be made by the third hospital day; patients in the ICU usually reach this point within seven days. It is recommended that the oral antibiotic be either the same drug or within the same drug class as the intravenous antibiotic. Patients can be discharged from the hospital as soon as clinical stability has been achieved, provided they have no comorbidities requiring inpatient care and have a safe home environment and reliable follow-up. The IDSA/ATS note the following criteria for determining clinical stability [235]:

- Temperature ≤37.8°C (100.04°F)

- Heart rate ≤100 beats per minute

- Respiratory rate ≤24 breaths per minute

- Systolic blood pressure ≥90 mm Hg

- Arterial oxygen saturation ≥90% or partial pressure of oxygen ≥60 mm Hg on room air

- Ability to maintain oral intake

- Normal mental status

The IDSA/ATS recommend that antibiotic therapy be given for a total of at least five days. The duration of therapy should be extended at least 48 to 72 hours beyond resolution of fever, assuming significant clinical improvement and no more than one pneumonia-associated active clinical sign [235]. A five- to seven-day course should suffice for most uncomplicated cases that show a prompt and satisfactory response to treatment.

The duration of treatment for gram-negative bacillary and staphylococcal pneumonia bears further comment. Unlike pneumococcal pulmonary infection, which usually heals without residual damage, these pathogens often cause destructive changes and small cavities in the lung, which clear slowly and heal by fibrosis. Thus, a more prolonged course of therapy (two to three weeks) should be considered, depending on severity of illness and response to therapy.

Treatment Failure

The clinical response to initial antibiotic therapy is unsatisfactory in approximately 15% of adults with CAP [47]. Failure to respond has no clear definition, and the IDSA/ATS guideline suggests using a systematic classification of cases, with attention to timing and character of response, as a guide to further evaluation and management. In general, treatment failures may be classified as persistent or non-responding, as a delay in achieving clinical stability, or as progressive pneumonia with clinical deterioration. Some clinical deterioration during therapy is not uncommon in the first 24 hours of treatment; as many as 45% of adults admitted to the hospital later require transfer to the ICU [47]. When the diagnosis of CAP is correct and guideline-recommended therapy has been used, the most common reason for treatment failure is an inadequate host response. For these patients, the appropriate management depends on individual case considerations, such as comorbidities, adequacy of pulmonary toilet, and whether the intravenous regimen has been reliably and consistently administered.

Benefits of Guideline-Adherent Antibiotic Therapy

Guideline-directed management of CAP has been associated with many benefits. In one study, use of guideline-recommended antibiotics was associated with a significantly shorter time to clinical stability; clinical stability was achieved by seven days in 71% of patients treated with guideline-recommended antibiotics and in 57% of those treated with nonadherent regimens [15]. Adherence to recommendations guiding the selection of antibiotics was also associated with a significantly shorter length of stay (8 vs. 10 days) and a significantly lower overall in-hospital mortality rate (8% vs. 17%) [15]. In a Canadian study of adults (mean age: 51 years) who, in the main, had mild pneumonia, guideline-adherent selection of antibiotic treatment was associated with a lower mortality rate (1%) than that found when treatment selection that was not adherent to guidelines (6%) [83]. The mortality rate associated with the use of macrolides was also significantly lower than that with the use of fluoroquinolones (0.2% vs. 3%) [83]. In a large study of 54,619 patients who were hospitalized at 113 community hospitals (not in the ICU), use of guideline-adherent treatment was associated with a lower in-hospital mortality rate, lower rate of sepsis and renal failure, and shorter length of stay and duration of parenteral therapy [17]. Decreased mortality has also carried over to populations with more severe disease, with nonadherent therapy being associated with an increase in inpatient mortality (25% vs. 11%) among older adults (median age: 71 years) who were admitted to an ICU [16]. In addition to the higher rates of adverse outcomes, the low rate of adherence has also resulted in the inappropriate use of antimicrobials in at least half of cases [21].

Despite the benefits of guideline-directed treatment and the wide dissemination of the guidelines for management of pneumonia in adults, adherence has been low, especially with regard to antibiotic selection, with rates ranging from 9% to 82% [15,16,17,18,20]. In a study of more than 34,000 patients in a managed care organization, adherence to the 2003 IDSA guidelines in ambulatory settings was 52% for patients who were previously healthy and had not had recent exposure to antibiotics [20]. The rate of adherence was better (82%) for patients who had comorbidities and no recent exposure to antibiotics [20]. One study found that most cases of guideline-discordant use of antibiotics for older adults represent undertreatment [15]. The use of recommended antibiotics in the emergency department significantly increased from 1993 through 2008, but the percentage of patients receiving these drugs is still not optimal, with 60% to 70% of patients not receiving recommended antibiotics [84].

Strategies to Enhance Adherence to Therapeutic Guidelines

As the low rate of guideline adherence demonstrates, disseminating clinical practice guidelines alone is not enough to change practice. Physician education should address barriers to guideline adherence, including lack of familiarity, concerns about the practicality of recommended antibiotics, increased cost, lack of documented improved outcomes, and potential conflict with other guidelines [23]. Physician practices and healthcare systems should implement strategies that have changed physician behavior in other health condition settings, such as face-to-face educational outreach, use of local opinion leaders, and individualized audit with peer-comparison feedback [85]. In a study of six Dutch hospitals, significant increases in adherence to guideline-recommended care were achieved with an intervention that included the establishment of a local committee, a lecture by a respected opinion leader, feedback on performance, and critical care pathway pocket cards [86]. The intervention also included a second phase that focused on aspects of treatment in most need of improvement. In another study, weekly e-mail reminders listing performance data on antibiotic administration recommendation for individual emergency physicians helped to increase guideline adherence [87]. The use of a standardized evidence-based order set was associated with a decrease in mortality and was also cost-effective [88].

Follow-Up Care

Evidence suggests that severe pneumonia is a cause of long-term morbidity and excess mortality among adults. In a population-based follow-up study of adults with CAP in Canada, conducted over a median of four years, the re-hospitalization rate for pneumonia was 16% to 72% for all causes [9].

The PSI classification and the time to clinical stability can both help predict adverse outcomes. Mortality has been reported to be higher for people originally classified as PSI class V than PSI classes I and II, with rates of 82% compared with 15% [9]. A time to clinical stability of more than 72 hours has been associated with a significantly higher rate of adverse outcomes than shorter times [90]. Overall, severe CAP has been associated with a 30-day re-hospitalization rate as high as 20%, a 30-day mortality rate as high as 23%, and all-cause mortality within one year as high as 28% [76].

These findings indicate that adults with severe pneumonia should be followed up closely to monitor for adverse events after discharge. The time to clinical stability is a useful guide for a follow-up plan; patients in whom clinical stability is not achieved until more than 72 hours after admission should be seen in follow-up soon after discharge [3,90]. Strategies to prevent influenza and pneumonia should also be emphasized for all hospitalized patients. When indicated, immunization against pneumococcal infection should be initiated before or shortly after discharge, as recommended by the Advisory Committee on Immunization Practices (ACIP) and others [47,91,227].

Patient and Family Education

After a diagnosis of pneumonia has been made, patient education should include directions for use of the antibiotic and information on potential untoward effects of the drug. Follow-up instructions, depending on the clinical situation, may include 24-hour telephone contact or follow-up in the office after 24 to 48 hours. This will improve adherence to the prescribed therapy, provide an opportunity to address side effects of drug therapy, and allow progress to be monitored. The need for hospitalization should be assessed throughout the course of the illness. Education should also include instructions to drink plenty of fluids and to use an antipyretic to control fever and myalgias when needed. Use of cough suppressants should be avoided, as the cough reflex and sputum expectoration enhance removal of thick secretions. However, in the event of a constant, nonproductive cough, as found especially with mycoplasmal infection, a narcotic such as codeine at night may allow for more restorative sleep.

Provisions for patients with limited English language proficiency are required under federal law, and the U.S. Department of Health and Human Services and the Office of Civil Rights view a lack of adequate interpretation as discrimination, based on the Civil Rights Act of 1964 [19]. According to U.S. Census Bureau data, nearly 68 million Americans speak a language other than English at home, with more than 25 million (8.2% of the population) reporting that they speak English less than "very well" [127]. Immigrant patients with chronic illness may feel unable to return to their home countries due to a lack of available medical care. Changes in healthcare law restricting federal funding of services to only legal residents may cause significant problems for certain facilities, with conflicts arising from providing life-saving care for patients who have no means of reimbursement and no medical services waiting for them in their home countries.

ILLUSTRATIVE CASE

A semi-retired man, 68 years of age, presents one Sunday morning to the emergency department with malaise, fever, productive cough, and right pleuritic chest pain of less than 24 hours duration. He has been active, works as a custodian, has never been hospitalized, takes no medications, and does not regularly see a physician. On review of systems, the patient states that he gave up smoking years ago, has a mild chronic cough and morning sputum production, and has noted mild dyspnea on exertion for the past six months. He drinks only beer, never after work, but every Saturday afternoon he likes to take a six-pack out into the backyard, where he relaxes in his lounge chair. When asked whether there was anything different about the Saturday before the onset of the illness, his wife relates that he consumed two six-packs and failed to come in that evening. She found him later, after dark, asleep in his lounge chair, and helped him in to bed. He awoke this morning with fever and chills. On exam, the patient's temperature is 102.6°F, blood pressure 154/80 mm Hg, pulse 94 beats per minute, and respiration 20 breaths per minute. He is alert, with signs of mild emphysema and crackles audible over the right lower posterolateral chest. The chest x-ray shows patchy alveolar opacification in the right lower lobe and slight cardiomegaly.

The working diagnosis here is CAP, likely caused by S. pneumoniae or H. influenzae, as the patient has no prodromal upper respiratory symptoms to suggest viral or mycoplasma infection.

Why is this happening now? COPD/chronic bronchitis appears to have developed in recent years. Such patients have damaged, poorly functioning mucociliary epithelium and rely on compensatory cough to promote tracheobronchial clearance. Moreover, they often have colonization with pneumococcus and H. influenzae. An additional risk factor in this patient may be mild heart failure with ambient alveolar edema in the basal segments of the lower lungs. Excessive beer consumption the evening before onset of illness made him somnolent and suppressed his cough reflex, thus rendering him vulnerable to aspiration and retention of upper tract secretions (if not gastroesophageal reflux and aspiration). Encumbered by alveolar edema, and perhaps impaired by the metabolic effects of alcohol, pulmonary macrophages in the basal segment of the right lung were simply overwhelmed.

What is the best site of care and treatment for this patient? While he does not meet the criteria for ICU admission, his age, comorbidities, degree of illness, and social situation taken together suggest the need for hospital admission, parenteral antibiotic therapy, and close observation, anticipating a short hospital stay. He was treated with a ß -lactam and macrolide, improved rapidly, and was discharged day ٣ on a matching oral regimen, to complete a ١٠-day course of therapy.

What preventive measures were taken to reduce the risk of this happening again? The 20-valent pneumococcal conjugate vaccine (PCV20) (Prevnar 20) was administered prior to discharge and arrangements were made for primary care follow-up. The patient and his wife were educated regarding the need for yearly influenza vaccination. The role of alcohol was discussed, as well as the importance of keeping the Saturday afternoon beer consumption within clearly defined limits.

PNEUMONIA IN THE PEDIATRIC PATIENT

Pneumonia is the leading infectious cause of death in children worldwide [228]. An estimated 808,000 children died of pneumonia in 2017, which accounts for 15% of all deaths in children younger than 5 years of age. Children and families in every country are affected, but childhood pneumonia is most prevalent in South Asia and sub-Saharan Africa. The most common etiologic agents are S. pneumoniae, H influenzae, RSV, and, in young children with HIV, Pneumocystis jiroveci. Childhood risk factors for contracting pneumonia include malnutrition, indoor air pollution (e.g., caused by cooking and heating with biomass fuels, parenteral smoking), and pre-existing illness such as active HIV infection and measles [228].

Etiology

Viral pathogens are reported to be responsible for most cases of CAP in preschool-aged children and as many as 80% of cases in children younger than 2 years of age [30]. In children younger than 2 years of age, the most common viral pathogen, occurring in up to 40% of cases, is RSV; other viral pathogens include adenoviruses, bocavirus, human metapneumovirus, influenza A and B viruses, parainfluenza viruses, coronaviruses, and rhinovirus [9,29,30,32].

RSV infection is common in infants and young children; it is estimated that most children have had RSV by 2 years of age [31]. It is the leading cause of pneumonia in infants younger than 1 year of age, with 25% to 40% of those infected developing signs of pneumonia or bronchiolitis [29]. Premature birth, very young age, compromised immune system, and impaired lung or heart function are all risk factors for RSV-related pneumonia in infants. In contrast to preschool-aged children, the percentage of viral cases is much lower among older children and adolescents (10 to 16 years of age), and pneumonia caused by RSV is rare in this population.

In older children, viral and atypical bacterial infection account for most mild CAP managed in the ambulatory setting, while pyogenic respiratory bacterial infection is responsible for the majority of CAP in seriously ill, hospitalized children [30]. S. pneumoniae is the most common bacterial pathogen in school-aged children. Studies show that atypical pathogens account for 3% to 23% of cases, most commonly mycoplasma in older children and chlamydia in infants and young children [30]. A 2009 European study examining causative agents in hospitalized pediatric patients with radiographic evidence of pneumonia found bacterial infection in 53% of patients and viral pathogens in 67% of patients, with 33% of children in the study showing evidence of both [63]. S. pneumoniae was the most common bacterial pathogen (46%), followed by M. pneumoniae and C. pneumoniae. The primary viral pathogens identified were influenza A or B, parainfluenza, rhinovirus, RSV and, human metapneumovirus [63].

As with adults, severe CAP caused by S. aureus is encountered during outbreaks of influenza [223]. Legionella spp. and fungal pathogens are uncommon in children. A combination of viral and bacterial pathogens occurs in up to half of children with CAP [30,32].

Clinical Features and Diagnosis

The clinical presentation of CAP in children is similar to that in adults, but can vary according to age and developmental stage. For example, cough productive of purulent sputum may be elicited in older children, but nonproductive cough is common in young children and infants [30,60]. Nonspecific irritability and restlessness may be the primary symptoms in infants.

During the physical examination of pediatric patients, the clinician should look for signs of hypoxia and dehydration, as well as retractions, tachypnea, and use of accessory muscles of respiration [60]. The clinician should also evaluate the upper respiratory tract for evidence of rhinorrhea, otitis media, and pharyngitis [60]. Auscultation of the chest should be carried out, and the Pediatric Infectious Diseases Society (PIDS)/IDSA guideline recommends pulse oximetry for children with suspected hypoxemia [30].

One of the most common reasons for pediatric emergency room visits is fever, and fever is present in 88% to 96% of identified pneumonia cases in developed countries [70]. However, children with fever and wheezing commonly have either upper respiratory disease or reactive airway disease. As with pneumonia in adults, the accuracy of any one sign or symptom in predicting the likelihood of pneumonia is limited [61]. Nonspecific symptoms such as vomiting and abdominal discomfort are common. Careful attention should be given to the chest exam, as diminished breath sounds and fine end-inspiratory crackles are subtle, important clues to the presence of pneumonia in the pediatric patient. In one study, non-specific crackles were present in more than 90% of children with pneumococcal or mycoplasma pneumonia [70]. Infants with pneumonia commonly present with poor feeding and irritability as well as tachypnea, retractions, grunting, and hypoxemia; cough is rare [64].

Several clinical rules have been developed for predicting the likelihood of pneumonia in children on the basis of discernible clinical signs. The presence of at least two of the following signs—fever, tachypnea, and reduced oxygen saturation—is associated with a high probability of the disease; the absence of all three indicates a low probability [61]. Other signs of respiratory distress, such as cough, nasal flaring (in infants), rales, and decreased breath sounds, have also been found to be independent predictors of pneumonia in infants and children [60,62]. Bronchial breath sounds, rales, and dullness to percussion are more likely to occur in older children and adolescents [60].

Unlike diagnosis in adults, a chest radiograph is not the diagnostic standard to be applied for all CAP in children. The PIDS/IDSA guideline notes that routine chest radiographs are not necessary for children who can be treated as outpatients [30]. However, posteroanterior and lateral chest radiographs should be obtained when there is fever and respiratory distress suspected or documented hypoxemia, or illness severe enough to warrant hospitalization [30]. In a study of 99 children hospitalized with what was later determined to be pneumonia, the most common abnormal finding was "diminished" breath sounds; only 21% were described as having "normal" breath sounds. Radiographic evidence of pulmonary consolidation was present in 79% of patients, and correlation between diminished breath sounds and a positive chest x-ray was 60.2% [63].

Laboratory Tests

Unlike the situation in adults, titers of shed virus in children are high [31]. Thus, rapid antigen testing of nasal or throat swabs for influenza and other respiratory viruses should be done for infants and young children [30]. However, it should be noted that negative results of influenza virus on rapid antigen tests do not conclusively rule out infection with influenza virus. Testing for C. pneumoniae is not recommended.

Blood cultures are not routinely needed but should be obtained in children hospitalized for moderate-to-severe pneumonia that is presumed to be bacterial [30]. Urinary antigen detection tests often have false-positive results in children and are therefore not recommended for the diagnosis of pneumococcal pneumonia.

Management of Community-Acquired Pneumonia in Children

The PIDS/IDSA guideline, published in 2011, addresses the management of CAP in children 3 months of age and older who are otherwise healthy; the guideline does not provide guidance for neonates and infants younger than 3 months of age or children with comorbidities [30]. The guidelines were developed in an effort to decrease morbidity and mortality, as had been shown with the guideline for adults. Similar to the IDSA/ATS guideline, the management issues addressed in the PIDS/IDSA guidelines are site of care and selection and duration of antibiotic therapy, as well as adjunctive surgical and nonantibiotic treatment for complications. As with the guideline for adults, treatment of pneumonia-related symptoms is not included in the pediatric guideline. The discussion here is limited to site of care and antibiotic therapy.

Site of Care

To aid in making site-of-care decisions, the PIDS/IDSA guidelines recommend that a child or infant with CAP be hospitalized if any of the following factors are present [30]:

- Moderate-to-severe illness, as defined by several features, including respiratory distress and hypoxia

- Suspected or documented infection caused by a pathogen with increased virulence, such as community-associated MRSA

- Uncertainty about care at home or availability for follow-up

Most children with pneumonia do not require care in an ICU. The guideline states that a child should be admitted to an ICU or a unit with continuous cardiorespiratory monitoring capabilities if the child [30]:

- Requires invasive ventilation via a nonpermanent artificial airway (endotracheal tube)

- Has impending respiratory failure or sustained tachycardia, inadequate blood pressure, or need for pharmacologic support of blood pressure or perfusion

- Has altered mental status as a result of pneumonia

- Has a pulse oximetry measurement <92% on inspired oxygen of ≥0.50

- Requires acute use of noninvasive positive pressure ventilation

Selection of Antibiotics or Antivirals

Evidence Based Practice Recommendation

The American Thoracic Society and the IDSA recommend that anti-influenza treatment, such as oseltamivir, be prescribed for adults with CAP who test positive for influenza in the inpatient setting, independent of duration of illness before diagnosis.

https://www.atsjournals.org/doi/full/10.1164/rccm.201908-1581ST

Last Accessed: August 29, 2024

Strength of Recommendation/Level of Evidence: Strong recommendation; moderate-quality evidence

The PIDS/IDSA guideline recommends empiric antibiotic therapy according to patient age, immunization status, and site of care. Among infants and children 3 months to 5 years of age, antibiotic therapy is not routinely recommended because viral infection is the predominate cause of CAP in this age group [30]. When influenza virus is the suspected cause of pneumonia, influenza antiviral therapy should be started as soon as possible, as maximal benefit is achieved when treatment begins within 48 hours of the onset of symptoms. (Treatment should not be delayed while waiting for the results of viral testing.) The PIDS/IDSA guideline recommends three U.S. Food and Drug Administration (FDA)-approved influenza antiviral therapies: oseltamivir (Tamiflu), zanamivir (Relenza), and amantadine (Symmetrel) [30]. A fourth antiviral therapy, rimantadine (Flumadine), is included in the guideline, with a note that the agent is FDA-approved for prophylaxis—not treatment—in children 1 year of age and older [30]. The guideline adds that data on the safety and efficacy of the agent for children 1 year of age and older have been published.

As in adults, S. pneumoniae is the most common bacterial cause of CAP in children; thus, if a bacterial pathogen is thought to be the cause, amoxicillin or amoxicillin/clavulanate is recommended as first-line therapy for mild-to-moderate illness in previously healthy children 3 months to 5 years of age who are up-to-date with immunization [30]. Several alternatives can be used for children who are allergic to amoxicillin (Table 8). Amoxicillin is also the preferred antibiotic for mild-to-moderate CAP in adolescents and children 5 years of age and older [30]. For children of all ages, especially children older than 5 years of age and adolescents, a macrolide is recommended if an atypical bacterial pathogen is thought (or documented) to be the cause.

Table 8: EMPIRIC ANTIBIOTIC THERAPY FOR COMMUNITY-ACQUIRED PNEUMONIA IN CHILDREN ACCORDING TO PIDS/IDSA GUIDELINE

Site of Care, Patient Characteristics

Presumed Bacterial Pneumonia

Presumed Atypical Pneumonia

Outpatient

<5 years

Amoxicillin

Alternative: amoxicillin clavulanate

Azithromycin

Alternatives: clarithromycin or erythromycin

≥5 years

Amoxicillina

Alternative: amoxicillin clavulanate

Azithromycin

Alternatives: clarithromycin, erythromycin, doxycycline (children >7 years)

Inpatient (all ages)

Fully immunizedb and minimal local penicillin resistance in invasive strains of pneumococcus

Ampicillin or penicillin G

Alternatives: ceftriaxone or cefotaxime (with vancomycin or clindamycin if MRSA suspected)

Azithromycin (with ß-lactam if atypical pneumonia is doubtful)

Alternatives: clarithromycin, erythromycin, doxycycline (children >7 years), or levofloxacin (children who have reached growth maturity or who cannot tolerate macrolides)

Not fully immunized and/or significant local penicillin resistance in invasive strains of pneumococcus

Ceftriaxone or cefotaxime (with vancomycin or clindamycin if MRSA suspected)

Alternative: levofloxacin (with vancomycin or clindamycin if MRSA suspected)

Azithromycin (with ß-lactam if atypical pneumonia is doubtful)

Alternatives: clarithromycin, erythromycin, doxycycline (children >7 years), or levofloxacin (children who have reached growth maturity or who cannot tolerate macrolides)

aA macrolide plus ß-lactam can be used for children 5 years of age and older with presumed bacterial pneumonia who have clinical, radiographic, or laboratory evidence to distinguish bacterial from atypical pneumonia.

bHas received conjugate vaccines for Haemophilus influenzae b and Streptococcus pneumoniae.

Source: [30]

For fully immunized infants and school-aged children who are hospitalized, treatment with ampicillin or penicillin G is recommended when local epidemiologic data show a low level of penicillin resistance to S. pneumoniae [30]. For children who are not fully immunized or are hospitalized in an area with a high level of penicillin-resistant S. pneumoniae, treatment with a third-generation cephalosporin (ceftriaxone or cefotaxime) should be given intravenously. If M. pneumoniae or C. pneumoniae is strongly suspected, treatment should include a macrolide (orally or intravenously) with a ß-lactam and diagnostic testing should be done as soon as possible [30]. The PIDS/IDSA guideline also recommends antimicrobial treatment for specific pathogens; however, a discussion of all possible pathogens is beyond the scope of this course.

According to a systematic review, zinc supplementation in addition to standard antibiotic therapy was not shown to have significant benefit on clinical recovery of severe or nonsevere pneumonia in children 2 to 59 months of age [89].

Duration of Therapy

Most studies have evaluated 10-day therapy, and this duration is associated with good outcomes. However, a shorter duration may be equally as effective, especially for mild disease treated on an outpatient basis [30].

Benefits of Guideline Adherence

Because the PIDS/IDSA guideline for management of CAP in children is relatively recent, data are lacking on the benefits of guideline-adherent treatment in the pediatric population. One study did show that more children received appropriate antibiotics after the development of a clinical practice guideline based on the PIDS/IDSA guideline and an antimicrobial stewardship program [14]. It is assumed that more data will become available over time.

Late Complications

Data on the long-term effects of pneumonia during childhood are lacking. A systematic review demonstrated that severe pneumonia in children younger than 5 years of age is associated with long-term sequelae, with restrictive lung disease being the most common sequela [95]. Overall, major respiratory sequelae (e.g., restrictive lung disease, obstructive lung disease, bronchiectasis) occurred in 5.5% of children treated on an outpatient basis and in 13.6% of children hospitalized for treatment [95]. Sequelae occurred in approximately 54% of children who had pneumonia caused by adenovirus.

7. PREVENTION OF PNEUMONIA

IMMUNIZATION

The primary preventive strategy for pneumonia is immunization with pneumococcal and influenza vaccines, especially for adults older than 65 years of age, young children, and other individuals in high-risk groups (Table 9) [91]. Additional preventive measures include improved hand hygiene compliance and adherence to healthy lifestyle behaviors, including cigarette smoking cessation.

Table 9: HIGH-PRIORITY AND HIGH-RISK GROUPS FOR VACCINATION

Vaccination

Priority Groups

Annual influenza vaccination

Adults 65 years of age and older

Children 6 to 59 months of age

Residents of long-term care facilities

Adults and children with chronic medical conditions

Women who are pregnant during the influenza season

Pneumococcal vaccination

Children younger than 5 years of age

Older children with certain high-risk conditions

Adults 65 years of age and older with no history of pneumococcal vaccination

Adults younger than 65 years of age with at least one of the following:

Chronic disease (e.g., lung, cardiovascular, or liver disease or diabetes)

Compromised immune system

Alcoholism

Cochlear implants

Cerebrospinal fluid leaks

Functional or anatomic asplenia

Resident of nursing home or long-term care facility

Current or recent past history of smoking

Source: [28,91]

Pneumococcal Vaccination

Pneumococcal vaccines have been improved over time by broadening the coverage of serotypes in the vaccine to include those that are causing the most common invasive infections. In the past, a single agent, the 23-valent polysaccharide vaccine (PPSV23) (Pneumovax), had been recommended for use in selected adults with conditions of impaired immunity, and for all adults older than 65 years of age [96]. This vaccine provided some protection against 85% to 90% of the pneumococcal serotypes that cause invasive disease in these populations [97]. In 2021, PCV15 (replacing PCV13) and PCV20 were introduced for adults [240].

The use of pneumococcal conjugate vaccines in the pediatric age group has been followed by a reduction in the incidence of pneumococcal disease among children, and, indirectly, among adults as well. By 2013, the incidence of invasive pneumococcal disease caused by serotypes represented in the PCV13 vaccine had declined in the adult population older than 65 years of age by approximately 50% compared with 2010 [227]. In 2012, upon approval by the FDA, the ACIP recommended the use of PCV13 for adults with immune deficits and other conditions that impose a heightened risk for invasive pneumococcal infection. After reviewing additional data in 2014, the ACIP extended its recommendation for PCV13 use to all adults older than 65 years age [227].

In 2021, the ACIP again amended its recommendation for PCV use in older adults, based on sharp declines in pneumococcal disease among adults since the advent of PCV13 use in children [227]. The ACIP now recommends a routine single dose of PCV20 for adults older than 65 years of age (Table 10). Alternatively, one dose of PCV15 may be administered followed by PPSV23 given at least one year after the PCV15 dose. A minimum interval of eight weeks between PCV15 and PPSV23 can be considered for adults with an immunocompromising condition, cochlear implant, or cerebrospinal fluid (CSF) leak to minimize the risk of invasive pneumococcal disease caused by serotypes unique to PPSV23 in these vulnerable groups [96,227,240].

Table 10: IMMUNIZATION SCHEDULE RECOMMENDED BY THE ACIP

Vaccination

Recommended Recipients

Influenza vaccination (annually)a

Adults and children 6 months of age and older

Pneumococcal vaccination (PCV20 OR PCV13 in series with PPSV23, 12 months apart)b,c

Adults 65 years of age and older

High-risk children and adults (5 to 64 years of age)

Haemophilus influenzaeb(series of 4)

Infants at 2, 4, 6, and 12 to 15 months of age

Pneumococcal conjugate vaccine (series of 4)

Infants at 2, 4, 6, and 12 to 15 months of age

aIn its 2012 immunization schedule for adults, the ACIP notes that the trivalent inactivated vaccine (TIV) may be used for all adults, including pregnant women. Adults older than 65 years of age may receive either standard-dose or high-dose TIV. The live, attenuated influenza vaccine (LAIV) may be used in healthy, nonpregnant adults who are younger than 50 years of age and have no high-risk medical conditions. Healthcare staff who care for severely immunocompromised patients should receive TIV rather than LAIV.

bWhen the decision is made to administer both the 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) to an adult, the vaccines should be given in series, beginning with PCV13. The dose of PPSV23 should be 12 months after a dose of PCV13.

cAs of June 2024, PCV21 is an option for adults aged ≥19 years of age.

Source: [91,92,227,239]

As of June 2024, ACIP recommends PCV21 as an option for adults aged 19 years of age or older who currently have a recommendation to receive a dose of PCV [239]. Current information, schedules, and guidance for adult immunizations is maintained at the CDC/ACIP website at https://www.cdc.gov/vaccines/schedules.

Influenza Vaccination

The influenza vaccine is developed each year to contain the three virus strains that are expected in the upcoming influenza season. The vaccine has traditionally been a trivalent inactivated vaccine (TIV), but in 2003, a trivalent live, attenuated influenza vaccine (LAIV) was introduced in the United States [97]. In 2010, a new high-dose formulation of TIV became available. The LAIV, which contains four times the amount of influenza antigens as other TIVs, is designed to induce a higher immune response in older people [97]. The LAIV is administered as a nasal spray.

The ACIP once recommended a risk-stratified approach to influenza vaccination, but it updated its recommendations to universal vaccination beginning in the 2010–2011 influenza season (Table 10) [91]. Routine annual influenza vaccination is recommended for all persons 6 months of age and older who do not have contraindications. The ACIP provides updated recommendations for the use of licensed and age-appropriate seasonal influenza vaccines in the United States. Current ACIP influenza vaccine recommendations are available at the CDC website [236].

In their guideline for the management of CAP, the IDSA/ATS make the following strong recommendations for prevention based on the ACIP recommendations [47]:

- All persons 50 years of age and older, others at risk for influenza complications, household contacts of high-risk persons, and healthcare workers should receive inactivated influenza vaccine as recommended by the ACIP (level I evidence).

- The intranasally administered LAIV is an alternative vaccine formulation for some persons 5 to 49 years of age without chronic underlying diseases, including immunodeficiency, asthma, or chronic medical conditions (level I evidence).

- Pneumococcal vaccines are recommended for persons 65 years of age and older and for those with selected high-risk concurrent diseases, according to the current ACIP guideline (level II evidence).

The IDSA/ATS recommends that vaccination status be assessed in all patients with CAP at the time of hospital admission, especially in those with underlying medical conditions [47]. If vaccination is needed, it may be done either at hospital discharge or during outpatient treatment.

The PIDS and the IDSA also echo the ACIP recommendations in their guideline [30]:

- Children should be immunized with vaccines for bacterial pathogens, includingS. pneumoniae, H. influenzae type b, and pertussis (strong recommendation, high-quality evidence).

- All infants 6 months of age or older and all children and adolescents should be immunized annually with vaccines for influenza virus (strong recommendation, high-quality evidence).

- Parents and caretakers of infants younger than 6 months of age, including pregnant adolescents, should be immunized with vaccines for influenza virus and pertussis to protect the infants from exposure (strong recommendation, weak-quality evidence).

- High-risk infants should be provided immune prophylaxis with RSV-specific monoclonal antibody to decrease the risk of severe pneumonia and hospitalization caused by RSV (strong recommendation, high-quality evidence).

Vaccine Efficacy

Declining rates of pneumonia and pneumonia-related deaths are thought to represent the effectiveness of influenza and pneumococcal vaccination [40,98,99]. In a study of a community-dwelling older population, influenza vaccination decreased the risk of hospitalization for pneumonia or influenza, as well as the risk of death, across 10 influenza seasons [7]. Systematic reviews and meta-analyses have shown that pneumococcal vaccination reduces the incidence of invasive pneumococcal disease in both older adults and children, although the findings are unclear for adults with chronic illness [100,101]. Other studies of adults have shown that pneumococcal vaccination is associated with benefit in terms of a lower risk of adverse outcomes associated with the disease. For example, in a study of nearly 3,500 older people (median age: 75 years) who were hospitalized for CAP, the rate of mortality or ICU admission was 40% lower among those who had received prior PPSV23 vaccination [8].

Among children, the introduction of the PCV7, PCV13, and later PCV15 has led to a substantial decrease in the rate of invasive pneumococcal disease, but the decrease in the rate of CAP has been less dramatic. Early studies showed substantial improvements in the hospitalization rate for CAP only among young children. In one study, the hospitalization rate decreased 39% for children younger than 2 years of age [98]. In another study, the decrease was substantial only for children younger than 1 year of age (22%) and was minimal for children 1 to 5 years of age; the rate increased for adolescents and children older than 5 years of age [4]. The rate of outpatient CAP visits has not changed significantly for this population [5,10].

Vaccination Rates

Despite the wide distribution of the ACIP immunization schedule and public campaigns about the importance of vaccination, rates of both pneumococcal and influenza vaccination remain relatively low. According to CDC estimates, influenza vaccination coverage for the 2021–2022 season among adults 18 years of age or older was 49.4%, a decrease of 0.8 percentage points from the prior season [102]. Coverage among children 6 months through 17 years of age was 57.8%. Roughly half (51.4%) of all persons 6 months and older were vaccinated during the 2021–2022 season. Influenza vaccination coverage was lower among Hispanic (37.9%) and non-Hispanic Black (42.0%) adults than White (53.9%) adults [102]. Coverage among adults 65 years of age or older (73.9%) was higher compared with younger age groups (37.1% to 52.4%). Among healthcare personnel, influenza vaccine coverage during the 2021–2022 influenza season was 79.9%. When analyzed by setting, vaccine coverage was highest among healthcare personnel in ambulatory care and hospital settings with vaccine requirements (81.2% and 92.0%, respectively), and lowest in medical settings without vaccination requirements or recommendations (48.1%) [103].

The national rate of influenza vaccination among all adults has improved over the past decade, yet racial disparities persist. Comparing rates at five-year intervals from 2005 to 2015, the rate of vaccination more than doubled for adults younger than 65 years of age in all ethnic categories (Table 11) [113]. The rate disparity between white adults (44.2%) and that observed for black (36.7%) and Hispanics (31.2%) remains evident. Previous studies have also shown higher rates of vaccination for white older adults compared with black and Hispanic older adults [104,105,106,107]. Racial disparities have also been found when rates of pneumococcal and influenza vaccination for residents of long-term care facilities were compared, with substantially lower rates for black residents [108,109,110].

Table 11: RATE OF INFLUENZA VACCINATION AMONG ADULTS ACCORDING TO AGE AND RACE/ETHNICITY, FIVE-YEAR INTERVALS, 2005–2015

Age/Ethnicity

Rate

2005

2010

2015

18 to 44 years of age

10.1%

24.6%

30.9%

45 to 64 years of age

20.2%

37.8%

45.1%

65 years of age and older

59.7%

63.9%

69.1%

White

22.5%

36.9%

44.2%

Black

15.5%

28.1%

36.7%

Hispanic

12.0%

26.5%

31.2%

Source: [113]

In 2018, the estimated overall rate of pneumococcal vaccination coverage among adults older than 65 years of age was 69% [237]. The rate was substantially lower (approximately 23%) among younger adults in high-risk groups. Selected data from this report are summarized in Table 12[237].

Table 12: RATE OF PNEUMOCOCCAL VACCINATION AMONG ADULTS 19 YEARS OF AGE AND OLDER, 2018

Race/Ethnicity

High-Risk Adults 19 to 64 Years

Adults 65 Years and Older

All races

23.3%

69.0%

White (non-Hispanic)

23.6%

72.6%

Black (non-Hispanic)

23.6%

59.8%

Hispanic or Latino

18.5%

54.3%

Asian

23.6%

55.0%

Source: [237]

In addition, adherence to recommendations for pneumococcal and influenza vaccination of older adults admitted to the hospital has been low. In a study of nearly 105,000 patients 65 years of age and older who had not received either vaccination before admission to the hospital, 99.4% did not receive the pneumococcal vaccine and 97.3% did not receive the influenza vaccine before hospital discharge [111].

Rates of both pneumococcal and influenza vaccination are higher among children than adults. Overall, approximately 83% of children 19 to 35 months of age have received at least four PCV13 doses [112]. The rate varies according to race/ethnicity, with the lowest rates among Asian and black children (Table 13) [112].

Table 13: RATE OF VACCINATION WITH AT LEAST FOUR PCV DOSES AMONG CHILDREN 19 TO 35 MONTHS OF AGE

Race/Ethnicity

Rate

White (non-Hispanic)

84.1%

Black (non-Hispanic)

74.5%

Hispanic

81.4%

American Indian/Alaska Native

80.1%

Asian

81.0%

Multiracial

83.6%

Total

83.3%

PCV = pneumococcal conjugate vaccine.

Source: [112]

Barriers to Vaccine Use

In its Healthy People 2030 initiative, the U.S. Department of Health and Human Services has set objectives for improving vaccination rates among adults and children [114]. To reach these targets, healthcare providers must address documented barriers to recommended vaccinations and gain a better understanding of other challenges to vaccination. Unequal access to health care appears to account for a low percent of racial disparities [105]. Rather, lack of awareness of the need for vaccination and misconceptions about vaccines have been reported as the primary barriers in several studies [104,105,106,115,116,117].

Among adults, misconceptions about vaccines range from the belief that healthy people do not need vaccinations to a fear of side effects [104,106,116]. Beliefs about vaccines vary by race/ethnicity, age, education, and gender. For example, in a survey of more than 6,700 older adults, lack of awareness that influenza vaccination was needed was more common among Hispanic (33%) and black individuals (25%) than among white individuals (21%) [105]. In contrast, concern about side effects was more common among white individuals (15%) than among black and Hispanic individuals (10% and 6%, respectively) [105]. The belief that vaccination would not prevent illness was consistent across the racial/ethnic groups. In other studies, lower rates of influenza vaccination among older black adults have been significantly associated with lower rates of positive attitudes about vaccination [105,118]. It is unclear whether the negative attitude represents mistrust of the vaccine itself or of healthcare/healthcare providers in general [105]. The findings of one study showed that, compared with white adults, more black and Hispanic adults believed that they had become sick from a previous influenza vaccination [106]. Language proficiency and level of acculturation have been associated with lower vaccination rates among older Hispanic adults [107,119].

Parental attitudes about vaccines are an important factor in vaccination rates among children. The primary attitude is concern about the safety and efficacy of the vaccine, including fear of adverse events, the discomfort associated with vaccination, distrust of advocates of vaccination, and belief that the vaccine should not be given when a child has a minor illness [117,120,121,122]. Difficulty remembering or confusion about the vaccination schedule for children is also a major challenge [120,122]. Changes in access to health care have been noted as a factor in the low rate of influenza vaccination among teenagers [117].

Healthcare provider-related factors should also be addressed. Slightly more than half of older adults have said that their healthcare provider did not recommend influenza vaccination, and this percentage has been consistent across races/ethnicities [105,106]. The lack of provider recommendation may be a misperception or may be a reality. It has been noted that nearly half of providers do not follow the ACIP recommendations for vaccination [116]. Provider recommendation is essential, as it has been found to be the strongest predictor of whether a person will receive vaccination, even among those who have negative attitudes toward vaccines [104,106,115,116,123]. Providers have said that the lack of an effective reminder system is a factor in low vaccination rates [116,123].

Strategies to improve rates of vaccination and other preventive measures rely on effective patient-clinician communication. Among the most important factors for effective communication across all healthcare settings are knowledge of the language preference of the patient and family; an awareness of the patient's and family's health literacy levels; and an understanding of and respect for the patient's and family's cultural values, beliefs, and practices [124,125,126]. These issues are significant, given the growing percentages of racial/ethnic populations. According to U.S. Census Bureau data from 2013, more than 60.3 million Americans speak a language other than English in the home, with more than 25.1 million of them (8.6% of the population) reporting that they speak English less than "very well" [127]. Clinicians should ask their patients what language is spoken at home and what language they prefer for their medical care information, as some patients prefer their native language even though they have said they can understand and discuss medical information in English [128]. When the healthcare professional and the patient speak different languages, a professional interpreter should be used. Studies have demonstrated that the use of professional interpreters rather than "ad hoc" interpreters (e.g., untrained staff members, family members, friends) facilitates a broader understanding, leads to better outcomes, and is better aligned with patient preferences [129,130,131].

Studies have indicated that as many as 26% of Americans have inadequate health literacy, which means they lack the ability to understand health information and make informed health decisions; an additional 20% have marginal health literacy [132,133,134]. Health literacy varies widely according to race/ethnicity, level of education, and gender. Clinicians are often unaware of the literacy level of their patients and family, but several instruments are available to test the health literacy level [126,135]. These instruments vary in the amount of time needed to administer and the reliability in identifying low literacy. Among the most recent tools is the Newest Vital Sign (NVS), an instrument named to promote the assessment of health literacy as part of the overall routine patient evaluation [136]. The NVS takes fewer than three minutes to administer, has correlated well with more extensive literacy tests, and has performed moderately well at identifying limited literacy [126,135]. Two questions have also been found to perform moderately well in identifying patients with inadequate or marginal literacy: "How confident are you in filling out medical forms by yourself?" and "How often do you have someone help you read health information?" [126]. Clinicians should adapt their discussions and educational resources to the patient's and family's identified health literacy level and degree of language proficiency and should also provide culturally appropriate and translated educational materials when possible.

Cultural competency is essential for addressing healthcare disparities among minority groups [124]. Clinicians should ask the patient about his or her cultural beliefs, especially those related to health, and should be sensitive to those beliefs.

Targeted evidence-based strategies can help clinicians improve vaccination rates (Table 14). Education about the importance of vaccination is the cornerstone of most strategies. Messages should be clear and emphasize the benefits of vaccination and the risks of not receiving vaccination. Acknowledging the risks of vaccines can help enhance patient trust [117]. Clinicians should give their patients a list of online resources that provide balanced information on vaccines (Table 15). Differences in beliefs about vaccines across racial/ethnic groups indicate that targeted messages developed for specific demographic subgroups may be useful [219]. In addition, language-specific educational resources may also help increase vaccination rates by enabling patients to better understand the need for vaccination and its safety.

Table 14: BARRIERS TO OPTIMAL VACCINATION AND POSSIBLE SOLUTIONS

Barriers

Solutions

Decreased knowledge about pneumonia and its seriousness

Provide education resources (language-specific, as appropriate) that highlight the potential severity of disease and the consequences of not receiving protection through vaccination.

Belief that vaccines are unsafe or will cause illness

Refer patient (or parent) to objective information about vaccines.

Lack of awareness for the need of vaccination

Take advantage of all visits (well and acute) to remind patients (or parents) about the need for vaccination, to administer vaccination, or to schedule appointment for vaccination.

Lack of provider recommendations

Identify high-risk patients and encourage them to receive vaccination.

Lack of effective practice systems

Implement effective reminder systems and standing orders.

Source: Compiled by Author

Table 15: RESOURCES ABOUT VACCINATIONS FOR PATIENTS AND PARENTS

American Academy of Pediatrics

https://www.aap.org

American Academy of Family Physicians

https://www.aafp.org

U.S. Department of Health and Human Services Vaccines

https://www.vaccines.gov

The History of Vaccines

https://www.historyofvaccines.org

Immunization Action Coalition

http://www.vaccineinformation.org

Centers for Disease Control and Prevention Vaccines for Children (VFC) Program

https://www.cdc.gov/vaccines/programs/vfc

Source: Compiled by Author

Education and provider recommendation are particularly important for people at high-risk for severe health impacts of pneumonia, as the lowest vaccination rates are reported for these patients [102,103]. One survey showed that provider recommendations for pneumococcal and influenza vaccination were low for this population; the rate of recommendation was lowest for people with a weakened immune system and those receiving radiation therapy or chemotherapy (Table 16) [116]. Clinicians should identify high-risk patients in their practice and take special steps to ensure that these patients receive appropriate vaccinations.

Table 16: HEALTHCARE PROVIDER RECOMMENDATIONS FOR INFLUENZA AND PNEUMOCOCCAL VACCINATIONS BY PATIENT TYPE

Patient Type

Influenza Vaccine

Pneumococcal Vaccine

Physicians

PA/NP/RNs

Physicians

PA/NP/RNs

All adults

39%

59%a

—

—

Aged ≥50 years

28%a

15%

4%

18%a

Aged ≥65 years

37%

28%

65%

55%

Chronic lung disease

45%

40%

68%

55%

Diabetes mellitus

31%

25%

44%a

26%

Heart disease

20%

11%

29%a

12%

Chronic liver disease

22%

16%

27%

20%

Chronic kidney disease

22%

12%

25%

17%

Weak immune system

17%

20%

24%

29%

Radiation/chemotherapy

14%

9%

17%

10%

Asplenia

—

—

27%a

8%

Complications or risk from other illness

25%

17%

28%

23%

Smoker

—

—

13%

11%

Close contact with someone at high risk

24%

22%

11%

10%

aSignificantly greater (P <0.05) than other provider group.

NP = nurse practitioner; PA = physician assistant; RN = registered nurse.

Source: Reprinted with permission from Johnson D, Nichol KL, Lipczynski K. Barriers to adult immunization. Am J Med. 2008;121:S28-S35.

Missed opportunities represent another practice-related area in which clinicians can improve vaccination rates. Although many clinicians check immunization status during well visits, most do not check the status during acute visits, nor do they take advantage of the visit to administer the vaccination [105,115]. Healthcare providers can close the gap on missed opportunities for vaccination by taking advantage of every office visit to administer vaccinations, reminding their patients about the need for vaccination, or scheduling a future appointment for vaccination [105,115,117]. Educational fliers and pamphlets in the waiting room and examination rooms can engage patients and parents and help prompt discussions about vaccination [116].

Patient reminder and recall systems in primary care settings have been effective in improving vaccination rates. A meta-analysis found that rates among both children and adults increased up to 20% with several types of reminders, including postcards, letters, and phone calls [137]. The most effective reminder system was phone calls, but it was also the most expensive. Given that about 25% of primary care physicians currently use reminder systems, increasing the number of physicians who use such systems can in turn increase vaccination rates [123]. Standing orders for vaccinations have been shown to substantially increase vaccination rates, yet are used by only 20% to 33% of physicians [123,138]. Again, adopting this system results in improved vaccination rates.

Many people have turned to facilities outside of their primary healthcare provider to receive vaccinations. Health fairs, pharmacies, grocery stores, senior centers, and workplaces have become more common settings for vaccination because of their convenience and lower cost [123,138]. Clinicians can also help increase vaccination rates by participating in community events that provide vaccinations and by promoting these settings as alternative options.

Programs to provide vaccinations to high-risk patients in the emergency room have been successful at increasing vaccination rates [139,140]. In a three-week intervention program at one inner city emergency department, participants were provided appropriate immunizations when they were at high risk for specific diseases [139]. During the study period, rates of influenza and pneumococcal vaccinations increased from 16% to 83% and from 18% to 84%, respectively. Such programs can help healthcare systems adhere to guideline recommendations for vaccinating hospitalized patients.

8. PNEUMONIA ASSOCIATED WITH HEALTHCARE FACILITIES

Pneumonia associated with healthcare facilities encompasses the broad category of cases that arise in persons who reside in, or have had significant recent exposure to, facilities such as hospitals, nursing homes, dialysis clinics, and transfusion centers. Despite advances in clinical care and prevention, this category of pneumonia remains a serious cause of morbidity and mortality and a challenging, costly public health issue. The IDSA and the ATS subdivide and defines this category of pneumonia as follows:

- HAP is hospital-acquired pneumonia that occurs 48 hours or more after admission and did not appear to be incubating at the time of admission.

- VAP is a separate type of HAP that develops more than 48 hours after endotracheal intubation.

- HCAP is defined as pneumonia occurring in a nonhospitalized patient with extensive healthcare contact, evidenced by one or more of the following:

- Intravenous therapy/chemotherapy or wound care within the prior 30 days

- Residence in a nursing home or other long-term care facility

- Discharge from an acute care hospital or chronic care facility within the prior 90 days

- Attendance at a hospital or hemodialysis clinic within the prior 30 days

HAP and VAP have been studied most often, and the bulk of data on causative pathogens comes from studies of VAP. All three categories of pneumonia carry an increased risk for drug-resistant infection, though the risk of multidrug-resistant infection has been more consistently applicable to HAP and VAP [28]. Within the category of HCAP, nursing home-acquired pneumonia is the type with the most published data and will be discussed in this course. The ATS and the IDSA have jointly published evidence-based recommendations, updated in 2016, for the diagnosis and treatment of HAP and VAP [28].

EPIDEMIOLOGY

Approximately 3 to 10 cases of HAP occur per 1,000 hospital admissions [26]. Pneumonia as a complication of hospitalization increases length of stay (by more than one week), increases mortality risk, and adds an additional cost of care that can reach $40,000 per case [26].

The rate of VAP is higher than that for HAP, with a reported rate of 1 to 4 cases per 1,000 ventilator-days, and rates as high as 10 cases per 1,000 in some neonatal and surgical populations [12,28,141]. An estimated 10% of patients requiring mechanical ventilation will develop VAP, and the mortality rate directly attributable to VAP is estimated at 13% [28]. Excess cost of care resulting from prolongation of hospital stay is estimated to range from $30,000 to $40,000 per patient [28]. Pediatric VAP has not been as well studied as in adults. It occurs most commonly in children 2 to 12 months of age [142].

Pneumonia develops in approximately 2.3% of nursing home residents [1]. The mortality rate attributed to nursing home-acquired pneumonia is 10% to 30% [143].

RISK FACTORS

Illness and injury requiring admission to a healthcare facility often confers an increased risk for infection. Multiple factors account for this, including weakness and debility, use of indwelling catheters, compromised immune function, and poor nutrition [26,144]. To these may be added sedating medication intended to promote sleep or permit invasive procedures; this in turn increases the risk for aspiration of nasopharyngeal secretions colonized with nosocomial bacterial pathogens.

The nasopharynx tends to become colonized by enteric gram-negative bacilli within a few days after admission to a hospital. Risk factors for colonization by multidrug-resistant pathogens include exposure to critical care units, prolonged hospital stay, prior antibiotic therapy, history of cigarette smoking, major surgery, multiple organ-system failure, and foreign bodies such as nasogastric and endotracheal tubes [26,144].

Hospital-Acquired Pneumonia

In a systematic review, the American College of Physicians found several patient-related and surgery-related factors that increased the risk of postoperative pulmonary complications. The most common patient-related factors were the presence of COPD and an age older than 60 years [145]. Other significant factors were an American Society of Anesthesiologists (ASA) class of 2 (defined as a patient with mild systemic disease) or higher, functional dependence, and congestive heart failure. Cigarette use was associated with a modest increase in risk, and obesity and mild or moderate asthma were not found to increase risk [145]. Use of a PPI or histamine2 receptor antagonist is also thought to be a risk factor [45]. Surgery-related factors included prolonged duration of surgery (i.e., more than three to four hours), emergency surgery, and surgical site, with abdominal surgery, thoracic surgery, neurosurgery, head and neck surgery, vascular surgery, and aortic aneurysm repair being associated with the greatest risks [145].

Ventilator-Associated Pneumonia

The risk for VAP appears to be greatest during the first week after intubation. In one study, the risk was estimated to be 3% per day during the five-day period following intubation, decreasing to 2% per day for days 5 through 10, and to 1% per day for longer durations [147]. In a population of children who had cardiothoracic surgery, pneumonia risk correlated with mechanical ventilation for longer than three days [144]. Nearly half of all cases of VAP develop within the first four days of mechanical ventilation [148].

Other identified risk factors among adults include prolonged placement of the patient's head in the supine position; use of a nasogastric tube, paralytic agents, or PPI or histamine2 receptor antagonist; advanced age; chronic lung disease; and head trauma [45,149]. Among children, VAP has been significantly associated with subglottic/tracheal stenosis, trauma, and tracheostomy [150]. In one study, VAP was most frequently associated with ICU admission diagnoses of postoperative care, neurologic conditions, sepsis, and cardiac complications [151].

Nursing Home-Acquired Pneumonia

The risk factors reported to be associated with nursing home-acquired pneumonia include profound disability, immobility, urinary incontinence, deteriorating health status, difficulty swallowing, and inability to take oral medications [42]. Older age, male gender, and antipsychotic and anticholinergic medications have also been reported to increase risk [23,42].

ETIOLOGY

Gram-negative enteric bacilli and Pseudomonas spp. rarely colonize the upper respiratory tract of healthy individuals, but often do so in persons with an underlying disease, such as alcohol use disorder, and in those who are hospitalized or reside in nursing homes. Therefore, a history of recent hospitalization or nursing home residency should heighten suspicion for a gram-negative pathogen when such a patient presents with clinical signs of infection.

Most cases of pneumonia that develop in a healthcare facility are caused by aspiration of oropharyngeal or gastric secretions colonized with hospital bacterial flora [26,28]. Consequently, the prevalent causation as well as the antibiotic sensitivity pattern of resident pathogens will vary from region to region in relation to the type of facility and burden of antimicrobial usage. The selection of initial antibiotic therapy in these cases is based on the patient's risk factors for infection with a multidrug-resistant organism, such as MRSA, P. aeruginosa, K. pneumoniae, or Acinetobacter. The ATS/IDSA lists the following risk factors for multidrug-resistant pathogens in patients presenting with HAP or VAP [233,28]:

- Prior intravenous antibiotic use within 90 days

- Septic shock at time of VAP

- ARDS prior to onset of VAP

- High frequency of antibiotic resistance in the community of residence or the hospital unit of residence

- Five or more days of hospitalization prior to onset of pneumonia

- Home infusion therapy

- Chronic dialysis within 30 days

- Family member with multidrug-resistant infection

- Immunosuppression

Viral and fungal pathogens are rare causes of HAP, VAP, and nursing home-acquired pneumonia in immunocompetent adults. Outbreaks of viral pneumonia may occur during influenza season, and influenza, parainfluenza, adenovirus, and RSV are involved in about 70% of those cases [28]. Candida spp. and Aspergillus fumigatus may cause pneumonia in patients who have had organ transplantation or who have a compromised immune system and neutropenia.

Hospital-Acquired Pneumonia

Among adults with no previous antibiotic exposure, the most common bacterial causes of HAP are S. pneumoniae, H. influenzae, Escherichia coli, K. pneumoniae, and S. aureus [26,28,35,148]. Gram-negative bacilli resistant to first-generation cephalosporins also frequently develop in late-onset HAP. For up to 40% of adults with previous antibiotic exposure, late-onset HAP is caused by potentially multidrug-resistant pathogens, including Pseudomonas aeruginosa, Acinetobacter baumannii, and MRSA [26]. In a study of more than 3,600 patients admitted to an ICU, Pseudomonas spp. was the cause of pneumonia in 25% of patients; MRSA in 18%; and Acinetobacter spp. in 6% [35]. Other studies have shown that S. aureus is common among patients who are in a coma or have diabetes or renal failure. P. aeruginosa is common among patients who have had a prolonged stay in the ICU, have received prior antibiotics or corticosteroids, or who have structural lung disease. Legionella is usually found in patients who have compromised immune systems [35].

The causes of HAP in children have not been well studied. However, outbreaks of pneumonia caused by RSV have been common in pediatric wards [28].

Ventilator-Associated Pneumonia

The most common pathogens associated with VAP in adults are S. aureus and P. aeruginosa, followed by Enterobacter spp., A. baumannii, and K. pneumoniae [26,148,152,153]. These bacteria are among those that have become resistant to antibiotics, and the frequency of infection with MRSA is increasing. Almost half of all cases are caused by infection with more than one pathogen [148]. Although bacteria are the primary causative agents, viruses and saprophytic fungi have also been implicated as well [154].

As with HAP, few data are available on the etiology of VAP in children. In one report, P. aeruginosa was the most common cause, accounting for 22% of cases [142].

Nursing Home-Acquired Pneumonia

The bacterial pathogens that cause pneumonia in residents of nursing homes (and other long-term care facilities) differ according to the severity of disease. S. pneumoniae and H. influenzae are the most common causes of mild-to-moderate pneumonia in long-term care facilities [155]. In cases requiring hospitalization, C. pneumoniae, S. aureus, and influenza virus are frequently observed as well. Patients with severe illness commonly are infected with methicillin-sensitive S. aureus or MRSA, gram-negative enteric pathogens, or P. aeruginosa [23,155].

DIAGNOSIS

The difficulty in recognizing HAP, VAP, or nursing home-acquired pneumonia has been well documented [28,147,156]. The clinical signs often resemble other, noninfectious conditions, and the specificity of clinical criteria is low [148]. According to the CDC definition, the diagnosis in adults is made on the basis of clinical signs and results of laboratory testing or imaging and must meet one of two criteria [157].

Criterion 1 is rales or dullness to percussion on physical examination of the chest and at least one of the following:

- New onset of purulent sputum or change in character of sputum

- Organisms cultured from blood

- Isolation of an etiologic agent from a specimen obtained by transtracheal aspirate, bronchial brushing, or biopsy

Criterion 2 is chest radiograph that shows new or progressive infiltrate, consolidation, cavitation, or pleural effusion and at least one of the following:

- New onset of purulent sputum or change in character of sputum

- Organisms cultured from blood

- Isolation of an etiologic agent from a specimen obtained by transtracheal aspirate, bronchial brushing, or biopsy

- Isolation of virus from or detection of viral antigen in respiratory secretions

- Diagnostic single antibody titer immune globulin M or fourfold increase in paired sera immune globulin G for pathogen

- Histopathologic evidence of pneumonia

A set of clinical diagnostic criteria for HCAP includes the presence of a new and persistent (more than 48 hours) infiltrate in addition to one of the following [148]:

- Radiographic evidence of cavitation or necrosis

- Histopathologic evidence of pneumonia

- Positive pleural or blood culture for the same micro-organism as that found in respiratory secretions

Plus two of the following signs:

- Core temperature >38.3°C (100.94°F)

- WBC count >10,000 cells/mm^3

- Purulent tracheal secretions

There are no compelling data to recommend a specific approach to diagnosing HAP and VAP. For patients who are not receiving mechanical ventilation, collection of a sputum specimen should be attempted before antibiotic therapy is begun [35,158]. Specimens for culture can be obtained by bronchoscopy with a protected specimen brush to limit contamination or by bronchoalveolar lavage. The latter method has been found to lead to higher rates of treatment than diagnosis based on the CDC definition, and one study showed that preferential sampling of the right lung (rather than the left) improved the diagnostic accuracy of bronchoalveolar lavage [35,159,160]. However, the invasive procedure has disadvantages, including high cost, need for technical expertise, and the potential for false-negative results [35,159].

The ATS/IDSA guideline recommends collecting specimens from the lower respiratory tract for culture, preferably by noninvasive techniques, and reliance on semiquantitative culture technique [28]. Noninvasive methods to obtain respiratory samples in patients with HAP (non-VAP) include spontaneous expectoration, sputum induction, nasotracheal suctioning (in a patient unable to produce a sample), and endotracheal aspiration in a patient with HAP who subsequently requires mechanical ventilation [28]. A 2012 meta-analysis found no evidence that the use of quantitative cultures of respiratory secretions resulted in decreased mortality, reduced time in ICU and on mechanical ventilation, or higher rates of antibiotic change compared with qualitative cultures in patients with VAP [161]. In addition, there was no difference in mortality whether invasive or noninvasive methods were used to obtain specimens.

TREATMENT

The treatment of HAP and VAP is complicated by two divergent needs: the need for empiric therapy with a broad-spectrum antibiotic, to aid in reducing mortality rates, and the need to avoid the indiscriminate use of antibiotics, to avoid the development of resistance. To address this complex issue, the strategy of de-escalation therapy was developed. With this treatment approach, a broad-spectrum antibiotic targeted to likely pathogens is administered, and the antibiotic regimen is modified after the results of cultures are known [154,162]. This strategy has reduced the mortality rate while achieving an overall objective of a more judicious use of antibiotics [154,163]. In one study, de-escalation led to a significantly lower mortality rate compared with either escalation therapy or therapy that was neither escalated nor de-escalated (17% vs. 43% and 24%, respectively) [151].

The empiric treatment of nosocomial pneumonia in general, requires knowledge of the infection history (hospital flora) of the healthcare facility and of individual patient units [35,148,164]. The selection of an empiric antibiotic regimen for HAP and VAP should be guided by local antibiotic-resistance data. The ATS/IDSA recommend that all hospitals regularly generate and disseminate a local antibiogram, ideally one that is specific to their intensive care population(s), if possible [28].

In managing a case of HAP and VAP, the clinician should review in detail the guidance provided by the ATS/IDSA, and consider consultation with appropriate subspecialty colleagues [28]. Recommendations governing selected issues of initial management emphasize the following principles [28]:

- Obtain sputum samples from the lower respiratory tract for culture before beginning antibiotic therapy. Do not delay initiation of therapy for critically ill patients in order to obtain specimens.

- Begin treatment promptly, selecting an empiric antibiotic regimen that covers S. aureus, P. aeruginosa, and other gram-negative bacilli.

- In selecting coverage for S. aureus, choose an agent active against MRSA (vancomycin or linezolid) for patients with risk factor(s) for antimicrobial resistance, treatment in hospital or units where >10% of isolates are methicillin-resistant, and patients in settings where the prevalence of MRSA is unknown.

- In selecting coverage for P. aeruginosa, one antibiotic active against this pathogen is satisfactory if the patient has no risk factors for antimicrobial resistance and <10% of gram-negative isolates from the patient's unit are resistant to the agent chosen; otherwise, prescribe two antipseudomonal antibiotics from different classes.

- Consider de-escalation of antibiotics after the results of cultures and sensitivities are known and the clinical response is satisfactory.

- After an optimal antibiotic regimen is confirmed, a seven-day course of therapy is recommended, provided the rate of improvement of clinical, radiographic, and laboratory parameter is satisfactory.

- For patients with HAP/VAP, it is suggested to use serum procalcitonin levels plus clinical criteria to guide discontinuation of antibiotic therapy, rather than clinical criteria alone.

Selection of specific antimicrobial therapy is influenced by the timing of onset of clinical signs, as well as the presence or absence of risk factors for infection with multidrug-resistant organisms. For early-onset pneumonia and/or patients with no such risk factors, limited-spectrum antibiotic therapy is recommended (Table 17) [28]. For late-onset pneumonia and/or patients at increased risk for multidrug-resistant organisms, a broad-spectrum antibiotic regimen is recommended.

Table 17: RECOMMENDED ANTIBIOTIC THERAPY FOR HEALTH FACILITY-ASSOCIATED PNEUMONIA ACCORDING TO SITE OF CARE

Site of Care

Recommended Regimen

Nursing home

Antipneumococcal fluoroquinolone or either a high-dose ß-lactam/ß-lactamase inhibitor or a second- or third-generation cephalosporin in combination with azithromycin

Hospital

Antipseudomonal cephalosporin, antipseudomonal carbapenem, or extended-spectrum ß-lactam/ß-lactamase inhibitor and antipseudomonal fluoroquinolone or aminoglycoside and anti-MRSA agent (vancomycin or linezolid)

Intensive care unit

Empiric MRSA and double coverage of Pseudomonas pneumonia

Source: [28]

Ventilator-Associated Pneumonia and Multi-Drug Resistant Pathogens

Evidence Based Practice Recommendation

For healthcare-associated or community-acquired MRSA pneumonia, the IDSA recommends IV vancomycin or linezolid 600 mg PO/IV twice daily, if the strain is susceptible, for 7 to 21 days, depending on the extent of infection.

https://academic.oup.com/cid/article/52/3/e18/306145

Last Accessed: August 29, 2024

Level of Evidence: A-II (Good evidence from one or more 1 well-designed clinical trial, without randomization to support a recommendation for use)

VAP is often caused by MRSA and gram-negative bacilli such as Acinetobacter spp. and Pseudomonas. Vancomycin has been considered the first choice for treatment of MRSA infections [154]. However, the ATS/IDSA guidelines note that linezolid may have advantages over vancomycin for pneumonia caused by MRSA [28]. Linezolid has been compared with vancomycin for the treatment of pneumonia caused by MRSA in many studies, and linezolid has been found to improve survival and to be more cost-effective [147,165,166,167,168]. In a 2008 study, the rate of early microbiologic cure was not significantly higher for linezolid than for vancomycin, although there were trends favoring linezolid in several secondary clinical outcomes, such as clinical cure; duration of ventilation, hospitalization, and stay in ICU; survival time not on a ventilator; and overall survival [169]. The findings led the authors to suggest that the benefit of linezolid may be related to factors other than bacterial clearance.

Role of Inhaled Antibiotic Therapy

For cases of VAP caused by gram-negative bacilli that are susceptible only to aminoglycosides or polymyxins, the ATS/IDSA suggests both inhaled and systemic antibiotics, rather than systemic antibiotics alone [28]. It is also reasonable to consider adjunctive inhaled antibiotic treatment as a last resort for patients who are not responding to intravenous antibiotics alone, whether or not the infecting organism is multi-drug resistant.

According to a meta-analysis, a short fixed-course (7 or 8 days) of antibiotic therapy may be more appropriate than a prolonged course (10 to 15 days) for patients with VAP not caused by nonfermenting gram-negative bacilli [170]. The short course reduced recurrence of pneumonia caused by multiresistant organisms without adversely affecting other outcomes. Among patients with nonfermenting gram-negative bacilli, recurrence was greater after the short course.

Nursing Home-Acquired Pneumonia

The 2019 ATS/IDSA guideline for CAP provides a rationale for choice of antibiotic therapy without specifying distinct protocols for nursing home-acquired pneumonia. The ATS/IDSA recommended abandoning the HCAP categorization for purposes of management decision. Instead, emphasis is placed on local epidemiology and validated risk factors to determine need for empiric MRSA or gram-negative bacillary coverage, followed by de-escalation of treatment if cultures are negative [235]. As indicated, the consistently strong individual risk factors for respiratory infection with MRSA, P. aeruginosa, or other gram-negative bacilli are prior isolation of these organisms, and/or recent hospitalization and exposure to parenteral antibiotics.

Adherence to Guideline-Directed Treatment

Evidence Based Practice Recommendation

For patients with ventilator-associated pneumonia, the American Thoracic Society and the IDSA recommend a seven-day course of antimicrobial therapy rather than a longer duration.

https://www.thoracic.org/statements/resources/tb-opi/hap-vap-guidelines-2016.pdf

Last Accessed: August 29, 2024

Strength of Recommendation/Level of Evidence: Strong recommendation; moderate-quality evidence

The lack of adherence to guideline-directed treatment of pneumonia cases associated with healthcare facilities is evidenced by wide variations in practice. For example, one study showed that more than 100 different antibiotic regimens had been prescribed as initial treatment and that de-escalation therapy was used for only 22% of patients [151]. Adherence rates for pneumonia associated with healthcare facilities have been reported to be lower than rates of adherence to guidelines for treatment of CAP. In one survey, guideline-recommended antibiotics were used 78% of the time for CAP, compared with 9% for HCAP [18]. This lack of adherence was not due to unfamiliarity or disagreement with the guidelines; 71% of the survey respondents said they were aware of the guidelines, and 79% said they agreed with and practiced according to them. In contrast, another survey showed that fewer than half of physicians were familiar with the ATS/IDSA guideline for treatment of nursing home-associated pneumonia [23]. It is reasonable to expect that strategies used to enhance adherence to guidelines in the setting of CAP would also be beneficial in the setting of pneumonia associated with healthcare facilities. Thus, feedback on performance, reminder systems, standardized order sets, and education emphasizing outcomes and cost-effectiveness would be valuable.

PREVENTION

The CDC has published a guideline for the prevention of HAP and VAP, with a focus on strategies to decrease or eliminate modifiable risk factors for pneumonia associated with healthcare facilities [93]. These strategies are related to preoperative and postoperative care and measures to reduce the risk of transmission of etiologic pathogens. In addition, steps to prevent the spread of influenza virus are essential, especially during influenza season.

Hospital-Acquired Pneumonia

The prevention of postoperative pneumonia has long been a part of initiatives to decrease complications among patients undergoing surgery. The Respiratory Risk Index was developed to classify patients as being at low, medium, or high risk for postoperative respiratory failure [26]. The factors in the index include the complexity of the surgery, the ASA status, and comorbidities.

Smoking triples the risk for pulmonary complications after surgery, and smoking cessation for at least eight weeks before surgery, when possible, is recommended for current smokers [26]. The risk for complications in patients with respiratory disease or congestive heart failure can be ameliorated by optimum treatment before surgery (e.g., treatment with steroids for patients with COPD or asthma) [26].

Effective pain management after surgery also helps to decrease the risk of pulmonary complications. For postoperative patients who are not mechanically intubated, the ability to cough and clear secretions is important for preventing pulmonary complications [26]. The use of incentive spirometry and deep breathing exercises are recommended, especially for people at high risk for pulmonary complications, as are frequent coughing and early movement (in bed and/or walking) [26,93,145]. Fair evidence supports the selective (rather than routine) use of a nasogastric tube after abdominal surgery [145].

Ventilator-Associated Pneumonia

Two guidelines were developed to focus specifically on the prevention of VAP; one was jointly developed by the Society for Healthcare Epidemiology of America (SHEA) and IDSA, and the other was jointly developed by the Canadian Critical Care Trials Group and the Canadian Critical Care Society [149,171]. In addition, the CDC guideline addresses the prevention of HAP and VAP [93]. All of these agencies suggest a multicomponent strategy for prevention of pneumonia. Compliance with guidelines, however, has been slow; nursing surveys demonstrate rates of adherence to specific preventive measures ranging from 15% to 50% [12,172]. Education is beneficial, and training sessions are a proven means to enhance knowledge and practice among healthcare professionals caring for intubated patients [173].

The Institute for Healthcare Improvement (IHI) found that implementation of its ventilator bundle, a collection of five prevention strategies drawn from these guidelines, led to a 45% reduction in the incidence of VAP [174]. The bundle includes the following interventions [174]:

- Assessment of readiness to extubate and daily interruptions of sedation

- Elevation of the head of the bed

- Daily oral care with chlorhexidine

- Prophylaxis of peptic ulcer disease

- Prophylaxis of deep venous thrombosis

The IHI how-to guide on preventing VAP provides several practical recommendations, and posting compliance with the ventilator bundle in a prominent place in the ICU can encourage and motivate staff (Table 18) [174].

Table 18: PRACTICAL STEPS IN FOLLOWING GUIDELINES TO PREVENT VENTILATOR-ASSOCIATED PNEUMONIA

Assessment of Readiness to Extubate and Sedative Interruptions

Implement a protocol to lighten sedation daily at an appropriate time to assess for neurologic readiness to extubate. Include precautions to prevent self-extubation, such as monitoring and vigilance, during the trial.

Include a sedative interruption strategy in the overall plan to wean the patient from the ventilator; add the strategy to the weaning protocol, if available.

Assess compliance each day on multidisciplinary rounds.

Consider implementation of a sedation scale, such as the Riker scale, to avoid oversedation.

Elevation of the Head of the Bed

Include the intervention on nursing flow sheets and discuss at multidisciplinary rounds.

Encourage respiratory therapy staff to notify nursing staff if the head of the bed is not elevated or empower respiratory therapy staff to place the bed in this position with the help of nursing staff.

Include the intervention on order sets for initiation and weaning of mechanical ventilation, delivery of tube feedings, and provision of oral care.

Oral Care with Chlorhexidine

Include the intervention as part of the intensive care unit admission order set and ventilator order set. Make application of prophylaxis the default value on the form.

Include intervention as an item for discussion on daily multidisciplinary rounds.

Post compliance with the intervention in a prominent place to encourage change and motivate staff.

Develop a comprehensive oral care process that includes the use of 0.12% chlorhexidine oral rinse.

Schedule chlorhexidine as a medication, which then provides a reminder for nursing staff and triggers the oral care process delivery.

Prophylaxis of Peptic Ulcer Disease

Include intervention as part of the intensive care unit admission order set and ventilation order set. Make application of prophylaxis the default value on the form.

Include intervention as an item for discussion on daily multidisciplinary rounds.

Empower pharmacy staff to review orders for patients in the intensive care unit to ensure that some form of prophylaxis is in place at all times for patients.

Prophylaxis of Deep Venous Thrombosis

Include intervention as part of the intensive care unit admission order set and ventilation order set. Make application of prophylaxis the default value on the form.

Include intervention as an item for discussion on daily multidisciplinary rounds.

Empower pharmacy staff to review orders for patients in the intensive care unit to ensure that some form of prophylaxis is in place at all times for patients.

Source: [174]

Assessment of Readiness to Extubate

Because of the increasing risk of infection as the duration of ventilation increases, the primary goal is to extubate patients as early as possible. Thus, assessment of the readiness for extubation and weaning protocols are key aspects in the preventive approach [28,35]. Daily interruption of sedation until the patient is awake has been shown to significantly decrease the number of days on mechanical ventilation, from 7.3 days to 4.9 days in one study [175]. There are risks to this approach, including the potential for increased pain, anxiety, and desaturation [174]. However, sedation interruption has been further demonstrated to reduce the complications of prolonged mechanical ventilation [176]. The SHEA/IDSA guideline recommends daily assessment of the readiness to wean and the use of weaning protocols [171]. For children, daily assessment of readiness to extubate should be carried out, but sedation interruption is not recommended because of the high risk of unplanned extubation [177].

Elevation of the Head of the Bed

Reducing the risk of aspiration and contamination with gastric secretions also helps to prevent the development of pneumonia. Positioning the head of the bed at an angle of 30 to 45 degrees reduces the risk of aspiration significantly [149,178,179]. In one randomized, controlled trial, there were 18% fewer cases of VAP among intubated patients in the group assigned to the recumbent position (45 degrees) compared with the group assigned to the supine position [179]. In another study, elevation of the head of the bed to 30 degrees was the most effective measure among a group of preventive interventions, resulting in a 52% variance in the rate of VAP [180]. Both the ATS/IDSA and SHEA/IDSA guidelines recommend maintaining the head of the bed at a 30- to 45-degree angle [28,171]. An angle of 30 to 45 degrees is also recommended for infants and children, but a lower angle (15 to 30 degrees) should be used for neonates [177].

Daily Oral Care with Chlorhexidine

Oral care interventions have been suggested by some, in part because of an association between a high level of dental plaque and a high rate of colonization with aerobic pathogens, including S. aureus, gram-negative bacilli, and P. aeruginosa[181]. Research has shown that oral decontamination with chlorhexidine leads to a significant reduction in the colonization of pathogens in the oropharynx. In most studies, the intervention has not had a significant effect on the rate of VAP or associated mortality, but more recent studies have shown a significant decrease in the rate of pneumonia [180,182,183,184,185,186]. Brushing the teeth with chlorhexidine does not seem to add benefit [183]. Regular oral care with an antiseptic solution or chlorhexidine is recommended in the ATS/IDSA and SHEA/IDSA guidelines [28,171].

Prophylaxis of Peptic Ulcer Disease

Prophylaxis of peptic ulcer disease has evolved with some conflicting views. Antacids, histamine2 receptor antagonists, and sucralfate have been traditionally given to patients receiving mechanical ventilation to prevent the formation of stress ulcers. However, reducing the amount of gastric acid can increase the risk of colonization of gram-negative bacilli in the stomach. As a result, the WHO recommends avoiding the use of these agents [187]. The CDC notes that there was insufficient evidence on the use of peptic ulcer prophylaxis and includes no recommendations in this regard in its guideline [93]. The ATS/IDSA guideline states that the risks and benefits of prophylaxis should be weighed carefully [28]. The most recent guideline, developed by SHEA/IDSA, notes that histamine2 receptor antagonists and PPIs should be avoided in patients who are not at high risk for developing a stress ulcer or stress gastritis [171]. However, peptic ulcer prophylaxis is recommended for children, as appropriate for age and health status [177].

Prophylaxis of Deep Venous Thrombosis

There is no clear relation between prophylaxis of deep vein thrombosis and VAP pneumonia, but the American College of Chest Physicians reported a decrease in the rate of VAP when such prophylaxis was implemented as part of a package of interventions and included this measure in its clinical practice guideline [188]. This recommendation also applies to children, as appropriate for age and health status [177].

Other Measures

In addition to the interventions in the ventilator bundle, other measures have been recommended to help prevent VAP. One such measure is selective decontamination of the digestive tract, which involves the use of either topical antiseptic, oral antibiotics, or a brief course of systemic antibiotics [26]. A meta-analysis of 28 studies showed that selective decontamination of the digestive or respiratory tract with use of topical antiseptic or antimicrobial agents helped reduce the frequency of VAP in the ICU [146]. The estimate of efficacy in prevention was 27% for antiseptics and 36% for antibiotics. Neither had an effect on mortality. This intervention is recommended in the SHEA/IDSA guideline [171].

Other preventive measures are targeted primarily to the care and use of ventilator equipment and practices in direct patient care. Meticulous attention to aseptic care of the equipment is necessary, and all reusable components, such as nebulizers, should be disinfected or sterilized. Tubing circuits should be replaced after 48 hours or earlier if there are signs of malfunction or contamination [93]. Changes in the design of the endotracheal tube have also been evaluated; for example, a tube with a suction port above the cuff allows for continuous aspiration of subglottic secretions. Use of this specially designed endotracheal tube has led to significantly lower rates of VAP as well as shorter durations of ventilation and shorter stays in the ICU [189,190]. Among patients who had major cardiac surgery, the greatest benefit was found for patients who received ventilation for more than 48 hours [190]. Although the cost of the tube is higher than traditional tubes, the overall cost savings in preventing VAP more than compensates [189]. In one meta-analysis, subglottic secretion drainage was significantly associated with a decreased incidence of VAP, shorter time on mechanical ventilation, and longer time to the development of pneumonia [191]. The CDC, the ATS/IDSA, and the SHEA/IDSA guidelines recommend subglottic secretion drainage with this tube when possible [28,93,171].

The use of noninvasive ventilation is another measure that has reduced the incidence of VAP [93,192,193,194]. In one study, the incidence decreased from 20% to 8% when noninvasive techniques were used routinely for critically ill patients with acute exacerbation of COPD or severe cardiogenic pulmonary edema [192]. Again, the CDC, the ATS/IDSA, and the SHEA/IDSA guidelines recommend the use of noninvasive ventilation when possible [28,93,171].

Quality Improvement Initiatives and Enhanced Infection Control Strategies

Quality improvement and infection control initiatives and strategies have led to a substantial decrease in the rates of VAP since the early 2000s [195]. The use of physician-led multidisciplinary rounds with team decision-making, checklists, and a focus on the ventilator bundle has led to significant reductions in the risk for pneumonia [196,197,198]. Strong downward trends were also found for the average length of stay in the ICU and the financial costs per patient [196].

Nursing Home-Acquired Pneumonia

As with HAP, strategies to decrease or eliminate modifiable risk factors for nursing home-acquired pneumonia should be implemented. A multidisciplinary panel made three recommendations for prevention of pneumonia among nursing home residents [199]:

- Pneumococcal vaccination of patients at admission, if indicated

- Annual influenza vaccination for residents

- Annual influenza vaccination for nursing facility staff

Influenza Outbreaks

The vaccination status of healthcare workers has been found to have a direct effect on transmission of influenza virus to patients. Outbreaks of influenza in healthcare settings have been associated with low rates of vaccination among healthcare workers, and lower rates of nosocomial influenza have been related to higher vaccination rates among healthcare workers [200,201]. Because of these findings, the ACIP recommends annual influenza vaccination for all healthcare workers, and the IDSA/ATS guideline endorses this recommendation [47]. The ACIP notes that the TIV is preferred over LAIV for workers who are in close contact with severely immunosuppressed people requiring protective isolation [112]. In addition, the Joint Commission began including vaccination programs in its accreditation standards in 2007 [123].

Despite these recommendations, only 29% to 69% of healthcare workers receive the influenza vaccination each year [202,203,204]. Healthcare workers have given many reasons for not being vaccinated, and the reasons vary among professions. Across all categories, shortage of the vaccine is the primary reason for not being vaccinated; other reasons include concern about side effects, inconvenience, and forgetfulness [204].

Efforts to increase the vaccination rate among healthcare workers are ongoing. A CDC guideline includes four level I recommendations to help increase rates of vaccination [205]:

- Offer influenza vaccine annually to all eligible healthcare workers.

- Provide influenza vaccination to healthcare workers at the work site and at no cost as one component of employee health programs. Use strategies that have been demonstrated to increase influenza vaccine acceptance, including vaccination clinics, mobile carts, vaccination access during all work shifts, and modeling and support by institutional leaders.

- Monitor influenza vaccination coverage and declination of healthcare workers at regular intervals during influenza season and provide feedback of ward-, unit-, and specialty-specific rates to staff and administration.

- Educate healthcare workers about the benefits of influenza vaccination and the potential health consequences of influenza illness for themselves and their patients, the epidemiology and modes of transmission, diagnosis, treatment, and non-vaccine infection control strategies, in accordance with their level of responsibility in preventing healthcare-associated influenza.

Hand Hygiene

Hand hygiene is the most important preventive measure in hospitals, and the Joint Commission mandates that hospitals and other healthcare facilities comply with the Level I recommendations in the CDC guideline for hand hygiene [206]. The CDC guideline states the specific indications for washing hands, the recommended hand hygiene techniques, and recommendations about fingernails and the use of gloves [207]. The guideline also provides recommendations for surgical hand antisepsis, selection of hand-hygiene agents, skin care, educational and motivational programs for healthcare workers, and administrative measures.

Despite the simplicity of the intervention, its substantial impact, and wide dissemination of the guideline, compliance with recommended hand hygiene has ranged from 16% to 81%, with an average of 30% to 50% [207,208,209,210,211,212]. Among the reasons given for the lack of compliance are inconvenience, understaffing, and damage to skin [207,210,213]. The development of effective alcohol-based handrub solutions addresses these concerns, and studies have demonstrated that these solutions have increased compliance [211,214,215]. The CDC guideline recommends the use of such solutions on the basis of several advantages, including [207]:

- Better efficacy against both gram-negative and gram-positive bacteria, mycobacteria, fungi, and viruses than either soap and water or antimicrobial soaps (such as chlorhexidine)

- More rapid disinfection than other hand-hygiene techniques

- Less damaging to skin

- Time savings (18 minutes compared with 56 minutes per eight-hour shift)

The guideline suggests that healthcare facilities promote compliance by making the handrub solution available in dispensers in convenient locations (such as the entrance to patients' room or at the bedside) and provide individual pocket-sized containers [207]. The handrub solution may be used in all clinical situations except for when hands are visibly dirty or are contaminated with blood or body fluids. In such instances, soap (either antimicrobial or nonantimicrobial) and water must be used.

However, there are many other reasons for lack of adherence to appropriate hand hygiene, including denial about risks, forgetfulness, and belief that gloves provide sufficient protection [207,210,213]. These reasons demand education for healthcare professionals to emphasize the importance of hand hygiene. Also necessary is research to determine which interventions are most likely to improve hand-hygiene practices, as no studies have demonstrated the superiority of any intervention [216]. Single interventions are unlikely to be effective.

ILLUSTRATIVE CASE

A man, 73 years of age, with a history of coronary disease, COPD, benign prostatic hyperplasia, and type 2 diabetes is hospitalized on transfer from an assisted-living facility because of weakness, loss of appetite, and low-grade fever. He had been admitted elsewhere for similar symptoms six months earlier and was diagnosed with urinary tract infection and treated with an unknown antibiotic. On evaluation, the patient's temperature is 37.6°C (99.8°F) and his other vital signs are stable; his exam is unremarkable. The WBC is normal, and the urinalysis shows pyuria. The admission chest x-ray shows hyperlucent lung fields and flattened diaphragms indicative of emphysema, but no infiltrate. Empiric treatment with a first-generation cephalosporin is begun for presumed urinary tract infection. The patient has no further fever, and his appetite and strength improve over the next 48 hours. He does have periods of mild agitation and insomnia, which are treated with a benzodiazepine at bedtime.

On the fourth day, as plans for discharge were in place, the patient appears worse, with a cough and a temperature of 38°C (100.4°F). A repeat chest x-ray shows a small focal opacity in the left upper lobe, thought to represent "aspiration." No change in antibiotics is made, and he is observed. Over the next 36 hours, the patient's condition worsens; he now has a cough productive of purulent sputum, fever (102°F to 103°F), shortness of breath, and tachypnea. A follow-up chest x-ray now shows an extensive opacification/infiltrate in the left upper lobe, with signs suggestive of either central cavitation or consolidation high-lighting emphysematous blebs.

In this elderly, somewhat debilitated man with chronic lung disease, who may be at risk of aspiration, a rapidly progressive, necrotizing (hospital-acquired) pneumonia developed while he was being treated with an oral cephalosporin for urinary tract infection, and receiving a nightly sedative medication for sleep.

What are the etiologic considerations and how should the patient be managed? Within days of admission to a hospital, and especially if treated with antibiotics, many patients develop nasopharyngeal colonization by hospital flora (e.g. gram-negative bacilli and occasionally S. aureus). When pneumonia supervenes, it reflects this colonization; moreover, prior antibiotic therapy tends to select out resistant pathogens. Therefore, the selection of empiric antibiotic treatment for this patient is based on the presumption of hospital-acquired bacterial infection in the lung caused by one or more pathogens resistant to first-generation cephalosporins. Cultures of blood and sputum should be obtained; gram stain of the sputum is often helpful in cases such as this, as it may demonstrate a predominate pathogen and whether it is gram-positive or gram-negative. Empiric antibiotic therapy, following ATS/IDSA recommendations for HAP, should be started promptly. A good choice would be an extended-spectrum ß-lactam/ß-lactamase inhibitor or a carbapenem (e.g., piperacillin/tazobactam or imipenem) combined with a fluoroquinolone and vancomycin, pending culture results.

Gram stain of the patient's sputum shows many polys and gram-negative bacilli; the culture is positive for K. pneumoniae and P. aeruginosa. His management, including empiric antibiotic therapy followed by de-escalation (of vancomycin) after culture data are available, conforms to ATS/IDSA recommendations. The patient is treated for 10 days and recovers following a brief period in the ICU.

This case illustrates that the pathogenesis of adult bacterial HAP is essentially the same as for CAP; namely, nasopharyngeal and upper respiratory colonization by virulent bacteria combined with aspiration of infected secretions during a period of impaired host pulmonary defenses. The difference lies in the burden of vulnerability imposed by hospitalization, including the propensity for colonization by gram-negative bacilli and the likelihood of antimicrobial resistance—so uncommon in healthy individuals outside of healthcare facilities, but so prevalent among patients hospitalized longer than 48 hours.

9. SUMMARY

Pneumonia-related mortality and morbidity have decreased since the late 1990s, but the disease still represents a substantial healthcare concern, especially for high-risk adults and children. Pneumonia is primarily classified according to the setting in which it develops, and the epidemiology, etiology, and risk factors vary according to setting. Diagnosis can be challenging because of differences in presentation and the lack of reliable, cost-effective, and rapidly available diagnostic testing methods. Specialty society guidelines for prevention, diagnosis, and treatment are available for CAP, HAP, and VAP. Guideline-directed treatment has been shown to improve the care of patients while promoting good antibiotic stewardship, minimizing exposure to inappropriate antibiotic treatment and reducing the emergence of antibiotic-resistant pathogens.

For CAP and nursing home-acquired pneumonia, determining the site of care is an important initial decision point. Guidelines from the IDSA/ATS, the PIDS/IDSA, and the ATS outline useful criteria for determining need for hospitalization and ICU care. These objective criteria are important factors in decision-making, but clinical judgment is also necessary for selecting the most appropriate site of care. Initial antibiotic treatment of all types of pneumonia is empirical. The selection is best made in relation to the most likely pathogens in a given clinical setting and to patient variables, such as comorbidities, recent exposure to antibiotics, and immunization status (for children). The timeliness of antibiotic treatment is also important; treatment should begin as soon as possible after diagnosis is made, administering the first dose promptly at the originating site of care.

Guideline-directed therapy of pneumonia has been shown to decrease morbidity and mortality, but adherence varies across settings and specialties and has been suboptimal. Physician practices and healthcare systems can improve adherence by implementing evidence-based strategies, such as standardized order sets, reminders, performance feedback, and easy-to-carry resources.

The incidence of pneumonia and its associated morbidity and mortality can be reduced further by adherence to effective preventive measures. Several guidelines are available for preventing specific types of pneumonia. The primary preventive strategy for CAP is immunization with influenza and pneumococcal vaccines, especially for individuals at high risk. These vaccinations have been shown to decrease the incidence and severity of pneumococcal pneumonia, as well as the risk of long-term morbidity and mortality. However, rates of vaccination vary across age, race/ethnicity, and risk. Two target populations with the lowest immunization rates are high-risk adults in need of pneumococcal vaccination and teenagers in need of influenza vaccination. Rates of vaccination among healthcare professionals are also low. Clinicians and healthcare systems should encourage vaccination and offer convenient access, especially during influenza season.

Lack of awareness about the need for vaccination, misconceptions about vaccines, and low level of knowledge about pneumonia have been reported to be the primary barriers to vaccination, especially among minority populations. Clinicians should promote practice strategies and public health efforts designed to target these barriers and address the populations in greatest need. Several strategies have been shown to increase vaccination rates, and education is the cornerstone. Clinicians should emphasize to patients the need and benefit of immunization, address concerns about the safety of vaccines, and incorporate routine immunization protocols into their practices. Provider recommendation is essential, as it is the strongest predictor of vaccination. System-related strategies such as automatic reminders and standing orders have also been effective.

Guidelines for prevention of HAP focus on measures to reduce pulmonary complications after surgery. Prevention of VAP relies on strategies to reduce the risk of transmission of etiologic agents. Use of a ventilator "bundle" (a set of interventions) has been shown to markedly reduce VAP. Although adherence to guidelines is suboptimal, healthcare facilities are increasingly implementing initiatives to help enhance adherence.

Works Cited

1. Hippocrates. On Regimen in Acute Disease. Available at http://classics.mit.edu/Hippocrates/acutedis.html. Last accessed August 21, 2024.

2. Centers for Disease Control and Prevention. Pneumonia. Available at https://www.cdc.gov/nchs/fastats/pneumonia.htm. Last accessed August 21, 2024.

3. Shorr A, Owens RC. Guidelines and quality for community-acquired pneumonia: measures from the Joint Commission and the Centers for Medicare and Medicaid Services. Am J Health Syst Pharm. 2009;66(12 Suppl 4):S2-S7.

4. Haessler S, Schimmel JS. Managing community-acquired pneumonia during flu season. Cleve Clin J Med. 2012;79(1):67-78.

5. Lee G, Lorch SA, Sheffler-Collins S, Kronman MP, Shah SS. National hospitalization trends for pediatric pneumonia and associated complications. Pediatrics. 2010;126(2):204-213.

6. National Center for Health Statistics. Health, United States, 2014. Hyattsville, MD: National Center for Health Statistics; 2015.

7. Nichol K, Nordin JD, Nelson DB, Mullooly JP, Hak E. Effectiveness of influenza vaccine in the community-dwelling elderly. N Engl J Med. 2007;357(14):1373-1381.

8. Johnstone J, Marrie TJ, Eurich DT, Majumdar SR. Effect of pneumococcal vaccination in hospitalized adults with community-acquired pneumonia. Arch Intern Med. 2007;167(18):1938-1943.

9. Johnstone J, Majumdar SR, Fox JD, Marrie TJ. Viral infection in adults hospitalized with community-acquired pneumonia: prevalence, pathogens, and presentation. Chest. 2008;134(6):1141-1148.

10. Grijalva C, Poehling KA, Nuorti JP, et al. National impact of universal childhood immunization with pneumococcal conjugate vaccine on outpatient medical care visits in the United States. Pediatrics. 2006;118(3):865-873.

11. O'Leary ST, Crane LA, Wortley P, et al. Adherence to expanded influenza immunization recommendations among primary care providers. J Pediatr. 2012;160(3):480-486.

12. Pogorzelska M, Stone PW, Furuya EY, et al. Impact of the ventilator bundle on ventilator-associated pneumonia in intensive care unit. Int J Qual Health Care. 2011;23(5):538-544.

13. Cason C, Tyner T, Saunders S, Broome L. Nurses' implementation of guidelines for ventilator-associated pneumonia from the Centers for Disease Control and Prevention. Am J Crit Care. 2007;16(1):28-37.

14. Wise PC, Finkelstein JA, Ray GT, et al. Aging population and future burden of pneumococcal pneumonia in the United States. J Infect Dis. 2012;205:1589-1592.

15. Arnold F, LaJoie S, Brock GN, et al. Improving outcomes in elderly patients with community-acquired pneumonia by adhering to national guidelines: Community-Acquired Pneumonia Organization International Cohort study results. Arch Intern Med. 2009;169(16):1515-1524.

16. Frei C, Attridge RT, Mortensen EM, et al. Guideline-concordant antibiotic use and survival among patients with community-acquired pneumonia admitted to the intensive care unit. Clin Ther. 2010;32(2):293-299.

17. McCabe C, Kirchner C, Zhang H, Daley J, Fisman DN. Guideline-concordant therapy and reduced mortality and length of stay in adults with community-acquired pneumonia. Arch Intern Med. 2009;169(16):1525-1531.

18. Seymann G, Di Francesco L, Sharpe B, et al. The HCAP gap: differences between self-reported practice patterns and published guidelines for health care-associated pneumonia. Clin Infect Dis. 2009;49(12):1868-1874.

19. Youdelman M, Perkins J. Providing Language Interpretation Services in Health Care Settings: Examples from the Field. Available at https://www.commonwealthfund.org/publications/fund-reports/2002/may/providing-language-interpretation-services-health-care-settings?redirect_source=/publications/fund-reports/2002/may/providing-language-interpretation-services-in-health-care-settings--examples-from-the-field. Last accessed August 26, 2024.

20. Wu J, Howard DH, McGowan JE Jr, Turpin RS, Henry Hu X. Adherence to Infectious Diseases Society of America guidelines for empiric therapy for patients with community-acquired pneumonia in a commercially insured cohort. Clin Ther. 2006;28(9):1451-1461.

21. Dellit T, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44(2):159-177.

22. Menéndez R, Torres A, Zalacaín R, et al. Guidelines for the treatment of community-acquired pneumonia: predictors of adherence and outcome. Am J Respir Crit Care Med. 2005;172(6):757-762.

23. El-Solh A, Alhajhusain A, Saliba RG, Drinka P. Physicians' attitudes toward guidelines for the treatment of hospitalized nursing home-acquired pneumonia. J Am Med Dir Assoc. 2011;12(4):270-276.

24. Templeton K, Scheltinga SA, van den Eeden WCJFM, Graffelman AW, van den Broek PJ, Claas ECJ. Improved diagnosis of the etiology of community-acquired pneumonia with real-time polymerase chain reaction. Clin Infect Dis. 2005;41(3):345-351.

25. Davis B, Aiello AE, Dawid S, Rohani P, Shrestha S, Foxman B. Influenza and community-acquired pneumonia interactions: the impact of order and time of infection on population patterns. Am J Epidemiol. 2012;175(5):363-367.

26. Kieninger A, Lipsett PA. Hospital-acquired pneumonia: pathophysiology, diagnosis, and treatment. Surg Clin N Am. 2009;89(2): 439-461.

27. Anand N, Kollef MH. The alphabet soup of pneumonia: CAP, HAP, HCAP, NHAP, and VAP. Semin Respir Crit Care Med. 2009;30(1):3-9.

28. American Thoracic Society, Infectious Diseases Society of America. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63:1-61.

29. Catia C, Santiago E, Eva P, et al. Microbial aetiology of community-acquired pneumonia and its relation to severity. Thorax. 2011;66:340-346.

30. Bradley J, Byington CL, Shah SS, et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011;53(7):e25-e76.

31. Falsey A, Walsh EE. Viral pneumonia in older adults. Clin Infect Dis. 2006;42(4):518-524.

32. Ruuskanen O, Lahti E, Jennings LC, Murdoch DR. Viral pneumonia. Lancet. 2011;377(9773):1264-1275.

33. Johansson N, Kalin M, Tiveljung-Lindell A, Giske CG, Hedlund J. Etiology of community-acquired pneumonia: increased microbiological yield with new diagnostic methods. Clin Infect Dis. 2010;50(2):202-209.

34. Jennings L, Anderson TP, Beynon KA, et al. Incidence and characteristics of viral community-acquired pneumonia in adults. Thorax. 2008;63(1):42-48.

35. Flanders S, Collard HR, Saint S. Nosocomial pneumonia: state of the science. Am J Infect Control. 2006;34(2):84-93.

36. Niederman M, Mandell LA, Anzueto A, et al. Guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med. 2001;163(7):1730-1754.

37. File TMJ. The science of selecting antimicrobials for community-acquired pneumonia (CAP). J Manag Care Pharm. 2009;15(2 Suppl):S5-S11.

38. Weycker D, Strutton D, Edesberg J, Sato R, Jackson LA. Clinical and economic burden of pneumococcal disease in older U.S. adults. Vaccine. 2010;28(31):4955-4960.

39. Jackson M, Neuzil KM, Thompson WW, et al. The burden of community-acquired pneumonia in seniors: results of a population-based study. Clin Infect Dis. 2004;39(11):1642-1650.

40. Ruhnke G, Coca-Perrallion M, Kitch BT, Cutler DM. Marked improvement in 30-day mortality among elderly inpatients and outpatients with community-acquired pneumonia. Am J Med. 2011;124(2):171-178.

41. Farr B, Bartlett CL, Wadsworth J, Miller DL. Risk factors for community-acquired pneumonia diagnosed upon hospital admission. Respir Med. 2000;94(10):954-963.

42. Marrie T. Community-acquired pneumonia in the elderly. Clin Infect Dis. 2000;31(4):1066-1078.

43. Müllerova H, Chigbo C, Hagan GW, et al. The natural history of community-acquired pneumonia in COPD patients: a population database analysis. Respir Med. 2012;106(8):1124-1133.

44. Sethi S, Maloney J, Grove L, Wrona C, Berenson CS. Airway inflammation and bronchial bacterial colonization in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;173:991-998.

45. Eom CS, Jeon CY, Lim J-W, Cho E-G, Park SM, Lee K-S. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis. CMAJ. 2011;183(3):310-319.

46. Jinno S, Jacobs MR. Pneumonia due to drug-resistant Streptococcus pneumoniae. Curr Infect Dis Rep. 2012;14(3):292-299.

47. Mandell L, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44:S27-S72.

48. Thiem U, Heppner HJ, Pientka L. Elderly patients with community-acquired pneumonia: optimal treatment strategies. Drugs Aging. 2011;28(7):519-537.

49. Moran G, Krishnadasan A, Gorwitz RJ, et al. Prevalence of methicillin-resistant Staphylococcus aureus as an etiology of community-acquired pneumonia. Clin Infect Dis. 2012;54(8):1126-1133.

50. File TM. Community-acquired pneumonia. Lancet. 2003;362(9400):1991-2001.

51. Metersky M, Sweeney TA, Getzow MB, Siddiqui F, Nsa W, Bratzler DW. Antibiotic timing and diagnostic uncertainty in Medicare patients with pneumonia: is it reasonable to expect all patients to receive antibiotics within 4 hours? Chest. 2006;130(1):16-21.

52. Fee C, Weber EJ. Identification of 90% of patients ultimately diagnosed with community-acquired pneumonia within four hours of emergency department arrival may not be feasible. Ann Emerg Med. 2007;49(5):553-559.

53. McGee SR (ed). Evidence-Based Physical Diagnosis. 3rd ed. Philadelphia, PA: Elsevier Inc.; 2012.

54. Heckerling P, Tape TG, Wigton RS, et al. Clinical prediction rule for pulmonary infiltrates. Ann Intern Med. 1990;113(9):664-670.

55. Campbell S, Marrie TJ, Anstey R, Ackroyd-Stolarz S, Dickinson G. Utility of blood cultures in the management of adults with community acquired pneumonia discharged from the emergency department. Emerg Med J. 2003;20(6):521-523.

56. Afshar N, Tabas J, Afshar K, Silbergleit R. Blood cultures for community-acquired pneumonia: are they worthy of two quality measures? A systematic review. J Hosp Med. 2009;4(2):112-123.

57. Nazarian D, Eddy OL, Lukens TW, et al. Clinical policy: critical issues in the management of adult patients presenting to the emergency department with community-acquired pneumonia. Ann Emerg Med. 2009;54(5):704-731.

58. Christ-Crain M, Opal SM. Clinical review: The role of biomarkers in the diagnosis and management of community-acquired pneumonia. Crit Care. 2010;14(1):203.

59. Berg P, Lindhardt BØ. The role of procalcitonin in adult patients with community-acquired pneumonia: a systematic review. Dan Med J. 2012;59(3):A4357.

60. Ostapchuk M, Roberts DM, Haddy R. Community-acquired pneumonia in infants and children. Am Fam Physician. 2004;70(5): 899-908.

61. Ebell M. Point-of-care guides: clinical diagnosis of pneumonia in children. Am Fam Physician. 2010;82(2):192-193.

62. Lynch T, Platt R, Gouin S, Larson C, Patenaude Y. Can we predict which children with clinically suspected pneumonia will have the presence of focal infiltrates on chest radiographs? Pediatrics. 2004;113(3 pt 1):e186-e189.

63. Cevey-Macherel M, Galetto-Lacour A, Gervaix A, et al. Etiology of community-acquired pneumonia in hospitalized children based on WHO clinical guidelines. Eur J Pediatr. 2009;168(12):1429-1436.

64. Mandell LA, Bartlett JG, Dowell SF, et al. Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Infect Dis. 2003;37(11):1405-1433.

65. Forgie S, Marrie TJ. Healthcare-associated atypical pneumonia. Semin Respir Crit Care Med. 2009;30(1):67-85.

66. Centers for Disease Control and Prevention. Mycoplasma pneumoniae Infection. Available at https://www.cdc.gov/mycoplasma/about/index.html. Last accessed August 26, 2024.

67. Chang C, Cheng AC, Chang AB. Over-the-counter (OTC) medications to reduce cough as an adjunct to antibiotics for acute pneumonia in children and adults. Cochrane Database Syst Rev. 2014;3:CD006088.

68. Niederman M. Making sense of scoring systems in community acquired pneumonia. Respirology. 2009;14(3):327-335.

69. Fine M, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336(4):243-250.

70. Lim W, van der Eerden MM, Laing R, et al. Defining community-acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 2003;58(5):377-382.

71. Chalmers J, Singanayagam A, Akram AR, et al. Severity assessment tools for predicting mortality in hospitalised patients with community-acquired pneumonia: systematic review and meta-analysis. Thorax. 2010;65(10):878-883.

72. Loke Y, Kwok CS, Niruban A, Myint PK. Value of severity scales in predicting mortality from community-acquired pneumonia: systematic review and meta-analysis. Thorax. 2010;65:884-890.

73. Charles P, Wolfe R, Whitby M, et al. SMART-COP: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia. Clin Infect Dis. 2008;47(3):375-384.

74. Yandiola P, Capelastegui A, Quintana J, et al. Prospective comparison of severity scores for predicting clinically relevant outcomes for patients hospitalized with community-acquired pneumonia. Chest. 2009;135(6):1572-1579.

75. España P, Capelastegui A, Quintana, JM, et al. Validation and comparison of SCAP as a predictive score for identifying low-risk patients in community-acquired pneumonia. J Infect. 2010;60(2):106-113.

76. File TMJ, Marrie TJ. Burden of community-acquired pneumonia in North American adults. Postgrad Med. 2010;122(2):130-141.

77. Kontou P, Kuti JL, Nicolau DP. Validation of the Infectious Diseases of America/American Thoracic Society criteria to predict severe community-acquired pneumonia caused by Streptococcus pneumoniae. Am J Emerg Med. 2009;27(8):968-974.

78. Chalmers J, Taylor JK, Mandal P, et al. Validation of the Infectious Diseases Society of America/American Thoracic Society minor criteria for intensive care unit admission in community-acquired pneumonia patients without major criteria or contraindications to intensive care unit care. Clin Infect Dis. 2011;53(6):503-511.

79. Kanwar M, Brar N, Khatib R, Fakih MG. Misdiagnosis of community-acquired pneumonia and inappropriate utilization of antibiotics. Chest. 2007;131:1865-1869.

80. Nicks B, Manthey DE, Fitch MT. The Centers for Medicare and Medicaid Services (CMS) community-acquired pneumonia core measures lead to unnecessary antibiotic administration by emergency physicians. Acad Emerg Med. 2009;16(2):184-187.

81. Yu K, Wyer PC. Evidence behind the 4-hour rule for initiation of antibiotic therapy in community-acquired pneumonia. Ann Emerg Med. 2008;51(5):651-652.

82. Quattromani E, Powell ES, Khare RK, et al. Hospital-reported data on the pneumonia quality measure "time to first antibiotic dose" is not associated with inpatient mortality: results of a nationwide cross-sectional analysis. Acad Emerg Med. 2011;18(5):496-503.

83. Asadi L, Eurich DT, Gamble JM, Minhas-Sandhu JK, Marrie TJ, Majumdar SR. Guideline adherence and macrolides reduced mortality in outpatients with pneumonia. Respir Med. 2012;106(3):451-458.

84. Neuman M, Ting SA, Meydani A, Mansbach JM, Camargo CA Jr. National study of antibiotic use in emergency department visits for pneumonia, 1993 through 2008. Acad Emerg Med. 2012;19(5):562-568.

85. Simpson S, Marrie TJ, Majumdar SR. Do guidelines guide pneumonia practice? A systematic review of interventions and barriers to best practice in the management of community-acquired pneumonia. Respir Care Clin North Am. 2005;11(1):1-13.

86. Schouten JA, Hulscher ME, Trap-Liefers J, et al. Tailored interventions to improve antibiotic use for lower respiratory tract infections in hospitals: a cluster-randomized, controlled trial. Clin Infect Dis. 2007;44(7):931-941.

87. Weiner S, Brown SF, Goetz JD, Webber CA. Weekly e-mail reminders influence emergency physician behavior: a case study using the Joint Commission and Centers for Medicare and Medicaid Services Pneumonia Guidelines. Acad Emerg Med. 2009;16(7):626-631.

88. Fleming NS, Ogola G, Ballard DJ. Implementing a standardized order set for community-acquired pneumonia: impact on mortality and cost. Jt Comm J Qual Patient Saf. 2009;35(8):414-421.

89. Haider B, Lassi ZS, Ahmed A, Bhutta ZA. Zinc supplementation as an adjunct to antibiotics in the treatment of pneumonia in children 2 to 59 months of age. Cochrane Database Syst Rev. 2011;10:CD007368.

90. Aliberti S, Di Pasquale M, Zanaboni AM, et al. Stratifying risk factors for multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia. Clin Infect Dis. 2012;54(4):470-478.

91. Kroger AT, Sumaya CV, Pickering LK, Atkinson WL. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2011;60(RR2);1-60.

92. Centers for Disease Control and Prevention. Recommended adult immunization schedule—United States, 2012. MMWR. 2012;61(4):1-7.

93. Tablan O, Anderson LJ, Besser R, Bridges C, Hajjeh R. Guidelines for preventing health-care-associated pneumonia, 2003: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR. 2004;53(RR3):1-36.

94. Infectious Disease Society of America. COVID-19 Resource Center. Available at https://www.idsociety.org/covid-19-real-time-learning-network/infection-prevention/battling-health-care-associated-infections-in-the-covid-19-era-compendium-best-practices/#/+/0/publishedDate_na_dt/desc/. Last accessed August 26, 2024.

95. Edmond K, Scott S, Korczak V, et al. Long term sequelae from childhood pneumonia: systematic review and meta-analysis. PLoS One. 2012;7(2):e31239.

96. Murthy N, Wodi AP, Bernstein H, McNally V, Cineas S, Ault K. Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years or older—United States, 2022. MMWR. 2022;71(7):229-233.

97. Immunization Action Coalition. Pneumococcal: PCV. Available at https://www.immunize.org/vaccines/a-z/pneumococcal/. Last accessed August 26, 2024.

98. Grijalva C, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, Griffin MR. Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis. Lancet. 2007;369(9568):1179-1186.

99. Klugman K, Chien YW, Madhi SA. Pneumococcal pneumonia and influenza: a deadly combination. Vaccine. 2009;27(Suppl 3): C9-C14.

100. Holden J, Tatham DP, Andrews RM. Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst Rev. 2013;1:CD000422.

101. Lucero M, Dulalia VE, Nillos LT, et al. Pneumococcal conjugate vaccines for preventing vaccine-type invasive pneumococcal disease and x-ray defined pneumonia in children less than two years of age. Cochrane Database Syst Rev. 2009;7(4):CD004977.

102. Centers for Disease Control and Prevention. Flu Vaccination Coverage, United States, 2021–22 Influenza Season. Available at https://www.cdc.gov/flu/fluvaxview/coverage-2022estimates.htm. Last accessed August 23, 2024.

103. Centers for Disease Control and Prevention. Influenza Vaccination Coverage Among Health Care Personnel—United States, 2021–22 Influenza Season. Available at https://www.cdc.gov/mmwr/volumes/71/wr/mm7142a2.htm?s_cid=mm7142a2_w. Last accessed August 23, 2024.

104. Santibanez T, Nowalk MP, Zimmerman RK, et al. Knowledge and beliefs about influenza, pneumococcal disease, and immunizations among older people. J Am Geriatr Soc. 2002;50(10):1711-1716.

105. Hebert P, Frick KD, Kane RL, McBean AM. The causes of racial and ethnic differences in influenza vaccination rates among elderly Medicare beneficiaries. Health Serv Res. 2005;40(2):517-537.

106. Winston C, Wortley PM, Lees KA. Factors associated with vaccination of Medicare beneficiaries in five U.S. communities: results from the racial and ethnic adult disparities in immunization initiative survey, 2003. J Am Geriatr Soc. 2006;54(2):303-310.

107. Haviland A, Elliott MN, Hambarsoomian K, Lurie N. Immunization disparities by Hispanic ethnicity and language preference. Arch Intern Med. 2011;171(2):158-165.

108. Marsteller J, Tiggle RB, Remsburg RE, Bardenheier B, Shefer A, Han B. Pneumococcal vaccination in nursing homes: does race make a difference? J Am Med Dir Assoc. 2008;9(9):641-647.

109. Bardenheier B, Wortley P, Ahmed F, Gravenstein S, Hogue CJ. Racial inequities in receipt of influenza vaccination among long-term care residents within and between facilities in Michigan. Med Care. 2011;49(4):371-377.

110. Bardenheier B, Wortley P, Shefer A, McCauley MM, Gravenstein S. Racial inequities in receipt of influenza vaccination among nursing home residents in the United States, 2008—a pattern of low overall coverage in facilities in which most residents are black. J Am Med Dir Assoc. 2012;13(5):470-476.

111. Bratzler DW, Houck PM, Jiang H, et al. Failure to vaccinate Medicare inpatients: a missed opportunity. Arch Intern Med. 2002;162(20):2349-2356.

112. Hill HA, Elam-Evans LD, Yankey D, et al. Vaccination coverage among children aged 19–35 months—United States, 2016. MMWR. 2017;66(43):1171-1177.

113. National Center for Health Statistics. Health, United States, 2016. Available at https://www.cdc.gov/nchs/data/hus/hus16.pdf. Last accessed August 23, 2024.

114. U.S. Department of Health and Human Services. Healthy People 2030: Vaccination. Available at https://health.gov/healthypeople/objectives-and-data/browse-objectives/vaccination. Last accessed August 26, 2024.

115. Burns I, Zimmerman RK. Immunization barriers and solutions. J Fam Pract. 2005;54(1):S58-S62.

116. Johnson D, Nichol KL, Lipczynski K. Barriers to adult immunization. Am J Med. 2008;121(7 Suppl 2):S28-S35.

117. Keeton V, Chen AK. Immunization updates and challenges. Curr Opin Pediatr. 2010;22(2):234-240.

118. Lindley M, Wortley PM, Winston CA, Bardenheier BH. The role of attitudes in understanding disparities in adult influenza vaccination. Am J Prev Med. 2006;31(4):281-285.

119. Pearson W, Zhao G, Ford ES. An analysis of language as a barrier to receiving influenza vaccinations among an elderly Hispanic population in the United States. Adv Prev Med. 2011:298787.

120. Mills E, Jadad AR, Ross C, Wilson K. Systematic review of qualitative studies exploring parental beliefs and attitudes toward childhood vaccination identifies common barriers to vaccination. J Clin Epidemiol. 2005;58(11):1081-1088.

121. Niederhauser V, Markowitz M. Barriers to immunizations: multiethnic parents of under- and unimmunized children speak. J Am Acad Nurse Pract. 2007;19(1):15-23.

122. Luthy K, Beckstrand RL, Peterson NE. Parental hesitation as a factor in delayed childhood immunization. J Pediatr Health Care. 2009;23(6):388-393.

123. Nichol K. Improving influenza vaccination rates among adults. Cleve Clin J Med. 2006;73(11):1009-1015.

124. Office of Minority Health. Cultural and Linguistic Competency. Available at https://minorityhealth.hhs.gov/cultural-and-linguistic-competency. Last accessed August 26, 2024.

125. Paez K, Allen JK, Beach MC, Carson KA, Cooper LA. Physician cultural competence and patient ratings of the patient-physician relationship. J Gen Intern Med. 2009;24(4):495-498.

126. Powers B, Trinh JV, Bosworth HB. Can this patient read and understand written health information? JAMA. 2010;304(1):76-84.

127. U.S. Census Bureau. Selected Social Characteristics in the United States: 2019. Available at https://data.census.gov/cedsci/table?q=english&tid=ACSSPP1Y2019.S0201. Last accessed August 26, 2024.

128. Karliner L, Napoles-Springer AM, Schillinger D, Bibbins-Domingo K, Pérez-Stable EJ. Identification of limited English proficient patients in clinical care. J Gen Intern Med. 2008;23(10):1555-1560.

129. Karliner L, Jacobs EA, Chen AH, Mutha S. Do professional interpreters improve clinical care for patients with limited English proficiency? A systematic review of the literature. Health Serv Res. 2007;42(2):727-754.

130. Flores G. The impact of medical interpreter services on the quality of health care: a systematic review. Med Care Res Rev. 2005;62(3):255-299.

131. Ngo-Metzger Q, Massagli MP, Clarridge BR, et al. Linguistic and cultural barriers to care: perspectives of Chinese and Vietnamese immigrants. J Gen Intern Med. 2003;18(1):44-52.

132. Committee on Health Literacy Board on Neuroscience and Behavioral Health. Health Literacy: A Prescription to End Confusion. Washington, DC: The National Academies Press; 2004.

133. Paasche-Orlow M, Parker RM, Gazmararian JA, Nielsen-Bohlman LT, Rudd RR. The prevalence of limited health literacy. J Gen Intern Med. 2005;20(2):175-184.

134. Kutner M, Greenberg E, Jin,Y, Paulsen C, White S. The Health Literacy of America's Adults: Results from the 2003 National Assessment of Adult Literacy. Washington, DC: National Center for Education Statistics; 2006.

135. Shah L, West P, Bremmeyr K, Savoy-Moore RT. Health literacy instrument in family medicine: the "newest vital sign" ease of use and correlates. J Am Board Fam Med. 2010;23(2):195-203.

136. Weiss B, Mays MZ, Martz W, et al. Quick assessment of literacy in primary care: the newest vital sign. Ann Fam Med. 2005;3(6):514-522.

137. Jacobson V, Szilagyi P. Patient reminder and patient recall systems to improve immunization rates. Cochrane Database Syst Rev. 2005;(3):CD003941.

138. Traeger M, Say KR, Hastings V, Yost DA. Achievement of Healthy People 2010 objective for adult pneumococcal vaccination in an American Indian community. Pub Health Rep. 2010;125(3):448-456.

139. Rimple D, Weiss SJ, Brett M, Ernst AA. An emergency department-based vaccination program: overcoming the barriers for adults at high risk for vaccine-preventable diseases. Acad Emerg Med. 2006;13(9):922-930.

140. Martin D, Brauner ME, Plouffe JF. Influenza and pneumococcal vaccinations in the emergency department. Emerg Med Clin North Am. 2008;26(2):549-570.

141. Society of Healthcare Epidemiology of America Research Committee. Enhancing patient safety by reducing healthcare-associated infections: the role of discovery and dissemination. Infect Control Hosp Epidemiol. 2010;31(2):118-123.

142. Richards MJ, Edwards JR, Culver DH, Gaynes RP. Nosocomial infections in pediatric intensive care units in the United States: National Nosocomial Infections Surveillance System. Pediatrics. 1999;103(4):e39.

143. Mills K, Graham AC, Winslow BT, Springer KL. Treatment of nursing home-acquired pneumonia. Am Fam Physician. 2009;79(11):976-982.

144. Foglia E, Meier MD, Elward A. Ventilator-associated pneumonia in neonatal and pediatric intensive care unit patients. Clin Microbiol Rev. 2007;20(3):409-425.

145. Qaseem A, Snow V, Fitteman N, et al. Risk assessment for and strategies to reduce perioperative pulmonary complications for patients undergoing noncardiothoracic surgery: a guideline from the American College of Physicians. Ann Intern Med. 2006;144(8):575-580.

146. Pileggi C, Bianco A, Flotta D, Nobile CG, Pavia M. Prevention of ventilator-associated pneumonia, mortality and all intensive care unit acquired infections by topically applied antimicrobial or antiseptic agents: a meta-analysis of randomized controlled trials in intensive care units. Crit Care. 2011;15(3):R155.

147. Kollef MH. Antibiotic management of ventilator-associated pneumonia due to antibiotic-resistant gram-positive bacterial infection. Eur J Clin Microbiol Infect Dis. 2005;24(12):794-803.

148. Kollef MH. What is ventilator-associated pneumonia and why is it important? Respir Care. 2005;50(6):714-721.

149. Dodek P, Keenan S, Cook D, et al. Evidence-based clinical practice guideline for the prevention of ventilator-associated pneumonia. Ann Intern Med. 2004;141(4):305-313.

150. Bigham M, Amato R, Bondurrant P, et al. Ventilator-associated pneumonia in the pediatric intensive care unit: characterizing the problem and implementing a sustainable solution. J Pediatr. 2009;154(4):582-587.

151. Kollef MH, Morrow LE, Niederman MS, et al. Clinical characteristics and treatment patterns among patients with ventilator-associated pneumonia. Chest. 2006;129(5):1210-1218.

152. Hidron A, Edwards JR, Patel J, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006–2007. Infect Control Hosp Epidemiol. 2008;29(11):996-1011.

153. Kollef MH, Micek ST. Staphylococcus aureus pneumonia: a "superbug" infection in community and hospital settings. Chest. 2005;128(3):1093-1097.

154. Depuydt P, Myny D, Blot S. Nosocomial pneumonia: aetiology, diagnosis and treatment. Curr Opin Pulm Med. 2006;12(3):192-197.

155. El-Solh A, Niederman MS, Drinka P. Nursing home-acquired pneumonia: a review of risk factors and therapeutic approaches.Curr Med Res Opin. 2010;26(12):2707-2714.

156. Davis KA. Ventilator-associated pneumonia: a review. J Intensive Care Med. 2006;21(4):211-226.

157. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control. 2008;36(5):309-332.

158. Porzecanski I, Bowton DL. Diagnosis and treatment of ventilator-associated pneumonia. Chest. 2006;130(2):597-604.

159. Miller PR, Johnson JC 3rd, Karchmer T, Hoth JJ, Meredith JW, Chang MC. National nosocomial infection surveillance system: from benchmark to bedside in trauma patients. J Trauma. 2006;60(1):98-103.

160. Zaccard CR, Schell RF, Spiegel CA. Efficacy of bilateral bronchoalveolar lavage for diagnosis of ventilator-associated pneumonia. J Clin Microbiol. 2009;47(9):2918-2924.

161. Berton D, Kalil AC, Teixeira PJ. Quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilator-associated pneumonia. Cochrane Database Syst Rev. 2014;10:CD006482.

162. Micek ST, Heuring TJ, Hollands JM, Shah RA, Kollef MH. Optimizing antibiotic treatment for ventilator-associated pneumonia. Pharmacotherapy. 2006;26(2):204-213.

163. Rello J, Vidaur L, Sandiumenge A, et al. De-escalation therapy in ventilator-associated pneumonia. Crit Care Med. 2004;32(11):2183-2190.

164. Sligl W, Taylor G, Brindley PG. Five years of nosocomial gram-negative bacteremia in a general intensive care unit: epidemiology, antimicrobial susceptibility patterns, and outcomes. Int J Infect Dis. 2006;10(4):320-325.

165. Mullins D, Kuznik C, Shaya FT, Obeidat NA, Levine AR, Liu LZ, Wong W. Cost-effectiveness analysis of linezolid compared with vancomycin for the treatment of nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus. Clin Ther. 2006;28(8):1184-1198.

166. Shorr AF, Susla GM, Kollef MH. Linezolid for treatment of ventilator-associated pneumonia: a cost-effective alternative to vancomycin. Crit Care Med. 2004;32(1):137-143.

167. Grau S, Alvarez-Lerma F, del Castillo A, Neipp R, Rubio-Terres C. Cost-effectiveness analysis of the treatment of ventilator-associated pneumonia with linezolid or vancomycin in Spain. J Chemother. 2005;17(2):203-211.

168. Kollef MH, Rello J, Cammarata SK, Croos-Dabrera RV, Wunderink RG. Clinical cure and survival in gram-positive ventilator-associated pneumonia: retrospective analysis of two double-blind studies comparing linezolid with vancomycin. Intensive Care Med. 2004;30(3):388-394.

169. Wunderink RG, Mendelson MH, Somero MS, et al. Early microbiological response to linezolid vs vancomycin in ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus. Chest. 2008;134(6):1200-1207.

170. Pugh R, Grant C, Cooke RP, Dempsey G. Short-course versus prolonged-course antibiotic therapy for hospital-acquired pneumonia in critically ill adults. Cochrane Database Syst Rev. 2015;8:CD007577.

171. Coffin SE, Klompas M, Classen D, et al. Strategies to prevent ventilator-associated pneumonia in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29:S31-S40.

172. van Nieuwenhoven CA, Vandenbroucke-Grauls C, van Tiel FH, et al. Feasibility and effects of the semirecumbent position to prevent ventilator-associated pneumonia: a randomized study. Crit Care Med. 2006;34(2):396-402.

173. Tolentino-Delos Reyes AF, Ruppert SD, Shiao SY. Evidence-based practice: use of the ventilator bundle to prevent ventilator-associated pneumonia. Am J Crit Care. 2007;16(1):20-27.

174. Institute for Healthcare Improvement. How-to Guide: Prevent Ventilator-Associated Pneumonia. Available at https://cha.com/wp-content/uploads/2018/03/IHI-HowtoGuidePreventVAP-with-bundle.pdf. Last accessed August 26, 2024.

175. Kress J, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342(20):1471-1477.

176. Schweickert W, Gehlbach BK, Pohlman AS, Hall JB, Kress JP. Daily interruption of sedative infusions and complications of critical illness in mechanically ventilated patients. Crit Care Med. 2004;32(6):1272-1276.

177. Antalová N, Klučka J, Říhová M, Poláčková S, Pokorná A, Štourač P. Ventilator-associated pneumonia prevention in pediatric patients: narrative review. Children (Basel). 2022;9(10):1540.

178. Bearman GM, Munro C, Sessler CN, Wenzel RP. Infection control and the prevention of nosocomial infections in the intensive care unit. Semin Respir Crit Care Med. 2006;27:310-324.

179. Drakulovic MB, Torres A, Bauer TT, Nicolar JM, Nogué S, Ferrer M. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet. 1999;354(9193):1851-1858.

180. Shay A, O'Malley P. Blue Ribbon Abstract Award: clinical outcomes of a ventilator associated pneumonia prevention program. Am J Infect Control. 2006;34(5):E19-E20.

181. El-Solh AA, Pietrantoni C, Bhat A, et al. Colonization of dental plaques: a reservoir of respiratory pathogens for hospital-acquired pneumonia in institutionalized elders. Chest. 2004;126(5):1575-1582.

182. Sona C, Zack JE, Schallom ME, et al. The impact of a simple, low-cost oral care protocol on ventilator-associated pneumonia rates in a surgical intensive care unit. J Intensive Care Med. 2009;24(1):54-62.

183. Munro C, Grap MJ, Jones DJ, McClish DK, Sessler CN. Chlorhexidine, toothbrushing, and preventing ventilator-associated pneumonia in critically ill adults. Am J Crit Care. 2009;18(5):428-437.

184. Fourrier F, Dubois D, Pronnier P, et al. Effect of gingival and dental plaque antiseptic decontamination on nosocomial infections acquired in the intensive care unit: a double-blind placebo-controlled multicenter study. Crit Care Med. 2005;33(8):1728-1735.

185. Pineda LA, Saliba RG, El Solh AA. Effect of oral decontamination with chlorhexidine on the incidence of nosocomial pneumonia: a meta-analysis. Crit Care. 2006;10(1):R35.

186. Bopp M, Darby M, Loftkin KC, Broscious S. Effects of daily oral care with 0.12% chlorhexidine gluconate and a standard oral care protocol on the development of nosocomial pneumonia in intubated patients: a pilot study. J Dent Hyg. 2006;80(3):9.

187. World Health Organization. Prevention of Hospital-Acquired Infections: A Practical Guide. 2nd ed. Geneva: WHO Press; 2002.

188. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):338S-400S.

189. Dezfulian C, Shojania K, Collard HR, Kim HM, Matthay MA, Saint S. Subglottic secretion drainage for preventing ventilator-associated pneumonia: a meta-analysis. Am J Med. 2005;118(1):11-18.

190. Bouza E, Pérez MJ, Muñoz P, Rincón C, Barrio JM, Hortal J. Continuous aspiration of subglottic secretions in the prevention of ventilator-associated pneumonia in the postoperative period of major heart surgery. Chest. 2008;134(5):938-946.

191. Wang F, Bo L, Tang L, et al. Subglottic secretion drainage for preventing ventilator-associated pneumonia: an updated meta-analysis of randomized controlled trials. J Trauma Acute Care Surg. 2012;72(5):1276-1285.

192. Girou E, Brun-Buisson C, Taille S, Lemaire F, Brochard L. Secular trends in nosocomial infections and mortality associated with noninvasive ventilation in patients with exacerbation of COPD and pulmonary edema. JAMA. 2003;290(22):2985-2991.

193. Isakow W, Kollef MH. Preventing ventilator-associated pneumonia: an evidence-based approach of modifiable risk factors. Semin Respir Crit Care Med. 2006;27(1):5-17.

194. Osmon S, Kollef MH. Prevention of pneumonia in the hospital setting. Clin Chest Med. 2005;26(1):135-142.

195. Craven DE, Hjalmarson K. Prophylaxis of ventilator-associated pneumonia: changing culture and strategies to trump disease.Chest. 2008;134(5):898-900.

196. Jain M, Miller L, Belt D, King D, Berwick DM. Decline in ICU adverse events, nosocomial infections and cost through a quality improvement initiative focusing on teamwork and culture change. Qual Saf Health Care. 2006;15(4):235-239.

197. Stone MJ, Snetman D, O'Neill A, et al. Daily multidisciplinary rounds to implement the ventilator bundle decreases ventilator-associated pneumonia in trauma patients: but does it affect outcome? Surg Infect (Larchmt). 2011;12(5):373-378.

198. Cachecho R, Dobkin E. The application of human engineering interventions reduces ventilator-associated pneumonia in trauma patients. J Trauma Acute Care Surg. 2012;73(4):939-943.

199. Hutt E, Kramer AM. Evidence-based guidelines for management of nursing home-acquired pneumonia. J Fam Pract. 2002;51(8):709-716.

200. Salgado CD, Giannetta ET, Hayden FG, Farr BM. Preventing nosocomial influenza by improving the vaccine acceptance rate of clinicians. Infect Control Hosp Epidemiol. 2004;25(11):923-928

201. Carman WF, Elder AG, Wallace LA, et al. Effects of influenza vaccination on health-care workers on mortality of elderly people in long-term care: a randomized controlled trial. Lancet. 2000;355(9198):93-97.

202. Dash GP, Fauerbach L, Pfeiffer J, et al. APIC position paper: Improving health care worker influenza immunization rates. Am J Infect Control. 2004;32(3):123-125.

203. Centers for Disease Control and Prevention. Estimated influenza vaccination coverage among adults and children—United States, September 1, 2004–January 1, 2005. MMWR. 2005;54(12):304-307.

204. Christini AB, Shutt KA, Byers KE. Influenza vaccination rates and motivators among healthcare worker groups. Infect Control Hosp Epidemiol. 2007;28(2):171-177.

205. Pearson ML, Bridges CB, Harper SA. Influenza vaccination of health-care personnel. MMWR. 2006;55(RR02):1-16.

206. U.S. Food and Drug Administration. Reprocessing of Reusable Ultrasound Transducer Assemblies Used for Biopsy Procedures. Available at https://wayback.archive-it.org/7993/20170112170658/http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm151526.htm. Last accessed August 26, 2024.

207. Boyce JM, Pittet D. Guideline for hand hygiene in health-care settings. MMWR. 2002;51(RR16):1-44.

208. Burke JP. Infection control-a problem for patient safety. N Engl J Med. 2003;348(7):651-656.

209. Leapfrog Group. Press Release: Eighty-Seven Percent of U.S. Hospitals Do Not Take Recommended Steps to Prevent Avoidable Infections. Available at https://www.infectioncontroltoday.com/view/leapfrog-group-survey-reveals-87-percent-us-hospitals-dont-take. Last accessed August 26, 2024.

210. Clark AP, Houston S. Nosocomial infections: an issue of patient safety: part 2. Clin Nurse Spec. 2004;18(2):62-64.

211. Pittet D, Hugonnet S, Harbarth S, et al. Effectiveness of a hospital-wide programme to improve compliance with hand hygiene. Lancet. 2000;356(9238):1307-1312.

212. Larson EL, Quiros D, Lin SX. Dissemination of the CDC's hand hygiene guideline and impact on infection rates. Am J Infect Control. 2007;35(10):666-675.

213. Weinstein R. Hospital-acquired infections. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Isselbacher KJ (eds.) Harrison's Principles of Internal Medicine. 16th ed. New York, NY: McGraw Hill; 2004.

214. Johnson PDR, Rhea M, Burrell LJ, et al. Efficacy of an alcohol/chlorhexidine hand hygiene program in a hospital with high rates of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection. Med J Aust. 2005;183(10):509-514.

215. Gordin FM, Schultz ME, Huber RA, Gill JA. Reduction in nosocomial transmission of drug-resistant bacteria after introduction of an alcohol-based handrub. Infect Control Hosp Epidemiol. 2005;26(7):650-653.

216. Gould DJ, Moralejo D, Drey N, Chudleigh JH, Taljaard M. Interventions to improve hand hygiene compliance in patient care.Cochrane Database Syst Rev. 2017;9:CD005186.

217. Mason CM, Nelson S. Pulmonary host defenses and factors predisposing to lung infection. Clin Chest Med. 2005;26(1):11-17.

218. Johnstone J, Eurich DT, Jamumdar SR, Jin Y, Marrie TJ. Long-term morbidity and mortality after hospitalization with community-acquired pneumonia: a population-based cohort study. Medicine (Baltimore). 2008;87(6):329-334.

219. Santibanez T, Mootrey GT, Euler GL, Janssen AP. Behavior and beliefs about influenza vaccine among adults ages 50–64 years. Am J Health Behav. 2010;34(1):77-89.

220. Griffin M, Zhu Y, Moore M, Whitney C, Grijalva C. U.S. hospitalizations for pneumonia after a decade of pneumococcal vaccination. N Engl J Med. 2013;369:155-163.

221. Nuorti J, Butler J, Farley M, et al. Cigarette smoking and invasive pneumococcal disease. N Engl J Med. 2000;342:681-689.

222. Marrie T, Poulin-Costello M, Beecroft M, Herman-Gnjidic Z. Etiology of community-acquired pneumonia in the ambulatory setting. Respir Med. 205;99:60-65.

223. Kallen AJ, Reed C, Patton M, et al. Staphylococcus aureus community-onset pneumonia in patients admitted to children's hospitals during autumn and winter of 2006–2007. Epidemiol Infect. 2010;138:666-672.

224. Musher D, Montoya R, Wanahita A. Diagnostic value of microscopic examination of Gram-stained sputum and sputum cultures in patients with bacteremic pneumococcal pneumonia. Clin Infect Dis. 2004;39:165-169.

225. Gutiérrez F, Masiá M, Rodríguez JC, et al. Evaluation of the immunochromatographic Binax NOW Assay for detection of Streptococcus pneumoniae urinary antigen in a prospective study of community-acquired pneumonia in Spain. Clin Infect Dis. 2003;36(3):286-292.

226. Toshihiko S, MD, Yoshinori N, Jackson J, et al. Systematic review and meta-analysis: urinary antigen tests for legionellosis. Chest. 2009;136:1576-1585.

227. Matanock A, Lee G, Gierke R, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged >/= 65 years: updated recommendations of the Advisory Committee on Immunization Practices. MMWR. 2019;68:1069-1075.

228. World Health Organization. Fact Sheet: Pneumonia. Available at: https://www.who.int/health-topics/pneumonia. Last accessed August 26, 2024.

229. Centers for Disease Control and Prevention. Legionella (Legionaires' Disease and Pontiac Fever). Available at https://www.cdc.gov/legionella/index.html. Last accessed August 26, 2024.

230. Hicks LA, Garrison LE, Nelson GE, Hampton LM. Legionellosis—United States, 2000–2009. MMWR. 2011;60(32):1083-1086.

231. Centers for Disease Control and Prevention. Chlamydophila pneumoniae Infection. Available at https://www.cdc.gov/cpneumoniae/index.html. Last accessed August 26, 2024.

232. Ramirez JA, Wiemken TL Peyrani P, et al. Adults hospitalized with pneumonia in the United States: incidence, epidemiology, and mortality. Clin Infect Dis. 2017;65:1806-1812.

233. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388-416.

234. Centers for Disease Control and Prevention. Underlying Cause of Death 1999–2021 on CDC WONDER Online Database. Available at https://wonder.cdc.gov/. Last accessed August 21, 2024.

235. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of community-acquired pneumonia in adults: an official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45.

236. Centers for Disease Control and Prevention. Influenza ACIP Vaccine Recommendations. Available at https://www.cdc.gov/acip-recs/hcp/vaccine-specific/flu.html. Last accessed August 23, 2024.

237. Lu P, Hung M, Scrivastav A, et al. Surveillance of vaccination coverage among adult populations—United States, 2018. MMWR. 2021;70(SS-3):1-26.

238. Faner R, Sibila O, Agusti A, et al. The microbiome in respiratory medicine: current challenges and future perspectives. Eur Respir J. 2017;49(4):1602086.

239. Centers for Disease Control and Prevention, Pneumococcal Vaccine Work Group. Pneumococcal Vaccines. Available at https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2024-06-26-28/01-Pneumococcal-Loehr-508.pdf. Last accessed August 26, 2024.

240. Centers for Disease Control and Prevention. Pneumococcal Vaccine Recommendations. Available at https://www.cdc.gov/vaccines/vpd/pneumo/hcp/recommendations.html. Last accessed August 26, 2024.

241. Ahn A, Edwards KM, Grijalva CG, et al. Secondhand smoke exposure and illness severity among children hospitalized with pneumonia. J Pediatr. 2015;167(4):869-874.e1.

Evidence-Based Practice Recommendations Citations

1. Kirsch J, Mohammed TH, Kanne JP, et al. ACR Appropriateness Criteria: Acute Respiratory Illness in Immunocompetent Patients. Reston, VA: American College of Radiology; 2018. Available at https://acsearch.acr.org/docs/69446/Narrative. Last accessed August 29, 2024.

2. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38. Available at https://academic.oup.com/cid/article/52/3/e18/306145. Last accessed August 29, 2024.

3. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia: an official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45-e67. Available at https://www.atsjournals.org/doi/full/10.1164/rccm.201908-1581ST. Last accessed August 29, 2024.

4. Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61-e111. Available at https://www.thoracic.org/statements/resources/tb-opi/hap-vap-guidelines-2016.pdf. Last accessed August 29, 2024.

95231 • Psychopharmacology

Carol Whelan, APRN

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

In the management of patients with mental health disorders, pharmacotherapy remains a vital part of optimal treatment. This course will review the approaches to incorporating pharmacotherapy into the management of the most common mental health disorders in the United States. A variety of potential adverse effects and considerations will also be included.

Table of Contents

95231 • Psychopharmacology

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. A BRIEF HISTORY OF PSYCHIATRY AND PSYCHOPHARMACOLOGY

EARLY CUSTODIAL CARE AND THE ADVENT OF INSTITUTIONS

THE BIRTH OF MODERN PSYCHIATRY AND PSYCHOPHARMACOLOGY

THE DEVELOPMENT OF PSYCHOPHARMACOLOGY

THE ORGANIC BASIS OF MENTAL ILLNESS AND THE ADVANCEMENT OF PSYCHOPHARMACOLOGY

NEW HORIZONS: PSYCHOPHARMACOLOGY AND ADDICTION MEDICINE

3. ANTIPSYCHOTIC MEDICATIONS

TYPICAL ANTIPSYCHOTICS

ATYPICAL ANTIPSYCHOTICS

LONG-ACTING INJECTABLE ANTIPSYCHOTICS

CLASS-WIDE ADVERSE EFFECTS AND WARNINGS

RISK MITIGATION STRATEGIES

CASE STUDY

4. ANTIDEPRESSANT MEDICATIONS

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS

TRICYCLIC ANTIDEPRESSANTS

MONOAMINE OXIDASE INHIBITORS

ATYPICAL ANTIDEPRESSANTS

SEROTONIN 5-HT1A RECEPTOR AGONIST

MULTIMODAL ANTIDEPRESSANTS

CLASS-WIDE ADVERSE EFFECTS

PEDIATRIC CONSIDERATIONS

TREATMENT-RESISTANT DEPRESSION

CASE STUDY

5. MOOD STABILIZERS AND BIPOLAR DISORDER

CASE STUDY

6. ANTIANXIETY MEDICATIONS

ANTIDEPRESSANTS

BENZODIAZEPINES

CASE STUDY

7. PHARMACOTHERAPY FOR SUBSTANCE USE DISORDERS

CASE STUDY

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

95231 • Psychopharmacology

Education Category. Pharmacology

Release Date. 10/01/2024

Expiration Date. 09/30/2027

Course Overview

In the management of patients with mental health disorders, pharmacotherapy remains a vital part of optimal treatment. This course will review the approaches to incorporating pharmacotherapy into the management of the most common mental health disorders in the United States. A variety of potential adverse effects and considerations will also be included.

Audience

This course is designed for nurses and pharmacy professionals involved in the care of patients with mental health conditions.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 10 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this continuing education activity for 10 ANCC contact hour(s). NetCE designates this continuing education activity for 10 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 12 hours for Alabama nurses. NetCE designates this activity for 10 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-24-040-H01-P. AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 1 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353 (valid through July 30, 2029); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2027; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Course Objective

The purpose of this course is to provide members of the interprofessional healthcare team with the information necessary to appropriate prescribe, administer, and dispense psychopharmacotherapy, with the ultimate goal of improving patient care and public health.

Learning Objectives

Upon completion of this course, you should be able to:

1. Outline the history of pharmacology in psychiatry.

2. Describe the action and use of typical antipsychotics.

3. Compare and contrast the various atypical antipsychotics.

4. Evaluate class-wide adverse effects of antipsychotics.

5. Identify available antidepressant medication and their use in the treatment of major depression.

6. Discuss potential adverse effects and warnings associated with antidepressants.

7. Describe medications used in the management of bipolar disorder.

8. Assess the role of antidepressants in the management of anxiety disorders.

9. Discuss the use of benzodiazepines for the treatment of anxiety.

10. Review available pharmacotherapy to incorporate into the treatment of substance use disorders.

Faculty

Carol Whelan, APRN, has been working in nursing education since 2000. She received her Master's degree in psychiatric/mental health nursing from St. Joseph College in West Hartford, Connecticut, and completed post-graduate nurse practitioner training at Yale University. Ms. Whelan is an Associate Clinical Professor and Lecturer at Yale University and works as an APRN at the Department of Veterans' Affairs in Connecticut, where she also serves as the Vice President of Medical Staff. She has authored many articles, textbook chapters, and books.

Faculty Disclosure

Contributing faculty, Carol Whelan, APRN, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

Mary Franks, MSN, APRN, FNP-C

Randall L. Allen, PharmD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Psychiatry and the medications prescribed for psychiatric issues are so intertwined with culture and society that it is impossible to discuss its history without also talking about the societal context and cultural beliefs that surround it. No orthopedic surgeon has ever had to convince a patient that a broken leg was not caused by demons and that the therapy prescribed is medically needed. The same cannot be said for psychiatry. Even in the 21st century, clinicians who deal with the complex medications used to treat psychiatric illness encounter patients who feel shame, guilt, and doubt associated with their diagnoses and the medications used to manage them.

The root of this skepticism can be traced to the French philosopher René Descartes in the 1500s and the famous Cartesian motto "I think therefore I am." According to this widely embraced philosophy, one exists because s/he thinks, not because the heart beats, the muscles work, or the lungs breathe. From this perspective, one is because their brain is healthy.

Given this belief that a disordered mental state calls one's very existence into question, it is no wonder patients are reluctant to seek help, ashamed to report their symptoms, and afraid that they may lose their job or custody of their children—there is an underlying belief that their existence will be questioned if something is wrong with their thoughts, emotions, and the inner core of their being. This is the world in which psychiatric medications are being prescribed. But how did we get here?

2. A BRIEF HISTORY OF PSYCHIATRY AND PSYCHOPHARMACOLOGY

In the United States, the first attempt at humane treatment of psychiatric disorders was by the Quakers, who, in 1752, used the Pennsylvania Hospital in Philadelphia to house patients in its basement; however, the environment in the hospital was damaging to patients, some of whom were shackled to walls[1]. Other early institutions for people deemed "mentally disturbed" were opened in the late 1700s in New York. In 1824, the Eastern Lunatic Asylum (now Eastern State Hospital) opened in Lexington, Kentucky. By 1890, every state had at least one publicly supported mental hospital, with populations that were rapidly expanding; by the 1950s, these institutions housed more than 500,000 patients [1]. One of the earliest practitioners of what could be called psychiatry was Dr. Benjamin Rush, who has been called the father of American psychiatry and who wrote the first American textbook on mental diseases (Medical Inquiries and Observations upon Diseases of the Mind) in 1812.

EARLY CUSTODIAL CARE AND THE ADVENT OF INSTITUTIONS

The Association of Medical Superintendents of American Institutions for the Insane was founded in 1844; in 1921, the name changed to the American Psychiatric Association (APA) [2]. In the 1800s, there was no real psychopharmacology or even a true appreciation of the biologic nature of mental illness. However, it is important to acknowledge Rush's decision to refer to "diseases of the mind," rather than more judgmental terminology common to the time, such as spiritual disease or weakness. In fact, Rush hypothesized that psychiatric disorders were caused by irritation of the blood vessels in the brain. This led to treatments such as bleeding and purging and to what could be called the first attempt at the development of a psychoactive medication—the use of mercury as a treatment for mental illness. While it is easy to dismiss such early attempts, this theory of a vascular cause of psychiatric symptoms is consistent with some current knowledge of vascular dementia, and while the theories seem ill-informed today, it is important to note that other popular theories of psychiatric etiology of the time attributed mental illness to demons, witchcraft, or moral turpitude.

During this early period, institutional care of the mentally ill was often a means to persecute women and others whom society wished to confine, which led to what some call the "coercive era" of psychiatric care. One of the most important of these cases was that of Elizabeth Packard in 1860. Elizabeth Packard was married to a clergyman who forcibly placed her in an Illinois asylum. In 1860, Illinois law allowed for involuntary hospitalization of a spouse (generally a wife) by request without any evidence. Ms. Packard was eventually able to obtain release from the hospital, but due to her husband's continuing campaign, she was forced to petition the court and was released in 1863 with a habeas corpus hearing. After gaining her freedom, Ms. Packard began a campaign for the protection of women's rights. As a result of her efforts and the efforts of others at the time, laws were passed requiring a jury trial prior to involuntary hospitalization. It is notable that the Association of Medical Superintendents of American Institutions for the Insane (now the APA) opposed these laws at the time. The damage done by these forcible hospitalizations was huge, and the association of psychiatry with coercion persists to this day. These beliefs influence both the public's acceptance of psychopharmacology as a valid and effective treatment and the acceptance of psychiatric diagnoses as true medical diagnoses, as opposed to an excuse to prescribe medications or force hospitalization.

Another leader in the development of humane custodial care of the psychiatric patients was Dorothea Dix, who, in addition to her other accomplishments, is credited with opening more than 30 state mental hospitals throughout the United States. Dix advocated for humane institutions, particularly for the poor and unhoused, and reformation of mental health treatment.

The landmark court case O'Connor v. Donaldson ruled that the government cannot confine an individual who is not dangerous and is capable of living outside the institution. This ruling was based on the case of Kenneth Donaldson, who in his youth had undergone a course of brief psychiatric care, but had recovered, married, and moved from Florida to Pennsylvania. In 1956, he travelled to Florida to visit his parents, where he made a remark (possibly a joke) that he believed someone in Pennsylvania may have been trying to poison his food. In response, his father hired a lawyer, and at a hearing (where he had no legal representation), Donaldson was civilly committed. He was then placed in a housing unit with dangerous and violent criminals. He received no treatment and, as a Christian Scientist, refused all medications and did not agree that he was experiencing mental illness, which was against the typical routine of admitting illness, accepting treatment, and being released. Donaldson spent more than 15 years in this asylum, despite friends petitioning the administrator for his release and guaranteeing that they would care for him. He eventually won his release by petitioning the courts directly and then proceeded to file suit against the administrator (O'Connor) who had blocked his release, on the constitutional ground of illegal confinement denying him his right to liberty.

The court found that mental illness alone cannot justify custodial confinement against the will of the individual. Further cases (e.g., Lake v. Cameron) introduced the concept of care in the least restrictive setting, and in 1999, the Supreme Court ruled in Olmstead v. L.C. that mental illness is a disability covered under the Americans with Disabilities Act.

At the same time that the courts were acknowledging the rights of persons with mental illness, pharmacologists were making breakthroughs; therapeutic use of chlorpromazine (Thorazine) had been discovered, and the world of psychiatry would never be the same.

THE BIRTH OF MODERN PSYCHIATRY AND PSYCHOPHARMACOLOGY

The history of psychopharmacology is intertwined with the history of neurology and psychiatry. During the 19th century, psychiatry and neurology were chiefly concerned with the treatment of psychosis and deviant behaviors. The treatment of less severe conditions (e.g., depression, neurosis) was considered outside the province of psychiatry or neurology.

At the beginning of the 20th century, Sigmund Freud published his famous theories on the unconscious roots of what he termed psychoneurosis [3]. He was especially interested in conversion disorders, whereby patients displayed paralysis or other somatic symptoms that could not be explained in a medical context. Freud developed psychoanalysis (talk therapy) and thus began the outpatient treatment of patients with psychiatric concerns.

By the mid-20th century, psychoanalysis became overwhelmingly popular and was employed not only in the treatment of patients with anxiety or neurosis but also in the treatment of patients with more severe psychiatric disorders, such as psychosis, for which talk therapy had little to offer. Some postulate that the development of psychoanalysis stunted the development of psychopharmacology by promoting the notion that talk therapy could effectively treat all mental health issues.

One of the first treatments of psychosis—electroconvulsive therapy or ECT—was developed in the 1930s. Its development arose from the observation that patients with both psychosis and epilepsy seemed to experience improvements in psychotic symptoms following a seizure. While this apparent improvement may have actually been a postictal phase of the seizure disorder, it spurred a search for ways to induce seizures in patients with severe psychiatric disorders. Initial attempts used high doses of stimulant drugs to produce seizures, and the term convulsive therapy was coined. Due to drawbacks evident with the use of stimulant drugs, Italian neurologist Ugo Cerletti experimented with inducing seizures using electrical shocks delivered to the head [4].

Despite its roots in somewhat dubious observations of the effects of electric shocks on livestock, ECT remains in use today as a valid psychiatric treatment. In fact, it was one of the only truly effective psychiatric treatments in the 1930s and 1940s. It was also arguably one of the first treatments to address mental illness as a biologic disorder. Some consider the advent of convulsive therapy as the true beginning of psychopharmacology, as it relied on alteration of brain chemistry to produce improvements in patients.

Building on these advances, psychopharmacology exploded in the 1950s with the development of chlorpromazine, early antidepressants, and early mood stabilizers.

THE DEVELOPMENT OF PSYCHOPHARMACOLOGY

The term psychopharmacology traces its roots to 1920, appearing first in the title of a paper by David Macht describing the use of quinine and antipyretics in tests on neuromuscular coordination. However, most experts date the true birth of psychopharmacology to 1951, when chlorpromazine was first synthesized [5].

Chlorpromazine was developed in the lab of Rhône-Poulenc (an early French pharmaceutical company) for use in general anesthesia to induce calmness. It was not long before French surgeons saw the potential for the use of chlorpromazine in the treatment of psychiatric illness. The first paper on chlorpromazine (titled "A new stabilizer") was published in February 1952 in La Presse Medicale [5].

The first documented clinical psychiatric use of chlorpromazine was on January 19, 1952, when 50 mg intravenous (IV) chlorpromazine was given to a patient, 24 years of age, with severe agitation, psychosis, and possibly mania. The effects were noted as calming but also were transient in nature. After 20 days of treatment with a cumulative total of 900 mg of chlorpromazine along with concomitant barbiturates and ECT, the patient was able to be discharged home [5]. By 1957, chlorpromazine had become internationally recognized, and the American Public Health Association presented Albert Lasker Awards for Medical Research to several scientists and physicians associated with the development of chlorpromazine and introduction of the drug into clinical practice.

Perhaps the greatest contribution of chlorpromazine was not in its clinical effects but rather in its ability to distinguish the biologic basis of schizophrenia. During the course of the 1950s, studies of chlorpromazine use led to an understanding of synaptic transmission and development of the theory that synaptic transmission was not a merely electrical event but rather a chemically mediated event. By the end of the 1950s, six neurotransmitters had been identified in the central nervous system, including dopamine, norepinephrine, and serotonin [5].

The success of chlorpromazine led to the development of more antipsychotics, including thioridazine (Mellaril), haloperidol (Haldol, decanoate), trifluoperazine (Stelazine), and fluphenazine (Prolixin). However, all of these early antipsychotics were noted to have neurologic side effects, most notably extrapyramidal symptoms with parkinsonian features.

Some consider the 1950s to be a "golden age" of psychopharmacology. Beginning in 1958, tricyclic compounds based on the structure of imipramine were synthesized; these are referred to as second-generation (atypical) antipsychotics. One of these compounds was clozapine (Clozaril, Versacloz), an antipsychotic still in use today. Interestingly, clozapine did not initially attract much attention. Small trials showed mixed results, and unlike chlorpromazine, there was no consensus as to its effectiveness. The lack of extrapyramidal side effects led many researchers to erroneously believe that it was not a true antipsychotic, as the dopamine blockade theory of schizophrenia was still widely held.

THE ORGANIC BASIS OF MENTAL ILLNESS AND THE ADVANCEMENT OF PSYCHOPHARMACOLOGY

The development of medications to treat psychiatric illnesses has greatly informed our understanding of the biologic nature of these illnesses—most notably the link between antipsychotics and schizophrenia. This translational research also led to the understanding of neurotransmitters and further informed the development of large classes of psychoactive medications.

The dopamine receptor D2 is a common target of the antipsychotics. Assessment of medications' ability to target receptors was made possible by the introduction of the spectrophotofluorimeter in 1955. This instrument allows for analysis of chemicals in the brain, including monoamines, which allowed for the further advancement of the field of psychopharmacology [5].

With their introduction in the 1950s, monoamine oxidase inhibitors (MAOIs) became the first class of medications used to treat depression. The incorporation of these agents into clinical practice further moved psychiatry away from inpatient care in institutions toward effective outpatient care.

Another historical breakthrough in psychopharmacology was the discovery of the use of lithium for the treatment of mania. While there is some evidence of usage in the 1800s, the seminal research reintroducing lithium for the treatment of mania was published in 1949 by John Cade [6]. Despite its ready availability and widespread use worldwide, lithium was not approved by the U.S. Food and Drug Administration (FDA) until 1970; the United States was the 50th country to approve the use of lithium for the management of mania [6].

The discovery of medications effective in the treatment of affective disorders induced a shift away from the talk therapy-only approach originally developed by Freud. Further, the ability of lithium to improve symptoms of depression supported the burgeoning biologic theory of mental illness. This change in understanding of mental illness had extensive and widespread influence on the practice of psychiatry. It extended beyond schizophrenia and bipolar disorder and helped transform etiologic theories of diseases such as autism from a focus on environmental influence (e.g., poor mothering in the case of autism) to a biologic understanding of psychiatric disorders prevalent today.

In the later part of the 20th century, psychopharmaceutical advancements continued at record pace. The development of benzodiazepines, lithium, barbiturates, and MAOIs led to an era of deinstitutionalization and the mainstream diagnosis and management of psychiatric disorders without a reliance on talk therapy. This seismic change was not without controversy, and proponents of talk therapy and psychoanalysis resisted the use of psychopharmacology to treat mental illness.

This philosophical conflict was clearly evident in the revision process for the APA's Diagnostic and Statistical Manual of Mental Disorders (DSM). In 1980, the DSM was extensively revised (creating the DSM-III), and psychoanalytic language was abandoned. In contrast to the DSM-II, the DSM-III focused on symptom-based descriptions of mental disorders for diagnostic criteria.

Psychiatry continued to evolve to accept the biologic basis of mental illness and embrace the use of pharmacologic treatment. The introduction of selective serotonin reuptake inhibitors (SSRIs), which were both well-tolerated and had better safety profiles than previous medications, revolutionized the treatment of depression. The first SSRI, fluoxetine (Prozac), was approved by the FDA in 1987. While there has been controversy regarding the possible overdiagnosing of depression or overprescribing of antidepressants, no one disputes the enormous impact fluoxetine has had on psychopharmacology [3].

At virtually the same time as the introduction of fluoxetine, a group of second-generation (atypical) antipsychotics were being approved in the United States. These medications, including risperidone (Perseris, Risperdal) and olanzapine (Zyprexa), challenged the traditional belief that only the D2 receptor/dopamine was involved in psychosis. This renewed interest in the forgotten medication clozapine and novel treatment approaches for schizophrenia.

While clozapine had been originally introduced in the 1950s and approved by the FDA in 1971, small studies had been unable to show efficacy. Use of the drug effectively ended in 1975, when the Finnish National Board of Health reported 18 individuals prescribed clozapine who developed severe blood disorders (most commonly agranulocytosis, a severe decrease or an absence of white blood cells increasing the risk of potentially fatal infection); 9 of these patients died [7]. Research since that time indicates that agranulocytosis occurs in about 1% of patients taking clozapine and neutropenia is seen in about 3% [8].

These early roadblocks to the use of clozapine were overcome, first by a system of monitoring white blood cell counts and secondly by longer studies that showed that the effects of clozapine continue to increase after four weeks of therapy, unlike chlorpromazine, which had a peak effect after two to three weeks [7]. As a result of these findings, clozapine was approved for the treatment of psychosis in the United States in 1990 [7]. The price of this drug when it was first approved, approximately $9,000 per patient per year for the medication and monitoring, was initially controversial, but it was more cost-effective than inpatient care or institutionalization [3,7].

The risk for leukopenia remains a barrier to wider use of clozapine; however, it has become a mainstay for treatment-resistant schizophrenia and is also acknowledged to reduce the risk of suicide in patients with schizophrenia. It is also used off-label in the management of treatment-resistant bipolar disorder and dementia- or Parkinson-related psychosis or agitation. With the availability of a generic version, the price of clozapine is now less than many other newer antipsychotics. Knowledge that the risk of agranulocytosis is highest in the first three months has also led to a reduction in the frequency of long-term monitoring.

NEW HORIZONS: PSYCHOPHARMACOLOGY AND ADDICTION MEDICINE

Substance use disorder is a significant issue in the United States, affecting approximately 48.5 million individuals annually, or 17.1% of the population [9]. Historically, addiction was considered a moral failing—a symptom of criminality or weak character. A variety of non-effective treatments were used until the 1900s, ranging from cocaine-based therapy, hydrotherapy, and institutionalization. In the 1930s, 12-step and self-help models were established for alcohol dependence treatment. In 1949, disulfiram (Antabuse) became the first drug approved to treat alcoholism [10]. The drug works by increasing the concentration of acetaldehyde, a toxic byproduct that occurs when alcohol is broken down in the body. Excess amounts of this byproduct (as when alcohol is consumed along with the medication) cause unpleasant symptoms, such as nausea and flushing of the skin. The anticipation of these effects can assist with cessation and abstinence. For more than 40 years, disulfiram was the only medication approved for the treatment of alcohol use disorder [10]. Since then, two additional medications—naltrexone (ReVia, Vivitrol) and acamprosate (Campral)—have been approved. The conceptualization of addiction and substance use disorder has also evolved and is now recognized to be a primary, chronic disease of brain reward, motivation, memory, and related circuitry. Dysfunction in these circuits leads to characteristic biologic, psychological, social, and spiritual manifestations [11]. As a primarily biologic illness, addiction is now recognized as a valid target for pharmacotherapy.

In the early 21st century, the United States experienced an unprecedented increase in opioid prescribing, use disorder, and fatal overdose [12]. In addition to the highly beneficial therapeutic effects, the toxic side effects and addictive potential of opioids have been known for centuries. These undesired effects have prompted a search for a potent synthetic opioid analgesic free of addictive potential and other complications. However, all synthetic opioids introduced into medical use share the same abuse liabilities of the classical opioids. The search for new opioid therapeutics has resulted in the synthesis of opioid antagonists and compounds with mixed agonist-antagonist properties, such as buprenorphine, which has expanded therapeutic options and provided the basis of expanded knowledge of opioid mechanisms [13].

Nonmedical use of prescription opioids was reported in literature as early as 1880. A report in 1928 documented that injection of opioids contributed to the development of nonmedical use and misuses of prescription opioids. Before 1930, the prevalence of nonmedical opioid injecting in the United States was low. But by the mid-1940s, more than one-half the admissions to the National Institute of Mental Health's Lexington Hospital were for the misuse of prescription opioids [14]. As of 2018, there were an estimated 2.1 million individuals with opioid use disorder in the United States [15]. In addition, more than 81,000 drug overdose deaths occurred in the United States in the 12 months ending in May 2020, the highest number of overdose deaths ever recorded in a 12-month period, and the rise was mainly attributed to synthetic opioids [16].

While methadone has long been in use in specialized clinics with strict licensing, the development of alternative treatments for opioid use disorder, including buprenorphine/naloxone (Suboxone), has revolutionized the approach to managing and treating this disorder.

3. ANTIPSYCHOTIC MEDICATIONS

Evidence Based Practice Recommendation

The American Psychiatric Association recommends that patients with schizophrenia be treated with an antipsychotic medication and monitored for effectiveness and side effects. This guideline statement should be implemented in the context of a person-centered treatment plan that includes evidence-based nonpharmacological and pharmacological treatments for schizophrenia.

https://psychiatryonline.org/doi/full/10.1176/appi.books.9780890424841.Schizophrenia02

Last Accessed: September 27, 2024

Strength of Recommendation/Level of Evidence: IA (High confidence that the evidence reflects the true effect)

With the development of clozapine, antipsychotic medications have been divided into typical antipsychotics (also referred to as first-generation antipsychotics) and atypical antipsychotics (also referred to as second-generation antipsychotics). In addition, a group of novel atypical antipsychotics have been developed and generally act on serotonin as well as dopamine receptors.

The choice of antipsychotic should be guided by the side effect profile, available route of administration (e.g., liquid forms, oral disintegrating tablets), and the patient's medical history, current medications, and preference. Many patients will be unwilling to switch from a drug that has been effective, even if a different drug may yield better results.

TYPICAL ANTIPSYCHOTICS

Typical antipsychotics (Table 1) have a primary site of action at the D2 receptor and are potent D2 receptor blockers. They also have noradrenergic, cholinergic, and histaminergic blocking action. These agents can also be described as high, intermediate, or low potency. High-potency antipsychotics are prescribed in lower doses, with the most widely prescribed of these being haloperidol (Haldol). Haloperidol is available in oral, intramuscular (IM), and long-acting IM decanoate formulations. Low-potency antipsychotics are prescribed in higher doses; the most widely used of these is chlorpromazine [17,18].

Table 1: TYPICAL ANTIPSYCHOTIC MEDICATIONS

Drug

Dose Range

Typical Starting Dose

Usual Maintenance Dosea

Route(s)

Indication(s)

Chlorpromazine

25–800 mg/day

25–50 mg/day

100–400 mg daily or BID

IM, IV, PO

Schizophrenia, bipolar disorder, intractable hiccups, agitation/aggression (severe, acute) associated with psychiatric disorders

Droperidol

0.625–10 mg/day

2.5–10 mg/day

10 mg/day

IM, IV

Postoperative nausea/vomiting, acute undifferentiated agitation (off-label)

Flupentixol

IM:5–40 mg/day

Oral:1–6 mg/day

IM:5–20 mg/day

Oral: 1 mg/day

IM: 20–40 mg every 2 to 3 weeks

Oral: 3–6 mg/day in divided doses

Oral, IM (depot)

Schizophrenia

Fluphenazine

2.5–40 mg/day

2.5–10 mg every 6 to 8 hours

Oral: 5–40 mg/day

IM: 12.5–25 mg every 2 to 4 weeks

PO, IM, decanoate

Psychotic disorders

Haloperidol (Haldol)

0.5–30 mg/day

Oral: 0.5–5 mg BID

5–15 mg BID

PO, IM, IV, decanoate

Bipolar disorder, hyperactive delirium, schizophrenia, Tourette-associated tics, acute/severe agitation (off-label)

Loxapine (Adasuve)

5–125 mg BID

10–25 mg BID

60–100 mg BID

PO, inhalation

Schizophrenia, acute agitation

Methotrimeprazine

6–200 mg/day

Mild: 6–25 mg/day in divided doses

Severe: 50–75 mg/day in divided doses

Oral: Up to 1 g/day in divided doses

IM: 75–100 mg/day in divided doses

PO, IM

Anxiety/tension disorders, insomnia, nausea/vomiting, pain, psychotic disorders

Molindone

5–75 mg TID

5–15 mg BID

10–25 mg TID

PO

Schizophrenia

Periciazine

5–40 mg/day

5–20 mg in the morning, followed by 10–40 mg in the evening

Titrate to lowest effective dose

PO

Psychosis

Perphenazine

2–24 mg BID

2–4 mg BID

8–24 mg BID

PO

Schizophrenia, nausea/vomiting

Pimozide

0.5–10 mg/day

1–2 mg/day in divided doses

Lowest effective dose (maximum: 10 mg)

PO

Tourette syndrome, delusional infestation (off-label)

Prochlorperazine (Compro)

2.5–25 mg/day

Oral: 5–10 mg every 6 to 8 hours

IM: 5–10 mg every 3 to 4 hours

IV: 2.5–10 mg every 3 to 4 hours

Rectal: 25 mg every 12 hours

Maximum: 40 mg/day

PO, IM, IV, rectal

Acute nausea and vomiting

Thioridazine

50–800 mg/day

50–100 mg TID

200–800 mg BID or QID

PO

Schizophrenia

Thiothixene

2–30 mg BID

2–5 mg BID

10–15 mg BID

PO

Schizophrenia

Trifluoperazine

2–40 mg/day

1–2 mg BID

15–20 mg/day

PO

Schizophrenia

Zuclopenthixol

10–400 mg/day

Oral: 10–50 mg/day in divided doses

IM: 50–150 mg/day

Oral: 20–40 mg/day

IM: Up to a maximum 400 mg/day

PO, IM

Schizophrenia, psychoses (acute and long-term)

aAll dosing is for adults. For pediatric uses, consult pediatric-specific literature.

BID = twice daily, IM = intramuscular, IV = intravenous, PO = oral, QID = four times per day, TID = three times per day.

Source: [17,18,19]

Adverse Effects

The adverse and side effect profiles of typical antipsychotics are generally poorer than the atypical antipsychotics. The prevention, detection, and treatment of extrapyramidal symptoms, most notably tardive dyskinesia, is the main challenge when prescribing typical antipsychotics.

Neurologic Effects

Patients who are prescribed typical antipsychotics should be monitored for neurologic side effects using the standardized Abnormal Involuntary Movement Scale (AIMS) (Figure 1). The AIMS consists of 12 items and can usually be completed within 10 minutes. It was developed specifically to detect and record the occurrence of tardive dyskinesia in any patient taking neuroleptic medication. Tardive dyskinesia is a syndrome characterized by abnormal involuntary movements of the patient's face, mouth, trunk, or limbs, and it affects 20% to 30% of patients who have been treated for months or years with neuroleptic medications. Patients who are older, are heavy smokers, or have diabetes are at increased risk of developing tardive dyskinesia. For most patients, this side effect develops three months after the initiation of neuroleptic therapy; in elderly patients, however, tardive dyskinesia can develop after as little as one month [20].

Figure 1: ABNORMAL INVOLUNTARY MOVEMENT SCALE (AIMS)

Source: [20]

Regular use of the AIMS allows the severity of symptoms to be followed over time. Initial AIMS testing should be done prior to the initiation of treatment and every three to six months during therapy. Either before or after completing the examination procedure, the patient should be observed unobtrusively at rest (e.g., in the waiting area). The chair used in the examination should be firm and without arms. The patient should remove his or her shoes and socks and any gum, candy, or food from his/her mouth prior to the examination. In addition to the examination and observation, the patient should be asked about:

- Dental/oral health (e.g., use of dentures, problems with teeth)

- Unintended movements in the extremities, mouth, or face and whether these movements are a bother or interfere with activities

Patients should be instructed to sit in a chair with their feet flat on the ground; a general observation of the patient's body may be made at this point. Patients should also be asked to drape their arms over their legs, with their hands hanging over their knees. Several additional tasks should be done, including:

- Opening the mouth to observe whether the tongue is moving or at rest

- Sticking the tongue out to observe for any abnormal movements

- Tapping the thumb with each finger as rapidly as possible to observe the flexibility of fingers as well as any other body movements that occur while the patient is concentrating on this manual task

- Flexing and extending the arms and wrists one at a time to monitor for rigidity and cogwheeling

- Walking around the room to observe for any parkinsonian-type movements

All findings during the examination should be recorded. It is important to note that repetitive, regular, rhythmic tremors are not recorded on the AIMS, as the tool is specific to tardive dyskinesia. However, these tremors may in fact be an adverse effect of neuroleptic treatment. If present, these movements should be monitored and considered when making treatment and pharmacotherapy decisions.

Metabolic Effects

Meta-analyses have shown that all antipsychotics are associated with an increased risk for weight gain, with the greatest gain seen with atypical agents (clozapine and olanzapine) and the least with typical agents (haloperidol). Numerous studies have concluded that H1 receptor antagonism action is most correlated with weight gain, although other receptor sites (including 5HT receptors) were also significantly associated with weight gain [21].

A reasonable approach to monitoring metabolic side effects involves measuring vital signs and weight prior to prescribing an antipsychotic agent and at every follow-up visit. Baseline blood work including a lipid profile, hemoglobin A1C, and a basic metabolic panel is also advised. Variances from baseline values and the presence or absence of weight gain can help guide the frequency of monitoring. However, obtaining laboratory studies at least yearly should be considered.

Cardiovascular Effects

Monitoring for QTc prolongation should be a consideration for all patients prescribed an antipsychotic. Obtaining a baseline electrocardiogram (EKG) prior to prescribing is good practice. Values greater than 500 msec should prompt referral to cardiology and a consideration to avoid medications that can prolong the QTc interval. Values of 450–500 msec require close follow-up EKG monitoring both after initiation of treatment and during any dosage adjustments.

ATYPICAL ANTIPSYCHOTICS

Antipsychotics remain a consistently popular option for the management of psychosis and schizophrenia. Since the reintroduction of clozapine in the 1990s, there has been a steady increase in the proportion of atypical antipsychotics prescribed compared with typical antipsychotics. By 2014, atypical antipsychotics accounted for almost 80% of total antipsychotics prescribed [22]. This has been partially attributed to treatment failure with typical antipsychotics (e.g., up to 30% of patients with schizophrenia fail to respond to typical antipsychotics), a desire to avoid extrapyramidal symptoms, and expansion of FDA-approved indications for atypical agents [17]. It should be noted that some of the lesser-used, low-potency typical antipsychotics may also avoid extrapyramidal effects.

As of 2024, there were 14 atypical antipsychotics approved for use in the United States (Table 2). Like the typical agents, these drugs are used primarily for the treatment of psychoses, although several are adjunctive treatments for major depressive disorder. Novel antipsychotics with various mechanisms of actions continue to be studied and approved; clinicians should consult the latest prescribing literature when selecting a medication for their patient.

Table 2: ATYPICAL ANTIPSYCHOTIC MEDICATIONS

Drug

Dose Range

Typical Starting Dose

Usual Maintenance Dosea

Route(s)

Indication(s)

Aripiprazole (Abilify)

2–30 mg/day

2.5–5 mg/day

10–20 mg/day

PO, decanoate

Bipolar disorder, treatment-resistant depression (adjunctive), schizophrenia

Asenapine (Saphris, Secuado)

5–10 mg BID

5 mg BID

10 mg BID

SL, transdermal patch

Bipolar disorder, schizophrenia

Brexpiprazole (Rexulti)

2–4 mg/day

1 mg/day

4 mg/day (with titration)

PO

Schizophrenia, treatment-resistant depression (adjunctive)

Cariprazine (Vraylar)

1.5–6 mg/day

1.5–6 mg/day

3–6 mg/day (with titration)

PO

Bipolar disorder, schizophrenia

Clozapine (Clozaril, Versacloz)

25–800 mg/day

25–800 mg/day

250–400 mg hourly or BID (Strict titration guidelines, must be in REMS)

PO (including oral disintegrating tablet)

Schizophrenia, suicidal behavior in schizophrenia or schizoaffective disorder

Iloperidone (Fanapt)

1–12 mg/day

1–2 mg BID

12 mg/day (lower doses in patients with hepatic dysfunction)

PO

Schizophrenia

Lumateperone (Caplyta)

42 mg/day

42 mg/day

42 mg/day

PO

Schizophrenia

Lurasidone (Latuda)

20–80 mg/day

20 mg/day

80 mg/day

PO

Bipolar major depression, schizophrenia

Olanzapine (Zyprexa)

2.5–20 mg/day

2.5–5 mg/day

15–20 mg/day

PO, IM, IV

Bipolar disorder, agitation/aggression associated with psychiatric disorders, schizophrenia

Paliperidone (Invega)

3–12 mg/day

3 mg/day

6 mg/day

PO, IM decanoate

Schizophrenia, schizoaffective disorder

Pimavanserin (Nuplazid)

34 mg/day

34 mg/day

34 mg/day

PO

Parkinson-associated psychosis

Quetiapine (Seroquel)

25–800 mg/day

50 mg/day

200–400 mg/day

PO, extended-release

Bipolar disorder, schizophrenia

Risperidone (Perseris, Risperdal)

0.5–6 mg/day

1–2 mg/day

4 mg/day

PO, IM decanoate

Bipolar disorder, schizophrenia

Ziprasidone (Geodon)

20–80 mg/day

40 mg BID

80 mg BID

PO, short-acting IM

Bipolar disorder (adjunctive), schizophrenia

aAll dosing is for adults. For pediatric uses, consult pediatric-specific literature.

BID = twice daily, IM = intramuscular, IV = intravenous, PO = oral, QID = four times per day, REMS = Risk Evaluation and Mitigation Strategy, SL = sublingual.

Source: [17,18,19]

When choosing an atypical antipsychotic, it is important that the clinician fully understand the mechanism of action of the drug being considered, as they have a wide variety of actions. There are also significant pharmacokinetic differences.

Aripiprazole

Aripiprazole is a partial dopamine agonist (not a blocker). Some research indicates that this medication may have a lower risk of tardive dyskinesia and metabolic syndrome. The initial effects of the oral preparation may be observed within days of treatment of bipolar disorder or acute mania and within one to two weeks in those with major depressive disorder or schizophrenia [19]. In all patients, continued improvement in efficacy is noted over the next several weeks. For bipolar/acute mania, maximal efficacy is seen in one to two weeks [19]. However, those with schizophrenia may see improvements for 4 to 6 weeks, and those with major depressive disorder may see maximal effects after 6 to 12 weeks [19].

Aripiprazole is metabolized hepatically and is primarily excreted in the feces (55%) and urine (25%). Peak plasma levels are noted in three to five hours following oral tablet administration, though high-fat meals can delay this time by hours. Following multiple IM doses of the extended-release formulation, peak plasma levels are noted in four days after deltoid administration or after five to seven days following gluteal administration [19].

The only absolute contraindication to the use of aripiprazole is hypersensitivity (including anaphylaxis) to the drug or any components of the formulation. The drug is associated with orthostatic hypotension and should be used with caution in patients predisposed to this effect or who are unable to tolerate transient hypotensive episodes [19]. Other possible adverse effects include increased serum glucose, weight gain, constipation, tremor, nausea/vomiting, agitation, anxiety, sedation/drowsiness, extrapyramidal reactions, headache, and insomnia [19].

Asenapine

Asenapine is a dibenzo-oxepino pyrrole atypical antipsychotic with mixed serotonin-dopamine antagonist activity. It is unique as the only atypical antipsychotic available in a sublingual formulation. When administered sublingually for the management of agitation, the onset of effects is seen within 15 minutes. In bipolar disorder/acute mania, initial effects are present within days, with continued improvements over one to two weeks [19]. In patients being treated for schizophrenia, the initial effects are observed within one to two weeks, and maximal effects are noted in four to six weeks.

Asenapine is metabolized by the liver and excreted primarily in the urine and feces [19]. Peak plasma levels are attained within 0.5 to 1.5 hours for the sublingual formulation and within 12 to 24 hours for the transdermal patch.

Severe hepatic impairment (Child-Pugh class C) and hypersensitivity are considered absolute contraindications to asenapine. Possible adverse effects include drowsiness/fatigue, insomnia, extrapyramidal reactions, headache, weight gain, increased serum triglycerides and serum glucose, and oral hypoesthesia [19].

Brexpiprazole

Brexpiprazole exhibits partial agonist activity for 5-HT1A and D2 receptors and antagonist activity for 5-HT2A receptors. As a partial dopamine agonist, it is associated with a decreased risk for extrapyramidal reactions (including tardive dyskinesia) and metabolic syndrome. The onset of action for the oral formulation is typically within 1 to 2 weeks, with increased efficacy over the following weeks (4 to 6 weeks in those with schizophrenia and 6 to 12 weeks in those with major depressive disorder) [19].

Brexpiprazole undergoes hepatic metabolism, primarily by CYP3A4 and CYP2D6. It is excreted in the feces and urine. Brexpiprazole reaches peak plasma levels within four hours [19].

The only absolute contraindication to the use of brexpiprazole is hypersensitivity reactions. However, it should be used with caution in patients with renal impairment. The most common adverse effects of brexpiprazole are increased serum triglycerides (typically <500 mg/dL), weight gain, and akathisia (inability to remain still) [19].

Cariprazine

Cariprazine acts as a partial dopamine (D2) and serotonin (5-HT1A) agonist, with antagonist activity at serotonin 5-HT2A receptors. Onset of initial effects varies from days (with bipolar disorder/acute mania) to up to two weeks (with schizophrenia) [19]. As with the other atypical antipsychotics, effects increase over time to peak efficacy experienced in up to 12 weeks.

Cariprazine is extensively metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 to active metabolites [19]. It is excreted through several routes, but most prominently through the urine. Peak plasma levels occur within three to six hours. Due to the long half-life of cariprazine and its active metabolites, changes in dose will not be fully reflected in plasma for several weeks.

There are no absolute contraindications to the use of cariprazine aside from hypersensitivity. Common adverse effects include extrapyramidal reactions, parkinsonian-like syndrome, akathisia, headache, nausea, and insomnia [19].

Clozapine

Clozapine has demonstrated efficacy in reducing the risk of suicide in patients with schizophrenia and known efficacy in treatment-resistant schizophrenia. It is believed to act through antagonism of the D2 and serotonin type 2A (5-HT2A) receptors [19]. The onset of action for the oral formulation is observed from within days up to two weeks, with increased effects for the subsequent weeks. For patients with treatment-resistant schizophrenia, longer trials of 8 to 12 weeks are recommended [19].

Metabolism of clozapine is extensively hepatic, with urinary and fecal excretion. Time to peak plasma levels is 2.2 to 2.5 hours, depending on the route of administration [19].

Serious hypersensitivity to clozapine or any component of the formulation is considered an absolute contraindication to its use [19]. Though not included in the U.S. labeling, Canadian labels include myeloproliferative disorders, impaired bone marrow function, active hepatic disease, severe renal impairment, paralytic ileus, uncontrolled epilepsy, severe nervous system dysfunction, and severe cardiovascular disease as additional contraindications. Common adverse effects are hypertension, hypotension, tachycardia, increased serum glucose levels, dyslipidemia, weight gain, constipation, decreased gastrointestinal motility, dyspepsia, nausea/vomiting, sialorrhea, dizziness, drowsiness/sedation, insomnia, vertigo, and fever [19].

The Clozapine REMS Program

Clozapine is associated with severe neutropenia (absolute neutrophil count [ANC] less than 500/mcL). The requirements to prescribe, dispense, and receive clozapine are incorporated into a single shared program called the Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program. A REMS is a strategy to manage known or potential risks associated with a drug or group of drugs and is required by the FDA for clozapine to ensure that the benefits of the drug outweigh the risk of severe neutropenia.

The Clozapine REMS Program provides a centralized point of access for prescribers and pharmacies to certify before prescribing or dispensing clozapine and to enroll and manage patients on clozapine treatment [23]. The monitoring requirements are established for the general population (most patients being prescribed clozapine) and for patients with benign ethnic neutropenia (BEN). BEN is a condition observed in certain ethnic groups whose average ANCs are lower than "standard" laboratory ranges for neutrophils. It is most commonly observed in individuals of African descent (approximate prevalence of 25% to 50%), some Middle Eastern ethnic groups, and in other non-White ethnic groups with darker skin; it is also more common in men [23]. At initiation of therapy, ANC monitoring should be conducted weekly for six months. If ANC levels remain ≥1,500/mcL in the general population or ≥1,000/mcL in patients with BEN, monitoring frequency may be reduced to every two weeks from 6 to 12 months, then monthly after 12 months. If neutropenia develops, monitoring may be more frequent, from three times weekly to daily depending on the severity of the neutropenia [23]. Prescribers are required to submit patients' ANC levels to the Clozapine REMS Program for every prescription of clozapine according to the patient's monitoring frequency.

Iloperidone

Iloperidone exhibits mixed dopamine (D2)/serotonin (5-HT2) antagonist activity. The agent's low affinity for histamine H1 receptors may decrease the risk for weight gain and somnolence, and its affinity for norepinephrine α1/α2C may improve cognitive function but increase the risk for orthostasis. With oral administration, the onset of antipsychotic action may be observed within one to two weeks of treatment, with four to six weeks to peak effect [19].

Hepatic metabolism of iloperidone results in creation of the active metabolites P88 and P95. These metabolites are excreted primarily in the urine and, less extensively, in the feces. Peak plasma levels are achieved in two to four hours [19].

Contraindications are limited to hypersensitivity reactions. The most common adverse effects are tachycardia, dizziness, drowsiness, increased serum prolactin, and weight gain [19].

Lurasidone

Lurasidone has documented mixed serotonin-dopamine antagonist activity, with high affinity for D2, 5-HT2A, and 5-HT7 receptors. Improvements in psychosis or bipolar disorder/depressive episode are noted within one to two weeks of treatment, although efficacy will improve for up to six weeks [19]. The medication should be given with food to improve absorption.

Hepatic metabolism is achieved primarily via CYP3A4 and results in two main active metabolites and two main nonactive metabolites [19]. Excretion is mainly in feces. Peak serum concentration occurs within one to three hours, with steady state concentrations achieved within seven days.

Lurasidone is contraindicated with hypersensitivity reactions or concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil) and inducers (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine) [19]. It should be used with caution and at the lowest possible dose in patients with hepatic impairment. Other common adverse effects include dyslipidemia, increased serum glucose, nausea, extrapyramidal reaction, drowsiness, akathisia, parkinsonian-like syndrome, and insomnia.

Olanzapine

Olanzapine displays potent antagonism of serotonin, dopamine, histamine, and alpha1-adrenergic receptors [19]. Its antipsychotic action is believed to be related to its effect on dopamine and serotonin. For acute agitation, effects are seen within 15 minutes with IM injection or within 5 to 10 minutes with IV administration. When administered orally for the management of bipolar disorder/acute mania or schizophrenia, initial effects are seen within days to two weeks; improvements may be noted for up to six weeks [19]. This agent is available in a long-acting injection formulation, and details about managing patients prescribed this route will be discussed in detail later in this course.

Olanzapine is metabolized via direct glucuronidation and cytochrome P450-mediated oxidation; 40% is removed via first-pass metabolism [19]. It is excreted in the urine (57%) and feces (30%). Maximum plasma concentrations after IM administration are five times higher than maximum plasma concentrations produced by an oral dose [19]. Clearance is increased in cigarette smokers and decreased in female patients. Following short-acting injection, peak plasma concentrations occur in 15 to 45 minutes; with extended-release injection, peak levels are noted in about one week. Following oral administration, peak serum concentrations are noted within six hours [19].

While there are no published contraindications to olanzapine, hypersensitivity is a likely barrier to use. This drug is associated with dose-related increases in prolactin levels, with associated menstrual-, sexual-, and breast-related effects [19]. Adverse reactions seen most commonly include dyslipidemia, increased serum glucose, weight gain, increased appetite, xerostomia, decreased serum bilirubin, akathisia, dizziness, drowsiness/fatigue, extrapyramidal reactions, headache, insomnia, parkinsonism, and asthenia [19].

Quetiapine

As with the other atypical antipsychotics, the antipsychotic effects of quetiapine are believed to be the result of its antagonism of dopamine (D2) and serotonin (5-HT2) receptors [19]. It also has antagonistic action against 5-HT1A, D1, histamine (H1), and adrenergic alpha1- and alpha2-receptors, some of which may result in adverse effects. After oral administration, initial effects are seen within days (for bipolar disorder/acute mania or bipolar disorder/depressive episode) or up to two weeks (for schizophrenia). Continued improvement in symptoms should be expected for 1 to 12 weeks [19]. If the extended-release formulation is used in the management of generalized anxiety disorder, the initial effects are observed within four to seven days, with continued improvement for eight weeks.

Quetiapine metabolism is primarily hepatic, with mainly urinary elimination. The time to peak plasma level is 1.5 hours for the immediate-release version and 6 hours for the extended-release formulation [19].

There are no absolute contraindications to the use of quetiapine, aside from hypersensitivity. Drowsiness is a common effect and may be severe enough to result in impairment, inability to safely carry out activities of daily living (increased fall risk), and nonadherence [19]. Other common adverse effects include hypertension, orthostatic hypotension (particularly among elderly patients), tachycardia, dyslipidemias, weight gain, increased appetite, xerostomia, agitation, dizziness, extrapyramidal reaction, headache, and withdrawal syndrome.

Risperidone

Risperidone's high 5-HT2 and dopamine-D2 receptor antagonist activity is responsible for its antipsychotic action. However, alpha1, alpha2 adrenergic, and histaminergic receptors are also antagonized with high affinity. Onset of action is within days to 2 weeks, though peak effect may be experienced after up to 12 weeks [19]. An orally disintegrating tablet may be used to manage acute agitation, with 70 minutes mean time to calm.

Risperidone undergoes extensive hepatic metabolism to create the active metabolite 9-hydroxyrisperidone [19]. It is primarily excreted in the urine. Time to peak plasma level is about 1 hour with oral administration (but it is 3 to 17 hours for the active metabolite). When administered subcutaneously, the first peak is in 4 to 6 hours; the second peak is in 10 to 14 days.

Hypersensitivity to risperidone, paliperidone, or any component is an absolute contraindication. Following each subcutaneous injection, a lump may develop and persist for several weeks. This is a self-limiting effect, and the injection site should not be rubbed or massaged [19]. Other common adverse effects include hyperprolactinemia, weight gain, constipation, nausea/vomiting, upper abdominal pain, akathisia, anxiety, dizziness, drowsiness/fatigue, extrapyramidal reaction, headache, insomnia, parkinsonism, and tremor.

LONG-ACTING INJECTABLE ANTIPSYCHOTICS

A subset of antipsychotics (both typical and atypical) are available as long-acting injectable forms (Table 3). When prescribing a long-acting injectable antipsychotic, clinicians first initiate treatment with the oral form for a long enough period to demonstrate tolerance. The oral formulation should be continued until the long-acting therapy has been established. Both fluphenazine and haloperidol use sesame oil in their suspension, which may cause allergic reactions in patients sensitive to sesame.

Table 3: LONG-ACTING INJECTABLE ANTIPSYCHOTICS

Drug

Usual Dosing

Onset

Oral Overlap

Comments

Fluphenazine decanoate

25 mg every 3 weeks

24 hours

24 hours

—

Haloperidol decanoate

50–200 mg every 4 weeks

One week

7 to 14 days

—

Paliperidone palmitate

117–156 mg monthly OR 273–819 mg every 3 months OR 1,092–1,560 mg every 6 months

—

None

Dosage will depend on the dose established prior to switching to the long-acting formulation.

Maintenance dose started 3 weeks after dose 2.

Risperidone (Risperdal Consta)

12.5–25 mg every 14 days

7 days

3 weeks

—

Olanzapine (Zyprexa Relprevv)

300 mg every 4 weeks

7 days

None

Post-injection syndrome limits usage.

Aripiprazole

300–400 mg every 30 days

7 days

7 days

High cost may limit access.

Source: [19]

There are no randomized controlled trials showing superiority of decanoate injections over other formulations; however, some small studies have shown at least similar efficacy of long-acting injected and oral haloperidol [24]. Plasma serum concentrations with steady-state decanoate yield lower plasma drug concentrations than with oral administration. This suggests that decanoate forms are at least as effective as oral agents and that lower doses may be effectively used with this formulation [24].

The efficacy of long-acting injectable antipsychotics other than haloperidol is not clear [25]. Studies have found varying results for different antipsychotics, both in terms of efficacy and side effect profile [24,25]. The ultimate decision to select a long-acting injectable antipsychotic is complicated and typically driven by a need to improve compliance.

CLASS-WIDE ADVERSE EFFECTS AND WARNINGS

There are a variety of adverse effects and special population warnings that apply across the class of antipsychotic medications. These should be taken into account when selecting an agent, structuring the treatment plan, and conducting follow-up assessments.

Dementia-Related Psychosis

In general, the management of behavioral and psychological symptoms of dementia (most prominently psychosis and agitation/aggression) relies on the off-label use of atypical antipsychotics, along with any effective behavioral interventions. Unfortunately, these drugs are often less than clinically effective, with many patients displaying no or only partial response [26]. Furthermore, elderly patients with dementia are much more likely to experience the adverse effects of antipsychotics. The FDA has included a boxed warning on the labels of all atypical antipsychotics regarding the increased mortality risk when these medications are used in elderly patients [26]. The APA recommends that nonemergency antipsychotic medication should "only be used for the treatment of agitation or psychosis in patients with dementia when symptoms are severe, are dangerous, and/or cause significant distress to the patient" [27].

Suicidality in Children, Adolescents, and Young Adults

Some antipsychotics are approved or used for the treatment of depressive episodes in bipolar disorder or as adjunctive treatment for unipolar depression. In this capacity, they are considered antidepressants, and antidepressants have been shown to increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (≤24 years of age) in the first months of treatment [28]. As such, a boxed warning has been added to the labeling information for these agents regarding this increased risk. This risk will be discussed in more detail later in this course.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome is a life-threatening idiosyncratic reaction to antipsychotic medications (including newer atypical agents, although it is more common with typical antipsychotics). It is a rare condition (occurring in approximately 0.01% to 0.02% of patients receiving antipsychotics), but it is unpredictable and potentially fatal, making it a significant concern [29]. Higher doses, higher potency, and long-acting formulations increase the risk of neuroleptic malignant syndrome.

Onset of symptoms is generally apparent within two weeks of treatment initiation. Clinical presentation consists of rigidity/stiffness, high fever, sweating, confusion, unstable blood pressure, and agitation. Signs and symptoms usually progress to a peak after three days. Prompt recognition is necessary to avoid significant morbidity and mortality, and treatment is immediate cessation of the antipsychotic medication and implementation of supportive measures (e.g., hydration, cooling) [30]. In more severe cases, administration of bromocriptine mesylate or dantrolene sodium may be indicated.

Elevated Prolactin Levels

An often-overlooked side effect of antipsychotics is elevated prolactin levels, which can present in men as gynecomastia or in women as galactorrhea and absence of menses. Elevated prolactin levels should be monitored and may necessitate changing agents.

Movement Disorders

As noted, extrapyramidal reactions can occur with antipsychotic therapy and can be a significant barrier to the effective use of these agents. There have also been anecdotal reports of dyskinesia seen with virtually all classes of medications, but the majority of patients with tardive dyskinesia have had exposure to antipsychotics. Studies estimate that up to 30% of patients on long-term antipsychotic therapy will develop various movement disorders [17,31]. The risk is also elevated in elderly patients.

The pathophysiology of tardive dyskinesia is believed to be related to abnormal functioning of the extrapyramidal tracks in the nervous system. Tardive literally means "late occurring," and although there are case reports of patients having symptoms after a single dose of a neuroleptic medication, the primary defining factor of tardive dyskinesia is that it is a later-occurring syndrome, as opposed to dystonia and akathisia, which usually develop in the early phases of treatment.

Tardive dyskinesia is also characterized by involuntary, uncontrollable movements. This differentiates it from dystonia, which is characterized by stiffness and decreased movement and can often be identified during AIMS testing by flexing the patient's wrists and elbows and observing for resistance. Akathisia is the perception of wanting to move and difficulty staying still; it often manifests as a constant need to pace or walk. In AIMS testing, akathisia can be identified in patients who have difficulty sitting without tapping feet, moving their legs, or otherwise having difficulties sitting still. Tardive dystonia typically presents with a fixed posturing of the face and neck, often a sideways tilt of the head, that the patient is unable to voluntarily correct. The most classic presentation of this is torticollis.

Proper diagnosis of movement disorders is essential, as treatment should be tailored to the specific disorder. Work-up of movement disorders should include consultation with appropriate specialists. This is especially important in the treatment of elderly patients for which the onset of parkinsonian movements may in fact be the hallmark of primary Parkinson disease as opposed to secondary parkinsonian side effects. Further assessment should be guided by neurologic consultation and may involve imaging.

After the specific movement disorder has been identified, treatment will focus on the goals of decreasing the movement disorder and the need to avoid destabilizing the patient's psychotic disorders.

Treatment of Tardive Dyskinesias

Treatment of tardive dyskinesia can be difficult and an impediment to the clinical stabilization of the patient. The primary consideration for patients receiving typical antipsychotics should be dose reduction or switching medications. Patients should be warned that tardive dyskinesia symptoms may initially worsen transiently as medication dosages are lowered (i.e., withdrawal-emergent dyskinesias). If a new medication will be used, clozapine should be considered first, as it has the lowest risk of tardive dyskinesia. However, it is vital to ensure that control of psychosis is maintained, particularly in patients at risk for self-harm or violence.

In 2017, the FDA approved the first medications for the treatment of tardive dyskinesia: valbenazine (Ingrezza) and deutetrabenazine (Austedo). The initial dose of valbenazine is 40 mg once daily. This is increased to 80 mg once daily after one week [19]. Continuation of a daily dose of 40 mg or 60 mg may be considered based on response and tolerability. Improvement is seen in 2 to 6 weeks, with the result stabilizing between 16 to 32 weeks. Deutetrabenazine is started at a dosage of 6 mg twice daily. This is increased as needed and tolerated in increments of 6 mg/day up to a maximum of 48 mg/day [19].

Although there is little evidence supporting this use, anticholinergics are often used to prevent extrapyramidal side effects caused by antipsychotics. Some clinicians will co-prescribe these drugs in an effort to prevent the development of extrapyramidal reactions. However, studies have shown that the numerous side effects associated with anticholinergics (e.g., cognitive impairment, urinary disturbances, vision changes, constipation) may preclude their use [31,32]. Elderly patients are particularly vulnerable to these effects, and male patients older than 40 years of age are especially susceptible to acute urinary retention. The Canadian Psychiatric Association recommends that clinicians consider discontinuation of anticholinergic medications for the treatment of tardive dyskinesia, keeping in mind that there is very little evidence to support this course of action and that drug-induced parkinsonism may worsen [33]. If anticholinergics are used, they should be prescribed at the lowest possible dose, patients should receive education on the potential risks and benefits, and informed consent should be obtained.

RISK MITIGATION STRATEGIES

As discussed, risk mitigation strategies should be initiated when prescribing any antipsychotics. Although only clozapine has a formal REMS program, there are steps that should be taken with any antipsychotic prescription to minimize the potential for adverse effects and manage associated risks (Table 4).

Table 4: RISK MITIGATION STRATEGIES FOR PATIENTS PRESCRIBED ANTIPSYCHOTICS

Risk Mitigation Strategy

Frequency of Assessmenta

AIMS testing

Every three months and after each dosage change

Electrocardiogram

One month after initiation, then yearly if QTc is less than 450 msec

Recheck after any major dosage change

Weight

At each visit

Vital signs

At each visit

Laboratory studiesb

With stable baseline values, consider monitoring every six months

Recheck with any significant weight gain or symptoms

aAll testing/assessment should occur prior to the initiation of therapy (to establish a baseline) and immediately after initiation.

bLaboratory studies should include hemoglobin A1C, basic metabolic panel, complete blood count, and prolactin level.

Source: Compiled by Author

Patients prescribed antipsychotics should receive education on the effects of the drugs, possible risks and benefits, and any recommended monitoring. However, this can be difficult if the patient has active psychosis or delusional paranoia. In these cases, caregivers and/or surrogate decision makers should be sought. All discussions should be fully documented. Patient education is an ongoing process (not a single event), and efficacy and adverse effects should be discussed regularly with patients as well as steps taken to treat or ameliorate adverse effects.

While Table 4 presents an example of risk mitigation strategies for all antipsychotics, the actual strategies used should be specific to the patient and agent(s); abnormalities should generate a consult to appropriate medical team members. Aside from prevention and early detection of adverse effects, risk mitigation strategies should include a treatment plan for any possible adverse reactions. As discussed, there are several class-wide potential adverse effects, and these known risks should be reviewed and planned for.

CASE STUDY

Patient A is 34 years of age with a history of schizoaffective bipolar disorder, first diagnosed at 18 years of age during his first year at college. His childhood was notable for several episodes of brief counseling for behavioral issues in school and at home, with a brief trial of methylphenidate (Ritalin) at 11 years of age. Patient A graduated from high school with his peers, but once at college, he developed delirious mania, paranoia, and psychosis. Treatment with olanzapine and valproic acid (Depakote) was initiated, but compliance has been an ongoing issue. During the past 16 years, the patient has had numerous episodes requiring hospitalization, one suicide attempt, and three arrests for breach of peace. He is now on probation and has been unable to maintain employment. He is living with his mother, who has communicated that he will have to leave the house if he does not take his medication. Patient A presents for medication management, stating that he does not like the weight gain he has experienced with many of the medications he has used in the past.

The nurse takes and documents a full history. On mental status exam, Patient A is alert and oriented. He scores 27 on a Mini-Mental State Exam (MMSE) and is mildly grandiose. His speech is slightly pressured but interruptible. At the time of presentation, Patient A is not taking any medications, having disagreed with his last provider's prescription of olanzapine, a drug that had been effective in the past.

Patient A is 6 feet 1 inch tall and weighs 235 pounds. His blood pressure is 124/86 mm Hg. Laboratory studies are requested, and all return normal. An EKG reveals a normal QTc and sinus rhythm.

The nurse asks Patient A what he wants to gain in his medication management, and his stated goals are to continue to live with his mother, to avoid future arrest, and to be able to maintain a job. The nurse discusses available typical and atypical oral and decanoate antipsychotics. After a long discussion, Patient A decides to try long-acting injection risperidone (Risperdal Consta). Patient education includes the risks of extrapyramidal reactions (e.g., movement disorders), weight gain, and prolactin elevation, which can lead to gynecomastia, as well as risk mitigation strategies if any of these develop.

A baseline AIMS test is conducted and is negative for any existing issues. The oral trial of risperidone is initiated, as required before using any long-acting injectable to demonstrate tolerance. The patient is titrated up to an oral dosage of 3 mg twice daily, which appears to resolve the patient's paranoia, pressured speech, and hypomania. Patient A reports that he is functioning better, but he reiterates that he does not think he will be able to comply with daily oral medication. The decision is made to progress to long-acting injected risperidone, which requires a three-week overlap with the oral medication.

While there is no exact dosage equivalency, the manufacturer recommends that a 6-mg total oral daily dose of risperidone should be converted to a bimonthly injectable dose of 37.5–50 mg long-acting risperidone. The patient is started at 37.5 mg IM every two weeks. After three weeks, the patient is stable and able to wean off the oral risperidone, decreasing to 4 mg in two divided doses for three days, then 2 mg in divided doses for three days, before total cessation. During this time, the nurse maintains frequent contact with Patient A to verify stability and compliance.

After six weeks, laboratory studies are ordered, including blood glucose level, lipids, and prolactin level, and a repeat EKG is done. All findings are normal. The nurse continues to administer the AIMS test every three months and to check weight and vital signs at every visit. While Patient A continues with this therapy, laboratory values are rechecked every three to six months.

Patient A responds well to treatment and is able to remain living with his mother. After six months, he has gained employment at a fast-food restaurant and has avoided any contact with law enforcement.

4. ANTIDEPRESSANT MEDICATIONS

Mood disorders affect approximately 9.7% of the U.S. population each year [34,35,36]. At least one major depressive episode occurs in approximately 21 million American adults, or about 8.3% of the U.S. population 18 years of age and older in a given year. The lifetime incidence of depression in the United States is 20% in women and 13% in men, or about 17% of all Americans.

There are five major classes of antidepressants available in the United States: tricyclic antidepressants (TCAs), MAOIs, SSRIs, serotonin-noradrenaline reuptake inhibitors (SNRIs), and atypical antidepressants; in 2023, the FDA approved gepirone, the first of a new class of antidepressants referred to as serotonin 5-HT1A receptor agonists (Table 5). Modern antidepressants were introduced in the 1950s following serendipitous discovery of antidepressant effects with TCAs and MAOIs. SSRIs were introduced in the late 1980s, followed by atypical antidepressants and SNRIs [37]. The monoamine hypothesis, proposed to explain the unexpected effects of TCAs/MAOIs in the 1950s, posits that depression results from deficient brain serotonin and/or norepinephrine levels. This remained the dominant paradigm of depression and the basis of nearly all FDA-approved antidepressants for the next five decades [38,39]. However, limitations of the monoamine hypothesis and mechanistic homogeneity of standard antidepressants are now understood. Major depressive disorder is more complex and diverse than previously assumed, and novel pathways that underlie its pathophysiology have been identified [40,41].

Table 5: ANTIDEPRESSANT MEDICATIONSa

Drug

Dose Range

Typical Starting Dose

Potential Adverse Effects

Comments

MAOIs

Selegiline (Emsam, Zelapar)

6–12 mg transdermal patch every 24 hours

6 mg transdermal patch every 24 hours

Serious food and drug interactions

Also used in treatment of Parkinson disease

Isocarboxazid (Marplan)

10–40 mg/day

10 mg BID

May take 3 to 6 weeks to see effects. Dose should be reduced once maximum clinical effect is seen. If no response obtained within 6 weeks, additional titration is unlikely to be beneficial.

Phenelzine (Nardil)

15–30 mg every 8 hours

15 mg every 8 hours

—

Tranylcypromine (Parnate)

10–60 mg BID

10–30 mg BID

—

Moclobemide

300–600 mg/day

300 mg/day in 2 divided doses

—

Tricyclic Antidepressants

Amitriptyline

50–300 mg/day

25–50 mg/day as a single dose at bedtime or in divided doses

Xerostomia, sedation

Follow levels and EKG/QTc

Clomipramine (Anafranil)

12.5–250 mg at night

12.5–50 mg at night

Approved for OCD, off-label for MDD

Doxepin (Silenor)

25–300 mg at night or in divided doses

25–50 mg at night

Usually reserved for treatment-resistant MDD

Imipramine

25–300 mg at night or in divided doses

25–50 mg at night or in divided doses

—

Trimipramine

25–300 mg at night or in divided doses

25–50 mg at night or in divided doses

—

Amoxapine

25–600 mg total (may be BID dosing)

25–50 mg at bedtime or BID

The maximum dose in outpatients is 400 mg/day; in hospitalized patients, it is 600 mg/day.

Desipramine (Norpramin)

25–300 mg daily or in divided doses

25–50 mg/day

—

Nortriptyline (Pamelor)

25–150 mg/day

25 mg at night

—

Protriptyline

10–60 mg daily divided in 3 to 4 doses

10–20 mg daily divided in 3 to 4 doses

—

SSRIs

Citalopram (Celexa)

20–40 mg/day

20 mg/day

GI upset

Few drug interactions

Lower maximum daily dose (20 mg) recommended for patients at risk for QTc prolongation

Escitalopram (Lexapro)

10–20 mg/day

10 mg/day

GI upset

Also approved for generalized anxiety disorder

Fluoxetine (Prozac)

20–80 mg/day

20 mg/day

GI upset, activation syndrome

Also approved for bulimia, panic disorder, generalized anxiety disorder, OCD, and PMDD

Fluvoxamine, immediate-release

50–300 mg at night

50 mg at night

Nausea

Approved for OCD, off-label for MDD

Fluvoxamine, controlled-release

100–300 mg at night

100 mg at night

Paroxetine (Brisdelle, Paxil, Pexeva)

20–50 mg/day

20 mg/day

Sedation

Also approved for generalized anxiety disorder, panic disorder, OCD, PTSD, PMDD, social anxiety disorder, and vasomotor symptoms of menopause

Paroxetine, controlled-release (Paxil CR)

25–62.5 mg/day

25 mg/day

Sedation

Sertraline (Zoloft)

50–200 mg/day

50 mg/day

GI upset

Also approved for OCD, panic disorder, PMDD, PTSD, and social anxiety disorder

SNRIs

Venlafaxine (Effexor)

37.5–375 mg BID

37.5–75 mg BID

Nausea, hypertension, xerostomia, drowsiness

Use with caution in patients with glaucoma

Venlafaxine, extended-release (Effexor XR)

37.5–225 mg/day

37.5–75 mg/day

Nausea, xerostomia, hypertension

Use with caution in patients with glaucoma

Also approved for generalized anxiety disorder, panic disorder, and social anxiety disorder

Levomilnacipran (Fetzima)

20–120 mg/day

20 mg/day

Orthostatic hypotension (dose related), nausea

—

Desvenlafaxine (Pristiq)

50–100 mg/day

25-50 mg/day

Dizziness, insomnia, hyperhidrosis, nausea, xerostomia, anxiety

No evidence that dosing over 50 mg is more effective

In patients who are sensitive to side effects (particularly anxiety), consider lower starting dose (25 mg/day)

Duloxetine (Cymbalta, Drizalma Sprinkle)

40–120 mg/day

40–60 mg/day

Activation syndrome, weight loss, GI upset, headache

Also approved for fibromyalgia, generalized anxiety disorder, chronic musculoskeletal pain, and diabetic neuropathic pain

Avoid in patients with renal impairment (CrCl <30 mL/min)

Milnacipran (Savella)

25–100 mg BID

25–50 mg BID

Nausea, headache, constipation, insomnia

Approved for fibromyalgia, off-label for MDD

Atypical Antidepressants

Bupropion (Aplenzin)

75–450 mg/day in divided doses

100 mg BID

Increased seizure threshold, weight loss, GI upset, agitation

Also approved for smoking cessation and seasonal affective disorder

No sexual side effects

Bupropion, sustained-release (Wellbutrin SR)

150–200 mg BID

150 mg/day in the morning

Bupropion, extended-release (Forfivo XL, Wellbutrin XL)

150–450 mg/day in the morning

150–175 mg/day in the morning

Mirtazapine (Remeron)

15–45 mg at bedtime

15 mg at bedtime

Weight gain, increased appetite, drowsiness

Weight gain may limit satisfaction and compliance

Trazodone

50–600 mg BID

50 mg BID

Drowsiness, dizziness, xerostomia, GI upset

—

Nefazodone

50–600 mg in divided doses

50–100 mg BID

Headache, xerostomia, drowsiness

Should not be initiated in individuals with active liver disease or elevated baseline serum transaminases

Brexanolone (Zulresso)

—

60-hour continuous IV infusion

(Total dose: 270 mg/kg)

Drowsiness, sedation, xerostomia, dizziness

Used only for inpatient treatment of postpartum depression

Requires REMS

Esketamine (Spravato)

56–84 mg intranasal twice weekly

56–84 mg intranasal twice weekly

Dissociation, anxiety, nausea, dizziness

Reserved for treatment-resistant MDD or MDD with suicidality

Requires REMS

Serotonin 5-HT1A Receptor Agonist

Gepirone (Exxua)

18.2–72.6 mg

18.2 mg/day

Nausea, dizziness

No sexual side effects or weight gain

Multimodal Agents

Vilazodone (Viibryd)

10–40 mg/day

10 mg/day

Headache, GI upset

Alternative agent

Vortioxetine (Trintellix)

5–20 mg/day

5–10 mg/day

Nausea, sexual dysfunction

aAll information provided is for reference only. Unless otherwise stated, all agents are approved for the treatment of major depressive disorder, unipolar.

BID = twice daily, EKG = electrocardiogram, GI = gastrointestinal, MAOI = monoamine oxidase inhibitor, MDD = major depressive disorder, OCD = obsessive-compulsive disorder, PMDD = premenopausal dysphoric disorder, PTSD = post-traumatic stress disorder, SNRI = serotonin and norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor.

Source: [17,19]

Unlike psychotic disorders, first-line therapy for mild depression should include nonpharmacologic interventions, such as cognitive behavioral therapy, guided self-help, interpersonal psychotherapy, and other lifestyle and psychosocial interventions. Evidence-based guidelines recommend that the process of treatment selection involve shared decision making between provider, patient, and family members, and that the values, priorities, and goals of the patient be included in discussions of risks and benefits of treatment options [42]. Ongoing communication with other providers involved in the care of a patient is essential for coordination and monitoring and can involve different care providers in the same primary care clinic or the primary care provider and therapist or psychiatrist [43].

Combining pharmacotherapy and psychotherapy treatments should be considered for patients with major depressive disorder when practical, feasible, available, and affordable. Both approaches combined show better outcomes than either as monotherapy. When unable to combine therapy because of patient preference or problems with availability or affordability, consider psychotherapy when the presentation is mild-to-moderate, and antidepressants when depression is severe or chronic. Patients with major depressive disorder with psychotic features should receive an antipsychotic and an antidepressant medication or ECT. Lithium can be added in patients unresponsive to antipsychotic/antidepressant therapy [43]. Other specific factors should be considered in treatment planning, including the presence of substance abuse, specific features, and other comorbid disorders. If a patient displays signs of potential suicide, increasing the treatment intensity, including hospitalization if needed, should be considered, and pharmacotherapy and psychotherapy should both be provided [43].

Prior to the prescription of antidepressants, patients should have a full history and physical exam and any relevant medical conditions (e.g., heart failure, renal disease) should be noted. A full medication reconciliation should be conducted, with special attention to potential interactions.

Treatment with antidepressant medications can involve dosage adjustments and/or trials of a different medication at some point to maximize response and minimize side effects [43]. Patient adherence to the medication regimen is essential in achieving the maximum clinical benefit. Providers should closely monitor patients for worsening depressive symptoms and emergent suicidality; appropriate intervention includes stopping or modifying the drug therapy or hospital admission [44]. Providers should instruct patients and caregiver(s) to be alert for emerging agitation/irritability, suicidality, and worsening depression, and to report this immediately to a healthcare provider [44].

The treatment efficacy of antidepressants in major depressive disorder is broadly similar. Other factors to help guide medication selection include previous patient or family member response to antidepressants (if any); impact on psychiatric or medical comorbidities; clinician familiarity; patient preference; safety in overdose; availability and cost; and drug-drug interactions [44]. Most second-generation antidepressant drugs are recommended as first-line treatment due to the quality of published data, side effect tolerability, and safety in overdose relative to TCAs and MAOIs [43,44,45].

The three most distressing side effects for patients treated with antidepressants are sleep disturbance, sexual dysfunction, and weight gain [46]. Choice of medication should be guided by knowledge of comparative side effects and patient priorities; some patients will be more concerned about sexual side effects, while for others, nausea, sleep disturbances, or weight gain may be more distressing [47]. In addition, available evidence regarding the optimal pharmacotherapeutic selection for the treatment of dimensions of depression and DSM-5-TR specifiers should be considered.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

SSRIs are thought to act by inhibiting serotonin transporters (SERT) that reuptake serotonin (5-HT) into the presynaptic cell, increasing 5-HT in the synaptic cleft. SSRIs have advantages of low overdose lethality and better tolerability than first-generation antidepressants, which can improve adherence. SSRIs are particularly effective in patients with obsessive-compulsive symptoms, but may initially worsen anxiety or panic symptoms [35,43,44]. This class includes the agents fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa), escitalopram (Lexapro), and vortioxetine (Brintellix). Escitalopram may have fewer drug-drug interactions than other SSRIs, and fluoxetine may be a better choice in patients with poorer adherence due to its long half-life [35,43,44].

Common Side Effects

The most common side effects with SSRIs are gastrointestinal (nausea, vomiting, and diarrhea), activation/insomnia (restlessness, agitation, anxiety, akathisia, and sleep disturbances), sexual, headache, fatigue, and weight gain [35,43,44]. Many of these side effects dissipate over time. Sertraline is particularly associated with diarrhea, and paroxetine with weight gain [35,43].

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS

SNRIs act by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine. This results in an increase in the extracellular concentrations of serotonin and norepinephrine and therefore an increase in neurotransmission [35,43,44]. Most SNRIs, including venlafaxine (Effexor), desvenlafaxine (Pristiq), levomilnacipran (Fetzima), and duloxetine (Cymbalta), are several-fold more selective for serotonin than norepinephrine.

Safety, tolerability, and side effect profiles of SNRIs resemble SSRIs, with the exception that the SNRIs have been associated (rarely) with sustained elevated blood pressure. SNRIs can be used as first-line agents, particularly in patients with significant fatigue or comorbid chronic pain, and have an important role as second-line agents in patients who have not responded to SSRIs [35,43,44].

Venlafaxine is especially beneficial in treating anxiety and panic attacks in patients with depression, and acts like an SSRI at lower doses (75 mg/day) but more like an SNRI at doses ≥150 mg/day [35,43,44].

Common Side Effects

SNRIs are associated with greater likelihood of increased pulse rate, dilated pupils, dry mouth, excessive sweating, and constipation [19]. Venlafaxine has a greater incidence of nausea and vomiting than SSRIs and may be associated with an increased risk for cardiovascular events [35,43].

TRICYCLIC ANTIDEPRESSANTS

TCAs are predominantly serotonin and/or norepinephrine reuptake inhibitors that act by blocking the serotonin transporter and the norepinephrine transporter, respectively, which results in an elevation of the extracellular concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission. TCAs also have varying but typically high affinity for the H1 and H2 histamine receptors and muscarinic acetylcholine receptors. As a result, they also act as potent antihistamines and anticholinergics. These properties are generally undesirable in antidepressants, however, and likely contribute to their large side effect profiles [48].

TCAs are classified by the nature of the final amine group on the side chain, with the tertiary amines amitriptyline (Elavil), clomipramine (Anafranil), doxepin (Sinequan), trimipramine (Surmontil), imipramine (Tofranil), and lofepramine (Lomont); the secondary amines nortriptyline (Pamelor), desipramine (Norpramin), and protriptyline (Vivactil); and the tetracyclic antidepressants amoxapine (Asendin) and maprotiline (Ludiomil).

TCAs are comparable in efficacy to SSRIs/SNRIs, but their side effect profile makes them seldom used as first-line therapy [35,43,44]. TCAs may initially worsen anxiety or panic symptoms. Due to side effect potential of cardiac arrhythmia, TCAs should be used very cautiously, if at all, in patients with heart problems. Secondary amine TCAs cause less orthostatic hypotension and sedation than tertiary amines, which should be avoided in elderly patients due to the risk for orthostatic hypotension, sedation, cognitive problems, and cardiac effects. The secondary amine nortriptyline is especially effective for elderly patients with moderate-to-severe depression. Clomipramine is particularly effective in patients with obsessive-compulsive symptoms [35,43,44].

Common Side Effects

Anticholinergic and antihistamine activity accounts for many side effects, including dry mouth, blurred vision, reduced gastrointestinal motility or constipation, urinary retention, cognitive and/or memory impairment, and increased body temperature [35,43,44]. Other side effects may include drowsiness, anxiety, emotional blunting (apathy/anhedonia), confusion, restlessness, dizziness, akathisia, hypersensitivity, changes in appetite and weight, sweating, sexual dysfunction, muscle twitches, weakness, nausea and vomiting, hypotension, tachycardia, and arrhythmia. Tolerance to side effects often occurs if treatment is continued. Side effects may also be less troublesome if treatment is initiated with low doses and gradually increased [48,49].

MONOAMINE OXIDASE INHIBITORS

MAOIs inhibit monoamine oxidase (MAO), an enzyme that degrades and inactivates 5-HT, norepinephrine, and dopamine. This increases monoamine levels and activity. Earlier MAOIs were irreversible MAO inhibitors, deactivating the enzyme until slowly replenished over a two-week period [50,51]. MAOIs includes phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), linezolid (Zyvox, Zyvoxam, Zyvoxid), moclobemide (Aurorix, Manerix), pirlindole (Pirazidol) (approved for use in parts of Europe), and selegiline (Deprenyl, Eldepryl, Emsam).

Most MAOIs appear broadly effective in a range of depressive and anxiety disorders, and may be more effective than other antidepressant classes in major depressive disorder with pronounced anxiety or panic symptoms [35,43,44]. Major depressive disorder with atypical features may preferentially respond to MAOIs over other antidepressant classes. Although effective, MAOIs are rarely the first- or second-line treatment choice due to serious side effect potential from medication interactions and dietary restriction. The selegiline transdermal patch (Emsam) used at the lowest strength (6 mg delivered over 24 hours) may lack the dietary restrictions required of oral MAOIs [52].

Common Side Effects

With oral ingestion, MAOIs inhibit the catabolism of dietary amines. When foods containing tyramine are consumed, the individual may suffer from hypertensive crisis [50]. If foods containing tryptophan are consumed, hyperserotonemia may result. The amount required to cause a reaction varies greatly from individual to individual and depends on the degree of inhibition, which in turn depends on dosage and selectivity.

MAOIs should not be combined with psychotropic drugs or with any other psychoactive substance except under expert care. This includes a wide range of prescribed, over-the-counter, and illicit drugs and nutritional supplements, such as St. John's wort. Common side effects include orthostatic hypotension, weight gain, sexual dysfunction, sedation, headache, and insomnia [50].

ATYPICAL ANTIDEPRESSANTS

The atypical antidepressants are diverse in monoamine activity and do not fit the profile of other classes. They include bupropion (Wellbutrin), nefazodone (Serzone), mirtazapine (Remeron), and trazodone (Desyrel). Nefazodone and trazodone block postsynaptic serotonin type-2 receptors and inhibit presynaptic serotonin reuptake. Bupropion inhibits activity of norepinephrine and dopamine transporters, and the active metabolite hydroxybupropion contributes to the drug's effects. Mirtazapine is a potent antagonist at 5-HT2, 5-HT3, alpha2, and H1 histamine receptors. As a group, these agents show low toxicity in overdose and may have an advantage over the SSRIs by causing less sexual dysfunction and gastrointestinal distress [35,43,44].

Each agent has apparent benefits and drawbacks, with some better suited for specific patient populations. Bupropion is associated with a risk of seizure at higher doses, especially in patients with a history of seizure or eating disorders, and should be used cautiously in anxious patients [35,43,44]. It may be more effective for atypical major depressive disorder than other antidepressants.

Mirtazapine can be very sedating and promotes appetite and weight increase, which in some patients may be desirable. It has a faster onset of action than fluoxetine, paroxetine, or sertraline, and may be superior to SSRIs in depression associated with severe insomnia and anxiety. Trazodone is also very sedating and is usually used as a sleep aid rather than as an antidepressant [35,43,44].

Common Side Effects

The side effects of atypical antidepressants vary considerably. With bupropion, the most common side effects are agitation, jitteriness, mild cognitive dysfunction, insomnia, gastrointestinal upset, and possible increased risk for seizures [35]. Patients taking mirtazapine may experience dry mouth, sedation, weight gain, and increased serum cholesterol [43]. Sedation is the most common side effect associated with trazodone, followed by cardiovascular side effects (such as orthostasis) and sexual side effects [43]. Finally, nefazodone is associated with sedation, dry mouth, nausea, constipation, orthostasis, visual alterations, and possible increased risk of hepatotoxicity; this has led to nefazodone being seldom prescribed [35].

SEROTONIN 5-HT1A RECEPTOR AGONIST

Gepirone is the first and only selective 5-HT1A receptor partial agonist approved by the FDA for the treatment of major depressive disorder [19]. Gepirone is in the azapirone group of compounds related to buspirone (which is approved for generalized anxiety disorder). It is noted for its absence of sexual side effects and weight gain and is being studied as a treatment for hypoactive sexual desire disorder in men and women [131,132]. It is hypothesized that the libido improvement seen in studies was independent of its antidepressant or antianxiety effects. The most common side effects are nausea and dizziness, but, according to the manufacturer, these are usually mild, transient, and associated with dosage increases [133].

MULTIMODAL ANTIDEPRESSANTS

Vilazodone and vortioxetine are multimodal antidepressants that combine SSRI properties with other pharmacologic actions affecting monoamine and non-monoaminergic targets. Evidence does not suggest greater efficacy than SSRI/SNRIs, but these agents may improve tolerability or efficacy on specific clinical domains [53].

Vilazodone, approved in 2011, primarily acts as a SERT inhibitor and 5-HT1A receptor partial agonist, and modestly inhibits dopamine and norepinephrine transporters. This antidepressant may be most helpful in patients lacking response to initial SSRIs. Vilazodone must be taken with food, which increases its absorption and bioavailability by 72% [54,55].

Vortioxetine, approved in 2013, acts through various serotonin receptors as an antagonist (5-HT3/7/1D), partial agonist (5-HT1B), or agonist (5-HT1A), and inhibits SERT. It also activates the glutamate system in the frontal cortex. Vortioxetine displays a specific clinical efficacy in the treatment of cognitive deficits associated with major depressive disorder. The most common side effects are nausea, vomiting, and constipation [53].

CLASS-WIDE ADVERSE EFFECTS

Sexual Dysfunction

Nearly all commercially available antidepressants are associated with sexual side effects. SSRI/SNRIs show the highest rates of sexual dysfunction, including impaired sexual motivation, desire, arousal, and orgasm affecting men and women. Prescribers greatly underestimate the prevalence and patient burden of sexual side effects from antidepressants and other medications [56]. Among antidepressants, prevalence rates of sexual side effects are highest with venlafaxine and SSRIs; moderate with TCAs and MAOIs; low with bupropion, trazodone, nefazodone, mirtazapine, agomelatine, and vilazodone; and lowest with the reversible MAOI moclobemide [57,58]. As noted, gepirone is not associated with sexual dysfunction. Compared to spontaneous patient reporting, systematic inquiry increases the rate of identifying sexual side effects by ≥60% [58].

Management of sexual side effects in men includes the use of phosphodiesterase-5 inhibitors such as sildenafil, vardenafil, tadalafil, and avanafil as first-line treatment or switching to bupropion [59]. In women, sexual side effect management considers symptoms, age, and potential hormonal contribution when peri- or post-menopausal.

Increased Suicidality

Several papers documenting an increased risk of suicidal thoughts and behavior with antidepressants, primarily SSRIs, have been published over the past decade. A review of the literature found that antidepressant use, including SSRIs, carried a small short-term risk of inducing suicidal thoughts and suicide attempts in persons younger than 25 years of age, with persons 30 to 40 years of age having a lower risk than those younger than 25 years. This risk should be balanced against the well-known beneficial effects of antidepressants that include reduced suicidal ideation and behavior, particularly in the long term. Clinical decision making should weigh the benefits and potential risks and strive to keep the potential risks of antidepressant treatment to a minimum [60,61].

Discontinuation Symptoms

Antidepressant discontinuation (more appropriately termed withdrawal) symptoms are described by the FINISH mnemonic (flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, hyperarousal), may be experienced by up to 40% of patients when antidepressants are stopped abruptly, and may occur with any antidepressant [62,63,64,65]. SSRI withdrawal symptoms are far more frequent with paroxetine. Common symptoms include dizziness, nausea, headache, confusion, low energy, weakness, sleep disturbance, flu-like symptoms, restlessness, agitation, anxiety, panic, anger, and irritability. Less common and more severe symptoms include electric-shock sensations, vertigo, paresthesia, intensified suicidal ideation, aggression, derealization, depersonalization, and visual/auditory hallucinations. Gradual tapering is a reasonable strategy but does not prevent the onset of SSRI withdrawal [66]. SSRI withdrawal syndrome is least likely with fluoxetine and vortioxetine [62].

Symptoms usually begin within five days of treatment cessation or occasionally during taper or after missed doses [67,68]. Symptoms may be severe enough to interfere with daily functioning, and although a four-week taper is usually suggested, some patients may require longer periods, particularly with paroxetine and venlafaxine [69]. Treatment is pragmatic. If symptoms are mild, reassure the patient that this is a common occurrence and that the symptoms will pass in a few days. If symptoms are severe, reintroduce the original antidepressant or a replacement from the same class with a longer half-life, and taper gradually while monitoring for symptoms. Patients should be emphatically informed that the possible or actual emergence of discontinuation symptoms is not a manifestation of addiction to the antidepressant [70]. SSRI withdrawal can also be approached by switching to a course of fluoxetine, such as 10 mg for several weeks, which is slowly tapered and discontinued [43].

PEDIATRIC CONSIDERATIONS

Among the antidepressants, only fluoxetine is approved for use in treating major depressive disorder in pediatric patients. In addition, fluoxetine, sertraline, fluvoxamine, and clomipramine are approved for obsessive-compulsive disorder (OCD) in pediatric patients. Other than these indications, all other use of antidepressants in children is off-label [71]. However, these off-label uses are relatively common, particularly among adolescents and pediatric patients with more severe disease.

Beginning in 2003, data have suggested an increase in attempted and completed suicides in children treated with antidepressants [72]. There is also compelling research indicating that the decrease in prescribing of antidepressant medications to adolescents in the period after 2003, both in the United States and the Netherlands, led to an increase in suicide rate [72]. In the Netherlands, the rate increased by 49% between 2003 and 2005, during which time there was a significant decrease in pediatric SSRI prescriptions.

Data for pediatric efficacy (defined as improvements in depressive symptoms) are strongest for fluoxetine, which is approved for children older than 8 years of age [72]. The best results are achieved with a combination of pharmacotherapy and cognitive-behavioral therapy. Due to the risks and complexities involved in the treatment of children with depression, it is recommended that a multidisciplinary team approach be utilized in the treatment of these patients.

Pediatric patients being treated with antidepressants for any indication should be closely observed for clinical worsening, as well as agitation, irritability, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. This monitoring should include daily observation by families and caregivers and frequent contact with the physician. It is also recommended that prescriptions for antidepressants be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose [71].

TREATMENT-RESISTANT DEPRESSION

Evidence Based Practice Recommendation

The American Psychiatric Association recommends optimizing the medication dose as a reasonable first step for patients treated with an antidepressant who have not responded fully to treatment if the side effect burden is tolerable and the upper limit of a medication dose has not been reached.

https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf

Last Accessed: September 26, 2024

Strength of Recommendation: II (Recommended with moderate clinical confidence)

Standard antidepressants fail to produce adequate response in 30% to 50% and remission in up to 70% of patients with major depressive disorder [73,74,75]. Partial response, instead of full remission, leaves patients with impairing residual symptoms and high risk of relapse. Each relapse increases symptom severity, decreases treatment response, and heightens risk of treatment-resistant depression [76].

Treatment-resistant depression is a problem increasingly encountered by primary care and mental health providers. Contributors to treatment-resistant depression include illness severity, medical and psychiatric comorbidity, and the limitations of FDA-approved drug options. The definition of treatment resistance lacks consensus, but the most common definition is an inadequate response to two or more antidepressants. This does not consider adjunctive strategies or distinguish patients with partial versus non-response [62,77].

In addition to augmentation strategies, a diverse and growing range of interventions are available as options for treatment-resistant depression [78,79,80]. Most engage novel therapeutic targets.

Neurostimulation Therapies

The limitations of standard antidepressants, frequent treatment resistance, and the paradigm shift in psychiatry away from specific neurotransmitter focus and toward an integrative neural network perspective has prompted the development of novel depression treatment approaches, such as neurostimulation therapy. Repetitive transcranial magnetic stimulation (rTMS) is a nonpharmacologic approach to the treatment of depression approved in 2008, and multiple randomized controlled studies have shown its use to be safe and effective [81]. Patient selection for rTMS is complex and should be done in conjunction with the specialist administering the therapy as well as the patient. Most clinicians refer patients after they have failed to improve on at least one antidepressant.

Electroconvulsive Therapy

The use of ECT in the treatment of treatment-resistant depression is long and varied. While there was historical misuse and abuse of this modality, particularly in the unethical care of patients in institutions, it has a proven record of efficacy for patients with severe or refractory depression.

ECT is effective as acute treatment, but multiple treatments are required and many who respond experience symptoms again within six months [82]. ECT generates electrical stimuli for seizure induction through electrodes applied to the scalp, with the patient under general anesthesia and pre-medicated with a muscle relaxant. Clinical outcomes are highly influenced by electrode placements, electrical intensity, and pulse width [83].

As first-line treatment, ECT is used for severe melancholic, catatonic, psychotic, or refractory depression and for patients who refuse to eat or drink, have very high suicide risk or severe distress, pregnant women with severe depression, or who have a previous positive ECT response [47,82,84].

Full ECT response requires at least four to six sessions delivered two to three times per week. Twice weekly ECT requires longer treatment duration, but more than three treatments per week is not recommended due to the greater cognitive side effect risk [83].

Headaches (45%), muscle soreness (20%), and nausea (1% to 25%) during ECT are transient and treated symptomatically; 7% of patients with major depression switch into a manic or mixed state [83]. Most distressing to some patients is loss of autobiographic memory recall, infrequently reported to persist beyond six months [84]. ECT lacks absolute contraindication, but increased safety risk is associated with space-occupying cerebral lesion, increased intracranial pressure, recent cerebral hemorrhage, or aneurysm [83,85].

Pharmacotherapy

Ketamine is an N-methyl-D-aspartate receptor (NMDA-R) antagonist that was approved for use as an anesthetic in 1970. Demonstration that a single IV dose in patients with treatment-resistant depression reliably produced rapid, robust antidepressant effects for one week was a breakthrough discovery for research and a turning point for patients for whom all other treatment approaches had failed [86]. The short-term efficacy of ketamine treatment of refractory major depressive disorder and bipolar depression is now established; more than one dozen placebo-controlled trials have shown that patients with refractory unipolar or bipolar depression have significantly greater response, remission, and depressive symptom reduction to single-dose IV ketamine than placebo from 40 minutes through days 10 to 12 post-treatment [87,88]. The approach has become standardized, using a sub-anesthetic dose: 0.5 mg/kg IV over a 40-minute infusion. In a 2015 analysis, ketamine was designated as one of two psychiatric treatments that had the highest potential impact on patient outcomes. This designation was based on the serious unmet need for fast-acting, well-tolerated antidepressants with efficacy in refractory major depression and bipolar depression [40].

In 2019, a ketamine derivative—esketamine—was approved by the FDA as an adjunctive agent for treatment-resistant depression. In 2020, the additional indication for short-term treatment of suicidal thoughts was added. This agent is administered by nasal spray and must be given under the direct supervision of a healthcare provider. Patients should be monitored for adverse effects for at least two hours following administration [19,89]. Due to an increased potential for abuse and misuse, it has an associated REMS program.

CASE STUDY

Patient B, 46 years of age, presents with a history of mild-to-moderate depression for the past six months. He has been undergoing cognitive-behavioral therapy, and while he has made some gains, he continues to experience depressive symptoms, as documented by a mood map and reports from his therapist. In addition, he is overweight and complains of insomnia.

The nurse does a complete psychiatric history and orders baseline laboratory studies and EKG. The patient reports no history of suicidal ideation and has never been hospitalized. He states that he is functioning well in his job but has been unable to maintain a steady relationship, despite a desire to have a long-term partner.

Patient B's main complaints are depressed mood and insomnia. He does not endorse anxiety or panic attacks and denies any drug or tobacco use. The patient is relatively healthy, has received regular medical care, and does not take any other medications. He has no history of seizure disorder. After a long discussion with the patient, the nurse decides to start a trial of sertraline 50 mg/day and trazodone 25 mg at night.

Patient B returns in two weeks and reports that his sleep has improved and the medications are well tolerated. He agrees to return in four more weeks to determine if the medications are helping his mood, which currently has not improved. During that period, he will continue working with his therapist weekly. The nurse and therapist are in good communication, with an understanding that any changes in symptoms or tolerability should be shared immediately.

After four weeks, Patient B comes back to the office. His mood is still described as depressed by both him and his therapist, so the sertraline dosage is increased to 100 mg/day, with a plan for the patient to return in one month.

When Patient B returns in four weeks, he reports that he is feeling better and has been going out and socializing. However, he is experiencing sexual side effects (erectile dysfunction). Several options are discussed, including transitioning from sertraline to a trial of bupropion or adding a trial of sildenafil. The patient decides that he would like to switch to bupropion, because he does not like the idea of having to take another medication.

After decreasing the dose of sertraline to 50 mg for two weeks, the patient is stable and plans are made to discontinue the sertraline and start bupropion (Wellbutrin XR) 150 mg every morning. When Patient B presents in two weeks, he is happy with the new medication, reporting full resolution of the sexual side effects, but reports some residual depressed mood. The dose of bupropion is increased to 300 mg every morning.

In another four weeks, Patient B's depression is in remission and his sleep quality is significantly improved. The medications remain well-tolerated. The patient also notes that he has lost about 5 pounds, which he attributes to decreased appetite. The patient continues to work with his therapist and agrees to return monthly for at least the next three months for continued monitoring.

5. MOOD STABILIZERS AND BIPOLAR DISORDER

Evidence Based Practice Recommendation

When using any psychotropic medication for bipolar disorder, the National Collaborating Centre for Mental Health recommends that clinicians ensure that the person is given information that is suitable for their developmental level about the purpose and likely side effects of treatment including any monitoring that is required, and give them an opportunity to ask questions. The choice of medication is made in collaboration with the person with bipolar disorder, taking into account the carer's views if the person agrees. The overall medication regimen is regularly reviewed so that medications that are not needed after the acute episode are stopped.

https://www.nice.org.uk/guidance/cg185

Last Accessed: September 27, 2024

Level of Evidence: Expert Opinion/Consensus Statement

Perhaps no diagnosis in psychiatry has undergone such a rapid change in diagnostic standards and pharmacologic management as bipolar disorder in the last 30 years. Intravenous chlorpromazine was first noticed to decrease mania in surgical patients with bipolar disorder. Shortly thereafter, chlorpromazine and other antipsychotics became mainstays in the treatment of primary psychotic disorders. At the same time, the treatment of bipolar disorder was revolutionized by the discovery of lithium.

Lithium is perhaps the oldest drug still in clinical use. While its utilization was formally standardized in 1954, its use in psychiatry dates to the mid-19th century [6]. One of the earliest recorded medical uses of lithium, for the treatment of gout, was in 1847 in London. Lithium continued to be prescribed for the treatment of gout and renal calculi into the 1930s. Psychiatric interest in lithium can be traced to the late 1800s. William Hammond is believed to be the first physician to prescribe lithium for mania (in 1871) [6]. As noted, the United States was the 50th country to approve lithium for clinical use in 1970 [6]. Lithium was originally studied in the prevention of depression and continues to be used off-label as an antidepressant [6,90].

Today, management of bipolar disorder may consist of lithium, anticonvulsants, and/or antipsychotic medications (Table 6). Antianxiety medications may be prescribed short term to improve sleep and manage agitation/anxiety. Lithium is one of the few drugs used in the treatment of bipolar disorder with proven efficacy in the prevention of suicide [79].

Table 6: MEDICATIONS USED IN THE TREATMENT OF BIPOLAR DISORDER

Drug

Dose Range

Typical Starting Dose

Potential Adverse Effects

Comments

Lithium (Lithobid)

600–1,800 mg/day in divided doses

300 mg BID

Xerostomia, tremor, thyroid-stimulating hormone elevation, leukocytosis, nausea

Lithium toxicity is closely related to serum lithium levels and can occur at doses close to therapeutic levels. Monitoring should be available before initiating therapy.

Anticonvulsants

Valproic acid (Divalproex)

250–1,500 mg BID based on levels

250–500 mg PO BID

Weight gain, hair loss, GI upset

Drug levels, complete blood count, and hepatic function should be followed.

Carbamazepine (Carbatrol, Epitol, Equetro, Tegretol)

100–800 mg BID

100–200 mg BID

Weight gain

Hepatic function, drug level, and CBC should be followed.

Lamotrigine (Lamictal, Subvenite)

Titrate to maximum 200 mg/day

25 mg/day

Nausea, tremor, rash, Stevens Johnson syndrome

—

Atypical Antipsychotics

Aripiprazole (Abilify)

2.5–30 mg/day

2.5–5 mg/day

Weight gain (least likely in this class), extrapyramidal symptoms, constipation, sedation

Available in long-acting IM formulation

Asenapine (Saphris, Secuado)

2.5–10 mg BID

2.5–5 mg PO BID

Weight gain, extrapyramidal symptoms, constipation, sedation

—

Cariprazine (Vraylar)

1.5–6 mg/day

1.5 mg/day

Weight gain, extrapyramidal symptoms, constipation, sedation

—

Lurasidone (Latuda)

40–160 mg/day

40 mg/day

Weight gain, extrapyramidal symptoms, constipation, sedation

—

Olanzapine (Zyprexa)

2.5–30 mg either BID or at night

2.5 mg/day

Weight gain (very likely), extrapyramidal symptoms, constipation, sedation

—

Olanzapine/fluoxetine (Symbyax)

Up to 18 mg/day olanzapine and 75 mg/day fluoxetine

6 mg/day olanzapine and 25 mg/day fluoxetine

Weight gain, extrapyramidal symptoms, constipation, sedation

Usually given at night

Quetiapine (Seroquel)

50–800 mg/day

50–100 mg daily or BID

Weight gain, extrapyramidal symptoms, constipation, sedation

Available in extended-release formulation

Risperidone (Perseris, Risperdal)

0.5–6 mg/day (may be given BID)

0.5–1 mg daily or BID

Weight gain, extrapyramidal symptoms, constipation, sedation, increased prolactin, male gynecomastia

Available in long-acting IM formulation

Ziprasidone (Geodon)

40–80 mg BID

40 mg BID

Weight gain, extrapyramidal symptoms, constipation, sedation, increased prolactin

Taken with food to improve absorption

BID = twice per day, CBC = complete blood count, GI = gastrointestinal, IM = intramuscular, PO = oral.

Source: [19,80]

CASE STUDY

Patient C, 23 years of age, presents with a history of increasing mood instability, with periods of depression lasting three to four months followed by periods of increasing disorganization, lack of need for sleep, and risky behaviors (e.g., gambling, shoplifting). After her third shoplifting arrest, Patient C agreed to a plea deal that requires her to seek and comply with psychiatric care.

The clinician conducts a full psychiatric history that is significant for school and employment problems. She attempted outpatient treatment at 16 and 21 years of age, both of which were ended by the patient due to her dislike for medications and their side effects and a perceived "loss of energy" when treatment was initiated with olanzapine during a manic episode at 19 years of age.

The workup reveals a healthy woman, normal laboratory studies, normal EKG, and no medical problems. She is gravida 0 para 0 and has a progestin intrauterine device for birth control. She describes her current mood as depressed, rated 3 on a Likert scale. She describes hypersomnia, sleeping about 10 hours per day. She is currently unemployed and living with her parents. She denies any psychotic symptoms and has never attempted suicide. The patient feels her parents are supportive but firm in stating that she must engage in treatment to continue living with them. She is a nonsmoker and has no known drug use, other than occasional cannabis (less than once per week), which she does not view as problematic. She has genetic loading, with an uncle and a sister who have been diagnosed with bipolar disorder.

Patient C is currently not seeing a therapist or receiving psychotherapy. In discussing goals of care, her main goal is compliance with her probation stipulations. She also indicates that she would like to be employed and to eventually move out of her parents' house. Weight gain is identified as an intolerable side effect of pharmacotherapy; the patient states she would like to lose weight. After much discussion, Patient C agrees to see a social worker for cognitive support and to assist with employment goals.

Given the patient's goals and concerns, antipsychotics are determined to be undesirable. The clinician and patient discuss the risks and benefits of valproic acid and lithium. Patient C states that her uncle did well on lithium and that she would like to try it. In preparation for lithium prescription, the patient's thyroid hormone and calcium levels are reviewed along with kidney function; all are normal. Patient C expresses a strong desire to take pills only once per day and does not think she can remember to take a morning dose. The clinician reviews literature, which indicates that once daily dosing of lithium results in similar efficacy, with lower total doses, decreased renal toxicity, and decreased urinary frequency [91]. The patient is started on controlled-release lithium 450 mg taken at night. Eventually, she is titrated to 900 mg daily, with an average serum lithium level of 0.7 mEq/L.

As part of the patient education process, the clinician emphasizes the need for reliable birth control, as lithium crosses the placenta and is associated with serious fetal malformations following exposure in the first trimester [92]. This conversation is documented fully, including a recommendation that the patient use dual birth control (e.g., add condoms). The need to use a different medication during any planned pregnancy is reviewed.

After 12 months of therapy, Patient C has not experienced any episodes of mania. However, she describes her mood as depressed and complains of amotivation, sadness, hypersomnia, and a 10-pound weight gain. Her lithium level is stable and within the therapeutic range, and the clinician is concerned that raising the lithium dose could increase the risk of toxicity.

To address these issues, bupropion (Wellbutrin XL) 150 mg/day is added to the patient's regimen. Augmentation with low-dose bupropion appears to have the lowest risk of inducing mania among available antidepressants [93]. In six weeks, Patient C reports a gradual improvement in mood, a slight weight loss (2 to 3 pounds), and no signs or symptoms of mania. She continues to meet with her social worker and has attained employment as a front desk clerk at a hotel. She is pursuing her goal of living independently and has had no further contact with law enforcement.

6. ANTIANXIETY MEDICATIONS

Anxiety disorders are characterized by states of chronic, excessive dread or fear of everyday situations. The fear and avoidance can be life-impairing and disabling. Anxiety disorders result from the interaction of biopsychosocial factors, whereby genetic vulnerability interacts with situations, stress, or trauma to produce clinically significant syndromes. Under the umbrella of anxiety disorders are specific phobia, social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, and separation anxiety disorder.

Each year in the United States, anxiety disorders impact approximately 42 million adults, or 19% of the population [94,95]. The pattern of sex distribution is consistent among anxiety disorders, and the overall female-to-male ratio is approximately 2:1 across all age ranges [96]. Guidelines for the treatment of anxiety disorders typically support combined psychotherapy (e.g., mindfulness, exposure therapy, cognitive therapy) and pharmacotherapy [97].

The first report of antidepressant use in anxiety treatment was published in 1962. In this account, patients with agoraphobia who were given the TCA imipramine showed reductions in panic attacks and improved exposure to feared situations [98]. The benzodiazepine chlordiazepoxide (Librium) was introduced to the U.S. market in 1960. This was followed by diazepam (Valium) in 1963, which became the most prescribed drug in the United States from 1969 to 1982; in 1978, more than 2.3 billion diazepam doses were sold in the United States [99]. Panic disorder was first formalized as a psychiatric disorder in the 1980 DSM-III, and alprazolam (Xanax) became the first FDA-approved drug for panic disorder treatment in 1981, remaining the most-prescribed benzodiazepine to date [100].

In the past two decades, antidepressant drugs have displaced benzodiazepines as the most widely prescribed and recommended anxiety disorder pharmacotherapy (Table 7). Antidepressants are generally recommended as first-line therapy for panic disorder because, unlike benzodiazepines, antidepressants treat comorbid depression and lack abuse risk and potential side effects of excessive sedation, cognitive impairment, and ataxia. All major antidepressant classes are comparably effective, but SSRIs and, increasingly, SNRIs are recommended over TCAs and MAOIs due to better safety and tolerability [101].

Table 7: MEDICATIONS USED IN THE TREATMENT OF ANXIETY DISORDERS

Drug

Dose Range

Typical Starting Dose

Potential Adverse Effects

Indication(s)

Antidepressants

Escitalopram (Lexapro)

10–20 mg/day

10 mg/day

Few

GAD

Fluoxetine (Prozac)

10–80 mg/day

10–20 mg/day

Few

OCD, PD

Fluvoxamine

100–300 mg/day

100 mg/day

Few

OCD, SP

Paroxetine (Brisdelle, Paxil, Pexeva)

10–50 mg/day

10–20 mg/day

Few

GAD, OCD, PD, SP

Sertraline (Zoloft)

25–200 mg/day

25–50 mg/day

Few

OCD, PD, SP

Duloxetine (Cymbalta, Drizalma Sprinkle)

30–120 mg/day

30–60 mg/day

Hypertension, headache

GAD

Venlafaxine (Effexor)

37.5–225 mg/day

37.5–75 mg/day

Hypertension, headache

GAD, PD, SP

Clomipramine (Anafranil)

25–250 mg/day

25 mg/day

QTc prolongation

OCD, PD

Doxepin (Silenor)

25–300 mg/day

25–50 mg/day

QTc prolongation

NSA

Imipramine

50–200 mg/day

50–100 mg

QTc prolongation

PD

Phenelzine (Nardil)

45–90 mg/day

45 mg/day

Drug- and food-drug interactions

PD

Benzodiazepines

Alprazolam (Xanax)

0.25–4 mg 2 to 3 times per day

0.25–1 mg/day

Dependence, rebound anxiety, increased dementia risk, increased risk of opioid overdose with concomitant use

NSA, PD

Chlordiazepoxide (Librium)

5–25 mg 3 to 4 times per day

5–10 mg/day

NSA

Clonazepam (Klonopin)

0.25–2 mg 2 times per day

0.25–1 mg/day

PD

Diazepam (Diastat, Valium, Valtoco)

2.5–10 mg 2 to 4 times per day

2.5–5 mg/day

NSA

Lorazepam (Ativan)

0.5–2 mg given 2 to 3 times per day

0.5–1 mg/day

NSA

Miscellaneous Agents

Hydroxyzine (Vistaril)

25.5 mg 2 to 4 times per day

25–50 mg/day

Xerostomia, drowsiness

NSA

Buspirone

10–20 mg 2 to 3 times per day

10 mg/day

Dizziness, headache

GAD

GAD = generalized anxiety disorder, NSA = nonspecific anxiety, OCD = obsessive-compulsive disorder, PD = panic disorder, SP = specific phobia.

Source: [19,102]

ANTIDEPRESSANTS

Evidence Based Practice Recommendation

The National Collaborating Centre for Mental Health asserts that all patients prescribed antidepressants for the management of anxiety should be informed that, although the drugs are not associated with tolerance and craving, discontinuation/withdrawal symptoms may occur on stopping or missing doses or, occasionally, on reducing the dose of the drug.

https://www.nice.org.uk/guidance/cg113

Last Accessed: September 27, 2024

Level of Evidence: Expert Opinion/Consensus Statement

SSRIs are considered first-line therapy for generalized anxiety disorder and panic disorder [101,103]. TCAs have comparable efficacy to SSRIs in panic disorder and generalized anxiety disorder [104,105]. TCAs are lethal in overdose and, compared with SSRIs, have a markedly broader, more problematic, and less tolerable side effect profile [101]. Nonetheless, TCAs may work when first-line agents do not [106]. Also, some patients with panic disorder are sensitive to both beneficial and adverse effects of TCAs, so cannot tolerate imipramine doses >10 mg/day but still experience panic blockade [101].

MAOIs are effective for panic disorder and social anxiety disorder and are thought by some to be superior options for severe, treatment-resistant anxiety disorders. As noted, MAOIs have a substantial side effect profile and impose the greatest safety burden of all antidepressants. Therefore, they are usually reserved as the last treatment option after other drug therapies have failed to achieve remission [107]. Clinicians do not routinely prescribe MAOIs for anxiety disorders, although they are probably not considered often enough in treatment-resistant patients [106].

BENZODIAZEPINES

Since their introduction in the early 1960s, benzodiazepines have been the most prescribed drugs for anxiety over the majority of the past half-century. Although SSRI/SNRI agents have replaced benzodiazepines as the top-prescribed anxiolytics, benzodiazepine prescribing remains common. In 2020, alprazolam, clonazepam, lorazepam, and diazepam were among the top 25 most frequently prescribed psychotropic medications in the United States; alprazolam ranked 9th, clonazepam ranked 12th, lorazepam ranked 16th, and diazepam ranked 23rd [108,109].

Pharmacology and Short-Term Effects

Numerous benzodiazepines are available and have similar pharmacodynamic properties and clinical actions; they mainly differ in pharmacokinetic properties (absorption, distribution, metabolism, elimination). Benzodiazepines bind to a specific receptor site in the gamma-aminobutyric acid (GABA) receptor complex. GABA is the primary inhibitory neurotransmitter in the central nervous system, and benzodiazepines cause non-selective GABA-A inhibitory effects throughout the brain that include drowsiness, cognitive impairment, dampening of fear and anxiety, memory impairment, anticonvulsant actions, and impairment of balance, motor control, muscle tone, and coordination. Adverse reactions to alprazolam also include amnesia, aggression, mood changes, and hostility. The newer Z drugs (e.g., zolpidem, zopiclone) have similar actions to benzodiazepines but are marketed for insomnia due to their pharmacokinetic profile, with high doses required for anxiolytic effects. There is evidence the Z drugs share similar risks to benzodiazepines [110,111].

Meta-analyses suggest alprazolam, lorazepam, and diazepam are effective but comparable in generalized anxiety disorder efficacy, while clonazepam shows much greater efficacy in the treatment of panic disorder than alprazolam, lorazepam, and diazepam, which all have modest efficacy [112].

Appropriate Prescribing

Benzodiazepine treatment of anxiety disorders is controversial. While effective in rapid anxiety reduction, the potential drawbacks with long-term use are substantial. These agents are indicated when potent, short-term anxiolytic effects are necessary to permit infrequent exposure to feared stimuli and potentially severe anxiety, such as airplane travel [103,106,113]. Clonazepam, lorazepam, and alprazolam are effective for short-term use in panic disorder, generalized anxiety disorder, and SAD, but ineffective for, and potentially worsening, comorbid depression [114]. The rapid anxiolytic effects make benzodiazepines highly appealing to patients with anxiety, but aside from this specific context, benzodiazepine prescribing for as-needed use is discouraged [106,115,116]. Benzodiazepines can reinforce pill taking, serve as a safety signal that undermines self-efficacy, and become incorporated into conditioned fear responses; these concerns are heightened with as-needed use. On-demand dosing links pill taking to rapid anxiety reduction, powerfully reinforcing avoidance in anxiety-provoking situations and encouraging longer-term reliance on the drug. This iatrogenic effect also contributes to poor response to cognitive-behavioral therapy.

The current recommended prescribing is for time-dependent use, instead of panic response-dependent use, to minimize the risks [103]. This would also seem to maximize risk of withdrawal syndrome from uninterrupted versus intermittent drug exposure.

Benzodiazepines are also useful in the initial weeks of SSRI/SNRI initiation to rapidly reduce anxiety and possible early anxiogenic medication side effects before the onset of SSRI/SNRI anxiolytic effects [103,106,113]. However, patients may discontinue the antidepressant when co-prescribed a rapidly effective benzodiazepine, believing the benzodiazepine's symptom relief makes the SSRI/SNRI unneeded. Supportive therapy with regular visits or phone contacts may also help patients remain adherent until the delayed onset of antidepressant benefits appears or early antidepressant side effects lessen [117].

Another indication for benzodiazepine use is for the short-term relief (two to four weeks only) of anxiety that is severe, disabling, or subjecting the individual to unacceptable distress. Perhaps the greatest prescribing challenge with benzodiazepines is preventing short-term use from insidiously developing into long-term use. Patients with the most severe anxiety may obtain the greatest relief and become most hesitant to discontinue use [118]. In many cases, clinicians ignore the recommended two- to four-week prescribing limit, mainly because alternative options with superior anxiolytic effects are not available [119]. Clinicians intending to prescribe alprazolam should carefully consider the likelihood that its use will remain restricted to the very short term—a few days to a couple weeks—to see the patient through a crisis [118].

Benzodiazepines may be prescribed to augment SSRI/SNRI therapy for improved response in select patients with significant residual anxiety or non-response. In one study, patients with SAD and sertraline nonresponse after 10 weeks were given sertraline plus clonazepam (≤3 mg/day), venlafaxine (≤225 mg/day), or sertraline plus placebo for 12 weeks. Those with sertraline augmented by clonazepam showed greatest reduction in SAD symptoms and a better overall response rate than comparator groups, although remission rates did not differ significantly [120]. These agents are third- or fourth-line treatment in patients unresponsive or intolerant to other anxiolytic drugs who remain highly symptomatic [103,106,113]. Generally, patients with a history of substance abuse, personality disorder, or chronic pain should not be treated with benzodiazepines because of the high risk for overuse of these medications [113]. While benzodiazepines should usually be reserved for patients lacking response to at least two treatments (i.e., non-response to an SSRI/SNRI and a psychologic treatment), concerns about potential problems in long-term use should not prevent their use in patients with persistent, severe, distressing, and impairing anxiety symptoms [121].

It seems the most appropriate guidance for benzodiazepine prescribing involves occasional, context-specific use or cautious use during SSRI/SNRI initiation [121,122]. Otherwise, benzodiazepines should be reserved for patients lacking response to three or more treatments, such as an SSRI, an SNRI, and a psychologic intervention, who remain highly symptomatic.

Risks/Drawbacks

While alprazolam remains the most-prescribed benzodiazepine for anxiety disorders, evidence suggests that relative to other benzodiazepines, alprazolam is no more effective and may have specific drawbacks [100]. Alprazolam may have greater potential for dependence than other benzodiazepines due to its rapid onset of anxiolysis and short half-life. With the short half-life, persons prescribed fixed-interval alprazolam (e.g., every six to eight hours) can experience morning withdrawal symptoms following the last nighttime dose. This is frequently mistaken as relapse in anxiety for which the drug was originally prescribed, confirming the continuing need for the drug [118]. The alprazolam product monograph states that such emergence of interdose symptoms reflect insufficient plasma levels, best managed by adding the same dose for four times daily administration (but breakthrough anxiety and alprazolam withdrawal are not differentiated). The document also states that alprazolam treatment of panic disorder differs from sub-syndromal anxiety, in that recommended dosing is as close to around-the-clock as possible, or three or four times per day [123].

Long-term benzodiazepine use can result in added symptoms during stable-dose maintenance, including increasing anxiety and withdrawal-associated symptoms such as perceptual disturbances and paresthesia. This emerging withdrawal syndrome despite ongoing benzodiazepine use is much more likely with highly potent and rapidly eliminated alprazolam or lorazepam and is temporarily alleviated by dose escalation. As craving, dysphoria, and other withdrawal symptoms develop over time between doses, the motivation to continue benzodiazepine use for anxiolysis gradually merges with the need to avoid withdrawal symptoms [124].

Benzodiazepine prescriptions are associated with nonmedical use and the development of benzodiazepine use disorder unrelated to co-occurring drug use or anxiety disorder diagnosis/severity [109]. Acute cognitive-impairing side effects are drowsiness, increased reaction time, ataxia, motor incoordination, and anterograde amnesia. In one study, long-term use of an average 17 mg/day diazepam equivalent led to substantial cognitive decline that did not resolve three months after cessation [125]. Motor vehicle accident risks during benzodiazepine therapy are comparable to driving with a blood alcohol concentration of 0.050% to 0.079% [126]. Hip fracture risk is increased by ≥50% in older persons who take benzodiazepines; with zolpidem, the risk is increased 200% in persons older than 65 years of age [127]. The risk of overdose is particularly great when benzodiazepines are combined with sedative drugs such as opioids or alcohol.

Personality traits associated with long-term use, emotional dependence, and more severe/protracted benzodiazepine withdrawal have been described. Long-term benzodiazepine users often have poor stress coping abilities. Benzodiazepines compensate for these deficits, but their use interferes with learning stress coping strategies, including behavioral therapy for agoraphobia. Passive-dependent personality traits and lack of internal and external stress coping resources increases vulnerability to withdrawal symptoms and motivation for continued use. In these patients, benzodiazepine deprivation renders them unprotected from stress and re-exposes their coping deficits. Chronically anxious people have been found innately hypersensitive to punishing stimuli and punishment; benzodiazepines can be described as "depunishing" drugs [124].

Withdrawal

Withdrawal symptoms following benzodiazepine cessation are appropriately concerning and a liability of this drug class that all prescribers should understand. In patients with panic disorder discontinuing alprazolam following 1.5 to 22 months of treatment, 33% to 100% were unable to completely taper [43]. These data did not include the 50% of long-term benzodiazepine users who do not consent to withdrawal studies or who later quit the study. The experience of benzodiazepine withdrawal is known to deter patients from future attempts [128]. An estimated 25% to 76% of patients prescribed benzodiazepines are long-term users. Defining high-dose benzodiazepine varies, but users of high-dose benzodiazepines commonly have comorbid disorders and are unlikely to benefit from current discontinuation and withdrawal strategies that expose them to greater risk of impairment and injury [128].

Despite comparable dosing, patients with panic disorder often show greater difficulty tapering than patients with generalized anxiety disorder. Problems during alprazolam tapering are most severe during the last half of the taper. Patients with panic disorder receiving diazepam or alprazolam had fewer problems during taper of the top 50% of daily dose. However, with abrupt discontinuation of the remaining dose, alprazolam caused significantly more anxiety, relapse, and rebound. This may reflect greater problems withdrawing from short half-life, high-potency benzodiazepines like alprazolam [43].

CASE STUDY

Patient D, 33 years of age, presents with a chief complaint of anxiety. He describes increasing anxiety symptoms for the last eight months, including persistent worrying that he finds challenging to control, overthinking plans, inability to let go of a worry, difficulty concentrating, fatigue, difficulty falling asleep, irritability, and nervousness. He is employed as a corrections officer with two young children. A medical workup is normal. He has engaged with a therapist for the past three months, and while he has made some gains with cognitive-behavioral therapy, his therapist has suggested a medication consultation to help with his ongoing symptoms.

Upon review of symptoms and consultation with the patient's therapist, a diagnosis of generalized anxiety disorder is confirmed. The clinician discusses goals of care with the patient; he states that he wants to avoid the medication side effects of daytime sedation or impaired concentration due to his job. Available medications are reviewed, and the decision is made to start escitalopram to address the continued symptoms of generalized anxiety. Treatment is initiated at a daily dose of 10 mg. Patient D asks about alprazolam (Xanax), as a friend told him that this medication worked for him. The clinician spends time on patient education explaining that alprazolam has a known risk of addiction and a potential for sedation. The patient agrees to the trial of escitalopram.

When Patient D returns for follow-up in four weeks, he reports improvement in his anxiety symptoms and is continuing his cognitive-behavioral therapy. After three months, the patient indicates that his symptoms are manageable and he has not experienced any adverse effects of the pharmacotherapy.

7. PHARMACOTHERAPY FOR SUBSTANCE USE DISORDERS

Evidence Based Practice Recommendation

The American Society of Addiction Medicine recommends that all FDA-approved medications for the treatment of opioid use disorder should be available to all patients. Clinicians should consider the patient's preferences, past treatment history, current state of illness, and treatment setting when deciding between the use of methadone, buprenorphine, and naltrexone.

https://www.asam.org/Quality-Science/quality/2020-national-practice-guideline

Last Accessed: September 27, 2024

Level of Evidence: Expert Opinion/Consensus Statement

Although perhaps the most concerning drug of abuse in the United States today is opioids, substance use disorders (as defined by the DSM-5-TR) are not limited to one specific drug. Even commonly used substances, such as alcohol and nicotine, may initiate use disorders. Substance use disorders are diagnosed based on the presence of at least two of the following criteria in the previous year [129]:

- Using the substance in larger amounts

- Wanting to cut down use but unable to

- Spending large amounts of time involved in procuring and using as well as recovering from use of the substance

- Cravings for the substance

- Not functioning normally at work, home, or school

- Continued use despite harm to relationships

- Decreasing other activities, including work or socialization

- Continued use despite harm or risk of harm

- Continued use despite medical or psychological problems made worse by continued use

- Increased tolerance leading to escalating dosages

- Withdrawal symptoms

The main stages of substance use disorder treatment are crisis intervention, harm reduction, detoxification/withdrawal, active treatment, and relapse prevention. To this end, a variety of medications have been approved to assist in cessation of the use of opioids, alcohol, and nicotine (Table 8). Some are used for detoxification, and others are used to prevent relapse. Research has shown that medications are most effective when used in conjunction with other therapies.

Table 8: MEDICATIONS USED IN THE TREATMENT OF SUBSTANCE USE DISORDERS

Drug

Dose Range

Typical Starting Dose

Potential Adverse Effects

Route(s)

Opioid Use Disorder

Buprenorphine/naloxone (Bunavail, Suboxone, Zubsolv)

Buprenorphine: 0.7–24 mg/day

Naloxone: 0.18–6 mg/day

4/1 mg/day

Pain, headache, nausea, diaphoresis

Buccal film, sublingual film, sublingual tablet

Methadone (Dolophine, Methadose, DISKETS)

20–120 mg/day

20–30 mg/day

Pruritus, constipation, cardiac abnormalities

PO, IV

Naltrexone (Vivitrol)

PO: 25–50 mg/day

IM: 380 mg/week

PO: 25 mg/day

IM: 380 mg/week

Injection site reactions, anxiety, syncope

PO, IM

Buprenorphine (Belbuca, Buprenex, Butrans, Probuphine, Sublocade)

SQ: 100–300 mg/month

SL:2–24 mg/day

SQ: 300 mg/month

Implant: 4 implants

SL:2–4 mg/day

Few

Sublingual tablet, subdermal implant, SQ injection

Alcohol Use Disorder

Acamprosate (Campral)

666 mg TID

666 mg TID

Diarrhea

PO

Naltrexone (Vivitrol)

PO: 25–100 mg/day

IM: 380 mg/month

PO: 50 mg/day

IM: 380 mg/month

Injection site reactions, anxiety, syncope

PO, IM

Disulfiram

125–500 mg/day

250 mg/day

Bitter taste, impotence, drowsiness

PO

Nicotine Use Disorder

Bupropion, sustained-release (Zyban)

150 mg daily or BID

150 mg/day

Weight loss, constipation, agitation, xerostomia, nausea

PO

Nicotine

Gum: Up to a maximum 30 pieces/day

Inhaler: 6–16 cartridges/day

Lozenge: Titrate to 1 lozenge every 4 to 8 hours

Nasal spray: Maximum 80 sprays/day

Patch: One patch/day for 8 weeks

Gum: 1 to 2 pieces/hour (2 mg/piece)

Inhaler: 6 cartridges/day

Lozenge: One lozenge every 1 to 2 hours

Nasal spray: 1 spray in each nostril once or twice per hour

Patch: One patch/day

Oral irritation, headache, dyspepsia, nasal discomfort, cough, rhinitis

PO, intranasal, transdermal

Varenicline (Chantix)a

1 mg BID up to 12 weeks

0.5 mg/day

Nausea, abnormal dreams, headache

PO

BID = two times per day, IM = intramuscular, IV = intravenous, PO = oral, SL = sublingual, SQ = subcutaneous, TID = three times per day.

aVarenicline production was halted and lots were voluntary recalled in 2021 due to unacceptable levels of nitrosamines.

Source: [19,130]

In addition to these approved medications, a variety of medications are used off-label for the management of several substance use disorders, including cocaine, methamphetamine, and cannabis.

CASE STUDY

Patient E, 54 years of age, presents with active opioid use disorder. He began using prescription opioids for back pain after having served in the infantry. His usage eventually resulted in his leaving military service prior to retirement, and he currently works in construction. The patient reports having relied on prescription opioids until three years ago, when he started using heroin. He buys 10 bundles per day of what is described as heroin but is most likely synthetic fentanyl. He has accidentally overdosed on two occasions, and emergency medical services used naloxone nasal spray to revive him. He is seeking care at an intensive outpatient program for treatment.

After reviewing goals of care with the patient, the clinician identifies that he has residual chronic back pain in addition to cravings for opioids when not using. The patient is diagnosed with opioid use disorder.

Patient E states that he recently sought care for his back pain and was referred to physical therapy and advised to take nonsteroidal anti-inflammatory drugs (NSAIDs) as needed for pain management. The possibility of methadone maintenance is discussed, but the patient does not want to have to go daily for dosing and is afraid that it will impair his ability to work around heavy machinery. Safety issues are also reviewed, and nasal naloxone is prescribed for emergency use. The patient's partner receives education on use as well.

The patient states he does not wish to take a medication, but he starts attending daily 12-step meetings and working with a drug counselor. Within five days, Patient E is able to successfully complete detoxification. However, after about six weeks he experiences a relapse. His partner administers nasal naloxone after finding him unconscious.

When Patient E returns for follow-up, various options for medication-assisted therapy are discussed, and he decides to enroll in buprenorphine/naloxone therapy, with a goal of eventually being maintained on monthly buprenorphine injection. The clinician emphasizes the need for continued counseling and the need to understand that, like all chronic diseases, patients with opioid use disorder are subject to relapse. The patient is advised of the importance of seeking help early in the event of a relapse. The biologic basis of substance use disorder is stressed; there is no judgement or shame.

Patient E does well on buprenorphine/naloxone therapy and is attending physical therapy for his back pain. He has continued with regular 12-step meetings and individual psychotherapy. At each follow-up appointment, the need to keep naloxone nasal spray available for emergency use is emphasized.

8. CONCLUSION

In the management of patients with mental health disorders, pharmacotherapy remains a vital part of optimal treatment. Only a portion of the psychopharmacologic options available have been discussed in this course. When providing care to special populations, such as pediatric patients and patients who are or may become pregnant, clinicians should consult the latest literature.

Works Cited

1. 1. http://www.netce.com/Ozarin L. Diseases of the Mind: Highlights of American Psychiatry through 1900. Available at https://www.nlm.nih.gov/hmd/diseases/index.html. Last accessed September 17, 2024.

2. Szasz T. Coercion as Cure: A Critical History of Psychiatry. 2nd ed. New Brunswick, NJ: Transaction Publishers; 2010.

3. Reidbord S. A brief history of psychiatry. Psychol Today. 2014.

4. Ruffalo M. A Brief History of Electroconvulsive Therapy. Available at https://www.psychologytoday.com/us/blog/freud-fluoxetine/201811/brief-history-electroconvulsive-therapy. Last accessed September 17, 2024.

5. Ban TA. Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat. 2007;3(4):495-500.

6. Shorter E. The history of lithium therapy. Bipolar Disord. 2009:11(Suppl 2):4-9.

7. Crilly J. The history of clozapine and its emergence in the US market: a review and analysis. Hist Psychiatry. 2007;18(1):39-60.

8. Atkin K, Kendall F, Gould D, et al. Neutropenia and agranulocytosis in patients receiving clozapine in the UK and Ireland. Br J Psychiatry. 1996;169:483-488.

9. Substance Abuse and Mental Health Services Administration. Key Substance Use and Mental Health Indicators in the United States: Results from the 2023 National Survey on Drug Use and Health. Available at https://www.samhsa.gov/data/report/2023-nsduh-annual-national-report. Last accessed September 16, 2024.

10. National Institute on Alcohol Abuse and Alcoholism. Medications Development Program. Available at https://www.niaaa.nih.gov/medications-development-program. Last accessed September 16, 2024.

11. American Society of Addiction Medicine. Public Policy Statement: Definition of Addiction. Available at https://www.asam.org/docs/default-source/public-policy-statements/1definition_of_addiction_long_4-11.pdf. Last accessed September 16, 2024.

12. Velander JR. Suboxone: rationale, science, and misconceptions. Ochsner J. 2018;18(1):23-29.

13. Yaksh T, Wallace M. Opioids, analgesia, and pain management. In: Brunton L, Hilal-Dandan R, Knollmann BC (eds). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill; 2017: 355-386.

14. Havens JR, Walker R, Leukefeld CG. Prevalence of opioid analgesic injection among rural nonmedical opioid analgesic users. Drug Alcohol Depend. 2007;87(1):98-102.

15. Dydyk AM, Jain NK, Gupta M. Opioid Use Disorder. Treasure Island, FL: StatPearls Publishing; 2024.

16. Centers for Disease Control and Prevention. Health Alert: Increase in Fatal Drug Overdoses Across the United States Driven by Synthetic Opioids Before and During the COVID-19 Pandemic. Available at https://archive.cdc.gov/#/details?url=https://emergency.cdc.gov/han/2020/han00438.asp. Last accessed September 16, 2024.

17. Tamminga C. Antipsychotic Drugs. Available at https://www.merckmanuals.com/professional/psychiatric-disorders/schizophrenia-and-related-disorders/antipsychotic-drugs. Last accessed September 17, 2024.

18. Medscape. Drugs and Diseases. Available at https://reference.medscape.com. Last accessed September 17, 2024.

19. LexiComp. Available at https://online.lexi.com. Last accessed September 16, 2024.

20. Missouri Department of Mental Health. Abnormal Involuntary Movement Scale (AIMS). Available at https://dmh.mo.gov/media/21821/download. Last accessed September 16, 2024.

21. Reynolds GP, Kirk SL. Metabolic side effects of antipsychotic drug treatment—pharmacological mechanisms. Pharmacol Ther. 2010;125(1):169-179.

22. Roberts R, Neasham A, Lambrinudi C, Khan A. A quantitative analysis of antipsychotic prescribing trends for the treatment of schizophrenia in England and Wales. JRSM Open. 2018;9(4):2054270418758570.

23. U.S. Food and Drug Administration. Clozapine and the Risk of Neutropenia: A Guide for Healthcare Providers. Available at https://www.accessdata.fda.gov/drugsatfda_docs/rems/Clozapine_2021_02_18_Clozapine_and_the_Risk_of_Neutropenia_A_Guide_for_Healthcare_Providers.pdf. Last accessed September 16, 2024.

24. Vasavan Nair NP, Suranyi-Cadotte B, Schwartz G, et al. A clinical trial comparing intramuscular haloperidol decanoate and oral haloperidol in chronic schizophrenic patients: efficacy, safety, and dosage equivalence. J Clin Psychopharmacol. 1986;6(1 Suppl):30S-37S.

25. Zhornitsky S, Stip E. Oral versus long-acting injectable antipsychotics in the treatment of schizophrenia and special populations at risk for treatment nonadherence: a systematic review. Schizophr Res Treatment. 2012;2012:407171.

26. Marcinkowska M, Śniecikowska J, Fajkis N, Paśko P, Franczyk W, Kołaczkowski M. Management of dementia-related psychosis, agitation and aggression: a review of the pharmacology and clinical effects of potential drug candidates. CNS Drugs. 2020;34(3):243-268.

27. Reus VI, Fochtmann LJ, Eyler AE, et al. The American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. Am J Psychiatry. 2016;173(5):543-546.

28. Centers for Medicare & Medicaid Services. Atypical Antipsychotic Medications: Use in Pediatric Patients. Available at https://www.cms.gov/Medicare-Medicaid-Coordination/Fraud-Prevention/Medicaid-Integrity-Education/Pharmacy-Education-Materials/Downloads/atyp-antipsych-pediatric-factsheet11-14.pdf. Last accessed September 16, 2024.

29. Stübner S, Rustenbeck E, Grohmann R, et al. Severe and uncommon involuntary movement disorders due to psychotropic drugs. Pharmacopsychiatry. 2004;37(Suppl 1):S54-S64.

30. Berman BD. Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist. 2011;1(1):41-47.

31. Brasic JR. Tardive Dyskinesia. Available at https://emedicine.medscape.com/article/1151826-overview. Last accessed September 17, 2021.

32. Ogino S, Miyamoto S, Miyake N, Yamaguchi N. Benefits and limits of anticholinergic use in schizophrenia: focusing on its effect on cognitive function. Psychiatry Clin Neurosci. 2014;68(1):37-49.

33. Ricciardi L, Pringsheim T, Barnes TRE, et al. Treatment recommendations for tardive dyskinesia. Can J Psychiatry. 2019;64(6):388-399.

34. National Institute of Mental Health. Statistics. Available at https://www.nimh.nih.gov/health/statistics/index.shtml. Last accessed September 17, 2024.

35. Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression. An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Reviews, No. 46. Rockville, MD: Agency for Healthcare Research and Quality; 2011.

36. Wang PS, Lane M, Olfson M, Pincus HA, Wells KB, Kessler RC. Twelve-month use of mental health services in the United States: results from the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):629-640.

37. Hasselmann HW. Ketamine as antidepressant? Current state and future perspectives. Curr Neuropharmacol. 2014;12(1):57-70.

38. Rosenblat JD, McIntyre RS, Alves GS, Fountoulakis KN, Carvalho AF. Beyond monoamines-novel targets for treatment-resistant depression: a comprehensive review. Curr Neuropharmacol. 2015;13(5):636-655.

39. Nasrallah HA. 10 recent paradigm shifts in the neurobiology and treatment of depression. Curr Psych. 2015;14(2).

40. Agency for Healthcare Research and Quality. Healthcare Horizon Scanning System Potential High-Impact Interventions: Priority Area 05: Depression and Other Mental Health Disorders. Rockville, MD: Agency for Healthcare Research and Quality; 2015.

41. Niciu MJ, Ionescu DF, Richards EM, Zarate CA Jr. Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder. J Neural Transm (Vienna). 2014;121(8):907-924.

42. O'Connor AM, Bennett C, Stacey D, et al. Do patient decision aids meet effectiveness criteria of the international patient decision aid standards collaboration? A systematic review and meta-analysis. Med Decis Making. 2007;27(5):554-574.

43. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Washington, DC: American Psychiatric Publishing, Inc.; 2010. (Reaffirmed October 31, 2015.)

44. American Psychological Association. Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. Available at https://www.apa.org/depression-guideline/guideline.pdf. Last accessed September 17, 2024.

45. Trivedi MH, Kleiber BA. Algorithm for the treatment of chronic depression. J Clin Psychiatry. 2001;62(Suppl 6):22-29.

46. Bostwick JM. A generalist's guide to treating patients with depression with an emphasis on using side effects to tailor antidepressant therapy. Mayo Clin Proc. 2010;85(6):538-550.

47. U.S. Department of Veterans Affairs, Department of Defense. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. Washington, DC: U.S. Department of Veterans Affairs; 2016.

48. Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol. 2007;151(6):737-748.

49. Sinclair LI, Christmas DM, Hood SD, et al. Antidepressant-induced jitteriness/anxiety syndrome: systematic review. Br J Psychiatry. 2009;194(6):483-490.

50. Amsterdam JD. Monoamine oxidase inhibitor therapy in severe and resistant depression. Psychiatric Ann. 2006;36(9):607-613.

51. Fowler JS, Logan J, Azzaro AJ, et al. Reversible inhibitors of monoamine oxidase-A (RIMAs): robust, reversible inhibition of human brain MAO-A by CX157. Neuropsychopharmacology. 2010;35(3):623-631.

52. U.S. Food and Drug Administration. FDA Approves Emsam (Selegiline) as First Drug Patch for Depression [Archive]. Available at https://wayback.archive-it.org/7993/20170113023146/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108607.htm. Last accessed September 17, 2024.

53. Caraci F, Leggio GM, Salomone S, Drago F. New drugs in psychiatry: focus on new pharmacological targets. F1000Res. 2017;6:397.

54. Deardorff WJ, Grossberg GT. A review of the clinical efficacy, safety and tolerability of the antidepressants vilazodone, levomilnacipran and vortioxetine. Expert Opin Pharmacother. 2014;15(17):2525-2542.

55. Sansone RA, Sansone LA. Emergency Psychiatry Update. Available at https://www.reliasmedia.com/articles/134475-emergency-psychiatry-update. Last accessed September 17, 2024.

56. Hu XH, Bull SA, Hunkeler EM, et al. Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. J Clin Psychiatry. 2004;65(7):959-965.

57. Rizvi SJ, Kennedy SH. Management strategies for SSRI-induced sexual dysfunction. J Psychiatry Neurosci. 2013;38(5):E27-E28.

58. Balon R. SSRI-associated sexual dysfunction. Am J Psychiatry. 2006;163(9):1504-1509.

59. American Urological Association. Clinical Guidelines: Erectile Dysfunction: AUA Guideline (2018). Available at https://www.auanet.org/guidelines-and-quality/guidelines/erectile-dysfunction-(ed)-guideline. Last accessed September 17, 2024.

60. Möller HJ, Baldwin DS, Goodwin G, et al. Do SSRIs or antidepressants in general increase suicidality? WPA section on pharmacopsychiatry: consensus statement. Eur Arch Psychiatry Clin Neurosci. 2008;258(Suppl 3):3-23.

61. Leon AC, Solomon DA, Li C, et al. Antidepressants and risks of suicide and suicide attempts: a 27-year observational study. J Clin Psychiatry. 2011;72(5):580-586.

62. Kennedy SH, Lam RW, McIntyre RS, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. pharmacological treatments. Can J Psychiatry. 2016;61(9):540-560.

63. Narayan V, Haddad PM. Antidepressant discontinuation manic states: a critical review of the literature and suggested diagnostic criteria. J Psychopharmacol. 2011;25(3):306-313.

64. U.K. Medicines and Healthcare Products Regulatory Agency. Selective Serotonin Reuptake Inhibitors (SSRIS) and Serotonin and Noradrenaline Reuptake Inhibitors (SNRIS): Use and Safety. Available at https://www.gov.uk/government/publications/ssris-and-snris-use-and-safety. Last accessed September 17, 2024.

65. Taylor D, Stewart S, Connolly A. Antidepressant withdrawal symptoms: telephone calls to a national medication helpline. J Affect Disord. 2006;95(1):129-133.

66. Fava GA, Gatti A, Belaise C, Guidi J, Offidani E. Withdrawal symptoms after selective serotonin reuptake inhibitor discontinuation: a systematic review. Psychother Psychosom. 2015;84(2):72-81.

67. Renoir T. Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved. Front Pharmacol. 2013;4:45.

68. Michelson D, Fava M, Amsterdam J, et al. Interruption of selective serotonin reuptake inhibitor treatment: double-blind, placebo-controlled trial. Br J Psychiatry. 2000;176:363-368.

69. Tint A, Haddad PM, Anderson IM. The effect of rate of antidepressant tapering on the incidence of discontinuation symptoms: a randomized study. J Psychopharmacol. 2008;22(3):330-332.

70. National Institute for Health and Clinical Excellence. Depression: The Treatment and Management of Depression in Adults. London: The British Psychological Society and the Royal College of Psychiatrists; 2010.

71. U.S. Food and Drug Administration. Suicidality in Children and Adolescents Being Treated With Antidepressant Medications. Available at https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/suicidality-children-and-adolescents-being-treated-antidepressant-medications. Last accessed September 17, 2024.

72. Garland EJ, Kutcher S, Virani A, Elbe D. Update on the use of SSRIs and SNRIs with children and adolescents in clinical practice.J Can Acad Child Adolesc Psychiatry. 2016;25(1):4-10.

73. Ménard C, Hodes GE, Russo SJ. Pathogenesis of depression: insights from human and rodent studies. Neuroscience. 2016;321:138-162.

74. Mathews DC, Henter ID, Zarate CA. Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. Drugs. 2012;72(10):1313-1333.

75. Kaster MP, Moretti M, Cunha MP, Rodrigues AL. Novel approaches for the management of depressive disorders. Eur J Pharmacol. 2016;771:236-240.

76. DeWilde KE, Levitch CF, Murrough JW, Mathew SJ, Iosifescu DV. The promise of ketamine for treatment-resistant depression: current evidence and future directions. Ann N Y Acad Sci. 2015;1345:47-58.

77. McIntyre RS, Filteau MJ, Martin L, et al. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014;156:1-7.

78. Kennedy SH. A review of antidepressant therapy in primary care: current practices and future directions. Prim Care Companion CNS Disord. 2013;15(2):12r01420.

79. Connolly KR, Thase ME. The clinical management of bipolar disorder: a review of evidence-based guidelines. Prim Care Companion CNS Disord. 2011;13(4):10r01097.

80. Butler M, Urosevic S, Desai P, et al. Treatment for Bipolar Disorder in Adults: A Systematic Review. Rockville, MD: Agency for Healthcare Research and Quality; 2018.

81. McClintock SM, Reti IM, Carpenter LL, et al. Consensus recommendations for the clinical application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. J Clin Psychiatry. 2018;79(1):16cs10905.

82. Perrin JS, Merz S, Bennett DM, et al. Electroconvulsive therapy reduces frontal cortical connectivity in severe depressive disorder.Proc Natl Acad Sci U S A. 2012;109(14):5464-5468.

83. Milev RV, Giacobbe P, Kennedy SH, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. neurostimulation treatments. Can J Psychiatry. 2016;61(9):561-575.

84. Malhi GS, Bassett D, Boyce P, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2015;49(12):1087-1206.

85. Brunoni AR, Boggio PS, De Raedt R, et al. Cognitive control therapy and transcranial direct current stimulation for depression: a randomized, double-blinded, controlled trial. J Affect Disord. 2014;162:43-49.

86. Garay RP, Zarate CA Jr, Charpeaud T, et al. Investigational drugs in recent clinical trials for treatment-resistant depression. Expert Rev Neurother. 2017;17(6):593-609.

87. Jaso BA, Niciu MJ, Iadarola ND, et al. Therapeutic modulation of glutamate receptors in major depressive disorder. Curr Neuropharmacol. 2017;15(1):57-70.

88. Kishimoto T, Chawla JM, Hagi K, et al. Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. 2016;46(7):1459-1472.

89. U.S. Food and Drug Administration. FDA Approves New Nasal Spray Medication for Treatment-Resistant Depression; Available Only at Certified Doctor's Office or Clinic. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified. Last accessed September 17, 2024.

90. Shultz E, Malone DA Jr. A practical approach to prescribing antidepressants. Cleve Clin J Med. 2013;80(10):625-631.

91. Kumar Singh L, Haque Nizamie S, Sayeed A, Kumar Praharaj S. Improving tolerability of lithium with a once-daily dosing schedule. Am J Ther. 2011;18(4):288-291.

92. Munk-Olsen T, Liu X, Viktorin A, et al. Maternal and infant outcomes associated with lithium use in pregnancy: an international collaborative meta-analysis of six cohort studies. Lancet Psychiatry. 2018;5(8):644-652.

93. Goren JL, Levin GM. Mania with bupropion: a dose-related phenomenon? Ann Pharmacother. 2000;34(5):619-621.

94. National Institute of Mental Health. Any Anxiety Disorder. Available at https://www.nimh.nih.gov/health/statistics/any-anxiety-disorder. Last accessed September 17, 2024.

95. National Institute of Mental Health. Anxiety Disorders. Available at https://www.nimh.nih.gov/health/topics/anxiety-disorders/index.shtml. Last accessed September 17, 2024.

96. Grassi M, Caldirola D, Di Chiaro NV, et al. Are respiratory abnormalities specific for panic disorder? A meta-analysis. Neuropsychobiology. 2014;70(1):52-60.

97. Gorman JM. Treatment of generalized anxiety disorder. J Clin Psychiatry. 2002;63 Suppl 8:17-23.

98. Klein DF, Fink M. Psychiatric reaction patterns to imipramine. Am J Psychiatry. 1962;119:432-438.

99. Dell'osso B, Lader M. Do benzodiazepines still deserve a major role in the treatment of psychiatric disorders? A critical reappraisal. Eur Psychiatry. 2013;28(1):7-20.

100. Spiegel DA. Efficacy studies of alprazolam in panic disorder. Psychopharmacol Bull. 1998;34(2):191-195.

101. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Panic Disorder. 2nd ed. Washington, DC: American Psychiatric Publishing; 2009.

102. Sayed S, Horn SR, Murrough JW. Current treatment for anxiety and obsessive-compulsive disorders. Curr Treat Options Psychiatry. 2014;1:248-262.

103. Locke AB, Kirst N, Shultz CG. Diagnosis and management of generalized anxiety disorder and panic disorder in adults. Am Fam Physician. 2015;91(9):617-624.

104. Mavissakalian MR. Imipramine vs. sertraline in panic disorder: 24-week treatment completers. Ann Clin Psychiatry. 2003;15(3-4):171-180.

105. Schmitt R, Gazalle FK, Lima MS, Cunha A, Souza J, Kapczinski F. The efficacy of antidepressants for generalized anxiety disorder: a systematic review and meta-analysis. Rev Bras Psiquiatr. 2005;27(1):18-24.

106. Farach FJ, Pruitta LD, Jun JJ, Jerud AB, Zoellner LA, Roy-Byrne PP. Pharmacological treatment of anxiety disorders: current treatments and future directions. J Anxiety Disord. 2012;26(8):833-843.

107. Santarsieri D, Schwartz TL. Antidepressant efficacy and side-effect burden: a quick guide for clinicians. Drugs Context. 2015;4:212290.

108. Grohol JM, Wright SA. Top 25 Psychiatric Medication Prescriptions for 2020. Available at https://psychcentral.com/blog/top-25-psychiatric-medications-for-2020. Last accessed September 17, 2024.

109. Johnson B, Streltzer J. Risks associated with long-term benzodiazepine use. Am Fam Physician. 2013;88(4):224-226.

110. Royal Australian College of General Practitioners. Prescribing Drugs of Dependence in General Practice, Part B: Benzodiazepines. Available at https://www.racgp.org.au/clinical-resources/clinical-guidelines/key-racgp-guidelines/view-all-racgp-guidelines/drugs-of-dependence/part-b. Last accessed September 17, 2024.

111. Royal Australian and New Zealand College of Psychiatrists. Australian and New Zealand clinical practice guidelines for the treatment of panic disorder and agoraphobia. Aust N Z J Psychiatry. 2003;37(6):641-656.

112. Bandelow B, Reitt M, Röver C, Michaelis S, Görlich Y, Wedekind D. Efficacy of treatments for anxiety disorders: a meta-analysis. Int Clin Psychopharmacol. 2015;30(4):183-192.

113. Katon WJ. Clinical practice: panic disorder. N Engl J Med. 2006;354(22):2360-2367.

114. Roy-Byrne P. Treatment-refractory anxiety; definition, risk factors, and treatment challenges. Dialogues Clin Neurosci. 2015;17(2):191-206.

115. Westra HA, Stewart SH, Conrad BE. Naturalistic manner of benzodiazepine use and cognitive behavioral therapy outcome in panic disorder with agoraphobia. J Anxiety Disord. 2002;16(3):233-246.

116. Watanabe N, Churchill R, Furukawa T. Combination of psychotherapy and benzodiazepines versus either therapy alone for panic disorder: a systematic review. BMC Psychiatry. 2007;7:18.

117. Goddard AW, Brouette T, Almai A, Jetty P, Woods SW, Charney D. Early coadministration of clonazepam with sertraline for panic disorder. Arch Gen Psychiatry. 2001;58(7):681-686.

118. Lampe L. Drug treatment for anxiety. Aust Prescr. 2013;36:186-189.

119. Hood SD, Norman A, Hince DA, et al. Benzodiazepine dependence and its treatment with low dose flumazenil. Br J Clin Pharmacol. 2014;77(2):285-294.

120. Pollack MH, Van Ameringen M, Simon NM, et al. A double-blind randomized controlled trial of augmentation and switch strategies for refractory social anxiety disorder. Am J Psychiatry. 2014;171(1):44-53.

121. Nutt DJ. Overview of diagnosis and drug treatments of anxiety disorders. CNS Spectr. 2005;10(1):49-56.

122. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28(5):403-439.

123. Pfizer Pharmaceuticals. Xanax (Alprazolam). Available at https://www.pfizer.com/products/product-detail/xanax. Last accessed September 17, 2024.

124. Ashton H. Risks of dependence on benzodiazepine drugs: a major problem of long-term treatment. BMJ. 1989;298(6666):103-104.

125. Stewart SA. The effects of benzodiazepines on cognition. J Clin Psychiatry. 2005;66(Suppl 2):9-13.

126. Movig KL, Mathjssen MP, Nagel PH, et al. Psychoactive substance use and the risk of motor vehicle accidents. Accid Anal Prev. 2004;36(4):631-636.

127. Finkle WD, Der JS, Greenland S, et al. Risk of fractures requiring hospitalization after an initial prescription for zolpidem, alprazolam, lorazepam, or diazepam in older adults. J Am Geriatr Soc. 2011;59(10):1883-1890.

128. Liebrenz M, Gehring M-T, Buadze A, Caflisch C. High-dose benzodiazepine dependence: a qualitative study of patients' perception on cessation and withdrawal. BMC Psychiatry. 2015;15:116.

129. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Publishing; 2013.

130. U.S. Food and Drug Administration. FDA Updates and Press Announcements on Nitrosamine in Varenicline (Chantix). Available at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-nitrosamine-varenicline-chantix. Last accessed September 5, 2024.

131. Fabre LF, Brown CS, Smith LC, Derogatis LR. Gepirone-ER treatment of hypoactive sexual desire disorder (HSDD) associated with depression in women. J Sex Med. 2011;8(5):1411-1419.

132. Fabre LF, Clayton AH, Smith LC, Goldstein I, Derogatis LR. The effect of gepirone-ER in the treatment of sexual dysfunction in depressed men. J Sex Med. 2012;9(3):821-829.

133. Fabre-Kramer. EXXUA for Major Depression. Available at https://fabrekramer.com/exxua-for-major-depression. Last accessed September 5, 2024.

Evidence-Based Practice Recommendations Citations

1. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Schizophrenia. 3rd ed. Washington, DC: American Psychiatric Association; 2020. Available at https://psychiatryonline.org/doi/full/10.1176/appi.books.9780890424841.Schizophrenia02. Last accessed September 27, 2024.

2. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Arlington, VA: American Psychiatric Association; 2010. Available at https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Last accessed September 27, 2024.

3. National Collaborating Centre for Mental Health, National Collaborating Centre for Primary Care. Bipolar Disorder: Assessment and Management. London: National Institute for Health and Clinical Excellence; 2023. Available at https://www.nice.org.uk/guidance/cg185. Last accessed September 27, 2024.

4. National Collaborating Centre for Mental Health, National Collaborating Centre for Primary Care. Generalised Anxiety Disorder and Panic Disorder (with or without Agoraphobia) in Adults: Management in Primary, Secondary and Community Care. London: National Institute for Health and Clinical Excellence; 2020. Available at https://www.nice.org.uk/guidance/cg113. Last accessed September 27, 2024.

5. Crotty K, Freedman KI, Kampman KM. Executive summary of the focused update of the ASAM national practice guideline for the treatment of opioid use disorder. Journal of Addiction Medicine. 2020;14(2):99-112. Available at https://www.asam.org/docs/default-source/quality-science/jam-exec-summary.pdf. Last accessed September 27, 2024.