MIMD26 • Michigan Physicians and PAs 2026-2027

Table of Contents

MIMD26 • Michigan Physicians and PAs 2026-2027

How to Receive Credit

NetCE 5 Hour Course #95501 • Opioid Safety: Balancing Benefits and Risks

95501 • Opioid Safety: Balancing Benefits and Risks

1. INTRODUCTION

2. TYPES OF PAIN AND THE ROLE OF OPIOIDS

3. CENTERS FOR DISEASE CONTROL AND PREVENTION OPIOID PRESCRIBING GUIDELINE

4. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

5. FEDERAL AND STATE LAW

6. PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

7. DISPARITIES IN PAIN MANAGEMENT

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 5 Hour Course #98190 • Supplements for Aging

98190 • Supplements for Aging

1. INTRODUCTION

2. SUPPLEMENT USE IN OLDER ADULTS

3. PHYSIOLOGICAL CHANGES IN OLDER AGE

4. SAFETY CONCERNS WITH NATURAL PRODUCTS

5. NUTRITIONAL SUPPLEMENTS

6. NATURAL PRODUCTS FOR PHYSICAL CHANGES

7. NATURAL PRODUCTS FOR COGNITIVE CHANGES

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #48854 • Pressure Injuries: Prevention and Management

48854 • Pressure Injuries: Prevention and Management

1. INTRODUCTION

2. EPIDEMIOLOGY

3. PATHOGENESIS

4. RISK FACTORS

5. STAGING OF PRESSURE INJURIES

6. PHASES OF WOUND HEALING: AN OVERVIEW

7. DIAGNOSIS

8. PREVENTION AND TREATMENT

9. WOUND MONITORING

10. COMPLICATIONS

11. TREATMENT OF COMORBIDITIES

12. ADVANCES IN PRESSURE INJURY CARE

13. MEDICO-LEGAL ASPECTS OF INJURY CARE

14. EDUCATING PATIENTS

15. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #90350 • Neuromodulation for Refractory Neuropsychiatric and Pain Disorders

90350 • Neuromodulation for Refractory Neuropsychiatric and Pain Disorders

1. INTRODUCTION

2. OVERVIEW OF BRAIN MODULATION APPROACHES

3. NEUROMODULATION IN SPECIFIC PSYCHIATRIC DISORDERS

4. ELECTROCONVULSIVE THERAPY

5. TRANSCRANIAL MAGNETIC AND ELECTRIC STIMULATION IN PSYCHIATRIC DISORDERS

6. NEUROMODULATION FOR MAJOR DEPRESSIVE DISORDER (MDD) AND AFFECTIVE DISORDERS

7. NEUROMODULATION FOR OTHER MENTAL HEALTH DISORDERS

8. INVASIVE NEUROSTIMULATION

9. NEUROMODULATION IN CHRONIC PAIN

10. INVASIVE NEUROSTIMULATION IN CHRONIC PAIN

11. SOCIAL ISSUES WITH NEUROSTIMULATORS

12. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

MIMD26 • Michigan Physicians and PAs 2026-2027

Mark Rose, BS, MA, LP

Chelsey McIntyre, PharmD

www.netce.com

Copyright © 2025 NetCE, All rights reserved.

MIMD26 • Michigan Physicians and PAs 2026-2027

Expiration Date: 02/28/2027

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.

95501 • Opioid Safety: Balancing Benefits and Risks

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2025 NetCE, All rights reserved.

Opioid analgesics are approved by the FDA for the treatment of moderate or severe pain. However, individual patients differ greatly in clinical response to different opioid analgesics, and patient populations show widely variable response to the same opioid and dose. These response variations make opioid prescribing challenging. Further, the important role of opioid analgesics is broadly accepted in acute pain, cancer pain, and palliative and end-of-life care, but it is controversial for the management of chronic noncancer pain. Previous opioid prescribing guidelines have been critiqued for lacking a patient-centered approach and failing to emphasize individualization of therapy. This prompted the 2022 revision of the CDC's opioid prescribing guidelines, the draft of which is outlined in this course. Opioids are not a panacea for pain, nor are they safe and effective for every patient. However, they can be a useful tool, and knowledge of medical advances can give clinicians greater confidence to safely and effectively prescribe these drugs.

Table of Contents

95501 • Opioid Safety: Balancing Benefits and Risks

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. TYPES OF PAIN AND THE ROLE OF OPIOIDS

ACUTE AND SUBACUTE PAIN

CHRONIC NON-CANCER PAIN

PALLIATIVE CARE AND PAIN AT THE END OF LIFE

3. CENTERS FOR DISEASE CONTROL AND PREVENTION OPIOID PRESCRIBING GUIDELINE

DETERMINING WHETHER OR NOT TO INITIATE OPIOIDS FOR PAIN

OPIOID SELECTION AND DOSAGE

OPIOID DURATION AND FOLLOW-UP

ASSESSING RISK AND ADDRESSING HARMS OF OPIOID USE

RESPONSE TO THE CDC'S OPIOID PRESCRIBING GUIDELINE UPDATE

4. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

5. FEDERAL AND STATE LAW

CONTROLLED SUBSTANCES LAWS/RULES

STATE-SPECIFIC LAWS AND RULES

6. PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

7. DISPARITIES IN PAIN MANAGEMENT

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

95501 • Opioid Safety: Balancing Benefits and Risks

Education Category. Pharmacology

Release Date. 10/01/2025

Expiration Date. 09/30/2028

Course Overview

Opioid analgesics are approved by the FDA for the treatment of moderate or severe pain. However, individual patients differ greatly in clinical response to different opioid analgesics, and patient populations show widely variable response to the same opioid and dose. These response variations make opioid prescribing challenging. Further, the important role of opioid analgesics is broadly accepted in acute pain, cancer pain, and palliative and end-of-life care, but it is controversial for the management of chronic noncancer pain. Previous opioid prescribing guidelines have been critiqued for lacking a patient-centered approach and failing to emphasize individualization of therapy. This prompted the 2022 revision of the CDC's opioid prescribing guidelines, the draft of which is outlined in this course. Opioids are not a panacea for pain, nor are they safe and effective for every patient. However, they can be a useful tool, and knowledge of medical advances can give clinicians greater confidence to safely and effectively prescribe these drugs.

Audience

This course is designed for all physicians, osteopaths, physician assistants, pharmacy professionals, and nurses who may alter prescribing and/or dispensing practices to ensure safe 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 5 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 5 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 5 ANCC contact hour(s). NetCE designates this continuing education activity for 5 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 6 hours for Alabama nurses. NetCE designates this activity for 5 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-25-057-H08-P. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 5 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. 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 5 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 5 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. AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 0.5 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 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. Outline the types of pain and effective approaches to managing different pain types.

2. Describe the Centers for Disease Control and Prevention's most recent guidelines for prescribing opioids.

3. Identify behaviors that are indicative of opioid seeking, diversion, addiction, and/or misuse.

4. Discuss federal and state laws pertaining to the prescription of controlled substances.

5. Create a plan to properly educate patients and families regarding safe opioid use.

6. Describe potential causes and effects of disparities in pain management, and approaches to minimize negative consequences.

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

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 nonopioid therapy or nonpharmacologic pain therapy without adequate pain relief, are considered to be candidates for a trial of opioid therapy. Initial treatment should always be considered individually determined and as a trial of therapy, not a definitive course of treatment [1; 2].

2. TYPES OF PAIN AND THE ROLE OF OPIOIDS

ACUTE AND SUBACUTE PAIN

Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute (less than one month) or subacute (one to three months) 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 [2].

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 [2].

CHRONIC NON-CANCER PAIN

Nonpharmacologic therapy and nonopioid pharmacologic therapy are the preferred first-line therapies for chronic non-cancer pain. 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 [2].

The following video, produced by the CDC, highlights the risks of opioids and offers some nonopioid options for chronic pain management.

To see this media go to http://www.NetCE.com/activities/ using a browser that supports Adobe Flash.

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 [3]. 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 [2,3].

If opioids are used, they should be combined with nonpharmacologic therapy and nonopioid 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 [4].

Evidence Based Practice Recommendation

According to the American Society of Interventional Pain Physicians, before starting opioid therapy, clinicians must take certain basic steps to prevent opioid abuse: distinguish individual opioid abuse risk factors; screen patients' potential for addiction and abuse during their initial visit; categorize patients in accordance with their level of risk and implement an appropriate level of monitoring; and refrain from judgments before a thorough assessment. Combining the above strategies with point-of-care urine drug testing as a confirmatory tool have been shown to contribute significantly to the identification of inconsistencies.

https://www.painphysicianjournal.com/current/pdf?article=NDIwNA%3D%3D&journal=103

Last Accessed: September 28, 2025

Level of Evidence: Expert Opinion/Consensus Statement

Opioid therapy for chronic pain should not be initiated without consideration by the clinician and patient on follow-up, taper, and exit strategy if opioid therapy is unsuccessful.. 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. The treatment plan should describe therapy selection, measures of progress, and other diagnostic evaluations, consultations, referrals, and therapies [1,2].

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. When starting opioid therapy for chronic pain, clinicians should prescribe short-acting instead of extended-release/long-acting (ER/LA) opioid formulations [1,2].

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 [2].

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 nonopioid and immediate-release opioids over ER/LA opioids. Taper opioid dose when no longer needed [4].

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. Although experts have noted that 90% of end-of-life pain can be managed effectively, rates of pain are high, even among people receiving palliative care [5,6,7].

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. This reluctance is related to a variety of attitudes and beliefs [5,8,9]:

- 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 [10]. It is important to acknowledge patients' fears individually and provide information to help them differentiate fact from fiction. For example, when discussing opioids with a patient who fears addiction, the clinician should explain that the risk of addiction is low. It is also helpful to note the difference between addiction and physical dependence [1,5].

There are several other ways clinicians can allay patients' fears about pain medication [1,8]:

- 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 [1,8].

Clinicians' attitudes, beliefs, and experiences also influence pain management, with addiction, tolerance, side effects, and regulations being the most important concerns. 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. As a result, many clinicians, especially primary care physicians, do not feel confident about their ability to manage pain in their patients [5,8,9].

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. Morphine, buprenorphine, oxycodone, hydromorphone, fentanyl, and methadone are the most widely used in the United States. Unlike nonopioids, opioids do not have a ceiling effect, and the dose can be titrated until pain is relieved or side effects become unmanageable. 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 [2,7].

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. Intramuscular injections should be avoided because injections are painful, drug absorption is unreliable, and the time to peak concentration is long [2,7].

3. CENTERS FOR DISEASE CONTROL AND PREVENTION OPIOID PRESCRIBING GUIDELINE

The Centers for Disease Control and Prevention (CDC) originally published Guideline for Prescribing Opioids for Chronic Pain—United States, 2016 in an effort to address an ongoing crisis of prescription opioid misuse, abuse, and overdose [2]. 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 updates to the guideline in 2022 [2]. 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 [2].

The 2022 clinical practice guideline includes 12 recommendations for clinicians who are prescribing opioids for outpatients 18 years of age or older with acute (duration <1 month) pain, subacute (duration of 1 to 3 months) pain, or chronic (duration of >3 months) pain outside of sickle cell disease related pain management, cancer pain treatment, palliative care, and end-of-life care. These recommendations are graded according to applicability and strength of the supporting evidence (Table 1) [2].

Table 1: CDC GUIDELINE RECOMMENDATION GRADING SCHEME

Grade/Level

Description

Recommendation Categories

A

Applies to all persons; most patients should receive the recommended course of action.

B

Individual decision making needed; different choices will be appropriate for different patients. Clinicians help patients arrive at a decision consistent with patient values and preferences and specific clinical situations.

Evidence Type

1

Randomized clinical trials or overwhelming evidence from observational studies.

2

Randomized clinical trials with important limitations, or exceptionally strong evidence from observational studies.

3

Observational studies or randomized clinical trials with notable limitations.

4

Clinical experience and observations, observational studies with important limitations, or randomized clinical trials with several major limitations.

Source: [2]

Each of the 12 recommendations is followed by considerations for implementation. These implementation considerations offer practical insights meant to further inform clinician-patient decision-making for the respective recommendation and are not meant to be rigidly or inflexibly followed. In addition, these five guiding principles should broadly inform implementation across recommendations:

- Acute, subacute, and chronic pain need to be appropriately and effectively treated independent of whether opioids are part of a treatment regimen.

- Recommendations are voluntary and are intended to support, not supplant, individualized, person-centered care. Flexibility to meet the care needs and the clinical circumstances of a specific patient are paramount.

- A multimodal and multidisciplinary approach to pain management attending to the physical health, behavioral health, long-term services and supports, and expected health outcomes and well-being of each person is critical.

- Special attention should be given to avoid misapplying this updated clinical practice guideline beyond its intended use or implementing policies purportedly derived from it that might lead to unintended consequences for patients.

- Clinicians, practices, health systems, and payers should vigilantly attend to health inequities, provide culturally and linguistically appropriate communi-cation, including communication that is accessible to persons with disabilities, and ensure access to an appropriate, affordable, diversified, coordinated, and effective nonpharmacologic and pharmacologic pain management regimen for all persons.

The following sections are reprinted from the 2022 guideline from the CDC [2].

DETERMINING WHETHER OR NOT TO INITIATE OPIOIDS FOR PAIN

All patients with pain should receive treatment that provides the greatest benefits relative to risks. See Recommendation 1 for determining whether to initiate opioids for acute pain (i.e., with a duration of less than one month) and Recommendation 2 for determining whether or not to initiate opioids for subacute (i.e., with a duration of at least one month and less than three months) or chronic pain (i.e., with a duration of three months or more).

Recommendation 1

Nonopioid therapies are at least as effective as opioids for many common types of acute pain. Clinicians should maximize use of nonpharmacologic and nonopioid pharmacologic therapies as appropriate for the specific condition and patient and only consider opioid therapy for acute pain if benefits are anticipated to outweigh risks to the patient. Before prescribing opioid therapy for acute pain, clinicians should discuss with patients the realistic benefits and known risks of opioid therapy (recommendation category: B, evidence type: 3).

Implementation Considerations

Nonopioid therapies are at least as effective as opioids for many common acute pain conditions, including low back pain, neck pain, pain related to other musculoskeletal injuries (e.g., sprains, strains, tendonitis, and bursitis), pain related to minor surgeries typically associated with minimal tissue injury and mild postoperative pain (e.g., simple dental extraction), dental pain, kidney stone pain, and headaches including episodic migraine.

Clinicians should maximize use of nonopioid pharmacologic (e.g., topical or oral nonsteroidal anti-inflammatory drugs [NSAIDs], acetaminophen) and nonpharmacologic (e.g., ice, heat, elevation, rest, immobilization, or exercise) therapies as appropriate for the specific condition.

Opioid therapy has an important role for acute pain related to severe traumatic injuries (including crush injuries and burns), invasive surgeries typically associated with moderate-to-severe postoperative pain, and other severe acute pain when NSAIDs and other therapies are contraindicated or likely to be ineffective.

Opioids are not first-line therapy for many common acute pain conditions, including low back pain, neck pain, pain related to other musculoskeletal injuries (such as sprains, strains, tendonitis, bursitis), pain related to minor surgeries typically associated with minimal tissue injury and only mild postoperative pain (e.g., dental extraction), dental pain, kidney stone pain, and headaches, including episodic migraine.

When diagnosis and severity of acute pain warrant the use of opioids, clinicians should prescribe immediate-release opioids (see Recommendation 3) at the lowest effective dose (see Recommendation 4) and for no longer than the expected duration of pain severe enough to require opioids (see Recommendation 6).

Clinicians should prescribe and advise opioid use only as needed (e.g., hydrocodone 5 mg/acetaminophen 325 mg, one tablet not more frequently than every 4 hours as needed for moderate-to-severe pain) rather than on a scheduled basis (e.g., one tablet every 4 hours) and encourage and recommend an opioid taper if opioids are taken around the clock for more than a few days (see Recommendation 6).

If patients already receiving opioids long term require additional medication for acute pain, nonopioid medications should be used when possible, and if additional opioids are required (e.g., for superimposed severe acute pain), they should be continued only for the duration of pain severe enough to require additional opioids, returning to the patient's baseline opioid dosage as soon as possible, including a taper to baseline dosage if additional opioids were used around the clock for more than a few days (see Recommendation 6).

Clinicians should ensure that patients are aware of expected benefits of, common and serious risks of, and alternatives to opioids before starting or continuing opioid therapy and should involve patients meaningfully in decisions about whether to start opioid therapy.

Recommendation 2

Nonopioid therapies are preferred for subacute and chronic pain. Clinicians should maximize use of nonpharmacologic and nonopioid pharmacologic therapies as appropriate for the specific condition and patient and only consider initiating opioid therapy if expected benefits for pain and function are anticipated to outweigh risks to the patient. Before starting opioid therapy for subacute or chronic pain, clinicians should discuss with patients the realistic benefits and known risks of opioid therapy, should work with patients to establish treatment goals for pain and function, and should consider how opioid therapy will be discontinued if benefits do not outweigh risks (recommendation category: A, evidence type: 2).

Implementation Considerations

To guide patient-specific selection of therapy, clinicians should evaluate patients and establish or confirm the diagnosis.

Clinicians should recommend appropriate noninvasive, nonpharmacologic approaches to help manage chronic pain, such as exercise (e.g., aerobic, aquatic, resistance exercises) or exercise therapy (a prominent modality in physical therapy) for back pain, fibromyalgia, and hip or knee osteoarthritis; weight loss for knee osteoarthritis; manual therapies for hip osteoarthritis; psychological therapy, spinal manipulation, low-level laser therapy, massage, mindfulness-based stress reduction, yoga, acupuncture, and multidisciplinary rehabilitation for low back pain; mind-body practices (e.g., yoga, tai chi, qigong), massage, and acupuncture for neck pain; cognitive-behavioral therapy [CBT], myofascial release massage, mindfulness practices, tai chi, qigong, acupuncture, and multidisciplinary rehabilitation for fibromyalgia; and spinal manipulation for tension headache.

Low-cost options to integrate exercise include walking in public spaces or use of public recreation facilities for group exercise. Physical therapy can be helpful, particularly for patients who have limited access to safe public spaces or public recreation facilities for exercise or whose pain has not improved with low-intensity physical exercise.

Health insurers and health systems can improve pain management and reduce medication use and associated risks by increasing reimbursement for and access to noninvasive, nonpharmacologic therapies with evidence for effectiveness.

Clinicians should review U.S. Food and Drug Administration (FDA)-approved labeling including boxed warnings and weigh benefits and risks before initiating treatment with any pharmacologic therapy.

When patients affected by osteoarthritis have an insufficient response to nonpharmacologic interventions such as exercise for arthritis pain, topical NSAIDs can be used in patients with pain in a single or few joints near the surface of the skin (e.g., knee). For patients with osteoarthritis pain in multiple joints or incompletely controlled with topical NSAIDs, duloxetine or systemic NSAIDs can be considered.

NSAIDs should be used at the lowest effective dose and shortest duration needed and should be used with caution, particularly in older adults and in patients with cardiovascular comorbidities, chronic renal failure, or previous gastrointestinal bleeding.

When patients with chronic low back pain have had an insufficient response to nonpharmacologic approaches such as exercise, clinicians can consider NSAIDs or duloxetine for patients without contraindications.

Tricyclic, tetracyclic, and serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants, selected anticonvulsants (e.g., pregabalin, gabapentin enacarbil, oxcarbazepine), and capsaicin and lidocaine patches can be considered for neuropathic pain.

Duloxetine and pregabalin are FDA-approved for the treatment of diabetic peripheral neuropathy, and pregabalin and gabapentin are FDA-approved for treatment of post-herpetic neuralgia.

In patients with fibromyalgia, tricyclic (amitriptyline) and SNRI antidepressants (duloxetine and milnacipran), NSAIDs (topical diclofenac), and specific anticonvulsants (pregabalin and gabapentin) are used to improve pain, function, and quality of life. Duloxetine, milnacipran, and pregabalin are FDA-approved for the treatment of fibromyalgia. In older adults, decisions to use tricyclic antidepressants should be made judiciously on a case-by-case basis because of risks for confusion and falls.

Patients with co-occurring pain and depression might be especially likely to benefit from antidepressant medication (see Recommendation 8).

Opioids should not be considered first-line or routine therapy for subacute or chronic pain. This does not mean that patients should be required to sequentially fail nonpharmacologic and nonopioid pharmacologic therapy or be required to use any specific treatment before proceeding to opioid therapy. Rather, expected benefits specific to the clinical context should be weighed against risks before initiating therapy. In some clinical contexts (e.g., serious illness in a patient with poor prognosis for return to previous level of function, contraindications to other therapies, and clinician and patient agreement that the overriding goal is patient comfort), opioids might be appropriate regardless of previous therapies used. In other situations, (e.g., headache or fibromyalgia), expected benefits of initiating opioids are unlikely to outweigh risks regardless of previous nonpharmacologic and nonopioid pharmacologic therapies used.

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.

Before opioid therapy is initiated for subacute or chronic pain, clinicians should determine jointly with patients how functional benefit will be evaluated and establish specific, measurable treatment goals.

For patients with subacute pain who started opioid therapy for acute pain and have been treated with opioid therapy for ≥30 days, clinicians should ensure that potentially reversible causes of chronic pain are addressed and that opioid prescribing for acute pain does not unintentionally become long-term opioid therapy simply because medications are continued without reassessment. Continuation of opioid therapy at this point might represent initiation of long-term opioid therapy, which should occur only as an intentional decision that benefits are likely to outweigh risks after informed discussion between the clinician and patient and as part of a comprehensive pain management approach.

Clinicians seeing new patients already receiving opioids should establish treatment goals, including functional goals, for continued opioid therapy. Clinicians should avoid rapid tapering or abrupt discontinuation of opioids (see Recommendation 5).

Patient education and discussion before starting opioid therapy are critical so that patient preferences and values can be understood and used to inform clinical decisions.

Clinicians should review available low-cost options for pain management for all patients, and particularly for patients who have low incomes, do not have health insurance, or have inadequate insurance.

Clinicians should ensure that patients are aware of expected benefits of, common and serious risks of, and alternatives to opioids before starting or continuing opioid therapy and should involve patients in decisions about whether to start opioid therapy.

OPIOID SELECTION AND DOSAGE

Recommendation 3

When starting opioid therapy for acute, subacute, or chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release and long-acting (ER/LA) opioids (recommendation category: A, evidence type: 4).

Implementation Considerations

Clinicians should not treat acute pain with ER/LA opioids or initiate opioid treatment for subacute or chronic pain with ER/LA opioids, and clinicians should not prescribe ER/LA opioids for intermittent or as needed use.

ER/LA opioids should be reserved for severe, continuous pain. The FDA has noted that some ER/LA opioids should be considered only for patients who have received certain dosages of opioids of immediate-release opioids daily for at least 1 week.

When changing to an ER/LA opioid for a patient previously receiving a different immediate-release opioid, clinicians should consult product labeling and reduce total daily dosage to account for incomplete opioid cross-tolerance.

Clinicians should use additional caution with ER/LA opioids and consider a longer dosing interval when prescribing to patients with renal or hepatic dysfunction because decreased clearance of medications among these patients can lead to accumulation of drugs to toxic levels and persistence in the body for longer durations.

Methadone should not be the first choice for an ER/LA opioid. Only clinicians who are familiar with methadone's unique risk profile and who are prepared to educate and closely monitor their patients, including assessing risk for QT prolongation and considering electrocardiographic monitoring, should consider prescribing methadone for pain.

Only clinicians who are familiar with the dosing and absorption properties of the ER/LA opioid transdermal fentanyl and are prepared to educate their patients about its use should consider prescribing it.

Recommendation 4

When opioids are initiated for opioid-naïve patients with acute, subacute, or chronic pain, clinicians should prescribe the lowest effective dosage. If opioids are continued for subacute or chronic pain, clinicians should use caution when prescribing opioids at any dosage, should carefully evaluate individual benefits and risks when considering increasing dosage, and should avoid increasing dosage above levels likely to yield diminishing returns in benefits relative to risks to patients (recommendation category: A, evidence type: 3).

Implementation Considerations

The recommendations related to opioid dosages are not intended to be used as an inflexible, rigid standard of care; rather, they are intended to be guideposts to help inform clinician-patient decision-making. Risks of opioid use, including risk for overdose and overdose death, increase continuously with dosage, and there is no single dosage threshold below which risks are eliminated. Therefore, the recommendation language emphasizes that clinicians should avoid increasing dosage above levels likely to yield diminishing returns in benefits relative to risks to patients rather than emphasizing a single specific numeric threshold. Further, these recommendations apply specifically to starting opioids or to increasing opioid dosages, and a different set of benefits and risks applies to reducing opioid dosages (see Recommendation 5).

When opioids are initiated for opioid-naïve patients with acute, subacute, or chronic pain, clinicians should prescribe the lowest effective dosage.

For patients not already taking opioids, the lowest effective dose can be determined using product labeling as a starting point with calibration as needed based on the severity of pain and other clinical factors such as renal or hepatic insufficiency (see Recommendation 8).

The lowest starting dose for opioid-naïve patients is often equivalent to a single dose of approximately 5–10 MME or a daily dosage of 20–30 MME/day.

If opioids are continued for subacute or chronic pain, clinicians should use caution when prescribing opioids at any dosage and should generally avoid dosage increases when possible.

Many patients do not experience benefit in pain or function from increasing opioid dosages to ≥50 MME/day but are exposed to progressive increases in risk as dosage increases. Therefore, before increasing total opioid dosage to ≥50 MME/day, clinicians should pause and carefully reassess evidence of individual benefits and risks. If a decision is made to increase dosage, clinicians should use caution and increase dosage by the smallest practical amount. The recommendations related to opioid dosages are not intended to be used as an inflexible, rigid standard of care; rather, they are intended to be guideposts to help inform clinician-patient decision-making.

Additional dosage increases beyond 50 MME/day are progressively more likely to yield diminishing returns in benefits for pain and function relative to risks to patients as dosage increases further. Clinicians should carefully evaluate a decision to further increase dosage based on individualized assessment of benefits and risks and weighing factors such as diagnosis, incremental benefits for pain and function relative to risks with previous dosage increases, other treatments and effectiveness, and patient values and preferences.

Again, the recommendations related to opioid dosages are not intended to be used as an inflexible, rigid standard of care; rather, they are intended to be guideposts to help inform clinician-patient decision making.

Recommendation 5

For patients already receiving opioid therapy, clinicians should carefully weigh benefits and risks and exercise care when changing opioid dosage. If benefits outweigh risks of continued opioid therapy, clinicians should work closely with patients to optimize nonopioid therapies while continuing opioid therapy. If benefits do not outweigh risks of continued opioid therapy, clinicians should optimize other therapies and work closely with patients to gradually taper to lower dosages or, if warranted based on the individual circumstances of the patient, appropriately taper and discontinue opioids. Unless there are indications of a life-threatening issue, such as warning signs of impending overdose (e.g., confusion, sedation, slurred speech), opioid therapy should not be discontinued abruptly, and clinicians should not rapidly reduce opioid dosages from higher dosages (recommendation category: B, evidence type: 4).

The following short video, produced by the CDC, describes when and how clinicians should initiate opioid tapering and outlines ways to support patients through the process.

To see this media go to http://www.NetCE.com/activities/ using a browser that supports Adobe Flash.

Implementation Considerations

Clinicians should carefully weigh both the benefits and risks of continuing opioid medications and the benefits and risks of tapering opioids. If benefits outweigh risks of continued opioid therapy, clinicians should work closely with patients to optimize nonopioid therapies while continuing opioid therapy.

When benefits (including avoiding risks of tapering) do not outweigh risks of continued opioid therapy, clinicians should optimize other therapies and work closely with patients to gradually taper to a reduced opioid dosage or, if warranted based on the individual clinical circumstances of the patient, appropriately taper and discontinue opioid therapy.

In situations where benefits and risks of continuing opioids are considered to be close or unclear, shared decision-making with patients is particularly important.

At times, clinicians and patients might not be able to agree on whether or not tapering is necessary. When patients and clinicians are unable to arrive at a consensus on the assessment of benefits and risks, clinicians should acknowledge this discordance, express empathy, and seek to implement treatment changes in a patient-centered manner while avoiding patient abandonment.

Patient agreement and interest in tapering is likely to be a key component of successful tapers.

For patients agreeing to taper to lower opioid dosages and for those remaining on higher opioid dosages, clinicians should establish goals with the patient for continued opioid therapy (see Recommendations 2 and 7) and maximize pain treatment with nonpharmacologic and nonopioid pharmacologic treatments as appropriate (see Recommendation 2).

Clinicians should collaborate with the patient on the tapering plan, including patients in decisions such as how quickly tapering will occur and when pauses in the taper may be warranted.

Clinicians should follow up frequently (at least monthly) with patients engaging in opioid tapering. Team members (e.g., nurses, pharmacists, behavioral health professionals) can support the clinician and patient during the ongoing taper process through telephone contact, telehealth visits, or face-to-face visits.

When opioids are reduced or discontinued, a taper slow enough to minimize symptoms and signs of opioid withdrawal (e.g., anxiety, insomnia, abdominal pain, vomiting, diarrhea, diaphoresis, mydriasis, tremor, tachycardia, or piloerection) should be used.

Longer duration of previous opioid therapy might require a longer taper. For patients who have taken opioids long-term (e.g., for ≥1 year), tapers can be completed over several months to years depending on the opioid dosage and should be individualized based on patient goals and concerns.

When patients have been taking opioids for longer durations (e.g., for ≥1 year), tapers of 10% per month or slower are likely to be better tolerated than more rapid tapers.

For patients struggling to tolerate a taper, clinicians should maximize nonopioid treatments for pain and should address behavioral distress. Clinically significant opioid withdrawal symptoms can signal the need to further slow the taper rate.

At times, tapers might have to be paused and restarted again when the patient is ready and might have to be slowed as patients reach low dosages.

Before reversing a taper, clinicians should carefully assess and discuss with the patient the benefits and risks of increasing opioid dosage.

Goals of the taper may vary (e.g., some patients might achieve discontinuation; others might attain a reduced dosage). If the clinician has determined with the patient that the ultimate goal of tapering is discontinuing opioids, after the smallest available dose is reached the interval between doses can be extended and opioids can be stopped when taken less frequently than once a day.

Clinicians should access appropriate expertise if considering tapering opioids during pregnancy because of possible risk to the pregnant patient and to the fetus if the patient goes into withdrawal.

Clinicians should advise patients of an increased risk for overdose on abrupt return to a previously prescribed higher dose, because of loss of opioid tolerance, provide opioid overdose education, and offer naloxone.

Clinicians should remain alert to signs of and screen for anxiety, depression, and opioid misuse or opioid use disorder (see Recommendations 8 and 12) that might be revealed by an opioid taper and provide treatment or arrange for management of these comorbidities.

Clinicians should closely monitor patients who are unable to taper and who continue on high-dose or otherwise high-risk opioid regimens (e.g., opioids prescribed concurrently with benzodiazepines) and should work with patients to mitigate overdose risk (e.g., by providing overdose education and naloxone—see Recommendation 8).

Clinicians can use periodic and strategic motivational questions and statements to encourage movement toward appropriate therapeutic changes and functional goals.

Clinicians have a responsibility to provide or arrange for coordinated management of patients' pain and opioid-related problems, including opioid use disorder.

Payers, health systems, and state medical boards should not use this clinical practice guideline to set rigid standards or performance incentives related to dose or duration of opioid therapy; should ensure that policies based on cautionary dosage thresholds do not result in rapid tapers or abrupt discontinuation of opioids; and should ensure that policies do not penalize clinicians for accepting new patients who are using prescribed opioids for chronic pain, including those receiving high dosages of opioids, or for refraining from rapidly tapering patients prescribed long-term opioid medications.

Although Recommendation 5 specifically refers to patients using long-term opioid therapy for subacute or chronic pain, many of the principles in these implementation considerations and supporting rationale, including communication with patients, pain management and behavioral support, and slower taper rates, are also relevant when discontinuing opioids in patients who have received them for shorter durations (see also Recommendations 6 and 7).

OPIOID DURATION AND FOLLOW-UP

Recommendation 6

When opioids are needed for acute pain, clinicians should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids (recommendation category: A, evidence type: 4).

Implementation Considerations

Nontraumatic, nonsurgical acute pain can often be managed without opioids (see Recommendation 1).

Opioids are sometimes needed for treatment of acute pain (see Recommendation 1). When the diagnosis and severity of acute pain warrant use of opioids, clinicians should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. For many common causes of nontraumatic, nonsurgical pain, when opioids are needed, a few days or less are often sufficient, and shorter courses can minimize the need to taper opioids to prevent withdrawal symptoms at the end of a course of opioids. However, durations should be individualized to the patients' clinical circumstances.

Clinicians should generally avoid prescribing additional opioids to patients "just in case" pain continues longer than expected.

For postoperative pain related to major surgery, procedure-specific opioid prescribing recommendations are available with ranges for amounts of opioids needed (on the basis of actual use and refills and on consensus).

To minimize unintended effects on patients, clinicians, practices, and health systems should have mechanisms in place for the subset of patients who experience severe acute pain that continues longer than the expected duration. These mechanisms should allow for timely re-evaluation to confirm or revise the initial diagnosis and to adjust management accordingly. Clinicians, practices, and health systems can help minimize disparities in access to and affordability of care and refills by ensuring all patients can obtain and afford additional evaluation and treatment, as needed.

Longer durations of opioid therapy are more likely to be needed when the mechanism of injury is expected to result in prolonged severe pain (e.g., severe traumatic injuries).

Patients should be evaluated at least every 2 weeks if they continue to receive opioids for acute pain.

If opioids are continued for ≥1 month, clinicians should ensure that potentially reversible causes of chronic pain are addressed and that opioid prescribing for acute pain does not unintentionally become long-term opioid therapy simply because medications are continued without reassessment. Continuation of opioid therapy at this point might represent initiation of long-term opioid therapy, which should occur only as an intentional decision that benefits are likely to outweigh risks after discussion between the clinician and patient and as part of a comprehensive pain management approach. Clinicians should refer to recommendations on subacute and chronic pain for initiation (Recommendation 2), follow-up (Recommendation 7), and tapering (Recommendation 5) of ongoing opioid therapy.

If patients already receiving long-term opioid therapy require additional opioids for superimposed severe acute pain (e.g., major surgery), opioids should be continued only for the duration of pain severe enough to require additional opioids, returning to the patient's baseline opioid dosage as soon as possible, including a taper to baseline dosage if additional opioids were used around the clock for more than a few days.

If opioids are used continuously (around the clock) for more than a few days for acute pain, clinicians should prescribe a brief taper to minimize withdrawal symptoms on discontinuation of opioids.

If a taper is needed, taper durations might need to be adjusted depending on the duration of the initial opioid prescription (see supporting rationale for this recommendation for additional details).

Tapering plans should be discussed with the patient prior to hospital discharge and with clinicians coordinating the patient's care as an outpatient. (See Recommendation 5 for tapering considerations when patients have taken opioids continuously for longer than one month.)

Recommendation 7

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 (recommendation category: A, evidence type: 4).

Implementation Considerations

In addition to evaluating benefits and risks of opioids before starting opioid therapy (see Recommendation 2), clinicians should evaluate patients to assess benefits and risks of opioids within 1 to 4 weeks of starting long-term opioid therapy or of dosage escalation.

Clinicians should consider follow-up intervals within the lower end of this range when ER/LA opioids are started or increased, given increased risk for overdose within the first 2 weeks of treatment, or when total daily opioid dosage is ≥50 MME/day. (Overdose risk is doubled across multiple studies for dosages of 50 to <100 MME/day relative to <20 MME/day. See Recommendation 4.)

Shorter follow-up intervals (every two to three days for the first week) should be strongly considered when starting or increasing the dosage of methadone, given the variable half-life of this drug (see Recommendation 3) and the potential for drug accumulation during initiation and during upward titration of dosage.

An initial follow-up interval closer to 4 weeks can be considered when starting immediate-release opioids at a dosage of <50 MME/day.

Clinicians should follow up with and evaluate patients with subacute pain who started opioid therapy for acute pain and have been treated with opioid therapy for 30 days to reassess the patient's pain, function, and treatment course; ensure that potentially reversible causes of chronic pain are addressed; and prevent unintentional initiation of long-term opioid therapy. Continuation of opioid therapy at this point might represent initiation of long-term opioid therapy, which should occur only as an intentional decision that benefits are likely to outweigh risks after discussion between the clinician and patient and as part of a comprehensive pain management approach (see Recommendation 2).

Clinicians should regularly reassess all patients receiving long-term opioid therapy, including patients who are new to the clinician but on long-term opioid therapy, with a suggested interval of every three months or more frequently for most patients.

Clinicians seeing new patients already receiving opioids should establish treatment goals, including functional goals, for continued opioid therapy (see Recommendation 2).

Clinicians should re-evaluate patients who are at higher risk for opioid use disorder or overdose (e.g., patients with depression or other mental health conditions, a history of substance use disorder, a history of overdose, taking ≥50 MME/day, or taking other central nervous system depressants with opioids) more frequently than every 3 months. Clinicians should regularly screen all patients for these conditions, which can change during the course of treatment (see Recommendation 8).

Clinicians, practices, and health systems can help minimize unintended effects on patients by ensuring all patients can access and afford follow-up evaluation.

In practice contexts where virtual visits are part of standard care (e.g., in remote areas where distance or other context makes follow-up visits challenging), or for patients for whom in-person follow-up visits are challenging (e.g., frail patients), follow-up assessments that allow the clinician to communicate with and observe the patient through telehealth modalities may be conducted.

At follow-up, clinicians should review patient perspectives and goals, determine whether opioids continue to meet treatment goals, including sustained improvement in pain and function and determine whether the patient has experienced common or serious adverse events or early warning signs of serious adverse events or has signs of opioid use disorder.

Clinicians should ensure that treatment for depression, anxiety, or other psychological comorbidities is optimized.

Clinicians should ask patients about their preferences for continuing opioids, considering their effects on pain and function relative to any adverse effects experienced. If risks outweigh benefits of continued opioid therapy (e.g., if patients do not experience meaningful, sustained improvements in pain and function compared with prior to initiation of opioid therapy; if patients are taking higher-risk regimens [e.g., dosages of ≥50 MME/day or opioids combined with benzodiazepines] without evidence of benefit; if patients believe benefits no longer outweigh risks; if patients request dosage reduction or discontinuation; or if patients experience overdose or other serious adverse events), clinicians should work with patients to taper and reduce opioid dosage or taper and discontinue opioids when possible, using principles from Recommendation 5.

Clinicians should maximize pain treatment with nonpharmacologic and nonopioid pharmacologic treatments as appropriate (see Recommendation 2).

ASSESSING RISK AND ADDRESSING HARMS OF OPIOID USE

Recommendation 8

Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk for opioid-related harms and discuss risk with patients. Clinicians should work with patients to incorporate into the management plan strategies to mitigate risk, including offering naloxone (recommendation category: A, evidence type: 4).

Implementation Considerations

Clinicians should ask patients about their drug and alcohol use and use validated tools or consult with behavioral specialists to screen for and assess mental health and substance use disorders.

When considering initiating long-term opioid therapy, clinicians should ensure that treatment for depression and other mental health conditions is optimized, consulting with behavioral health specialists when needed.

Clinicians should offer naloxone when prescribing opioids, particularly to patients at increased risk for overdose, including patients with a history of overdose, patients with a history of substance use disorder, patients with sleep-disordered breathing, patients taking higher dosages of opioids (e.g., ≥50 MME/day), patients taking benzodiazepines with opioids (see Recommendation 11), and patients at risk for returning to a high dose to which they have lost tolerance (e.g., patients undergoing tapering or recently released from prison).

Practices should educate patients on overdose prevention and naloxone use and offer to provide education to members of their households.

Naloxone co-prescribing can be facilitated by clinics or practices with resources to provide naloxone training and by collaborative practice models with pharmacists or through statewide protocols or standing orders for naloxone at pharmacies.

Resources for prescribing naloxone in primary care and emergency department settings can be found through Prescribe to Prevent at https://prescribetoprevent.org; additional resources are at https://samhsa.gov.

In part because of concerns about cost of naloxone and access for some patients and reports that purchasing of naloxone has in some cases been required to fill opioid prescriptions, including for patients without a way to afford naloxone, this recommendation specifies that naloxone should be offered to patients. To that end, clinicians, health systems, and payers can work to ensure patients can obtain naloxone, a potentially lifesaving treatment.

Clinicians should avoid prescribing opioids to patients with moderate or severe sleep-disordered breathing when possible to minimize risk for respiratory depression.

When making decisions about whether to initiate opioid therapy for pain during pregnancy, clinicians and patients together should carefully weigh benefits and risks. For pregnant people already receiving opioids, clinicians should access appropriate expertise if tapering is being considered because of possible risk to the pregnant patient and to the fetus if the patient goes into withdrawal (see Recommendation 5).

For pregnant people with opioid use disorder, medication for opioid use disorder (buprenorphine or methadone) is the recommended therapy and should be offered as early as possible in pregnancy to prevent harms to both the patient and the fetus (see Recommendation 12).

Clinicians should use additional caution and increased monitoring (see Recommendation 7) to minimize risks of opioids prescribed for patients with renal or hepatic insufficiency and for patients aged ≥65 years. Clinicians should implement interventions to mitigate common risks of opioid therapy among older adults, such as exercise or bowel regimens to prevent constipation, risk assessment for falls, and patient monitoring for cognitive impairment.

For patients with jobs that involve potentially hazardous tasks and who are receiving opioids or other medications that can negatively affect sleep, cognition, balance, or coordination, clinicians should assess patients' abilities to safely perform the potentially hazardous tasks (e.g., driving, use of heavy equipment, climbing ladders, working at heights or around moving machinery, or working with high-voltage equipment).

Clinicians should use prescription drug monitoring program (PDMP) data (see Recommendation 9) and toxicology screening (see Recommendation 10) as appropriate to assess for concurrent substance use that might place patients at higher risk for opioid use disorder and overdose.

Clinicians should provide specific counseling on increased risks for overdose when opioids are combined with other drugs or alcohol (see Recommendation 2) and ensure that patients are provided or receive effective treatment for substance use disorders when needed (see Recommendation 12).

Although substance use disorder can alter the expected benefits and risks of opioid therapy for pain, patients with co-occurring pain and substance use disorder require ongoing pain management that maximizes benefits relative to risks. (See Recommendation 12 Pain Management for Patients with Opioid Use Disorder for additional considerations specific to these patients.)

If clinicians consider opioid therapy for chronic pain for patients with substance use disorder, they should discuss increased risks for opioid use disorder and overdose with patients, carefully consider whether benefits of opioids outweigh increased risks, and incorporate strategies to mitigate risk into the management plan, such as offering naloxone and increasing frequency of monitoring (see Recommendation 7).

If patients experience nonfatal opioid overdose, clinicians should evaluate for opioid use disorder and treat or arrange treatment if needed. Clinicians should work with patients to reduce opioid dosage and to discontinue opioids when indicated (see Recommendation 5) and should ensure continued close monitoring and support for patients prescribed or not prescribed opioids. If clinicians continue opioid therapy in patients with prior opioid overdose, they should discuss increased risks for overdose with patients, carefully consider whether benefits of opioids outweigh substantial risks, and incorporate strategies to mitigate risk into the management plan, such as considering offering naloxone and increasing frequency of monitoring (see Recommendation 7).

Recommendation 9

When prescribing initial opioid therapy for acute, subacute, or chronic pain, and periodically during opioid therapy for chronic pain, clinicians should review the patient's history of controlled substance prescriptions using state PDMP data to determine whether the patient is receiving opioid dosages or combinations that put the patient at high risk for overdose (recommendation category: B, evidence type: 4).

Implementation Considerations

Ideally, PDMP data should be reviewed before every opioid prescription for acute, subacute, or chronic pain. This practice is recommended in all jurisdictions where PDMP availability and access policies, as well as clinical practice settings, make it practicable (e.g., clinician and delegate access permitted).

At a minimum, during long-term opioid therapy, PDMP data should be reviewed before an initial opioid prescription and then every three months or more frequently. Recommendation category B acknowledges variation in PDMP availability and circumstances. However, because PDMP information can be most helpful when results are unexpected, and to minimize bias in application, clinicians should apply this recommendation when feasible to all patients rather than differentially based on assumptions about what they will learn about specific patients.

Clinicians should use specific PDMP information about medications prescribed to their patient in the context of other clinical information, including their patient's history, physical findings, and other relevant testing, to help them communicate with and protect their patient.

Clinicians should review PDMP data specifically for prescription opioids and other controlled medications patients have received from additional prescribers to determine whether a patient is receiving total opioid dosages or combinations (e.g., opioids combined with benzodiazepines) that put the patient at risk for overdose.

PDMP-generated risk scores have not been validated against clinical outcomes such as overdose and should not take the place of clinical judgment. Clinicians should not dismiss patients from their practice on the basis of PDMP information. Doing so can adversely affect patient safety and could result in missed opportunities to provide potentially lifesaving information (e.g., about risks of prescription opioids and about overdose prevention) and interventions (e.g., safer prescriptions, nonopioid pain treatment [see Recommendations 1 and 2], naloxone [see Recommendation 8], and effective treatment for substance use disorder [see Recommendations 8 and 12]).

Clinicians should take actions to improve patient safety:

- Discuss information from the PDMP with their patient and confirm that their patient is aware of any additional prescriptions. Because clinicians often work as part of teams, prescriptions might appropriately be written by more than one clinician coordinating the patient's care. Occasionally, PDMP information can be incorrect (e.g., if the wrong name or birthdate has been entered, the patient uses a nickname or maiden name, or another person has used the patient's identity to obtain prescriptions).

- Discuss safety concerns, including increased risk for respiratory depression and overdose, with patients found to be receiving overlapping prescription opioids from multiple clinicians who are not coordinating the patient's care or patients who are receiving medications that increase risk when combined with opioids (e.g., benzodiazepines; see Recommendation 11) and offer naloxone (see Recommendation 8).

- Use particular caution when prescribing opioid pain medication and benzodiazepines concurrently, understanding that some patient circumstances warrant prescribing of these medications concomitantly. Clinicians should communicate with others managing the patient to discuss the patient's needs, prioritize patient goals, weigh risks of concurrent benzodiazepine and opioid exposure, and coordinate care (see Recommendation 11).

- Consider the total MME/day for concurrent opioid prescriptions to help assess the patient's overdose risk (see Recommendation 4). Buprenorphine should not be counted in the total MME/day in calculations given its partial agonist properties at opioid receptors that confer a ceiling effect on respiratory depression. If patients are found to be receiving total daily dosages of opioids that put them at risk for overdose, discuss safety concerns with the patient, consider in collaboration with the patient whether or not benefits of tapering outweigh risks of tapering (see Recommendation 5), and offer naloxone (see Recommendation 8).

- Discuss safety concerns with other clinicians who are prescribing controlled substances for their patient. Ideally, clinicians should first discuss concerns with their patient and inform him or her that they plan to coordinate care with the patient's other clinicians to improve the patient's safety.

- Screen for substance use and discuss concerns with their patient in a nonjudg-mental manner (see Recommendations 8 and 12).

- When diverting (sharing or selling prescription opioids and not taking them) might be likely, consider toxicology testing to assist in determining whether prescription opioids can be discontinued without causing withdrawal (see Recommendations 5 and 10). A negative toxicology test for prescribed opioids might indicate the patient is not taking prescribed opioids, although clinicians should consider other possible reasons for this test result, such as false negative results or misinterpretation of results (see Recommendation 10).

Recommendation 10

When prescribing opioids for subacute or chronic pain, clinicians should consider the benefits and risks of toxicology testing to assess for prescribed medications as well as other prescribed and non-prescribed controlled substances (recommendation category: B, evidence type: 4).

Implementation Considerations

Toxicology testing should not be used in a punitive manner but should be used in the context of other clinical information to inform and improve patient care.

Clinicians should not dismiss patients from care based on a toxicology test result. Dismissal could have adverse consequences for patient safety, potentially including the patient obtaining opioids or other drugs from alternative sources and the clinician missing opportunities to facilitate treatment for substance use disorder.

Prior to starting opioids and periodically (at least annually) during opioid therapy, clinicians should consider the benefits and risks of toxicology testing to assess for prescribed opioids as well as other prescription and nonprescription controlled substances that increase risk for overdose when combined with opioids, including nonprescribed and illicit opioids and benzodiazepines.

Clinicians, practices, and health systems should aim to minimize bias in testing and should not apply this recommendation differentially based on assumptions about patients.

Predicting risk is challenging, and currently available tools do not allow clinicians to reliably identify patients who are at low risk for substance use or substance use disorder. Clinicians should consider toxicology screening results as potentially useful data, in the context of other clinical information, for all patients, and consider toxicology screening whenever its potential limitations can be addressed.

Clinicians should explain to patients that toxicology testing will not be used to dismiss patients from care and is intended to improve their safety.

Clinicians should explain expected results (e.g., presence of prescribed medication and absence of drugs, including non-prescribed controlled substances, not reported by the patient) and ask patients in a nonjudgmental manner about use of prescribed and other drugs and whether there might be unexpected results.

Limited toxicology screening can be performed with a relatively inexpensive presumptive immunoassay panel that tests for opiates as a class, benzodiazepines as a class, and several non-prescribed substances. Toxicology screening for a class of drugs might not detect all drugs in that class. For example, fentanyl testing is not included in widely used toxicology assays that screen for opiates as a class.

Clinicians should be familiar with the drugs included in toxicology screening panels used in their practice and should understand how to interpret results for these drugs. For example, a positive "opiates" immunoassay detects morphine, which might reflect patient use of morphine, codeine, or heroin, but does not detect synthetic opioids and might not detect semisynthetic opioids. In some cases, positive results for specific opioids might reflect metabolites from opioids the patient is taking and might not mean the patient is taking the specific opioid that resulted in the positive test. Confirmatory testing should be used when:

- Toxicology results will inform decisions with major clinical or nonclinical implications for the patient

- A need exists to detect specific opioids or other drugs within a class, such as those that are being prescribed, or those that cannot be identified on standard immunoassays

- A need exists to confirm unexpected screening toxicology test results

Restricting confirmatory testing to situations and substances for which results can reasonably be expected to affect patient management can reduce costs of toxicology testing.

Clinicians might want to discuss unexpected results with the local laboratory or toxicologist and should discuss unexpected results with the patient. Clinicians should discuss unexpected results with patients in a nonjudgmental manner, avoiding use of potentially stigmatizing language (e.g., avoid describing a specimen as testing "clean" or "dirty").

Discussion with patients prior to specific confirmatory testing can sometimes yield a candid explanation of why a particular substance is present or absent and remove the need for confirmatory testing during that visit. For example, a patient might explain that the test is negative for prescribed opioids because they felt opioids were no longer helping and discontinued them. If unexpected results from toxicology screening are not explained, a confirmatory test on the same sample using a method selective enough to differentiate specific opioids and metabolites (e.g., gas or liquid chromatography/mass spectrometry) might be warranted.

Clinicians should use unexpected results to improve patient safety (e.g., optimize pain management strategy [see Recommendation 2], carefully weigh benefits and risks of reducing or continuing opioid dosage [see Recommendation 5], re-evaluate more frequently [see Recommendation 7], offer naloxone [see Recommendation 8], and offer treatment or refer the patient treatment with medications for opioid use disorder [see Recommendation 12], all as appropriate).

Recommendation 11

Clinicians should use particular caution when prescribing opioid pain medication and benzodiazepines concurrently and consider whether benefits outweigh risks of concurrent prescribing of opioids and other central nervous system depressants (recommendation category: B, evidence type: 3).

Implementation Considerations

Although in some circumstances it might be appropriate to prescribe opioids to a patient who is also prescribed benzodiazepines (e.g., severe acute pain in a patient taking long-term, stable low-dose benzodiazepine therapy), clinicians should use particular caution when prescribing opioid pain medication and benzodiazepines concurrently. In addition, clinicians should consider whether benefits outweigh risks of concurrent use of opioids with other central nervous system depressants (e.g., muscle relaxants, non-benzodiazepine sedative hypnotics, potentially sedating anticonvulsant medications such as gabapentin and pregabalin).

Buprenorphine or methadone for opioid use disorder should not be withheld from patients taking benzodiazepines or other medications that depress the central nervous system.

Clinicians should check the PDMP for concurrent controlled medications prescribed by other clinicians (see Recommendation 9) and should consider involving pharmacists as part of the management team when opioids are co-prescribed with other central nervous system depressants.

In patients receiving opioids and benzodiazepines long-term, clinicians should carefully weigh the benefits and risks of continuing therapy with opioids and benzodiazepines and discuss with patients and other members of the patient's care team.

Risks of concurrent opioid and benzodiazepine use are likely to be greater with unpredictable use of either medication, with use of higher-dosage opioids and higher-dosage benzodiazepines in combination, or with use with other substances including alcohol (compared with long-term stable use of lower-dosage opioids and lower-dosage benzodiazepines without other substances).

In specific situations, benzodiazepines can be beneficial, and stopping benzodiazepines can be destabilizing.

If risks are determined to outweigh benefits of continuing opioid and benzodiazepine therapy at current dosages and a decision is made to taper, it might be safer and more practical to taper opioids first. There can be greater risks of benzodiazepine withdrawal relative to opioid withdrawal, and tapering opioids can be associated with anxiety (see Recommendation 5).

Clinicians should taper benzodiazepines gradually prior to discontinuation because abrupt withdrawal can be associated with rebound anxiety, hallucinations, seizures, delirium tremens, and, rarely, death. The rate of tapering should be individualized.

If benzodiazepines prescribed for anxiety are tapered or discontinued, or if patients receiving opioids require treatment for anxiety, evidence-based psychotherapies (e.g., CBT) and/or specific antidepressants or other nonbenzodiazepine medications, or both, approved for anxiety should be offered.

Clinicians should communicate with other clinicians managing the patient to discuss the patient's needs, prioritize patient goals, weigh risks of concurrent benzodiazepine and opioid exposure, and coordinate care.

Recommendation 12

Clinicians should offer or arrange treatment evidence-based medications to treat patients with opioid use disorder. Detoxification on its own, without medications for opioid use disorder, is not recommended for opioid use disorder because of increased risks for resuming drug use, overdose, and overdose death (recommendation category: A, evidence type: 1).

Implementation Considerations

Although stigma can reduce the willingness of individuals with opioid use disorder to seek treatment, opioid use disorder is a chronic, treatable disease from which people can recover and continue to lead healthy lives.

If clinicians suspect opioid use disorder, they should discuss their concern with their patient in a nonjudgmental manner and provide an opportunity for the patient to disclose related concerns or problems.

Clinicians should assess for the presence of opioid use disorder using criteria from the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders.

For patients meeting criteria for opioid use disorder, particularly if moderate or severe, clinicians should offer or arrange for patients to receive evidence-based treatment with medications for opioid use disorder.

Clinicians should not dismiss patients from their practice because of opioid use disorder because this can adversely affect patient safety.

Medication treatment of opioid use disorder has been associated with reduced risk for overdose and overall deaths. Identification of opioid use disorder represents an opportunity for a clinician to initiate potentially life-saving interventions, and should the clinician collaborate with the patient regarding their safety to increase the likelihood of successful treatment.

For pregnant persons with opioid use disorder, medication for opioid use disorder (buprenorphine or methadone) is the recommended therapy and should be offered as early as possible in pregnancy to prevent harms to both the patient and the fetus.

Clinicians unable to provide treatment themselves should arrange for patients with opioid use disorder to receive care from a substance use disorder treatment specialist, such as an office-based buprenorphine or naltrexone treatment provider, or from an opioid treatment program certified by Substance Abuse and Mental Health Services Administration to provide methadone or buprenorphine for patients with opioid use disorder.

All clinicians, and particularly clinicians prescribing opioids in communities without sufficient treatment capacity for opioid use disorder, should obtain a waiver to prescribe buprenorphine for opioid use disorder.

Clinicians prescribing opioids should identify treatment resources for opioid use disorder in the community, establish a network of referral options that span the levels of care that patients might need to enable rapid collaboration and referral, when needed, and work together to ensure sufficient treatment capacity for opioid use disorder at the practice level.

Although identification of an opioid use disorder can alter the expected benefits and risks of opioid therapy for pain, patients with co-occurring pain and opioid use disorder require ongoing pain management that maximizes benefits relative to risks.

Management of Opioid Misuse that Does Not Meet Criteria for Opioid Use Disorder

Clinicians can have challenges distinguishing between opioid misuse behaviors without opioid use disorder and mild or moderate opioid use disorder. For patients with opioid misuse that does not meet criteria for opioid use disorder (e.g., taking opioids in larger amounts than intended without meeting other criteria for opioid use disorder), clinicians should reassess the patient's pain, ensure that therapies for pain management have been optimized (see Recommendation 2), discuss with patients, and carefully weigh benefits and risks of continuing opioids at the current dosage (see Recommendation 5). For patients who choose to but are unable to taper, clinicians may reassess for opioid use disorder and offer buprenorphine treatment or refer for buprenorphine or methadone treatment if criteria for opioid use disorder are met. Even without a diagnosis of opioid use disorder, transitioning to buprenorphine for pain can also be considered given reduced overdose risk with buprenorphine compared with risk associated with full agonist opioids (see Recommendation 5).

Pain Management for Patients with Opioid Use Disorder

Although identification of an opioid use disorder can alter the expected benefits and risks of opioid therapy for pain, patients with co-occurring pain and substance use disorder require ongoing pain management that maximizes benefits relative to risks. Clinicians should use nonpharmacologic and nonopioid pharmacologic pain treatments as appropriate (see Recommendations 1 and 2) to provide optimal pain management [11]. For patients with pain who have an active opioid use disorder but are not in treatment, clinicians should consider buprenorphine or methadone treatment for opioid use disorder, which can also help with concurrent management of pain [11]. For patients who are treated with buprenorphine for opioid use disorder and experience acute pain, clinicians can consider temporarily increasing the buprenorphine dosing frequency (e.g., to twice a day) to help manage pain, given the duration of effects of buprenorphine is shorter for pain than for suppression of withdrawal [11,12]. For severe acute pain (e.g., from trauma or unplanned major surgery) in patients receiving buprenorphine for opioid use disorder, clinicians can consider additional as-needed doses of buprenorphine. In supervised settings, adding a short-acting full agonist opioid to the patient's regular dosage of buprenorphine can be considered without discontinuing the patient's regular buprenorphine dosage; however, if a decision is made to discontinue buprenorphine to allow for more mu-opioid receptor availability, patients should be monitored closely because high doses of a full agonist opioid might be required, potentially leading to oversedation and respiratory depression as buprenorphine's partial agonist effect lessens. For patients receiving naltrexone for opioid use disorder, short-term use of higher-potency nonopioid analgesics (e.g., NSAIDs) can be considered to manage severe acute pain. Patients receiving methadone for opioid use disorder who require additional opioids as treatment for severe acute pain management should be carefully monitored, and when feasible should optimally be treated by a clinician experienced in the treatment of pain in consultation with their opioid treatment program. [11]. The American Society of Addiction Medicine National Practice Guideline for the Treatment of Opioid Use Disorder (2020 Focused Update) provides additional recommendations for the management of patients receiving medications for opioid use disorder who have planned surgeries for which nonopioid therapies are not anticipated to provide sufficient pain relief [11].

RESPONSE TO THE CDC'S OPIOID PRESCRIBING GUIDELINE UPDATE

It is important to note that the CDC's guidelines are voluntary, and the changes may not result in changes to state laws and rules established to restrict opioid prescribing and help curb opioid misuse following publication of the 2016 guideline. The 2022 draft guideline emphasizes prescriber decision-making and access to necessary opioid analgesics to address unrelenting pain. The guideline states that some policies have extended even beyond the 2016 recommendations, contributing to patient harm, including untreated and undertreated pain, serious withdrawal symptoms, worsening pain outcomes, psychological distress, overdose, and suicidal ideation and behavior [2]. However, state governments seem reluctant to make similar changes, especially as opioid overdose deaths have increased [13].

The American Academy of Pain Medicine, which had expressed dismay with the 2016 CDC guideline and how it was misapplied by insurance companies, state governments, and healthcare organizations, indicated general support for the 2022 revision [14].

4. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

Urine drug tests can give insight into patients who are misusing opioids. A random sample of urine drug test results from 800 pain patients treated 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 [15]. Negative urine drug test 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 urine drug test results and that a negative result for the prescribed opioid or a positive urine drug test may serve as the pretense to terminate a patient rather than guide him/her into addiction treatment or an alternative pain management program; the CDC states that "clinicians should not dismiss patients from care on the basis of a toxicology test result. Dismissal could have adverse consequences for patient safety, potentially including the patient obtaining opioids from alternative sources and the clinician missing opportunities to facilitate treatment for a substance use disorder" [2].

In addition to aberrant urine screens, there are certain behaviors that are suggestive of an emerging opioid use disorder. The most suggestive behaviors are [4,16,17]:

- 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 [4,16,17]:

- 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

This CDC video addresses the various risk factors likely to increase susceptibility to opioid-associated harms and suggests strategies for mitigating these risks.

To see this media go to http://www.NetCE.com/activities/ using a browser that supports Adobe Flash.

5. FEDERAL AND STATE LAW

In response to the rising incidence in prescription opioid misuse, dependence, diversion, and overdose, in 2018 the FDA mandated opioid-specific REMS (i.e., Opioid Analgesic REMS or OA REMS) to reduce the potential negative patient and societal effects of prescribed opioids. Other elements of opioid risk mitigation include the 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 [18].

Several regulations and programs at the state level have been enacted in an effort to reduce prescription opioid abuse, diversion, and overdose, including [19]:

- 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 [19].

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 [20]. 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.

6. 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 OA REMS for extended-release/long-acting opioids (discussed later in this course), the FDA requires a patient counseling document 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. A copy of this form may be accessed online at https://www.opioidanalgesicrems.com/Resources/Docs/patient_counseling_document.pdf [21].

When prescribing opioids, clinicians should counsel patients on the following [18]:

- Importance of adherence to prescribed dosing regimen

- Patients should use the least amount of medication necessary to treat pain and for the shortest amount of time

- The risk of serious adverse events that can lead to death

- The risk of addiction that can occur even when product is used as recommended

- Known risk factors for serious adverse events, including signs and symptoms of overdose and opioid-induced respiratory depression, GI obstruction, and allergic reactions, among others

- The most common side effects, along with the risk of falls, working with heavy machinery, and driving

- When to call the prescriber (e.g., managing adverse events, ongoing pain)

- How to handle missed doses

- The importance of full disclosure of all medications and supplements to all healthcare professionals and the risks associated with the use of alcohol and other opioids/benzodiazepines

- Product-specific concerns, such as not to crush or chew ER products; transdermal systems and buccal films should not be cut, torn, or damaged before use, etc.

- How to safely taper dose to avoid withdrawal symptoms

- Safe storage and disposal, risks of theft by family members and household visitors

- Never share any opioid analgesic with another person

- How and when to use naloxone products and their various means of administration

- Seeking emergency medical treatment if an opioid overdose occurs

- How to report adverse events and medication errors to FDA

In addition, in July 2025, the FDA announced that all opioid manufacturers must change safety labels (within 30 days) with new evidence regarding long-term use of opioids. The change is intended to assist healthcare professionals and patients to make fully informed treatment decisions when considering or already taking opioids for an extended period of time. The labeling changes must include the following [22]:

- Clearer risk information: A summary of study results showing the estimated risks of addiction, misuse, and overdose during long-term use.

- Dosing warnings: Stronger warnings that higher doses come with greater risks and that those risks remain over time.

- Clarified use limits: Removing language which could be misinterpreted to support using opioid pain medications over indefinitely long duration

- Treatment guidance: Labels will reinforce that long-acting or extended-release opioids should only be considered when other treatments, including shorter-acting opioids, are inadequate.

- Safe discontinuation: A reminder not to stop opioids suddenly in patients who may be physically dependent, as it can cause serious harm.

- Overdose reversal agents: Additional information on medications that can reverse an opioid overdose.

- Drug interactions: Enhanced warning about combining opioids with other drugs that slow down the nervous system—now including gabapentinoids.

- More risks with overdose: New information about toxic leukoencephalopathy—a serious brain condition that may occur after an overdose.

- Digestive health: Updates about opioid-related problems with the esophagus.

There are no universal recommendations for the proper disposal of unused opioids, although efforts toward patient education on what to do with unused or expired medications have increased in recent years. According to the FDA, the best way to dispose of most types of unused or expired medications (both prescription and over-the-counter) is to immediately use a take-back option, such as a designated take-back location or by mailing medications back using a prepaid drug mail-back envelope. As of April 2025, the FDA began requiring OA REMS Program Companies to provide prepaid mail-back envelopes upon request to pharmacies and other dispensers of opioid analgesics to improve proper and equitable disposal of this class of drugs [23].

If these options are not available, it is recommended to consult the list of medications recommended for disposal by flushing down the toilet. For example, the FDA recommends that certain medications, including oxycodone/acetaminophen (Percocet), oxycodone (OxyContin tablets), and transdermal fentanyl patches (Duragesic Transdermal System), be flushed down the toilet instead of thrown in the trash. Patients should be advised to flush prescription drugs down the toilet only if the label or accompanying patient information specifically instructs doing so. If medication is not on the flush list, it is recommended to mix the medication with an undesirable substance (e.g., cat litter, dirt, used coffee grounds), and put it into an impermeable, nondescript container (e.g., disposable container with a lid or a sealed bag) before throwing in trash at home. Any personal information should be obscured or destroyed [23,24].

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.

7. DISPARITIES IN PAIN MANAGEMENT

At greatest risk of unrelieved pain from stigma and bias are children, the elderly, racial and ethnic minorities, active duty or military veterans, and those with cancer, HIV, or sickle cell disease. Pain undertreatment in Black patients is especially widespread, from prevalent misperceptions (often unconscious) that this group has higher pain tolerance and is more likely to abuse their opioid prescription [25]. As a result, prescribers, dispensers, and administrators would benefit from considering both the tenets of appropriate opioid prescribing and the impact of culture on experiences of pain and effective pain management.

It is clear that health disparities exist among racial and ethnic minority groups, and this is true for pain management services and medications. A large-scale national study in the United States found racial differences in the prescription of analgesics for patients with migraine, low back pain, and bone fractures [26]. Specifically, Black Americans were less likely to be prescribed analgesics for their pain compared with their White counterparts. Racial minority patients are also more likely to experience longer wait times for medication compared with White patients [27].

Analysis of a national dataset found that Black Americans were less likely to be prescribed opioids for back pain and abdominal pain compared with non-Hispanic White Americans [28]. The authors speculate that racial biases may influence prescribing behaviors. An examination of Medicaid patients who received epidural analgesia during vaginal childbirth also found statistically significant racial/ethnic differences [29]. In this study, 59.6% of the White patients received epidural analgesia, compared with 49.5% of Black Americans, 48.2% of Asians, and 35.2% of Hispanics. Even after the researchers controlled for age, urban/rural residence, and the availability of anesthesiologists, race and ethnicity still predicted epidural analgesia prescribing trends [29].

In a meta-analysis of ethnicity and pain management researchers found that professionals under-rated ethnic minority patients' levels of pain and were less likely to indicate their pain scores on their charts compared with their White counterparts [30]. In addition, Black American and Hispanic patients were less likely to have been given analgesics than White patients.

Studies have not definitively isolated the factors that contribute to these disparities. One of the challenges in understanding health disparities, and particularly pain management disparities, is the fact that racial and ethnic minority groups are heterogeneous [31,32]. Healthcare professional barriers may include professionals' beliefs about appropriate pain management; lack of training and knowledge about the intersection of pain and culture, race, and ethnicity; lack of culturally sensitive assessment for pain; and expectations about racial and ethnic minority pain patients based on stereotypes [33]. Consequently, practitioners may underestimate and minimize racial minority patients' pain experiences. In a qualitative study, Native American individuals described their complaints of pain being dismissed, receiving inadequate care, and neglected aftercare [34].

Studies have also shown that the language and race/ethnicity of the healthcare professional influences pain management. For example, the ratings of pain tend to be comparable when the patient and healthcare provider speak the same language. When there is a native language, pain ratings tend to diverge. When literacy and language barriers are eliminated, assessment and treatment improve and racial and ethnic minority patients with pain fare better [35]. In addition, healthcare professionals' level of empathy appears to increase when the patient and healthcare professional share the same skin color or are of the same ethnic group [36,37].

It is important to note that disparities in pain management are not typically intentional. Instead, they are the result of a myriad of issues, including healthcare system, socioeconomic, and cultural factors. However, prescriber and dispenser unconscious bias can contribute to the undertreatment of pain in certain groups. Promoting positive emotions such as empathy and compassion can help reduce implicit biases. This can involve strategies like perspective taking and role playing [38]. In a study examining analgesic prescription disparities, nurses were shown photos of White or Black American patients exhibiting pain and were asked to recommend how much pain medication was needed; a control group was not shown photos. Those who were shown images of patients in pain displayed no differences in recommended dosage along racial lines; however, those who did not see the images averaged higher recommended dosages for White patients compared with Black patients [39]. This suggests that professionals' level of empathy (enhanced by seeing the patient in pain) affected prescription recommendations.

8. CONCLUSION

Opioid analgesics are approved by the FDA for the treatment of moderate or severe pain. However, individual patients differ greatly in clinical response to different opioid analgesics, and patient populations show widely variable response to the same opioid and dose. These response variations make opioid prescribing challenging. Further, the important role of opioid analgesics is broadly accepted in acute pain, cancer pain, and palliative and end-of-life care, but it is controversial for the management of chronic noncancer pain. Previous opioid prescribing guidelines have been criticized for lacking a patient-centered approach and failing to emphasize individualization of therapy. This prompted the 2022 revision of the CDC's opioid prescribing guidelines, which is outlined in this course.

Opioids are not a panacea for pain, nor are they safe and effective for every patient. However, they can be a useful tool, and knowledge of medical advances can give clinicians greater confidence to safely and effectively prescribe these drugs.

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24. U.S. Food and Drug Administration. Drug Disposal: FDA's Flush List for Certain Medicines. Available at https://www.fda.gov/drugs/disposal-unused-medicines-what-you-should-know/drug-disposal-fdas-flush-list-certain-medicines. Last accessed September 1, 2025.

25. University of Wisconsin School of Medicine and Public Health, Pain and Policy Studies Group. Achieving Balance in State Pain Policy: A Progress Report Card (CY 2013). Available at https://scholarworks.iupui.edu/handle/1805/699. Last accessed September 1, 2025.

26. Tamayo-Sarver JH, Hinze SW, Cydulka RK, Baker DW. Racial and ethnic disparities in emergency department analgesic prescription. Am J Public Health. 2003;93(12):2067-2073.

27. Robinson-Lane SG, Booker SQ. Culturally responsive pain management for black older adults. J Gerontol Nurs. 2017;43(8):33-41.

28. Singhal A, Tien Y, Hsia RY. Racial-ethnic disparities in opioid prescriptions at emergency department visits for conditions commonly associated with prescription drug abuse. PLoS One. 2016;11(8):1-14.

29. Rust G, Nembhard WN, Nichols, et al. Racial and ethnic disparities in the provision of epidural analgesia to Georgia Medicaid beneficiaries during labor and delivery. Am J Obstet Gynecol. 2004;191(2):456-462.

30. Cintron A, Morrison RS. Pain and ethnicity in the United States: a systematic review. J Palliat Med. 2006;9(6):1454-1473.

31. Ezenwa MO, Ameringer S, Ward SE, Serlin RC. Racial and ethnic disparities in pain management in the United States. J Nurs Scholarsh. 2006;38(3):225-233.

32. Hastie BA, Riley JL 3rd, Kaplan L, et al. Ethnicity interacts with the OPRM1 gene in experimental pain sensitivity. Pain. 2012;153(8):1610-1619.

33. Anderson KO, Green CR, Payne R. Racial and ethnic disparities in pain: causes and consequences of unequal care. J Pain. 2009;10(12):1187-1204.

34. Haozous EA, Doorenbos AZ, Stoner S. Pain management experiences and the acceptability of cognitive behavioral strategies among American Indians and Alaska Natives. J Transcult Nurs. 2016;27(3):233-240.

35. Pillay T, van Zyl HA, Blackbeard D. Chronic pain perception and cultural experience. Procedia Soc Behav Sci. 2014;113:151-160.

36. Campbell CM, Edwards RR. Ethnic differences in pain and pain management. Pain Manag. 2012;2(3):219-230.

37. Gagnon CM, Matsuura JT, Smith CC, Stanos SP. Ethnicity and interdisciplinary pain treatment. Pain Pract. 2014;14(6):532-540.

38. Sukhera J, Watling CA. A framework for integrating implicit bias recognition into health professions education. Acad Med. 2018;93(1):35-40.

39. Drwecki BB, Moore CF, Ward SE, Prkachin KM. Reducing racial disparities in pain treatment: the role of empathy and perspective-taking. Pain. 2011;152(5):1001-1006.

Evidence-Based Practice Recommendations Citations

1. 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(2S):S111-S133. Available at https://www.painphysicianjournal.com/current/pdf?article=NDIwNA%3D%3D&journal=103. Last accessed September 28, 2025.

98190 • Supplements for Aging

Chelsey McIntyre, PharmD

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

Aging causes a number of changes to the body that affect physical function, cognitive function, and overall quality of life. Older adults frequently report using supplements, often for the purpose of improving overall health, but also for the purposes of improving musculoskeletal health, nutrition, cardiovascular health, and more. It is important for healthcare professionals to be aware that supplements can interact with drugs and medical conditions, and that some supplements carry serious health risks for certain patients. However, some supplements may be a reasonable option for older patients who are looking to improve their health and quality of life and can be safely recommended.

Table of Contents

98190 • Supplements for Aging

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. SUPPLEMENT USE IN OLDER ADULTS

3. PHYSIOLOGICAL CHANGES IN OLDER AGE

4. SAFETY CONCERNS WITH NATURAL PRODUCTS

BEERS CRITERIA

DRUG INTERACTIONS

CONDITION INTERACTIONS

PRODUCT QUALITY

5. NUTRITIONAL SUPPLEMENTS

MULTIVITAMINS

INDIVIDUAL MICRONUTRIENTS

OTHER NUTRITIONAL SUPPLEMENTS

6. NATURAL PRODUCTS FOR PHYSICAL CHANGES

MUSCULOSKELETAL HEALTH

EYE HEALTH

CARDIOVASCULAR HEALTH

JOINT HEALTH

7. NATURAL PRODUCTS FOR COGNITIVE CHANGES

LIFESTYLE INTERVENTIONS

NUTRIENT SUPPLEMENTS

HERBAL SUPPLEMENTS

ENDOGENOUS SUBSTANCES

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

98190 • Supplements for Aging

Education Category. Alternative Medicine

Release Date. 06/01/2024

Expiration Date. 05/31/2027

Course Overview

Aging causes a number of changes to the body that affect physical function, cognitive function, and overall quality of life. Older adults frequently report using supplements, often for the purpose of improving overall health, but also for the purposes of improving musculoskeletal health, nutrition, cardiovascular health, and more. It is important for healthcare professionals to be aware that supplements can interact with drugs and medical conditions, and that some supplements carry serious health risks for certain patients. However, some supplements may be a reasonable option for older patients who are looking to improve their health and quality of life and can be safely recommended.

Audience

This course is designed for healthcare professionals whose older patients are taking or are interested in supplements.

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 5 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 5 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 5 ANCC contact hour(s). NetCE designates this continuing education activity for 5 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 5 pharmacology hour(s) for physician assistants. NetCE designates this continuing education activity for 6 hours for Alabama nurses. NetCE designates this activity for 5 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-24-017-H04-P. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 5 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. 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 0.5 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 healthcare professionals in all practice settings the knowledge necessary to increase their understanding of the supplements that may be used by their older adult patients.

Learning Objectives

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

1. List the dietary supplements most commonly used for age-related changes.

2. Explain the safety concerns associated with the use of natural products in older adults.

3. Discuss the risks and benefits of common vitamins and minerals in older adults.

4. Review the evidence for the use of dietary supplements for age-related changes in physical health.

5. Describe the proposed and actual effects of dietary supplements for dementia.

Faculty

Chelsey McIntyre, PharmD, is a clinical pharmacist who specializes in drug information, literature analysis, and medical writing. She earned her Bachelor of Science degree in Genetics from the University of California, Davis. She then went on to complete her PharmD at Creighton University, followed by a clinical residency at the Children’s Hospital of Philadelphia (CHOP). Dr. McIntyre held the position of Drug Information and Policy Development Pharmacist at CHOP until her move to Washington state in 2017, after which she spent the next six years as a clinical editor for Natural Medicines, a clinical reference database focused on natural products and alternative therapies. She continues to create rigorous professional analysis and patient education materials for various publications while also practicing as a hospital pharmacist. Her professional interests include provider and patient education, as well as the application of evidence-based research to patient care.

Faculty Disclosure

Contributing faculty, Chelsey McIntyre, PharmD, 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

As the population ages, maintaining both physical and cognitive health becomes increasingly important. In recent years, the use of dietary supplements, including vitamins, minerals, fibers, and proteins, has gained significant attention for their potential to improve various aspects of health. Older adults may turn to these supplements to address age-related deficiencies, enhancing physical vitality, and supporting cognitive function. This course is designed to provide a comprehensive review of the role of supplements in promoting well-being among older adults.

2. SUPPLEMENT USE IN OLDER ADULTS

Older adults, defined as those at least 65 years of age, are a rapidly growing portion of the United States population that is expected to make up 20% of the country's total population by 2030 [1]. As life expectancy and overall quality of life continues to improve for this age group, many older adults have shown an increased interest in taking an active role in their health, often seeking out alternative and complementary options for both prevention and treatment.

The term "complementary therapy" covers a wide range of modalities, from breathing exercises and yoga, to healing touch and massage, to herbs and vitamins. For many Americans, the most commonly utilized complementary therapy is dietary supplements, a category that includes herbal products, vitamins, minerals, fibers, probiotics, fish oil, and many more.

In fact, as of 2017, 70% of older adults reported using at least one dietary supplement. A full 54% reported taking two supplements and 29% reported taking four or more supplements. The most frequently used supplements were multivitamins, Vitamin D, calcium, and omega-3s. At least 9% also reported using an herbal/botanical product, a number that is likely to have increased since the time of this survey [2].

Most older adults reported using these products to improve overall health. Other commonly cited reasons included bone health, nutritional supplementation, heart health and cholesterol, and eye health. Women, who reported using supplements more often than men, were more likely to use supplements for musculoskeletal health. Not surprisingly, most of this use was not related to recommendations from healthcare professionals, although the use of calcium, vitamin D, iron, and fiber products, specifically, was more likely to be associated with a recommendation from a healthcare professional [2].

3. PHYSIOLOGICAL CHANGES IN OLDER AGE

There are many physiological changes that occur as the body ages. These changes affect almost every organ system and can alter the way that the body responds to activity, food, and medications.

Some of the most striking changes occur in the musculoskeletal system. These changes often manifest as a reduced tolerance for physical activity, changes in overall mobility, and an increase in various forms of pain. As the body ages, it naturally loses muscle and water content and increases fat stores. It also loses bone mass and experiences a reduction in joint lubrication [3].

Most older adults are also aware of changes to their cardiovascular system. As the body ages, cardiac output decreases, along with resting and maximal heart rate. Conversely, systemic vascular resistance increases, which leads to increased blood pressure. The cardiovascular system in general has a reduced response to stress and a reduction in baroreceptor activity. Many older adults also have high levels of cholesterol. These changes increase the risk for various adverse cardiovascular outcomes, as well as an increased likelihood for cardiovascular adverse effects from medications and natural products [3].

Another commonly recognized change occurs in the nervous system. As the central nervous system ages, portions of the brain, such as the hippocampus and the frontal and temporal lobes, shrink in size, which reduces the capacity for short-term memory and executive function. Sleep patterns also change, commonly resulting in insomnia. Older adults also undergo a reduction in neuroreceptors and an increase in receptor sensitivity. This can increase sensitivity to medications and natural products that affect the nervous system, such as those with anticholinergic or sedating activity [3].

Reduced production of hormones, specifically estrogen in women and testosterone in men, can cause a myriad of changes to the body. Older adults also often experience a reduction in taste perception [3].

Many of the other changes that occur with aging are more likely to alter the body's response to foods and medications, without necessarily causing noticeable changes in physical function [3,4,5]:

- The liver undergoes a reduction in volume and blood flow, reducing the functional capacity to metabolize chemicals.

- The large intestine becomes less motile, which may impact the absorption of various nutrients and chemicals.

- The kidneys undergo a gradual reduction in overall mass and blood flow, which reduces the glomerular filtration rate (GFR). These changes can reduce the clearance of medications and other chemicals that are normally eliminated by the kidneys.

- Thinning skin can increase the absorption of chemicals that are applied topically, whether absorption is intended or not.

4. SAFETY CONCERNS WITH NATURAL PRODUCTS

As mentioned, various physiologic changes place older adults at an increased risk for adverse reactions to medications and natural products. The most predictable effects occur in relation to reduced kidney and/or liver function. However, reduced body water and increased body fat can also significantly alter the distribution and storage of chemicals in the body, which can increase sensitivity to the chemical and alter the likelihood for adverse effects.

In fact, medication-related adverse effects occur up to seven times more frequently in older adults when compared with younger adults. As many natural products are physiologically active and are cleared by the kidney and/or liver, this increased risk applies to natural products as well [6].

BEERS CRITERIA

Many healthcare professionals are familiar with the Beers Criteria, a list of drugs and drug classes that an expert panel, led by the American Geriatrics Society (AGS), considers to be potentially inappropriate for use in older adults. These include medications that are potentially harmful in all older adults, as well as those considered to be of concern in older adults with specific conditions or who are taking specific medications. In essence, this list identifies medications and medication classes for which potential harm is thought to outweigh expected benefit [7].

Although this list does not specifically include natural products, healthcare professionals should keep in mind that many supplements have pharmacological effects, some of which fall into classes listed on the Beers Criteria.

For example, sedative medications are a concern in older adults and should be used with caution. Many natural products are known to have clinically significant sedative effects and should thus be used with caution. Some common examples include kava, hops, passionflower, and valerian [8]. Anticholinergic medications are also considered to be of high concern in older adults. Some natural products, including bitter yam, European barberry, muira puama, and scopolia, have potent anticholinergic effects [9].

Various supplements also have anti-inflammatory activity, which may introduce many of the risks associated with nonsteroidal anti-inflammatory drugs (NSAIDs). Similarly, many supplements can increase the risk of bleeding and should be used with caution in this population.

DRUG INTERACTIONS

Older adults are often prescribed multiple medications, which increases their risk of drug-drug and drug-supplement interactions. In fact, in the 2017 survey discussed earlier, older adults that reported taking at least three prescription drugs were more likely to also take dietary supplements, further increasing the risk for interactions [2].

Many of the same principles apply to drug-drug interactions and drug-supplement interactions:

- Many supplements are metabolized by the same enzymes that metabolize drugs, including the cytochrome P450 (CYP) enzyme family. Drugs that inhibit or induce these enzymes can alter the effects of natural products.

- Some supplements can cause significant inhibition of drug metabolizing enzymes, which can increase or decrease the effects and adverse effects of prescribed medications.

- Drug transporters, such as P-glycoprotein and the organic anion transporter (OAT) family, also transport the chemicals contained in supplements.

- Because supplements can have significant physiological effects, taking a supplement and drug with similar activity can cause additive effects. Examples of this type of interaction include additive reductions in blood glucose or blood pressure, additive antiplatelet activity, and additive photo-sensitization.

However, it is important to understand that there is much greater uncertainty and risk associated with drug-supplement interactions. This is due to two major factors. The first is the low quantity and quality of evidence available for drug-supplement interactions. Because there are no regulations requiring the evaluation of possible interactions with supplements, very few human studies are available. Thus, most of the proposed interactions are based on extrapolation from case reports, proposed physiological effects, and laboratory research. And more importantly, many possible interactions remain completely unknown.

The second factor is the variability of contents in natural products. Natural products do not necessarily contain reliable quantities of each ingredient, as is expected with medications. Some of this variability is due to inaccurate labelling and poor quality assurance by manufacturers. But in the case of herbs and botanicals, this variability is completely natural. Growing conditions, seasonal weather variations, harvesting practices, and extraction methods can all alter the chemical composition of herbal products. This makes it difficult to predict the likelihood for effects and interactions.

CONDITION INTERACTIONS

As with medications, natural products also carry a risk for condition interactions, particularly conditions that are more prevalent in older adults. Many of the physiological changes discussed previously can alter the effects of medications and natural products in the body.

Liver Disease

As mentioned, natural products are metabolized by many of the same enzymes involved in drug metabolism. Patients with liver disease may require lower doses, and natural products that have been associated with hepatoxicity should be avoided completely. These include some relatively well-known supplements, such as green tea extract, kava, garcinia, ephedra, turmeric, red yeast rice, and black cohosh [10].

Kidney Disease

Similarly, many natural products are excreted by the kidneys and should thus be used with caution in patients with kidney disease. Natural products that have been associated with nephrotoxicity should be avoided completely, including cannabis, colloidal silver, horse chestnut, saffron, and yohimbine [11].

Anticoagulation

Certain natural products have demonstrated clinically relevant antiplatelet or anticoagulant effects. In patients requiring the use of antiplatelet or anticoagulant medications, these products should be avoided. Some examples include garlic, ginseng, ginkgo, high doses of vitamin E or fish oil, and many others [12].

PRODUCT QUALITY

Variable Quality

As mentioned, the actual contents of supplements can vary, either due to inaccurate labelling or poor quality assurance by the manufacturer. To ensure the selection of a high-quality product, look for third-party quality certification stamps, such as those from United States Pharmacopeia (USP) or NSF.

USP

The USP is typically considered the standard for verifying the quality of dietary supplements. In addition to inspecting manufacturing facilities for compliance with Good Manufacturing Practices (GMP) at least two times in a three-year period, USP will also conduct random off-the-shelf analyses of verified products to ensure that the contents of the product match those listed on the label. This random testing holds manufacturers to a high standard. The USP verification stamp can be found on a product's label.

NSF

NSF is also a strong source of dietary supplement quality verification. However, general NSF certification does not always imply the same quality standards as USP verification. For a manufacturer to list NSF certification on their website, they must pass an NSF inspection of GMP compliance every six months. However, NSF does not conduct off-the-shelf analyses of products unless the manufacturer is enrolled in the "Contents Tested and Certified" or "Certified for Sport" programs. Under these programs, products are subject to random off-the-shelf testing. These products can carry the NSF seal of approval on the label. The seal will typically state "NSF: Contents Certified" or "NSF: Certified SPORT."

5. NUTRITIONAL SUPPLEMENTS

The class of dietary supplements most commonly used by older adults is micronutrients, which includes vitamins and minerals. There are a number of reasons that these products may be used, including for the improvement of overall health and bone health and for supplementation of the diet.

MULTIVITAMINS

Formulations

About 40% of all older adults that take dietary supplements report using a multivitamin [2]. Many people consider multivitamins to be a quick and easy well-rounded supplement to the diet. These products contain 20 to 30 different micronutrients. However, each multivitamin product contains different ingredients and different ingredient quantities.

All dietary supplement labels are required to provide the % daily value (DV) for each nutrient included in the product. This DV derives from the Dietary Reference Intakes established by the Institute of Medicine [13,14,15]. This can act as a helpful way to determine whether the product contains too much or too little of a specific micronutrient. In some cases, products will contain only a small portion of the dietary requirement (1% to 20%). In other cases, they may contain much more than is recommended in the daily diet (more than 1,000%). There is no legal limit on the amount of any micronutrient that can be included in a dietary supplement.

Although older adults may be using a wide range of specific multivitamin products, some of the best-selling multivitamins on the market are specifically targeted to older men and women, with formulas that claim to specifically address nutrient concerns related to age and biological sex. These best sellers (e.g., Centrum Silver) can be used as an example of the multivitamin composition that many older adults are likely to be taking. As with other multivitamins, these products contain more than 25 individual ingredients, with percent of DVs ranging from 17% to 1,042%.

Safety

The safety of taking doses that are much higher than the DV depends on the specific nutrient in question. Fat-soluble vitamins, which are stored in the body, can cause toxicity over time. These include vitamins A, D, E, and K. Water-soluble vitamins are typically eliminated by the kidneys when quantities exceed physiological needs. Thus, toxicity is much less likely when these vitamins are taken in large quantities.

In addition to developing DVs for each nutrient, the Institute of Medicine also developed tolerable upper intake levels (ULs) to help guide patients and healthcare professionals in preventing toxicity and adverse effects. Some ULs are based on the risk for long-term toxicity, as is the case for vitamin D [13]. Other ULs, such as that of vitamin C, are based on the risk for temporary adverse effects, including gastrointestinal upset [15].

It is important to keep in mind that many patients who take multivitamins also take individual vitamin or mineral supplements. For example, it is not uncommon for patients to take a multivitamin along with a vitamin D/calcium supplement. Healthcare professionals should be aware of these duplicate therapies so that they can prevent a total intake of doses above the UL.

One simple way to avoid consuming too much of any one micronutrient is to first attempt to obtain all of these nutrients from foods in the diet. If a patient is concerned about adequate intake, encourage them to consider how much of each nutrient is obtained from both food and drinks and to identify ways to boost dietary intake. If the patient is already taking a multivitamin or other supplements, remind them to also consider the quantity of each nutrient found in these products.

Another consideration that is not often addressed with multivitamins is the potential for reduced or enhanced absorption of various micronutrients in the presence of other micronutrients. For example, vitamin C (ascorbic acid) can increase the absorption of chromium and iron [16,17]. The presence of vitamin D increases the absorption of calcium in the intestine [18]. Iron and zinc can interfere with each other's absorption when taken on an empty stomach [19,20]. Thus, it can be difficult to predict the actual benefits and risks with these products, particularly in patients with specific nutritional needs or medical conditions.

Many multivitamin tablets and capsules are large, which may increase the risk of choking in some patients, particularly older adults. From 2006 to 2015, about 20% of the reports submitted to the U.S. Food and Drug Administration (FDA) Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS) concerning dietary supplements involved choking or other swallowing problems. About 73% of these reports involved multivitamin supplements, and most of the adverse reports occurred in older adult patients [22]. Clinicians should ensure that older patients with swallowing difficulties are not placing themselves at risk for choking with the use of multivitamins.

Benefits

Despite the widespread use of multivitamin products, the evidence to-date, which includes many large randomized controlled trials, does not support their use. The U.S. Preventive Services Task Force (USPSTF) currently states that there is insufficient evidence to recommend the use of multivitamins for the prevention of cardiovascular disease (CVD) or cancer [21]. Research evaluating these products for reducing overall mortality has shown no benefit.

Considering this lack of benefit in the context of high product costs and variable quality, consider steering patients away from taking multivitamins or relying on them for adequate nutrition.

INDIVIDUAL MICRONUTRIENTS

Unlike multivitamins, there is supportive evidence for the use of various individual micronutrients in older adults. Although the recommended daily intake for the majority of nutrients is the same for older adults as for younger adults, there are some important exceptions.

Vitamin B12 (Cyanocobalamin)

The recommended daily intake for vitamin B12 is the same for all adults, regardless of age. However, as humans age, their ability to absorb vitamin B12 from the intestinal tract decreases. Additionally, many older adults take medications that have the potential to further reduce the absorption of vitamin B12. Some examples of these medications include metformin and proton pump inhibitors (PPIs), such as pantoprazole and omeprazole [22,23]. Due to this reduced absorption, it is recommended that older adults consume fortified foods, such as breakfast cereal. However, some may also require vitamin B12 supplements to meet their needs [24].

Vitamin B6 (Pyridoxine)

It is recommended that older adults obtain more vitamin B6 from the diet than younger adults. Prior to 51 years of age, all adults are recommended to consume 1.3 mcg per day. Beginning at 51 years of age, the recommendation for women increases to 1.5 mcg; for men, it increases to 1.7 mcg [24]. This recommendation is related to an increased rate of vitamin B6 deficiency in older adults, which is thought to be due to reduced absorption and increased catabolism [25]. As with vitamin B12, vitamin B6 can be obtained from fortified foods. Supplements can be considered if dietary intake is inadequate.

Calcium and Vitamin D

One of the most popular combination supplements available on the market is calcium-vitamin D. Although calcium and vitamin D have distinctive effects, they are often discussed, and provided, in combination for bone health. While calcium is the nutrient that directly builds and maintains bone, vitamin D is crucial to the appropriate absorption of calcium from the intestine. Thus, adequate vitamin D intake is an important component of adequate calcium intake and bone health.

Due to age-related bone loss, the recommended daily intake for both calcium and vitamin D increases with age. And due to hormonal changes associated with menopause, the recommended intake for calcium increases faster for women than for men [13]. The recommended vitamin D intake is [13]:

- 1 to 70 years of age: 600 IU (15 mcg)

- 71 years of age and older: 800 IU (20 mcg)

The recommended intake of calcium is [13]:

- Women:

- 19 to 50 years of age: 1,000 mg

- 51 years of age and older: 1,200 mg

- Men:

- 19 to 69 years of age: 1,000 mg

- 70 years of age and older: 1,200 mg

Many older adults take calcium-vitamin D supplements to improve bone health and ensure adequate intake of both nutrients. However, this may not always be necessary or even appropriate. Whenever possible, experts recommend obtaining these nutrients from the diet. In fact, due to a lack of strongly supportive evidence, guidelines have not recommended the routine use of calcium and vitamin D supplements in many older adults [26,27]. For the prevention of fractures in community-dwelling, postmenopausal adults, the USPSTF found insufficient evidence to assess the balance of benefits and harms when calcium and vitamin D are supplemented in doses of at least 1,000 mg daily and 400 IU daily, respectively. The USPSTF also recommends against daily supplementation with lower doses of calcium and/or vitamin D. For the primary prevention of fractures in men and premenopausal women, the current evidence is insufficient to assess the balance of the benefits and harms of vitamin D and calcium supplementation, alone or combined.

The Bone Health and Osteoporosis Foundation (BHOF) recommends a diet with adequate total calcium intake based on the recommended daily intake, incorporating calcium supplements if intake is insufficient. They also recommend maintenance of serum vitamin D sufficiency (a 25-hydroxyvitamin D level of 30–50 ng/mL), with the use of supplemental vitamin D as needed to achieve sufficient vitamin D levels.

In 2024, the Endocrine Society published a new evidence-based guideline for using vitamin D supplementation in select patient populations [118]. The Endocrine Society Panel advises against routine use of vitamin D supplements in most healthy adults younger than 75 years of age and recommends against testing for vitamin D blood levels in the general population. The Panel does suggest empiric vitamin D supplementation for the following groups [118]:

- Children 1 to 18 years of age, to prevent rickets and potentially lower the risk of respiratory infections

- Adults older than 75 years of age, because of its potential to lower the risk of mortality

- Pregnant individuals, because of its potential to lower the risk of pre-eclampsia, intra-uterine mortality, preterm birth, and other neonatal complications

- Adults with prediabetes who are at high risk for progression to type 2 diabetes

The Panel advises that empiric vitamin D supplementation may include daily intake of fortified foods, vitamin formulations that contain vitamin D, and/or daily intake of a vitamin D supplement [118]. For nonpregnant older adults for whom vitamin D is indicated, the panel suggests supplementation via daily administration of vitamin D, approximating the age-adjusted dosage specified by the Institute of Medicine (600 IU for persons 1 to 70 years of age; 800 IU for those older than 70 years of age) rather than intermittent use of higher doses [13,118].

There has also been interest in the use of vitamin D supplements for reducing fall risk. However, high-quality research on this topic has yielded negative results. The USPSTF actually recommends against vitamin D supplementation to prevent falls in community-dwelling older adults [28].

Potassium

There is no recommendation for increased intake of potassium in older adults. However, the 2017 American Heart Association (AHA)/American College of Cardiology (ACC) Guidelines recommend increased intake of potassium in patients with elevated blood pressure or hypertension [112]. This recommendation should be considered with caution in older adults, who may have reduced kidney function or be taking medications that reduce potassium excretion. In fact, the guideline specifies that potassium supplementation should be obtained through the intake of potassium-rich foods as opposed to potassium supplements. This reduces the risk of excessive potassium intake or hyperkalemia.

Magnesium

Magnesium is an important nutrient for bone health. Magnesium deficiency can increase the formation and activity of osteoclasts, which resorb bone. Increased bone resorption causes release of magnesium and calcium from the bone, which can increase magnesium levels in times of deficiency. However, no large prospective studies have been conducted to evaluate the benefits of magnesium supplementation for the prevention of osteoporosis.

Regardless, it is important for patients to ensure adequate intake of magnesium from the diet. The daily recommended intake for magnesium is 320 mg for all adults 31 years and older [24]. Many foods are rich in magnesium and will allow most patients to attain this intake level.

However, some older adults may be at increased risk for magnesium deficiency due to the use of certain medications. The most important culprits are diuretics and PPIs. For diuretics, loop diuretics are the greatest cause for concern. This risk increases when taken with other magnesium-depleting drugs like PPIs. For patients taking PPIs long-term, the FDA recommends checking serum magnesium levels at baseline and annually thereafter. Although some patients may need to discontinue the PPI permanently, others with hypomagnesemia can take a PPI and magnesium supplement concurrently [29].

OTHER NUTRITIONAL SUPPLEMENTS

Protein

Due to the loss of muscle mass that occurs with age, protein consumption becomes particularly important for older adults. However, research shows that many older adults do not consume enough protein to keep up with the daily requirements, and that protein consumption actually decreases with age. The recommended daily intake of protein for all adults 18 years of age and older is 0.8 grams/kg [24].

However, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) recommends a higher protein intake for women older than 50 years of age. This recommendation calls for 1–1.2 grams/kg, as postmenopausal women experience an even greater loss in muscle mass [30].

As with other nutrients, patients should be counseled to obtain adequate protein intake from a well-rounded diet whenever possible. Although protein supplements may be appropriate for some patients, most patients are able to obtain adequate protein by making healthy changes to their diet. Common protein supplements, including whey, pea, and soy protein, will be discussed later in this course.

Fibers

Fiber is an important component of the diet. It is recommended that older women consume 25 grams daily and that older men consume 28 grams daily [24]. These intakes are actually less than those recommended for adults younger than 51 years of age. However, research shows that, as with protein, many older adults are not obtaining enough fiber from the diet.

The FDA has an established definition for what can be called a dietary fiber on a product label. This definition essentially states that the fiber must be a naturally occurring, nondigestible carbohydrate obtained from plants that has beneficial effects in the body. Fiber can be either water-soluble or water-insoluble. Water-soluble fibers, such as oats, beta-glucans, and barley, help to lower both blood glucose and cholesterol levels. Water-insoluble fibers, such as wheat bran and rice bran, help the body digest food and improve bowel health [31].

Most people will be able to meet their dietary fiber needs by increasing their intake of certain foods, such as oatmeal, whole wheat cereals, and grains. However, some patients may wish to take a fiber supplement as well. Most of the popular fiber supplements on the market contain blond psyllium (Plantago ovata), which is a water-soluble fiber that has shown benefits for constipation, coronary heart disease, hyperlipidemia, and diabetes. In these studies, patients typically consumed 10–20 grams of supplemental psyllium daily [32].

6. NATURAL PRODUCTS FOR PHYSICAL CHANGES

Almost all systems of the body are affected by age. Some changes can be directly tied to specific events, such as menopause, whereas other changes simply happen slowly over time. This section will explore some of the natural products most commonly used to counteract the physical changes that occur with age.

MUSCULOSKELETAL HEALTH

As mentioned, one of the best ways to improve musculoskeletal health in older age is to ensure adequate dietary intake of calcium, vitamin D, and protein. However, for those who would like to improve their overall physical performance and ability to recover from exercise, other natural products may be considered.

Physical Activity

First and foremost, it is important to ensure that patients are getting adequate physical activity for their age. This can be key to combatting the increased weight gain that is seen after menopause. In addition, it can help to reverse age-related muscle loss (sarcopenia) and even slow bone loss in all older adults.

The Centers for Disease Control and Prevention (CDC) recommends that all adults older than 65 years of age [33]:

- Obtain at least 150 minutes of moderate-intensity activity per week, such as brisk walking. Alternatively, this can be replaced with 75 minutes of vigorous-intensity activity, such as hiking, jogging, or running.

- Participate in muscle-strengthening exercises at least two days per week

- Participate in activities that improve balance at least three days per week

Muscle-strengthening exercises can include a wide range of options and are not solely limited to weightlifting. Patients can also consider the use of resistance bands; exercises that use their own body weight for resistance, such as push-ups, sit-ups, and certain forms of yoga and Pilates; and even heavy gardening [33]. Balance exercises are more specific and involve activities such as walking backwards, standing on one leg, or using a wobble board [33].

If a patient has had only limited physical activity and is interested in initiating a new exercise program, encourage them to seek guidance from a physical therapist. To avoid injury, patients should also be evaluated before initiating a new exercise program involving compressive or contractile stressors (such as running or weightlifting).

Supplements for Physical Performance

Some older adults may struggle to complete these recommendations due to fatigue or reduced muscle mass. Others may wish to exceed these recommendations but feel that they do not have adequate strength or energy to do so.

Protein Supplements

Protein was briefly discussed in the last section, within the context of ensuring adequate protein intake throughout the day. For a small number of older adults who cannot obtain adequate protein from the diet, protein supplements may be considered. There is also increasing interest in the use of protein supplements to improve physical performance and exercise endurance.

There are many protein supplement products on the market. The majority of these products use whey protein, which is derived from milk [34]. Other products use pea protein or soy protein. All three of these are considered complete proteins, meaning they contain all essential amino acids, which are amino acids that cannot be made by the body and must be obtained from the diet. Collagen is also becoming popular as a protein supplement. It is important to note that all collagen protein products are derived from animals and that collagen is not a complete protein [35]. Older adults should not rely on collagen protein supplements as a primary source of protein in the diet.

It is not clear if the form of protein used affects outcomes. Some small studies in young athletes suggests that whey, soy, beef, chicken, and dairy protein are similarly beneficial for improving muscle strength [36]. However, there is no researching comparing protein sources in older adults, so it is unclear if different protein formulations can be interchanged.

Some research suggests that taking 35 grams of whey protein three times weekly, either before or after resistance training, can modestly increase muscle mass, muscle strength, and functional capacity [37,38]. However, it is unclear if these benefits are clinically significant. Additionally, it is unclear if there are any benefits to muscle mass in people who are not regularly exercising [39].

There is very little, inconclusive research available for using soy protein to improve physical performance in older adults. To date, pea protein and collagen have not been studied for this purpose.

Branched-Chain Amino Acids (BCAAs)

Although branched-chain amino acids (BCAAs) are not protein supplements, they are comprised of amino acids, the building blocks of protein. BCAA products typically contain leucine, isoleucine, and valine, which are all essential amino acids.

Research on the use of BCAAs in older adults has mostly been limited to those who are relatively malnourished or are known to have inadequate dietary protein intake. The small studies that are available have overall shown no benefit for muscle strength or physical function [40,41].

Creatine

Most research shows that taking creatine while taking part in a resistance training program can increase upper and/or lower body muscle strength in older adults. Research also suggests that creatine improves total muscle mass in older adults [42,43]. In the available research, most participants took a loading dose of up to 20 grams daily for up to 7 days, followed by a maintenance dose of 2.25–10 grams daily for up to 12 weeks. The benefits of creatine at larger doses or for longer than 12 weeks is unknown.

Some case reports have suggested that taking creatine can worsen kidney dysfunction in some people. Additionally, creatine has been reported to cause water retention and edema in some adults [44]. In most clinical studies, participants did not experience these adverse effects. However, because older adults are more likely to have reduced kidney function, as well as cardiovascular dysfunction, recommend that patients monitor their fluid intake and output when initiating creatine supplementation.

Hydroxymethylbutyrate (HMB)

Hydroxymethylbutyrate (HMB), a metabolite of the amino acid leucine, is a naturally occurring molecule that is thought to be involved in protein synthesis. This has led to some interest in its use for performance enhancement.

Studies in older adults suggest that it might increase muscle mass or minimize the loss of muscle mass, particularly in those adults who have already experienced a loss of muscle mass [45,46,47]. However, it does not seem to improve muscle mass or overall exercise tolerance when used in conjunction with exercise [48,49].

Beta-Alanine

Beta-alanine, a beta-amino acid, is naturally found in the diet. Over the years, it has become a popular supplement for improving exercise performance.

The available research in older adults does show that taking beta-alanine 2.4–3.2 grams daily for 4 to 12 weeks improves exercise capacity and reduces fatigue by a small amount. However, it does not improve strength or exercise performance [50,51,52]. Beta-alanine is generally well-tolerated, but some people experience a dose-dependent feeling of pins and needles, as well as skin flushing [53,54].

EYE HEALTH

One of the leading causes of vision impairment in adults older than 55 years of age is age-related macular degeneration (AMD). Although it does not cause complete blindness, this condition blurs a person's central vision. This can significantly limit the ability to complete activities of daily living by making it harder to see faces, read, drive, or do close-up tasks like cooking or repairs [55].

The most common form of AMD, dry AMD, occurs in three stages—early, intermediate, and late. People with early and intermediate AMD typically do not experience symptoms. However, those with late AMD tend to notice a blurry area in their field of vision, which may get bigger over time.

Evidence Based Practice Recommendation

According to the American Academy of Ophthalmology, antioxidant vitamin and mineral supplementation as per the Age-Related Eye Disease Study (AREDS2) should be considered in patients with intermediate or advanced AMD. There is no evidence to support the use of these supplements for patients who have less than intermediate AMD and no evidence of any prophylactic value for family members without signs of AMD.

https://www.aaojournal.org/article/S0161-6420(19)32091-3/pdf

Last Accessed: May 29, 2024

Level of Evidence: Expert Opinion/Consensus Statement

One of the recommended preventive measures for AMD is a multinutrient supplement. Extensive research, referred to as the Age-Related Eye Disease Studies (AREDS), has been conducted on the use of very specific nutrient formulations to limit the progression of AMD. The American Academy of Ophthalmology Guideline recommends one of these formulations, AREDS2, for all patients who have progressed to intermediate or advanced AMD in at least one eye [55].

Because there is still some confusion regarding the appropriate product to recommend for patients with AMD, it can be helpful to review the formulations that have been studied (Table 1) [55]. Both formulations contain the same quantities of vitamin C, vitamin E, and copper. However, they differ in relation to the type of carotenoid provided. Carotenoids are dietary precursors to vitamin A that are converted to vitamin A in the body. The Original AREDS formulation provided beta-carotene, whereas the AREDS2 formulation provides a mixture of two carotenoids, lutein and zeaxanthin.

Table 1: MULTI-NUTRIENT SUPPLEMENTATION FOR AMD

Nutrient

Dose

Original AREDS

Vitamin C

500 mg

Vitamin E

400 IU

Beta-Carotene

15 mg

Zinc (zinc oxide)

80 mg

Copper (cupric oxide)

2 mg

AREDS2

Vitamin C

500 mg

Vitamin E

400 IU

Lutein/zeaxanthin

10 mg/2 mg

Zinc (zinc oxide)

80 mg OR 25 mg

Copper (cupric oxide)

2 mg

Source: [55]

One of the primary reasons that beta-carotene was removed from the AREDS2 formulation was safety concerns. Multiple studies have shown that heavy smokers who take beta-carotene supplements have an increased risk of lung cancer and an increased rate of mortality. In fact, these known risks led the USPSTF to recommend against the use of beta-carotene supplements [21].

The quantity of zinc in these products also differs. In AREDS2 studies, two different doses of zinc were evaluated. Importantly, only the higher dose of zinc was found to be beneficial, suggesting that only products containing 80 mg of zinc should be used. Research also suggests that taking zinc alone, or taking the other ingredients found in AREDS2 without zinc, results in reduced benefits for patients with advanced AMD. Thus, patients should be counseled to take the specific combination product studied in AREDS2 providing 80 mg zinc [55].

CARDIOVASCULAR HEALTH

Another common area of concern for older adults is cardiovascular health. As discussed, many older adults experience elevated blood pressure and cholesterol. Additionally, there is interest in using supplements to assist in maintaining optimal cardiac function and health for as long as possible.

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends against the use of beta carotene or vitamin E supplements for the prevention of cardiovascular disease or cancer.

https://jamanetwork.com/journals/jama/fullarticle/2793446

Last Accessed: May 29, 2024

Level of Evidence: D (Evidence is insufficient to assess the balance of benefits and harms)

As noted, multivitamins are incredibly popular with older adults, and one of the stated reasons for use is cardiovascular health. However, the USPSTF has concluded that there is insufficient evidence to assess the balance of benefits and harms with the use of multivitamin supplements for the prevention of CVD or cancer in community-dwelling adults [21]. Similarly, the USPSTF has found that there is insufficient evidence to assess the balance of benefits and harms for the use of single or paired nutrient supplements for these purposes [21]. In general, multivitamins and vitamin/mineral supplements should not be recommended for cardiovascular health.

Omega-3 Fatty Acids

Some of the supplements most frequently used by older adults are omega-3 fatty acid supplements. These supplements typically contain fish oil, which is high in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Many fish contain large amounts of omega-3 fatty acids, and fish oil supplements can be derived from various fish, ranging from anchovy to mackerel to sturgeon. Fish oil supplements can vary significantly in contents and quality, with EPA content ranging from 18% to 51% and DHA content ranging from 12% to 32% [113].

Omega-3 fatty acids are generally considered "healthy fats" and are found in high concentrations in the human brain, retina, and spermatozoa. The reason that these are popular for cardiovascular health ties in to multiple purported and confirmed benefits. However, research has identified significant differences between the benefits of fish oil supplements and fish oil obtained from dietary intake of fish.

Prescription vs. Supplemental Fish Oil

Two prescription fish oil products have been approved by the FDA. The first product, with the original brand name Lovaza, provides omega-3 acid ethyl esters. It was approved for triglyceride levels greater than 500 mg/dL in patients who do not have adequate reduction in triglycerides after lifestyle and dietary modifications. For this purpose, the medication is taken as 4 grams daily. The other product, with the original brand name Vascepa, provides icosapent ethyl, which is a derivative of EPA. Similar to the omega-3-acid ethyl esters, this product is approved for the treatment of hypertriglyceridemia at a dose of 4 grams daily. For both products, the daily dose is obtained by taking four capsules [114].

It is important to note that the contents of these prescription products have been purified and standardized and that each capsule contains the exact amount of each omega-3 fatty acid stated on the label. In general, fish oil supplements have not been purified and also may not be standardized.

Another important note to consider is that the quantity of omega-3 fatty acids found in prescription products is significantly higher than that found in supplements. Although some fish oil supplements may have some benefit for reducing triglycerides, these forms of fish oil are generally considered inadequate in comparison to prescription products because doses of up to 12 capsules, as opposed to four capsules of the prescription preparation, may be needed to produce the same effect [56].

Cardiovascular Disease (CVD)

Clinical and observational research has found that routinely eating fatty fish, such as salmon or mackerel, as part of the diet may reduce the risk of developing heart disease and all-cause mortality in adults without a history of CVD [57,58]. In fact, the AHA recommends one to two weekly servings of non-fried fish in place of less healthy sources of protein and fat to reduce the risk of CVD [59]. However, the use of fish oil supplements for the primary prevention of heart disease does not seem to be beneficial. In addition, neither increased dietary intake of fish oil nor fish oil supplements are associated with a benefit in patients who already have CVD [57,58].

The best evidence to date shows that fish oil supplements, which are typically taken in doses of 1 gram daily, are not beneficial for primary or secondary prevention of CVD. Additionally, prescription fish oil products in higher doses of 4 grams daily do not seem to be beneficial for the prevention of CVD. Although the benefits of consuming fish oil as part of the diet might offer only modest benefits for the primary or secondary prevention of CVD, people should continue to eat fish and other foods that provide omega-3 fatty acids, as these foods make up part of a healthy diet. In fact, in 2019, the FDA determined that it would allow a qualified health claim stating that foods containing EPA and DHA may reduce the risk of CVD. However, the FDA states that this claim is based on supportive, rather than conclusive, evidence [60].

Hypertension

There is some promising research on using fish oil supplements for blood pressure reduction, although most research suggests that this benefit may only occur in patients with very elevated blood pressure as opposed to those with mild hypertension. A meta-analysis of clinical research shows that, overall, fish oil reduces systolic blood pressure by about 3–5.5 mm Hg and diastolic blood pressure by 2–3.5 mm Hg in patients with hypertension. It is not clear whether the hypotensive effect of fish oil is dose-dependent [61,62].

Interestingly, some studies have suggested that different antihypertensive medications can alter the effect of fish oil on blood pressure. Some clinical evidence shows that adding fish oil 5 grams daily for six weeks does not provide additive blood pressure reduction in patients being treated with ACE inhibitors. However, other clinical research shows that fish oil provides additive reduction of systolic and diastolic blood pressure in hypertensive patients taking beta-blockers or diuretics [63].

If patients are interested in taking fish oil to reduce blood pressure, remind them that fish oil supplements have not been shown to provide any benefit for preventing CVD. Also, counsel patients that supplements containing only DHA or EPA, the omega-3 fatty acids in fish oil, have not been shown to provide the same benefits as fish oil for either blood pressure or CVD. Finally, the doses used in studies of fish oil supplements for hypertension are very high and can be difficult to obtain. This is similar to the need to take 12 capsules of supplemental fish oil versus 4 capsules of prescription fish oil for the treatment of hypertriglyceridemia.

Safety Concerns

Older adults may be at risk for some specific potential side effects from fish oil products. One commonly discussed adverse effect of omega-3 fatty acids is a potential increased risk for bleeding. This concern is due to some older research which suggested that doses greater than 3 grams per day can inhibit blood coagulation and potentially increase bleeding risk [64]. The most rigorous research to date shows that short-term doses of fish oil 10 grams daily and long-term doses of 1.5 grams daily for up to one year do not increase the risk of bleeding or affect coagulation parameters in chronically ill patients [64]. However, the doses studied for hypertension and hypertriglyceridemia exceed 1.5 grams daily; use caution when recommending fish oil supplements for older adults.

More recently, large randomized controlled trials have identified a possible increased risk for atrial fibrillation in people taking prescription fish oil. One large clinical study, called the STRENGTH trial, found that taking prescription fish oil 4 grams daily for up to six years was associated with an increased risk for atrial fibrillation, with a number needed to harm of 114 when compared with a corn oil control [65]. Also, meta-analyses show that taking omega-3 fatty acid supplements increases the incidence rate ratio for atrial fibrillation by up to 37% when compared with placebo. This incidence rate seems to increase with doses of more than 1 gram daily [66,67]. Thus, fish oil supplements should be used with caution in older adults at risk for atrial fibrillation.

Other adverse effects of fish oil are milder in nature and are typically limited to the gastrointestinal tract. Some patients experience fishy hiccups and a fishy breath odor and/or aftertaste. If patients experience diarrhea, heartburn, bloating, discomfort, or indigestion, they should be encouraged to start at a lower dose and increase slowly, and to take their supplements with meals.

Some fish may contain unsafe levels of certain toxins, including dioxins, mercury, and polychlorinated biphenyls (PCBs). PCBs are found in fish living in polluted waters and in some farmed fish, such as salmon. Freshwater fish frequently contain high levels of these chemicals, which may be carcinogenic [68]. Dioxins may be found in high concentrations in the feed given to farmed fish. Farmed salmon, the most common store-bought salmon in North America, is more likely to contain high concentrations of dioxin than wild-caught salmon [69]. Thus, fish should be consumed in moderation.

For patients who would like to take a fish oil supplement, make sure to only recommend products with appropriate quality certifications, including USP-Verified and NSF: Contents Certified. These supplements have been verified to reliably contain what is stated on the label and to be free of unsafe levels of contaminants, such as pesticides and heavy metals.

JOINT HEALTH

Joint health is another common concern that comes with aging. While some people may already have osteoarthritis, others are interested in taking supplements to prevent the development or slow the progression of the condition.

Glucosamine and Chondroitin

The most popular supplements for joint health are glucosamine and chondroitin, often taken together in a combination product. Glucosamine is an amino sugar that occurs naturally in humans. It is necessary for the synthesis of glycoproteins, glycolipids, and glycosaminoglycans. These compounds are found in tendons, ligaments, cartilage, synovial fluid, mucous membranes, blood vessels, heart valves, and structures of the eye. There are multiple forms of glucosamine available on the market [70]. Glucosamine sulfate is the most common form. This form must be created semi-synthetically in a lab. Glucosamine hydrochloride is the second most common form. This salt occurs naturally and can be obtained from shellfish, fungi, or corn via a simple extraction process. N-acetyl glucosamine, the acetylated derivative of glucosamine, is the least common form found in supplements [71].

Chondroitin sulfate is a glycosaminoglycan found naturally in the body, particularly in connective tissues. It is a very large molecule; the species or tissue of origin, as well as the extraction method used, can affect its final size [72].

Extensive research has been conducted on the use of glucosamine for the management of osteoarthritis. Thus far, the best evidence is for glucosamine sulfate. Glucosamine hydrochloride has not shown any real benefit in clinical research.

Glucosamine

Most research has focused on the use of oral glucosamine sulfate for the management of knee osteoarthritis. Meta-analyses of the available research show that taking glucosamine sulfate 1,500 mg daily for up to three years modestly improves pain and function when compared with placebo [73]. Individual studies have shown a 28% to 41% pain reduction and 21% to 46% improvement in function [74]. Small studies comparing glucosamine sulfate with NSAIDs, such as ibuprofen 400 mg three times daily or piroxicam 20 mg daily, suggest that these treatments provide similar benefit. However, NSAIDs appear to relieve symptoms within two weeks, whereas glucosamine sulfate can take four to eight weeks [75].

The benefits of glucosamine sulfate seem to vary depending on the product used. To date, the most consistently positive evidence for glucosamine sulfate has been seen with Dona, a specific, pharmaceutical-grade, crystalline glucosamine sulfate product. This formulation of glucosamine sulfate has demonstrated high bioavailability resulting in high plasma concentrations, although the clinical relevance of this is unclear [76]. Experts currently disagree as to whether the benefit seen with this product is due to bias introduced by industry funding or due to a higher quality product.

Chondroitin Sulfate

Chondroitin sulfate, when taken alone, has demonstrated modest benefit for reducing pain and improving function in some patients with knee osteoarthritis. Meta-analyses of the available research show that taking chondroitin sulfate 800–2,000 mg in single or divided doses daily for at least three months can modestly reduce pain and disability when compared with placebo [77]. Other clinical research in adults with knee or hip osteoarthritis shows that taking chondroitin sulfate daily at a dose of at least 800 mg for two years might modestly reduce joint degeneration and narrowing when compared with placebo or celecoxib [78,79].

Glucosamine Sulfate and Chondroitin Sulfate Combinations

Although most evidence evaluating glucosamine sulfate or chondroitin sulfate alone suggests modest benefit for knee osteoarthritis, research on the use of combination products is less conclusive. Some long-term studies in patients with osteoarthritis show that taking this combination modestly reduces joint space narrowing when compared with a control group [71,80]. But not all research is positive. Some individual clinical studies, as well as meta-analyses of the available research, have not shown a reduction in pain in patients taking chondroitin sulfate in combination with either glucosamine hydrochloride or glucosamine sulfate [81].

The place of glucosamine and chondroitin in clinical practice is unclear. In fact, clinical guidelines provide conflicting recommendations [71,82]. The American College of Rheumatology (ACR) strongly recommends against the use of any glucosamine or chondroitin products for any form of osteoarthritis. Conversely, the European Society of Clinical and Economic Aspects of Osteoarthritis (ESCEO) strongly recommends for the use of pharmaceutical-grade glucosamine sulfate or chondroitin sulfate products in patients with osteoarthritis. The ESCEO also provides a weak recommendation against the use of glucosamine and chondroitin in combination.

These conflicting recommendations are related to differing interpretations of the previously discussed evidence. The ACR has determined that the positive benefits identified in industry-funded studies indicates the introduction of industry bias [82]. The ESCEO, on the other hand, has determined that the positive benefits identified in industry-funded studies is due to the higher quality and bioavailability of the products used [71].

If a patient would like to use these products, be sure to recommend one that carries a third-party quality certification to minimize concerns related to product quality and potency.

Safety

Both glucosamine and chondroitin are relatively safe for most adults. The most commonly reported adverse effects are minor gastrointestinal disturbances, such as abdominal pain, bloating, constipation, diarrhea, and heartburn.

Some case reports have suggested that glucosamine and/or chondroitin may interact with warfarin, causing an elevation in international normalized ratio (INR). Although the likelihood of this risk is unclear, use caution in patients taking warfarin and monitor INR closely.

Collagen

Another supplement that has gained popularity for osteoarthritis and joint health is collagen. Collagen is a hard, insoluble protein that occurs naturally in the human body and is found in the bones, cartilage, muscles, skin, and tendons. It is a structural protein, meaning that it is crucial to the shape and structure of cells and tissues in the body [83].

Some supplements contain intact collagen, often either collagen type I, II, or III. However, much more often, collagen supplements contain hydrolyzed collagen, or collagen peptides, that are derived from these intact forms of collagen. This is also sometimes referred to on labels as collagen hydrolysate.

Benefits

Collagen types I and II have been evaluated for use in knee osteoarthritis, with small studies suggesting the potential for modest benefit with certain formulations. However, the most extensive research has been conducted with collagen peptides [84,85].

Some clinical studies in adults with knee osteoarthritis suggest that collagen peptides 5–10 grams, taken for three to six months, may modestly reduce pain. However, any improvements appear to be small, and not all research has yielded positive findings. One clinical study shows that taking oral collagen peptides reduces pain by at least 30% in 42% more patients when compared with placebo. However, there was no improvement when the Western Ontario and McMaster Universities (WOMAC) scale was used [84]. In another study, taking collagen peptides reduced pain by about two points on a 100-point scale, compared with a 0.9-point reduction in those taking glucosamine sulfate 1,500 mg. There was no reduction in the use of ibuprofen in these patients [85].

Although some research suggests the potential for modest benefit, it is not clear that collagen peptides can improve pain to a clinically meaningful degree. Patients should not rely on collagen peptides for the management of knee osteoarthritis, although it may be considered as an adjunct therapy in patients with more severe disease.

Safety

Overall, collagen appears to be safe for adults when taken by mouth at doses evaluated in clinical research. There are very limited reports of adverse effects with collagen products. Some minor gastrointestinal upset has been reported rarely with the use of collagen peptides.

7. NATURAL PRODUCTS FOR COGNITIVE CHANGES

One of the major concerns that comes with age is a decline in cognitive function, which can present as either cognitive impairment or dementia. Because there are no approved or confirmed preventive strategies for reducing the risk of age-related cognitive impairment or dementia, many people consider the use of supplements. Similarly, some people use supplements to slow the advancement of cognitive impairment and/or dementia.

It should be noted that many studies of supplements for the improvement of cognitive function in older adults are small and may be of low quality. For example, some studies do not use a placebo control, and the majority of these products have not been compared to prescription drugs for dementia. Although this does not invalidate all of the available research, the results should be interpreted with caution.

LIFESTYLE INTERVENTIONS

First, it is worth noting that lifestyle changes are the most commonly recommended preventive measures for mild cognitive decline or dementia. The World Health Organization (WHO) recommends that all adults, with or without cognitive impairment, get adequate physical activity (as discussed) to reduce the risk of cognitive impairment. The organization also recommends that all adults consume a Mediterranean-like diet in order to slow cognitive decline (Table 2) [86]. However, it should be noted that the research identifying a benefit for age-related cognitive impairment involved strict adherence to the Mediterranean diet; people who had only moderate adherence did not experience a benefit [87,88].

Table 2: WHAT IS A MEDITERRANEAN-LIKE DIET?

A Mediterranean-like diet emphasizes foods such as olive oil, fruits, vegetables, legumes, and whole grains. This is intended to provide a high ratio of monounsaturated-to-saturated fat. The diet also emphasizes fish and reduces overall meat intake, while allowing for moderate-to-modest amounts of red wine and dairy. In general, the diet avoids highly processed foods, refined grains, and sugars.

Source: Author

In general, regular consumption of fruits, vegetables, and fish is most consistently associated with a reduced risk of dementia. This has led to interest in the use of fish oil to prevent cognitive decline. However, the observational research that has been conducted to date has not found an association between risk of mild cognitive impairment or dementia and the use of fish oil supplements [89,90,91].

The WHO also recommends weight loss for people who are overweight or obese, as well as reducing alcohol consumption. Both of these changes can have multiple downstream health benefits, but there is also some early evidence suggesting that they can reduce cognitive decline [86].

Finally, the WHO recommends social participation and social support, which "are strongly connected to good health and well-being throughout life and social inclusion should be supported over the life-course" [86]. However, it is important to note that there is no evidence showing a direct association between social participation and cognitive function. For now, encourage social support and participation due to the many other benefits it can offer, including to mental health [86].

NUTRIENT SUPPLEMENTS

Vitamin E

Vitamin E is one of the most popular vitamin supplements for dementia and cognitive impairment. In fact, there is some evidence to show that taking vitamin E can modestly slow cognitive function decline in patients with Alzheimer disease. However, it does not seem to prevent the onset of Alzheimer disease or prevent cognitive decline in general. Thus, the WHO recommends against the use of vitamin E for prevention [86].

Additionally, there are concerns about the safety of vitamin E in older adults. Most of the studies showing benefit for Alzheimer disease used a dose of 2,000 IU daily. Some research in middle-aged and older patients with chronic diseases suggests that vitamin E in doses above 400 IU daily may increase the risk of adverse outcomes and mortality [115]. On the other hand, these doses appear to be safe in otherwise healthy adults. It is not entirely clear which population is safe to use large supplemental doses of vitamin E, but it should be used with caution in older adults, particularly those with multiple comorbidities.

Idebenone

Another nutrient-like supplement that is sometimes touted for cognitive function is idebenone. This is a synthetic analogue of coenzyme Q10. Some older studies have shown that taking 90–120 mg three times daily for six months slows the decline of cognitive function in adults with Alzheimer disease [92]. However, there is no available research in adults with mild cognitive impairment or other forms of dementia.

Idebenone seems to be well tolerated by most adults although it can cause some gastrointestinal side effects such as nausea and vomiting, abdominal pain, and loose stools.

HERBAL SUPPLEMENTS

Ginkgo

Ginkgo (Ginkgo biloba) is one of the most popular herbal supplements for dementia and cognitive impairment. The leaves of this plant have a long history of use in traditional Chinese medicine, and there is some evidence to support their use in people who already have dementia. Research in people with Alzheimer disease, vascular dementia, or mixed dementia shows that taking ginkgo 240 mg daily for about six months modestly improves cognition and activities of daily living when compared with placebo. A lower dose of 120 mg daily does not seem to offer the same benefit [93,94,95,96].

It is important to note that the product used in these studies was a specific ginkgo supplement—Egb 761. This supplement differs from other ginkgo products because it has been standardized to contain 22% to 27% flavone glycosides and 5% to 7% terpene lactones, which includes ginkgolides A, B, and C. Other ginkgo supplements may not be standardized to these same chemicals, and thus they may have different (or lower) activity [97].

As with vitamin E, ginkgo has not shown benefit for the prevention of dementia in those with normal cognitive function or in those with mild cognitive impairment. It also does not seem to prevent disease progression in people with Alzheimer disease. Thus, the WHO guidelines do not recommend ginkgo for the prevention of MCI or dementia [86].

Ginkgo is considered generally safe for most adults. There have been some rare reports of arrhythmia in patients who take ginkgo supplements. It is unclear if this relationship is coincidental or causative, but there have been enough reports to lead Health Canada and the WHO to release warnings about the use of these products [86,98].

There is also significant interest in the use of ginkgo supplements for tinnitus, another issue that becomes more common with age. In fact, tinnitus can even contribute to cognitive impairment and lack of social participation. Unfortunately, clinical studies show that taking ginkgo leaf extract does not improve symptoms of tinnitus [99,100]. It should not be recommended for this purpose.

Huperzine A

Huperzine A is a chemical that is isolated from a type of moss, called the Chinese club moss (Huperzia serrata). Because it is derived from moss, this chemical is sometimes sold as a supplement, either as a single ingredient or in combination with other ingredients. There are multiple reasons that this chemical is of interest for dementia and mild cognitive impairment, including its antioxidant and anti-apoptotic effects, as well as its possible activity against beta-amyloid.

Clinical research in adults with Alzheimer disease shows that taking huperzine A 200–800 mg in divided doses daily for two to nine months improves cognitive function on the Mini-Mental State Exam (MMSE) when compared with placebo [101,102]. It should be noted that most research has been conducted in China, where this chemical is an approved drug. One clinical study conducted in the United States shows that taking 400 mg twice daily improves performance on the MMSE and the Alzheimer Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) when compared with placebo. A lower dose of 200 mg twice daily was not consistently beneficial [103].

Huperzine can cause cholinergic side effects such as dizziness, sweating, insomnia, nausea, vomiting, and diarrhea. However, it is generally well tolerated by most adults.

Bacopa

Another herbal supplement that is sometimes touted for cognitive health in older adults is bacopa (Bacopa monnieri). This plant is found in India and has been used for centuries in Ayurvedic medicine. There is interest in its use for dementia and cognitive impairment because it has demonstrated cholinergic activity in laboratory studies. However, only one small study has evaluated bacopa in adults with Alzheimer disease or mild cognitive impairment. This study showed that taking bacopa 300 mg daily for 12 months did not offer any benefits when compared with donepezil or baseline [104].

Bacopa has been reported to cause increased stool frequency, nausea, and abdominal cramps in 16% to 30% of patients in clinical studies [116]. Considering that it has not shown benefit for cognitive function in older adults, steer patient away from bacopa supplements.

ENDOGENOUS SUBSTANCES

Alpha-L-Carnitine

Alpha-L-carnitine is an ester of L-carnitine, which is an amino acid derivative that is found naturally in the body. It is made in the brain, liver, and kidneys, and the body can convert it to and from L-carnitine as needed. Alpha-L-carnitine is structurally similar to acetylcholine, which has led to interest in its use for dementia and mild cognitive impairment. Small clinical studies show that taking 1.5–2 grams daily for three months can improve some measures of cognitive function in older adults with mild cognitive impairment [105,106]. Similarly, small clinical studies show that taking 1.5–3 grams daily for three to 12 months can slow the rate of Alzheimer disease progression and improve some measures of cognitive function [107].

Alpha-L-carnitine is generally well tolerated by most adults, although it can cause headache, insomnia, and agitation in some people. Let patients know that it can also cause the breath, urine, and sweat to have a fishy odor, which is not harmful [108].

Phosphatidylserine

Phosphatidylserine is a phospholipid that is naturally made by the human body. It is a component of the cell membrane and is found in high quantities in the brain. Thus, there is interest in its use for improving cognitive function in all age groups.

To date, the best evidence for the use of phosphatidylserine is for the improvement of cognitive function in adults with age-related mild cognitive impairment or Alzheimer disease. This research shows that taking phosphatidylserine, usually as 300 mg daily in divided doses, for six weeks to six months improves attention, verbal fluency, and memory. However, it should be noted that these studies were very small, and some did not use blinding or a placebo control group. Additionally, the studies are old and may not be representative of current standards of care [109,110].

As for preventing the development of Alzheimer disease or mild cognitive impairment, clinical research has not shown a benefit. Also, there is currently no research on the use of phosphatidylserine in other types of dementia. However, phosphatidylserine is generally safe to use, with the most common adverse effects being flatulence and nausea. This may be a reasonable option for patients interested in taking a supplement.

Citicoline

Citicoline is a chemical that occurs during the synthesis of choline from phosphatidylcholine in the body. Some small clinical studies in older adults with MCI have shown that taking citicoline 500–2,000 mg daily for up to three months moderately improves memory scores when compared with placebo [111]. The research in patients with Alzheimer disease is relatively limited, and there is no available research in patients with other forms of dementia. Citicoline is well tolerated by most adults.

Alpha-GPC

Alpha-GPC is another chemical that is related to choline, except that this chemical is naturally produced by the body from choline. It is a precursor to acetylcholine, a neurotransmitter. There has been some research on the use of this supplement in patients with vascular dementia and Alzheimer disease that shows modest benefit, but these studies are small and should not be relied upon [117]. The most common adverse effects with alpha-GPC are diarrhea, heartburn, nausea, and vomiting.

8. CONCLUSION

Aging causes a number of changes to the body that affect physical function, cognitive function, and overall quality of life. Older adults frequently report using supplements, often for the purpose of improving overall health, but also for the purposes of improving musculoskeletal health, nutrition, cardiovascular health, and more. It is important for healthcare professionals to be aware that supplements can interact with drugs and medical conditions, and that some supplements carry serious health risks for certain patients. However, some supplements may be a reasonable option for older patients who are looking to improve their health and quality of life and can be safely recommended.

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97. Decker L, Basta D, Burkart M, Ernst A. Balance training with vibrotactile neurofeedback and Ginkgo biloba extract in age-related vertigo. Front Neurol. 2021;12:691917.

98. Health Canada. Ginkgo Biloba-Containing Products and the Risk of Cardiac Arrhythmias. Available at https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/health-product-infowatch/february-2021.html#ginkgo_biloba. Last accessed May 17, 2024.

99. Chauhan B, Arya S, Chauhan K. Ginkgo biloba administered singly and combined with antioxidants in tinnitus patients. J Audiol Otol. 2023;27(1):37-44.

100. Sereda M, Xia J, Scutt P, Hilton MP, El Refaie A, Hoare DJ. Ginkgo biloba for tinnitus. Cochrane Database Syst Rev. 2022;11(11):CD013514.

101. Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ. Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis. J Neural Transm Vienna Austria. 2009;116(4):457-465.

102. Cui CC, Sun Y, Wang XY, Zhang Y, Xing Y. The effect of anti-dementia drugs on Alzheimer disease-induced cognitive impairment: a network meta-analysis. Medicine (Baltimore). 2019;98(27):e16091.

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104. Prabhakar S, Vishnu VY, Modi M, et al. Efficacy of Bacopa monnieri (brahmi) and donepezil in Alzheimer's disease and mild cognitive impairment: a randomized double-blind parallel phase 2b study. Ann Indian Acad Neurol. 2020;23(6):767-773.

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Evidence-Based Practice Recommendations Citations

1. American Academy of Ophthalmology. Age-Related Macular Degeneration: Preferred Practice Pattern. Washington, DC: American Academy of Ophthalmology; 2019. Available at https://www.aaojournal.org/article/S0161-6420(19)32091-3/pdf. Last accessed May 29, 2024.

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48854 • Pressure Injuries: Prevention and Management

John M. Leonard, MD

www.netce.com

Copyright © 2025 NetCE, All rights reserved.

Pressure injuries are among the most common conditions encountered in patients who suffer prolonged hospitalization or require long-term institutional care. The prevalence varies widely by clinical setting, age, and geographical region. Although generally preventable, not all pressure injuries can be classified as preventable or potentially curable, due to impaired blood circulation, sensory loss, and immobility, causing some patients to become more vulnerable to them. Several dynamics give rise to the occurrence of pressure injuries, but compression leading to ischemia is the ultimate communal culprit. Furthermore, cognitive impairment of some patients has made some preventive measures extremely challenging to employ. This course will outline the etiology, pathogenesis, identification, prevention, and treatment of pressure injuries in any practice setting.

Table of Contents

48854 • Pressure Injuries: Prevention and Management

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

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. EPIDEMIOLOGY

3. PATHOGENESIS

4. RISK FACTORS

EXTRINSIC FACTORS

INTRINSIC RISK FACTORS

RISK ASSESSMENT

5. STAGING OF PRESSURE INJURIES

DEEP TISSUE PRESSURE INJURY

STAGE 1: NONBLANCHABLE ERYTHEMA

STAGE 2: PARTIAL-THICKNESS SKIN LOSS WITH EXPOSED DERMIS

STAGE 3: FULL-THICKNESS SKIN LOSS

STAGE 4: FULL-THICKNESS SKIN AND TISSUE LOSS WITH EXPOSED BONE, TENDON, OR MUSCLE

UNSTAGEABLE

MEDICAL DEVICE-RELATED PRESSURE INJURY

MUCOSAL MEMBRANE PRESSURE INJURY

6. PHASES OF WOUND HEALING: AN OVERVIEW

INFLAMMATORY PHASE

PROLIFERATION PHASE

MATURATION PHASE

7. DIAGNOSIS

8. PREVENTION AND TREATMENT

SKIN CARE AND PRESSURE-RELIEVING STRATEGIES

NUTRITIONAL SUPPORT

WOUND CLEANSING

DEBRIDEMENT

DRESSINGS

PAIN MANAGEMENT

SURGICAL CLOSURE

INFECTION MANAGEMENT

ADJUNCTIVE TREATMENTS

INDIVIDUAL STAGING TREATMENT PLANS

9. WOUND MONITORING

WOUND ASSESSMENT

WOUND EDGE AND SURROUNDING SKIN

PAIN

PRESENCE OF INFECTION

10. COMPLICATIONS

CELLULITIS

SEPSIS AND SEPTIC SHOCK

BONE AND JOINT INFECTIONS

MALIGNANCY

GAS GANGRENE

NECROTIZING FASCIITIS

RECURRENCE

11. TREATMENT OF COMORBIDITIES

DIABETES

URINARY AND FECAL INCONTINENCE

PERIPHERAL VASCULAR DISEASE

HYPOTENSION AND HYPOXIA

GASTROINTESTINAL DISORDERS AND MALABSORPTION

MALIGNANCY

END-STAGE RENAL DISEASE

DEPRESSION

COGNITIVE IMPAIRMENT

12. ADVANCES IN PRESSURE INJURY CARE

REPOSITIONING ALERTS

DETECTION

DOCUMENTATION

ULTRASOUND

SKIN SUBSTITUTES OR GRAFTS

GENE THERAPY

NEGATIVE PRESSURE WOUND DEVICES

GROWTH FACTORS AND BIOLOGIC WOUND PRODUCTS

OTHER TREATMENT MODALITIES

13. MEDICO-LEGAL ASPECTS OF INJURY CARE

AVOIDABLE VERSUS UNAVOIDABLE INJURIES

DETERMINATION OF NEGLECT

14. EDUCATING PATIENTS

PATHOGENESIS OF PRESSURE INJURIES

REDUCTION OF RISK

REDUCTION OF FRICTION AND SHEAR

SKIN INSPECTION AND PROTECTION

NUTRITION

PROCEDURE FOR RECURRENCES

MANAGEMENT OF PRESSURE INJURY

PROPER DRESSING CHANGE PROCEDURE

15. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

48854 • Pressure Injuries: Prevention and Management

Education Category. Infection Control / Internal Medicine

Release Date. 05/01/2025

Expiration Date. 04/30/2028

Course Overview

Pressure injuries are among the most common conditions encountered in patients who suffer prolonged hospitalization or require long-term institutional care. The prevalence varies widely by clinical setting, age, and geographical region. Although generally preventable, not all pressure injuries can be classified as preventable or potentially curable, due to impaired blood circulation, sensory loss, and immobility, causing some patients to become more vulnerable to them. Several dynamics give rise to the occurrence of pressure injuries, but compression leading to ischemia is the ultimate communal culprit. Furthermore, cognitive impairment of some patients has made some preventive measures extremely challenging to employ. This course will outline the etiology, pathogenesis, identification, prevention, and treatment of pressure injuries in any practice setting.

Audience

This course is designed for physicians, primary care providers, and physician assistants involved in the care of patients at risk for pressure injury development.

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 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. 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. 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. NetCE is authorized by IACET to offer 1 CEU(s) for this program.

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, physician assistants, and nurse practitioners a current review of the pathogenesis, diagnosis, and treatment of pressure injuries, with an emphasis on clinical recognition and staging, risk factor assessment and prevention, and management strategies for collaborative care to improve patient outcomes.

Learning Objectives

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

1. Discuss the epidemiology, etiology, and pathogenesis of pressure injuries.

2. Identify patients at risk based on extrinsic and intrinsic factors important to pathogenesis.

3. Recognize and define the severity and progression of pressure injuries by stage.

4. Analyze techniques available for the diagnosis of pressure injuries.

5. Develop an effective strategy for skin care and prevention of pressure injuries.

6. Choose appropriate options for wound cleansing, debridement, and dressing based on wound types.

7. Manage other aspects of the care of patients with pressure injuries, including pain management and infectious complications.

8. Create individual treatment plans based on patient characteristics and pressure injury stage.

9. Identify the qualities of a pressure injury that should be monitored.

10. Outline possible complications and comorbidities of pressure injuries and their treatment.

11. Describe the medico-legal aspects of pressure injuries and the significance of correct documentation and patient education.

Faculty

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, 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

Ronald Runciman, MD

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

A pressure injury is a localized skin erosion and subcutaneous crater, usually over a bony prominence, caused by the mechanical effect of unrelenting pressure [1,2]. The skin and soft tissues become vulnerable when extrinsic factors, such as prolonged pressure, shearing forces, friction, and moisture, coincide with intrinsic (host) factors, such as immobility, poor nutritional state, and incontinence. The most common areas where pressure injuries occur include the sacrum, coccyx or tailbone, hips, heels, and elbows. These injuries can range from superficial to deep and may even penetrate through deep muscle layers to bone. Without proper attention to risk factors, preventive measures, and early vigorous care and treatment, superficial areas of pressure injury to the skin can evolve into deep soft tissue necrosis and ulceration, from which life-threatening complications may ensue.

In 400 B.C.E., Hippocrates was the first physician to document a pressure injury, but it is assumed they have existed for all of human history. The problem is commonly associated with the frail elderly, those with neurologic injury or disease, and with prolonged hospitalization and nursing home care. In fact, anyone with limited mobility, confined to bed or chair, and unable to shift position with relative frequency is at risk.

2. EPIDEMIOLOGY

Pressure injuries are among the most common conditions encountered in patients who suffer prolonged hospitalization or require long-term institutional care. The prevalence varies widely by clinical setting, age, and geographical region. Between the years 2000 to 2010, the reported prevalence of pressure injuries in the United States ranged from 0.4% to 38% in acute care settings, 2.2% to 23.9% in long-term care facilities, and 0.1% to 17% in the course of home care [3,4,5]. In general, the rate of newly acquired pressure injury in patients hospitalized for acute illness is estimated to be 5.85%, and approximately 14% of intensive care unit (ICU) patients develop pressure injuries [2]. The annual rate of pressure injuries in persons with neurologic impairment, such as spinal cord injury, stroke, or dementia, is estimated to be 5% to 8%, and the lifetime risk is 25% to 85%. Pressure injuries are listed as a primary cause of death in 7% to 8% of patients with spinal cord injury, the population at greatest risk for pressure injury formation [6]. Unfortunately, in spite of modern advances in clinical care, the recurrence rate in patients with healed pressure injuries remains as high as 74% [6].

A large-scale nation-wide epidemiologic study of the incidence and clinical outcomes of hospital-acquired pressure injuries was conducted utilizing the Medicare Patient Safety Monitoring System (MPSMS) database [7]. The MPSMS is designed to monitor adverse events within the hospitalized Medicare population. The MPSMS pressure injury study analyzed 51,842 inpatient discharges across 50 states between 2006 and 2007. The prevalence rate of pressure injury on admission was 5.8%, and the incidence rate for hospital-acquired pressure injury was determined to be 4.5%. Of 2,999 patients who entered the hospital with a pressure injury, 16.7% developed at least one new injury at a different location during the inpatient stay. The majority of hospital-acquired pressure injuries were located on the coccyx or sacrum (41%), the hip and buttock region (23%), and the heels (23%). Underlying chronic disease, corticosteroid use, and obesity were identified as significant risk factors. In contrast to patients without pressure injuries, the development of hospital-acquired pressure injuries was significantly associated with longer length of stay (11.6 days vs. 4.9 days), higher in-hospital mortality (11.2% vs. 3.3%), and higher mortality within 30 days of discharge (15.3% vs. 4.4%) [7].

The incidence of pressure injuries acquired in the outpatient setting is derived primarily from clinical studies and surveys conducted by home health agencies. In one cohort study of 1,711 non-hospitalized patients older than 60 years of age who did not have a pressure injury at initiation of home care, 108 (6.3%) subsequently developed a stage 1 to 4 pressure injury during the period of active home care [8].

According to data compiled by the Agency for Healthcare Research and Quality, an estimated 2.5 million patients develop pressure injuries each year, and approximately 60,000 die as a direct result of this condition. The individual cost of care ranges from $20,000 to $150,000 per case; the total aggregate annual health care cost is estimated to be between $9.1 billion and $11.5 billion [9].

3. PATHOGENESIS

In susceptible individuals, the combination of immobility and extended periods of pressure or friction over bony prominences leads to reduction in capillary blood flow, tissue hypoxia, and ischemic tissue injury. This in turn evokes an inflammatory response that further impairs perfusion and augments soft tissue and skin injury. Current understanding favors a "bottom-up" model of tissue damage beginning deep in the muscle layer [10]. Muscle is more sensitive to pressure injury than skin because it is the more metabolically active layer and thus more susceptible to ischemic injury.

The age and health of overlying skin determine the ease with which ulceration of the superficial layers occurs. In the elderly, skin and subcutaneous tissue gradually lose regenerative, protective, and sensory functions. Chronic conditions or intercurrent illness such as diabetes, arthritis, incontinence, neurologic impairment, cigarette use, and hypotension are all associated with increased susceptibility and prevalence of pressure injuries [6]. As noted, pressure injuries develop most commonly over the sacrum and coccyx, hips and buttocks, and heels [7].

4. RISK FACTORS

The development of pressure-induced skin injury and subsequent ulceration usually arises in the setting of failing health and loss of independent mobility. In a community-based study of 12,650 patients older than 60 years of age enrolled in a primary care panel, 366 (2.9%) subsequently developed a pressure injury during the 40-month surveillance period [11]. The two most prominent risk factors were prior history of pressure injury and placement in a long-term care facility, followed by comorbid conditions such as diabetes, falls, cataracts, renal insufficiency, and cardiovascular disease. In a national study of 1,524 adults residing in 95 long-term care facilities, 443 (29%) developed a new pressure injury during the 12-week observational period; factors associated with increased risk included higher initial severity of illness, history of previous pressure injury, weight loss, feeding difficulty, use of catheters, and use of positioning devices [12].

For a given patient, immobility that leads to unrelieved pressure to the skin over a boney prominence is the most important factor in the development of pressure injuries [5,10]. Individual risk factors for pressure injuries may be categorized as extrinsic or intrinsic. Extrinsic factors are external conditions in the immediate environment that place a vulnerable individual at risk (e.g., moisture, compression from an applied device). Intrinsic factors are conditions and comorbidities peculiar to the individual that confer risk (e.g., advanced age, poor nutrition, smoking history).

EXTRINSIC FACTORS

Pressure and Shear

Pressure that results in injury and subsequent skin breakdown is defined as compression of soft tissues between two rigid surfaces. For example, skin, muscle, subcutaneous fat, and vasculature may be compressed between an underlying boney prominence and a rigid external surface, such as a bed or chair. All the tissues between the two points of pressure are affected, but the tissue closest to the bony prominence suffers the greatest damage. It is important to note that low-intensity pressure over a long period of time can create tissue damage, just as high-intensity pressure over a short period of time can result in damage [10].

The capillary level is the end point of circulation. From the capillaries, oxygen and nutrients diffuse into the tissues, and carbon dioxide and waste products are removed. A collapsed capillary bed is nonfunctioning and useless to the tissues. The minimal amount of pressure required to collapse a capillary is referred to as the capillary closing pressure [13]. Studies have shown that an average of 32 mm Hg will collapse the arterial side of the capillary circulation, and 18 mm Hg of pressure will collapse the venous end. However, these values cannot be accepted as universal; capillary pressures vary among persons, sites, and times [10]. Furthermore, the studies that elicited these values were done on healthy adult males, not debilitated or elderly patients. Other studies have shown that the functional capillary pressure in the peripheral tissues is around 17 mm Hg [14]. Extended pressure resulting in capillary collapse will cause tissue damage.

Shear is the result of gravity pushing down on the body and resistance (friction) between the patient and a surface, such as the bed or the chair, holding the skin in place [10]. For example, when the head of the bed is raised (e.g., high Fowler's position), gravity facilitates forward slide, pulling the body down toward the foot of the bed. The skin on the patient's lower back and gluteal area resists the motion and is held in place by the bed's surface while the bones and tissues beneath the area begin to slide. This causes puckering of the skin, stretching and angulation of small vessels, impedance of blood flow, and traction on subcutaneous tissue and muscle. Left unchecked, the net effect may result in ischemic injury to tissues at the fascia layer. When the head of the bed is elevated more than 30 degrees, shear force occurs over the sacrum and coccyx. Shear injury is not usually visible at the skin level, but shear is responsible for much of the damage associated with initiation of pressure injuries [15]. The areas of the body most vulnerable to shearing forces are shoulder blades, elbows, sacrum, ischial tuberosities, and heels. Signs of shear injury include irregular deep lesions, undermining, and tunneling.

Friction

As noted, friction occurs when one surface moves across another surface, such as when a patient's skin slides across a bed sheet. This can result in the "sanding away" of the epidermal layer and upper part of the dermis, causing abrasions [10]. Friction injuries often present as erythema and tenderness followed by skin loss and usually appear under restraints, braces, and on the elbows, or with repetitive rubbing or repetitive cleansing. Patients with uncontrollable movements or spasticity are also at high risk for friction injury, often referred to as "sheet burn." Friction injury occurs more frequently when the skin is fragile or macerated, and tissues subjected to friction are more susceptible to pressure injury damage [15].

Moisture

Moisture weakens the resilience of the epidermis to external forces. Maceration causes softening of the connective tissue, and a macerated epidermis erodes more easily, as overhydrated skin has decreased tensile strength. Skin can appear "water-logged," with areas of denuded skin and fissure formation. Shear and friction damage is increased when there is a moderate amount of moisture present, but it has been reported that shear and friction decrease in the presence of high levels of moisture. The role moisture plays in pressure injury development is an area of ongoing research [16,17,18].

Major sources of moisture are incontinence, wound drainage, tube leakage, and sweating. Urinary and fecal incontinence expose the skin to excessive amounts of moisture and chemical irritation. There is a higher risk for skin breakdown and infection with fecal incontinence than urinary incontinence because of the pathogens in stool.

INTRINSIC RISK FACTORS

Age

Patients older than 65 years of age experience pressure injuries most frequently [13]. With aging, the skin becomes more fragile; the skin layers adhere less securely to each other and can appear paper thin and almost transparent. There is also evidence of increased dryness, decreased vascularization, and increased vascular fragility.

In elderly individuals, there is a decrease in surface barrier function. The ability of the soft tissue to evenly distribute the mechanical load without compromising blood flow is impaired. There is less subcutaneous tissue to cushion boney prominences. This, in addition to decreased sensory perception, makes elderly skin more vulnerable to pressure, shear, and friction [10]. Research has shown that, in the geriatric population, blood flow in the area of the ischial tuberosity while sitting on an unpadded surface is lower than in younger adults [15].

Although much less common, children can also develop pressure injuries. These injuries usually develop in the occipital region in infants and toddlers and on the sacrum in young children [13].

Immobility

Immobile individuals carry the greatest risk of developing pressure injuries. While sleeping, a healthy individual changes body position approximately once every 10 to 12 minutes. This constant change of position maintains healthy blood circulation, stimulates body organs, and ensures movement of body fluids. However, when an individual is immobile, decreased vascularization and prolonged pressure pair with possible loss of sensation to make the patient extremely vulnerable to pressure injuries. Immobility may be the result of multiple traumas or injuries, spinal cord injuries, stroke, prolonged hospitalization, coma, recovery after surgery, or cognitive deficits [15].

Sensory Loss

Patients with spinal cord injury, neurologic disease, or even advanced diabetes carry an increased risk of developing pressure injuries as a result of loss of protective sensation. Patients with sensory loss may not feel discomfort or the need to be repositioned.

Poor Nutrition and/or Volume Depletion

Poor nutrition, intravascular volume depletion, and peripheral vascular disease can each lead to unhealthy skin and impaired wound healing, which in turn increases the risk of developing pressure injuries. Low body weight is also a concern. Weight less than 119 pounds or a body mass index (BMI) less than 20 indicates increased risk for pressure injury development [19].

Recent weight loss, decreased nutritional intake, inadequate dietary protein, and impaired ability to feed oneself have been identified as risk factors for pressure injury development. An estimated 50% of elderly patients admitted to hospitals have suboptimal protein nutrition [19]. When there is a sustained deficit of protein as an energy source, skin and soft tissues become more vulnerable to injury. In managing patients with pressure injury, or those at risk, the amount of protein in the diet appears to influence prognosis for recovery and prevention. In one study, patients who received a 24% increase in protein intake had significant improvements in pressure injury healing and prevention of new skin injury compared to those who received a 14% increase [20]. The potential role of nutritional supplementation on pressure injury management and prevention is an area of ongoing research [21,22].

Vitamin A, C, and E deficiencies have been associated with pressure injury formation. Vitamin A works in the body to maintain epithelial integrity and is involved in collagen synthesis. It also plays a role in protection against infection. A deficiency of vitamin A can inhibit collagen synthesis, delay re-epithelialization, and decrease cellular cohesion. Vitamin C is also involved in collagen synthesis, immune function, and wound repair. A deficiency of vitamin C can result in capillary fragility. Vitamin E deficiency often decreases the immune function of the skin.

Incontinence

Both urinary incontinence and bowel incontinence can result in excessive moisture on the skin, which decreases the tensile strength and increases skin breakdown. In addition, infection may occur more frequently.

Skin Perfusion Status

Maintenance of tissue health requires an adequate perfusion pressure in the systemic circulation for delivery of oxygen and nutrients to the cells and removal of waste products. Healthy tissue (in persons with normal sensation and movement) is able to tolerate brief, intermittent periods of inadequate perfusion; however, sustained ischemia leads to tissue damage and, with regard to skin, potentiates the development of pressure injuries.

Low arterial blood pressure (hypotension), defined as systolic blood pressure less than 100 mm Hg and diastolic pressure less than 60 mm Hg, has been linked to increased risk for pressure injury development. In response to hypotension, the body redirects blood flow to the vital internal organs at the expense of the peripheral vascular system, which serves the skin. As the perfusion level drops, so does the skin's ability to tolerate external pressure. Capillaries subsequently close at lower levels of interface pressure, and there is an increased risk of damage due to ischemia [13].

Smoking

Nicotine impedes blood flow to the tissues in two ways: it is a potent vasoconstrictor, and it increases the adhesiveness of platelets, resulting in clot formation. Carbon monoxide contained in cigarette smoke prevents oxygen from attaching to the hemoglobin molecule. This significantly reduces the amount of oxygen circulating in the blood stream. The same reaction occurs to some extent in people exposed to secondhand smoke. Studies have shown that cigarette smoking is associated with a higher incidence of pressure injury development, and patients who smoke also have a higher rate of recurrence of pressure injuries [15,23].

Stress

Stress is a primitive response to injury or anticipated injury. Research has shown that during periods of stress, blood vessels in the peripheral tissues constrict. In a study designed to mimic the body's response to stress, healthy subjects were given an infusion of exogenous epinephrine [13]. The increased levels of epinephrine decreased the levels of subcutaneous tissue oxygen by 45%. Other studies have shown that psychologic stress has a negative impact on healing [13].

Obesity

Obesity, or a BMI of 30 or greater, is common (more than 40%) in the United States; morbid ("severe") obesity, defined as a BMI greater than 40, is prevalent but less common [24,25]. Factors that contribute to pressure injury development in obese individuals include decreased blood supply in adipose tissue, difficulty in turning and repositioning, moisture within skin folds, incontinence, skin-to-skin friction, immobility, and poor nutrition. Obese patients are particularly at risk for "unusual" pressure injuries resulting from pressure within skin folds. Obese patients may have large panniculi ("aprons") weighing up to 50 pounds, and the abdominal panniculus must be regularly repositioned in order to prevent pressure injury. This can be accomplished by placing the patient on his or her side and lifting the panniculus away from the underlying skin surface in order to simultaneously relieve pressure and allow air to reach the area.

Comorbidities

People with severe mental health conditions, such as uncontrolled schizophrenia or severe depression, have an increased risk of pressure injuries. This is thought to be related to these patients having little interest in self-care and nutrition. In addition, patients may have comorbid health conditions, such as diabetes or incontinence, that compound the risk of pressure injury development.

Chronic disease often confers multiple risk factors for developing a pressure injury and for prolonging injury healing as well. Conditions that lead to low tissue perfusion, reduced sensation, poor cognition, and altered posture predispose a patient to the development and/or recurrence of injuries. Common medical conditions associated with an increased risk for pressure injury include:

- Diabetes

- End-stage renal disease (ESRD)

- Thyroid disease

- Congestive heart failure

- Peripheral vascular disease

- Collagen vascular disorders and vasculitis

- Immune deficiency states

- Malignancies

- Chronic obstructive pulmonary disease

- Depression and psychosis

- Drugs that delay healing

- Joint contractures

Tubes or catheters can also cause pressure by burrowing into skin folds. Poorly fitting bed, chairs, or wheelchairs may also be a source of friction, shear, and sustained pressure [26].

RISK ASSESSMENT

Evidence Based Practice Recommendation

When conducting a pressure injury risk assessment, the National Pressure Ulcer Advisory Panel, the European Pressure Ulcer Advisory Panel, and the Pan Pacific Pressure Injury Alliance recommend using a structured approach, including a comprehensive skin assessment, supplementing use of a risk assessment tool with assessment of additional risk factors, and interpreting the assessment outcomes using clinical judgment.

https://static1.squarespace.com/static/6479484083027f25a6246fcb/t/6553d3440e18d57a550c4e7e/1699992399539/CPG2019edition-digital-Nov2023version.pdf

Last Accessed: April 28, 2025

Level of Evidence: Good Practice Statement (The recommendation is not supported by a body of evidence but considered to be significant for clinical practice.)

No step is more important in preventing pressure injuries than understanding a patient's risk. Risk assessment is used to identify:

- Populations at risk

- Level of risk

- Type of risk

An informal risk assessment cannot take the place of a formal risk assessment, such as the one conducted using the Braden Scale. Research shows that without formal risk assessment, clinicians tend to intervene consistently only at the highest levels of risk [27]. In some studies, repositioning or turning, an important part of pressure injury prevention, was prescribed for fewer than 50% of the patients at mild-to-moderate risk for pressure injury development [15]. Although several scales/tools have been developed to assess pressure injury risk, the Braden Scale is probably the most widely used.

The Braden Scale

The Braden Scale was developed in 1987 by Barbara Braden and Nancy Bergstrom [27]. Since then, it has undergone testing in several clinical settings, and its validity has been established by expert opinion. It is considered one of the most reliable tools for identifying patients at risk for pressure injury development. The Braden Scale scores factors that contribute to prolonged pressure and factors that result in diminished tissue tolerance for pressure (Table 1) [27]. There are six items scored in the assessment [27]:

- Sensory perception

- Moisture

- Activity

- Mobility

- Nutrition

- Friction and shear

Table 1: THE BRADEN SCALE FOR PREDICTING PRESSURE ULCER RISK

Domain

Scorea

1

2

3

4

Sensory perception: The ability to respond meaningfully to pressure-related discomfort

Completely limited: Unresponsive (does not moan, flinch, or grasp) to painful stimuli due to diminished level of consciousness or sedation OR limited ability to feel pain over most of body surface.

Very limited: Responds only to painful stimuli and cannot communicate discomfort except by moaning or restlessness OR has a sensory impairment that limits the ability to feel pain or discomfort over half of body.

Slightly limited: Responds to verbal commands, but cannot always communicate discomfort or need to be turned OR has some sensory impairment that limits ability to feel pain or discomfort in one or two extremities.

No impairment: Responds to verbal commands and has no sensory deficit that would limit ability to feel or voice pain or discomfort.

Moisture: Degree to which skin is exposed to moisture

Constantly moist: Skin is kept moist almost constantly by perspiration, urine, etc. Dampness is detected every time patient is moved or turned.

Very moist: Skin is often, but not always, moist. Linen must be changed at least once a shift.

Occasionally moist: Skin is occasionally moist, requiring an extra linen change approximately once a day.

Rarely moist: Skin is usually dry. Linen only requires changing at routine intervals.

Activity: Degree of physical activity

Bedfast: Confined to bed

Chairfast: Ability to walk severely limited or non-existent. Cannot bear own weight and/or must be assisted into chair or wheelchair.

Walks occasionally: Walks occasionally during day, but for very short distances, with or without assistance. Spends majority of each shift in bed or chair.

Walks frequently: Walks outside the room at least twice a day and inside the room every two hours during waking hours.

Mobility: Ability to change and control body position

Completely immobile: Does not make even slight changes in body or extremity position without assistance.

Very limited: Makes occasional slight changes in body or extremity position but unable to make frequent or significant changes independently.

Slightly limited: Makes frequent though slight changes in body or extremity position independently.

No limitations: Makes major and frequent changes in position without assistance.

Nutrition: Usual food intake pattern

Very poor: Never eats a complete meal. Rarely eats more than one-third of any food offered. Eats two servings or less of protein per day. Takes fluids poorly. Does not take a liquid dietary supplement. OR is nothing by mouth and/or maintained on clear liquids or intravenous for more than five days.

Probably inadequate: Rarely eats a complete meal and generally eats only about half of any food offered. Protein intake includes only three servings of meat or dairy products per day. Occasionally will take a dietary supplement. OR receives less than optimum amount of liquid diet or tube feeding.

Adequate: Eats more than half of most meals. Eats a total of four servings of protein each day. Occasionally will refuse a meal but will usually take a supplement if offered. OR is on a tube feeding or total parental nutrition regimen that probably meets most of nutritional needs.

Excellent: Eats most of every meal. Never refuses a meal. Usually eats a total of four or more servings of protein. Occasionally eats between meals. Does not require supplementation.

Friction and shear

Problem: Requires moderate-to-maximum assistance in moving.

Potential problem: Moves feebly or requires minimum assistance. During a move, skin probably slides to some extent against sheets, chair restraints, or other devices. Maintains relatively good position in chair or bed most of the time, but occasionally slides down.

No apparent problem: Moves in bed and in chair independently and has sufficient muscle strength to lift up completely during move. Maintains good position in bed or chair at all times.

—

aA lower Braden Scale Score indicates a lower level of functioning and, therefore, a higher level of risk for pressure ulcer development. Risk levels assigned to each score range: ≤9 is very high risk, 10–12 is high risk, 13–14 is moderate risk, and 15–18 is mild risk. Scores of 19 or greater are considered very low or no risk.

Source: Copyright Barbara Braden and Nancy Bergstrom, 1988. Reprinted with permission. All Rights Reserved.

Each item is scored on a scale between 1 and 4, with the exception of friction and shear, which is scored between 1 and 3. The lower the score, the more severe the impairment or problem in that area. Therefore, the lower the overall score, the higher the patient's risk for pressure injury development. Various studies have shown cut-off scores from 15 to 18 as being at risk [10]. Although cut-off scores vary, usually a score of 13–14 is considered moderate risk, 10–12 indicates high risk, and 9 or less is very high risk.

The Braden Scale should be used for assessment on admission to a care facility or after return from a hospital. Research shows that a repeat assessment done 48 hours to 72 hours after admission further defines pressure injury risk. In nursing home populations, the majority of pressure injuries develop during the first two weeks following admission [13]. Most facilities set their own policies regarding reassessment frequency (e.g., quarterly). However, it is important to note that any change in a patient's condition warrants reassessment.

Braden Scale assessment is completed by licensed personnel familiar with the patient and is shared with all staff caring for the patient; good communication is essential to ensure a meaningful assessment [15]. Licensed and unlicensed staff must have a basic knowledge of Braden scores and how it directs patient care. Accuracy of scoring is very important to determining the appropriate intervention.

The Norton Scale

The Norton Scale was developed in the 1960s and also is used to assess the risk for pressure injury in adults (Table 2). The five items in the assessment are scored from 1 to 4, with 1 indicating a low level of functioning and 4 indicating the highest level of functioning. A score of 14 or less generally indicates the patient is at risk [28]. The Norton Scale should be used in conjunction with the clinical assessment [28].

Table 2: THE NORTON SCALE FOR PREDICTING PRESSURE ULCER RISK

Score

Physical condition

Mental condition

Activity

Mobility

Incontinent

4

Good

Alert

Ambulant

Full

Not

3

Fair

Apathetic

Walk-help

Slightly limited

Occasional

2

Poor

Confused

Chair-bound

Very limited

Usually (urine)

1

Very bad

Stupor

Stupor

Immobile

Doubly

Source: [28]

5. STAGING OF PRESSURE INJURIES

The National Pressure Ulcer Advisory Panel (NPUAP), in conjunction with a consensus conference format involving 400 health professionals, redefined the definition of pressure injuries in 2016 and provided an illustrated staging scheme that classifies pressure injuries by the depth and extent of tissue injury into six stages [29,30]. The NPUAP announced that it was changing its preferred terminology from pressure ulcer to pressure injury on the grounds that the latter term better described this injury process in both intact and ulcerated skin [31]. The term "pressure injury" will be used throughout this course as appropriate.

In November 2019, the NPUAP changed its name to the National Pressure Injury Advisory Panel (NPIAP) [31]. The NPIAP defines pressure injury as [30]:

... localized damage to the skin and underlying soft tissue usually over a bony prominence or related to a medical or other device. The injury can present as intact skin or an open ulcer and may be painful. The injury occurs as a result of intense and/or prolonged pressure or pressure in combination with shear. The tolerance of soft tissue for pressure and shear may also be affected by microclimate, nutrition, perfusion, comorbidities, and condition of the soft tissue.

In addition to redefining the definition of pressure injuries, the NPUAP added two additional pressure injury types [30]:

- Medical device-related pressure injury

- Mucosal membrane pressure injury

DEEP TISSUE PRESSURE INJURY

Deep tissue injury is described as a purple or maroon localized area of discolored, intact or non-intact skin or a blood-filled blister caused by damage of underlying soft tissue from pressure and/or shear (Image 1). The area may be preceded by tissue that is painful, firm, mushy, boggy, warmer, or cooler as compared to adjacent tissue.

Image 1: ILLUSTRATIONS OF DEEP TISSUE PRESSURE INJURY

Source: Used with permission of the National Pressure Ulcer Advisory Panel, 2016.

Deep tissue injury may be difficult to detect in individuals with dark skin tones. The injury may also present as a thin blister over a dark wound bed. The wound may further evolve and become covered by thin eschar. Evolution may be rapid, exposing additional layers of tissue even with optimal treatment. If necrotic tissue, subcutaneous tissue, granulation tissue, fascia, muscle, or other underlying structures are visible, this indicates a full thickness pressure injury.

STAGE 1: NONBLANCHABLE ERYTHEMA

Stage 1 is characterized by intact skin with nonblanchable redness of a localized area, usually over a bony prominence (Image 2). Darkly pigmented skin may not have visible blanching, making detection difficult, but its color may differ from the surrounding area. The area may be painful, firm, soft, warmer, or cooler as compared to adjacent tissue.

Image 2: ILLUSTRATION OF A STAGE 1 PRESSURE INJURY

Source: Used with permission of the National Pressure Ulcer Advisory Panel, 2016.

Stage 1 lesions may indicate "at risk" persons (a heralding sign of risk). No tissue destruction occurs, and it is a reversible condition.

STAGE 2: PARTIAL-THICKNESS SKIN LOSS WITH EXPOSED DERMIS

Stage 2 injuries present with partial-thickness skin loss into the dermis, presenting as a shallow, open injury with a red-pink wound bed, without slough (Image 3). This stage of injury may also present as an intact or open/ruptured, serum-filled or serosanguineous-filled blister.

Image 3: ILLUSTRATION OF A STAGE 2 PRESSURE INJURY

Source: Used with permission of the National Pressure Ulcer Advisory Panel, 2016.

Stage 2 injuries present as shiny or dry, shallow injuries without slough or bruising; bruising indicates suspected deep tissue injury. This stage should not be used to describe skin tears, tape burns, perineal dermatitis, maceration, or excoriation. Patients with stage 2 injuries now have an entry point for pathogens; therefore, cleaning the wound and providing some type of dressing is of utmost importance.

STAGE 3: FULL-THICKNESS SKIN LOSS

In the stage 3 injury, there is penetration into subcutaneous tissue but not through fascia; fat tissue may be visible, but bone, tendon, and muscle are neither exposed nor directly palpable (Image 4). Slough and/or eschar may be present but does not obscure the depth of tissue loss. These wounds may include undermining and tunneling. The depth of a stage 3 injury varies by anatomical location. The bridge of the nose, ear, occiput, and malleolus do not have subcutaneous tissue, and stage 3 injuries in these areas can be shallow. In contrast, areas of significant adiposity can develop extremely deep stage 3 injuries. Because infection is a very strong risk at this stage, irrigation of the wound is done each time the dressing is changed. Wound debridement may be necessary for healing.

Image 4: ILLUSTRATION OF A STAGE 3 PRESSURE INJURY

Source: Used with permission of the National Pressure Ulcer Advisory Panel, 2016.

STAGE 4: FULL-THICKNESS SKIN AND TISSUE LOSS WITH EXPOSED BONE, TENDON, OR MUSCLE

In stage 4 pressure injuries, slough or eschar may be present on some parts of the wound bed (Image 5). Undermining and tunneling are often present. The depth of a stage 4 injury varies by anatomical location. As with stage 3 injuries, wounds on the bridge of the nose, ear, occiput, and malleolus may be shallow. Stage 4 injuries can extend into muscle and/or supporting structures (e.g., fascia, tendon, or joint capsule), making osteomyelitis possible. Exposed bone/tendon is visible or directly palpable. At this stage, the pressure injury is often infected, with deep ulceration and tissue loss; therefore, the patient may need repair with myocutaneous flaps to close the defect. If slough or eschar obscures the extent of tissue loss, this is an unstageable pressure injury.

Image 5: ILLUSTRATION OF A STAGE 4 PRESSURE INJURY

Source: Used with permission of the National Pressure Ulcer Advisory Panel, 2016.

UNSTAGEABLE

Unstageable pressure injuries are defined as full-thickness skin and tissue loss in which the base of the injury is covered by slough (yellow, tan, gray, green, or brown) and/or eschar (tan, brown, or black), obscuring the wound bed (Image 6). Until enough slough and/or eschar is removed to expose the base of the wound, the true depth, and therefore stage, cannot be determined.

Image 6: ILLUSTRATION OF AN UNSTAGEABLE PRESSURE INJURY

Source: Used with permission of the National Pressure Ulcer Advisory Panel, 2016.

MEDICAL DEVICE-RELATED PRESSURE INJURY

Medical device-related pressure injuries describe injuries or ulcers that result from the use of devices designed and applied for diagnostic or therapeutic purposes. The injury is generally in the shape or pattern of the device and should be staged using the staging system.

MUCOSAL MEMBRANE PRESSURE INJURY

Mucosal membrane pressure injury is found on the mucous membranes and is typically attributed to use of a medical device. Due to the nature of this type of tissue, these injuries cannot be staged.

6. PHASES OF WOUND HEALING: AN OVERVIEW

There are three phases of wound healing: inflammation, proliferation, and maturation. Wounds heal by two possible mechanisms: regeneration or scar tissue formation. The depth of the wound (i.e., the number of tissue layers involved) will determine the mechanism by which the wound will heal. Partial-thickness wounds and stage 1 and 2 injuries usually heal by tissue regeneration. Stage 3 and 4 injuries and full-thickness wounds heal by scar formation and contraction. In one study, 20% shrinkage in wound size in a period of two weeks was a reliable predictive indicator of healing [32].

Pressure injuries are notoriously difficult to heal. Only 75% of stage 2 injuries and 17% of stage 3 or 4 injuries heal in eight weeks [33]. Up to 23% of stage 2 pressure injuries and 48% of stage 4 injuries remain unhealed after one year [34].

INFLAMMATORY PHASE

The standard signs and symptoms of inflammation are erythema, swelling, increased temperature, and pain. In normal healing, these signs are only minimally noticeable, and during the inflammatory phase of wound healing, they are considered a normal response [35]. In general, this phase occurs in the first 0 to 3 days after injury development but may last longer if healing is impaired.

The first part of inflammation is hemostasis, which begins soon after the wound develops. During the inflammatory phase, vasoconstriction results in platelets adhering to damaged endothelium, causing clumping of the thrombocytes and stopping bleeding. Polymorphonuclear leukocytes engorge the wound and clear the debris. Macrophages continue the cleansing process and stimulate growth factors, including cytokines, interleukin-1 (IL-1), tumor growth factor, tumor necrosis factor, and platelet-derived growth factor.

PROLIFERATION PHASE

The proliferation phase lasts approximately 3 to 12 days. During this phase, angiogenesis results in a new network of blood vessels in the wound. Production of epithelial cells starts. Collagen synthesis and improved vascularity ensure healthy granulation tissue. Wounds in the proliferation phase are usually pink in color and do not bleed easily.

In full-thickness wounds, the process of re-epithelialization occurs only from the wound edges [10]. Margin basal cells attached to the dermis eventually loosen and start migrating across the wound. The horizontal movement comes to a halt when the cells meet, which is referred to as contact inhibition. Wound contraction is the final part of the proliferative phase. Fibers in the wound contract to bring the wound edges closer together.

MATURATION PHASE

Maturation and remodeling of the wound involves rearranging collagen fibers from type III to type I, and increasing the tensile strength of scar tissue. The number of blood vessels in the wound regresses and cellular activity is reduced. Scar tissue regains about 80% of normal tissue strength within three months, but it never achieves the full strength of the original tissue [10]. Therefore, the healed site of an old wound is vulnerable to further breakdown.

7. DIAGNOSIS

Diagnosis of pressure injuries involves careful assessment of symptoms, medical history, physical examination, and certain medical tests. Usually, individuals will have a history of decreased mobility. Patients may complain about the appearance of a wound that may or may not be painful. In cases of infected wounds, fever may be present.

Careful examination in patients with pressure injuries reveals skin ulceration surrounded by erythema. The size and depth of the injury should be determined and documented at this point. Bleeding, malodor, and fluids or debris in the wound indicate severe infection.

Blood tests may be ordered to assess nutritional status and overall health status. No laboratory study of nutritional status can absolutely predict pressure injuries; however, monitoring a patient's protein status is of value. There are many serologic markers used to assess a patient's nutritional status; prealbumin level is one of the most sensitive. Prealbumin is a protein with a much shorter half-life than the other serologic markers; therefore, its level gives a more accurate picture of current conditions.

If infection is suspected, culture of the pressure injury is important to determine the pathogen. In some cases, a wound biopsy is performed to rule out vasculitis and skin cancers. An x-ray is done if bone infection is suspected and to rule out osteomyelitis. A bone scan is carried out when x-ray findings are equivocal.

8. PREVENTION AND TREATMENT

The principles and management strategies discussed in this section are applicable to prevention in high-risk patients, control of early stage injury, and treatment of established pressure injuries. The NPIAP, in conjunction with two international agencies, published evidence-based guidelines for risk assessment, prevention, and management of pressure injuries in 2014 and released an update to this guideline in 2019 [29,36]. The fourth edition, released in 2025, was developed as a living document that will be continuously updated. This guideline is available online at https://internationalguideline.com/the-international-guideline.

The primary objectives for prevention and arrest of progression are:

- Preventive skin care

- Pressure reduction, minimizing or eliminating friction and shear forces

- Adequate nutrition

- Exudate management

- Prevention of wound infection

- Managing moist wound environments

- Decreasing the frequency of dressing changes

The general treatment of established injuries involves:

- Pressure-relieving strategies

- Optimal nutritional support, including protein and micronutrient supplementation

- Intense injury care

- Pain management

- Prevention/eradication of infection

- Adjunctive treatment or surgery

The actual treatment plan is individualized based on the injury stage, patient health, and short- and long-term goals.

SKIN CARE AND PRESSURE-RELIEVING STRATEGIES

The principles of preventive skin care include [29,36]:

- Avoid positioning the patient over an area of erythema.

- Keep the skin clean and dry.

- Do not massage or vigorously rub skin that is at risk for pressure injury.

- Develop an individualized continence plan.

- Protect the skin from exposure to excessive moisture and friction.

For the at-risk patient, a strategy to avoid or relieve pressure is essential for the prevention and treatment of pressure injuries [37]. This is best accomplished by a three-pronged approach of:

- Careful patient positioning

- Use of protective devices

- Judicious use of support surfaces

Positioning

Bedbound Patients

Bedbound patients should be properly positioned and frequently repositioned, at least every two hours. When in lateral decubitus position, patients' heads should be maintained at an angle of 30 degrees in order to mitigate pressure in the trochanteric region. Pillows or foam wedges should be placed between the legs, at the knees and ankles, to prevent pressure at these sites when patients have little or no ability to move legs and feet.

To the extent the patient is able, regular physical activity should be encouraged and assisted. Even a few steps done frequently will help maintain current activity level, mobility, and range of motion. Lifting devices, such as an overhead trapeze or bed linen, are helpful when moving patients. It is important to avoid or minimize dragging the patient during transfers and position changes. Patients require protection from environmental factors leading to skin drying, such as low humidity (less than 40%) and exposure to cold [15]. Posting an individualized turning schedule in patient rooms can be helpful to healthcare professionals and families.

The heels are especially vulnerable, and pressure injuries at this location are very painful, difficult to heal, and prone to infection with easy access to adjacent bone. Heel pressure injuries can develop infection, and advanced cases may lead to amputation of the foot. To protect the heels, place a pillow under the calf to float the heels off the bed. There are also devices available that eliminate pressure on heels and prevent foot drop (e.g., suspension boots). Current guidelines state that heels are to be kept off the bed [10,36].

Chairbound Patients

Evidence Based Practice Recommendation

The National Pressure Ulcer Advisory Panel, the European Pressure Ulcer Advisory Panel, and the Pan Pacific Pressure Injury Alliance recommend using a seating support surface with pressure redistribution properties for individuals at risk of pressure injuries when in a seated position.

https://internationalguideline.com/the-international-guideline

Last Accessed: April 28, 2025

Strength of Recommendation/Level of Evidence: Strong recommendation based on moderate-quality evidence (The recommendation is supported by level 1,2, and 3 studies of moderate or low quality providing direct evidence.)

Chairbound patients require special attention to positioning as well. The risk of pressure injuries from prolonged sitting is greater than that from reclining in bed, as sitting puts the patient's weight on the relatively small surface areas of the buttocks, thighs, and soles of the feet. Much of this weight is centered over the small area of tissue covering the ischial tuberosities. It is important for patients who sit in a chair to regularly change position. A dependent patient must have his/her position changed in a chair at least every hour. Patients who are able to move themselves should shift their weight (even slightly) every 15 minutes.

A patient should be properly positioned in a chair for postural alignment, distribution of weight, balance, and stability. Patients should sit with their back erect and against the back of the chair, thighs parallel to the floor, knees comfortably parted, and arms horizontal and supported by the arms of the chair. This position distributes weight evenly over the available body surface area. Slouching can cause shearing and friction and places undue pressure on the sacrum and coccyx. Feet should be kept flat on the floor to protect the heels from pressure and distribute the weight of the legs over the largest available surface area. The thighs and arms should remain parallel to ensure that weight is evenly distributed instead of being focused on the ischial tuberosities and elbows. Parting the knees will prevent the knees and ankles from rubbing together. If a patient uses a footstool, it is vital that his or her knees are not above hip level, because this shifts the weight from the back of the thighs to the ischial tuberosities. This same problem can occur if the chair is too short for the patient.

Protective Devices

Protective padding and pillows should be utilized for pressure reduction whenever possible. Heel protectors, foam, and pillows can be helpful for patients in supine positions. Cutting a window through the cast can greatly reduce pressure at certain sites in patients immobilized by fractures. Patients should be provided soft seat cushions when sitting in a chair. Sheepskin and donut-shaped devices should not be used for treating pressure injuries; ring cushions can reduce blood flow to an even wider area of tissue.

Support Surfaces

Support surfaces are indicated when patients are not able to reposition themselves or when periodic repositioning care is not available. In a comprehensive literature review researchers founds good evidence that specially designed support surfaces effectively prevent pressure injuries [38].

An ideal support surface will manage microclimate, tissue loads, and other curative functions. Seat cushions, overlays, mattresses, and integrated bed systems are commonly used to prevent pressure injuries. The type of device or surface selected is based on level of risk as well as degree of assistance necessary for repositioning or mobility (Table 3).

Table 3: THERAPEUTIC SUPPORT SURFACE SELECTION TOOL

Validated Risk Assessment Category or Pressure Ulcer Description

At risk

OR

Redness present that fades quickly when pressure is removed

Moderate risk

OR

One pressure ulcer (excluding the heels) where the patient can be positioned off the ulcer

High risk

OR

One pressure ulcer (excluding the heels) and redness over another area

Very high risk

OR

Multiple pressure ulcers (excluding the heels) or the patient cannot be positioned off of an ulcerated area

Ability to change position in bed (e.g., bed mobility)

Total assist to change position in bed.

Reactive support surface (non-powered) (e.g., air/gel/foam overlay)

Reactive support surface (non-powered) (e.g., air/gel/foam overlay)

Active support surface:

Multi-zoned surface (e.g., alternating pressure mattress, rotational surface), or powered reactive support surface (e.g., low air loss)

Active support surface:

Multi-zoned surface (e.g., alternating pressure mattress, rotational surface) or powered reactive support surface (e.g., low air loss)

Moderate assistance with bed mobility required.

Reactive support surface (non-powered) (e.g., air/gel/foam overlay or high-density foam mattress)

Reactive support surface (non-powered) (e.g., foam overlay with air section inset in the area of the wound)

Reactive support surface (non-powered) (e.g., foam overlay with air section inset in the area of the wound)

Active support surface:

Multi-zoned surface (e.g., alternating pressure mattress, rotational surface) or powered reactive support surface (e.g., low air loss)

Patient independent with or without a device with bed positioning. (Light assist may be required.)

Reactive support surface (non-powered) (e.g., high-density foam mattress)

Reactive support surface (non-powered) (e.g., foam overlay with air section insert)

Reactive support surface (non-powered) (e.g., air/gel/foam overlay)

Reactive support surface (powered if the control is within the patient's reach)

Instructions for use of this clinical tool: Determine the patient's level of risk and level of mobility in bed and follow the column-and-row intersection to determine the appropriate reactive or active support system.

Source: Reprinted from Norton L, Coutts P, Sibbald RG. A model for support surface selection as a part of pressure ulcer prevention and management: a preliminary study. WCET Journal. 2008;28(3):25-29.

Types of Support Surfaces

Overlays are filled with water, air, gel, or foam (or a combination of these products) and are applied to the top of a mattress. Foam overlays should be a minimum of 3 inches thick. If a patient's weight completely compresses an overlay, it is not effective.

Pressure relief mattresses are made of a combination of foam, water, or gel or layers of varying foam densities. They are usually indicated in place of standard mattresses used in hospitals and at home. Studies have shown that people at high risk of developing pressure injuries should use higher-specification foam mattresses instead of standard hospital foam mattresses [39].

Air-fluidized beds are embedded with tiny, silicone-coated beads suspended by pressurized, temperature-controlled air. They are recommended for immobile patients who carry higher risk for posterior pressure injuries. These beds reduce pressure against the patient's skin surface, resulting in increased capillary blood flow to the skin. This greatly increases granulation and healing of injuries. These beds are beneficial in patients with multiple large injuries; however, they are unsuitable for patients who are ambulatory, have pulmonary disease, or have spinal instability. They are usually used as an adjunct to comprehensive care.

Low-air-loss beds are made of numerous interconnected air-filled pillows designed to lose air through the cushions at a controlled rate. These beds distribute the patient's weight evenly, which in turn reduces friction, provides pressure relief, and increases capillary blood flow. They are indicated in patients with stage 3 or 4 injuries or stage 1 injuries with hyperemia.

Combination air-fluidized/low-air-loss beds combine the benefits of both types of beds. The low-air-loss component is placed on the upper half of the bed, while the air-fluidized component is placed on the lower half of the bed.

The most important consideration when choosing a support surface is ease of use. Patient goals and overall care plan are also considerations when selecting a support surface. Pressure injury risk, bed mobility, transfer, posture and positioning, financial resources, and advantages and disadvantages of the support surfaces should all be taken into account prior to coming to a decision.

NUTRITIONAL SUPPORT

The role of nutrition, including evidence-based strategies for management, has recently been reviewed in connection with the NPIAP 2019 practice guideline for prevention and treatment of pressure injury [36]. Consultation with a nutritionist should be considered for every patient with, or at high risk for, a pressure injury.

Malnutrition has been shown to increase the risk of developing a pressure injury and to delay wound healing [40,41]. For this reason, nutritional assessment, including food intake and recent weight loss, is an essential component of effective prevention and care. The goal of the assessment is to identify the patient's current nutritional status and any changes that have occurred in recent months or weeks, including the patient's overall level of functioning. The patient's state of hydration should also be assessed, as blood volume depletion impairs circulation and the delivery of oxygen and nutrients to healing wounds [35,36].

A number of clinical and laboratory parameters have been used to screen for poor nutritional status and increased risk of pressure injuries, particularly in elderly patients admitted to a hospital and nursing home. These include serum albumin, prealbumin, and weight less than 80% of ideal. Other signs of malnutrition thought to be useful are:

- Loss of subcutaneous tissue

- Muscle wasting

- Generalized edema

- Dry, pluckable hair

- Dry, flaky, itchy skin

- Cracks in the mucous membranes

- Delayed wound healing/failure to granulate

The provision of an optimal diet (e.g., 30–35 kcalories/kg body weight for adults who are at risk for malnutrition), including the addition of supplemental protein, amino acids, zinc, and vitamins, has been shown to reduce risk of pressure-induced skin injury and to speed wound healing. The recommended daily protein intake for healthy adults (0.8 g/kg of body weight) may not be adequate in the frail elderly or under conditions of chronic inflammation and loss of lean body mass. For dietetic management of adults at high risk of pressure injury or delayed wound healing, the recommended intake is 1.25–1.5 g protein/kg body weight daily [29,42].

Protein is synthesized from amino acids, and specific amino acids (e.g., arginine and glutamine) become essential during periods of protracted metabolic stress (e.g., recovery from trauma, sepsis, pressure injuries). A deficiency in micronutrients, specifically vitamin A, vitamin C, zinc, and copper, is thought to impede injury healing. Zinc is important for the synthesis of protein and nucleic acid, for epithelial cell proliferation, and, along with copper, is essential for healthy collagen formation [42].

The benefit of a high-protein, arginine- and micronutrient-rich diet was evaluated in a prospective study among institutionalized, older adults with pressure injuries. Patients were randomized to receive either a standard diet with 16% energy from protein (control group) or a standard diet plus a 500-calorie supplement with 34 g protein, 6 g arginine, 500 mg vitamin C, and 18 mg zinc (treatment group). A standard protocol to measure rate of wound healing and reduction in injury size was used to monitor the progress of patients in each group. A significant difference in injury area (favoring the treatment group) was evident at week 8; an improved rate of healing, as evidenced by a difference in wound healing score (favoring treatment), reached significance at week 12 [43].

Interventions to Promote Nutrition

For patients with inadequate nutrition, strategies should be employed to increase oral intake. The preferred route of nutritional support is oral; whenever possible, the gastrointestinal tract should be used for feeding. It is the easiest and most comfortable way to provide supplementation, and it is also the least expensive and most convenient way. Patients should have diets prescribed with protein and caloric content sufficient to meet metabolic needs, with consideration of the patient's preferences and special needs (e.g., mechanical soft diets) [15]. Daily multivitamin supplementation may be implemented. Mouth care should be performed prior to eating. Additionally, toileting and hand washing should be offered prior to meals.

It is important to provide an environment conducive to eating. Position the patient properly; an upright position is preferred. Make sure the food is at the right temperature for the patient. Do not rush eating, particularly if the patient is elderly and requires more time to be oriented. Many patients benefit from the inclusion of snacks high in calories and protein in the diet (e.g., a peanut butter sandwich with milk). Consider adding powdered milk to yogurt and puddings to maximize caloric intake and protein levels. Commercial nutritional supplements, such as breakfast shakes, are also a common adjunct.

It is vital to maintain patient control as far as medically feasible. Some patients may not like ice in their water; others may prefer soup lukewarm. Patient preferences should be accommodated as much as possible.

Remind the patient to chew food thoroughly. If necessary, liquids may be offered between bites; some patients require this to help swallow their food.

Assuring adequate fluids and the maintenance of intravascular volume homeostasis are equally important. Vigilance is required to detect early signs of volume depletion or dehydration (e.g., change in weight, loss of skin turgor, falling urine output, hypernatremia); patients identified to be at risk should be listed on assignment/report sheets as a reminder to monitor these patients closely. Fluids should be scheduled between meals at least three times a day. Patient preferences for fluids (e.g., straws, temperature, ice, etc.) should be observed and noted. Refill water pitchers frequently and keep them within reach of patients, especially those with restricted mobility. Patients should be offered something to drink at every interaction. Ambulatory patients should be provided with a water bottle. As with nutrition and positioning, it is necessary to educate patients/families about the importance of regular fluid intake. When, despite these measures, patients are unable to consume adequate levels of water or nutrients, tube feeding or parenteral feeding should be considered. Patient and family preferences and the overall goals of treatment guide these decisions [19].

WOUND CLEANSING

Careful, regular wound cleansing and meticulous skin care is essential. Cleaning and gentle debridement are necessary to remove necrotic debris, contaminants, bacteria, and remnants of previous dressings from the wound surface and adjacent area, usually with the help of fluids (irrigation). This process helps accelerate the healing process and decreases the likelihood of infection [31,44]. One must remember that cleansing is "clearing" a wound, not sterilizing it. Minimal mechanical force is used while cleansing the wound in order to minimize trauma to the wound bed and surrounding healthy tissue. Irrigation at a pressure in the 4 to 5 pounds per square inch range should be used.

The injury and surrounding skin should be cleansed at least daily. If the dressing is being changed more than once daily, wound cleansing should be done during each dressing change.

Generally, normal saline is used for cleansing pressure injuries. In injuries with necrotic tissue, debris, or confirmed or suspected infection, antimicrobials or surfactants should be considered. For infected wounds, diluted povidone-iodine may be used as the irrigation fluid. However, it should not be used during the granulation phase of healing. Acetic acid (0.5%) is highly effective in fungating lesions, especially against Pseudomonas aeruginosa. There are various cleansing agents available in the market, but normal saline is usually the best option [31,45]. Normal saline also should be used as a rinse after other solutions are used to irrigate the wound and minimize fluid shifts within newly forming tissue. Normal saline solution can reduce the drying effects that some irrigants may have on tissue [31].

DEBRIDEMENT

Debridement has been shown to accelerate the healing process in some patients with advanced injuries. In addition to helping move the wound through the stages of healing, debridement is often necessary to visualize the wound bed and to stage the wound; a wound covered with necrotic tissue cannot be staged [15,31]. An exception is eschar on the heels, which acts as a natural biologic cover and should not be removed unless infection is present.

The method of debridement used depends on the amount of necrotic tissue present, the location of the wound, and the patient's overall condition [35]. Patients with stage 3 or 4 pressure injuries who have undermining and/or tunneling or extensive necrotic tissue should have a surgical evaluation for possible surgical debridement of the wound, if this is consistent with their condition and goals of care [29]. Infected wounds may require systemic antibiotic treatment and immediate surgical debridement [15]. Maintenance debridement should be continued until there is a covering of granulation tissue in the wound bed and the wound is free of necrotic tissue [29]. Debridement is contraindicated if there is inadequate blood supply to support wound healing.

Autolytic Debridement

Autolytic debridement uses the body's own enzymes and moisture to heal the injury. To be successful, there must be sufficient white blood cells available to the wound and a moist environment [13]. A layer of wound exudate should be kept in contact with the surface of the wound, usually using a moisture-retaining dressing [10,15,35]. This allows fluid to accumulate in the wound, rehydrating necrotic tissue and making it possible for enzymes in the wound to digest the dead tissue [35]. For a wound covered with dry eschar, it is appropriate to crosshatch the eschar, as this allows a faster build-up of moisture in the wound [35]. In their clinical practice guidelines for pressure injury treatment, the Agency for Healthcare Research and Quality recommends autolytic and enzymatic debridement as the preferred approach for patients in long-term care or home care and for patients who cannot tolerate other methods of debridement [35,46]. In general, this type of debridement is ideal for patients with stage 3 or 4 injuries with light-to-moderate exudates.

Autolytic debridement is highly selective; healthy tissue is spared and only necrotic tissue is liquefied. It is considered very safe, as it uses the patient's own immune system to promote healing and clean the wound of necrotic tissue. Autolytic debridement is easy to perform, very effective, and can be combined with other approaches. It is almost painless for the patient, making it a very attractive option.

However, there are disadvantages as well. It is comparatively slow in efficacy compared to surgical debridement, with progress usually seen in about one week [35]. Close monitoring of the injury is necessary to detect signs of infection. There is a risk of anaerobic growth when an occlusive hydrocolloid dressing is used, and this approach should not be used in infected injuries.

Mechanical Debridement

Mechanical debridement is a nonselective type of debridement that loosens and removes devitalized tissue and debris as well as viable tissue. This method is usually accomplished by means of mechanical force, such as wet-to-dry dressings, pulsatile lavage, or wound irrigation [31]. Pulse lavage may require special knowledge or training on equipment. Although it is a low-cost procedure, mechanical debridement is time consuming and can be painful.

Mechanical debridement is indicated for both acute and chronic wounds with moderate-to-large amounts of necrotic tissue, regardless of the presence of an active infection [47]. Depending on the modality used, the contraindications to mechanical debridement include the presence of granulation tissue in a higher amount than the devitalized tissue, inability to control pain, patients with poor perfusion, and an intact eschar with no gross clinical evidence of an underlying infection [47]. Mechanical debridement also is not indicated for clean wounds.

Surgical Debridement

Surgical debridement is indicated for wounds with thick exudate and necrotic tissue. Approaches include hydrotherapy, laser, maggot debridement therapy (MDT), ultrasound, whirlpool, or excision (with a scalpel or scissors). Extensive or deep injuries should be debrided in operating rooms, although a moderate amount of necrotic tissue can be debrided at the bedside. Newer approaches, such as laser debridement, limit collateral damage, but these approaches can be prohibitively expensive [48]. Hydrotherapy can result in tissue maceration, and there is a risk of infection. Therefore, it is considered a less attractive option. The use of ultrasound waves to debride wounds also has been explored. With this technique, low-frequency ultrasound creates small bubbles in the wound that implode, causing the necrotic tissue to liquefy [49]. This method is generally less painful and less traumatic than traditional methods, with faster healing rates compared with other types of mechanical debridement [50]. However, further comparative evidence is necessary before it can be recommended as a replacement for established treatment modalities. Sharp surgical debridement is contraindicated in patients with intact eschar and no clinical evidence of an underlying infection [47]. The decision to attempt inpatient surgical debridement should take into account the patient's surgical risk stratification [47].

Maggot Debridement Therapy

Debridement with maggots, an approach popular at the early 20th century, is finding a new place in wound care debridement [15]. MDT is an efficient, simple, cost-effective and reliable biosurgery method that uses mostly larvae of the Lucilia sericata species of the green bottle fly [51]. The larvae stimulate wound healing by activating molecular processes in the wound area through proteolytic enzymes, including collagenase, in their excretions/secretions that break down the necrotic tissue, ingest and digest micro-organisms, and inhibit bacterial growth by releasing ammonia into the would bed, which increases the wound pH [13,47]. Studies have shown that the excretions/secretions have antibacterial, antifungal, anti-inflammatory, and tissue-regenerating effects; the enzymes are still mostly unidentified [51]. Maggots have the ability to access moist tissue throughout the wound bed and clean small areas without harming healthy tissue [52]. MDT involves the application of sterilized larvae to the wound bed every two to three days [15]. The maggots can be applied to the wound directly or in a containment pouch [15]. The most appropriate dressing for wounds treated with maggots is one that keeps the larvae in place, allows for a flow of oxygen, and is suitable for the characteristics of the wound [35].

MDT is indicated for pressure injuries with necrotic tissue with or without infection [52]. Maggots work well in wounds in which moisture and oxygen are readily available and the pH is fairly stable [35]. The therapy is considered mainly for the treatment of wounds for which other forms of treatment are either not appropriate or not successful, and it is contraindicated in patients who have bleeding abnormalities or deep tunneled wounds [10,15,47].

Precautions should be taken to prevent the larvae from coming in contact with healthy skin, as there is a possibility of enzymatic damage [13]. Otherwise, there are no reported side effects from MDT [13]. However, some patients complain of a crawling or tingling feeling [13]. MDT also may cause psychologic distress for many patients, and its use should be discussed thoroughly with the patient and/or family prior to commencing therapy [15]. This therapy should only be used with appropriately informed consent.

Enzymatic Debridement

Enzymatic debridement is a selective method of debridement in which concentrated enzymes (e.g., collagenase, papain, becaplermin, trypsin) attack collagen and liquefy necrotic wound debris without damaging viable tissue. Enzymatic debridement is used either alone or in combination with other techniques to remove necrotic tissue and promote wound healing [53,54]. For instance, collagenase and moisture retentive dressings can work in synergy, thereby enhancing debridement [47].

Usually, stage 3 or 4 injuries are considered candidates for enzymatic debridement. Application of the enzyme should be discontinued when the wound is free of necrotic tissue. If eschar is present, it should be crosshatched prior to introduction of the enzyme to improve efficacy, as enzymes are not active on a dry surface.

Enzymatic debridement is relatively fast acting, with progress evident in 48 to 72 hours. However, complete debridement may be a long process, so other methods (e.g., surgical removal of loosely adherent necrotic tissue) are often used in conjunction.

Enzymatic debridement should not be used for heavily infected wounds or in conjunction with silver-based products or Dakin solution [47].

DRESSINGS

Wound dressings are a cardinal component in the treatment of pressure injuries. There is a variety of available dressings, each with its own benefits and drawbacks (Table 4) [55]. The selection of dressing for an injury is determined by several parameters. These include:

- Condition of the injury and wound bed

- Size and depth

- Necrosis/slough

- Dry/exudating

- Epithelializing

- Presence of tunneling

- Infection

- Over-granulating

- Malodorous

- Malignant

- Pain

- Aim of treatment

- Facilitate healing

- Promote debridement

- Combat infection

- Relieve pain

- Absorb exudates or add moisture

- Prevent or treat scarring

- Combat odor

- Cosmetic/provide concealment

- Condition of surrounding skin

- Fragile

- Macerated

- Anatomical location

- Difficult to dress

- Dressing affects use of normal clothing or shoes

- Etiology

- External compression

- Prospect of healing

- Palliation

- Indication of specific topical therapies (e.g., enzymatic debridement, antibiotics)

- Economics/cost

- Availability (reimbursement issues)

Table 4: OVERVIEW OF DIFFERENT DRESSINGS FOR PRESSURE ULCERS

Dressing Type

Description

Indication

Advantages

Disadvantages

Transparent film

Adhesive, semipermeable, polyurethane membrane that allows water to vaporize and cross the barrier

Management of stage 1 and 2 pressure ulcers with light or no exudates; may be used with hydrogel or hydrocolloid dressings for full-thickness wounds

Retains moisture

Impermeable to bacteria and other contaminants

Facilitates autolytic debridement

Allows for wound observation

Does not require secondary dressing (e.g., tape, wrap)

Not recommended for infected wounds or wounds with drainage

Requires border of intact skin for adhesion

May dislodge in high-friction areas

Not recommended on fragile skin

Hydrogel

Water- or glycerin-based amorphous gels, impregnated gauze, or sheet dressings; amorphous and impregnated gauze fill the dead tissue space and can be used for deep wounds

Management of stage 2, 3, and 4 ulcers; deep wounds; and wounds with necrosis or slough

Soothing, reduces pain

Rehydrates wound bed

Facilitates autolytic debridement

Fills dead tissue space

Easy to apply and remove

Can be used in infected wounds or to pack deep wounds

Not recommended for wounds with heavy exudate

Dehydrates easily if not covered

Difficult to secure (amorphous and impregnated gauze need secondary dressing)

May cause maceration

Alginate

Derived from brown seaweed; composed of soft, nonwoven fibers shaped into ropes or pads

May be used as primary dressing for stages 3 and 4 ulcers, wounds with moderate-to-heavy exudate or tunneling, and infected or noninfected wounds

Absorbs up to 20 times its weight

Forms a gel within the wound

Conforms to the shape of the wound

Facilitates autolytic debridement

Fills in dead tissue space

Easy to apply and remove

Not recommended with light exudate or dry scarring or for superficial wounds

May dehydrate the wound bed

Requires secondary dressing

Foam

Provides a moist environment and thermal insulation; available as pads, sheets, and pillow dressings

May be used as primary dressing (to provide absorption and insulation) or as secondary dressing (for wounds with packing) for stage 2 to 4 ulcers with variable drainage

Nonadherent, although some have adherent borders

Repels contaminants

Easy to apply and remove

Absorbs light-to-heavy exudate

May be used under compression

Recommended for fragile skin

Not effective for wounds with dry eschar

May require a secondary dressing

Hydrocolloid

Occlusive or semiocclusive dressings composed of materials such as gelatin and pectin; available in various forms (e.g., wafers, pastes, powders)

May be used as primary or secondary dressing for stage 2 to 4 ulcers, wounds with slough and necrosis, or wounds with light to moderate exudates; some may be used for stage 1 ulcers

Impermeable to bacteria and other contaminants

Facilitates autolytic debridement

Self-adherent, molds well

Allows observation, if transparent

May be used under compression products (compression stockings, wraps, Unna boot)

May be applied over alginate dressing to control drainage

Not recommended for wounds with heavy exudate, sinus tracts, or infection

May curl at edges

May injure fragile skin upon removal

Contraindicated for wounds with packing

Moistened gauze

2×2- or 4×4-inch square of gauze soaked in saline for packing

May be used for stage 3 and 4 ulcers and for deep wounds, especially those with tunneling or undermining

Accessible

Must be remoistened often

Time-consuming to apply

Source: Reprinted with permission from Bluestein D, Javaheri A. Pressure ulcers: prevention, evaluation, and management. Am Fam Physician. 2008;78(10):1186-1194.

One of the most important factors in the selection of a dressing is moisture maintenance in and around the injury. A dressing that absorbs but does not dry out the wound is needed for injuries with excessive exudates. For injuries with minimal drainage, a dressing that restores moisture and prevents drying is needed. Frequency of dressing change also depends on the quantity of drainage.

Transparent Films

For injuries with limited exudates, transparent films should be used; however, their use over cavities is contraindicated. These dressings should be changed every three to seven days, and application of triple antibiotic ointment is also recommended by some experts [55].

Hydrogels

Hydrogel dressings are useful for patients with very shallow, dry, or minimally exuding injuries and for painful pressure injuries [29]. These gels, sheets, sprays, or ribbons of cross-linked polymers require a secondary dressing to affix them to the patient. Hydrogels not only rehydrate the wound bed but also aid autolytic debridement and reduce pain. These dressings can be used in infected injuries and are easily applied and removed from the wound. However, they are not recommended for pressure injuries with heavy exudation. They also dehydrate easily and can cause maceration.

Hydrocolloids

Hydrocolloid dressings contain a gel that promotes the growth of new skin and are indicated for clean, uninfected stage 2 and shallow stage 3 injuries in body areas where they will not roll or melt [29]. They are available as pastes, powders, or wafers composed of gelatin, pectin, and carboxymethylcellulose. These dressings promote angiogenesis, autolysis, and granulation. Some hydrocolloids are self-adhering, but secondary dressings are required when powders and pastes are used. These dressings are especially beneficial on heels and sacral injuries that require contouring. They are recommended for partial and full-thickness injuries with or without necrotic tissue.

Hydrocolloid dressings can produce an odor upon removal [15]. In the absence of other signs of clinical infection, this is not an abnormal finding and should be explained to concerned patients and staff [15]. Hydrocolloids may also leave a residue in the wound bed, which should be gently irrigated out at dressing change [13]. These dressings lose their effectiveness if they are changed too frequently and should not be used for wounds that must be monitored daily [13].

Calcium Alginates

Calcium alginate dressings, or alginates, are polysaccharide seaweed derivatives containing alginic acid. Alginate dressings either form a moist gel when they come in contact with exudates or retain their original shape while absorbing exudates. They are hemostatic, protect surrounding skin from maceration, promote healing, and may reduce risk of infection. These dressings are available in the form of ribbons, pads, and ropes.

Alginate dressings should be considered for the treatment of moderately and heavily exuding pressure injuries and for clinically infected injuries when there is concurrent antimicrobial therapy [29]. They may also be used to control bleeding after surgical debridement. A secondary dressing is necessary to secure these dressings, and they should be changed every 12 hours to four days. Wounds treated with alginate dressings may smell fishy or like "low tide" [15].

Foam Dressings

Foam dressings are protective and absorbent and potentiate wound healing by providing a moist environment. They are also permeable to gas and provide good insulation. These dressings are a good choice for stage 2 and shallow stage 3 injuries with drainage and for painful injuries.

In patients with incontinence, waterproof versions of foam dressings are prescribed in order to protect the skin. They can also be used under compression to prevent damage from shear. However, foam dressings are not effective in removing necrotic tissue, and after the dressing becomes saturated, maceration of skin around the wound can develop quickly. Therefore, these dressings should be paired with alginates for wounds with a high level of exudate.

Silver-Impregnated Dressings

Silver-impregnated dressings are a treatment option for infected or heavily colonized wounds or wounds that are at increased risk for infection [29]. Silver has an antimicrobial effect on a broad spectrum of organisms and has been shown to reduce the bacterial count in wounds [13]. Sustained-release sliver dressings are toxic to bacteria and fungi but do not adversely affect healthy wound tissue [10]. However, silver-resistant organisms do exist, and the judicious use of silver is advised, similar to the approach adopted with antibiotics [13]. It is recommended that the use of silver dressings be limited to a two- to four-week period [13]. As stated, silver-based products should not be used for enzymatic debridement [47].

Cadexomer Iodine Dressings

Cadexomer iodine dressings are used for wounds with moderate-to-high amounts of drainage. They should not be used for patients who are sensitive to iodine or individuals with thyroid disease [29]. Cadexomer iodine dressings are antimicrobial and maintain a moist environment for wound healing [15]. Although these dressings are capable of reducing bacteria counts in wounds, they do not replace the need for systemic antibiotic therapy and are regarded as an adjunct in the treatment of wound infections [15].

Gauze

Gauze packing was used frequently in the past, but it is now regarded as less effective in coping with wound drainage than calcium alginate or hydrocolloid fiber dressings [10]. Gauze dressings do not provide a barrier against bacteria, lower wound temperature, and can pull healthy granulating tissue out of the wound on removal [10]. When other forms of moisture-retentive dressings are not available, continually moist gauze is preferable to dry gauze, and one should avoid the use of wet-to-dry gauze dressings [29]. Gauze dressings are also labor intensive, requiring several dressing changes daily, which adds to the cost of the overall care [15].

Composite Dressings

Composite dressings are a combination of more than one material used to fulfill several important functions in the wound [15]. They provide an effective barrier to bacterial contamination of the wound and include an absorptive layer and either foam, hydrocolloid, or hydrogel [15]. Composite dressings can have either a semi-adherent or non-adherent surface placed in contact with the wound bed [15]. Composite dressings are comfortable and are available in various shapes and sizes [13]. These dressings should not be cut, as this compromises the structure of the dressing [15].

Collagen Dressings

Some dressings incorporate collagen, which is an important protein involved in wound healing and repair [13]. The dressings can be 100% collagen or combined with other products, such as alginates [15]. They provide a high level of absorption while keeping the wound bed moist and are easily removed [15]. For wounds with very little drainage, collagen gel can be applied in a layer one-quarter inch thick [13]. Collagen used in most wound dressings is derived from cowhide [15]. Therefore, it should not be used in patients who are allergic to bovine products [15].

PAIN MANAGEMENT

A research study concluded that severity of pain was correlated to pressure injury stage, and patients with later-staged pressure injuries may experience excruciating pain [56]. The goal of pain management in the pressure injury patient is to eliminate the cause of pain and to provide analgesia. There are several interventions and practice modifications that can prevent or manage wound-associated pain.

Skin care and assessments should be performed at a time of day when the patient is less fatigued [2]. All procedures should be thoroughly explained before they are performed. If a patient has questions, this should be addressed, and healthcare professionals should be encouraging and provide positive reinforcement. It is important to avoid trauma (shearing and tear injuries) to fragile skin during transferring, positioning, or holding a patient. If necessary, adjunctive medications may be administered to improve sleep and reduce anxiety, which can contribute to experiences of pain.

Dressing changes are often very painful. An analgesic may be administered 30 minutes before dressing changes, and if possible, the number of daily changes should be kept to a minimum. Tape should always be avoided on fragile skin. If patients are able, they should be allowed to remove their own dressings or set the pace of dressing changes. All patients should be assessed for pain before, during, and after dressing changes, and these findings must be documented [2].

Evidence Based Practice Recommendation

The National Pressure Ulcer Advisory Panel, the European Pressure Ulcer Advisory Panel, and the Pan Pacific Pressure Injury Alliance recommend clinicians consider applying a topical opioid to manage acute pressure injury pain, if required and when there are no contraindications.

https://static1.squarespace.com/static/6479484083027f25a6246fcb/t/6553d3440e18d57a550c4e7e/1699992399539/CPG2019edition-digital-Nov2023version.pdf

Last Accessed: April 28, 2025

Level of Evidence: B1 (The recommendation is supported by level 1 studies of moderate or low quality providing direct evidence or level 2 studies of high or moderate quality providing direct evidence)

Physical therapy and occupational therapy may be helpful to decrease contractures and muscle spasm. Of course, ensuring proper seating and positioning can improve pain scores and decrease the risk for further pressure injuries.

For mild-to-moderate pain, nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen may be used. Opioids should be avoided as much as possible, as the sedative effects boost immobility; however, they may be necessary during dressing changes and/or debridement.

SURGICAL CLOSURE

Surgical closure is required for large defects, particularly when musculoskeletal structures are exposed. In case of large but shallow defects, skin grafts may be beneficial. The most widely used reconstructions performed for pressure injuries are local flaps. In this reconstruction, well-vascularized skin is transferred with underlying structures (such as subcutaneous tissue, fascia, and muscle) to the wound area. These procedures are classified as [57]:

- Simple cutaneous: Includes skin and subcutaneous tissue only

- Fasciocutaneous: Includes skin, subcutaneous tissue, and fascia

- Myocutaneous: Includes all soft tissue layers from skin to muscle

There are benefits of surgical closure of pressure injuries, including more rapid healing of the wound and short-term resolution of complications [58]. Flaps containing muscle provide a physiologic barrier to infection, eliminate dead space in the wound, and improve vascularity [31]. Surgery may be difficult for some patients, however, particularly elderly and frail persons. The patient should be medically stable, of good nutritional status, and able to benefit from the procedure [31]. Complications as a result of surgical closure are considerable and include hematoma, seroma, wound dehiscence, and wound infection [31]. In addition, injuries frequently recur, even in younger patients.

INFECTION MANAGEMENT

Continuous assessment of pressure injuries for infection is vital. Signs of infection include erythema, fever, increased drainage, and increased leukocyte count, and these parameters should be monitored periodically. Topical treatment with silver sulfadiazine, triple antibiotic, or metronidazole is recommended for patients with infected injuries or who are at risk for infection. In general, noninfected wounds produce little or no odor.

Systemic antibiotic therapy is indicated when there are signs of cellulitis, purulent wound drainage, fever, or osteomyelitis. The choice of systemic agent should be supported by clinical assessment, imaging studies, and deep tissue culture.

Prophylaxis of infection is also important, as infected wounds are associated with pain, longer healing times, and greater impairments in patient functioning. Topical application of silver sulfadiazine and oral antibiotics are effective in infection prevention in pressure injuries [59,60].

ADJUNCTIVE TREATMENTS

There are many adjunctive treatments used in wound management. They include electrical stimulation, growth factors, hyperbaric oxygen, normothermic infrared and temperature therapy, and negative pressure wound therapy.

Electrical Stimulation

Electrical stimulation is effective in increasing the healing rate of chronic pressure injuries [61]. It is generally indicated for persons with spinal cord instability and difficult-to-heal injuries. In one study of individuals with spinal cord injury and pressure injuries, low-frequency pulsed current (i.e., alternating current) was compared to direct current and control groups [62,63]. Researchers found that injuries treated with electrical stimulation healed faster compared to controls and to standard treatment. Electrical stimulation is recommended by the ACP as adjunctive therapy in patients with pressure injuries to accelerate wound healing [64,65].

This therapy consists of the placement of a high-voltage, pulsed electrical current onto the wound bed (direct) or near the wound (induced), usually once daily for several weeks. The electrical settings (e.g., the polarity, amplitude and voltage, amperage) are established according to wound and patient characteristics. The Institute for Clinical Systems Improvement 2012 guideline recommends considering the use of direct contact electrical stimulation in the management of recalcitrant stage 2 as well as stage 3 and 4 pressure injuries to facilitate wound healing [61]. Although electrical stimulation is used for the treatment of pressure ulcers, a 2020 Cochrane review found that available evidence is insufficient to support its widespread use apart from its use in research [66].

Growth Factors

Fluids taken from chronic pressure injuries have a significant degradation of growth factor activity compared to acute wounds [67,68,69]. The application of topical gels containing platelet-derived growth factor can increase fibroblast activity and accelerate healing for chronic wounds [68,70]. The application of 100 mcg/g becaplermin gel once daily has been found to increase the incidence of complete healing compared to placebo [71].

Hyperbaric Oxygen

The use of hyperbaric oxygen in the treatment of pressure injuries is controversial. Hyperbaric oxygen therapy consists of 100% oxygen administered at a pressure of 2 to 3 atmosphere for a duration of one to two hours daily. This results in hemoglobin becoming saturated and oxygen spilling into the blood plasma. The vasoconstrictive effects result in reduction of edema in compromised flaps, pressure injuries, burns, and crush injuries. Improved oxygenation causes increased fibroblast activity and antimicrobial activity, with the stimulation of the phagocytic activity of the white blood cells [72]. It has been hypothesized that hyperbaric oxygen therapy could promote healing of pressure injuries; however, more research is necessary to evaluate the risks, benefits, and associated costs [73].

Normothermic Infrared and Temperature Therapy

Studies have shown that pressure injuries treated with radiant heat heal faster and result in shrinking of the injury [74]. Because this requires special equipment and trained clinicians, however, it is not yet widely used.

Therapeutic Ultrasound

Theoretically, therapeutic ultrasound can be beneficial in healing pressure injuries based on both thermal and non-thermal effects (Table 5). The NPIAP recommends that high-frequency ultrasound be considered as an adjunct for the treatment of infected pressure injuries. However, both a meta-analysis and a comprehensive review of available data on the efficacy of ultrasound in the treatment of pressure injuries were inconclusive [75,76].

Table 5: THERMAL AND NON-THERMAL EFFECTS OF THERAPEUTIC ULTRASOUND

Thermal

Non-Thermal

Increased collagen elasticity

Decreased muscle and joint stiffness

Decreased pain

Decreased muscle spasm

Increased oxygen transport

Hyperemia

Speeds up inflammatory process

Increases release of growth factors

Fibroblast and endothelial cell proliferation

Increased collagen production

Accelerated angiogenesis

Better organization of collagen matrix

Source: Reprinted from Lin VW, Cardenas DD, Cutter NC, et al. (eds). Spinal Cord Medicine: Principles and Practice. New York, NY: Demos Medical Publishing; 2003.

Pulsed Electromagnetic Field Energy

Pulsed electromagnetic field therapy can be an alternative treatment when pressure injuries are resistant to conventional therapies. This technique has been found to increase synthesis of DNA, improve revascularization, reduce bacterial growth, and increase neurotransmitter receptor and hormone receptor activity [77,78,79]. Researchers have demonstrated complete healing within a few weeks of initiating this treatment in patients with stage 3 and 4 injuries [80,81].

Negative Pressure Wound Therapy (Vacuum-Assisted Closure)

Negative pressure wound therapy is useful for advanced (stage 3 or 4) pressure injuries and poorly healing wounds with copious drainage. In general, it consists of a foam sponge dressing placed into the injury and connected by a drainage tube to a pump that exerts intermittent or continuous negative pressure on the wound bed. The negative pressure reduces edema and facilitates removal of excessive fluid and infectious debris from the bed of the injury. The effect is to increase local blood flow, promote granulation tissue, and speed wound healing

Negative pressure wound therapy has cost-saving advantages. It reduces the frequency of dressing change to three or less times a week, decreases nursing time and cost, and often permits earlier discharge and follow-up care in the ambulatory setting. Patients experience less of the pain associated with manipulation of the wound.

When considering negative pressure therapy for wound management, patient selection and plan of care should be made with caution and always in consultation with wound care specialists and/or experienced surgeons. Adverse events, such as serious bleeding and unrecognized deep infection, have been reported [82]. Moreover, this modality is not effective for injuries and wounds with necrotic tissue or malignancy in the margins.

INDIVIDUAL STAGING TREATMENT PLANS

An individualized treatment plan for the patient with a pressure injury is based on the stage of the injury, the patient's physical and psychosocial status, and whether infection is present (Figure 1) [83]. The following sections outline the general goals of treatment based on the stage of the wound, but it is important to individualize treatment as well.

Figure 1: ALGORITHM FOR THE TREATMENT OF PRESSURE ULCERS

Source: Reprinted with permission from Hess CT. Clinical Guide to Skin and Wound Care. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2008 © Wolters Kluwer.

Suspected Deep Tissue Pressure Injury

At this stage, injuries often heal with proper care and treatment, but some will deteriorate further. The aim is to quantify the extent of the wound, increase blood circulation, and prevent further breakdown of skin. Treatment should focus on:

- Pressure redistribution

- Prevention of shear and friction

- Moisture maintenance

- Physical therapy and nutritional support

- Periodic assessment of the patient

- Pain management

- Prevention and treatment of infection

Stage 1

The aim for patients with stage 1 pressure injuries is to prevent further deterioration of the injury and improve circulation. The same treatment plan implemented for suspected deep tissue injury should be the starting point. Skin should be cleansed and lightly moisturized. Massage on the affected area is contraindicated as it can lead to further tissue injury. If indicated, hydrocolloid dressings and transparent film dressings should be used. Surgical treatment and debridement are not indicated.

Stage 2

Promoting healing is the main goal for stage 2 injuries, with a focus on prevention of progression to full-thickness injury. Beginning with the same treatment plan implemented for previous stages, steps should be added to protect against infection. An appropriate dressing should be applied to promote healing and keep the wound bed clean. The skin is fragile at this stage, so adhesives should be avoided. Nutritional status should be re-evaluated, and supplements added, if necessary. Surgical treatment is not indicated, and debridement is rarely necessary.

Stage 3

Maintenance of a clean, moist wound bed to prevent infection and promote healthy granulation tissue is the prime goal in the treatment of stage 3 injuries. Infection impedes healing and may lead to complications such as sepsis and osteomyelitis. Careful assessment and follow-up are important at this stage; at the first clinical sign of infection, deep wound cultures should be obtained and appropriate antimicrobial therapy initiated promptly.

Along with the measures described for the previous stages, debridement should be carried out if indicated. Autolytic or enzymatic debridement is recommended for stage 3 injuries with light-to-moderate exudate; surgical debridement is necessary if there is necrotic tissue and infection [83].

Wound gels may be used if the injury is partially or completely covered with necrotic tissue. Foam dressings and cavity fillers are indicated if the injury bed is free of necrotic tissue and debris. Alginate dressings can also be applied if the wound has excessive exudates.

Stage 3 injuries usually heal spontaneously with appropriate cleaning and dressing. However, when treated conservatively, they have a recurrence rate of between 32% and 77% [84]. Surgical management can reduce the rate of recurrence in some patients [84]. However, according to a Cochrane review, randomized evidence neither supports nor refutes the role of surgery in the management of stage 2 or above pressure injuries [85].

Stage 4

For patients with stage 4 injuries, the focus of treatment is to provide an environment for new tissue growth. This can also involve removal of necrotic tissue and drainage reduction.

First, the injury should be assessed for bone involvement and signs of infection. If indicated, antibiotics should be started. Surgical management is often indicated in stage 4 injuries to address or prevent complications due to the large size of the wound. Debridement is often necessary to remove necrotic tissue.

Unstageable

When treating patients with unstageable pressure injury, practitioners should focus on providing a moist environment and preventing further deterioration. Injury stage should be reassessed when the base is visible and the treatment plan adjusted accordingly. The wound should be assessed for signs of infection, and antibiotics may be indicated. As with all stages, pain management and patient comfort should be ensured.

The wound should be debrided of nonviable tissue in the wound bed. One exception is the eschar on the heels, which should never be debrided unless infected.

9. WOUND MONITORING

During the treatment of pressure injuries, routine evaluation of improvement or wound progression is essential and wounds should be assessed at each dressing change. In addition, a holistic patient assessment is indicated, which encompasses systemic factors, psychosocial factors, and local factors. Systemic factors include assessment of etiology, duration, and blood flow to the injury; infection; medications; and comorbidities. Determination of the patient's knowledge, beliefs, social support, and financial health (psychosocial factors) is also important. Finally, factors specific to the wound itself, such as amount of exudate, recurrent injury, and tissue necrosis, must be evaluated and documented.

WOUND ASSESSMENT

When evaluating the wound, the most important factor to consider is whether the wound is progressing toward the goals established at the onset of treatment [13]. Clinical signs of improvement are expected to appear within two to four weeks [10]. If the wound is not progressing, further assessment and adjustment of the treatment approach are warranted [13].

For nonhealing wounds, the first factor to evaluate is the quality of wound care. This includes determining if dressing changes are being carried out at the recommended intervals, if the dressings are applied appropriately, and if the manufacturer's instructions for product use are being followed [13]. Factors affecting the patient's condition should be taken into consideration and addressed appropriately [10]. Failure of a wound to improve is often due to systemic factors, such as ischemia, infection, or malnutrition, or continuation of the causative factors [10]. These issues must be addressed first to achieve optimum wound healing. A change in the dressing treatment is indicated if any of the following problems occur [10]:

- Maceration of the surrounding skin

- Inadequate control of wound drainage

- A change in the amount of drainage or the depth of the wound

Reverse staging of pressure injuries is not an acceptable approach to gauging the level of wound healing. Healed pressure injuries do not replace lost muscle, subcutaneous fat, or dermis [29]. Tools that appropriately measure degrees of healing include the Bates-Jensen Wound Assessment Tool and the Pressure Ulcer Scale for Healing (PUSH) tool [15,86]. The Bates-Jensen Wound Assessment Tool has thirteen variables that provide a composite picture of the status of the wound [15]. The PUSH tool uses scores in three domains (i.e., size, exudate amount, and tissue type) to indicate improvement or deterioration of the injury (Table 6) [87]. When using this tool, surface area is calculated by multiplying the greatest length (head to toe) by the greatest width (side to side) in centimeters. After removal of the dressing and before applying any topical agent to the injury, the amount of exudate is estimated as none, light, moderate, or heavy. Finally, the type(s) of tissue present in the wound bed is evaluated (i.e., necrotic, slough, granulation, epithelial, or closed). A score of 0 on the PUSH tool indicates the wound has healed, whereas the highest score of 17 indicates wound degeneration [15]. Results of the assessment should be recorded; a decrease in score over time indicates improvement.

Table 6: THE PRESSURE ULCER SCALE FOR HEALING (PUSH) TOOL

Factor

Points

Size (surface area)

0 cm^2

0

<0.3 cm^2 (but more than 0 cm^2)

1

0.3–0.6 cm^2

2

0.7–1.0 cm^2

3

1.1–2.0 cm^2

4

2.1–3.0 cm^2

5

3.1–4.0 cm^2

6

4.1–8.0 cm^2

7

8.1–12.0 cm^2

8

12.1–24.0 cm^2

9

>24.0 cm^2

10

Exudate amount

None

0

Light

1

Moderate

2

Heavy

3

Tissue in wound bed

Closed wound

0

Epithelial tissue

1

Granulation tissue

2

Slough

3

Necrotic tissue

4

Source: [87]

Wound assessment also includes wound location, size and depth, signs of infection, and exudates. The wound is examined for presence of tissue debris, base tissues, quality and amount of exudate, odor, and pain.

Location

Documentation of location is paramount for proper monitoring of pressure injuries. Placement can affect healing and treatment decisions. Wounds that may be exposed to urine or feces should be provided special attention and care, and peripheral wounds may require more time to resolve.

The location of the wound should be stated in a manner that is clearly understood, such as the sacrum or right or left ischium [49]. Anatomical markings should be used when possible.

Size and Depth

Accurate measurement of the wound is probably the most important feature of wound assessment [35]. It provides information on the initial size and progression or non-progression of healing, allowing for valuable feedback on the effectiveness of clinical interventions [15]. Decreasing wound size is generally regarded as a sign of wound healing, but an increase in wound area is not necessarily indicative of deterioration [15].

Wounds should always be measured in centimeters, using a plastic or paper ruler. Wound length is measured from head to toe; width is measured from hip to hip [13]. The depth of the wound can be obtained by gently inserting a sterile cotton-tipped applicator into the wound bed and marking it at skin level. The applicator is then measured using a metric ruler [13].

Undermining/Tunneling

Sinus tracts and undermining impair healing, and it is important to immediately identify their presence. A sinus tract is a tunnel that extends from any part of the wound and can bore through subcutaneous tissue and muscle. This tunnel creates dead space, which can result in abscess formation and further impede the healing process. A sinus tract can be measured using a sterile cotton swab.

Undermining is defined as destruction of the tissue under the skin around the edges of the wound. This frequently occurs in pressure injuries that have been subjected to shear force as well as pressure. It is important to document the location and extent of undermining.

The easiest way to measure and describe undermining is by using the face of the clock [15]. With the patient's head representing 12 o'clock, sweep the area of undermining or probe the tunneling to ascertain the depth. For example, undermining along the right border would be recorded as extending from 1 o'clock to 5 o'clock with a depth of 4 cm. It is important to check around the entire perimeter of the wound, as undermining can occur in more than one location.

Wound Bed

It is also vital to assess and document the appearance of the wound bed (Table 7). If the wound bed has a mixture of tissue in it, this should be documented by an approximate percentage (e.g., 75% granulation tissue and 25% slough). Granulation results in "beefy" red tissue consisting of new capillaries, fibroblasts, and collagen fibers with a shiny, moist granular appearance. Grey or purple granulation is a sign of poor vascularization. Granulation present in the wound denotes healing.

Table 7: WOUND BASE COLOR DESCRIPTIONS

Color

Description and Clinical Implications

Red

Clean and uniformly pink to red in color.

Usually heals by secondary intention.

Dressings need to be changed less often, but the wound should be moist at all times.

Yellow

Varies from ivory to canary yellow or even green in color, depending on whether or not infection is present.

Caution: Tendon may appear as yellow or white.

The goal of care is to manage exudate and remove slough through surgical, sharp, mechanical, enzymatic, or autolytic debridement.

Not all yellow is detrimental to healing; granulation grows through yellow fibrin.

Black or brown

Ranges in color from dark brown and gray to black.

The goal for most individuals is to remove the necrotic tissue by surgical, sharp, enzymatic, or autolytic debridement.

Where there is no drainage or there is boggy surrounding tissue, leave the hard, dry eschar or black scab intact on the lower legs, feet, or heels of individuals whose healing potential is compromised by inadequate circulation. It provides a protective covering for the wound.

Source: [13]

Necrosis is gray, brown, or black unviable tissue that usually must be removed in order for healing to take place. Eschars are typically gray to black and dry or leathery in appearance. Slough tissue is yellow/white to gray in color. It may be stringy or thick and appear as a layer over the wound bed. Epithelial tissue will often begin to grow in from the edges over the wound surface. This tissue is generally pink and shiny. As a quick reference color guide, red is associated with normal healing, yellow indicates slough or dead tissue, and black is necrosis.

Exudates

Exudates are an indication of inflammation in the wound. The presence of large amount of exudate can delay healing and increase the risk of infection. As such, this factor has a significant impact on treatment decisions, particularly dressing type. The amount and quality of any exudates should be noted. Amount may be denoted as:

- Large/copious: Extends beyond dressing

- Moderate: Contained within the dressing

- Small/slight: Small amount of exudate in the center of dressing

- None: Absence of exudate

The quality of the exudates may be described as [88]:

- Purulent: Thick exudate that may be malodorous and tan, yellow, green, or opaque in appearance and denotes presence of infection

- Serosanguineous: Thin and pink or light red in color

- Serous: Thin/watery and clear or straw colored, with no blood or debris

- Hemorrhagic: Red and thick, consisting mainly of blood

- Fibrinous: Cloudy and thin with strands of fibrin

Odor

Malodor with purulent exudates suggests mixed infection often combined with ischemic necrosis. However, the majority of wounds (even those free of infection) do have some odor. As previously discussed, gram-negative and gram-positive infections have distinct odors. If present, an injury's odor (quality and strength) should be documented.

WOUND EDGE AND SURROUNDING SKIN

Wound edges are open and closed. Healthy wound edges are open and allow cell migration. Closed wound edges prevent cell migration and may delay healing. These edges may be described as calloused, approximated, or rolled. The presence or absence of erosion, papules, excoriation, denudement, pustules, or other lesions should be noted.

The condition of the surrounding skin surface up to 4 cm from the edge of the wound circumferentially must also be assessed and documented. Its characteristics should be noted, particularly color and integrity [10]. Maceration from excessive drainage may indicate that the dressing used is not appropriate and a different product is needed. Circumferential erythema and/or induration up to 2 cm from the wound are indicative of cellulitis.

PAIN

Pressure injuries cause considerable pain and suffering, ranging from sore to excruciating [30]. In one study, 75% of patients rated their pain as mild, discomforting, or distressing; 18% rated their pain as horrible or excruciating [89]. Pain and odor control are a major concern for patients, and studies have shown that patients rank pain control as more important than healing [15]. The level of pressure injury pain depends both on the stage of the injury and on manipulation of the area (e.g., if a dressing change is done at the time of assessment), although the majority of patients report pressure injury pain at rest as well as with dressing changes. Pressure injury pain may be due to tissue trauma, inflammation, damaged nerve endings, infection, and procedures such as debridement and dressing changes [90].

The gold standard for assessing pain intensity is self-reporting using standard pain intensity instruments. Two of the most widely used pain assessment scales are the numeric pain intensity scale and the Wong-Baker Faces Pain Rating Scale [91]. The numeric pain intensity scale consists of ratings from 0 (no pain) to 10 (worst possible pain). This scale can be used for pain assessment with adults and children older than 7 years of age [92]. Visual presentation of the numeric pain intensity scale is helpful with hearing impaired patients, and the scale has been translated into many languages.

The Wong-Baker Faces Pain Rating Scale consists of six faces ranging from a happy smiling face (no pain), to a crying, frowning face (worst pain). The patient is asked to choose the face that best reflects his or her pain. The Faces Pain Rating Scale is the preferred scale for use with children and may also be used with the geriatric population, cognitively impaired patients, and those for whom English is a second language.

After the initial pain assessment has been completed, reassessment should be done at regular intervals. As noted, pain intensity should be rated by the patient, not a healthcare professional. The following questions may be used to help determine patients' pain levels:

- What kind of pain are you experiencing?

- What word(s) would you use to best describe it (e.g., burning, aching, shooting)?

- What makes the pain better?

- What makes it worse?

- Where is the pain located?

- Does the pain radiate?

- Would you describe your pain as none, mild, moderate, severe, or excruciating?

- How would you rate your pain on a scale of 0 to 10, with 0 representing no pain and 10 being the worst imaginable pain?

- What is the pain intensity at its worst, best, and now?

- Is the pain better or worse at any particular time of the day or night?

- When does it start and when does it stop?

PRESENCE OF INFECTION

Infections remain a significant cause of both pain and poor outcomes in patients with pressure injuries. At each wound assessment, the patient should be evaluated for signs of local or systemic infection. Common signs and symptoms include:

- Systemic signs (e.g., fever, chills, sweats)

- Local signs (e.g., rubor, calor, color of adjacent tissues)

- Unusual odor

- Friable or dysmorphic granulation

- Purulent exudates

If any of these are present, infection should be suspected and treated. Culturing the wound may also be helpful, particularly for patients with refractory or recurring wound infections. Obtaining a good culture requires that a semi-quantitative swab collection also be taken. The gold standard is quantitative biopsy, but this procedure is invasive and expensive.

10. COMPLICATIONS

The prevention of complications in pressure injuries begins with injury recognition. As soon as an injury is diagnosed, pressure relief and prevention and control of infection begin. Without proper care and treatment, a superficial stage 1 or 2 injury can evolve to a more serious and severe stage 3 or 4 injury. The near-term complications of pressure injuries include cellulitis, abscess, sepsis, and osteomyelitis. Indolent, non-healing deep injuries may eventually lead to malignancy.

CELLULITIS

Cellulitis can occur when infection spreads from the site of the injury to a deeper layer of skin, causing acute infection of connective tissue and possibly leading to sepsis. Staphylococci and streptococci are the most common causative agents of cellulitis.

Physical exam may reveal signs of infection, including erythema, edema, warmth, and possibly increased drainage. Lymphadenopathy may be present near the area of cellulitis. Diagnosis may be confirmed by blood culture, complete blood count (CBC), or fluid or exudate culture from the affected area.

Treatment usually involves a course of antibiotics. Analgesics may be necessary if the area is painful.

SEPSIS AND SEPTIC SHOCK

Sepsis is one of the most serious complications of a pressure injury that has become secondarily infected. Sepsis occurs when bacteria or the products of bacterial infection in the wound enter the bloodstream, producing a systemic inflammatory response syndrome (SIRS) marked by fever, hemodynamic changes, and organ dysfunction. The SIRS designation is not specific to infection and may be used in reference to any serious, ongoing inflammatory process resulting in end-organ damage and multisystem failure. While sepsis is a common and important cause, SIRS may be encountered in association with noninfectious insults such as trauma, burns, pancreatitis, anaphylaxis, adrenal insufficiency, and pulmonary embolism.

In 2014, a task force of the European and American societies of critical care medicine was convened to reexamine current concepts and definitions of sepsis and septic shock in light of improved understanding of the pathophysiology and management of sepsis. The task force concluded that previous definitions are limited by excessive focus on inflammation, and that the SIRS criteria have inadequate specificity and sensitivity for defining sepsis. The task force report and new, consensus definitions for sepsis and septic shock were published in 2016 [93].

Sepsis is now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection [93]. This definition emphasizes the loss of adaptive homeostasis in response to infection and the potential lethality of infection when any degree of organ dysfunction is present. Even modest organ dysfunction has been found to confer a mortality risk in excess of 10%, hence the importance of urgent assessment and prompt treatment [7]. The presence and extent of organ dysfunction can be assessed with various scoring systems that rely on clinical and laboratory parameters, such as the following [7,94,95]:

- Acute lung injury: a ratio of arterial oxygen tension to fraction of inspired oxygen of 280 or less

- The presence of a metabolic acidosis, e.g. lactate >2 mmol/L

- Oliguria (urinary output of less than 0.5 mL/kg body weight/hour for at least two hours in a patient with a urinary catheter in place)

- Coagulation abnormalities (international normalized ratio [INR] >1.5)

- Thrombocytopenia (platelet count <100,000/mcL)

- Bilirubin >2 mg/dL

- An acute alteration in mental status

The scoring system currently utilized in most critical care units is the Sequential Organ Failure Assessment (SOFA) score, which grades abnormality by organ system and accounts for clinical interventions [95]. A higher SOFA score is associated with an increased probability of mortality. Organ dysfunction can be identified by an acute change in SOFA score ≥2 points consequent to the infection. This score reflects an overall mortality risk of approximately 10% in a general hospital population with suspected infection [7].

Working from a model derived from a large inpatient data base, the sepsis task force was able to identify, and validate, a simple "bedside" clinical measure that can be used to identify which patients with suspected infection are at risk for developing sepsis. Designated the qSOFA (for quick SOFA), this measure consists of three elements [93,96]:

- Respiratory rate ≥22/min

- Altered mentation (Glasgow Coma Scale <15)

- Systolic blood pressure ≤100 mm Hg

The data analysis demonstrated that patients with infection who are positive for two or more of these elements are likely to have a prolonged ICU stay (i.e., three or more days) or die in the hospital.

Physicians and nurses can employ the qSOFA in the office, emergency department, or inpatient facility to quickly identify which patients with an infection (e.g., pressure injury) are on the clinical threshold of sepsis and thus at risk of further clinical deterioration. The task force suggests that positive qSOFA criteria be used to prompt clinicians to further investigate for organ dysfunction, to initiate or escalate therapy as appropriate, and to consider referral to critical care [7].

Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. Within the clinical construct of sepsis, the patient with septic shock can be identified by the presence of the following two criteria [93]:

- Persisting hypotension requiring vasopressors to maintain mean arterial blood pressure (MAP) ≥65 mm Hg

- Blood lactate >2 mmol/L despite adequate volume resuscitation

The hospital mortality rate for patients meeting these criteria is in excess of 40%, or four times greater than for patients with sepsis [7].

For patients with an infected pressure injury, the confirmation and etiology of sepsis is determined by blood cultures, wound culture and Gram staining of exudate and/or tissue obtained from the base of the injury, and/or by selective application of the polymerase chain reaction.

Antimicrobial Therapy

In addition to fluid and metabolic resuscitation, treatment of sepsis requires parenteral antibiotics and, when necessary, surgical debridement and/or drainage of deep tissue suppurative fluid collections. Vasopressors and inotropic therapy may be necessary to restore adequate blood pressure and perfusion. The initial choice of antibiotics will depend on the most likely pathogens associated with the source of infection as well as the prevalent micro-organisms in the local community and health facility. The anticipated susceptibility profile of prevalent local pathogens and the ability of the antibiotic to penetrate to the source of the infection should also be considered. A combination of drugs with activity against all likely pathogens should be administered initially, but the regimen should be reassessed in light of culture results, the goal being to identify a single, narrow-spectrum antibiotic that will best control the infection [97]. A common approach is to initiate empiric therapy with a carbapenem or extended-spectrum penicillin/beta-lactamase inhibitor (e.g., ticarcillin/tazobactam) to cover gram-negative enteric bacilli, anaerobes, and Pseudomonas, often in combination with vancomycin to cover Staphylococcus aureus pending culture results.

Proper support for organ failure is indicated for patients with severe sepsis, and sedation, mechanical ventilation, and analgesia are often required in late-stage disease. Adequate nutrition (usually administered parenterally) and glucose control are necessary. The patient should be stabilized prior to restarting injury treatments.

BONE AND JOINT INFECTIONS

When the infection from a full-thickness tissue injury, generally stage IV, spreads to bone and joints, periosteitis, septic or infectious arthritis, or osteomyelitis can result. If the injury crater can be probed to bone (i.e., one can see or palpate bone at the base of the crater), then the likelihood of bone infection approaches 80%. Confirmation of the diagnosis relies on imaging studies and needle aspiration or bone biopsy for histopathology and culture.

Plain bone radiographs are useful for diagnosing chronic osteomyelitis when infection has been present for many weeks; however, false-positive or false-negative results are common. Computed tomography scans are helpful for demonstrating fluid collections, bony erosion, and joint involvement. Radionuclide bone scanning (with technetium methylene-99m diphosphate) can be diagnostic, but it only has a moderate degree of sensitivity and specificity. Magnetic resonance imaging is the most sensitive and specific imaging modality for identifying the presence of osteomyelitis.

Bone biopsy is the definitive diagnostic test. Bone biopsy for histologic examination and culture not only verifies bone involvement but also helps to establish the bacterial etiology and antibiotic sensitivities upon which optimal treatment depends.

Treatment

In the presence of underlying osteomyelitis, satisfactory healing of the pressure injury is usually not possible unless the bone infection is eradicated. This requires parenteral followed by oral antimicrobial therapy for a minimum of six to eight weeks, combined, if necessary, with surgical debridement of necrotic bone. Any surgical approach to (presumed) infected bone, whether needle aspiration, biopsy, or debridement, should include submission of bone specimens for culture.

In the surgical management of stage 4 injury cases with little or no overt clinical or radiographic sign of bone infection, submission of bone specimens for culture is useful for identifying early, limited osteomyelitis and thus the need for post-operative antimicrobial treatment. Examples are cases requiring partial ostectomy or ablative surgery of stage 4 injuries with resection of bone from the base of the injury crater.

MALIGNANCY

Long-standing pressure injuries can develop into malignant tumors called Marjolin ulcers. These tumors were named for surgeon Jean-Nicolas Marjolin, who first described the condition in 1820 [98,99]. They are very aggressive ulcerating squamous cell carcinoma found in the area of injuries and other long-standing indolent wounds. It can develop many years after the initial trauma.

The first sign of Marjolin ulcer is a change in the character of the wound. Drainage increases, and the odor of the drainage becomes putrid. In some cases, there is frank bleeding. Diagnosis is made after histologic examination of a specimen removed from the injury, usually at the time of a flap closure. Confirmation of the diagnosis requires a preoperative tissue biopsy; wedge biopsy is the method of choice.

Excision of the lesion with 1-cm margin is required. Oncologic assistance is also necessary in the management of this condition, and extensive treatment is often necessary.

GAS GANGRENE

Gas gangrene is a rare but serious form of Clostridium perfringens infection. These obligate anaerobes release gas and harmful toxins that can result in gas gangrene, sepsis, and septic shock. The most common symptoms are severe pain and rapid swelling of the skin around or near the injury.

Surgical debridement is usually necessary [100]. In very serious cases, excision with amputation is required to prevent spread of the infection [101]. Penicillin is administered as adjuvant therapy. Hyperbaric oxygen therapy is effective in growth inhibition and killing C. perfringens [102,103]. However, results of a Cochrane review could not determine the efficacy and safety of hyperbaric oxygen therapy for the treatment of gas gangrene [101].

NECROTIZING FASCIITIS

People with stage 3 and 4 injuries are at a risk for contracting the rapidly progressive infection necrotizing fasciitis. Necrotizing fasciitis is defined as a group A streptococcal infection of the fascia with accompanying necrosis of the subcutaneous tissues. It is an uncommon consequence of pressure ulceration [104,105].

Initial signs of this condition are fever, pain, and massive swelling. Visual and microscopic evaluation of the tissues confirms the diagnosis. Emergency treatment is required, and aggressive surgical debridement is vital to prevent spreading [106]. In some cases, early amputation of affected tissues and maximum intensive care treatment (e.g., in case of sepsis) are required [106].

As soon as necrotizing fasciitis is suspected, antibiotics should be started. A combination of intravenous antibiotics, usually clindamycin, vancomycin, and penicillin, is administered. One review recommended aminopenicillin plus sulbactam in combination with clindamycin and/or metronidazole as initial treatment [106]. Hyperbaric oxygen therapy can also be effective.

RECURRENCE

Recurrence of a pressure injury is a common complication of treatment. As noted, as many as 90% of patients with a healed wound will experience a recurrence [6,9]. Compared to normal tissue, scar tissue has lower tensile strength, poor blood supply, and poor ability to withstand trauma, making it vulnerable to recurrent episodes. If an injury recurs at the same site within four months of the initial injury, it is likely due to incomplete healing rather than a true recurrence [107]. Risk factors for recurrence include male sex, younger age, African/black race, lower socioeconomic status, nursing home residence, and previous pressure injury surgery [107].

11. TREATMENT OF COMORBIDITIES

Comorbid conditions both increase susceptibility to pressure injuries and impair the healing process. Therefore, comorbid conditions should be addressed as part of the overall treatment plan. Common comorbid conditions in patients with pressure injuries include:

- Diabetes

- Incontinence

- Peripheral vascular disease (PVD)

- Hypotension and hypoxia

- Dehydration, poor nutritional status, or malnutrition

- Cancers

- ESRD

- Depression and cognitive impairment

Even with the best medical care and preventive measures, pressure injuries can occur [108]. It is unclear which combination of comorbid conditions can lead to injury formation, but changes in skin with comorbidities are believed to result in injuries. Recent acute illnesses or acute exacerbation of comorbid conditions may cause lethargy and reduced mobility, increasing the risk of pressure injuries. In patients with comorbid conditions, special attention to the drugs being used is necessary. Chemotherapeutic agents, systemic corticosteroids, and NSAIDs can impair healing.

DIABETES

In patients with long-standing diabetes, both macro- and microvasculature can be severely damaged, particularly if the disease is poorly controlled. Diabetes also causes neuropathy, and the resultant loss of sensation and protective reflexes is a risk factor for pressure injury progression. Patients with diabetes have elevated glucose levels that result in rigid blood cell walls and decreased blood flow through microvasculature. The disease also impairs oxygen release by the hemoglobin, resulting in hypoxia. Leukocytes have less effective chemotaxis and phagocytosis, which makes the patient susceptible to infection. Diabetics are prone to fungal rashes that can result in perineal irritation and skin breakdown. Impaired granulocyte function inhibits wound healing. All of these factors contribute to the increased risk of pressure injury development in a patient with diabetes.

The aim of diabetes management is to keep blood glucose levels close to normal (i.e., glycosylated hemoglobin less than 7%). Usually, pharmacotherapy and/or insulin therapy is necessary for optimum disease control. In addition, eating habits should be modified and physical activity should be increased.

URINARY AND FECAL INCONTINENCE

Approximately 10 to 13 million Americans have transient or chronic urinary incontinence [109]. It is also estimated that 50% to 70% of patients with urinary incontinence fail to seek medical intervention or treatment [109]. The high prevalence of incontinence among certain populations (e.g., nursing home residents) makes this an important factor in pressure injury development and healing.

Extended exposure of skin to urine and feces can result in breakdown, making the patient more susceptible to injuries [110]. Urinary incontinence results in maceration, which causes increased skin irritation and fragility. Coliform bacteria and C. difficile contamination of existing wounds can lead to severe infections.

The treatment of these patients is dependent on determining the incontinence etiology. General approaches include regular assessment of skin; hydration and infection should not be ignored. Patients should be checked for incontinence every two hours. For patients who are cooperative and aware of bladder filling, a toilet program should be instituted, including planned voiding every two hours. For patients who are uncooperative or unaware of bladder filling, consider the use of absorptive products or condom catheters for men. It is important to use diapers and underpads that wick moisture away from patients' skin. Incontinent patients should be cleaned as soon as possible after soiling using specialized incontinence skin cleansers or soaps.

For patients with severe diarrhea, all potential causative factors should be explored and addressed. A rectal pouch may be useful for these patients. In cases of chronic incontinence, an every other day suppository or enema may be considered. In addition, barrier ointments help protect the skin from incontinent episodes. If used, apply a thick coat of ointment, wipe off the soiled top layer, and apply another layer. Do not clean off the paste to skin level when bathing or cleaning.

PERIPHERAL VASCULAR DISEASE

PVD is an important contributory factor in the development of vascular injuries, particularly diabetic foot ulcerations (as the cause of 10% to 30% of all cases) [111]. The wounds of patients with severe PVD heal poorly as a result of inadequate blood supply, and minor trauma or pressure often leads to ulceration.

When conducting a thorough physical examination, signs and symptoms consistent with PVD should be documented and ankle-brachial index or pulse volume recordings should be recorded. The ankle-brachial index is not specific in patients with advanced calcific atherosclerotic disease, and for patients with this condition, photoplethysmography or magnetic resonance angiogram is more accurate [112,113].

Treatment of PVD first relies on assessment and management of modifiable risk factors (e.g., smoking, physical activity). Pharmacologic management with antiplatelets is the gold standard for patients whose disease is not well controlled with lifestyle changes [114]. In addition, comorbidities should be treated aggressively.

HYPOTENSION AND HYPOXIA

Prolonged hypotension and hypoxia can cause tissue hypoperfusion, especially in anatomical locations already at risk for developing injuries. Patients with septic shock have microvascular endothelial dysfunction, which results in tissue hypoxia despite adequate oxygenation [115,116]. Tissue hypoxia and hypoperfusion may also be caused by hemorrhagic shock. Anemia and low cardiac output limit the blood's oxygen-carrying capacity and perpetuate tissue hypoperfusion. It is necessary to check vital signs, CBC, blood gas, and echocardiogram and manage accordingly.

GASTROINTESTINAL DISORDERS AND MALABSORPTION

As discussed, optimal nutrition is important for the prevention and treatment of pressure injuries. Therefore, intestinal diseases and acquired disorders that adversely affect nutrient absorption should be identified and treated as part of a management plan. Conditions like celiac disease, Crohn disease, and gastrointestinal malignancy often lead to malabsorption and micronutrient deficiencies. C. difficile colitis can cause severe diarrhea and hypoalbuminemia, making patients nutritionally and hemodynamically compromised. Patients who have undergone surgical bowel resections and fecal diversion are also at risk for malabsorption, fluid depletion, and electrolyte deficiency.

In addition to correction of nutritional deficiencies, the primary cause of malabsorption should be identified and treated. The plan of care will include interventions to increase nutritional intake, keeping in mind that the patient's and family's preferences play an important role in establishing a diet plan.

MALIGNANCY

Malignancy often leads to cachexia, a syndrome characterized by weight loss, malnutrition, weakness, and anemia. However, there is limited research exploring the link between pressure injuries and cancer [117]. Radiation therapy can cause dermatitis and desquamation and increase the risk for skin breakdown. Both the malignancy and associated treatments may cause immunosuppression and increase the likelihood and severity of infections.

Patients with cancer who are also experiencing skin breakdown should be assessed for nutritional status, and medications may be prescribed to combat the anorexia associated with chemotherapy. Optimum skin care, particularly in areas affected by radiation therapy, is a necessity.

END-STAGE RENAL DISEASE

Severe uremia associated with ESRD necessitates the use of dialysis to remove uremic toxins and prevent or control complications, and pruritus and xerosis are common in these patients. Malnutrition and dehydration are also risks. Dietary management of patients with ESRD should be aimed at control of electrolytes (including calcium, phosphorus, and potassium), prevention of malnutrition, and maintenance of acceptable fluid volume status.

DEPRESSION

The National Institute of Mental Health estimates that 8.4% of adults in the United States are suffering from depression, and major depression is the leading cause of disability worldwide [118]. Depressed patients often have little interest in self-care and nutrition, both of which may predispose an individual to pressure injuries [15]. Pressure injuries have also been found to contribute to depressive symptoms [119]. Patients should be regularly assessed for depression or other psychologic illnesses and referred to mental health care.

COGNITIVE IMPAIRMENT

Loss of cognition is associated with increased risk for pressure injuries, and impaired mental status leads to a lack of awareness of discomfort or pressure and may be associated with incontinence. The ability to respond appropriately or to inform others of the need for assistance may be lost completely. As such, these patients often require intensive care.

12. ADVANCES IN PRESSURE INJURY CARE

Research and technical innovations are producing sophisticated technology and analytic devices to diagnose, prevent, and treat pressure injuries. These new innovations are changing the way injuries are cared for and prevented in a variety of settings.

REPOSITIONING ALERTS

Studies have shown that patients with less nocturnal periodic movements are at risk for pressure injuries, but sleeping patients may be unaware of their lack of movement [120]. Alert systems have been implemented to remind staff to reposition the patient every two hours. Because repositioning is one of the basic hallmarks of pressure injury prevention, alerts may help address this risk factor better.

DETECTION

Early detection is of utmost importance in pressure injury management. Advanced technology and devices can be used to achieve better sensitivity and specificity in the diagnosis of injuries. These techniques include laser Doppler, visible and near-infrared spectroscopy, ultrasound, and pulse oximetry [121]. Each of these approaches ascertains clinical parameters associated with blood flow and hemoglobin concentration, and combining such measures with clinical information allows for a high degree of sensitivity and specificity in identifying impending chronic wounds in patients with any skin color [121].

DOCUMENTATION

New methodologies for documenting and measuring wounds can help both with monitoring treatment and preventing legal complications. Highly advanced computerized documentation is being used by many organizations. Techniques are now available to thoroughly assess the geometric, physiologic (i.e., pressure and degree of wound perfusion), and biochemical (i.e., concentrations of various enzymes involved in tissue degradation and healing) aspects of the wound.

Electronic records and images are preferred by many institutions. The role of wound photography is growing and is a vital aspect of monitoring response to treatment and in defending against possible future litigation. Most home health agencies in the United States include wound photography as part of the patient's medical record [35].

ULTRASOUND

Ultrasound has been explored as a diagnostic and monitoring tool. High-frequency ultrasound provides greater resolution than other ultrasound techniques, but the depth of penetration of the sound waves is less. Therefore, it is ideal for imaging near-surface pathology. High-resolution ultrasound can easily detect the fluid content of tissue and measure skin thickness. More research is necessary to determine the efficacy and cost effectiveness of ultrasound for the routine care of pressure injuries.

SKIN SUBSTITUTES OR GRAFTS

Although the available skin substitutes are not perfect, they do offer benefits when treating pressure injuries, particularly those resistant to healing. Research in the field of skin tissue engineering focuses on improving the skin barrier properties and the structural interaction of the epidermal and dermal equivalent of composite grafts. There are two types of bioengineered skin replacements available: biosynthetic skin substitutes and skin grafts.

Biosynthetic skin substitutes are developed without allogenic cells and consist of a mesh coated with a dermal analogue (bilayer) or an acellular dressing (monolayer). They act as starting points to promote ingrowth of tissue in the wound. The bilayer options also include a removable silicone layer that functions as a protective dressing.

Skin grafts may be categorized as xenografts, autografts, or allografts. A xenograft is derived from a non-human source, usually porcine skin. An autograft is a graft taken from the patient, while an allograft is transplanted from a genetically non-identical individual, often from a cadaver donor. Grafts may be further identified as dermal or epithelial/epidermal (or both) and as cultured or processed. Within these categories, there are several specific options, each with their own benefits and drawbacks [122]. It has been suggested that the properties inherent to skin grafts, such as the presence of hair follicles, may make them a good option to accelerate wound healing [123]. Selection of the best option is dependent on the features of the wound, the goals of treatment, and patient preferences.

GENE THERAPY

Gene therapy has a tremendous potential, but use of the technology in the treatment of pressure injuries is still in its infancy. Gene therapy has been proposed to accelerate wound healing and also to reduce healing complications such as keloid formation or chronic ulceration.

Genetically modified skin grafts have a potential use for treatment of large wounds. Smaller wounds may be amenable to in vivo delivery of genetic material using a variety of approaches including gene injection, gene gun, microseeding, and liposomal gene delivery. The preclinical studies of genetically modified skin grafts are promising, but more tests are necessary to determine the effectiveness of this treatment option [124,125].

NEGATIVE PRESSURE WOUND DEVICES

Negative pressure wound devices provide an environment that resolves edema and hematoma and results in increased local perfusion. Newer negative pressure wound devices are smaller and more portable than earlier devices, and some deliver continuous subatmospheric pressure to the wound bed to promote healing. It should be noted that these devices have been associated with extensive bleeding, particularly in patients with blood vessel grafts in the leg, with breastbone or groin wounds, or who are receiving anticoagulant therapy [126]. Hemorrhage may also occur when dressings attached to the tissues are removed.

GROWTH FACTORS AND BIOLOGIC WOUND PRODUCTS

Biologic wound products accelerate healing by augmentation or modulation of inflammatory mediators. Growth factors that hold great promise in wound healing include eicosanoids, prostaglandin E1, cytokines, and interleukin-1.

OTHER TREATMENT MODALITIES

Lasers may also accelerate the process of tissue repairing [127]. The lasers appear to simulate fibroblastic activity, although the mechanism is not yet fully understood.

Nanoparticles containing chitosan have been shown to have effective antimicrobial activity against Staphylococcus saprophyticus and Escherichia coli [127]. These materials could be used to prevent infection and facilitate wound healing.

Researchers have shown that a novel peptide (UN3) created by the combination of two naturally occurring peptides found in platelet-rich plasma stimulates wound vascularization and promotes epithelial proliferation. This could lead to new treatments for pressure injuries [128]. The use of novel peptides derived from platelet-derived growth factor (PDGF-BB) also shows promise for wound healing and treatment [129]. PDGF stimulates bone cell replication and DNA synthesis.

Electrical stimulation may also accelerate healing in pressure injuries, but its effect on time to complete healing is uncertain compared with no electrical stimulation [130,131]. Free radical scavengers and special drug delivery systems can also be effective in prevention of injuries [132,133,134].

13. MEDICO-LEGAL ASPECTS OF INJURY CARE

Pressure injuries are the second most common medicolegal claim after wrongful death, resulting in more than 17,000 lawsuits annually in the United States [135]. Results of a retrospective study published in 2019 examined 141 cases related to pressure injuries over a 32-year period from 1987 to 2019 [136]. Of the 141 cases, 75.9% were for negligence and 22.7% were for malpractice. Hospitals were listed as the defendant 61.7% of the time, nursing homes 31.2% of the time, and individual providers 7.1% of the time. Hospitals lost 63% of the cases brought against them, nursing homes lost 75%, and individual providers lost 20%. Hospitals paid out approximately $1.6 million to plaintiffs, nursing homes $4 million, and individual providers an average of $400,000 [136].

As litigation is becoming more common, adherence to established standards of care is very important and has legal implications [137]. Some experts have suggested that if institutional neglect is responsible for development of pressure injuries, caregivers could be liable to criminal prosecution.

AVOIDABLE VERSUS UNAVOIDABLE INJURIES

Federal law establishes standards for long-term care facilities [138]. Based on the comprehensive assessment of a resident, the facility must ensure that 1) a resident who enters the facility without pressure sores does not develop pressure sores unless the individual's clinical condition demonstrates that they were unavoidable; and 2) a resident having pressure sores receives necessary treatment and services to promote healing, prevent infection, and prevent new sores from developing.

As noted, despite best patient care and treatment, not all pressure injuries are avoidable [139]. In long-term care, the NPIAP defines an unavoidable injury as one that occurs even though "the facility had evaluated the individual's clinical condition and pressure injury risk factors; defined and implemented interventions that are consistent with individual needs, goals, and recognized standards of practice; monitored and evaluated the impact of the interventions; and revised the approaches as appropriate" [140]. In addition to establishing the definition for long-term care facilities, in 2014 the NPIAP sought to establish consensus (80% agreement among conference delegates) on whether pressure injury development may be unavoidable in some individuals and whether there is a difference between pressure injuries and end-of-life skin changes. Unanimous consensus was reached for the following statements [141]:

- Most (but not all) pressure injuries are avoidable.

- Comorbid conditions can contribute to unavoidable pressure injuries.

- Some situations render pressure injury development unavoidable, including:

- Hemodynamic instability worsened by physical movement

- Poor nutrition/hydration status and/or advanced directive that prohibits artificial nutrition/hydration

- Pressure redistribution surfaces cannot replace turning/repositioning

- Skin cannot always survive even when pressure from external body skin is alleviated

In light of the significant changes to pressure injury prevention in acute care hospitals brought about by the COVID-19 pandemic, the NPIAP additionally published position statements on pressure injuries that develop during COVID-19 crisis situations in these healthcare settings [141].

Facilities should institute adequate measures to prevent wounds, and in the case an injury develops, staff should respond appropriately to prevent worsening of the wound. Wounds detected in the early stages have a greater chance of cure than later stage wounds that are infected or necrotic. Therefore, regular assessment and early intervention are required for all injuries, avoidable or not. The presence of risk factors, including comorbidities, inability to maintain adequate nutrition and hydration status (e.g., if an advance directive prohibits artificial feeding), certain drugs, and immobility, is an indicator of avoidability. After assessment of risk factors, the next step is to ascertain if the response was timely according to documentation of all interventions. If any skin ulceration develops in spite of timely, appropriate interventions, the injury may be considered unavoidable.

DETERMINATION OF NEGLECT

Suspicion that improper medical care resulting in the development and/or worsening of a pressure injury requires a full, document-intensive investigation. Because many factors can be indicative of medical neglect, each domain of care should be assessed (Table 8). Furthermore, the best defense against a claim of neglect is complete documentation of appropriate care.

Table 8: FACTORS LEADING TO A DETERMINATION OF NEGLECT

Inadequate prevention

Poor documentation

Inadequate nutrition

Inadequate medical care

No family notification

Poor care planning

Wound severity and outcome

Source: Compiled by Author

New or worsening pressure injuries are generally due to poor administrative organization, understaffing, and poor training. The medico-legal implications of proper care cannot be overlooked, as those injuries are responsible for a significant proportion of healthcare litigation.

Medical Record

The medical chart should be examined to determine the level of care planning, assessment, and interventions. Wound neglect is usually associated with improper treatment, inadequate nutrition, and/or poor survey results.

Family diaries, stage surveys, in-service records, complaint files, minutes of quality assurance meetings, and photographs can also be helpful for identification of deviations from standard injury care.

Wound Documentation

Documentation of pressure injury care must be timely and detailed. Regular and consistent descriptions of the injury should be documented, as should responses to treatment. Improper, irregular, or "late entries" are absolutely impermissible and unacceptable.

In patients with multiple injuries, progression of each wound should be documented and tracked. With the growing awareness of the possibility of litigation in wound care, many facilities have instigated a policy of photo documentation. Wounds present on admission are photographed, and some facilities require serial photographs to track wound progress and status at the time of discharge. Signed consent is required before wound photographs can be taken, and in most instances, the photographs become a permanent part of the patient's medical record.

Nutritional Assessments

It has been found that 30% to 85% of nursing home residents are malnourished and 30% to 50% are considered underweight [112]. Pressure injury treatment requires proper nutritional assessment and intervention during every stage. Weight loss, lab results, protein consumption, and vitamin levels should be documented, as should attempts to address abnormalities. If tube feeding is indicated, it should be discussed with the family prior to initiation.

Treatment Records

Treatment administration records should be examined to ensure that treatments were carried out per orders. Documentation should also include staffing records and time-sheets. Dates and times should always be included.

Minimum Data Sets and Care Plans

Minimum data sets are required for all residents of skilled nursing facilities. Improper and inaccurate entries in the minimum data sets indicate a facility with under-staffing and disorganized structure providing poor treatment to the resident. Scrutiny of this document can lead to litigation.

14. EDUCATING PATIENTS

A vital component of any pressure injury program is patient/family education, with an overall goal of decreasing the incidence of injury development or recurrence. If possible, pressure injury prevention should not be a passive process for the patient and his/her family members. Rather, it should be a dialogue in which the patient and family feel comfortable asking questions and discussing problems. Patients should have as much control as possible in the plan of care. Empowerment is very important in maintaining the patient's physical and emotional well-being, and the plan of care should be explained thoroughly to cognitively aware patients and/or their family. It is important for everyone involved to appreciate that the prevention of pressure injury formation is a lifelong process [142].

At the same time, it is necessary to evaluate the patient's/family's existing knowledge regarding pressure and pressure injuries. Healthcare professionals should show patients what they can do to facilitate pressure relief (e.g., how to make small position changes while in the chair). If possible, teach patients how to do simple range-of-motion exercises. Take time to train the patient as often as is appropriate; not everyone will absorb the information the first time they hear it [4]. It is important not to let noncompliance or a bad attitude from the patient or family discourage the teaching process. The subject should be approached as often as is reasonable. Include the family members and caregivers in the instructions; as well as assisting with care, they can encourage compliance. All efforts at patient and family/caregiver education should be documented, along with the patient's response (both verbal and behavioral).

Different methods of teaching, such as photographs, videos, charts, diagrams, and written materials in the patient's native language, should be used. Education should be reinforced regularly and consistently [143]. The information provided to patients and/or their families should be specific to the individual treatment plan and goals.

Patient education programs should include all of the following areas:

- Etiology of pressure injuries

- Reduction of risk

- Reduction of friction and shear

- Skin protection and inspection

- Importance of nutrition

- Proper and safe cleansing procedures and agents

- Procedure for recurrence(s)

- Management approaches

- Proper dressing change procedure

PATHOGENESIS OF PRESSURE INJURIES

Patients should be provided information about factors involved in pressure injury development. The role of pressure, friction, shear, and moisture in the development of injuries should be explained. Other conditions that can impact pressure injury development should be outlined, including:

- Immobility (partial or total)

- Excessive moisture and/or incontinence

- Poor local or systemic circulation

- Uncontrolled diabetes

- Severe trauma

- Dehydration

- Hypoxia

- Malnutrition

- Sepsis

- Previous history of pressure injury

REDUCTION OF RISK

Pressure reduction techniques should be thoroughly explained. Proper use of mattresses, cushions, and overlays and the placement of pillows, heel protectors, and wedges are essential. The role of repositioning and turning of the patient should be stressed. If the patient will be sitting in a chair for a long period of time, pressure release tactics should be included. Repositioning should be done every one to two hours, depending on the patient's condition [49].

REDUCTION OF FRICTION AND SHEAR

Patients and/or caregivers should have a clear understanding of measures to decrease friction and shear. Education should include the proper body alignments that should be maintained when sitting in a chair or lying on a bed. The importance of using lifting devices for repositioning or transferring should be stressed.

SKIN INSPECTION AND PROTECTION

Careful skin inspection is paramount in the care of pressure injuries. The patient or caregiver should carefully inspect the skin for new openings or breaks in the skin at every repositioning. Any discoloration or redness of the skin that does not resolve within 30 minutes after changing position should be reported.

Maintaining skin cleanliness and moisturizing frequently can protect skin integrity. The skin should be cleaned with water and a gentle soap, preferably a pH-balanced cleanser. Alkaline products remove skin lipids, which increases water loss and weakens the barrier function of the skin [2]. Avoid hot water for bathing and scrubbing or using harsh cleaning agents. A soft cloth should be used to pat rather than rub the skin dry. Thromboembolic deterrent hose should be removed when bathing, and the nurse or physician should be notified of any redness, discoloration, or skin breakdown.

It is important to individualize the frequency of skin cleansing based on the patient's age, skin texture, and dryness or excessive oiliness of the skin. A daily bath may not be needed for all patients.

The epidermis is about 30% water, but through a process called trans-epidermal water loss, skin can lose its natural moisture. Without sufficient moisture, skin can become dry, brittle, and vulnerable to breakdown [10]. Therefore, products should be used to keep the skin supple. Emollients, such as mineral oil, petrolatum, and lanolin, penetrate into the stratum corneum to increase the lipid component and add softness to the skin. The oil film on the skin surface also prevents water loss and helps to rehydrate the stratum corneum [10]. Moisture barriers such as dimethicone can prevent water loss and help to retain lipids and water within the skin cells [10].

Humectants, such as glycerin, urea, and lactic acid, increase the water content of the stratum corneum by pulling water from the environment. All moisturizers should be applied to clean, slightly moist skin. Special attention should be paid to bony prominences, heels, ears, and the back of the head.

NUTRITION

Adequate nutrition is an essential area of patient education, as malnutrition makes individuals susceptible to the development of pressure injuries and at increased risk for infections, including sepsis, necrotizing fasciitis, and gangrene. Patients must also understand that adequate hydration is essential to improve tissue perfusion and excreting waste products. Patients/caregivers should make sure they comply with dietitian recommendations for diet, adequate fluid intake, and nutritional supplements.

PROCEDURE FOR RECURRENCES

Patients should be advised to take the following actions should a pressure injury develop:

- Increase the frequency of repositioning and turning.

- Note the size, location, odor, color, and drainage of the wound and adjacent tissue.

- Notify the physician immediately about this new development.

- If the patient is receiving home care services, the home health nurse should be notified immediately.

MANAGEMENT OF PRESSURE INJURY

After a treatment plan is set, all aspects should be explained to the patient or caregiver again. Key education points include:

- Products being used for wound prevention or healing

- Where to procure dressings and pressure redistribution surfaces

- Signs and symptoms of pressure injury deterioration

- The importance of compliance to the established plan

Patients should be advised to look for new necrotic tissue in the wound bed, wound drainage with odor, and erythema and induration around the injury. If a clean wound enlarges or becomes deeper, the patient should be instructed to contact his or her physician immediately.

PROPER DRESSING CHANGE PROCEDURE

Proper dressing change technique should be demonstrated. The patient/caregiver should be able to change the dressing without any assistance from the supporting staff, and clean technique should be used. Hand washing, use of gloves, and infection prevention should all be a part of basic patient education.

15. CONCLUSION

Pressure injuries are a common but preventable condition frequently seen in elderly individuals and those with comorbid conditions. In the United States, the incidence of pressure injuries in critical care patients ranges from 12% to 33%, depending on treatment setting [2].

Pressure injuries are a major psychologic, physical, and social burden to patients and often result in significantly decreased quality of life. In addition, they are a major source of healthcare expenditures. The healthcare costs related to the care of patients with pressure injuries exceeds $11 billion annually in the United States [9].

Evolution of pressure injuries is multifactorial, and individuals with specific risk factors are more susceptible to injury development. Without proper care and treatment, superficial injuries progress to more serious deep tissue wounds, often with life-threatening complications. Satisfactory resolution of a well-established pressure injury is difficult, time-consuming, and costly; it is far better to prevent the injury in the first place. An interdisciplinary approach of creating a care plan that includes steps for the prevention of injuries is the best practice.

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Evidence-Based Practice Recommendations Citations

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2. National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel, Pan Pacific Pressure Injury Alliance. Prevention and Treatment of Pressure Ulcers: Clinical Practice Guideline. 4th ed. Washington, DC: National Pressure Ulcer Advisory Panel; 2025. Available at https://internationalguideline.com/the-international-guideline. Last accessed April 28, 2025.

90350 • Neuromodulation for Refractory Neuropsychiatric and Pain Disorders

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2025 NetCE, All rights reserved.

This course will provide an overview of neuromodulation therapy for neuropsychiatric diseases and conditions and will examine the potential short- and long-term benefits and risks; clinical indications; patient selection; and potential ethical issues associated with neuromodulation therapies, including their non-therapeutic use for cognitive and performance enhancement. Refractory psychiatric disorders are emphasized, as several psychiatric disorders are poorly responsive to standard therapies, leaving patients distressed and functionally impaired. Neuromodulation therapies (aside from ECT for refractory major depressive disorder) are a more recent option for psychiatric disorders, a rapidly growing indication for use. Refractory chronic pain is another therapeutic area discussed in this course.

Table of Contents

90350 • Neuromodulation for Refractory Neuropsychiatric and Pain Disorders

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. OVERVIEW OF BRAIN MODULATION APPROACHES

ELECTROCONVULSIVE THERAPY

NON-INVASIVE TRANSCRANIAL STIMULATION

OTHER MAGNETIC STIMULATION THERAPIES

OTHER ELECTRICAL STIMULATION THERAPIES

3. NEUROMODULATION IN SPECIFIC PSYCHIATRIC DISORDERS

MAJOR DEPRESSIVE DISORDER (MDD)

ANXIETY DISORDERS AND ANXIETY-RELATED DISORDERS

POST-TRAUMATIC STRESS DISORDER

OBSESSIVE-COMPULSIVE DISORDER

SCHIZOPHRENIA

SUBSTANCE USE DISORDERS

EATING DISORDERS

DEPERSONALIZATION/DEREALIZATION DISORDER

4. ELECTROCONVULSIVE THERAPY

CANDIDATES FOR ECT

TREATMENT PARAMETERS IN ECT

EFFICACY

PREDICTORS OF ECT RESPONSE AND RELAPSE

POST-ECT MAINTENANCE

ADVERSE EFFECTS OF ECT

5. TRANSCRANIAL MAGNETIC AND ELECTRIC STIMULATION IN PSYCHIATRIC DISORDERS

TRANSCRANIAL MAGNETIC STIMULATION (rTMS) IN PSYCHIATRY

TRANSCRANIAL DIRECT CURRENT STIMULATION (tDCS) IN PSYCHIATRY

6. NEUROMODULATION FOR MAJOR DEPRESSIVE DISORDER (MDD) AND AFFECTIVE DISORDERS

REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION (rTMS)

TRANSCRANIAL DIRECT CURRENT STIMULATION IN MDD

7. NEUROMODULATION FOR OTHER MENTAL HEALTH DISORDERS

NEUROMODULATION FOR BIPOLAR II DEPRESSION AND BIPOLAR DISORDER

ANXIETY DISORDERS AND ANXIETY-RELATED DISORDERS

POST-TRAUMATIC STRESS DISORDER

OBSESSIVE-COMPULSIVE DISORDER (OCD)

TOURETTE SYNDROME

SCHIZOPHRENIA WITH AUDITORY VERBAL HALLUCINATIONS

SCHIZOPHRENIA, NEGATIVE SYMPTOMS

SUBSTANCE USE DISORDERS

EATING DISORDERS

DEPERSONALIZATION/DEREALIZATION DISORDER

EXTERNAL TRIGEMINAL NERVE STIMULATION (eTNS)

MAJOR DEPRESSIVE DISORDER

PTSD AND COMORBID MDD

PANIC DISORDER

8. INVASIVE NEUROSTIMULATION

VAGUS NERVE STIMULATION

DEEP BRAIN STIMULATION

9. NEUROMODULATION IN CHRONIC PAIN

OVERVIEW OF NONINVASIVE BRAIN STIMULATION IN PAIN

CHARACTERISTICS OF CHRONIC PAIN CONDITIONS

TRANSCRANIAL MAGNETIC AND ELECTRIC STIMULATION

TRANSCRANIAL DIRECT CURRENT STIMULATION

COMPARISONS OF rTMS AND tDCS IN PAIN TREATMENT

10. INVASIVE NEUROSTIMULATION IN CHRONIC PAIN

MOTOR CORTEX STIMULATION

DEEP BRAIN STIMULATION

THALAMIC DEEP BRAIN STIMULATION

NEUROMODULATION SAFETY IN PAIN TREATMENT

11. SOCIAL ISSUES WITH NEUROSTIMULATORS

RISING CONSUMER USE

REGULATORY CHALLENGES AND SAFETY CONCERNS

12. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

90350 • Neuromodulation for Refractory Neuropsychiatric and Pain Disorders

Education Category. Medical / Surgical

Release Date. 08/01/2025

Expiration Date. 07/31/2028

Course Overview

This course will provide an overview of neuromodulation therapy for neuropsychiatric diseases and conditions and will examine the potential short- and long-term benefits and risks; clinical indications; patient selection; and potential ethical issues associated with neuromodulation therapies, including their non-therapeutic use for cognitive and performance enhancement. Refractory psychiatric disorders are emphasized, as several psychiatric disorders are poorly responsive to standard therapies, leaving patients distressed and functionally impaired. Neuromodulation therapies (aside from ECT for refractory major depressive disorder) are a more recent option for psychiatric disorders, a rapidly growing indication for use. Refractory chronic pain is another therapeutic area discussed in this course.

Audience

This course is designed for physicians, PAs, and nurses involved in the care of patients with refractory pain or neuropsychiatric disorders.

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 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 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. 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. 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.

Special Approvals

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

Course Objective

As the therapeutic landscape evolves beyond traditional pharmacologic and surgical approaches, neuromodulation offers a promising option for patients with refractory conditions who have not responded adequately to standard treatments. The purpose of this continuing education course is to enhance physician and nurse understanding of neuromodulation therapies for the treatment of neuropsychiatric and chronic pain disorders.

Learning Objectives

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

1. Outline the background and underlying concepts supporting neuromodulation therapy.

2. Describe the mechanisms, benefits, and risks of electroconvulsive therapy (ECT).

3. Review the implementation of transcranial magnetic and electric stimulation in psychiatric disorders.

4. Evaluate the use of neuromodulation approaches to the management of treatment-refractory major depression disorder (MDD).

5. Compare the efficacy of neuromodulation techniques for the treatment of other psychiatric disorders.

6. Analyze the efficacy and safety of invasive neurostimulation for the management of psychiatric disorders.

7. Formulate strategies for integrating neuromodulation therapies into comprehensive treatment plans for refractory pain conditions.

8. Discuss the potential role of invasive neurostimulation in patients with chronic pain.

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

Margo A. Halm, RN, PhD, NEA-BC, FAAN

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

Neuromodulation, neurostimulation, brain modulation, and brain stimulation are synonymous and describe noninvasive, minimally invasive or invasive techniques that deliver electrical or magnetic stimulation to specific brain region targets for the treatment of psychiatric and pain conditions.

Electroconvulsive therapy (ECT) is the oldest and most established brain stimulation mode in current use. Over the past decade, the most-studied brain stimulation modality in the treatment of psychiatric and pain conditions has been transcranial magnetic stimulation (TMS), followed by transcranial direct current stimulation (tDCS). Several recent modifications of TMS and tDCS are under development to improve efficacy or accelerate treatment response. External trigeminal nerve stimulation (eTNS) is a recent but highly promising approach. Minimally invasive vagus nerve stimulation (VNS) is modestly effective in refractory depression, and invasive stimulation requiring surgical implantation into brain targets has a limited yet highly valuable role in treatment of severe, refractory conditions.

In the context of this course, ECT is given its own section because the indicated use for ECT involves one condition (depression). The non-invasive modalities TMS and tDCS are the most extensively researched brain stimulation approaches and are combined in discussions of specific psychiatric disorders and pain conditions. Invasive brain stimulation is discussed in the last sections of psychiatric disorders and pain conditions.

2. OVERVIEW OF BRAIN MODULATION APPROACHES

Numerous brain stimulation modalities are in varying stages of research development or clinical use in the treatment of psychiatric and pain conditions. Their general characteristics are described in this section. Characteristics specific to treatment of psychiatric or pain disorders are discussed in later sections.

Therapeutic brain stimulation intends to induce durable treatment effects by exploiting brain capacity for plasticity. Neuroplasticity is the process where alterations in brain structure promote functional changes, and represents the process of normal brain functions during learning, adaptation to change, and recovery from brain injury. It is thought that early changes with brain stimulation involve alteration in synaptic strength, with longer exposures trigger longer-lasting anatomical changes such as neuronal sprouting and alterations of dendritic spines. Brain stimulation is best viewed as an intervention that targets specific brain circuits, rather than brain transmitter chemicals (neurotransmitters) [1,2]. Two processes that occur during brain stimulation-induced neuroplasticity [1]:

- Long-term potentiation: Reinforcement of synaptic strength

- Long-term depression: Weakening of synaptic strength

Parameters refers to the range of settings with stimulation devices, adjusted to manipulate energy output and desired treatment effects. Parameters include the location of electrode, magnet or lead placement; and the intensity, duration and pattern of delivered energy. Montage refers to configurations of externally placed or implanted electrode.

Brain stimulation therapy is not new to the 20th century. In the Roman era, electric torpedo fish were placed on the scalp to treat headache or epilepsy, and gouty arthritis was treated by placing painful extremities in pools with torpedo fish. In the mid-1700s, advances in electrophysiology inspired the use of transcranial electrical stimulation with direct currents to treat mental disorders [3,4]. Transcranial electrical stimulation machines for private use became widely available, and study of transcranial electrical stimulation intensified in the 1800s. Transcranial electrical stimulation was claimed to generate euphoria and improve mental performance by some patients and physicians, who advised that currents to the head not exceed 10 mA from risks of burning and shock. Common side effects were headaches, dizziness and nausea; Benjamin Franklin suffered retrograde amnesia after accidentally administering an electric shock to his head [3].

Erratic results and the advent of ECT led to waning interest in direct current brain stimulation [4]. ECT was introduced in 1938 to replace drug-induced convulsive therapy of severe psychosis; epilepsy was mistakenly believed antagonistic to schizophrenia. Depression was later known as a more suitable indication [5]. Psychosurgery using stereotactic lesioning in specific deep brain structures was introduced in 1947 to avoid the side effects of the widely used frontal lobotomy. Deep brain stimulation followed in the early 1950s as treatment for psychiatric illness, Parkinson disease, and pain [5,6]. Primitive forms of magnetic stimulation were first investigated in the 1890s, first shown to stimulate isolated nerves in 1959, and the first modern device was introduced in 1976, the precursor for the first TMS technique in 1985 [3].

These crude, earlier forms of brain stimulation were abandoned or curtailed with replacement by drug therapies, or stigma and rejection over unethical practices and side effects. All have been reintroduced in substantially safer and more effective forms with ethical safeguards; ECT is prohibited without full patient consent [5,6].

ELECTROCONVULSIVE THERAPY

Although not often considered non-invasive due to seizure induction, ECT remains established as a potent and rapidly acting treatment for severe or refractory major depressive disorder (MDD). ECT is considered unrivaled among all therapeutic options for rapidly inducing antidepressant effects, although multiple ECT treatments are usually required [7].

ECT generates electrical stimuli through electrodes applied to the scalp for seizure induction, with the patient in general anesthesia and pre-medicated with a muscle relaxant. Clinical outcomes are highly influenced by electrode placements, electrical intensity and pulse width, and these are described in a later section [8].

ECT is thought to work by generating seizure-induced changes in neurotransmitter activity, neuroplasticity, and functional connectivity. ECT increases levels of brain-derived neurotrophic factor (BDNF), which may promote neuroplasticity and contribute to the antidepressant effect [8,9].

Stigma surrounds this treatment mode and may interfere with patient acceptance of initiating ECT therapy.

NON-INVASIVE TRANSCRANIAL STIMULATION

The preponderance of research on non-invasive neuromodulation involves magnetic or electric stimulation using repetitive transcranial magnetic stimulation (rTMS) or tDCS. Both modalities allow external manipulation of the brain, performed safely without requiring neurosurgical procedures or general anesthesia [10].

Repetitive Transcranial Magnetic Stimulation

First demonstrated in 1985, TMS projects a fluctuating magnetic field (magnetic pulses) through the skull into the brain via an inductor coil placed against the scalp. This generates electrical currents in brain tissue (via electromagnetic induction) of sufficient strength to modulate neuronal firing. Multiple TMS pulses given consecutively are termed repetitive TMS. rTMS is noninvasive, and unlike ECT does not require anesthesia [2,8].

Frequency

Frequency is the intensity of stimulation energy [2]. High-frequency (5–20 Hz) rTMS (HF-rTMS) increases neuronal activity and cortical excitability and increases relative regional cerebral blood flow (with exceptions). Low-frequency (≤1 Hz) rTMS (LF-rTMS) reduces neuronal activity and cortical excitability. HF-rTMS and LF-rTMS, applied to the same brain site, can induce dissimilar effects on brain circuits.

Stimulation strength is tailored to the motor threshold of each patient that is determined by the amount of current, with single-pulse TMS applied to the primary motor cortex (M1), that produces a twitch in a peripheral muscle (a motor-evoked potential) [11,12]. rTMS is usually applied in "trains" of pulses interspersed with rest periods, because prolonged high-frequency stimulation increases seizure risk [13].

Coil Type

Most rTMS studies use a standard figure-8 coil, which has the drawback of poor brain penetration that limits the depth of stimulation delivery, although superficial areas of the prefrontal cortex (PFC) such as the dorsolateral PFC represent important targets fully amenable to rTMS stimulation. This partially explains the preponderance of rTMS studies in MDD, as the dorsolateral PFC is highly relevant in depression [12].

The deep (H) coil delivers pulses deeper than the figure-8 coil to stimulate broader and deeper frontal cortex regions such as the insula and ventrolateral prefrontal cortex, as well as the dorsolateral PFC. This may come at the expense of specificity, where deeper penetration expands the magnetic field to stimulate regions and circuits that interfere with therapeutic response or contribute to adverse effects [2,12].

Mechanism

Trains of magnetic pulses with rTMS temporarily summate to alter neural activity that can modulate cortical excitability. LF-rTMS mostly stimulates low-threshold inhibitory interneurons, and HF-rTMS excite projection neurons [13]. The effects of rTMS are not limited to the brain areas under the stimulation coil, and remote brain areas connected to the stimulated site are affected [14]. Because of synaptic connections, distal effects (cortical and subcortical, ipsilateral and contralateral) on neural activity, regional cerebral blood flow, and neurotransmitter activity may differ from proximal effects. rTMS can be viewed as targeting brain circuits instead of neurotransmitters, although behavioral effects depend on neurotransmitter systems within the manipulated brain circuit [2]. Long-lasting therapeutic effects with rTMS are related to long-term potentiation and long-term depression mediated through N-methyl-D-aspartate (NMDA) synaptic plasticity [15].

Transcranial Direct Current Stimulation (tDCS)

tDCS is a non-invasive, painless brain stimulation treatment in numerous psychiatric and chronic pain conditions. tDCS is delivered through a device that transfers low-intensity (0.5–3 mA) electrical current to the scalp surface with 2 large (20–35 cm^2) saline-soaked sponge-electrodes, an anode and a cathode. The anode and cathode are attached to distinct areas of the scalp with a rubber headband. The current penetrates the skull and enters the brain from the anode, travels through the tissue, and exits via the cathode [16].

In contrast to other non-invasive brain stimulation modes, tDCS does not induce neuron action potentials but instead modulates neuron membrane excitability [15]. Parameters that influence patient response and functional outcomes with tDCS are current polarity, delivered dose, and electrode positions.

Stimulation Types and Effects

The tDCS current is too weak to induce neuron firing, but alters neuron excitability by shifting the resting membrane potentials of neurons in a depolarizing or hyperpolarizing direction, making them more or less likely to re-fire. Changes in spontaneous neuron firing induced by stimulation type [4,10]:

- Anodal stimulation: Depolarizes (raises) neuron membrane potentials, which excites neuronal function and increases cortical excitability.

- Cathodal stimulation: Hyperpolarizes (lowers) neuron membrane potentials, which decreases neuronal function and cortical excitability.

Thus, effects of tDCS on cortical excitability are polarity-dependent (anodal or cathodal), and both cause changes in spontaneous firing.

Mechanisms

With repeated use, tDCS modulates synaptic connectivity by inducing long-term potentiation and depression, mediated in part by NMDA receptor-dependent mechanisms; neuroplastic changes regulated by neurotransmitters systems such as dopamine, acetylcholine, gamma-aminobutryic acid (GABA), serotonin and BDNF; and changes in neuronal membrane channels including sodium and calcium pumps [8,17,18]. tDCS can also upregulate and downregulate functional connectivity within brain networks, including those important for cognitive, motor, and pain processing [18].

OTHER MAGNETIC STIMULATION THERAPIES

While rTMS and tDCS are the dominant techniques, other novel or modified forms of non-invasive magnetic and electric current neuromodulation have been developed and are actively under investigation.

Theta-Burst Stimulation

Theta-burst stimulation is a form of rTMS that delivers a 50-Hz burst of three pulses every 200 ms [19]. Intermittent theta-burst stimulation delivers 600 pulses of stimulation for 2 seconds, followed by an 8-second rest, over two to three minutes. Intermittent theta-burst stimulation is considered excitatory. In contrast, continuous theta-burst stimulation is applied in 40 second trains to result in long-term depression-like decreases in motor cortex excitability. Continuous theta-burst stimulation is considered inhibitory [8].

Magnetic Seizure Therapy

Magnetic seizure therapy is a noninvasive convulsive neurostimulation therapy currently investigated as an alternative to ECT. A neurostimulator and coil are placed directly on the skull. Electrical current passing through the coil generates a strong focal magnetic field (2 Tesla). This passes unimpeded through the skull and soft tissue to reach brain tissue, where an electrical current is induced that causes neuronal depolarization triggering a generalized tonic-clonic seizure. Magnetic seizure therapy and ECT both induce seizures in patients under general anesthesia with assisted ventilation and EEG monitoring, but magnetic seizure therapy may have fewer side effects, particularly cognitive impairment [8,20].

OTHER ELECTRICAL STIMULATION THERAPIES

Transcranial Electrical Stimulation

An early approach to brain stimulation, transcranial electrical stimulation applied high-voltage electric stimuli through electrodes on the scalp. Most of the current travelled along the scalp between the electrodes, but a small portion penetrated the brain to activate neurons. This method was refined in 1980 and termed transcranial electrical stimulation. Transcranial electrical stimulation is credited as the pioneering neurophysiological approach for noninvasive brain stimulation, but interest in transcranial electrical stimulation declined rapidly with the introduction of TMS in 1985 [19].

Transcranial Alternating Current Stimulation (tACS)

Most published research on transcranial electrical stimulation efficacy has involved tDCS. Only recently has tACS attracted attention as a promising alternative approach to directly interact with ongoing oscillatory cortical activity. To date, evaluation of tACS has been primarily limited to possible cognitive enhancing effects in healthy adults, and in the elderly with normal, age-related cognitive declines [21].

Transcranial Random Noise Stimulation (tRNS)

tRNS is a variant of tACS that uses a constantly changing current. While tACS stimulates at a set frequency to entrain oscillatory activity, tRNS stimulates at a randomly changing frequency between 0.1–640 Hz. tRNS at higher frequencies (>100 Hz) may induce larger excitability changes than stimulation with a direct current such as tDCS, because the sodium channels of underlying neurons are repeatedly opened by stimulation. Neuronal homeostatic mechanisms are prevented because the underlying neurons cannot adjust to the constantly randomly changing electrical field. As a relatively new technique, the number of published reports on tRNS treatment in psychiatric and pain disorders is sparse [22].

External Trigeminal Nerve Stimulation (eTNS)

eTNS is an external neuromodulatory device originally developed for use in refractory seizures. The theoretical basis for eTNS is that bilateral electrical stimulation over the trigeminal cranial nerve may neuromodulate cortical and subcortical areas related to neuropsychiatric disorders, such as the amygdala, insular cortex, prefrontal cortex, hippocampus, thalamus, locus coeruleus, nucleus of the solitary tract, and the anterior cingulate cortex. eTNS involves a bottom-up mechanism where stimuli propagate from the cranial nerve in the direction of the brainstem and central brain regions. As such, this represents a novel approach that differs from transcranial stimulation involving top-down mechanisms [23,24].

Two eTNS protocols are described for psychiatric disorder treatment. Both protocols use stimulation frequencies of 120 Hz, asymmetrical alternate current, pulse duration of 0.25 ms and intensity based on patient sensitivity and pain threshold. Protocol I delivers eTNS in 8-hour sessions during sleep for 8 weeks, with a 30 seconds on/30 seconds off cycle, while Protocol II uses 30-minute sessions in 10 weekdays for 2 weeks, with continuous stimulation [24].

Low-Intensity Focused Ultrasound

The concept of using focused ultrasound beams deep in the brain to treat movement disorders was conceived in the 1950s, but the need to make a cranial window in the skull led to its development abandoned. Low-intensity focused ultrasound can be delivered through the intact skull, making ultrasound neuromodulation the focus of considerable interest [7]. An advantage is its ability for deep brain delivery without causing permanent damage or effects [25]. Potential indications include acute symptoms such as seizures, and chronic conditions such as depression where plasticity may be important. Ultrasound neuromodulation is at a much earlier stage of development than TMS or tDCS [7].

Vagus Nerve Stimulation (VNS)

VNS is a minimally invasive therapy, first approved in 1997 for refractory seizure disorders and in 2005 for treatment-refractory MDD. Vagus nerves are cranial nerve with fibers that transmit nerve impulses from the periphery to the brain. Electrical stimulation of the vagus nerve stimulates the nucleus tractus solitaries, enhancing its capacity to modulate brain areas through its neuronal connections distributed to subcortical and cortical brain regions [8].

With VNS, an implantable pulse generator is surgically inserted in the chest region. The lead from the device is attached to the left vagus nerve in the neck, where a small electrical current is delivered. Stimulation is around-the-clock, with typical stimulation periods or "trains" lasting 30 seconds, with 5 minutes of rest between trains. The device parameters (pulse width, frequency, duration of stimulation, and duty cycle) can be modified transcutaneously (as with cardiac pacemakers) using a wand attached to a small handheld programming computer [26].

Motor Cortex Stimulation

Motor cortex stimulation is an invasive procedure, with use in chronic refractory pain first documented in the early 1990s. With motor cortex stimulation, the skull is surgically opened and an electrode array is inserted [13]. In epidural motor cortex stimulation, the electrodes are attached to the dura directly above the motor cortex. In subdural motor cortex stimulation, the dural layer is penetrated for electrode placement.

Motor cortex stimulation affects structures involved in affective, cognitive, and emotional aspects of pain. The analgesic mechanisms of motor cortex stimulation involve extensive changes at various CNS levels, with a likely entry point at the thalamic level that triggers distant effects on limbic, cingulate and orbitofrontal cortices, and descending modulation that reaches the spinal horn. Activation of the endogenous opioid system or gamma-aminobutyric acid transmission in these areas is thought to underlie long-term pain relief with motor cortex stimulation [13,27].

Deep Brain Stimulation

Deep brain stimulation is an invasive neurosurgical procedure performed under MRI guidance, where electrodes are implanted through the skull and dura into discrete brain targets for stimulation. The electrodes are internalized and connected to an implantable pulse generator implanted into the chest below the right clavicle. The implantable pulse generator is accessible with a handheld device, which allows remote monitoring and/or programming of stimulation parameters. The deep brain stimulation parameters of pulse width, frequency, and amplitude (voltage or current) are programmed by the treating physician and titrated to clinical effect. Deep brain stimulation has been extensively developed and refined for use in later-stage Parkinson disease, where it is a standard of care. Deep brain stimulation is also used in other movement disorders, but severe refractory psychiatric and pain disorders represent a growing research field [8].

3. NEUROMODULATION IN SPECIFIC PSYCHIATRIC DISORDERS

Among psychiatric disorders, depression has been the most extensively researched condition, followed by schizophrenia and substance use disorders. The most extensively studied brain stimulation modality is rTMS, followed by tDCS. While non-invasive brain stimulation approaches were developed to provide the efficacy of ECT without the adverse effects, ECT remains established in treating severe or refractory depression. Aside from ECT, deep brain stimulation is its current form has been in clinical use longer than other brain stimulation modes, but its invasive nature and restricted use to severe, refractory patients partially accounts for fewer published deep brain stimulation studies compared to rTMS and tDCS.

With noninvasive neurostimulation in psychiatric disorders and especially rTMS and tDCS, the speed at which the knowledge base is expanding cannot be overstated. Important factors that influence patient response to rTMS or tDCS are absent from earlier studies. Among these factors, perhaps the greatest efficacy-disrupting effect is found with smoking or benzodiazepine user on tDCS response.

In neurostimulation studies of psychiatric disorders, the Clinical Global Impression-Severity (CGI-S) scale may be used to measure patient response and clinical outcomes. This is a clinician rating scale of general improvement. More specific scales may be used to measure response for specific conditions.

MAJOR DEPRESSIVE DISORDER (MDD)

MDD is a disorder of mood involving disturbances in emotional, cognitive, behavioral, and somatic regulation which manifest in depressed mood and feelings of worthlessness or guilt; social withdrawal and agitation; impairments in concentration or decision-making; and insomnia or fatigue [28]. MDD is highly prevalent and associated with serious personal suffering, societal costs, severe symptoms and functional impairment. An estimated 30% of MDD patients do not adequately respond to pharmacotherapy and psychotherapy. Treatment-resistant depression is loosely defined as failure to achieve remission despite therapeutic interventions [29].

The dorsolateral PFC functions to regulate affective states through cognitive control over stress and emotion responsive, and is hypoactive during depressive episodes [30]. The dorsolateral PFC and rostral anterior cingulate cortex areas are closely inter-connected; decreased neuronal activity in these frontal areas underlies apathy, psychomotor slowness, and impaired executive functioning common in MDD [31,32].

Two different scales may be used to assess patient response. The first is the Hamilton Depression Rating Scale (HDRS or HAM-D), a 21-item measure of depression symptoms. In clinical trials, remission is defined as HDRS score <8. The other is the Montgomery-Åsberg Depression Rating Scale (MADRS), a depression scale that measures affective, cognitive, and vegetative symptoms.

ANXIETY DISORDERS AND ANXIETY-RELATED DISORDERS

Generalized Anxiety Disorder (GAD)

Generalized anxiety disorder (GAD) is a chronic psychiatric condition defined by excessive and uncontrollable worry, with at least three of six hyperarousal symptoms (restlessness, muscle tension, fatigue, irritability, difficulty in sleeping, concentration problems). Lifetime prevalence is 5.7%, with higher rates in primary care and psychiatric outpatient samples. GAD is frequently comorbid with depression, complicating presentation, treatment and prognosis. At the individual level, GAD is associated with significant quality-of-life impairments and diminished physical health. At the systems level, GAD is associated with high use of health care services and high costs [33].

Pharmacotherapy (antidepressants, anxiolytics) and cognitive-behavioral therapy are standard treatments for GAD, but fail to achieve symptom remission in 33% to 50% of patients. The best existing treatments leave many patients with GAD without relief, and alternative treatments are needed [33].

GAD is characterized by abnormalities in frontal and limbic structures primarily involving the prefrontal cortex, anterior cingulate cortex, and amygdala; decreased structural and functional connectivity between frontal and limbic regions; and impairments in emotion regulation associated with abnormal functioning in neural circuits that encompass frontolimbic regions including the dorsolateral PFC [34].

Panic Disorder

Panic disorder is characterized by sudden unexpected panic attacks and apprehension about the possible causes and consequences of the attacks. Comorbid agoraphobia is characterized by behavioral avoidance of situations from which escape might be difficult if a panic attack occurred [35].

Patients with panic disorder with and without agoraphobia have shown PFC hypoactivity paired with fear-relevant brain structure (amygdala) hyperactivity, suggesting inadequate PFC inhibition of responses to anxiety-related stimuli [36]. Hypofrontality is shown in patients with panic disorder during cognitive tasks without emotional content, and in responses to emotional stimuli. Altered activation patterns in the left inferior PFC are associated with panic attacks, and altered right anterior PFC associated with severity of agoraphobic avoidance [35,36,37].

A variety of scales are available to assess response of patients with anxiety disorders to neuromodulation therapies, including:

- Generalized Anxiety Disorder 7-item (GAD-7) scale

- Hamilton Anxiety Rating Scale (HARS or HAM-A)

- Panic and Agoraphobia Scale (PAS)

- Panic Disorder Severity Scale (PDSS)

- Clinician-Administered PTSD Scale

- Yale-Brown obsessive-compulsive scale (Y-BOCS) (the standard obsessive-compulsive disorder [OCD] measure)

- Yale Global Tic Severity Scale (YGTSS) (the standard Tourette syndrome measure)

POST-TRAUMATIC STRESS DISORDER

Formerly classed as anxiety disorders, post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder are now separately classed in the fifth revised edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) [28]. PTSD is a severe, potentially chronic and disabling disorder that can develop following exposure to a traumatic event involving actual or threatened death, serious injury, or sexual assault. Common symptoms include intrusive thoughts, nightmares and flashbacks of the traumatic event, avoidance of trauma reminders, hypervigilance, and sleep disturbance. These symptoms can be highly distressing and substantially impair social, occupational, and interpersonal functioning [28].

PTSD becomes chronic in as many as 40% of cases [38]. An estimated 8% of Americans currently meet PTSD diagnostic criteria, but less than half receive minimally adequate treatment [39]. PTSD is often comorbid with depression, substance misuse, and suicidality, and often responds poorly to conventional treatments [40]. Few therapies target the trauma memories, considered the root cause of clinical expression, symptom chronicity and impairment in PTSD. The potential of neurostimulation to modulate dysfunctional brain regions led to clinical trials in PTSD [40].

OBSESSIVE-COMPULSIVE DISORDER

OCD has a lifetime prevalence of 2% to 3% and an early onset in adolescence or young adulthood. The core OCD symptoms are:

- Obsessions, which are unwanted, disturbing, and intrusive thoughts, images, or impulses generally perceived by the patient as excessive or irrational

- Compulsions, defined as repetitive behaviors and mental acts that serve to ameliorate obsessions and reduce emotional distress

The obsessions and compulsions are often highly distressing to the patient. OCD is a frequently debilitating and often severe [28].

Even with the currently available treatment options, OCD has a tendency to chronicity and can have a devastating effect on occupational functioning, relationships and social life. With standard therapies involving selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy plus exposure and response prevention, around half of patients achieve 40% to 60% symptom reduction. Roughly 10% of patients are refractory to standard therapies and may become profoundly disabled. OCD pathology is thought to involve dysfunction of the cortico-striato-pallido-thalamo-cortical pathway, failure of ventral striatum inhibition, and pathological hyper-connectivity between cortical and striatal structures [41].

SCHIZOPHRENIA

Schizophrenia is a chronic psychotic disorder characterized by disordered cognition, emotion and perception of reality, Patients may experience positive symptoms (hallucinations, delusions) and exhibit behaviors perceived as odd and bizarre. Negative symptoms may be present at any disease stage, and persistent symptoms can include affective flattening, attentional/motor impairment, alogia, avolition, asociality and anhedonia. These are grouped into the subdomains of diminished expression (affective flattening) and amotivation (avolition/apathy) [17].

Traditionally viewed as an illness defined by psychosis, successful schizophrenia treatment was defined as resolution of delusions and hallucinations. Recently recognized is the substantial impact of negative symptoms on functional impairment. Resolution of positive symptoms, even in early-stage schizophrenia, may not translate into functional recovery. Full functional/social recovery occurs in less than 15% of schizophrenics, largely due to negative symptoms [42].

Efforts have expanded the definition of successful treatment outcome beyond clinical recovery to incorporate functional recovery. This recent focus on the relevance of negative and cognitive symptom in functional recovery prompted research efforts into more broadly effective treatments, including brain stimulation. Neurostimulation targets were suggested by the results of modafinil treatment studies. Modafinil increases dorsolateral PFC activity, and in schizophrenic patients, improved working memory, emotion recognition, cognitive flexibility, motor activity, and quality of life [42].

To assess patient response to therapy, clinicians may use the Auditory Hallucinations Rating Scale (AHRS), a seven-item scale that assesses the number of voices experienced and voice frequency, loudness, vividness, attentional salience, length, and distress caused [22]. For schizophrenia with negative symptoms, the Positive and Negative Syndrome Scale (PANSS) may be useful. Using this measure, moderate-to-severe negative symptoms score ≥15 on the Negative Subscale [43].

SUBSTANCE USE DISORDERS

Substance use disorder is a chronic relapsing disorder even following optimal detoxification and treatment, and substance craving is an important contributor to relapse. The reward effects of alcohol and abused drugs are mediated by the mesocorticolimbic system, comprised of the ventral tegmental area (VTA), nucleus accumbens, amygdala, and prefrontal cortex [44]. Also involved in substance use disorder is abnormal reinforcement in brain reward circuitry, and inhibitory control mechanisms exerted by the dorsolateral PFC and other prefrontal cortical networks [17].

Nicotine dependence imposes significant morbidity, mortality, and socio-economic burdens. It remains among the leading causes of mortality worldwide, and of preventable deaths in developed countries. Despite availability of approved medications for nicotine dependence, only 6% of smokers who report wanting to quit each year are successful in doing so for longer than one month. This mostly results from poor abstinence rates, and therapeutic alternatives are urgently needed. Emerging positive evidence suggests that non-invasive brain stimulation with TMS or tDCS can reduce smoking-related behaviors [45].

EATING DISORDERS

Anorexia Nervosa

Anorexia nervosa is a disorder characterized by a pathological fear of food, eating and gaining weight, and sustained (more than three years) duration of significant underweight (body mass index [BMI] <18.5 kg/m^2) [46,47]. Onset is usually peri-pubertal and anorexia nervosa mainly affects girls and women. The lifetime prevalence of anorexia nervosa in women is 2% to 4%, median duration is 5 to 7 years, and illness duration is more than 15 years in 30% [47]. The disorder has a high mortality rate, and only 10% to 30% of adults with anorexia nervosa recover through the best available therapies [46].

Patients with anorexia nervosa have limited treatment options, especially with prior treatment nonresponse [47]. Pharmacotherapy is largely ineffective and poorly accepted [46]. Patients underweight for three to five years have worse treatment response and outcome, possibly from the neurotoxic effects of starvation and stress hormones (cortisol) to the brain. This makes the first years from onset critical for successful intervention [47].

Anorexia nervosa is associated with structural changes such as reduced grey matter in fronto-limbic-striatal areas; functional changes with over-active limbic drives from the insula and amygdala, and diminished prefrontal activity; and hypoactivity of PFC regions during response inhibition and set-shifting tasks, a marker of poor inhibitory control that promotes anorexia nervosa chronicity. Improved, neuroscience-based treatments are needed that target the neural substrates of anorexia nervosa [46].

The Eating Disorder Examination Questionnaire (EDE-Q) measures eating disorder symptoms and general psychopathology. This has been the most common measure of response to therapy in the literature.

Bulimia Nervosa

Bulimia nervosa is an eating disorder with recurrent episodes of binge eating characterized by eating large amounts of food in a discrete amount of time (i.e., within a two-hour period) and feeling of lack of control over eating during episodes; and recurrent inappropriate compensatory behavior to prevent weight gain (purging). The binge eating and compensatory behaviors both occur at least once a week, on average, for three months, and patient self-evaluation is unduly influenced by body shape and weight [28].

Similar to anorexia, reduced PFC activity may contribute to symptoms in bulimic patients through impaired inhibitory control of binge eating and purging; poor cognitive flexibility that perpetuates compulsive body checking and exercise; and obsessive pre-occupation with eating, weight and shape [46].

Binge-Eating Disorder

The lifetime prevalence of binge-eating disorder is roughly 5% of the U.S. adult population, and 1.2% to 4.5% are diagnosed with subthreshold binge-eating disorder and any binge eating. Compared to obese individuals who do not binge-eat, patients with binge-eating disorder are more prone to depression, anxiety, body dissatisfaction, low self-esteem, and social withdrawal [48].

Cognitive-behavioral therapy can reduce binge symptoms, but many patients lack response and treatment-related weight-loss is minimal. Effective and lasting treatments for binge-eating disorder are needed to alleviate symptoms of this psychological disorder and the medical consequences of obesity [48].

DEPERSONALIZATION/DEREALIZATION DISORDER

Depersonalization/derealization disorder is characterized by distressing feelings of unreality and alteration, with persistent or recurrent experiences of feeling detached from, as if an outside observer of, one's mental processes or body. The condition has an estimated prevalence of 1%, commonly begins in early adulthood and tends to become chronic [28]. Depersonalization/derealization disorder can appear as a symptom of other psychiatric disorders, including 12% of cases of panic disorder [49]. Depersonalization is a commonly described symptom in patients with temporal lobe epilepsy, and may occur with use of some illicit substances [50]. Several pharmacotherapies have been trialed but most have not led to sufficient symptom improvement [51,52]. The Cambridge Depersonalization Scale (CDS) may be used with these patients to assess response.

4. ELECTROCONVULSIVE THERAPY

CANDIDATES FOR ECT

During the course of its long history, ECT became stigmatized in the viewpoints of patients, most psychiatrists and the lay public. While not undeserved considering the past misuse and crude technique of this procedure, the persistence of stigma has outlived substantial refinements in method and established efficacy and represents a barrier to treatment.

ECT is reserved for use in complex and acutely severe clinical presentations of MDD; in these patients, ECT is considered unrivaled for rapid induction of antidepressant effects [7]. ECT is recommended as first-line treatment in the following patients: extremely severe melancholic depression; those who refuse to eat or drink; have a very high suicide risk; very high levels of distress; psychotic depression; refractory MDD; catatonia; or previous positive ECT response [53].

With psychotic depression, ECT is a first-line option, and highly effective; a large study of bitemporal ECT efficacy reported remission rates of 95% in study completers [53,54].

TREATMENT PARAMETERS IN ECT

ECT outcomes are highly influenced by electrode placements, electrical intensity, and pulse width. Electrode placements are generally right unilateral, bitemporal, or bifrontal [8].

Electrical intensity is the ECT "dose." The delivered electrical intensity dose is individualized and based on seizure threshold—the minimum intensity to induce a generalized seizure. Doses five to eight times seizure threshold maximize the efficacy of unilateral placement, while doses 50% to 100% above seizure threshold for bilateral placement are usually sufficient [53].

Pulse width in ECT includes brief pulse width and ultra-brief pulse width (≤0.5 ms) [8]. The recommended first-line parameter for ECT in MDD is right unilateral or bifrontal placement; second-line placement is ultra-brief pulse right unilateral or bifrontal, or brief pulse bitemporal placement [8]. If there is no response to right unilateral after four to six sessions, switch to bilateral bitemporal or bifrontal.

Twice/week ECT has similar efficacy to three times/week but requires longer treatment duration; more than three treatments/week are not recommended due to greater cognitive side effects [8].

Dose level above seizure threshold determines the relative efficacy of electrode placements but can increase cognitive side effects. Generally, bitemporal ECT is more effective than unilateral, but cognitive side effects are greater. At six times threshold, unilateral efficacy approaches bitemporal ECT, but cognitive impairment is greater than with lower doses. Bifrontal ECT is less studied, but appears as effective as high-dose unilateral and bitemporal placement. Research evidence is insufficient to conclude a cognitive benefit for bifrontal over bitemporal ECT, but clinical experience suggests bifrontal ECT may induce fewer cognitive side effects than bitemporal. Bifrontal ECT may be associated with lower rates of ECT-induced cardiac arrhythmia, suggesting a safety advantage over unilateral and bitemporal ECT in patients with cardiovascular comorbidity [53,55].

Ultra-brief pulse width unilateral ECT allows effective treatment with markedly fewer cognitive side effects. Ultra-brief pulse efficacy appears comparable to standard brief pulse unilateral ECT but may require more treatments to achieve remission. Ultra-brief pulse bifrontal ECT is effective in cognitive sparing but ultra-brief pulse bitemporal is ineffective and not recommended [53,56,57,58].

Efficacy is balanced against side effects. ECT for most patients should begin with ultra-brief pulse unilateral ECT, as this has fewer cognitive side effects but may require a longer treatment course. When speed and reliability of ECT response is crucial, as with patients who are dehydrated or at extreme risk for suicide, bifrontal or bitemporal ECT should be considered [53].

EFFICACY

ECT is one of the most rapidly effective treatments for MDD. Response rates can reach 70% to 80% and remission rates 40% to 50% or higher, depending on the patient population and electrode placements; remission rates of 55% for right unilateral, 61% for bifrontal, and 64% for bitemporal were reported in a population of patients with unipolar (77%) or bipolar (23%) depression [8,59].

After an acute course of ECT, relapse rates are high, and greatest in the first six months post-ECT (37.7%). Even patients receiving post-ECT maintenance showed high relapse rates at one year (51.1%) and two years (50.4%) [60].

PREDICTORS OF ECT RESPONSE AND RELAPSE

ECT nonresponse is strongly predicted by severity of previous treatment resistance. In highly treatment resistant patients, ECT response rates were roughly 50% versus 65% in patients without previous treatment failure [61,62].

Highest response rates are associated with older age, psychotic features, shorter MDD duration, less previous treatment non-response, and possibly lower depressive severity [8]. Lower relapse rates are found in MDD cohorts with higher proportions of psychotic patients and older patients. Pre-ECT medication resistance is not associated with relapse risk [8].

POST-ECT MAINTENANCE

Initial ECT response can be maintained with medication or ECT. Post-ECT antidepressant use reduces relapse rates by roughly 50% [60]. Strongest evidence supports the post-ECT relapse reduction efficacy of nortriptyline plus lithium or venlafaxine plus lithium, and both show comparable efficacy [63,64].

Patients continuing their antidepressants during ECT show lower relapse rates versus antidepressant initiation after ECT (29.2% vs 41.6%), suggesting concurrent instead of sequential use of ECT and medication improves long-term outcomes [60]. Lithium during ECT may increase risks of cognitive side effects, encephalopathy, and spontaneous seizures; benzodiazepines and anticonvulsants may raise seizure threshold and decrease seizure efficacy, but lamotrigine may be less problematic than other anticonvulsants [8,65].

Continuation/maintenance ECT is safe and effective for reducing relapse, and shows comparable efficacy to nortriptyline plus lithium in relapse rates at six months (37.2% vs 37.7%) [66,67]. The frequency of continuation/maintenance ECT should be tailored to the patient, but is typically weekly for four weeks, then biweekly for eight weeks, and then monthly. More frequent sessions can be added with signs of relapse [8].

There are few psychotherapy studies of post-ECT relapse prevention, but patients randomized to cognitive-behavioral group therapy plus continuation medication have shown lower relapse rates at 6 and 12 months compared to continuation/maintenance ECT plus medication or medication continuation alone [68,69].

ADVERSE EFFECTS OF ECT

The use of general anesthesia, muscle relaxants, oxygenation and monitoring has minimized ECT-related morbidity, and mortality is estimated at less than one death per 73,440 treatments. ECT-related damage to brain structures has not been found. Adverse effects of headaches (45%), muscle soreness (20%) and nausea (1% to 25%) during treatment are transient and treated symptomatically. Roughly 7% of patients with MDD switch into a manic or mixed state [8].

Cognitive impairment is the greatest concern, and includes transient post-ECT disorientation due to postictal confusion and general anesthesia; retrograde amnesia (difficulty recalling information learned pre-ECT), and anterograde amnesia (difficulty retaining information learned post-ECT) (Table 1). Mild, short-term impairment in memory and other cognitive domains often occur during, and just after, ECT [53].

Table 1: ECT-RELATED FACTORS WITH HIGHER VERSUS LOWER RISK OF SHORT-TERM COGNITIVE IMPAIRMENT

ECT-Related Factors

Short-Term Cognitive Impairment

Higher Risk

Lower Risk

Electrode placement

Bitemporal

Bifrontal, unilateral

Pulse width

Brief (1.0–1.5 ms)

Ultrabrief (0.3–0.5 ms)

Stimulation dose

Suprathreshold

Lower electrical dose

Treatment frequency

3 times/week

2 times/week

Concurrent medications

Lithium, agents with known cognitive side effects

Reducing or discontinuing these agents

Anesthesia

High–dose

Lower doses

Source: [8]

Anterograde and retrograde memory are variably affected. Within two to four weeks, impaired anterograde memory usually returns to normal or may improve versus pre-ECT levels [70]. Retrograde impairment can persist for prolonged periods [71]. Perhaps most distressing to some patients is loss of autobiographical memory recall. Patients have reported persistent retrograde amnesia beyond six months; researchers counter by stating these subjective complaints could not be confirmed with objective testing, concluding they reflect persistent depressive symptoms [72,73]. Patients and their immediate family/partner should be informed of the potential effects on memory before undergoing ECT [53].

Absolute contraindications to ECT have not been identified, but several factors are associated with increased safety risk, including [8,9]:

- Space-occupying cerebral lesion

- Increased intracranial pressure

- Recent myocardial infarction

- Recent cerebral hemorrhage

- Vascular malformation or unstable aneurysm

- Pheochromocytoma

- Class 4 or 5 anesthesia risk

5. TRANSCRANIAL MAGNETIC AND ELECTRIC STIMULATION IN PSYCHIATRIC DISORDERS

Important background information on rTMS and tDCS use that spans the range of psychiatric disorders is presented in this section, including factors that influence patient response, safety, and contraindications. Disorder-specific information is discussed further later in this course.

TRANSCRANIAL MAGNETIC STIMULATION (rTMS) IN PSYCHIATRY

Many psychiatric disorders have been evaluated in rTMS treatment, with the greatest evidence of efficacy in treatment-resistant depression [13]. Nicotine dependence is the most studied substance use disorder [12].

Concurrent Medications and rTMS Safety

Evidence Based Practice Recommendation

The safety guidelines for rTMS were determined in study participants who were largely free of antidepressant medications. While it is possible that psychotropic medication can affect the motor threshold, the National Network of Depression Centers and the American Psychiatric Association indicate there are no known absolute contraindications to psychotropic medication usage during rTMS. All medication use and change should be documented.

https://pmc.ncbi.nlm.nih.gov/articles/PMC5846193

Last Accessed: July 24, 2025

Level of Evidence: Expert Opinion/Consensus Statement

Potentially problematic medications commonly used in psychiatry and pain includes tricyclic antidepressants (nortriptyline, amitriptyline), antipsychotic drugs (chlorpromazine, clozapine), and antiviral medications. Abuse of alcohol or some illicit substances can increase cortical excitability and risk of a TMS-induced seizure. Withdrawal from CNS sedatives, including alcohol and benzodiazepines, increases seizure risk and patients must be asked about recent and current use. Recent substance abuse should be a contraindication to rTMS therapy [13]. The antidepressant bupropion is associated with increased seizure risk in some populations, raising concerns of its use during rTMS therapy. A systematic review found no evidence that supports excluding patients taking bupropion from rTMS [74].

Adverse Effects with rTMS

Seizure induction is the most serious adverse effects with rTMS, but fewer than 25 cases have been reported worldwide to date. The estimated incidence of spontaneous seizures is 0.01% to 0.1% with rTMS, 0.1% to 0.6% with antidepressant drugs, and 0.07% to 0.09% in the general population. HF-rTMS is contraindicated in patients with seizure history. Safety of LF-rTMS has been demonstrated in patients with epilepsy but is not established in patients with depression and seizures. Seizure history is usually considered an absolute contraindication [8].

Contraindications to rTMS

Evidence Based Practice Recommendation

According to the National Network of Depression Centers and the American Psychiatric Association, a comprehensive review of the patient's health status (including historical and current medical, surgical, neurologic, and psychiatric conditions and medications) and physical examination are evaluation components to determine the medical safety and necessity of rTMS.

https://pmc.ncbi.nlm.nih.gov/articles/PMC5846193

Last Accessed: July 24, 2025

Level of Evidence: Expert Opinion/Consensus Statement

Absolute contraindications to rTMS are ferromagnetic metal in the head (e.g., plates or pins, bullets, shrapnel) and metallic hardware anywhere in the head, except the mouth (e.g., Cochlear implants, brain stimulators or electrodes, aneurysm clip) [8,13]. Relative contraindications include [8,13]:

- Presence of a brain lesion (vascular, traumatic, neoplastic, infectious or metabolic) or major head trauma

- Ferromagnetic metal in neck or chest

- Microprocessor implants in the neck, such as vagus nerve stimulator

- History of epilepsy or induced seizures

- Microprocessor implants below the neck: Spinal pumps or stimulators, cardiac pacemaker, implantable defibrillator

- Medications that lower seizure threshold

- Recent withdrawal from CNS sedatives that raise seizure risk (e.g., alcohol, benzo-diazepines)

- Pregnancy

- Hearing loss, tinnitus

TRANSCRANIAL DIRECT CURRENT STIMULATION (tDCS) IN PSYCHIATRY

Compared with rTMS, tDCS is more recently introduced, with fewer published efficacy and safety studies in psychiatric disorders. Antagonist effects on tDCS treatment response from two drug agents were first identified in a 2016 review of tDCS in psychiatric disorders [16]. Nicotine inhibits schizophrenic patient response to tDCS. This effect is confirmed experimentally, and evident empirically in tDCS studies outcomes of schizophrenia; higher rates of current smokers repeatedly showed direct association with lower tDCS response rates [16]. In patients with MDD, co-use of benzodiazepines blunts therapeutic response to tDCS [16].

The efficacy-disrupting effects of concurrent benzodiazepine use in MDD trials and cigarette smoking in schizophrenia trials was not previously known, and throws reported outcomes of tDCS studies with negative or ambiguous findings into question (unless patient prevalence of benzodiazepine use or smoking was recorded) [16].

Serotonergic neurotransmission is enhanced by SSRI antidepressants, which facilitates neural excitation of anodal tDCS, but switches the inhibited excitability of cathodal tDCS to facilitated excitability. Similar effects are found with amphetamine, and the NMDA receptor agonist D-cycloserine [18].

Mood stabilizer antiepileptic agents interfere with tDCS-elicited excitability changes by blocking voltage-gated sodium and calcium channels [75].

Dopaminergic agents variously interact with tDCS to amplify or block the intended effects. Neuroleptics and other dopamine receptor antagonists suppress tDCS effects, while dopaminergic agonists have a non-linear synergistic effect on tDCS-induced excitability, and a prolonging effect on excitability inhibition. This may be relevant to the reduced tDCS effects in smokers during nicotine withdrawal [76].

Several biological, psychological, and lifestyle factors have been identified that influence tDCS response and contribute to the variable efficacy in tDCS trials [16]. COMT gene polymorphism moderated tDCS effects in patients with schizophrenia [77]. Prefrontal tDCS intensified cravings in patients with substance use disorder with drug-related cues present [78]. tDCS shows greater therapeutic effect in more severe MDD than in mild/moderate MDD [79]. Finally, severity of treatment-resistance in MDD negatively influences tDCS response, although attention should be paid to how treatment-resistance is defined [16].

Safety

Using conventional tDCS protocols (sessions ≤40 min, ≤2 times/day, ≤4 mA, electrodes that minimize skin burns), repeated sessions in more than 1,000 subjects receiving more than 33,200 sessions has not produced any reports of serious adverse events or irreversible injury to date. This includes diverse subject populations and patients from vulnerable populations [16,80]. Reports in the published evidence include patients receiving more than 100 tDCS sessions without adverse events from cumulative exposure; lack of unexpected or serious adverse events in more than 40 studies with more than 600 older adults; lack of decrements in behavior or mood in stroke populations; and no finding of drug agents that increase risk of serious adverse effects [80].

Seizure concerns with TMS have spread to tDCS, but evidence of increased seizure risk with tDCS is absent. tDCS produces static and not pulsed electric fields that are two orders of magnitude below those of rTMS, ECT and transcranial electrical stimulation, and thus, no apparent seizure risk [80].

6. NEUROMODULATION FOR MAJOR DEPRESSIVE DISORDER (MDD) AND AFFECTIVE DISORDERS

REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION (rTMS)

As a medical intervention with seizure risk, rTMS should only be performed in a medical setting under physician guidance and supervision. The medical team should include a psychiatrist when used as treatment for acute depression, and psychiatrists who use TMS benefit from training in brain stimulation methods [19].

Clinical guidance regarding the recommended approach to administering rTMS and theta-burst stimulation has been established for patients with MDD [8]. The initial session should stimulate at 110% to 120% of resting motor threshold (or 70% to 80% for theta-burst stimulation). The stimulation frequency and site should be selected (Table 2). Stimulations should be performed five times per week. The initial course is usually 20 sessions over a four-week period; this may be extended to 30 sessions (over six weeks) in non-remitting partial responders. Patients may return to this therapy as needed to maintain response.

Table 2: RECOMMENDED rTMS AND TBS PROTOCOLS IN MDD

Approach

Intensity and Site

First-line

HF-rTMS to left DLPFC

LF-rTMS to right DLPFC

Second-line

Bilateral rTMS to DLPFC (left HF and right LF)

LF-rTMS to right DLPFC (if nonresponse to left DLPFC HF-rTMS)

HF-rTMS to left DLPFC (if nonresponse to right DLPFC LF-rTMS)

TBS protocols:

- Intermittent TBS to left DLPFC

- Left intermittent and right continuous TBS to DLPFC

- Intermittent TBS to bilateral DMPFC

Third-line

HF-rTMS to bilateral DMPFC

DLPFC = dorsolateral prefrontal cortex, DMPFC = dorsomedial prefrontal cortex HF-rTMS = high-frequency rTMS, LF-rTMS = low-frequency rTMS, MDD = major depressive disorder, rTMS = repetitive transcranial magnetic stimulation, TBS = theta-burst stimulation.

Source: [8]

Unless otherwise stated, in the studies discussed in this section, HF-rTMS is applied to the left dorsolateral PFC, and LF-rTMS to the right dorsolateral PFC.

Most studies of rTMS in MDD have involved patients with some degree of treatment resistance (at least one to two failed antidepressant trials). Overall, rTMS is considered a first-line treatment for patients with MDD and at least one failed antidepressant trial [8].

Efficacy is established with both HF-rTMS and LF-rTMS of the left and right dorsolateral PFC, respectively. Differences in outcome are few, although LF may require shorter treatment duration. Non-responders of HF may respond to LF, and vice versa. Bilateral stimulation combines HF left and LF right dorsolateral PFC, but requires intensive setup but is not superior to unilateral approaches [8].

Evidence Based Practice Recommendation

A European consortium of experts found definite antidepressant efficacy of deep HF-rTMS over the left DLPFC in major depression.

https://www.sciencedirect.com/science/article/pii/S1388245719312799

Last Accessed: July 24, 2025

Level of Evidence: A (Definitely effective or ineffective based on at least two Class I studies or one Class I study and at least two Class II studies)

rTMS efficacy is established in treatment-resistant depression using the most stringent criteria. A meta-analysis of HF-rTMS in patients with treatment-resistant depression found significantly greater efficacy and effect size over sham [81]. randomized sham-controlled trials of HF-rTMS using adequate sessions (20 to 30) and treatment durations (≥4 weeks) achieved 40% to 55% response and 25% to 35% remission rates, similar to results of uncontrolled trials showing 58% response and 37% remission rates [82]. A meta-analysis also found superior remission rates with LF-rTMS (35%) versus sham (10%) [83].

HF-rTMS of the dorsomedial PFC (DMPFC) produces antidepressant effects. A randomized controlled trial found slightly better outcomes for DMPFC rTMS, while an uncontrolled trial of DMPFC rTMS reported 50% response and 36% remission rates [84,85,86].

Post-rTMS Maintenance of Efficacy

Relapse is frequent after successful rTMS without maintenance treatment. An uncontrolled study reported a median 120 days until relapse, with 25%, 40%, 57%, and 77% relapsing at 2, 3, 4, and 6 months, respectively [87]. In contrast, rTMS maintenance as needed over 12 months in 257 patients was able to sustain remission in 71% of remitters, and response in 63% of responders [88]. Another study found 38% of rTMS responders relapsed within 24 weeks (mean: 109 days post-treatment). With reinstatement of as-needed rTMS, 73% met response and 60% met remission at 24 weeks [89].

A 20-week gradual taper of maintenance rTMS (from 3 sessions/week to 1 session/month) was compared to no maintenance, and relapse rates were 38% with maintenance versus 82% without maintenance. Five "clustered" maintenance sessions over three days every month extended the mean relapse to 10.8 months [8,90,91].

rTMS versus ECT

The available evidence suggests ECT is generally more rapid and effective in antidepression effects, with greater side effects and lower patient acceptance than rTMS. An open-label study compared efficacy and patient acceptance of ECT versus rTMS in outpatients with treatment-resistant depression. While both therapies significantly improved depression scores, benefits were greater with ECT than rTMS, and anxiety symptoms decreased with ECT but not rTMS. Patients who received ECT reported they would have chosen rTMS if it had been financially available, even when informed rTMS was less effective than ECT for treatment-resistant depression. The authors stated this reflects the level of stigma that surrounds ECT [29].

A meta-analysis compared the efficacy of ECT and rTMS in MDD. ECT was superior to HF-rTMS in response (64.4% vs 48.7%) and remission (52.9% vs 33.6%), and discontinuation was similar (8.3% vs 9.4%). ECT was superior in psychotic depression, but HF-rTMS and ECT were comparable in non-psychotic depression. ECT had a slight advantage over rTMS in overall improvement in HAM-D scores. Data on medium or long-term efficacy was insufficient. The same results were found with ECT versus LF-rTMS. ECT led to greater impairment in cognitive domains such as visual memory and verbal fluency. ECT and rTMS seemed comparably effective in patients with MDD without psychosis, but ECT was more effective with psychotic depression [92].

Other meta-analyses found larger differences favoring ECT for all outcomes, especially in MDD with psychotic features. rTMS response is poor in patients with ECT failure, and rTMS should be considered before pursuing ECT because patients lacking ECT response are unlikely to benefit from rTMS [8].

rTMS and Antidepressants

rTMS has mostly been evaluated as an add-on therapy to stable antidepressant regimens, and no evidence shows outcomes are improved by discontinuing antidepressants before rTMS. However, some evidence suggests that initiating antidepressants during rTMS promotes higher response and remission rates than rTMS alone [8,83].

In patients with treatment-resistant depression receiving LF-rTMS, responders showed lower psychomotor retardation at baseline than non-responders, and ex-smokers showed substantially higher response rates than current smokers [93].

Adverse Effects

The most frequent adverse effects were scalp pain during stimulation (40%) and transient headache after stimulation (30%). Both diminish with repeated treatment, respond to over-the-counter analgesics, and resulted in few study dropouts. The cognitive safety profile of rTMS appears benign; studies that assessed rTMS and cognitive performance found no differences between active and sham rTMS [8,94].

Unresolved Issues

Although published evidence suggests that daily prefrontal rTMS has a significantly greater antidepressant effect than sham, with a magnitude of effect at least as large as antidepressant drugs, some issues remain unresolved [19]. The optimal hemisphere and position of coil placement remains unclear in depression treatment. Whether coil placement using individualized location via neuronavigated methods is superior to general algorithms for probabilistic positioning is not clear. Also, duration of rTMS treatment and patient follow-up are inadequate in many older studies.

Deep rTMS

Personality traits such as extraversion and neuroticism have attracted increasing attention as characteristics in predicting MDD response to pharmacotherapy, psychotherapy, and more recently, neuromodulation. Deep rTMS allows stimulation of deeper cortical regions, and the influence of personality dimensions in antidepressant response to deep rTMS in treatment-resistant depression was evaluated. After four weeks of daily deep rTMS (20 Hz, 3,000 pulses/session) of the left dorsolateral FPC, clinical remission was associated with higher baseline levels of agreeableness and conscientiousness. Levels of agreeableness and extraversion were linearly associated with antidepressant response. Neuroticism was not associated with antidepressant effects. Five-factor personality assessment may have prognostic value in deep rTMS for treatment-resistant depression, as agreeableness, extraversion, and conscientiousness were associated with reductions in depressive symptoms during treatment [95].

Theta-Burst Stimulation

A variation of rTMS is theta-burst stimulation. In MDD, theta-burst stimulation is delivered at lower intensities than rTMS (70% to 80% of active motor threshold) and requires only one to three minutes of stimulation [8]. Studies of both theta-burst stimulation types suggest lasting effects on cortical excitability that exceed standard rTMS. Increased cortical excitability with intermittent theta-burst stimulation has persisted longer than HF-rTMS. With continuous theta-burst stimulation, persistence in reduction of cortical excitability has been less consistent. Enthusiasm over the promising rapid effects on synaptic plasticity with theta-burst stimulation should be tempered by the highly variable patient response [19].

Small randomized controlled trials of dorsolateral PFC theta-burst stimulation showed superiority over sham with left intermittent theta-burst stimulation but not right continuous theta-burst stimulation, with bilateral stimulation (left intermittent/right continuous) showing mixed results. Data on bilateral DMPFC theta-burst stimulation suggest similar outcomes between intermittent theta-burst stimulation and longer conventional 10-Hz rTMS. Randomized controlled trial of conventional rTMS and theta-burst stimulation are in progress [8].

A randomized sham-controlled trial of 20 sessions found intermittent theta-burst stimulation safe, and resulted in immediate statistically significant decreases in depressive symptoms versus sham. After the two-week double-blind protocol, only 28% of patients showed ≥50% reduction in depression scores, but response rates increased to 38% an extra two weeks later to indicate delayed clinical effects. Importantly, 30% of the responders were in clinical remission. The findings suggest that only four days of accelerated intermittent theta-burst stimulation treatment in treatment-resistant depression may lead to meaningful clinical responses within two weeks post-stimulation [96].

Intermittent theta-burst stimulation was examined in a crossover randomized sham-controlled trial of 50 suicidal, antidepressant-free patients with treatment-resistant depression. Patients received 20 intermittent theta-burst stimulation sessions over four days, and the alternate condition (active or sham) at study day 7. This study found a significant decrease in suicide risk, lasting up to one month, unrelated to active or sham stimulation and unrelated to depression response. A high placebo response to sham was noted in those receiving sham intermittent theta-burst stimulation before they crossed over to active intermittent theta-burst stimulation. None of the patients committed suicide until six months after intermittent theta-burst stimulation treatment [97].

Magnetic Seizure Therapy

A randomized controlled trial of magnetic seizure therapy versus unilateral ECT found similar rates of response (60% vs 40%) and remission (30% vs 40%). A large uncontrolled magnetic seizure therapy trial reported a 69% response rate and a 46% remission rate, similar to published ECT outcomes [98,99]. Studies evaluating magnetic seizure therapy versus sham stimulation, relapse following magnetic seizure therapy, or relapse prevention await publication [8].

Magnetic seizure therapy has shown lower rates of headaches and muscle aches than ECT, without noticeable anterograde or retrograde amnesia. Reorientation time (time from seizure and anesthesia emergence to fully oriented by person, place, and time) was briefer with magnetic seizure therapy (2 to 7 minutes) than ECT (7 to 26 minutes). The sole randomized controlled trial in magnetic seizure therapy (versus unilateral ECT) found comparable neuropsychological testing results after 12 treatments [98,100].

TRANSCRANIAL DIRECT CURRENT STIMULATION IN MDD

The first published trial of tDCS in depressive disorders appeared in 2006. Almost all affective disorder studies have evaluated tDCS treatment in unipolar MDD [17,101].

The number of sessions, and anode/cathode polarity are thought to influence tDCS efficacy [16]. Most MDD have trials consist of placement of the anode over the left dorsolateral PFC and cathode over a noncortical region, or left dorsolateral PFC anodal stimulation combined with right dorsolateral PFC cathodal stimulation (bilateral tDCS). Minimum stimulation with 2 mA for ≥30 minutes per day over two weeks is required for an antidepressant effect.

With these parameters, six-week remission rates were higher in tDCS plus sertraline (47%) versus tDCS (40%) or sertraline (30%) alone, suggesting tDCS may potentiate antidepressant effects [102,103]. tDCS may also enhance psychotherapy outcomes [8,9]. Data from randomized sham-controlled trials suggest that multiple session tDCS can induce durable benefit in patients with MDD [16].

Treatment of Acute MDD Episodes

A review of six randomized sham-controlled trials found active tDCS significantly superior to sham in response (34% vs 19%), remission (23.1% vs 12.7%), and improvement in depression. Treatment-resistant depression and higher tDCS "doses" were negative and positive predictors of tDCS efficacy, respectively. The authors concluded the tDCS treatment effect size was comparable to those of rTMS and antidepressant drug treatment in primary care [104].

A meta-analysis of tDCS in MDD evaluated improvement in HAM-D scores, and a moderate-large effect size was found that favored active tDCS over sham. Two additional randomized sham-controlled trials were added, effect sizes were calculated for response and remission, and active tDCS was found not superior to sham in response or remission. Closer examination of the involved studies indicated that tDCS showed negative results in studies with high treatment resistance samples, and positive results in studies where subjects were lower in treatment non-response. Concurrent use of antidepressants, mood stabilizers, or benzodiazepines hampered patient response to tDCS. As such, tDCS seems efficacious for the treatment of depression, but it is not recommended in treatment-resistant depression or as an add-on to medication [75].

Maintenance of Acute Response

Several studies have evaluated persistence of acute effects and relapse following initial tDCS treatment, and strategies to prevent relapse. In one study, three months after completion of acute tDCS treatment, antidepressant effects persisted in almost half (47.8%) of patients without maintenance tDCS, and the need to prolong acute tDCS efficacy was noted [105].

Following clinical response to acute treatment, subjects received continuation tDCS every week for three months, and then every two weeks the final three months. Cumulative relapse-free survival was 83.7% at three months and 51.1% at six months; with decreased continuation tDCS at three months, relapse increased from 16.3% to 48.9%. Medication resistance was the greatest predictor of relapse during continuation tDCS [106].

Another study of tDCS relapse followed subjects 24 weeks. After response to acute treatment, subjects received up to nine tDCS sessions every two weeks for three months, followed by one tDCS session/month for three months. The mean response duration was 11.7 weeks, and relapse-free survival rate at 24 weeks was 47%. Patients with treatment-resistant MDD showed substantially worse 24-week survival versus patients with non-depression (10% vs 77%) [107].

tDCS versus Antidepressants

In a double-blind trial, patients with MDD were randomized to active tDCS, sham tDCS and fluoxetine 20 mg. More rapid improvement in depressive symptoms occurred with active tDCS than with fluoxetine, and after six weeks, active tDCS and fluoxetine showed the same improvement in depression scores and were significantly superior to sham [108].

Another study randomized 120 patients with MDD to active or placebo sertraline 50 mg plus active or sham tDCS in a four-arm trial. The combined active sertraline plus active tDCS was superior to all other groups, both groups with one active agent (sertraline or tDCS) did not differ and were superior to the group with placebo plus sham. Of note is that sertraline and tDCS were started concurrently in non-resistant patients, which could account for the additive effect rather than blocked response seen with tDCS as an add-on to stable but marginally ineffective antidepressants [109].

Side Effects

At present, tDCS trials are reviewed and conducted in accordance with the Non-Significant Risk U.S. Food and Drug Administration (FDA) designation for medical devices [80]. tDCS is generally well-tolerated. Frequent adverse events (>50%) include reddening of the skin, itching, burning, heat, and tingling sensations at the site of electrode placement. Sporadically reported adverse events with similar rates between active tDCS and sham include nausea, euphoria, reduced concentration, and anxiety. Study dropout rates from adverse events are comparable for tDCS and sham (both 3%), but long-term data on safety and tolerability are lacking [8]. No post-acute side effects emerged during follow-up in the longer-term maintenance studies [105].

tDCS is recommended as a third-line treatment for MDD, with more research needed to establish optimal stimulation parameters [8]

7. NEUROMODULATION FOR OTHER MENTAL HEALTH DISORDERS

NEUROMODULATION FOR BIPOLAR II DEPRESSION AND BIPOLAR DISORDER

The depressive phase of bipolar disorder has few published studies, and treatment of manic symptoms in even fewer studies. Brain stimulation in bipolar disorder has used the parameters in unipolar depression treatment, but important differences between the two disorders require tailored stimulation for bipolar disorder [110].

In patients with bipolar II depression, quetiapine plus four weeks of HF-rTMS, LF-rTMS, or sham found quetiapine/active rTMS did not differ from quetiapine/sham on any outcome measure [111]. The few tDCS studies in bipolar depression or mania found some support but used small patient numbers [17,101].

ANXIETY DISORDERS AND ANXIETY-RELATED DISORDERS

Unless stated otherwise in this section, rTMS targets are HF-rTMS of the left dorsolateral PFC, and LF-rTMS of the right dorsolateral PFC. The efficacy of rTMS in anxiety symptom reduction was evaluated in 14 randomized sham-controlled trials, primarily involving patients with PTSD or OCD. Active TMS was not clinically or statistically superior to sham in reducing anxiety symptoms in patients with OCD, PTSD, or panic disorder [112]. It should be noted that while clinically relevant anxiety can be present in patients with PTSD or OCD, these conditions are no longer classified as anxiety disorders by the DSM-5-TR because their core features differ in pathological basis and clinical presentation from anxiety disorders (e.g., GAD, panic disorder) [28].

Few studies have evaluated tDCS in anxiety disorders. However, tDCS modulation of dorsolateral PFC activity led to significant reductions in fear vigilance to threatening stimuli, similar to that observed with anxiolytic treatments. This finding that tDCS acutely altered the processing of threatening information suggests a potential mechanism that could be harnessed for treatment of clinical populations. These results were obtained from healthy volunteers [113].

Generalized Anxiety Disorder

A randomized sham-controlled trial evaluated 30-session (over six weeks) LF-rTMS in 25 patients with GAD. Patients undergoing active rTMS (versus sham) experienced higher response rates (71% vs 25%) and significant reductions in anxiety, worry, and depressive symptoms. At three months post-rTMS, 43% of active rTMS patients showed remission, versus 8% with sham. Response rates with active rTMS were maintained during follow-up, with some additional gains in remission rates. At post-treatment, right dorsolateral PFC activation was increased for active rTMS only, and changes in neuroactivation significantly correlated with changes in worry symptoms. These findings provide preliminary evidence that rTMS may improve GAD symptoms by modifying neural activity in the stimulation site [114].

A secondary analysis study was performed to determine if dorsolateral PFC neuromodulation improved emotion regulation in patients with GAD [114]. Statistically significant improvements in self-reported emotion regulation difficulties were found at post-treatment and three-month follow-up with active rTMS only. Improvements primarily involved the domains of goal-directed behaviors and impulse control, and were significantly associated with global clinician ratings of improvement. These preliminary results support rTMS as a treatment for GAD and suggest improved emotion regulation as a possible mechanism of change [34].

Bilateral LF-rTMS was evaluated in 13 patients with comorbid GAD and MDD, who received 24 to 36 rTMS sessions over five to six weeks. Following the last treatment, 11 of 13 (84.6%) patients achieved remission in anxiety symptoms (<5 on the GAD-7), and 10 of 13 patients (76.9%) achieved remission in depressive symptoms (<8 on the HAM-D). In this small pilot study, most patients with comorbid GAD/MDD achieved significant improvement in anxiety and depressive symptoms after bilateral rTMS [115].

Panic Disorder

In two randomized sham-controlled trials of LF-rTMS, patients with panic disorder were treated for two or four weeks as augmentation therapy. Active rTMS was superior to sham in reducing panic symptoms in one trial, and all patients showed improvement with no differences between active and sham in the other trial. The available data were insufficient to draw conclusions about rTMS efficacy in panic disorder [14].

Deep rTMS and Anxiety Reduction

The anxiolytic effects of deep rTMS in MDD patients were reviewed. Data from six open-label studies found that relative to baseline, large anxiolytic and antidepressant outcomes were obtained after 20 daily sessions of high-frequency deep rTMS. Unlike the antidepressant effect, anxiolytic effects were more heterogeneous across studies, and unrelated to concurrent antidepressant treatment [116].

POST-TRAUMATIC STRESS DISORDER

In 20 veterans, LF-rTMS for 10 sessions led to significant improvement in core symptoms of PTSD and depression versus sham. Improvements persisted for two months post-rTMS, and declined over time [117].

A meta-analysis of five randomized sham-controlled trials found rTMS significantly superior to sham in reducing PTSD core symptom scores. No single stimulation frequency (1 Hz vs 20 Hz) target (left vs right dorsolateral PFC) or mode (rTMS vs deep TMS) differed markedly in effect [118].

In a chart review of 10 patients who received five treatments of 5-Hz rTMS for comorbid PTSD and MDD, significant reductions were observed in 80% patients for PTSD symptoms, and 60% patients for MDD symptoms. The intermediate pulse frequency of 5-Hz may be effective in patients with PTSD and serious comorbidity and was well-tolerated without serious adverse effects [119].

Deep rTMS in PTSD

Following three sessions per week for four weeks of deep rTMS or sham to the medial prefrontal cortex (mPFC) in 30 patients with PTSD, significant improvement in intrusive symptoms was observed (mean reduction: 31%) with active but not sham deep rTMS. This suggested the potential of deep rTMS to treat core PTSD symptoms and suggests a role of mPFC hypoactivity in presentation of the disorder [40,120].

OBSESSIVE-COMPULSIVE DISORDER (OCD)

rTMS and tDCS have been increasingly researched in OCD. In clinical trials, LF-rTMS of the supplementary motor area, orbital frontal cortex, or right dorsolateral PFC shows the most promising efficacy, while older studies targeting the prefrontal dorsal cortex were not as successful. Larger-scale investigations of tDCS have yet to be published in OCD [1].

Patients with OCD were randomized to rTMS frequencies of 1 Hz, 10 Hz, or sham of the right dorsolateral PFC for 10 sessions. Patients were assessed after the last session and three months later. Compared with 10 Hz or sham, 1 Hz led to significantly greater improvements in obsessive-compulsive and anxiety symptoms, greater clinical benefit, and significantly larger percentage change in global improvement. One Hz LF-rTMS of the right dorsolateral PFC is a promising treatment approach in OCD [121].

The efficacy of rTMS in OCD was evaluated by reviewing 15 randomized sham-controlled trials. rTMS was significantly superior to sham for OCD symptom reduction. The risk of publication bias was low, and between-study heterogeneity was low. Meta-regression showed no particular influence of any variable on the results. In all, rTMS was superior to sham for amelioration of OCD symptoms [122].

In two trials, patients with treatment-resistant OCD received rTMS or sham for two and four weeks. Compared with sham, active rTMS led to significantly greater improvements in symptom severity; and cognitive performance in auditory perception, visual perception, short-term memory, and processing speed [123,124].

TOURETTE SYNDROME

Open-label trials suggested LF-rTMS of the supplementary motor area in patients with Tourette syndrome may be effective, but a randomized sham-controlled trial found no benefit [125].

SCHIZOPHRENIA WITH AUDITORY VERBAL HALLUCINATIONS

In rTMS studies of patients with schizophrenia with auditory verbal hallucinations, evaluation of placebo response found a significant effect size of placebo response in parallel studies but not crossover studies. The authors suggest that placebo effect should be considered a source of bias in open-label trials and randomized sham-controlled trials without documented efforts to improve concealment of active rTMS [126].

Studies of rTMS treatment in schizophrenic symptoms such as auditory hallucinations have found contradictory results. A review of 10 randomized sham-controlled trials using LF-rTMS reported a positive effect size favoring rTMS over sham, with the left temporoparietal cortex appearing an effective target [127]. Studies published after 2013 were not available for this review. A study of HF-rTMS to the left temporoparietal cortex over 2 days found no difference between active rTMS or sham [128]. The overall sham-controlled outcomes of rTMS to the left temporoparietal cortex are mixed; even when rTMS was effective following 10 sessions, treatment effect began dissipating one month later [129].

Auditory verbal hallucinations are commonly observed persistent symptoms in schizophrenia, even when patients are stabilized by antipsychotic medication. The primary indication for tDCS in psychotic disorders is reduction of auditory verbal hallucinations. Eliminating or reducing these debilitating residual symptoms requires inhibition of neuronal activity of the left temporoparietal junction (TPJ) that mediates auditory verbal hallucinations [17].

Most tDCS treatment studies in schizophrenia have used anode placement over the l-dorsolateral PFC and the cathode over the left TPJ. After 10 twice-daily sessions, this placement has been consistently shown in sham-controlled randomized controlled trials to ameliorate symptoms of the illness, with robust reductions in auditory verbal hallucinations at acute and three-month follow-up, improvements in other schizophrenic symptoms, and substantive decreases in treatment-resistant auditory verbal hallucination frequency. Further support for this tDCS protocol comes from uncontrolled trials of schizophrenic patients with persistent auditory verbal hallucinations, with significant reductions in psychotic and auditory verbal hallucination symptoms reported. Several case reports described refractory schizophrenic patients who achieved responses ranging from significant reductions in psychotic and auditory verbal hallucinations, to full remission. Greater therapeutic response in nonsmokers was noted [16].

In a randomized sham-controlled trial of tDCS to the left TPJ in patients with schizophrenia with auditory verbal hallucination and negative symptoms, acute beneficial effects in negative symptoms and prolonged (up to three months) reductions in auditory verbal hallucination were observed with active tDCS [130].

Active vs sham frontotemporal tDCS was evaluated by functional MRI for effects on auditory verbal hallucinations and resting-state functional connectivity of the left temporo-parietal junction in schizophrenic patients. Reductions in hallucination severity following active tDCS correlated with decreased functional connectivity between the left TPJ, the left anterior insula and the right inferior frontal gyrus; and with increased functional connectivity between the left TPJ, the left angular gyrus, left dorsolateral PFC and the precuneus, regions that mediate language-related and self-other recognition networks [131].

A series of motor-evoked potential studies in schizophrenic patients found diminished excitability and enhanced neuroplasticity with anodal or cathodal tDCS [17].

SCHIZOPHRENIA, NEGATIVE SYMPTOMS

Earlier meta-analyses found rTMS benefitted negative symptoms, with effect sizes ranging from non-significant and small to very large. This large range reflected differences in study duration, stimulus frequency, outcome measures, and illness duration [42]. A randomized sham-controlled trial found treatment response with active rTMS was sustained over 24-week follow-up, but a large, randomized sham-controlled trial failed to show greater benefit with active versus sham rTMS [132,133]. Many factors known to influence rTMS response make it difficult to reconcile negative findings with those from numerous earlier reports [42].

In patients with schizophrenia with predominant negative symptoms, 15 sessions of 10-Hz rTMS to the left dorsolateral PFC for three weeks was not superior to sham for improving schizophrenic cognitive domains, in contrast to previous preliminary findings [134].

A randomized sham-controlled trial evaluated 2 mA tDCS of the bilateral dorsolateral PFC. After 10 daily sessions, statistically significant reductions in PANSS negative, general, and total scores occurred with active tDCS, but not sham [135].

tDCS-induced neural changes, measured by EEG oscillations, were assessed in patients with schizophrenia following tDCS to the left dorsolateral PFC. A significant increase in gamma synchronization in the dorsolateral PFC was found with 2-mA tDCS but not 1-mA or sham. Increased gamma synchronization correlated with improved working memory performance, suggesting that 2-mA tDCS may modulate neural synchrony, and restore neural and behavioral functioning in schizophrenia [136].

Building on this, 20 patients with schizophrenia with predominant negative symptoms were randomized to 10 sessions of active 2-mA or sham tDCS to the left dorsolateral PFC and received imaging by functional connectivity MRI (fcMRI). Negative symptom scores decreased 36% with tDCS (sham: 0.7%). Analysis of MRI indicated changes in subgenual cortex and dorsolateral PFC connectivity within frontal-thalamic-temporo-parietal networks in the active but not sham group [137].

Smoking Status and tDCS Response

The rate of current tobacco use disorder in clinical samples of patients with schizophrenia is 62%, significantly higher than in the general population and in other psychiatric disorders [138]. This high prevalence is thought to arise from nicotine-induced improvements in working memory, selective attention, and cognitive impairments in patients with schizophrenia. These nicotine effects are linked to stimulation of the alpha7-nicotinic acetlycholine receptor, which enhances thalamo-cortical functional connectivity and dopamine release regulation. Nicotine can modify neuroplasticity, and in contrast to nonsmokers, single-session, excitability-diminishing cathodal tDCS does not induce plasticity in patients with schizophrenia who smoke [139].

Neural plasticity induced by tDCS may differ between patients with schizophrenia who do and do not smoke. This was explicitly investigated in the first-ever study that evaluated the effects of cigarette smoking on tDCS response in patients with schizophrenia. Patients with schizophrenia with treatment-resistant auditory verbal hallucination received 10 sessions of frontotemporal tDCS (2 mA). Auditory verbal hallucinations symptoms decreased 20% in the entire sample, 46% in nonsmokers, and 6% in smokers. When response was defined as ≥25% symptom reduction, 83% of non-smokers vs 20% of smokers were responders. tDCS had no effect on cigarette use. This was the first published report to describe the impairing effect on tDCS response and efficacy in patients with hallucinatory schizophrenia who are actively smoking. Adjustment for age, medication use, and illness duration did not impact this effect [140].

Combined Therapies in Refractory Schizophrenia

Many (40% to 70%) patients with treatment-resistant schizophrenia remain symptomatic despite an adequate clozapine trial [141]. Brain stimulation approaches are promising for these patients, but clozapine co-administration has raised safety concerns. Studies have been reviewed to determine if this safety issue was resolved. While ECT is effective in clozapine-refractory schizophrenia, safety with the combination is not known. Until sufficient data accumulate, vigilance for adverse effects related to lowered seizure threshold, cognitive impairment, and cardiovascular events is required. In patients receiving clozapine, HF-rTMS over the dorsolateral PFC and LF-rTMS over the temporo-parietal cortex are safe, but efficacy is uncertain [141].

SUBSTANCE USE DISORDERS

The dorsolateral PFC plays a key role in self-regulatory control mechanisms and is a common brain stimulation target in disorders of fronto-limbic dysregulation. rTMS of the dorsolateral PFC has demonstrated potential in reducing addictive behaviors and craving for nicotine, alcohol, and cocaine [46].

Placement of right-anodal plus left-cathodal tDCS over the bilateral dorsolateral PFC has reduced a variety of substance cravings in patients with substance use disorders, and bilateral stimulation with both polarities may be equally effective [142]. tDCS can enhance patient ability to inhibit potent responses, a clinical important finding because impaired inhibitory control contributes to relapse in patients with substance use disorder [17].

Smoking Cessation/Tobacco Use Disorder

Relapse is common within days after smoking cessation, and combining the anti-craving effects of rTMS with nicotine replacement therapy (NRT) may attenuate withdrawal symptoms and craving to increase abstinence rates in smokers with severe nicotine dependence attempting to quit [143].

The day after quitting, smokers who failed to quit with standard treatments started NRT (21-mg patch) and received active 1-Hz rTMS or sham of the right dorsolateral PFC (10 sessions) for two weeks. Abstinence rates and craving were measured during combined treatment and up to 12 weeks after quitting. At the end of combined treatment, more participants were abstinent with active rTMS (89%) than sham (47%). Compulsive craving was significantly decreased with active rTMS but not sham, but no lasting effect was found [143].

Similar results were shown by an earlier randomized sham-controlled trial of 10-Hz rTMS to the left dorsolateral PFC for 10 daily sessions. Active rTMS, but not sham, led to significantly reduced cigarette consumption and blocked craving during treatment, but the effects dissipating after the rTMS sessions ended [144].

Deep rTMS was evaluated in 115 smokers randomized to 13 daily sessions of HF, LF, or sham deep rTMS to the lateral PFC and bilateral insula. HF (but not LF or sham) deep rTMS significantly reduced cigarette consumption and nicotine dependence. The combination of high-frequency deep rTMS and exposure to smoking cues enhanced cigarette reduction, with abstinence rates of 44% at the end of the treatment and 33% at six-month follow-up [145].

Results from two studies provided data to encourage larger trials in determining the clinical usefulness of this intervention. A single-session randomized sham-controlled trial of 1-mA anodal stimulation over the left dorsolateral PFC found that active tDCS (versus sham) significantly increased latency to smoking and decreased total number of cigarettes smoked [146].

Cathodal tDCS stimulation is a way to manipulate cortical excitability through inhibition. tDCS inhibition of the frontal-parietal-temporal association area (FPT) was examined for effects on attention bias to smoking-related cues and smoking behavior in a small short-term trial. Bilateral cathodal tDCS stimulation of the FPT area modestly decreased attention to smoking-related cues and significantly decreased daily cigarette use [147].

Alcohol Use Disorder

Most rTMS studies in alcohol use disorder have investigated craving but not drinking reduction. As with studies in nicotine dependence, most used HF-rTMS to target the dorsolateral PFC. The effect of rTMS on craving for alcohol was mixed, with some studies showing an effect while others do not [12].

More promising results came with using H-coil rTMS, but these were preliminary open trials. A small study of bilateral H coil stimulation of the PFC in patients with comorbid alcohol use disorder and dysthymic disorder found improvements in depressive symptoms and reductions in craving for alcohol. Another pilot study using H-coil stimulation of the medial PFC reported decreased alcohol intake by mean drinks per day and mean drinks on days of maximum alcohol use [12].

Four sessions of HF-rTMS was evaluated in a randomized sham-controlled trial of 17 residents of an alcohol detoxification program. At one-month follow-up, active (but not sham) HF-rTMS led to significantly decreased depressive symptoms and fast EEG frequencies, significantly increased inhibitory control and executive function, but no effect was found on craving or drinking reduction [148].

Published randomized controlled trials of tDCS in alcohol use disorder have shown mixed results. In 13 subjects with alcohol use disorder, one session of tDCS to the bilateral dorsolateral PFC significantly decreased alcohol craving (versus sham), which remained suppressed during exposure to alcohol cues [149].

In a relapse reduction study, 33 outpatients with severe alcohol use disorder received twice-daily 2 mA tDCS to the bilateral dorsolateral PFC for five days. At six-month follow-up, tDCS did not diminish craving, but 50% treated with active tDCS versus 11.8% with sham remained alcohol-abstinent. Active tDCS also led to improved perception of quality of life [150].

A disconnect between alcohol craving and alcohol use was also reported in a study of 13 patients with alcohol use disorder who received five weekly sessions of anodal tDCS to the left dorsolateral PFC. Active tDCS suppressed cravings but showed an unexpected trend for more frequent relapse; neither was found with sham [151].

Stimulant Use Disorders

Very promising results came from a pilot study in which 18 subjects with cocaine use disorder received 12 sessions of 10-Hz H-coil rTMS or sham to the bilateral PFC. After four weeks of stimulation, cocaine use in active and sham groups both decreased without difference, but decreases in cocaine use showed a significant difference at three months and six months post-baseline favoring the active rTMS group. Transient mild headaches were reported during stimulation [152].

Patients with addiction to crack cocaine received five sessions of active or sham bilateral dorsolateral PFC stimulation. The active tDCS group showed a higher percentage of abstinence at three-month follow-up versus sham [153]. This study protocol was replicated in a larger group of patients whose crack cocaine cravings were suppressed for at least one week by active versus sham tDCS. Effects on crack cocaine use were not studied [154].

Abstinent methamphetamine users received single-session anodal tDCS or sham to the right dorsolateral PFC. Active tDCS acutely reduced craving at rest, but significantly increased methamphetamine craving during methamphetamine-related cue exposure. Neither effect was found with sham [78].

Mixed Substance Abuse Disorders

The effect of rTMS on craving in substance addiction was evaluated in a review of eight randomized sham-controlled trials. Active TMS was significantly superior to sham, but only in studies targeting the right dorsolateral PFC with HF-rTMS. This finding was consistent throughout the reviewed studies [155].

EATING DISORDERS

Eating behavior and eating disorder treatment is an area of study in noninvasive neurostimulation, and the sole evaluated modalities are rTMS and tDCS. The dorsolateral PFC is a complex brain region involved in executive functions that support cognitive control of food intake. Enhanced dorsolateral PFC activity may alter the reward-cognition balance toward facilitation of cognitive control, and possible suppression of reward-related mechanisms that drive food craving and overeating [10].

Anorexia Nervosa

The dorsolateral PFC is implicated in emotion regulation. HF-rTMS may improve food restriction and other maladaptive emotion regulation strategies in anorexia nervosa by remediating prefrontal region hypoactivity associated with poor impulse control and impaired cognitive flexibility in anorexia nervosa [46].

In a uncontrolled trial, 10 patients with anorexia nervosa received single-session HF-rTMS to the left dorsolateral PFC, and showed short-term improvements in anxiety, feeling full, and feeling fat [156]. In patients with chronic anorexia nervosa receiving HF-rTMS to the left dorsolateral PFC, significant improvements in eating disorder symptoms and mood were found after six months in 60%, with 40% deemed "recovered" based on psychometric scores. However, most participants lost weight, and therapeutic effects on psychopathology waned by 12 months [157].

Bulimia Nervosa

Several single-session rTMS studies in small numbers of patients with bulimia were performed, and reported positive short-term effects of reduced binge-eating episodes and food craving [46]. Sham-controlled single-session studies of HF-rTMS of the left dorsolateral PFC reported inconsistent effects, with positive effects reported in one study of 38 patients and no effects in a study of 10 patients [158,159]. Randomized controlled trial with sham control using 20 rTMS sessions did not find benefit beyond sham [46,160].

Binge-Eating Disorder

A trial of 30 subjects with binge-eating disorder evaluated singles-session 2-mA tDCS or sham to the dorsolateral PFC. Compared with sham, tDCS decreased craving for sweets and savory proteins with greatest reductions in men; decreased total and preferred food intake by 11% and 17.5% regardless of sex; and reduced desire to binge eat in men on the day following active tDCS. Reductions in craving and food intake were predicted by eating less often for reward motives, and greater intent to restrict calories, respectively. The findings of enhanced cognitive control and/or decreased need for reward may reflect tDCS action on functional mechanisms, and should be further researched [48].

DEPERSONALIZATION/DEREALIZATION DISORDER

Patients with chronic refractory depersonalization/derealization disorder received 17 to 20 sessions of LF-rTMS to the right ventrolateral PFC (VLPFC) over 10 weeks. Mean depersonalization symptom scores decreased 44.4%. After one session, 71% of patients showed partial response (symptom reduction ≥25%). After trial completion, 28% of patients showed full response (symptom reduction ≥50%), 57% had partial response, and 14% had no response. Mean anxiety scores decreased 28.4% from baseline. Side effects were transient mild headache [52].

Several subjects showed transient disinhibitory behaviors immediately after rTMS, including wearing the physician's jacket, labile affect, spontaneous laughter without apparent origin, and spontaneous discussion of provocative subjects. None were persistent or clinically concerning. Patients commented the measuring scales that assessed treatment response did not capture the phenomenological changes they experienced [52].

EXTERNAL TRIGEMINAL NERVE STIMULATION (eTNS)

eTNS is an emerging external neuromodulation approach originally developed for refractory seizures. Early evidence of safety and improved mood led to trials in MDD. Brain projections of the trigeminal system suggest eTNS may alter activity in structures regulating mood, anxiety, and sleep [161].

MAJOR DEPRESSIVE DISORDER

Initial open-label trials showed response rates of 54.5%, 75%, and 100%, and remission rates of 63.6% and 90.9%. A randomized sham-controlled trial of 40 patients found high placebo response to sham, but active eTNS still led to a significant mean reduction of 6.36 points in HDRS scores versus sham. An open-label eTNS trial in older patients with MDD (mean age: 73 years) found 80% response and 40% remission rates [163].

PTSD AND COMORBID MDD

Patients with PTSD and comorbid MDD received eTNS eight hours nightly for eight weeks as a pharmacotherapy adjunct. After eight weeks, significant improvement was found in depression, core PTSD symptoms, and quality-of-life measures. eTNS was well-tolerated with few adverse events [161]. Another open-label eTNS trial in comorbid PTSD/MDD reported the same positive outcomes [162].

PANIC DISORDER

Seven patients with panic disorder received ten daily sessions of TNS. At day 10, panic disorder symptom severity showed a significant decrease from baseline, remaining stable at follow-up day 45. Significant global clinical gains were also reported at days 10 and 45. Cognitive function was unchanged. All patients reported mild paresthesia underneath the electrodes during stimulation. One patient dropped out after four sessions from stimulation-related headaches. No other adverse events were observed [164].

eTNS is well-tolerated, without reports of serious adverse events or changes in cognitive performance. These data, while impressive, mostly come from small, short-term uncontrolled trials [23,24,163].

8. INVASIVE NEUROSTIMULATION

Most invasive neurostimulation studies in psychiatric disorders have been performed in treatment-resistant MDD, but this is currently expanding into refractory Tourette syndrome, OCD, and addictive disorders.

VAGUS NERVE STIMULATION

The FDA approved VNS in 2005 as adjunctive therapy in refractory MDD with four or more failed adequate antidepressant trials. Some studies below also enrolled patients with treatment-resistant bipolar depression, and VNS outcomes were similar for both [165].

Worth noting in the VNS studies is the severity of MDD in the patient population, distinguished by chronicity (average duration of illness: >25 years, and current episode: 7 years), treatment-resistance (average of seven drug failures, and ECT failure in >50%), high rates of lifetime hospital admissions and suicide attempts [165]. However, VNS was found ineffective in patients with eating disorders or schizophrenia [10,166].

Dose Response

VNS "dose" is measured by electrical output, in mA of current. A comparison of low (0.25 mA), medium (0.5–1.0 mA) and high (1.25–1.5 mA) dose VNS found greater improvement in depressive symptoms with higher doses, greater sustained antidepressant response and less frequent suicide attempts with medium- and high-dose versus low-dose VNS [167].

Efficacy

Open-label studies found an average 31.8% response rate, but a randomized sham-controlled trial found no difference between VNS and sham at 12 weeks [168]. VNS efficacy may increase over time, and six trials comparing VNS to treatment as usual found at 12, 24, 48, and 96 weeks that VNS/treatment as usual remission rates were 3%, 5%, 10%, and 14% versus 1%, 1%, 2%, and 4% for treatment as usual alone [169]. Median time to VNS response was nine months in one study. In patients with response by 3 months (35%), response was maintained by 61.5% at 12 months, and 50% at 24 months [170,171].

High retention and low dropout rates suggest that patients without measurable response or remission gain therapeutic benefits undetected by depression rating scales [165]. Higher success rates with VNS in treatment-resistant depression were reported with careful patient selection to screen out comorbid personality disorders or active substance use disorders [26].

Adverse Effects

The most common adverse events after one year of VNS were voice alteration (69.3%), dyspnea (30.1%), pain (28.4%), and increased cough (26.4%), mostly from active VNS and resolved by halting stimulation. VNS tolerability improves over time, and adverse effect reports diminish. Compared to treatment as usual, patients with treatment-resistant depression receiving VNS showed lower all-cause mortality rates, including suicide [8].

DEEP BRAIN STIMULATION

Treatment-Resistant Depression

Deep brain stimulation treatment for treatment-resistant depression remains investigational. Deep brain stimulation is mostly used to augment antidepressants, and few patients are free of psychotropic drugs when implanted [8]. The main deep brain stimulation brain targets are [8]:

- Subcallosal cingulate white matter

- Ventral capsule/ventral striatum (VC/VS)

- Nucleus accumbens

- Medial forebrain bundle

The most common target in treatment-resistant depression is the subcallosal cingulate. Patients in deep brain stimulation trials are refractory to antidepressants, psychotherapy, and (often) ECT [8].

Short-term outcomes with deep brain stimulation show 30% to 60% response rates and 20% to 40% remission rates at three or six months, and medial forebrain bundle deep brain stimulation in seven patients reported response and remission rates of 85.7% and 57.1% [172,173].

As with VNS, two randomized sham-controlled trials of deep brain stimulation were halted early from lack of benefit, later seen as premature with recognition that efficacy increases with longer stimulation [8]. Outcomes of four studies showed depression severity was significantly reduced by 12 months. At 3, 6, and 12 months, response rates were 36.6%, 53.9%, and 39.9%, with remission rates 16.7%, 24.1%, and 26.3% [174].

Subcallosal cingulate deep brain stimulation studies of greater than one year duration reported response rates of 36% and 92% at one and two years, and a 58% remission rate at two years. A longer trial reported 62.5%, 46.2%, and 75% response rates at one, two, and three years, with 20% and 40% remission rates at two and three years. Long-term subcallosal cingulate and medial forebrain bundle deep brain stimulation led to improved health-related quality of life [173,175,176].

Maintaining Response

A small trial suggested that maintaining remission requires ongoing deep brain stimulation. Patients were treated to remission with subcallosal cingulate deep brain stimulation, and then randomized to on/off or off/on stimulation for three months. Most patients relapsed with deep brain stimulation turned off, and none with deep brain stimulation on [177].

Adverse Effects

Adverse events during long-term deep brain stimulation have been secondary to implantation (e.g., intracranial hemorrhage), perioperative risks (e.g., wound infection), effects of specific brain region stimulation, or deep brain stimulation parameters. Deep brain stimulation is generally well tolerated despite the risks of invasive neurosurgical procedures, and the pooled one-year dropout rate with subcallosal cingulate deep brain stimulation was 10.8%. Worsening neuropsychological performance has not been observed with any brain target, but improved cognitive performance has been reported [174].

Transient psychosis and hypomania have emerged when changing parameters during nucleus accumbens stimulation, resolved by switching parameters. No hypomania episodes were reported with subcallosal cingulate deep brain stimulation, including patients with bipolar disorder. Oculomotor adverse events of blurred vision and strabismus occurred in all patients receiving higher amplitude medial forebrain bundle deep brain stimulation. Reports of suicidality and completed suicide were deemed not device-related, but risk of suicidality may be increased by a history of pre-deep brain stimulation suicidality or major life stressors [8].

Tourette Syndrome

Deep brain stimulation is an emerging treatment option for patients with severe refractory Tourette syndrome. In 156 published cases, deep brain stimulation led to an overall 52.68% improvement of symptoms. Outcomes of controlled trials significantly favored stimulation versus sham. Significant symptom reductions were found across deep brain stimulation targets, with no differences in outcome indicating modulation of a common network. Despite the small patient numbers, deep brain stimulation for Tourette syndrome is a valid option for medically intractable patients [178].

Treatment-Resistant Obsessive-Compulsive Disorder

Deep brain stimulation efficacy in severe, refractory OCD was reviewed in 25 trials. Outcome was change in Y-BOCS scores; response was ≥35% improvement in Y-BOCS (Table 3) [41]. Reported adverse effects included serious events during surgery (i.e., two seizures, three intracerebral hemorrhages), device-related adverse events, and stimulation-related events. Device-related events included breaks in stimulation leads and battery failure resulting in acute psychiatric symptoms until replacement [41]. Stimulation-related adverse events were acute increases in anxiety and hypomania, induced by changing stimulation parameters or battery depletion. All cases resolved with parameter adjustment. Cognitive problems resolved with time or parameter adjustment. No personality changes during deep brain stimulation were observed.

Table 3: DEEP BRAIN STIMULATION (DBS) TARGET OUTCOMES IN OCD

Trial Characteristics

ALIC

Nucleus Accumbens

Ventral Capsule/Ventral Striatum

Subthalamic Nucleus

Inferior Thalamic Peduncle

Number of trials

5

8

4

5

1

Follow-up, months

23–51

3–24

12–36

3–6

36

Mean DBS response rate

75%

45.5%

50.0%

57.1%

100%

Mean reduction in Y-BOCS

46.5%

37.8%

41.5%

45.3%

82.5%

ALIC = anterior limb of the internal capsule.

Source: [41]

Neural circuits involved in OCD and depression include the VC/VS and anterior cingulate gyrus. VC/VS deep brain stimulation combined with anterior cingulotomy was evaluated in patients with refractory OCD and MDD. Mean baseline Y-BOCS scores were 34.7, decreasing to 23.0 at three months, and stable two years post-surgery at 19.0. These outcomes were comparable, but not superior, to published outcomes for VC/VS deep brain stimulation alone, and deep brain stimulation may be sufficient to control refractory OCD [179].

Substance Addiction

A few small deep brain stimulation studies have been performed in severely addicted patients. Five severely alcohol dependent patients received nucleus accumbens deep brain stimulation. Followed an average 38 months, all five showed significant craving reductions, two remained abstinent for more than four years, and three had truncated relapses [180]. Two patients with heroin dependence received nucleus accumbens deep brain stimulation; depressive and anxiety symptoms improved, with drug use reduced but not ceased [181].

9. NEUROMODULATION IN CHRONIC PAIN

Pain processing in the brain is not limited to one area or sensory system. The cerebral pain processing neural network is complex, and mediates the vegetative, sensory-discriminative, affective, and cognitive aspects of pain. The vegetative and neuroendocrine effects of pain perception are mainly linked to subcortical regions such as the amygdala and hypothalamus. The sensory-discriminative aspects of pain involve the spinothalamic tract, lateral thalamus, somatosensory areas, and the posterior insula with input from the descending corticothalamic pathways originating in the motor cortex. The affective/cognitive processing of pain involves the anterior insula, cingulate cortex, and prefrontal regions [18,182].

Brain stimulation is not usually considered for acute nociceptive/inflammatory pain, because the standard of care involves resolution of the underlying cause [13]. Brain stimulation is solely used in chronic pain, typically in patients for whom standard therapies have failed to relieve pain. In most forms of chronic pain, the mechanisms that generate pain have dissociated from the original peripheral tissue injury source. Instead, pain is perpetuated by alteration in CNS structures involved in transmitting, processing and response to pain signals. Alteration in these regions is termed central sensitization [183].

OVERVIEW OF NONINVASIVE BRAIN STIMULATION IN PAIN

In the early 1990s, epidural motor cortex stimulation (eMCS) showed repeated efficacy in pharmaco-resistant neuropathic pain. These methods were adopted by TMS researchers in chronic pain using stimulation to the primary motor cortex (M1) and precentral gyrus in the hemisphere contralateral to pain [27]. Stimulation parameters were refined over time to maximize efficacy. An early 10-day protocol of 5 Hz rTMS of M1 in patients with diverse chronic neuropathic pain reported minimal benefit, the result of using low frequency (5 Hz) stimulation and small number of pulses (500) per session. A subsequent five-day protocol of 20 Hz HF-rTMS of M1 led to durable pain reduction in patients with post-stroke pain, trigeminal neuropathic pain, and phantom limb pain [19].

Several rTMS targets have been evaluated in neuropathic pain, and M1 is preferable to premotor or primary somatosensory cortical regions. In refractory pain, dorsolateral PFC stimulation is less studied, despite efficacy of this target in depression and the established link between depression and chronic pain [19].

When used in pain treatment, a figure-8 coil delivering biphasic pulses should be placed over the precentral gyrus (M1) contralateral to the painful side with a posteroanterior orientation [13,27]. HF-rTMS (10–20 Hz) is used to activate projecting axons and local interneurons and applied below the motor activation threshold to avoid inducing muscle contractions. Focal neuropathic pain can be relieved by HF-rTMS (but not LF-rTMS) to the contralateral M1 area. Repeated rTMS sessions can induce cumulative pain reductions for at least several weeks following 10 consecutive sessions, but optimal timing for long-term efficacy and safety remain studied.

Investigation of tDCS in pain treatment began more recently than rTMS, and there are fewer published studies on treatment outcomes and parameter settings. However, the positive pain outcomes are found with using current intensities of 1–2 mA delivered for 15 to 20 minutes, and electrode size 25–35 cm^2. Treatment is given daily (consecutive or with breaks) over one or more weeks. Within these dose parameters, tDCS has extensive evidence of safety and tolerability [18,184].

The properties of tDCS make it a promising approach for pain treatment, including the potential to address pathological alterations in neural activity, excitability, and connectivity at multiple levels and sites of cerebral pain processing. Reversal of maladaptive plasticity in cerebral pain processing systems is associated with pain relief. The potential of tDCS to prevent or reverse such maladaptive changes, or enhance adaptive neuroplastic changes in pain processing networks is highly relevant in pain management [18]. Proposed mechanism of action in chronic pain include [27]:

- M1 stimulation reduces thalamic and brainstem nuclei hyperactivity that underlies pain.

- Dorsolateral PFC stimulation is thought to mediate analgesic effects by modulating pain-related affective-emotional networks

Higher stimulation intensity or duration to enhance efficacy has been examined, but prolonged M1 stimulation at higher intensities may reverse the intended effects on neural excitability [185].

CHARACTERISTICS OF CHRONIC PAIN CONDITIONS

Brain stimulation therapies have been evaluated for efficacy, safety, and tolerability in the following pain conditions.

Neuropathic Pain

Neuropathic pain is caused by abnormality, trauma, or disease of the somatosensory nervous system, resulting from various etiologies including traumatic or surgical injuries to peripheral nerves, infectious diseases (e.g., herpes zoster, postherpetic neuralgia), metabolic disorders (e.g., diabetic peripheral neuropathy), and injuries or diseases that affect the CNS such as stroke or spinal cord injury. Nearly 25% of people with chronic diabetes have neuropathic pain [186,187].

Among adults in the general population, an estimated 7% to 8% have chronic pain with neuropathic features, and 5% have moderate-to-severe pain with neuropathic features [188]. Neuropathic pain is associated with significant loss of productive time, withdrawal from the workforce, development of mood disorders, and disruption of family and social life [189]. Neuropathic pain is reported to be more severe than non-neuropathic pain and the management of chronic neuropathic pain is challenging; more than 50% of patients experience partial or no pain relief, and the adverse effects of medications used to manage the pain may limit their clinical utility in general and in elderly patients in particular [186,187].

Spinal Cord Injury Pain

In the United States, spinal cord injury occurs in 17,000 persons annually, and an estimated 282,000 patients are living with spinal cord injury. Six months after discharge, 27% of patients with spinal cord injury report pain that is severe enough to interfere with most daily activities. Spinal cord injury pain can develop at or below the level of spinal injury and does not correlate well with the magnitude or location of the lesion. Injury from gunshot is associated with more severe pain. Neuropathic, musculoskeletal, and/or visceral pain can contribute to spinal cord injury pain, and central neuropathic pain can develop weeks to months following injury [190,191].

Central Poststroke Pain

Pain is reported by 11% to 55% of stroke survivors, and can arise from muscles, joints or viscera, or from the peripheral or central nervous system. The most common types of poststroke pain include hemiplegic shoulder pain, pain due to spasticity, and central poststroke pain. Along with spinal cord injury pain, central poststroke pain is a central neuropathic pain condition with pain
arising from a cerebrovascular lesion in the central somatosensory nervous system. Sensory descriptors used in patients with central poststroke pain include burning, aching, pricking, lacerating, shooting, squeezing, throbbing, sharp, stabbing, painful pins and needles, dull, and cramping. Treatment of central poststroke pain is difficult, due to the limited efficacy and dose-limiting side effects of available drugs [192].

Failed Back Surgery Syndrome

In the United States, more than 300,000 spinal surgeries are performed annually, mainly in the lumbar spine, and as many as 100,000 result in failure where the patient experiences new-onset pain in addition to unresolved pain from the original problem. The level of pain is widely variable and may occur with neurologic deficits. Contributors to pain and the clinical features of failed back surgery syndrome include recurrent disk herniation, epidural abscess, scar tissue formation around the nerve root, facet joint syndrome, and muscle spasm. Patients with persistent radicular pain, usually from chronic nerve injury, greatly benefit from treatment that addresses the neuropathic pain [193].

Lumbosacral Radiculopathy Pain

Lumbosacral radiculopathy results from nerve root irritation and compression, resulting in a symptom distribution of the affected lumbar or sacral nerve root such as numbness, weakness, or paresthesia. Sciatica is the most common symptom of lumbar radiculopathy and refers to pain that radiates down the leg below the knee in the distribution of the sciatic nerve to indicate nerve root compromise from mechanical pressure or inflammation [194].

Chronic low back and neck pain are highly prevalent but largely unaddressed in brain stimulation trials because origin is usually multifactorial, psychosocial contribution is often prominent and the torso has less cortical representation [13].

Temporomandibular Disorders

Temporomandibular disorders (TMDs) involve persistent pain in the cheek and jaw area of the face and have an estimated 11% prevalence in community samples. TMD pain considerably impedes quality of life, with nearly 80% of patients with TMD reporting regular discomfort eating and more than 40% reporting difficulty performing their jobs. The importance of CNS factors in TMD etiology is established, and neuroimaging has revealed structural, functional, and neurochemical aberrations in TMD pain [195].

Phantom Limb Pain

Phantom limb pain is painful or unpleasant sensation in the distribution of the lost or deafferentated body part. Phantom limb pain can resemble neuropathic pain with descriptors such as sharp, shooting, or electrical-like; or resemble nociceptive pain with dull, squeezing, or cramping pain. The pain can be widespread throughout the missing limb or confined to a smaller limb area. The prevalence of phantom limb pain following amputation may be as high as 85%. Phantom limb pain remains an extremely difficult pain condition to treat, and most pharmacologic therapies are not successful [196].

Postherpetic Neuralgia

Postherpetic neuralgia is persistent neuropathic pain after the healing of herpes zoster infection. Risk of developing postherpetic neuralgia increases with age, and the duration can be months to years. Pain levels range from mild to excruciating, with pain severity placing the patient at risk for suicide. In the United States, postherpetic neuralgia is the most common cause of suicide in patients with chronic pain older than 70 years of age. In postherpetic neuralgia, peripheral and CNS sensitization generate pain characterized by severe or excruciating pain from light touch (allodynia) or severe spontaneous pain without allodynia. Postherpetic neuralgia pain is highly resistant to conventional pain treatment [197].

Complex Regional Pain Syndrome

Complex regional pain syndrome is thought to result from injury to autonomic, central, and peripheral nervous systems. It presents as pain affecting one or multiple limbs without following a dermatomal distribution. The pain is disproportionate to the inciting injury, and pain severity can be disabling. The affected limb(s) undergo marked changes in skin color, texture, and/or temperature. Absence of nerve injury is termed CRPS-I, with CRPS-II describing complex regional pain syndrome that develops after nerve damage. However, recent studies have shown nerve damage in patients classified as CRPS-I, suggesting a false dichotomy [198]. The pathophysiology of complex regional pain syndrome is multifactorial, and while multimodal conventional treatment is indicated, some patients with complex regional pain syndrome do not respond to standard approaches and develop refractory disease [199].

Migraine Headache Pain

Most patients with chronic refractory headaches have medication overuse headache, alleviated by detoxification from their headache medication. A subset remains with chronic refractory headache pain. Neuromodulation options can be considered in selected cases [200].

Migraine has a lifetime prevalence of 18%, and women experience higher past-year rates (13% to 18%) than men (5% to 10%). The main clinical feature of migraine is a unilateral or bilateral throbbing or pulsating headache of moderate-to-severe pain, often preceded by an aura. Other symptoms include gastrointestinal disturbances (nausea or vomiting) and intense sensitivity to light or sound. Medical treatment is particularly challenging, with non-response to high-dose preventive medications or side effects that complicate treatment course in many cases [200].

Cluster Headache

The main clinical feature of cluster headaches is severe, excruciating pain with unilateral distribution around and above the eye and along the side of the head or face; pain sensation described as sharp, boring, burning, throbbing, or tightening; and restlessness or agitation during the headache. Autonomic features associated with cluster headache include ipsilateral conjunctival injection and lacrimation, rhinorrhea or nasal blockage, and ptosis. The pain is more severe than any other headache type and ranks among the most severe known to humans, which has earned cluster headache the term "suicide headache" from reports of suicidal behavior in patients desperate to stop the pain [201]. Treatments for cluster headache are effective in some patients, but patients may not respond to medication, and ablative or destructive methods can be ineffective [200].

Fibromyalgia

Fibromyalgia afflicts an estimated 5 million adults in the United States, of whom 80% to 90% are women [202]. The cardinal features of fibromyalgia are widespread pain and tenderness in multiple regions of the body, not attributable to another condition. Abnormal reactivity to painful stimuli or discomfort is characteristic of fibromyalgia. Pain with fibromyalgia is described as a persistent, diffuse, deep, aching, throbbing sensation in muscles that is most often continuous. Patients with fibromyalgia suffer from a complex symptom spectrum that includes pain, as well as sleep problems, fatigue, cognition difficulties, and depression [203].

The pathophysiology of fibromyalgia involves CNS dysfunction and neurotransmitter dysregulation that results in central sensitization to pain, where disordered processing in central afferent neurons accounts for the dominant symptoms of pain and tenderness in fibromyalgia [204].

TRANSCRANIAL MAGNETIC AND ELECTRIC STIMULATION

Daily rTMS sessions for at least one week can produce durable cumulative effects, but maintenance of efficacy requires additional rTMS sessions at regular intervals [27]. Two systematic reviews synthesized the results of published rTMS studies in chronic pain. Both found rTMS effective, with strongest evidence in neuropathic pain. A consortium of European experts found definite efficacy for HF-rTMS of the M1 in neuropathic pain [129].

Neuropathic Pain

Evidence Based Practice Recommendation

According to a European consortium of experts, HF-rTMS of M1 contralateral to pain side displays definite analgesic efficacy for neuropathic pain; LF-rTMS is probably ineffective.

https://www.sciencedirect.com/science/article/pii/S1388245719312799

Last Accessed: July 24, 2025

Level of Evidence: A (Definitely effective or ineffective based on at least two Class I studies or one Class I study and at least two Class II studies)

Of nine randomized controlled trials evaluated, three had major limitations from using less than 1,000 pulses per session and studies used 5-day or 10-day stimulations. HF-rTMS (5–20 Hz) to M1 showed efficacy at short-term (≤1 week from last session) and mid-term (1 to 6 weeks from last session) follow-up. Pain scores were reduced by 20% to 45% following active stimulation, and 35% to 60% of patients were responders (>30% pain relief). These analgesic effects were obtained in neuropathic pain regardless of anatomical origin or whether the pain had central or peripheral nervous system involvement [27].

HF-rTMS to M1 contralateral to the pain side received a Level A recommendation for consistent analgesia in patients with neuropathic pain. This was based on results of 511 patients indicating significant efficacy, with pain relief >30% in 46% to 62% of patients, and >50% pain relief in 29% of patients [129]. There were also modest but significant analgesic long-term effects with repeated sessions.

In contrast, LF-rTMS to M1 contralateral to the pain side received a Level B recommendation (probably ineffective) in patients with neuropathic pain. This was based on results of 138 patients in six randomized sham-controlled trials, which consistently reported the absence of any significant analgesic effect of active rTMS versus sham [129].

Of the few rTMS studies targeting the dorsolateral PFC in neuropathic pain, the results were inconsistent and tended to show lack of efficacy [27].

Evidence Based Practice Recommendation

A European consortium of experts has found probable efficacy of HF-rTMS of the left M1 or the left DLPFC in improving quality of life of patients with fibromyalgia.

https://www.sciencedirect.com/science/article/pii/S1388245719312799

Last Accessed: July 24, 2025

Level of Evidence: B (Probably effective based on at least two Class II studies or the combination of one Class I or II study and at least two Class III studies)

Neuropathic pain syndromes tend to show greatest benefit from rTMS to the M1, but some nonneuropathic chronic pain syndromes, such as CRPS-I or fibromyalgia, may have a neuropathic component. Focal lesions with defined onset, such as pain from shingles or trauma, have advantages of known localization and time of onset, but early cases often improve spontaneously which complicates treatment outcomes in research; thus, established cases with pain duration of at least one year are preferable [13].

rTMS should be applied contralaterally for localized neuropathic pain, or to the left hemisphere for widespread neuropathic pain or fibromyalgia. HF-rTMS (≥5 Hz) stimulation should be used, delivered by a figure-8 coil oriented parallel to the midline over M1 for ≥1 week with ≥1,000 pulses per session. Increasing the total pulses per session and repeating the sessions over several days or weeks may enhance rTMS analgesia [27].

CRPS-I

One randomized controlled trial using 10 daily sessions of 10 Hz rTMS in patients with refractory CRPS-I pain found significantly greater analgesic effects with active than sham rTMS over the three-week treatment period [27,205].

HF-rTMS of M1 in patients with CRPS-I showed significant and rapid reductions in pain intensity, but persistence after stimulation was, on average, short-term. There was high variation in duration of treatment response, with total pain relief for three months post-rTMS reported [129].

Fibromyalgia

HF-rTMS to the left M1 was evaluated in several controlled trials. Significant reductions in global pain on a numerical scale, and improvements in quality of life up to one month following 10 daily sessions were found, as well as extension of these effects for several months with maintenance sessions after completion of the original treatment course [129].

HF-rTMS to M1 was effective in five randomized sham-controlled trials at short term but not at mid-term follow-up. Results of one trial were negative for pain intensity but positive for improvement in quality of life, and another study with 14 sessions of left M1 rTMS over 21 weeks reduced pain for only one month beyond stimulation [27].

HF-rTMS to the left dorsolateral PFC also showed analgesic efficacy, with a mean 29% difference in pain relief between active and sham conditions. This degree of analgesia was also found with LF-rTMS to the left dorsolateral PFC. LF-rTMS to the right dorsolateral PFC showed mixed results, with open-label trials showing positive effect that was not replicated by a sham-controlled trial [129].

Most studies conducted in fibromyalgia using LF-rTMS (1 Hz) to the right dorsolateral PFC or HF-rTMS (10–20 Hz) to the left dorsolateral PFC reported results suggesting that analgesic effects were independent of antidepressant effects. Outcomes with highest-quality evidence show durable and clinically relevant pain reduction preceding improvements in depression [27].

Migraine

HF-rTMS of the motor cortex, in contrast to the left dorsolateral PFC, has shown consistent efficacy in multiple trials that showed significant improvement in headache frequency, pain score and functional disability after active rTMS versus sham. LF-rTMS to M1 showed no benefit beyond placebo effect [129].

HF-rTMS of the left dorsolateral PFC showed mixed results in sham-controlled trials, with significant decreases in migraine attack frequency and intensity, and reductions in oral medication found up to 1 month after 12 sessions in one study, and 23 sessions of active rTMS over 8 weeks less effective than sham in decreasing the number of headache days in another trial [129].

Facial Pain and Cluster Headache

HF-rTMS to the M1 in 19 sessions over six months led to significant relief of refractory facial pain, including cluster headache, with a 40% response rate at six-month follow-up. The analgesic effect remained when session duration was shortened from 20 to 10 minutes while keeping pulses per session (2,000) constant [206].

The effectiveness of maintenance rTMS to prolong analgesia and increase long-term pain reduction was evaluated in 55 patients with chronic refractory facial pain, including cluster headache, trigeminal neuropathic pain, and atypical facial pain. Subjects received 10 HF-rTMS treatments of M1 over two weeks, two sessions in week 3, one session in weeks 4 and 6, and monthly sessions the next 5 months. Pain intensity was measured on a 0–10 scale. Significant decreases from baseline to day 15 were found in permanent pain (5.2 to 3.2) and paroxysmal pain (8.6 to 4.5) intensities, and daily number of pain attacks (5.6 to 2.3). At day 15, 73% had a pain reduction ≥30%, decreasing to 40% at day 180. The analgesic effect was similar for all pain types, but significantly lower when session duration was shortened [206].

Phantom Limb Pain

Land mine victims with phantom limb pain received 10-Hz rTMS or sham of the M1 contralateral to the amputated leg in 10 daily sessions. Follow-up, in days, began after the last session. Active rTMS led to significantly greater reduction in pain intensity scores at 15 days vs sham, but the difference was non-significant at 30 days. At 15 days, 70.3% with rTMS versus 40.7% with sham attained clinically significant pain reduction (≥30%). Traumatic amputees with phantom limb pain were able to experience clinically significant pain reduction following 10-session HF-rTMS without side effects, and further work will identify protocols to extend analgesia [207].

Postherpetic Neuralgia

A randomized controlled trial evaluated high-frequency rTMS in 40 patients with postherpetic neuralgia. After 10 sessions of active or sham rTMS of the M1, active rTMS led to an overall 16.89% greater pain reduction than sham at final stimulation, and one and three months post-stimulation. Analgesic effects were associated with long-term improvement in quality of life [208].

Postoperative Pain Secondary to Gastric Bypass Surgery

HF-rTMS of the left dorsolateral FPC led to immediate, short-term analgesic effects and significant reduction of morphine consumption in small open-label trials [129].

Concomitant Medications and Substances

Potentially problematic prescription medications used by some pain patients include tricyclics (e.g., nortriptyline, amitriptyline), antiviral medications, and antipsychotic medications (e.g., chlorpromazine, clozapine). Consuming or discontinuing commonly abused substances can increase cortical excitability and risk of a TMS-induced seizure. Withdrawal from sedatives (e.g., alcohol, benzodiazepines) increases seizure risk, so patients should be asked about recent and current use, and recent substance abuse should be an exclusion criterion [13].

TRANSCRANIAL DIRECT CURRENT STIMULATION

Pain outcomes with tDCS are highly influenced by the brain state of the chronic disorder, adjunct pharmacological interventions, and the number of tDCS treatment sessions is a critical factor for pain relief effectiveness [18,209]. tDCS has been evaluated in diverse pain conditions, including difficult-to-treat pain syndromes such as fibromyalgia, complex regional pain syndrome, central pain due to spinal cord injury or stroke, headaches, and acute post-operative pain. Published evidence ranges from case reports to randomized controlled trials [18].

A main drawback with tDCS is that it produces diffuse brain current flow. High-definition tDCS was introduced to increase the specificity of targeted brain stimulation. High-definition tDCS uses five electrodes. With the M1 target, the anode is placed over the left M1, with the four return cathodal electrodes placed 5 cm radially from the cathode [209].

Fibromyalgia

The efficacy of 2 mA tDCS over the M1 or dorsolateral PFC (10 sessions over 2 weeks) was evaluated in a randomized sham-controlled trial of patients with chronic medically refractory fibromyalgia. Both M1 and dorsolateral PFC stimulation (but not sham) resulted in significant decreases in pain intensity and a positive benefit on quality-of-life measures immediately following the sessions, but only the M1 stimulation produced longer-lasting pain relief thorough 60-day follow up. The analgesic effects of dorsolateral PFC stimulation dissipated by 30-day follow up [210].

Prefrontal areas are involved in the affective/cognitive processing of pain, and tDCS to the dorsolateral PFC may be more relevant to modulation of the emotional experience of pain than for the somatosensory aspect of pain or pain intensity [18].

An optimized protocol for fibromyalgia pain treatment with tDCS has been published. High-definition 2-mA tDCS of M1 led to clinically significant benefits of ≥50% pain reduction in 50% of patients, with both responders and nonresponders benefiting from a cumulative treatment effect of significant pain reduction and improved quality of life over time. An estimated 15 high-definition tDCS sessions (median) are needed for ≥50% pain reduction [209].

Temporomandibular Disorders

TMD has a high prevalence and in many patients, pain and masticatory dysfunction persist despite a range of treatments. Women with chronic myofascial TMD pain received five sessions of active or sham 2-mA high-definition tDCS to the M1. Compared with sham, active tDCS led to significantly higher number of subjects with ≥50% pain reduction at four weeks, pain-free mouth opening at one-week follow-up, and sectional pain area, intensity and their sum measures contralateral to M1 stimulation during the treatment week. There were no changes on emotional measures. high-definition tDCS M1 stimulation led to clinically meaningful improvement in sensory-discriminative pain and motor measures up to four weeks post-treatment in patients with chronic myofascial TMD pain [211].

Phantom Limb Pain

Eight subjects with unilateral lower or upper limb amputation and chronic phantom limb pain received active or sham 1.5 mA anodal tDCS to M1 daily for five days. Active but not sham tDCS decreased background pain and frequency of phantom limb pain paroxysms through one-week post-tDCS. Also, on each treatment day, active tDCS patients reported immediate pain relief and increased ability to move their phantom limb. Immediate patient response to sham was variable, with increased or decreased pain from baseline [212].

Burn Pain

Burn pain severity and anxiety are highly correlated in burn patients, and a randomized sham-controlled trial assessed the effect of single-session cathodal 1-mA tDCS to the sensory cortex on pain anxiety in 60 patients with severe burn. Following stimulation, pain anxiety scores were significantly reduced with tDCS compared to sham. Post-stimulation assessment was followed by burn dressing; afterwards, pain anxiety scores remained significantly lower with tDCS versus sham. Acute pain anxiety reduction in patients with burns may be attained with cathodal tDCS [213].

Interferon-Induced Pain

Interferon-alpha (IFN) is a standard treatment for chronic hepatitis C infection, and many patients develop painful symptoms during the three- to six-month treatment course. BDNF is a marker of inflammatory-mediated pain, and tDCS was evaluated for effects on pain and plasma BDNF in 28 patients with hepatitis C infection. Following five days of 2-mA anodal stimulation of M1, active tDCS (compared with sham) reduced pain scores with a mean 56% reduction, enhanced BDNF levels with a mean increase of 37.48%, reduced chronic pain scores and analgesic use. Multivariate regression identified a significant interaction between pain reduction and BDNF level increase with active tDCS only [214].

COMPARISONS OF rTMS AND tDCS IN PAIN TREATMENT

Lumbosacral Radiculopathy Pain

Patients with neuropathic pain due to lumbosacral radiculopathy received rTMS (10 Hz) and tDCS (anodal 2-mA) in a sham-controlled crossover trial. Active rTMS was superior to tDCS and sham in pain intensity reduction. tDCS was not superior to sham, but its analgesic effects correlated to rTMS, suggesting common mechanisms of action. Lowered cold pain thresholds with rTMS correlated to its analgesic efficacy, but had no effect on individual neuropathic symptoms. rTMS was more effective than tDCS and sham in patients with neuropathic pain due to lumbosacral radiculopathy, and may modulate sensory and affective dimensions of pain [215].

Fibromyalgia

The treatment efficacy of rTMS and tDCS of fibromyalgia was evaluated by reviewing 16 randomized sham-controlled trials. Significant improvements in fibromyalgia domains were found [204]. Overall treatment effect sizes were large for pain, sleep disturbance, fatigue, and tender points. Effect sizes were medium for depression and general health/function. rTMS showed a significantly greater effect size than tDCS. Primary motor cortex (M1) stimulation produced a subtle but greater effect size in pain reduction versus dorsolateral PFC, and dorsolateral PFC stimulation may be better for depression improvement. Clinically meaningful improvements in anxiety or cognition, or dose-response effect in fibromyalgia pain reduction, were not found for either modality.

Several studies delivered stimulation for two to four weeks, which possibly led to underestimated efficacy because rTMS in treatment-resistant MDD usually requires four to six weeks of daily treatment for durable response/remission.

Adverse events were generally minor, most commonly skin discomfort at the stimulation site, headache, neck pain, and dizziness. Many studies found no significant difference between active and sham stimulation. Some temporary neurobehavioral adverse effects were observed, including insomnia, sleepiness, restlessness, and worsening of depressive symptoms. Detrimental cognition effects or seizures were not observed [204].

10. INVASIVE NEUROSTIMULATION IN CHRONIC PAIN

Deep brain stimulation is more invasive than motor cortex stimulation because electrodes are implanted through the skull, dura, and brain to stimulate deep targets. Morbidity associated with motor cortex stimulation and deep brain stimulation have greatly improved over time since their introduction [13]. For intractable pain, patients selected for motor cortex stimulation/deep brain stimulation should have evidence of exhaustive but failed conservative management, screening for secondary gain, and receive a psychological evaluation. Trial stimulation is mandatory with deep brain stimulation, but is symptom dependent with motor cortex stimulation. Motor cortex stimulation/deep brain stimulation in chronic intractable pain are both proven effective in specific pain indications (>40% pain reduction for ≥12 months) [216].

MOTOR CORTEX STIMULATION

Motor cortex stimulation is based on observations in the 1990s that stimulation
of the precentral gyrus below motor thresholds relieved pain in patients with thalamic pain. Subsequent investigations have shown efficacy in trigeminal neuropathic pain, deafferentation syndromes such as post-stroke pain and spinal cord injury pain, and brachial plexus injuries [187].

Stimulation of central motor systems (e.g., cerebral cortex, pyramidal tracts) can influence descending inhibition of nociceptive spinal and thalamic transmission and induce analgesia. Motor cortex stimulation is increasingly used in chronic, refractory neuropathic pain, with efficacy supported by clinical trials that show response (≥30% pain reduction) in 55% to 64% of patients [27]. Few studies have evaluated long-term outcomes [217].

Refractory Neuropathic Pain

A review of 17 open-label trials reported mixed pain outcomes, but analgesic efficacy may have been underestimated by brief study durations. Motor cortex stimulation has shown delayed, fluctuating analgesic effects, and randomized sham-controlled trials have found substantial pain relief at one year with initial non-responders [27].

Some, but not all studies have strongly correlated preoperative M1 rTMS response with follow-up response to motor cortex stimulation. Other studies found improved motor cortex stimulation outcomes using (versus not using) preoperative rTMS. Positive preoperative rTMS response predicts better motor cortex stimulation outcomes and can improve patient selection [27]. In 20 patients with refractory neuropathic pain followed a mean 6.1 years after motor cortex stimulation, mean pain reduction at any time ranged from 28.9% to 37.2%, and immediate post-rTMS improvement predicted long-term pain reduction. Greatest long-term benefit occurred in physical pain and dependence (autonomy in daily activities); little changed were disability, anxiety, stress and depression [217].

Motor cortex stimulation is safe and effective in central and peripheral neuropathic pain (≥40% to 50% pain reduction in approximately 50% of patients), with best outcomes in central post-stroke pain and neuropathic facial pain [218]. Benefit is established in spinal cord injury pain. Multiple randomized sham-controlled trials with ≥12-month follow-up show sustained response rates in 60% of patients with central and peripheral neuropathic pain. Intracranial motor cortex stimulation is more effective than non-invasive stimulation, and partial rTMS responders should be considered for motor cortex stimulation [13,219,220].

DEEP BRAIN STIMULATION

Deep brain stimulation is effective in relieving diverse intractable pain, including chronic pain refractory to medication, conservative approaches, and TMS. Deep brain stimulation shows efficacy in failed back surgery syndrome, phantom limb pain and peripheral neuropathic pain, and possibly greater efficacy in nociceptive versus neuropathic pain. Deep brain stimulation shows superior outcomes in cluster headaches. Although deemed investigational by the FDA, deep brain stimulation has a clear role in chronic refractory pain [221].

Deep brain stimulation sites in pain treatment differ from those in refractory psychiatric disorders. Effective deep brain stimulation targets in pain control [27]:

- The sensory ventral posterior lateral and medial (VPL/VPM) thalamus

- Periventricular and periaqueductal gray (PVG, PAG) matter

- Internal capsule

- Anterior cingulate cortex

The PVG and VPL/VPM overlap in analgesic mechanisms; some deep brain stimulation studies target both for synergistic effects [8,222]. Greatest long-term deep brain stimulation efficacy is found with PVG/PAG, with/without sensory thalamus or internal capsule stimulation (87% or 79%). Less effective is thalamus stimulation alone (58%) [223]. Deep brain stimulation of the ventral PVG/PAG is thought to trigger non-opioid analgesia and acts through autonomic mechanisms, with dorsal PVG deep brain stimulation triggering endogenous opioid release [27].

The early excitement over deep brain stimulation for pain was dampened when two open-label studies sponsored by Medtronic failed to reach their defined efficacy targets. The first trial enrolled 196 chronic pain patients from 1989–1993 but did not achieve ≥50% pain reduction in ≥50% of patients. The second trial began in 1992 but failed from lack of accrual by 1998 [224].

Without this large-scale prospective data, the FDA has not approved deep brain stimulation for pain and only permits off label use [225]. Due to its off-label status for pain treatment in the United States, only a few surgeons publish their deep brain stimulation pain outcomes [222].

Subsequent large deep brain stimulation trials showed beneficial outcomes. Patients with diverse neuropathic pain syndromes were followed for one to eight years. The best long-term pain outcomes were found in failed back surgery syndrome, and CRPS-II (66% with ≥50% pain reduction). Central pain from spinal cord injury or post-stroke pain showed poor response [225,226].

Following deep brain stimulation of the PVG/PAG grey area or VPL/VPM/internal capsule, patients were followed a mean 78 months and ≥50% pain reduction was attained in patients with failed back surgery syndrome (74%), peripheral neuropathy (60%), thalamic pain (20%), and in patients with trigeminal neuropathy or phantom limb pain but not spinal cord injury or postherpetic neuralgia [227].

Consistent findings of earlier trials were deep brain stimulation efficacy in failed back surgery syndrome and neuropathic pain of peripheral origin; poor response in spinal cord injury or post-stroke pain; and initial benefit may be lost after several years [225].

Intractable Neuropathic Pain

Deep brain stimulation study reviews found long-term pain relief in more than 80% of patients with intractable failed back surgery syndrome, 58% with post-stroke pain, and higher rates in peripheral neuropathic pain (phantom limb pain, polyneuropathies) [13].

In 59 patients with long-term follow-up after deep brain stimulation of the PVG (53.8%), VPL/VPM (12.8%), or both (33.3%), ≥50% pain reduction was attained in patients with phantom limb pain (89%), brachial plexus injury (50%), post-stroke (69%) and spinal cord injury (57%) pain, and chronic headache (54%) [228]. Complications included implantable pulse generator changes (42%), lead revisions (18%), lead erosion requiring removal, and infection, with two treated by antibiotics and five requiring device removal [222].

In seven open-label studies in peripheral or central neuropathic pain, mean pain reduction approached 50%, although pain relief varied largely across studies. The best outcomes occurred with somatosensory thalamus deep brain stimulation in peripheral neuropathic pain [27]. The dorsal anterior cingulate cortex is a potential deep brain stimulation target in chronic neuropathic pain that warrants further study, given its central role in cognitive and affective processing [189].

Intractable Cluster Headache

The American Headache Society practice recommendation for unilateral hypothalamic deep brain stimulation was downgraded to Negative B, based on a study showing active deep brain stimulation no different from sham in pain reduction and serious adverse effects during deep brain stimulation treatment [201].

THALAMIC DEEP BRAIN STIMULATION

Thalamic deep brain stimulation of refractory pain was largely abandoned from inadequate efficacy. Diffusion tensor imaging-based segmentation is a new method to improve thalamic lead positioning and clinical outcome, and was evaluated in five intractable pain patients receiving sensory thalamus deep brain stimulation. Diffusion tensor imaging identified the narrowly specific lead placement shared by four patients with significant post-deep brain stimulation pain relief, and ineffective lead placement in one patient lacking deep brain stimulation response. Diffusion tensor imaging confirmed thalamic lead placement and may be useful for guiding the procedure in the future [229].

Deep brain stimulation is generally safe, with an overall frequency of adverse events of 8% to 9%. These include lead fractures, wound infections, intraoperative seizure and postoperative burr-hole site erosion. Contraindications to pain treatment include psychiatric disorders, coagulopathy, and ventriculomegaly that preclude direct electrode passage to the surgical target [27].

NEUROMODULATION SAFETY IN PAIN TREATMENT

A systematic review concluded all neurostimulation techniques, including invasive procedures, were found safe to very safe. Reports of deaths or serious adverse events after invasive procedures in thousands of patients are conspicuously few. By far the most common side effects of invasive neurostimulation involved stimulation device malfunction or electrode movement. However, due to the invasive nature, implanted neurostimulation should be reserved for patients in whom conventional pain management is ineffective, intolerable or contraindicated; with clearly defined pain conditions; and after an optimal selection process [27].

11. SOCIAL ISSUES WITH NEUROSTIMULATORS

Consumer use of neurostimulators is rapidly expanding, far outpacing regulatory oversight and known safety implications. While patients can obtain devices through purchase, assembly of parts, or clinician prescribing, direct-to-consumer tDCS devices with non-medical product use claims are increasingly available. tDCS is the dominant modality in product availability and consumer demand [7]. Fueling this tDCS 'home use' movement is perception of safety, low device cost, published benefit in some neuropsychiatric disorders, and popularized media accounts of enhancement in normal neuropsychological function.

RISING CONSUMER USE

tDCS may reduce the symptoms of several neuropsychiatric disorders. Patients with these conditions can be highly motivated to seek tDCS therapy, but access is limited to clinical trial enrollment because tDCS remains investigational. Access to clinical trials of tDCS is not pragmatic or possible for many. Even after completing a study, patients have few options for therapy continuity, and unable to access tDCS under medical care, are seeking alternative routes of access [230,231]. This increasingly involves the Internet-mediated "do-it-yourself" tDCS movement of individuals who stimulate their own brains with tDCS outside of research or medical settings for self-improvement goals [231,232].

Some tDCS trials suggest improved cognition, attention, memory, language, and learning ability in healthy subjects [4]. These interesting results began attracting media attention, such as a New York Times article titled "Jump-Starter Kits for the Mind" [233]. The popularized positive effects of neuromodulation have spurred a growth industry in tDCS devices for non-therapeutic enhancement [7].

REGULATORY CHALLENGES AND SAFETY CONCERNS

The FDA designates medical devices by risk level for illness or injury as Class I (low-risk; bandages, dental floss); Class II (medium-risk; breast pump kits, over-the-counter TENS devices for pain); or Class III (high-risk; heart replacement valves, deep-brain stimulating electrodes) devices [232]. The definition of "medical device" is based on intended use and not mechanism of action. A product is a medical device if it is intended for use in diagnosis or treatment, or intended to affect the structure or function of the body [232].

The FDA classifies a product as a medical device according to its representation by the manufacturer, and the level of product regulation is greatly impacted by the intended use claims. This is relevant to how consumer tDCS devices makers represent their product. The websites of most direct-to-consumer tDCS devices tend to imply that intended use was for enhancing or optimizing brain function. Other makers have used the term "kit" to distance their product from possible FDA device classing. "Wellness," but not therapeutic, claims generally place a product outside the definition of a medical device, avoiding FDA regulation. The FDA states this solely applies to low-risk consumer "wellness" devices, but risk level only defines the regulatory process once a device is deemed within FDA jurisdiction [232].

A strong contributor to consumer demand is perceived safety. Safety reviews of tDCS trials treating more than 1,000 subjects with more than 33,200 sessions found no reports of serious adverse effects, irreversible injury or cognitive impairment with standard tDCS protocols (sessions ≤40 min, ≤2 times/day, ≤4 mA, electrodes that minimize skin burns) [16,231]. Another review noted that adverse effects were mentioned in only 56% of 172 published trials, indicating that systematic assessment and reporting of adverse effects was absent from a large portion of the evidence base [235].

A case report described respiratory and motor paralysis, muscle cramping, and nausea in a patient who, during electrical stimulation therapy, was accidentally delivered a current 10 times higher than intended. This report was shown to underscore the risk of applying electrical stimulation outside of established parameters, with clinically unsupervised home use of tDCS increasing the risk of permanent injury [234,235]. The efficacy and high overall safety reported in tDCS trials is specific to the device and clinical protocol. Changing any aspect of the device, electrode placement, or delivered dose is likely to obviate the desired effect. Direct-to-consumer tDCS products cannot claim the benefits of illness treatment or enhancement of normal function found by tDCS trials because they deviate in these aspects [235].

Other concerns with home use of tDCS include data that suggest cognitive enhancement mediated by tDCS may occur at the expense of other cognitive functions; the lack of long-term safety data; and the innumerable scenarios of inept home use and potential harm that may arise. An ethical concern is the media "neuro-hype" surrounding tDCS can shape public risk-benefit perception, promote therapeutic misconceptions, and impact the uptake of this technology. This increases the potential for desperate and vulnerable patients to overestimate tDCS benefits and under-estimate the risks [16,234].

12. CONCLUSION

A diverse array of brain stimulation modalities are available or being evaluated for the treatment of chronic psychiatric and pain conditions. Noninvasive approaches include ECT, which remains established as the most reliable means for rapid antidepressant induction; the more recent rTMS and tDCS, introduced to rival ECT efficacy without cognitive adverse effects or need for general anesthesia; several very recent variants of rTMS and tDCS; and trigeminal nerve stimulation (eTNS). The most-studied non-invasive brain stimulation is rTMS, followed by tDCS.

Unlike ECT, use of rTMS and tDCS have expanded beyond MDD. Efficacy in MDD is established with rTMS and more modest with tDCS. rTMS shows greater efficacy in anxiety-related disorders, substance use and eating disorders, while tDCS shows greater efficacy in alleviating residual audio verbal hallucinations and negative symptoms in schizophrenia. In diverse chronic pain conditions, rTMS is somewhat more effective than tDCS. VNS may have a role in severely treatment-resistant MDD, and motor cortex stimulation is effective in central refractory neuropathic pain. Deep brain stimulation is the most invasive modality, and may provide long-term, clinically meaningful symptom reduction and improved quality of life in patients with a range of intractable psychiatric or chronic pain conditions.

The current rate of knowledge expansion and publication output involving rTMS and tDCS cannot be overstated. The continuous refinement and improvements in specificity of stimulation and duration of response is rapidly making non-recent publications obsolete.

Many brain stimulation devices show consistent and significant treatment responses in various psychiatric and pain conditions. From a rigid, evidence-based perspective, the strength of evidence for efficacy is considered weak in many stimulation-responsive conditions. This does not imply the therapy is ineffective, but instead reflects the small numbers of treated patients in many clinical conditions [187]. Compared to long-term efficacy, safety and adverse effects are much more established in rTMS and tDCS; with ECT and deep brain stimulation, all three dimensions of treatment outcome are established. However, in real world clinical care, decision-making weighs potential benefits against known risks across the range of options. Most patients evaluated for response to brain stimulation have multiple prior failed treatments. Brain stimulation offers the potential to offset patient non-response or intolerance to standard therapies.

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