VAMD22 • Virginia Physicians and Physician Assistants 2021-2022

Table of Contents

VAMD22 • Virginia Physicians and Physician Assistants 2021-2022

How to Receive Credit

NetCE 10 Hour Course #94673 • Pneumonia

94673 • Pneumonia

1. HISTORICAL BACKGROUND

2. DEFINITIONS

3. EPIDEMIOLOGY AND SCOPE

4. GUIDELINE-DIRECTED MANAGEMENT AND PREVENTION OF PNEUMONIA

5. PATHOGENESIS AND CLASSIFICATION OF PNEUMONIA

6. COMMUNITY-ACQUIRED PNEUMONIA

7. PREVENTION OF PNEUMONIA

8. PNEUMONIA ASSOCIATED WITH HEALTHCARE FACILITIES

9. SUMMARY

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #90240 • Pancreatic Cancer

90240 • Pancreatic Cancer

1. INTRODUCTION

2. EPIDEMIOLOGY

3. PATHOPHYSIOLOGY

4. PANCREATIC CANCER SCREENING

5. CLINICAL EVALUATION OF PANCREATIC CANCER

6. THE DIAGNOSTIC AND STAGING WORKUP

7. TREATMENT APPROACHES FOR PANCREATIC CANCER

8. PALLIATION AND SYMPTOMATIC MANAGEMENT

9. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

10. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #96963 • Opioid Use Disorder

96963 • Opioid Use Disorder

1. INTRODUCTION

2. DEFINITIONS

3. BACKGROUND

4. EPIDEMIOLOGY OF OPIOID USE DISORDER

5. CLASSIFICATION

6. OPIOID SYNTHESIS

7. PHARMACOLOGY

8. CLINICAL EFFECTS

9. SPECIFIC OPIOID DRUGS

10. NATURAL HISTORY OF OPIOID DEPENDENCE

11. PATHOPHYSIOLOGY

12. EFFECTS OF OPIOID USE DISORDER

13. OPIOID OVERDOSE

14. OPIOID WITHDRAWAL

15. LIABILITY OF MISUSE OF LEGITIMATELY PRESCRIBED OPIOID DRUGS

16. MANAGEMENT OF OPIOID USE DISORDER

17. MANAGEMENT OF COMORBID PSYCHOPATHOLOGY

18. OPIOID USE DURING PREGNANCY

19. PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

20. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

VAMD22 • Virginia Physicians and Physician Assistants 2021-2022

John M. Leonard, MD

Carol Whelan, APRN

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

VAMD22 • Virginia Physicians and Physician Assistants 2021-2022

Expiration Date: 05/22/2023

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.

94673 • Pneumonia

John M. Leonard, MD

Carol Whelan, APRN

www.netce.com

Copyright © 2021 NetCE, All rights reserved.

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

Table of Contents

94673 • Pneumonia

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. HISTORICAL BACKGROUND

2. DEFINITIONS

3. EPIDEMIOLOGY AND SCOPE

4. GUIDELINE-DIRECTED MANAGEMENT AND PREVENTION OF PNEUMONIA

5. PATHOGENESIS AND CLASSIFICATION OF PNEUMONIA

6. COMMUNITY-ACQUIRED PNEUMONIA

EPIDEMIOLOGY

RISK FACTORS

ETIOLOGY

CLINICAL PRESENTATION IN ADULTS

DIAGNOSIS AND MANAGEMENT OF COMMUNITY-ACQUIRED PNEUMONIA IN ADULTS

ILLUSTRATIVE CASE

PNEUMONIA IN THE PEDIATRIC PATIENT

7. PREVENTION OF PNEUMONIA

IMMUNIZATION

8. PNEUMONIA ASSOCIATED WITH HEALTHCARE FACILITIES

EPIDEMIOLOGY

RISK FACTORS

ETIOLOGY

DIAGNOSIS

TREATMENT

PREVENTION

ILLUSTRATIVE CASE

9. SUMMARY

Works Cited

Evidence-Based Practice Recommendations Citations

94673 • Pneumonia

Education Category. Infection Control / Internal Medicine

Release Date. 09/01/2021

Expiration Date. 08/31/2024

Course Overview

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

Audience

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

Accreditations & Approvals

In support of improving patient care, NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is approved by the California Nursing Home Administrator Program as a provider of continuing education. Provider number 1622. NetCE is approved to offer continuing education through the Florida Board of Nursing Home Administrators, Provider #50-2405. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU. NetCE is approved as a provider of online continuing education for certified nursing assistants through the California Department of Public Health Licensing and Certification Division. Nurse Aide Certification (NAC) Provider #7005.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 10 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 10 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 10 ANCC contact hour(s). NetCE designates this continuing education activity for 5 pharmacology hour(s) for physician assistants. NetCE designates this continuing education activity for 5 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 12 hours for Alabama nurses. NetCE designates this activity for 10 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-21-103-H01-P. 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. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. This home study course is approved by the Florida Board of Nursing Home Administrators for 10 credit hour(s). This course is approved by the California Nursing Home Administrator Program for 10 hour(s) of continuing education credit - NHAP#1622010-9397/P. California NHAs may only obtain a maximum of 10 hours per course. 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 29,2025); Alabama, Provider #ABNP0353, (valid through July 29, 2025); 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 12/31/2025; South Carolina, Provider #50-2405; South Carolina, Provider #50-2405. West Virginia RN and APRN, Provider #50-2405.

Special Approvals

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

Course Objective

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

Learning Objectives

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

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

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

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

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

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

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

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

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

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

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

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

Faculty

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

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

Faculty Disclosure

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

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

Division Planners

John V. Jurica, MD, MPH

Jane C. Norman, RN, MSN, CNE, PhD

Randall L. Allen, PharmD

Shannon E. Smith, MHSC, CST, CSFA

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. HISTORICAL BACKGROUND

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

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

2. DEFINITIONS

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

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

3. EPIDEMIOLOGY AND SCOPE

Pneumonia is a substantial healthcare concern, ranking among the most common reasons for emergency department and outpatient visits, hospitalizations, and deaths among both adults and children [2,3,4,5,6]. The World Health Organization (WHO) lists pneumonia as the world's fourth leading cause of death, accounting for an estimated 2.6 million lives lost to lower respiratory infection in 2019 [228]. Collected data consistently demonstrate a bimodal distribution of mortality, with peaks in children younger than 5 years of age and adults older than 75 years of age. Worldwide, pneumonia was responsible for an estimated 808,000 deaths in children younger than 5 years of age in 2017, mainly in developing countries [228]. In the United States, pneumonia is the leading cause of death from infectious disease and the eighth most common cause of death overall. According to data from the National Center for Health Statistics, there were 43,881 deaths from bacterial and viral pneumonias in 2019, a rate of 13.4 per 100,000 population [234]. There is seasonal variation in the incidence of pneumonia, with most cases occurring in the winter months.

U.S. hospital discharge statistics show that the rate of hospitalization for pneumonia varies with age, being highest among adults 75 to 84 years of age. In recent decades, the rate of hospitalization for pneumonia has been relatively stable for adults younger than 65 years of age and has declined somewhat for adults older than 65 years (Table 1) [6]. In 2010, there were 1.1 million U.S. hospital discharges for which the leading discharge diagnosis was pneumonia, and the average length of stay for these patients was 5.2 days [2].

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

Age

Rate (per 10,000)

1990

2000

2009–2010

18 to 44 years

12.5

10.9

9.5

45 to 64 years

33.5

35.3

32.6

65 to 74 years

98.1

121.3

83.8

75 to 84 years

224.6

263.5

179.3

85 years and older

501.0

514.9

355.3

Source: [6]

The mortality rate for pneumonia and influenza combined has decreased substantially in the United States over the past 20 years, falling from 23.7 per 100,000 in 2000 to 15.2 per 100,000 in 2019 [234]. Two important public health factors, which may account for this trend, are the increased utilization of pneumococcal and influenza vaccines among adults and children and the decline in cigarette smoking [220,221].

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

4. GUIDELINE-DIRECTED MANAGEMENT AND PREVENTION OF PNEUMONIA

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

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

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

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

5. PATHOGENESIS AND CLASSIFICATION OF PNEUMONIA

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

Clinically, pneumonia is often described in reference to suspected or established causative pathogens (i.e., viral, bacterial, fungal, or parasitic); however, the precise etiology cannot be identified in more than half the cases in which testing is done [9,24,25]. Classifying pneumonia according to setting in which it develops is more useful for clinical purposes because the most common pathogens, as well as clinical outcomes, are similar within distinct clinical settings [26,27]. Pneumonia was once broadly classified as either community-acquired (developing outside of a hospital or other healthcare facility) or nosocomial (developing 48 hours or more after hospital admission, usually postoperatively). In its 2005 guideline, the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) noted three distinct categories within the broader classification of pneumonia associated with healthcare facilities: HAP, VAP, and HCAP (Table 2) [3,28]. These three categories of pneumonia are similar in that they often result from colonization, then infection, by resistant gram-negative bacilli and methicillin-resistant Staphylococcus aureus (MRSA), necessitating broader empiric antibiotic therapy than that commonly used for CAP [27].

Table 2: TYPES OF PNEUMONIA

Type

Definition

Community-acquired

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

Hospital-acquired

New infection occurring more than 48 hours after hospital admission

Ventilator-associated

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

Healthcare-associated

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

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

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

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

Source: [28]

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

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

6. COMMUNITY-ACQUIRED PNEUMONIA

EPIDEMIOLOGY

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

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

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

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

The rate of pediatric outpatient visits for CAP has been reported to be 35 to 52 per 1,000 children 3 to 6 years of age and 74 to 92 per 1,000 children 2 years of age and younger [10]. The hospitalization rate for children up to 18 years of age is 201.1 per 100,000; the highest rate is for infants younger than 1 year of age (912.9 per 100,000) and lowest for teenagers (62.8 per 100,000) [4]. According to data from the Centers for Disease Control and Prevention (CDC), 525 infants and children (up to 15 years of age) in the United States died as a result of pneumonia (or another lower respiratory tract infection) in 2006 [30].

RISK FACTORS

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

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

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

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

ETIOLOGY

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

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

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

Age and/or Setting

Most Likely Pathogens

Adults

Outpatient

Streptococcus pneumoniae

Mycoplasma pneumoniae

Chlamydophila pneumoniae

Haemophilus influenzae

Respiratory viruses

Legionellaspp.

Inpatient, not intensive care unit

S. pneumoniae

M. pneumoniae

C. pneumoniae

H. influenzae

Legionellaspp.

Respiratory viruses

Intensive care unit

S. pneumoniae

Staphylococcus aureus

Legionella spp.

Gram-negative bacilli

H. influenzae

Children

Birth to 3 weeks

Group B streptococci

Listeria monocytogenes

Gram-negative bacilli

Cytomegalovirus

3 weeks to 3 months

S. pneumoniae

Respiratory viruses

Bordetella pertussis

S. aureus

Chlamydia trachomatis (transnatal exposure)

4 months to 4 years

S. pneumoniae

Respiratory viruses

M. pneumoniae (in older children)

Group A streptococci

5 to 15 years

S. pneumoniae

M. pneumoniae

C. pneumoniae

Source: [29,47]

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

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

Patient Characteristic

Suspect Pathogen(s)

Alcoholism

Oral anaerobes

Streptococcus pneumoniae

Gram-negative bacilli

COPD, tobacco use

Haemophilus influenzae

S. pneumoniae

Moraxella catarrhalis

Nursing home resident

S. pneumoniae

Gram-negative bacilli

H. influenzae

Staphylococcus aureus

Poor dental hygiene

Oral anaerobes

Recent exposure to contaminated plumbing or water

Legionella organisms

Exposure to exotic birds and/or decaying bird nesting sites

Chlamydia psittaci

Histoplasma capsulatum (histoplasmosis)

HIV infection

Pneumocystis carinii

S. pneumoniae

H. influenzae

Mycobacterium tuberculosis

Exposure to excreta of wild rodents

Sin nombre virus (hantavirus pulmonary syndrome)

COPD = chronic obstructive pulmonary disease.

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

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

Bacterial Pathogens

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

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

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

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

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

Viral Pathogens

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

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

Mixed Pathogens

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

CLINICAL PRESENTATION IN ADULTS

Clinical Features

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

- Productive cough, purulent sputum

- Fever with rigors (shaking chills)

- Dyspnea

- Pleuritic chest pain

- Tachypnea

- Tachycardia

- Hypoxemia

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

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

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

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

Chest Radiography

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

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

- Temperature >37.8°C (100.04°F)

- Heart rate >100 beats per minute

- Crackles on auscultation

- Decreased breath sounds

- Absence of asthma

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

Atypical Pneumonia

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

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

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

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

Legionellosis

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

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

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

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

DIAGNOSIS AND MANAGEMENT OF COMMUNITY-ACQUIRED PNEUMONIA IN ADULTS

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

Laboratory Diagnosis

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

Blood Culture

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

- Cavitary infiltrates

- Leukopenia

- Active alcohol abuse

- Chronic liver disease

- Asplenia

- COPD

- Pleural effusion

- Illness severity requiring admission to the ICU

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

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

Sputum Culture and Gram Stain

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

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

Newer Diagnostic Techniques

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

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

Testing for Viruses

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

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

Biomarkers

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

Site of Care

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

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

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

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

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

Characteristic

Points Assigneda

Nursing home resident

+10

Demographic factor (age)

Men

Age (yr)

Women

Age (yr)-10

Coexisting illnessesb

Neoplastic disease

+30

Liver disease

+20

Congestive heart failure

+10

Cerebrovascular disease

+10

Renal disease

+10

Physical-examination findings

Altered mental statusc

+20

Respiratory rate ≥30 breaths/min

+20

Systolic blood pressure <90 mm Hg

+20

Temperature <35°C or ≥40°C

+15

Pulse ≥125 beats/min

+10

Laboratory and radiographic findings

Arterial pH <7.35

+30

Blood urea nitrogen ≥30 mg/dL

+20

Sodium <130 mmol/L

+20

Glucose ≥250 mg/dL

+10

Hematocrit <30%

+10

Partial pressure of arterial oxygen <60 mm Hgd

+10

Pleural effusion

+10

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

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

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

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

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

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

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

- Increased respiratory rate (≥30 breaths per minute)

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

- Multilobar infiltrates

- Confusion/disorientation

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

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

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

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

- Hypotension requiring aggressive fluid resuscitation

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

Selection of Antibiotics

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

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

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

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

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

Site of Care and Patient Characteristics

Recommended Drug Class

Specific Drug Options

Level of Evidence

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

Amoxicillin

—

Strong recommendation, moderate quality of evidence

Tetracycline or macrolide

Doxycycline, azithromycin, or clarithromycin

Conditional recommendation, low-to-moderate quality of evidence

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

Monotherapy with a respiratory fluoroquinolone

Moxifloxacin, gemifloxacin, or levofloxacin

Strong recommendation, moderate quality of evidence

Combination therapy with a ß-lactam + macrolide or doxycycline

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

Conditional recommendation, low quality of evidence

Inpatient (not ICU)

Respiratory fluoroquinolone

—

Strong recommendation, high quality of evidence

ß-lactam + macrolide

—

Strong recommendation, high quality of evidence

Inpatient (ICU)

ß-lactam + azithromycin

OR

ß-lactam + respiratory

fluoroquinolone

Alternative for penicillin allergy: respiratory fluoroquinolone

and aztreonam

Cefotaxime, ceftriaxone, or ampicillin-sulbactam

Strong recommendation, high quality of evidence

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

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

Source: [235]

Evidence Based Practice Recommendation

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

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

Last Accessed: August 16, 2021

Strength of Recommendation: 9

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

Evidence Based Practice Recommendation

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

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

Last Accessed: August 16, 2021

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

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

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

Pathogen

Preferred Antibiotic

Alternative Options

Streptococcus pneumoniae, not penicillin resistant

Penicillin G, amoxicillin

Macrolide, cephalosporins, clindamycin, doxycycline, respiratory fluoroquinolone

Streptococcus pneumoniae, penicillin resistant

Based on susceptibility (cefotaxime, ceftriaxone, fluoroquinolone)

Vancomycin, linezolid, high-dose amoxicillin

Haemophilus influenzae, non-ß-lactamase producing

Amoxicillin

Fluoroquinolone, doxycycline, azithromycin, clarithromycin

Haemophilus influenzae, ß-lactamase producing

Second- or third-generation cephalosporin, amoxicillin-clavulanate

Fluoroquinolone, doxycycline, azithromycin, clarithromycin

Mycoplasma pneumoniae/Chlamydophila pneumoniae

Macrolide, a tetracycline

Fluoroquinolone

Legionella spp.

Fluoroquinolone, azithromycin

Doxycycline

Pseudomonas aeruginosa

Antipseudomonal ß-lactam plus ciprofloxacin or levofloxacin or aminoglycoside

Aminoglycoside plus ciprofloxacin or levofloxacin

Acinetobacter spp.

Carbapenem

Cephalosporin-aminoglycoside, ampicillin-sulbactam, colistin

Staphylococcus aureus, methicillin susceptible

Antistaphylococcal penicillin

Cefazolin, clindamycin

Staphylococcus aureus, methicillin resistant

Vancomycin or linezolid

Trimethoprim/sulfamethoxazole

Source: [47]

For adults who present with presumed viral CAP, it is unclear whether antibiotic treatment is beneficial. However, when the patient with CAP has epidemiologic, clinical, or laboratory evidence of active influenza, a neuraminidase inhibitor should be included in the treatment regimen [32,235]. During the COVID-19 pandemic, patients with upper respiratory tract infection progressing to clinical and/or radiographic signs suspicious for viral pneumonia should immediately receive SARS-CoV-2 diagnostic testing and consideration for COVID-19 treatment protocol. Updated guidance for managing patients with COVID-19 pneumonia is available at the National Institutes of Health and IDSA websites [94,239].

Timing of Initial Antibiotic Therapy

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

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

Duration of Therapy

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

- Temperature ≤37.8°C (100.04°F)

- Heart rate ≤100 beats per minute

- Respiratory rate ≤24 breaths per minute

- Systolic blood pressure ≥90 mm Hg

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

- Ability to maintain oral intake

- Normal mental status

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

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

Treatment Failure

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

Benefits of Guideline-Adherent Antibiotic Therapy

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

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

Strategies to Enhance Adherence to Therapeutic Guidelines

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

Follow-Up Care

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

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

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

Patient and Family Education

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

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

ILLUSTRATIVE CASE

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

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

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

What is the best site of care and treatment for this patient? While he does not meet the criteria for ICU admission, his age, comorbidities, degree of illness, and social situation taken together suggest the need for hospital admission, parenteral antibiotic therapy, and close observation, anticipating a short hospital stay. He was treated with a ß -lactam and macrolide, improved rapidly, and was discharged day 3 on a matching oral regimen, to complete a 10-day course of therapy.

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

PNEUMONIA IN THE PEDIATRIC PATIENT

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

Etiology

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

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

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

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

Clinical Features and Diagnosis

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

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

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

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

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

Laboratory Tests

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

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

Management of Community-Acquired Pneumonia in Children

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

Site of Care

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

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

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

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

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

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

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

- Has altered mental status as a result of pneumonia

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

- Requires acute use of noninvasive positive pressure ventilation

Selection of Antibiotics or Antivirals

Evidence Based Practice Recommendation

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

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

Last Accessed: August 16, 2021

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

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

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

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

Site of Care, Patient Characteristics

Presumed Bacterial Pneumonia

Presumed Atypical Pneumonia

Outpatient

<5 years

Amoxicillin

Alternative: amoxicillin clavulanate

Azithromycin

Alternatives: clarithromycin or erythromycin

≥5 years

Amoxicillina

Alternative: amoxicillin clavulanate

Azithromycin

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

Inpatient (all ages)

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

Ampicillin or penicillin G

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

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

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

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

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

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

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

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

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

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

Source: [30]

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

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

Duration of Therapy

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

Benefits of Guideline Adherence

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

Late Complications

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

7. PREVENTION OF PNEUMONIA

IMMUNIZATION

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

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

Vaccination

Priority Groups

Annual influenza vaccination

Adults 65 years of age and older

Children 6 to 59 months of age

Residents of long-term care facilities

Adults and children with chronic medical conditions

Women who are pregnant during the influenza season

Pneumococcal vaccination

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

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

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

Compromised immune system

Alcoholism

Cochlear implants

Cerebrospinal fluid leaks

Functional or anatomic asplenia

Resident of nursing home or long-term care facility

Current or recent past history of smoking

Source: [28,91]

Pneumococcal Vaccination

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

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

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

Table 10: IMMUNIZATION SCHEDULE RECOMMENDED BY THE ACIP

Vaccination

Recommended Recipients

Influenza vaccination (annually)a

Adults and children 6 months of age and older

Pneumococcal vaccination (PCV20 OR PCV15 in series with PPSV23, 12 months apart)b

Adults 65 years of age and older

High-risk children and adults (2 to 64 years of age)

Haemophilus influenzae b (series of 4)

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

Pneumococcal conjugate vaccine (series of 4)

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

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

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

Source: [91,92,227]

Influenza Vaccination

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

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

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

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

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

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

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

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

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

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

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

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

Vaccine Efficacy

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

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

Vaccination Rates

Despite the wide distribution of the ACIP immunization schedule and public campaigns about the importance of vaccination, rates of both pneumococcal and influenza vaccination remain relatively low. According to CDC estimates, influenza vaccination coverage for the 2019–2020 season among adults 18 years of age or older was 48.4%, an increase of 3.1 percentage points from the prior season [102]. Coverage among children 6 months through 17 years of age was 63.8%. Roughly half (51.8%) of all persons 6 months and older were vaccinated during the 2019–2020 season. Influenza vaccination coverage was lower among Hispanic (46.4%) and non-Hispanic Black (45.7%) adults than White (54.8%) adults [102]. Coverage among adults 65 years of age or older (69.8%) was higher compared with younger age groups. Among healthcare personnel, influenza vaccine coverage during the 2019–2020 influenza season was 80.6%. When analyzed by setting, vaccine coverage was highest among healthcare personnel in ambulatory care and hospital settings with vaccine requirements (96.1% and 95.7%, respectively), and lowest in ambulatory care or hospital settings without vaccination requirements, promotion, or on-site offer (47.7% and 49.9%, respectively) [103].

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

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

Age/Ethnicity

Rate

2005

2010

2015

18 to 44 years of age

10.1%

24.6%

30.9%

45 to 64 years of age

20.2%

37.8%

45.1%

65 years of age and older

59.7%

63.9%

69.1%

White

22.5%

36.9%

44.2%

Black

15.5%

28.1%

36.7%

Hispanic

12.0%

26.5%

31.2%

Source: [113]

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

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

Race/Ethnicity

High-Risk Adults 19 to 64 Years

Adults 65 Years and Older

All races

23.3%

69.0%

White (non-Hispanic)

23.6%

72.6%

Black (non-Hispanic)

23.6%

59.8%

Hispanic or Latino

18.5%

54.3%

Asian

23.6%

55.0%

Source: [237]

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

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

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

Race/Ethnicity

Rate

White (non-Hispanic)

84.1%

Black (non-Hispanic)

74.5%

Hispanic

81.4%

American Indian/Alaska Native

80.1%

Asian

81.0%

Multiracial

83.6%

Total

83.3%

PCV = pneumococcal conjugate vaccine.

Source: [112]

Barriers to Vaccine Use

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

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

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

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

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

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

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

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

Table 14: BARRIERS TO OPTIMAL VACCINATION AND POSSIBLE SOLUTIONS

Barriers

Solutions

Decreased knowledge about pneumonia and its seriousness

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

Belief that vaccines are unsafe or will cause illness

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

Lack of awareness for the need of vaccination

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

Lack of provider recommendations

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

Lack of effective practice systems

Implement effective reminder systems and standing orders.

Source: Compiled by Author

Table 15: RESOURCES ABOUT VACCINATIONS FOR PATIENTS AND PARENTS

American Academy of Pediatrics

https://www.aap.org

American Academy of Family Physicians

https://www.aafp.org

U.S. Department of Health and Human Services Vaccines

https://www.vaccines.gov

The History of Vaccines

https://www.historyofvaccines.org

Immunization Action Coalition

http://www.vaccineinformation.org

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

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

Source: Compiled by Author

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

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

Patient Type

Influenza Vaccine

Pneumococcal Vaccine

Physicians

PA/NP/RNs

Physicians

PA/NP/RNs

All adults

39%

59%a

—

—

Aged ≥50 years

28%a

15%

4%

18%a

Aged ≥65 years

37%

28%

65%

55%

Chronic lung disease

45%

40%

68%

55%

Diabetes mellitus

31%

25%

44%a

26%

Heart disease

20%

11%

29%a

12%

Chronic liver disease

22%

16%

27%

20%

Chronic kidney disease

22%

12%

25%

17%

Weak immune system

17%

20%

24%

29%

Radiation/chemotherapy

14%

9%

17%

10%

Asplenia

—

—

27%a

8%

Complications or risk from other illness

25%

17%

28%

23%

Smoker

—

—

13%

11%

Close contact with someone at high risk

24%

22%

11%

10%

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

NP = nurse practitioner; PA = physician assistant; RN = registered nurse.

Source: Reprinted with permission from Johnson D, Nichol KL, Lipczynski K. Barriers to adult immunization. Am J Med. 2008;121:S28-S35.

Missed opportunities represent another practice-related area in which clinicians can improve vaccination rates. Although many clinicians check immunization status during well visits, most do not check the status during acute visits, nor do they take advantage of the visit to administer the vaccination [105,115]. Healthcare providers can close the gap on missed opportunities for vaccination by taking advantage of every office visit to administer vaccinations, reminding their patients about the need for vaccination, or scheduling a future appointment for vaccination [105,115,117]. Educational fliers and pamphlets in the waiting room and examination rooms can engage patients and parents and help prompt discussions about vaccination [116].

Patient reminder and recall systems in primary care settings have been effective in improving vaccination rates. A meta-analysis found that rates among both children and adults increased up to 20% with several types of reminders, including postcards, letters, and phone calls [137]. The most effective reminder system was phone calls, but it was also the most expensive. Given that about 25% of primary care physicians currently use reminder systems, increasing the number of physicians who use such systems can in turn increase vaccination rates [123]. Standing orders for vaccinations have been shown to substantially increase vaccination rates, yet are used by only 20% to 33% of physicians [123,138]. Again, adopting this system results in improved vaccination rates.

Many people have turned to facilities outside of their primary healthcare provider to receive vaccinations. Health fairs, pharmacies, grocery stores, senior centers, and workplaces have become more common settings for vaccination because of their convenience and lower cost [123,138]. Clinicians can also help increase vaccination rates by participating in community events that provide vaccinations and by promoting these settings as alternative options.

Programs to provide vaccinations to high-risk patients in the emergency room have been successful at increasing vaccination rates [139,140]. In a three-week intervention program at one inner city emergency department, participants were provided appropriate immunizations when they were at high risk for specific diseases [139]. During the study period, rates of influenza and pneumococcal vaccinations increased from 16% to 83% and from 18% to 84%, respectively. Such programs can help healthcare systems adhere to guideline recommendations for vaccinating hospitalized patients.

8. PNEUMONIA ASSOCIATED WITH HEALTHCARE FACILITIES

Pneumonia associated with healthcare facilities encompasses the broad category of cases that arise in persons who reside in, or have had significant recent exposure to, facilities such as hospitals, nursing homes, dialysis clinics, and transfusion centers. Despite advances in clinical care and prevention, this category of pneumonia remains a serious cause of morbidity and mortality and a challenging, costly public health issue. The IDSA and the ATS subdivide and defines this category of pneumonia as follows:

- HAP is hospital-acquired pneumonia that occurs 48 hours or more after admission and did not appear to be incubating at the time of admission.

- VAP is a separate type of HAP that develops more than 48 hours after endotracheal intubation.

- HCAP is defined as pneumonia occurring in a nonhospitalized patient with extensive healthcare contact, evidenced by one or more of the following:

- Intravenous therapy/chemotherapy or wound care within the prior 30 days

- Residence in a nursing home or other long-term care facility

- Discharge from an acute care hospital or chronic care facility within the prior 90 days

- Attendance at a hospital or hemodialysis clinic within the prior 30 days

HAP and VAP have been studied most often, and the bulk of data on causative pathogens comes from studies of VAP. All three categories of pneumonia carry an increased risk for drug-resistant infection, though the risk of multidrug-resistant infection has been more consistently applicable to HAP and VAP [28]. Within the category of HCAP, nursing home-acquired pneumonia is the type with the most published data and will be discussed in this course. The ATS and the IDSA have jointly published evidence-based recommendations, updated in 2016, for the diagnosis and treatment of HAP and VAP [28].

EPIDEMIOLOGY

Approximately 3 to 10 cases of HAP occur per 1,000 hospital admissions [26]. Pneumonia as a complication of hospitalization increases length of stay (by more than one week), increases mortality risk, and adds an additional cost of care that can reach $40,000 per case [26].

The rate of VAP is higher than that for HAP, with a reported rate of 1 to 4 cases per 1,000 ventilator-days, and rates as high as 10 cases per 1,000 in some neonatal and surgical populations [12,28,141]. An estimated 10% of patients requiring mechanical ventilation will develop VAP, and the mortality rate directly attributable to VAP is estimated at 13% [28]. Excess cost of care resulting from prolongation of hospital stay is estimated to range from $30,000 to $40,000 per patient [28]. Pediatric VAP has not been as well studied as in adults. It occurs most commonly in children 2 to 12 months of age [142].

Pneumonia develops in approximately 2.3% of nursing home residents [1]. The mortality rate attributed to nursing home-acquired pneumonia is 10% to 30% [143].

RISK FACTORS

Illness and injury requiring admission to a healthcare facility often confers an increased risk for infection. Multiple factors account for this, including weakness and debility, use of indwelling catheters, compromised immune function, and poor nutrition [26,144]. To these may be added sedating medication intended to promote sleep or permit invasive procedures; this in turn increases the risk for aspiration of nasopharyngeal secretions colonized with nosocomial bacterial pathogens.

The nasopharynx tends to become colonized by enteric gram-negative bacilli within a few days after admission to a hospital. Risk factors for colonization by multidrug-resistant pathogens include exposure to critical care units, prolonged hospital stay, prior antibiotic therapy, history of cigarette smoking, major surgery, multiple organ-system failure, and foreign bodies such as nasogastric and endotracheal tubes [26,144].

Hospital-Acquired Pneumonia

In a systematic review, the American College of Physicians found several patient-related and surgery-related factors that increased the risk of postoperative pulmonary complications. The most common patient-related factors were the presence of COPD and an age older than 60 years [145]. Other significant factors were an American Society of Anesthesiologists (ASA) class of 2 (defined as a patient with mild systemic disease) or higher, functional dependence, and congestive heart failure. Cigarette use was associated with a modest increase in risk, and obesity and mild or moderate asthma were not found to increase risk [145]. Use of a PPI or histamine2 receptor antagonist is also thought to be a risk factor [45]. Surgery-related factors included prolonged duration of surgery (i.e., more than three to four hours), emergency surgery, and surgical site, with abdominal surgery, thoracic surgery, neurosurgery, head and neck surgery, vascular surgery, and aortic aneurysm repair being associated with the greatest risks [145].

Ventilator-Associated Pneumonia

The risk for VAP appears to be greatest during the first week after intubation. In one study, the risk was estimated to be 3% per day during the five-day period following intubation, decreasing to 2% per day for days 5 through 10, and to 1% per day for longer durations [147]. In a population of children who had cardiothoracic surgery, pneumonia risk correlated with mechanical ventilation for longer than three days [144]. Nearly half of all cases of VAP develop within the first four days of mechanical ventilation [148].

Other identified risk factors among adults include prolonged placement of the patient's head in the supine position; use of a nasogastric tube, paralytic agents, or PPI or histamine2 receptor antagonist; advanced age; chronic lung disease; and head trauma [45,149]. Among children, VAP has been significantly associated with subglottic/tracheal stenosis, trauma, and tracheostomy [150]. In one study, VAP was most frequently associated with ICU admission diagnoses of postoperative care, neurologic conditions, sepsis, and cardiac complications [151].

Nursing Home-Acquired Pneumonia

The risk factors reported to be associated with nursing home-acquired pneumonia include profound disability, immobility, urinary incontinence, deteriorating health status, difficulty swallowing, and inability to take oral medications [42]. Older age, male gender, and antipsychotic and anticholinergic medications have also been reported to increase risk [23,42].

ETIOLOGY

Gram-negative enteric bacilli and Pseudomonas spp. rarely colonize the upper respiratory tract of healthy individuals, but often do so in persons with an underlying disease, such as alcohol use disorder, and in those who are hospitalized or reside in nursing homes. Therefore, a history of recent hospitalization or nursing home residency should heighten suspicion for a gram-negative pathogen when such a patient presents with clinical signs of infection.

Most cases of pneumonia that develop in a healthcare facility are caused by aspiration of oropharyngeal or gastric secretions colonized with hospital bacterial flora [26,28]. Consequently, the prevalent causation as well as the antibiotic sensitivity pattern of resident pathogens will vary from region to region in relation to the type of facility and burden of antimicrobial usage. The selection of initial antibiotic therapy in these cases is based on the patient's risk factors for infection with a multidrug-resistant organism, such as MRSA, P. aeruginosa, K. pneumoniae, or Acinetobacter. The ATS/IDSA lists the following risk factors for multidrug-resistant pathogens in patients presenting with HAP or VAP [233,28]:

- Prior intravenous antibiotic use within 90 days

- Septic shock at time of VAP

- ARDS prior to onset of VAP

- High frequency of antibiotic resistance in the community of residence or the hospital unit of residence

- Five or more days of hospitalization prior to onset of pneumonia

- Home infusion therapy

- Chronic dialysis within 30 days

- Family member with multidrug-resistant infection

- Immunosuppression

Viral and fungal pathogens are rare causes of HAP, VAP, and nursing home-acquired pneumonia in immunocompetent adults. Outbreaks of viral pneumonia may occur during influenza season, and influenza, parainfluenza, adenovirus, and RSV are involved in about 70% of those cases [28]. Candida spp. and Aspergillus fumigatus may cause pneumonia in patients who have had organ transplantation or who have a compromised immune system and neutropenia.

Hospital-Acquired Pneumonia

Among adults with no previous antibiotic exposure, the most common bacterial causes of HAP are S. pneumoniae, H. influenzae, Escherichia coli, K. pneumoniae, and S. aureus [26,28,35,148]. Gram-negative bacilli resistant to first-generation cephalosporins also frequently develop in late-onset HAP. For up to 40% of adults with previous antibiotic exposure, late-onset HAP is caused by potentially multidrug-resistant pathogens, including Pseudomonas aeruginosa, Acinetobacter baumannii, and MRSA [26]. In a study of more than 3,600 patients admitted to an ICU, Pseudomonas spp. was the cause of pneumonia in 25% of patients; MRSA in 18%; and Acinetobacter spp. in 6% [35]. Other studies have shown that S. aureus is common among patients who are in a coma or have diabetes or renal failure. P. aeruginosa is common among patients who have had a prolonged stay in the ICU, have received prior antibiotics or corticosteroids, or who have structural lung disease. Legionella is usually found in patients who have compromised immune systems [35].

The causes of HAP in children have not been well studied. However, outbreaks of pneumonia caused by RSV have been common in pediatric wards [28].

Ventilator-Associated Pneumonia

The most common pathogens associated with VAP in adults are S. aureus and P. aeruginosa, followed by Enterobacter spp., A. baumannii, and K. pneumoniae [26,148,152,153]. These bacteria are among those that have become resistant to antibiotics, and the frequency of infection with MRSA is increasing. Almost half of all cases are caused by infection with more than one pathogen [148]. Although bacteria are the primary causative agents, viruses and saprophytic fungi have also been implicated as well [154].

As with HAP, few data are available on the etiology of VAP in children. In one report, P. aeruginosa was the most common cause, accounting for 22% of cases [142].

Nursing Home-Acquired Pneumonia

The bacterial pathogens that cause pneumonia in residents of nursing homes (and other long-term care facilities) differ according to the severity of disease. S. pneumoniae and H. influenzae are the most common causes of mild-to-moderate pneumonia in long-term care facilities [155]. In cases requiring hospitalization, C. pneumoniae, S. aureus, and influenza virus are frequently observed as well. Patients with severe illness commonly are infected with methicillin-sensitive S. aureus or MRSA, gram-negative enteric pathogens, or P. aeruginosa [23,155].

DIAGNOSIS

The difficulty in recognizing HAP, VAP, or nursing home-acquired pneumonia has been well documented [28,147,156]. The clinical signs often resemble other, noninfectious conditions, and the specificity of clinical criteria is low [148]. According to the CDC definition, the diagnosis in adults is made on the basis of clinical signs and results of laboratory testing or imaging and must meet one of two criteria [157].

Criterion 1 is rales or dullness to percussion on physical examination of the chest and at least one of the following:

- New onset of purulent sputum or change in character of sputum

- Organisms cultured from blood

- Isolation of an etiologic agent from a specimen obtained by transtracheal aspirate, bronchial brushing, or biopsy

Criterion 2 is chest radiograph that shows new or progressive infiltrate, consolidation, cavitation, or pleural effusion and at least one of the following:

- New onset of purulent sputum or change in character of sputum

- Organisms cultured from blood

- Isolation of an etiologic agent from a specimen obtained by transtracheal aspirate, bronchial brushing, or biopsy

- Isolation of virus from or detection of viral antigen in respiratory secretions

- Diagnostic single antibody titer immune globulin M or fourfold increase in paired sera immune globulin G for pathogen

- Histopathologic evidence of pneumonia

A set of clinical diagnostic criteria for HCAP includes the presence of a new and persistent (more than 48 hours) infiltrate in addition to one of the following [148]:

- Radiographic evidence of cavitation or necrosis

- Histopathologic evidence of pneumonia

- Positive pleural or blood culture for the same micro-organism as that found in respiratory secretions

Plus two of the following signs:

- Core temperature >38.3°C (100.94°F)

- WBC count >10,000 cells/mm^3

- Purulent tracheal secretions

There are no compelling data to recommend a specific approach to diagnosing HAP and VAP. For patients who are not receiving mechanical ventilation, collection of a sputum specimen should be attempted before antibiotic therapy is begun [35,158]. Specimens for culture can be obtained by bronchoscopy with a protected specimen brush to limit contamination or by bronchoalveolar lavage. The latter method has been found to lead to higher rates of treatment than diagnosis based on the CDC definition, and one study showed that preferential sampling of the right lung (rather than the left) improved the diagnostic accuracy of bronchoalveolar lavage [35,159,160]. However, the invasive procedure has disadvantages, including high cost, need for technical expertise, and the potential for false-negative results [35,159].

The ATS/IDSA guideline recommends collecting specimens from the lower respiratory tract for culture, preferably by noninvasive techniques, and reliance on semiquantitative culture technique [28]. Noninvasive methods to obtain respiratory samples in patients with HAP (non-VAP) include spontaneous expectoration, sputum induction, nasotracheal suctioning (in a patient unable to produce a sample), and endotracheal aspiration in a patient with HAP who subsequently requires mechanical ventilation [28]. A 2012 meta-analysis found no evidence that the use of quantitative cultures of respiratory secretions resulted in decreased mortality, reduced time in ICU and on mechanical ventilation, or higher rates of antibiotic change compared with qualitative cultures in patients with VAP [161]. In addition, there was no difference in mortality whether invasive or noninvasive methods were used to obtain specimens.

TREATMENT

The treatment of HAP and VAP is complicated by two divergent needs: the need for empiric therapy with a broad-spectrum antibiotic, to aid in reducing mortality rates, and the need to avoid the indiscriminate use of antibiotics, to avoid the development of resistance. To address this complex issue, the strategy of de-escalation therapy was developed. With this treatment approach, a broad-spectrum antibiotic targeted to likely pathogens is administered, and the antibiotic regimen is modified after the results of cultures are known [154,162]. This strategy has reduced the mortality rate while achieving an overall objective of a more judicious use of antibiotics [154,163]. In one study, de-escalation led to a significantly lower mortality rate compared with either escalation therapy or therapy that was neither escalated nor de-escalated (17% vs. 43% and 24%, respectively) [151].

The empiric treatment of nosocomial pneumonia in general, requires knowledge of the infection history (hospital flora) of the healthcare facility and of individual patient units [35,148,164]. The selection of an empiric antibiotic regimen for HAP and VAP should be guided by local antibiotic-resistance data. The ATS/IDSA recommend that all hospitals regularly generate and disseminate a local antibiogram, ideally one that is specific to their intensive care population(s), if possible [28].

In managing a case of HAP and VAP, the clinician should review in detail the guidance provided by the ATS/IDSA, and consider consultation with appropriate subspecialty colleagues [28]. Recommendations governing selected issues of initial management emphasize the following principles [28]:

- Obtain sputum samples from the lower respiratory tract for culture before beginning antibiotic therapy. Do not delay initiation of therapy for critically ill patients in order to obtain specimens.

- Begin treatment promptly, selecting an empiric antibiotic regimen that coversS. aureus, P. aeruginosa, and other gram-negative bacilli.

- In selecting coverage for S. aureus, choose an agent active against MRSA (vancomycin or linezolid) for patients with risk factor(s) for antimicrobial resistance, treatment in hospital or units where >10% of isolates are methicillin-resistant, and patients in settings where the prevalence of MRSA is unknown.

- In selecting coverage for P. aeruginosa, one antibiotic active against this pathogen is satisfactory if the patient has no risk factors for antimicrobial resistance and <10% of gram-negative isolates from the patient's unit are resistant to the agent chosen; otherwise, prescribe two antipseudomonal antibiotics from different classes.

- Consider de-escalation of antibiotics after the results of cultures and sensitivities are known and the clinical response is satisfactory.

- After an optimal antibiotic regimen is confirmed, a seven-day course of therapy is recommended, provided the rate of improvement of clinical, radiographic, and laboratory parameter is satisfactory.

- For patients with HAP/VAP, it is suggested to use serum procalcitonin levels plus clinical criteria to guide discontinuation of antibiotic therapy, rather than clinical criteria alone.

Selection of specific antimicrobial therapy is influenced by the timing of onset of clinical signs, as well as the presence or absence of risk factors for infection with multidrug-resistant organisms. For early-onset pneumonia and/or patients with no such risk factors, limited-spectrum antibiotic therapy is recommended (Table 17) [28]. For late-onset pneumonia and/or patients at increased risk for multidrug-resistant organisms, a broad-spectrum antibiotic regimen is recommended.

Table 17: RECOMMENDED ANTIBIOTIC THERAPY FOR HEALTH FACILITY-ASSOCIATED PNEUMONIA ACCORDING TO SITE OF CARE

Site of Care

Recommended Regimen

Nursing home

Antipneumococcal fluoroquinolone or either a high-dose ß-lactam/ß-lactamase inhibitor or a second- or third-generation cephalosporin in combination with azithromycin

Hospital

Antipseudomonal cephalosporin, antipseudomonal carbapenem, or extended-spectrum ß-lactam/ß-lactamase inhibitor and antipseudomonal fluoroquinolone or aminoglycoside and anti-MRSA agent (vancomycin or linezolid)

Intensive care unit

Empiric MRSA and double coverage of Pseudomonas pneumonia

Source: [28]

Ventilator-Associated Pneumonia and Multi-Drug Resistant Pathogens

Evidence Based Practice Recommendation

For healthcare-associated or community-acquired MRSA pneumonia, the IDSA recommends IV vancomycin or linezolid 600 mg PO/IV twice daily, if the strain is susceptible, for 7 to 21 days, depending on the extent of infection.

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

Last Accessed: August 16, 2021

Level of Evidence: A-II (Good evidence from one or more 1 well-designed clinical trial, without randomization to support a recommendation for use)

VAP is often caused by MRSA and gram-negative bacilli such as Acinetobacter spp. and Pseudomonas. Vancomycin has been considered the first choice for treatment of MRSA infections [154]. However, the ATS/IDSA guidelines note that linezolid may have advantages over vancomycin for pneumonia caused by MRSA [28]. Linezolid has been compared with vancomycin for the treatment of pneumonia caused by MRSA in many studies, and linezolid has been found to improve survival and to be more cost-effective [147,165,166,167,168]. In a 2008 study, the rate of early microbiologic cure was not significantly higher for linezolid than for vancomycin, although there were trends favoring linezolid in several secondary clinical outcomes, such as clinical cure; duration of ventilation, hospitalization, and stay in ICU; survival time not on a ventilator; and overall survival [169]. The findings led the authors to suggest that the benefit of linezolid may be related to factors other than bacterial clearance.

Role of Inhaled Antibiotic Therapy

For cases of VAP caused by gram-negative bacilli that are susceptible only to aminoglycosides or polymyxins, the ATS/IDSA suggests both inhaled and systemic antibiotics, rather than systemic antibiotics alone [28]. It is also reasonable to consider adjunctive inhaled antibiotic treatment as a last resort for patients who are not responding to intravenous antibiotics alone, whether or not the infecting organism is multi-drug resistant.

According to a meta-analysis, a short fixed-course (7 or 8 days) of antibiotic therapy may be more appropriate than a prolonged course (10 to 15 days) for patients with VAP not caused by nonfermenting gram-negative bacilli [170]. The short course reduced recurrence of pneumonia caused by multiresistant organisms without adversely affecting other outcomes. Among patients with nonfermenting gram-negative bacilli, recurrence was greater after the short course.

Nursing Home-Acquired Pneumonia

The 2019 ATS/IDSA guideline for CAP provides a rationale for choice of antibiotic therapy without specifying distinct protocols for nursing home-acquired pneumonia. The ATS/IDSA recommended abandoning the HCAP categorization for purposes of management decision. Instead, emphasis is placed on local epidemiology and validated risk factors to determine need for empiric MRSA or gram-negative bacillary coverage, followed by de-escalation of treatment if cultures are negative [235]. As indicated, the consistently strong individual risk factors for respiratory infection with MRSA, P. aeruginosa, or other gram-negative bacilli are prior isolation of these organisms, and/or recent hospitalization and exposure to parenteral antibiotics.

Adherence to Guideline-Directed Treatment

Evidence Based Practice Recommendation

For patients with ventilator-associated pneumonia, the American Thoracic Society and the IDSA recommend a seven-day course of antimicrobial therapy rather than a longer duration.

https://www.thoracic.org/statements/resources/tb-opi/hap-vap-guidelines-2016.pdf

Last Accessed: August 16, 2021

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

The lack of adherence to guideline-directed treatment of pneumonia cases associated with healthcare facilities is evidenced by wide variations in practice. For example, one study showed that more than 100 different antibiotic regimens had been prescribed as initial treatment and that de-escalation therapy was used for only 22% of patients [151]. Adherence rates for pneumonia associated with healthcare facilities have been reported to be lower than rates of adherence to guidelines for treatment of CAP. In one survey, guideline-recommended antibiotics were used 78% of the time for CAP, compared with 9% for HCAP [18]. This lack of adherence was not due to unfamiliarity or disagreement with the guidelines; 71% of the survey respondents said they were aware of the guidelines, and 79% said they agreed with and practiced according to them. In contrast, another survey showed that fewer than half of physicians were familiar with the ATS/IDSA guideline for treatment of nursing home-associated pneumonia [23]. It is reasonable to expect that strategies used to enhance adherence to guidelines in the setting of CAP would also be beneficial in the setting of pneumonia associated with healthcare facilities. Thus, feedback on performance, reminder systems, standardized order sets, and education emphasizing outcomes and cost-effectiveness would be valuable.

PREVENTION

The CDC has published a guideline for the prevention of HAP and VAP, with a focus on strategies to decrease or eliminate modifiable risk factors for pneumonia associated with healthcare facilities [93]. These strategies are related to preoperative and postoperative care and measures to reduce the risk of transmission of etiologic pathogens. In addition, steps to prevent the spread of influenza virus are essential, especially during influenza season.

Hospital-Acquired Pneumonia

The prevention of postoperative pneumonia has long been a part of initiatives to decrease complications among patients undergoing surgery. The Respiratory Risk Index was developed to classify patients as being at low, medium, or high risk for postoperative respiratory failure [26]. The factors in the index include the complexity of the surgery, the ASA status, and comorbidities.

Smoking triples the risk for pulmonary complications after surgery, and smoking cessation for at least eight weeks before surgery, when possible, is recommended for current smokers [26]. The risk for complications in patients with respiratory disease or congestive heart failure can be ameliorated by optimum treatment before surgery (e.g., treatment with steroids for patients with COPD or asthma) [26].

Effective pain management after surgery also helps to decrease the risk of pulmonary complications. For postoperative patients who are not mechanically intubated, the ability to cough and clear secretions is important for preventing pulmonary complications [26]. The use of incentive spirometry and deep breathing exercises are recommended, especially for people at high risk for pulmonary complications, as are frequent coughing and early movement (in bed and/or walking) [26,93,145]. Fair evidence supports the selective (rather than routine) use of a nasogastric tube after abdominal surgery [145].

Ventilator-Associated Pneumonia

Two guidelines were developed to focus specifically on the prevention of VAP; one was jointly developed by the Society for Healthcare Epidemiology of America (SHEA) and IDSA, and the other was jointly developed by the Canadian Critical Care Trials Group and the Canadian Critical Care Society [149,171]. In addition, the CDC guideline addresses the prevention of HAP and VAP [93]. All of these agencies suggest a multicomponent strategy for prevention of pneumonia. Compliance with guidelines, however, has been slow; nursing surveys demonstrate rates of adherence to specific preventive measures ranging from 15% to 50% [12,172]. Education is beneficial, and training sessions are a proven means to enhance knowledge and practice among healthcare professionals caring for intubated patients [173].

The Institute for Healthcare Improvement (IHI) found that implementation of its ventilator bundle, a collection of five prevention strategies drawn from these guidelines, led to a 45% reduction in the incidence of VAP [174]. The bundle includes the following interventions [174]:

- Assessment of readiness to extubate and daily interruptions of sedation

- Elevation of the head of the bed

- Daily oral care with chlorhexidine

- Prophylaxis of peptic ulcer disease

- Prophylaxis of deep venous thrombosis

The IHI how-to guide on preventing VAP provides several practical recommendations, and posting compliance with the ventilator bundle in a prominent place in the ICU can encourage and motivate staff (Table 18) [174].

Table 18: PRACTICAL STEPS IN FOLLOWING GUIDELINES TO PREVENT VENTILATOR-ASSOCIATED PNEUMONIA

Assessment of Readiness to Extubate and Sedative Interruptions

Implement a protocol to lighten sedation daily at an appropriate time to assess for neurologic readiness to extubate. Include precautions to prevent self-extubation, such as monitoring and vigilance, during the trial.

Include a sedative interruption strategy in the overall plan to wean the patient from the ventilator; add the strategy to the weaning protocol, if available.

Assess compliance each day on multidisciplinary rounds.

Consider implementation of a sedation scale, such as the Riker scale, to avoid oversedation.

Elevation of the Head of the Bed

Include the intervention on nursing flow sheets and discuss at multidisciplinary rounds.

Encourage respiratory therapy staff to notify nursing staff if the head of the bed is not elevated or empower respiratory therapy staff to place the bed in this position with the help of nursing staff.

Include the intervention on order sets for initiation and weaning of mechanical ventilation, delivery of tube feedings, and provision of oral care.

Oral Care with Chlorhexidine

Include the intervention as part of the intensive care unit admission order set and ventilator order set. Make application of prophylaxis the default value on the form.

Include intervention as an item for discussion on daily multidisciplinary rounds.

Post compliance with the intervention in a prominent place to encourage change and motivate staff.

Develop a comprehensive oral care process that includes the use of 0.12% chlorhexidine oral rinse.

Schedule chlorhexidine as a medication, which then provides a reminder for nursing staff and triggers the oral care process delivery.

Prophylaxis of Peptic Ulcer Disease

Include intervention as part of the intensive care unit admission order set and ventilation order set. Make application of prophylaxis the default value on the form.

Include intervention as an item for discussion on daily multidisciplinary rounds.

Empower pharmacy staff to review orders for patients in the intensive care unit to ensure that some form of prophylaxis is in place at all times for patients.

Prophylaxis of Deep Venous Thrombosis

Include intervention as part of the intensive care unit admission order set and ventilation order set. Make application of prophylaxis the default value on the form.

Include intervention as an item for discussion on daily multidisciplinary rounds.

Empower pharmacy staff to review orders for patients in the intensive care unit to ensure that some form of prophylaxis is in place at all times for patients.

Source: [174]

Assessment of Readiness to Extubate

Because of the increasing risk of infection as the duration of ventilation increases, the primary goal is to extubate patients as early as possible. Thus, assessment of the readiness for extubation and weaning protocols are key aspects in the preventive approach [28,35]. Daily interruption of sedation until the patient is awake has been shown to significantly decrease the number of days on mechanical ventilation, from 7.3 days to 4.9 days in one study [175]. There are risks to this approach, including the potential for increased pain, anxiety, and desaturation [174]. However, sedation interruption has been further demonstrated to reduce the complications of prolonged mechanical ventilation [176]. The SHEA/IDSA guideline recommends daily assessment of the readiness to wean and the use of weaning protocols [171]. For children, daily assessment of readiness to extubate should be carried out, but sedation interruption is not recommended because of the high risk of unplanned extubation [177].

Elevation of the Head of the Bed

Reducing the risk of aspiration and contamination with gastric secretions also helps to prevent the development of pneumonia. Positioning the head of the bed at an angle of 30 to 45 degrees reduces the risk of aspiration significantly [149,178,179]. In one randomized, controlled trial, there were 18% fewer cases of VAP among intubated patients in the group assigned to the recumbent position (45 degrees) compared with the group assigned to the supine position [179]. In another study, elevation of the head of the bed to 30 degrees was the most effective measure among a group of preventive interventions, resulting in a 52% variance in the rate of VAP [180]. Both the ATS/IDSA and SHEA/IDSA guidelines recommend maintaining the head of the bed at a 30- to 45-degree angle [28,171]. An angle of 30 to 45 degrees is also recommended for infants and children, but a lower angle (15 to 30 degrees) should be used for neonates [177].

Daily Oral Care with Chlorhexidine

Oral care interventions have been suggested by some, in part because of an association between a high level of dental plaque and a high rate of colonization with aerobic pathogens, including S. aureus, gram-negative bacilli, and P. aeruginosa [181]. Research has shown that oral decontamination with chlorhexidine leads to a significant reduction in the colonization of pathogens in the oropharynx. In most studies, the intervention has not had a significant effect on the rate of VAP or associated mortality, but more recent studies have shown a significant decrease in the rate of pneumonia [180,182,183,184,185,186]. Brushing the teeth with chlorhexidine does not seem to add benefit [183]. Regular oral care with an antiseptic solution or chlorhexidine is recommended in the ATS/IDSA and SHEA/IDSA guidelines [28,171].

Prophylaxis of Peptic Ulcer Disease

Prophylaxis of peptic ulcer disease has evolved with some conflicting views. Antacids, histamine2 receptor antagonists, and sucralfate have been traditionally given to patients receiving mechanical ventilation to prevent the formation of stress ulcers. However, reducing the amount of gastric acid can increase the risk of colonization of gram-negative bacilli in the stomach. As a result, the WHO recommends avoiding the use of these agents [187]. The CDC notes that there was insufficient evidence on the use of peptic ulcer prophylaxis and includes no recommendations in this regard in its guideline [93]. The ATS/IDSA guideline states that the risks and benefits of prophylaxis should be weighed carefully [28]. The most recent guideline, developed by SHEA/IDSA, notes that histamine2 receptor antagonists and PPIs should be avoided in patients who are not at high risk for developing a stress ulcer or stress gastritis [171]. However, peptic ulcer prophylaxis is recommended for children, as appropriate for age and health status [177].

Prophylaxis of Deep Venous Thrombosis

There is no clear relation between prophylaxis of deep vein thrombosis and VAP pneumonia, but the American College of Chest Physicians reported a decrease in the rate of VAP when such prophylaxis was implemented as part of a package of interventions and included this measure in its clinical practice guideline [188]. This recommendation also applies to children, as appropriate for age and health status [177].

Other Measures

In addition to the interventions in the ventilator bundle, other measures have been recommended to help prevent VAP. One such measure is selective decontamination of the digestive tract, which involves the use of either topical antiseptic, oral antibiotics, or a brief course of systemic antibiotics [26]. A meta-analysis of 28 studies showed that selective decontamination of the digestive or respiratory tract with use of topical antiseptic or antimicrobial agents helped reduce the frequency of VAP in the ICU [146]. The estimate of efficacy in prevention was 27% for antiseptics and 36% for antibiotics. Neither had an effect on mortality. This intervention is recommended in the SHEA/IDSA guideline [171].

Other preventive measures are targeted primarily to the care and use of ventilator equipment and practices in direct patient care. Meticulous attention to aseptic care of the equipment is necessary, and all reusable components, such as nebulizers, should be disinfected or sterilized. Tubing circuits should be replaced after 48 hours or earlier if there are signs of malfunction or contamination [93]. Changes in the design of the endotracheal tube have also been evaluated; for example, a tube with a suction port above the cuff allows for continuous aspiration of subglottic secretions. Use of this specially designed endotracheal tube has led to significantly lower rates of VAP as well as shorter durations of ventilation and shorter stays in the ICU [189,190]. Among patients who had major cardiac surgery, the greatest benefit was found for patients who received ventilation for more than 48 hours [190]. Although the cost of the tube is higher than traditional tubes, the overall cost savings in preventing VAP more than compensates [189]. In one meta-analysis, subglottic secretion drainage was significantly associated with a decreased incidence of VAP, shorter time on mechanical ventilation, and longer time to the development of pneumonia [191]. The CDC, the ATS/IDSA, and the SHEA/IDSA guidelines recommend subglottic secretion drainage with this tube when possible [28,93,171].

The use of noninvasive ventilation is another measure that has reduced the incidence of VAP [93,192,193,194]. In one study, the incidence decreased from 20% to 8% when noninvasive techniques were used routinely for critically ill patients with acute exacerbation of COPD or severe cardiogenic pulmonary edema [192]. Again, the CDC, the ATS/IDSA, and the SHEA/IDSA guidelines recommend the use of noninvasive ventilation when possible [28,93,171].

Quality Improvement Initiatives and Enhanced Infection Control Strategies

Quality improvement and infection control initiatives and strategies have led to a substantial decrease in the rates of VAP since the early 2000s [195]. The use of physician-led multidisciplinary rounds with team decision-making, checklists, and a focus on the ventilator bundle has led to significant reductions in the risk for pneumonia [196,197,198]. Strong downward trends were also found for the average length of stay in the ICU and the financial costs per patient [196].

Nursing Home-Acquired Pneumonia

As with HAP, strategies to decrease or eliminate modifiable risk factors for nursing home-acquired pneumonia should be implemented. A multidisciplinary panel made three recommendations for prevention of pneumonia among nursing home residents [199]:

- Pneumococcal vaccination of patients at admission, if indicated

- Annual influenza vaccination for residents

- Annual influenza vaccination for nursing facility staff

Influenza Outbreaks

The vaccination status of healthcare workers has been found to have a direct effect on transmission of influenza virus to patients. Outbreaks of influenza in healthcare settings have been associated with low rates of vaccination among healthcare workers, and lower rates of nosocomial influenza have been related to higher vaccination rates among healthcare workers [200,201]. Because of these findings, the ACIP recommends annual influenza vaccination for all healthcare workers, and the IDSA/ATS guideline endorses this recommendation [47]. The ACIP notes that the TIV is preferred over LAIV for workers who are in close contact with severely immunosuppressed people requiring protective isolation [112]. In addition, the Joint Commission began including vaccination programs in its accreditation standards in 2007 [123].

Despite these recommendations, only 29% to 69% of healthcare workers receive the influenza vaccination each year [202,203,204]. Healthcare workers have given many reasons for not being vaccinated, and the reasons vary among professions. Across all categories, shortage of the vaccine is the primary reason for not being vaccinated; other reasons include concern about side effects, inconvenience, and forgetfulness [204].

Efforts to increase the vaccination rate among healthcare workers are ongoing. A CDC guideline includes four level I recommendations to help increase rates of vaccination [205]:

- Offer influenza vaccine annually to all eligible healthcare workers.

- Provide influenza vaccination to healthcare workers at the work site and at no cost as one component of employee health programs. Use strategies that have been demonstrated to increase influenza vaccine acceptance, including vaccination clinics, mobile carts, vaccination access during all work shifts, and modeling and support by institutional leaders.

- Monitor influenza vaccination coverage and declination of healthcare workers at regular intervals during influenza season and provide feedback of ward-, unit-, and specialty-specific rates to staff and administration.

- Educate healthcare workers about the benefits of influenza vaccination and the potential health consequences of influenza illness for themselves and their patients, the epidemiology and modes of transmission, diagnosis, treatment, and non-vaccine infection control strategies, in accordance with their level of responsibility in preventing healthcare-associated influenza.

Hand Hygiene

Hand hygiene is the most important preventive measure in hospitals, and the Joint Commission mandates that hospitals and other healthcare facilities comply with the Level I recommendations in the CDC guideline for hand hygiene [206]. The CDC guideline states the specific indications for washing hands, the recommended hand hygiene techniques, and recommendations about fingernails and the use of gloves [207]. The guideline also provides recommendations for surgical hand antisepsis, selection of hand-hygiene agents, skin care, educational and motivational programs for healthcare workers, and administrative measures.

Despite the simplicity of the intervention, its substantial impact, and wide dissemination of the guideline, compliance with recommended hand hygiene has ranged from 16% to 81%, with an average of 30% to 50% [207,208,209,210,211,212]. Among the reasons given for the lack of compliance are inconvenience, understaffing, and damage to skin [207,210,213]. The development of effective alcohol-based handrub solutions addresses these concerns, and studies have demonstrated that these solutions have increased compliance [211,214,215]. The CDC guideline recommends the use of such solutions on the basis of several advantages, including [207]:

- Better efficacy against both gram-negative and gram-positive bacteria, mycobacteria, fungi, and viruses than either soap and water or antimicrobial soaps (such as chlorhexidine)

- More rapid disinfection than other hand-hygiene techniques

- Less damaging to skin

- Time savings (18 minutes compared with 56 minutes per eight-hour shift)

The guideline suggests that healthcare facilities promote compliance by making the handrub solution available in dispensers in convenient locations (such as the entrance to patients' room or at the bedside) and provide individual pocket-sized containers [207]. The handrub solution may be used in all clinical situations except for when hands are visibly dirty or are contaminated with blood or body fluids. In such instances, soap (either antimicrobial or nonantimicrobial) and water must be used.

However, there are many other reasons for lack of adherence to appropriate hand hygiene, including denial about risks, forgetfulness, and belief that gloves provide sufficient protection [207,210,213]. These reasons demand education for healthcare professionals to emphasize the importance of hand hygiene. Also necessary is research to determine which interventions are most likely to improve hand-hygiene practices, as no studies have demonstrated the superiority of any intervention [216]. Single interventions are unlikely to be effective.

ILLUSTRATIVE CASE

A man, 73 years of age, with a history of coronary disease, COPD, benign prostatic hyperplasia, and type 2 diabetes is hospitalized on transfer from an assisted-living facility because of weakness, loss of appetite, and low-grade fever. He had been admitted elsewhere for similar symptoms six months earlier and was diagnosed with urinary tract infection and treated with an unknown antibiotic. On evaluation, the patient's temperature is 37.6°C (99.8°F) and his other vital signs are stable; his exam is unremarkable. The WBC is normal, and the urinalysis shows pyuria. The admission chest x-ray shows hyperlucent lung fields and flattened diaphragms indicative of emphysema, but no infiltrate. Empiric treatment with a first-generation cephalosporin is begun for presumed urinary tract infection. The patient has no further fever, and his appetite and strength improve over the next 48 hours. He does have periods of mild agitation and insomnia, which are treated with a benzodiazepine at bedtime.

On the fourth day, as plans for discharge were in place, the patient appears worse, with a cough and a temperature of 38°C (100.4°F). A repeat chest x-ray shows a small focal opacity in the left upper lobe, thought to represent "aspiration." No change in antibiotics is made, and he is observed. Over the next 36 hours, the patient's condition worsens; he now has a cough productive of purulent sputum, fever (102°F to 103°F), shortness of breath, and tachypnea. A follow-up chest x-ray now shows an extensive opacification/infiltrate in the left upper lobe, with signs suggestive of either central cavitation or consolidation high-lighting emphysematous blebs.

In this elderly, somewhat debilitated man with chronic lung disease, who may be at risk of aspiration, a rapidly progressive, necrotizing (hospital-acquired) pneumonia developed while he was being treated with an oral cephalosporin for urinary tract infection, and receiving a nightly sedative medication for sleep.

What are the etiologic considerations and how should the patient be managed? Within days of admission to a hospital, and especially if treated with antibiotics, many patients develop nasopharyngeal colonization by hospital flora (e.g. gram-negative bacilli and occasionally S. aureus). When pneumonia supervenes, it reflects this colonization; moreover, prior antibiotic therapy tends to select out resistant pathogens. Therefore, the selection of empiric antibiotic treatment for this patient is based on the presumption of hospital-acquired bacterial infection in the lung caused by one or more pathogens resistant to first-generation cephalosporins. Cultures of blood and sputum should be obtained; gram stain of the sputum is often helpful in cases such as this, as it may demonstrate a predominate pathogen and whether it is gram-positive or gram-negative. Empiric antibiotic therapy, following ATS/IDSA recommendations for HAP, should be started promptly. A good choice would be an extended-spectrum ß-lactam/ß-lactamase inhibitor or a carbapenem (e.g., piperacillin/tazobactam or imipenem) combined with a fluoroquinolone and vancomycin, pending culture results.

Gram stain of the patient's sputum shows many polys and gram-negative bacilli; the culture is positive for K. pneumoniae and P. aeruginosa. His management, including empiric antibiotic therapy followed by de-escalation (of vancomycin) after culture data are available, conforms to ATS/IDSA recommendations. The patient is treated for 10 days and recovers following a brief period in the ICU.

This case illustrates that the pathogenesis of adult bacterial HAP is essentially the same as for CAP; namely, nasopharyngeal and upper respiratory colonization by virulent bacteria combined with aspiration of infected secretions during a period of impaired host pulmonary defenses. The difference lies in the burden of vulnerability imposed by hospitalization, including the propensity for colonization by gram-negative bacilli and the likelihood of antimicrobial resistance—so uncommon in healthy individuals outside of healthcare facilities, but so prevalent among patients hospitalized longer than 48 hours.

9. SUMMARY

Pneumonia-related mortality and morbidity have decreased since the late 1990s, but the disease still represents a substantial healthcare concern, especially for high-risk adults and children. Pneumonia is primarily classified according to the setting in which it develops, and the epidemiology, etiology, and risk factors vary according to setting. Diagnosis can be challenging because of differences in presentation and the lack of reliable, cost-effective, and rapidly available diagnostic testing methods. Specialty society guidelines for prevention, diagnosis, and treatment are available for CAP, HAP, and VAP. Guideline-directed treatment has been shown to improve the care of patients while promoting good antibiotic stewardship, minimizing exposure to inappropriate antibiotic treatment and reducing the emergence of antibiotic-resistant pathogens.

For CAP and nursing home-acquired pneumonia, determining the site of care is an important initial decision point. Guidelines from the IDSA/ATS, the PIDS/IDSA, and the ATS outline useful criteria for determining need for hospitalization and ICU care. These objective criteria are important factors in decision-making, but clinical judgment is also necessary for selecting the most appropriate site of care. Initial antibiotic treatment of all types of pneumonia is empirical. The selection is best made in relation to the most likely pathogens in a given clinical setting and to patient variables, such as comorbidities, recent exposure to antibiotics, and immunization status (for children). The timeliness of antibiotic treatment is also important; treatment should begin as soon as possible after diagnosis is made, administering the first dose promptly at the originating site of care.

Guideline-directed therapy of pneumonia has been shown to decrease morbidity and mortality, but adherence varies across settings and specialties and has been suboptimal. Physician practices and healthcare systems can improve adherence by implementing evidence-based strategies, such as standardized order sets, reminders, performance feedback, and easy-to-carry resources.

The incidence of pneumonia and its associated morbidity and mortality can be reduced further by adherence to effective preventive measures. Several guidelines are available for preventing specific types of pneumonia. The primary preventive strategy for CAP is immunization with influenza and pneumococcal vaccines, especially for individuals at high risk. These vaccinations have been shown to decrease the incidence and severity of pneumococcal pneumonia, as well as the risk of long-term morbidity and mortality. However, rates of vaccination vary across age, race/ethnicity, and risk. Two target populations with the lowest immunization rates are high-risk adults in need of pneumococcal vaccination and teenagers in need of influenza vaccination. Rates of vaccination among healthcare professionals are also low. Clinicians and healthcare systems should encourage vaccination and offer convenient access, especially during influenza season.

Lack of awareness about the need for vaccination, misconceptions about vaccines, and low level of knowledge about pneumonia have been reported to be the primary barriers to vaccination, especially among minority populations. Clinicians should promote practice strategies and public health efforts designed to target these barriers and address the populations in greatest need. Several strategies have been shown to increase vaccination rates, and education is the cornerstone. Clinicians should emphasize to patients the need and benefit of immunization, address concerns about the safety of vaccines, and incorporate routine immunization protocols into their practices. Provider recommendation is essential, as it is the strongest predictor of vaccination. System-related strategies such as automatic reminders and standing orders have also been effective.

Guidelines for prevention of HAP focus on measures to reduce pulmonary complications after surgery. Prevention of VAP relies on strategies to reduce the risk of transmission of etiologic agents. Use of a ventilator "bundle" (a set of interventions) has been shown to markedly reduce VAP. Although adherence to guidelines is suboptimal, healthcare facilities are increasingly implementing initiatives to help enhance adherence.

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192. Girou E, Brun-Buisson C, Taille S, Lemaire F, Brochard L. Secular trends in nosocomial infections and mortality associated with noninvasive ventilation in patients with exacerbation of COPD and pulmonary edema. JAMA. 2003;290(22):2985-2991.

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194. Osmon S, Kollef MH. Prevention of pneumonia in the hospital setting. Clin Chest Med. 2005;26(1):135-142.

195. Craven DE, Hjalmarson K. Prophylaxis of ventilator-associated pneumonia: changing culture and strategies to trump disease.Chest. 2008;134(5):898-900.

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202. Dash GP, Fauerbach L, Pfeiffer J, et al. APIC position paper: Improving health care worker influenza immunization rates. Am J Infect Control. 2004;32(3):123-125.

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205. Pearson ML, Bridges CB, Harper SA. Influenza vaccination of health-care personnel. MMWR. 2006;55(RR02):1-16.

206. U.S. Food and Drug Administration. Reprocessing of Reusable Ultrasound Transducer Assemblies Used for Biopsy Procedures. Available at https://wayback.archive-it.org/7993/20170112170658/http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm151526.htm. Last accessed August 6, 2021.

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208. Burke JP. Infection control-a problem for patient safety. N Engl J Med. 2003;348(7):651-656.

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210. Clark AP, Houston S. Nosocomial infections: an issue of patient safety: part 2. Clin Nurse Spec. 2004;18(2):62-64.

211. Pittet D, Hugonnet S, Harbarth S, et al. Effectiveness of a hospital-wide programme to improve compliance with hand hygiene. Lancet. 2000;356(9238):1307-1312.

212. Larson EL, Quiros D, Lin SX. Dissemination of the CDC's hand hygiene guideline and impact on infection rates. Am J Infect Control. 2007;35(10):666-675.

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214. Johnson PDR, Rhea M, Burrell LJ, et al. Efficacy of an alcohol/chlorhexidine hand hygiene program in a hospital with high rates of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection. Med J Aust. 2005;183(10):509-514.

215. Gordin FM, Schultz ME, Huber RA, Gill JA. Reduction in nosocomial transmission of drug-resistant bacteria after introduction of an alcohol-based handrub. Infect Control Hosp Epidemiol. 2005;26(7):650-653.

216. Gould DJ, Chudleigh JH. Moralejo D, Drey N. Interventions to improve hand hygiene compliance in patient care. Cochrane Database Syst Rev. 2007;(2):CD005186.

217. Mason CM, Nelson S. Pulmonary host defenses and factors predisposing to lung infection. Clin Chest Med. 2005;26(1):11-17.

218. Johnstone J, Eurich DT, Jamumdar SR, Jin Y, Marrie TJ. Long-term morbidity and mortality after hospitalization with community-acquired pneumonia: a population-based cohort study. Medicine (Baltimore). 2008;87(6):329-334.

219. Santibanez T, Mootrey GT, Euler GL, Janssen AP. Behavior and beliefs about influenza vaccine among adults ages 50–64 years.Am J Health Behav. 2010;34(1):77-89.

220. Griffin M, Zhu Y, Moore M, Whitney C, Grijalva C. U.S. hospitalizations for pneumonia after a decade of pneumococcal vaccination. N Engl J Med. 2013;369:155-163.

221. Nuorti J, Butler J, Farley M, et al. Cigarette smoking and invasive pneumococcal disease. N Engl J Med. 2000;342:681-689.

222. Marrie T, Poulin-Costello M, Beecroft M, Herman-Gnjidic Z. Etiology of community-acquired pneumonia in the ambulatory setting. Respir Med. 205;99:60-65.

223. Kallen AJ, Reed C, Patton M, et al. Staphylococcus aureus community-onset pneumonia in patients admitted to children's hospitals during autumn and winter of 2006–2007. Epidemiol Infect. 2010;138:666-672.

224. Musher D, Montoya R, Wanahita A. Diagnostic value of microscopic examination of Gram-stained sputum and sputum cultures in patients with bacteremic pneumococcal pneumonia. Clin Infect Dis. 2004;39:165-169.

225. Gutiérrez F, Masiá M, Rodríguez JC, et al. Evaluation of the immunochromatographic Binax NOW Assay for detection of Streptococcus pneumoniae urinary antigen in a prospective study of community-acquired pneumonia in Spain. Clin Infect Dis. 2003;36(3):286-292.

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227. Matanock A, Lee G, Gierke R, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged >/= 65 years: updated recommendations of the Advisory Committee on Immunization Practices. MMWR. 2019;68:1069-1075.

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Evidence-Based Practice Recommendations Citations

1. Kirsch J, Mohammed TH, Kanne JP, et al. ACR Appropriateness Criteria: Acute Respiratory Illness in Immunocompetent Patients. Reston, VA: American College of Radiology; 2018. Available at https://acsearch.acr.org/docs/69446/Narrative. Last accessed August 16, 2021.

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90240 • Pancreatic Cancer

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2021 NetCE, All rights reserved.

Pancreatic cancer, also referred to as pancreatic ductal adenocarcinoma (PDAC), is the most lethal solid malignancy, predicted to become the second leading cause of cancer death in the United States by 2030. The complexity of this aggressive cancer has been vexing to investigators and tragic for patients and their families. It is now clear that even early-stage PDAC is a systemic disease and that new-onset metabolic and neuropsychiatric symptoms/syndromes are prodromal rather than comorbid or secondary. This recognition has also called for a re-thinking of pancreatic cancer from a more integrative, multi-system perspective.

Table of Contents

90240 • Pancreatic Cancer

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. EPIDEMIOLOGY

RACIAL SURVIVAL DISPARITIES

NON-GENETIC RISK FACTORS

3. PATHOPHYSIOLOGY

PRIMARY MUTATIONAL DRIVERS IN PDAC

MUTATIONAL SEQUENCE OF PDAC DEVELOPMENT

NATURAL HISTORY OF PDAC ONCOGENESIS

HEREDITARY PDAC

4. PANCREATIC CANCER SCREENING

GERMLINE AND SOMATIC TESTING AND MOLECULAR ANALYSIS

5. CLINICAL EVALUATION OF PANCREATIC CANCER

NEUROPSYCHIATRIC SYMPTOMS AND PANCREATIC CANCER

FAMILY HISTORY

COMMON PRESENTING SYMPTOMS AND SIGNS

PHYSICAL EXAMINATION

METASTATIC DISEASE

LABORATORY TESTING

DIFFERENTIAL DIAGNOSIS

6. THE DIAGNOSTIC AND STAGING WORKUP

IMAGING

BIOPSY

CARBOHYDRATE ANTIGEN 19-9 (CA19-9)

THE STAGING WORKUP

7. TREATMENT APPROACHES FOR PANCREATIC CANCER

PATIENT FUNCTIONAL STATUS

RECOMMENDED TREATMENT OPTIONS BY CLINICAL STAGE

RESECTION OF PANCREATIC CANCER

CHEMOTHERAPIES IN PANCREATIC CANCER

RADIATION THERAPY FOR PANCREATIC CANCER

NEOADJUVANT THERAPY

LOCALLY ADVANCED PANCREATIC CANCER

METASTATIC DISEASE

8. PALLIATION AND SYMPTOMATIC MANAGEMENT

VENOUS THROMBOEMBOLISM PROPHYLAXIS

PERI-PANCREATIC COMPLICATIONS

PAIN CONTROL INTERVENTIONS

CACHEXIA, WEIGHT LOSS, AND NUTRITIONAL COMPROMISE

9. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

10. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

90240 • Pancreatic Cancer

Education Category. Medical / Surgical

Release Date. 09/01/2021

Expiration Date. 08/31/2024

Course Overview

Pancreatic cancer, also referred to as pancreatic ductal adenocarcinoma (PDAC), is the most lethal solid malignancy, predicted to become the second leading cause of cancer death in the United States by 2030. The complexity of this aggressive cancer has been vexing to investigators and tragic for patients and their families. It is now clear that even early-stage PDAC is a systemic disease and that new-onset metabolic and neuropsychiatric symptoms/syndromes are prodromal rather than comorbid or secondary. This recognition has also called for a re-thinking of pancreatic cancer from a more integrative, multi-system perspective.

Audience

This course is designed for physicians, nurses, and other members of the interprofessional healthcare team involved in the care of patients with pancreatic cancer.

Accreditations & Approvals

In support of improving patient care, NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is approved by the California Nursing Home Administrator Program as a provider of continuing education. Provider number 1622. NetCE is approved to offer continuing education through the Florida Board of Nursing Home Administrators, Provider #50-2405. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

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 9 pharmacology hour(s) for physician assistants. NetCE designates this continuing education activity for 9 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 12 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 10 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. 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®. This activity has been designated for 10 Lifelong Learning (Part II) credits for the American Board of Pathology Continuing Certification Program. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. This home study course is approved by the Florida Board of Nursing Home Administrators for 10 credit hour(s). This course is approved by the California Nursing Home Administrator Program for 10 hour(s) of continuing education credit - NHAP#1622010-9369/P. California NHAs may only obtain a maximum of 10 hours per course. 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 29,2025); Alabama, Provider #ABNP0353, (valid through July 29, 2025); 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 12/31/2025; South Carolina, Provider #50-2405; 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 with the knowledge and skills necessary to recognize and appropriately manage pancreatic cancer in their patients.

Learning Objectives

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

1. Outline the epidemiology of and risk factors for pancreatic cancer.

2. Describe the pathophysiology of pancreatic cancers.

3. Discuss recommendations for screening for pancreatic cancer in various patient populations.

4. Describe key aspects of the clinical evaluation of patients with suspected pancreatic cancer.

5. Select the appropriate tools for diagnosis and staging of pancreatic cancer.

6. Apply models of assessing the functional performance status of patients with diagnosed pancreatic cancer.

7. Discuss the role of resection in pancreatic cancer treatment, including most appropriate approaches.

8. Compare and contrast chemotherapy regimens used in the treatment of pancreatic cancer.

9. Describe the use of radiation therapy as a component of pancreatic cancer treatment according to evidence-based guidelines.

10. Evaluate available interventions to manage symptoms and provide palliative care to patients with pancreatic cancer.

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

Jane C. Norman, RN, MSN, CNE, PhD

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

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of any common cancer. The five-year overall survival rate is approximately 10% and has improved only marginally in five decades [1]. There are four fundamental challenges that underlie the high mortality of PDAC: pancreatic anatomy, aggressive biology, systemic effects, and treatment resistance.

The retroperitoneal position of the pancreas is situated deep within the upper abdomen, behind the stomach, and between the aorta and its major upper abdominal branches. Shielded from detection, the tumors often grow around and encase these vessels, making the cancer inoperable in nearly 85% of patients [2]. With this aggressive cancer, more than 50% of patients have distant metastases at diagnosis, and micrometastases are already present in most patients undergoing resection for apparently localized tumors [2,3,4].

At diagnosis, up to 80% of patients with PDAC present with cachexia, a wasting syndrome and physiologic effect of PDAC. Cachexia dramatically weakens patients, limiting their ability to withstand aggressive treatment. The poor treatment tolerance of patients with cachexia is evidenced by decreased survival after resection or chemotherapy [2].

The complex tumor microenvironment and heterogeneity of gene mutations make PDAC one of the most drug-resistant cancers. Most treatment options are ineffective, with rapid progression and low complete responses to the most effective chemotherapy and radiotherapy [1,4].

Surgical resection of the pancreas with microscopically free margins (R0 resection) followed by chemotherapy remains the only realistic option for remission, but this is potentially achievable in only a fraction of patients [4,5]. Nonetheless, incremental gains have been increasingly frequent over the past decade, and more substantive gains are anticipated, pending clinical trial results. This course will describe the current standard of care for patients with pancreatic cancer and present information that may help increase earlier detection of this malignancy and improve the symptom burden and quality of life in these patients, regardless of disease stage.

Clinical practice guidelines for patients with pancreatic cancer have been published by the American Society of Clinical Oncology (ASCO), the NCCN (National Comprehensive Cancer Network), the American Society for Radiation Oncology (ASTRO), the European Society for Medical Oncology (ESMO), the National Institute for Health and Care Excellence (NICE), and others [6,7,8,9,10,11,12,13,14,15]. The recommendations are largely concordant on what constitutes multidisciplinary standards of care in the management of pancreatic cancer [2,16].

Most pancreatic cancers arise in the exocrine pancreas (95%). Tumors of the endocrine pancreas (<5%) are distinct from exocrine pancreas cancers and will not be discussed in this course [4].

PDACs account for more than 95% of exocrine pancreatic cancers. PDAC and pancreatic cancer are commonly used as interchangeable terms in the literature and will be in this course [17].

2. EPIDEMIOLOGY

During 2021 in the United States, an estimated 60,430 people will be diagnosed with pancreatic cancer, which represents 3.2% of all new cancer cases and the 11th most common new cancer diagnosis. The median age at diagnosis is 70 years [18].

Approximately 1.7% of men and women will be diagnosed with pancreatic cancer at some point during their lifetime, based on 2016–2018 data. In 2018, an estimated 83,777 people were living with PDAC in the United States [19].

With an estimated 48,220 deaths in 2021, pancreatic cancer is the third leading cause of cancer death (after lung and colorectal cancer) in both men and women; it is expected to become the second leading cause of cancer death by 2030 [2,19,20]. The median age at death is 72 years [18].

Pancreatic cancer stage at diagnosis strongly influences the length of survival, as shown by data from 2011 to 2017 (Table 1) [19]. The five-year survival of PDAC, 10.8%, remains the lowest of all common cancers [19,21].

Table 1: PANCREATIC CANCER STAGE AT DIAGNOSIS AND ASSOCIATED SURVIVAL

Stage

Progression at Diagnosis

Five-Year Survival

Localized

11%

41.6%

Regional

30%

14.4%

Distant

52%

3.0%

Unknown

7%

6.5%

Source: [19]

During 2013–2017, annual pancreatic cancer incidence and mortality rates (per 100,000 persons) were higher among men (14.9 and 12.7) than women (11.6 and 9.6). These rates were highest for Blacks (15.3 and 13.3), followed by non-Hispanic Whites (13.1 and 10.9) and Hispanics. The rates were lowest for Asian/Pacific Islanders and American Indian/Alaska Natives [2].

Since 2010, both incidence and mortality rates increased by an average of 0.3% per year. Underlying these trends is a combination of an aging population, a longer lifespan, and the high prevalence of obesity and diabetes [11,18]. In 2015, lost earnings from person-years of life lost from pancreatic cancer were estimated at more than $6 billion [2].

RACIAL SURVIVAL DISPARITIES

In examining PDAC survival disparities over 2004–2015, the unadjusted median overall survival was slightly longer for White patients than Black patients (6.6 months vs. 6.0 months). Decreased survival for Black patients persisted after controlling for sociodemographic parameters. Conversely, controlling specifically for clinical parameters (e.g., disease stage, treatment) found a modest survival advantage for Black patients [22].

Black patients with PDAC present at younger ages with more advanced disease than White patients, possibly suggesting differences in tumor biology. Black patients receive less treatment stage-for-stage and fewer surgeries for resectable PDAC than White patients; these findings may be only partly associated with socioeconomic differences. In one study, when disease stage and treatment were controlled for, Black patients had no decrease in survival compared to other races [22].

Role of Implicit Bias

Health professionals' implicit biases shape behaviors, communications, and interactions, which then produce differences in diagnoses and ultimately treatments and interventions. Implicit biases are subtle and unconscious and may unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider.

Racial and socioeconomic differences in surgical intervention rates, treatment at high-volume hospitals/centers, and morbidity and mortality rates have been noted, with the largest disparities between Black (and to a slightly lesser extent Hispanic) and White Americans [23]. Several factors are implicated, but implicit biases and insurance status are identified as potentially modifiable contributors.

NON-GENETIC RISK FACTORS

The most common recognized risk factor for pancreatic cancer is cigarette smoking followed by obesity. Others include pancreatitis, diabetes, and family history of pancreatic cancer (Table 2) [13,24]. Periodontal disease is increasingly linked to pancreatic and other gastric cancers. Chronic pancreatitis substantially elevates the risk of developing pancreatic cancer and represents an opportunity for surveillance and monitoring. Most importantly, new-onset hyperglycemia or diabetes is now recognized as an early symptom of PDAC in an otherwise asymptomatic patient. Many recognized risk factors are modifiable for prevention of pancreatic cancer.

Table 2: COMMON RISK FACTORS FOR THE DEVELOPMENT OF PANCREATIC CANCER

Factor

Relative Risk

Cigarette smoking

1.7-fold to 2.6-fold

Obesity

1.1-fold to 1.5-fold

Diabetes

1.5-fold to 2-fold

Family history

1.7-fold to 2.3-fold

Chronic pancreatitis

13.3-fold

Source: [2]

Smoking

Cigarette smokers have at least a two-fold greater risk for pancreatic cancer than nonsmokers. The risk increases with the amount of cigarettes consumed and duration of smoking. In heavy smokers with polymorphism in the carcinogen-metabolizing enzyme gene glutathione S-transferase theta 1 (GSTT1), the risk is up to five-fold greater [25,26].

Excess risk decreases with smoking cessation. The risk of pancreatic cancer among current smokers (relative risk: 2.5) decreased 48% two years after smoking cessation, and within 10 to 15 years after cessation, it approximated that of nonsmokers [26].

In the United States, estimates indicate that 11% to 32% of deaths from PDAC are attributable to tobacco smoking. It is estimated that cessation of smoking could eliminate up to 25% of pancreatic cancer deaths [24,26].

Alcohol Consumption

Limited evidence suggests alcohol consumption may be associated with risk of developing PDAC, but findings of population-based studies are inconsistent. In pooled cohort data of 1.5 million light, heavy, or never-drinkers, heavy drinkers had a greater relative risk of developing PDAC than never-drinkers (relative risk: 1.29) or light drinkers (relative risk: 1.36). Light drinkers had no difference compared to never-drinkers (relative risk: 0.96) [27].

Smoking and Drinking

Most studies have assumed additivity between average effects of smoking and alcohol and oversimplified their impact on burden of pancreatic cancer. However, the combined effect of smoking and total alcohol intake on risk of PDAC is likely non-additive. It appears that only heavy consumption of liquor (but not wine or beer) increases the risk of PDAC in ever-smokers [27].

Obesity

A number of studies have associated obesity with a higher incidence of pancreatic cancer. Obesity (defined as a body mass index [BMI] >30) during early adulthood was associated with a greater risk of PDAC and younger age of disease onset. Tumorigenesis is enhanced by excess adipose tissue. Obesity is associated with a 20% to 40% higher mortality rate from PDAC, and obesity at an older age is associated with lower overall survival [13; 28].

Although BMI is widely used as a marker for general adiposity, visceral obesity has a stronger correlation to metabolic syndrome, insulin resistance, and certain gastrointestinal (GI) malignancies. The close proximity to visceral organs and drainage via the portal system may explain the strong correlation of inflamed visceral adipose tissue (VAT) in obese subjects with metabolic dysfunction and pancreatic cancer [29].

Diet

There is some evidence that higher consumption of red/processed meat is associated with elevation in pancreatic cancer risk, but other studies have failed to identify dietary risk factors for PDAC [11]. Pancreatic cancer incidence may be lower in persons with higher intake of fresh fruits and vegetables rich in folate and lycopenes (e.g., tomatoes) [30].

A link between vitamin D and risk for pancreatic cancer is inconsistent, but some data suggest low plasma 25-hydroxyvitamin D levels may increase the risk for pancreatic cancer, especially in those with low retinol/vitamin A intake [31]. Coffee and tea consumption are not associated with pancreatic cancer risk, despite early reports to the contrary [24].

Systemic/Nonmodifiable Risks

Numerous studies and meta-analyses have found systemic/nonmodifiable factors that increased the relative risk, hazard ratio, or odds ratio of developing pancreatic cancer. These include individuals with greater height (relative risk: 1.81); individuals with blood groups A, AB, and B (hazard ratio: 1.32, 1.51, and 1.72, respectively); and patients with hepatitis B infection (odds ratio: 1.50) or systemic lupus erythematosus (hazard ratio: 1.43). Biologic explanations for some of these associations are not yet understood, and some data may have potential confounders. Infectious etiologies warrant more investigation [11,32].

Periodontal Disease

Periodontitis describes a chronic inflammatory response to a disease-associated, multispecies bacterial community in the subgingival region. Periodontal disease is associated with pancreatic cancer, even when controlling for gender, smoking, BMI, diabetes, and alcohol consumption [33]. The inflammatory processes of periodontitis occur locally, but systemic dissemination of inflammatory mediators, subgingival species, and bacterial components contribute to digestive cancers (including PDAC) by activating proinflammatory pathways, inducing gene expression related to cell proliferation, apoptosis, and immune responses linked to carcinogenesis, cell migration, invasion, and metastasis [34].

Chronic Pancreatitis

A high-risk subgroup for PDAC are patients with chronic pancreatitis, often secondary to chronic alcohol use disorder, smoking, hypertriglyceridemia, diabetes, or renal failure [2]. Patients with chronic pancreatitis show a 26-fold increase in risk of developing PDAC. This risk increases with duration. Among patients with chronic pancreatitis of 20 years' duration, approximately 5% will progress to PDAC.

Concomitant smoking enhances the risk of neoplastic progression [2,35]. Hereditary pancreatitis further increases the risk of pancreatic cancer by more than 50-fold. In these individuals, the cumulative risk of pancreatic cancer by age 70 years is 40% [24].

Long-Standing Diabetes

Pancreatic cancer has complex relationships with diabetes and obesity that are only recently becoming understood. A population cohort study underscored the complex relationship between metabolic abnormalities and PDAC. Glycemic status, insulin resistance, and hyperinsulinemia were independently associated with an increased risk of pancreatic cancer mortality, even in individuals without diabetes [36].

The association between pancreatic cancer and diabetes was noted as early as 1833, clearly documented by the 1930s, and characterized in a large cohort of patients with pancreatic cancer from Mayo Clinic in 1958 [37]. Several meta-analyses have greatly refined the risk-factor status of diabetes.

Long-standing (i.e., more than five years) diabetes (both type 1 and type 2) is associated with increased risk of developing PDAC [13]. The overall risk for PDAC increases 4- to 7-fold in those with diabetes of a duration less than three years [38]. The relative risk associated with diabetes levels off after five years, with a 1.5-fold greater risk [39]. Increased baseline hemoglobin A1C (HbA1C) levels correlate with subsequent development of PDAC [40].

Long-standing diabetes modestly increases the risk of PDAC, which decreases with diabetes duration [11,37]. The initial three-year period after diabetes diagnosis is high risk for PDAC, as confirmed by prospective pancreatographic screening [41].

With diabetes medications, insulin use has been associated with increased risk of PDAC, but this finding is attributed to reverse causality [11,42]. Metformin use in patients with diabetes and PDAC was associated with improved two-year survival (30.1% vs. 15.4%) and median overall survival (15.2 months vs. 11.1 months) in patients without metastases [43]. One metformin study reported negative findings [44].

Long-standing diabetes in patients who develop PDAC is associated with significantly lower overall survival (14.4 months vs. 21.7 months) and significantly higher mortality (harm ratio: 1.52) compared with patients without diabetes who develop PDAC [11,45].

Postpancreatitis Diabetes Mellitus

Diabetes of the exocrine pancreas (formerly type 3c diabetes) is the second most common type of new-onset diabetes in adults (behind type 2 diabetes) [42]. Acute or chronic pancreatitis is one of the most prevalent risk factors for PDAC and the most frequent cause of diabetes of the exocrine pancreas. Pancreatitis leads to postpancreatitis diabetes mellitus in up to 83% of patients [42]. In a registry study involving 139,843 individuals, the proportion of pancreatic cancer was 3.1% among those with postpancreatitis diabetes mellitus, compared with 2.3% in those with type 2 diabetes followed by pancreatitis, 2.0% in those with pancreatitis alone, and 0.6% in individuals with type 2 diabetes alone [42].

Prediagnostic Metabolic and Soft Tissue Changes

Numerous studies have identified new-onset diabetes, weight loss, and soft tissue changes in patients with PDAC at diagnosis, but their inter-relationship and connection to PDAC remained unaddressed. From 2000 through 2015, temporal changes in the five years preceding PDAC diagnosis of 219 patients diagnosed with PDAC were compared to 657 controls [46]. From 60 to 30 months before PDAC diagnosis, patients did not significantly differ from controls. However, starting at 30 months prediagnosis, PDAC showed three distinct metabolic phases, each marked by onset and significant progressive worsening of one or more metabolic abnormalities [46]:

- Phase 1, hyperglycemia (30 to 18 months before PDAC diagnosis): A significant proportion of patients develop hyperglycemia, without soft tissue changes.

- Phase 2, pre-cachexia (18 to 6 months before PDAC diagnosis): Decreases in serum lipids, weight loss, and the first soft tissue change (subcutaneous abdominal tissue loss) are seen. A profile appears of advanced prediabetes (i.e., fasting blood glucose 120–126 mg/dL or A1c of 6% to 6.5%). In type 2 diabetes, this is associated with weight gain and hyperlipidemia due to insulin resistance. In PDAC, decreases in weight and serum lipids despite rising glucose levels are paradoxical.

- Phase 3, cachexia (less than 6 months before PDAC diagnosis): Onset of muscle loss, visceral adipose tissue loss, and decreasing high-density lipoprotein. Continued decreases in all other serum lipids, subcutaneous abdominal tissue, and weight. Fasting blood glucose continues rising.

Based on evidence of increases in body temperature before PDAC diagnosis, browning and loss of subcutaneous abdominal tissue is estimated to begin 18 months before PDAC. Browning of white abdominal tissue is a mechanism of subcutaneous abdominal tissue loss in cancer; its purpose is to generate heat [46].

Symptoms of cachexia and muscle loss (e.g., anorexia, fatigue, reduced exercise tolerance) appear shortly (less than six months) before PDAC diagnosis. The onset of objective weight loss precedes PDAC diagnosis by one year or more. New-onset diabetes appears a median of six to nine months before PDAC diagnosis [46].

Pancreatic Cancer Cachexia and Diabetes

Cancer cachexia is a paraneoplastic syndrome characterized by pronounced weight loss and muscle wasting triggered by cancer-induced systemic inflammation [47]. Cachexia develops in about 80% of patients with PDAC during the disease course, often before the tumor is clinically apparent. Cachexia negatively impacts treatment response and survival, and one-third of patients with PDAC die from cachexia-associated complications, including impaired immunity and cardiopulmonary dysfunction. No curative treatments exist [47].

Pancreatic cancer-associated diabetes mellitus might be a major contributor to PDAC-induced cachexia. The co-occurrence is frequent, and the relationship between pancreatic cancer-associated diabetes and PDAC-induced cachexia was clarified in a 2020 study [47]. Compared with patients without pancreatic cancer-associated diabetes, those with pancreatic cancer-associated diabetes did not have a higher risk of cachexia, a greater degree of weight loss, or lower skeletal muscle mass. Among patients with cachexia, weight loss and skeletal muscle mass were comparable between patients with and without pancreatic cancer-associated diabetes. Fasting blood glucose levels and PDAC-derived diabetogenic factors did not correlate with weight loss or muscle mass or predict cachexia in patients with pancreatic cancer-associated diabetes. A notable finding was the consistently high prevalence of cachexia and muscle wasting regardless of tumor size and stage in PDAC [47]. These results argue against pancreatic cancer-associated diabetes and hyperglycemia in mediating PDAC-induced cachexia.

Cancer cachexia is characterized by systemic inflammation with resultant skeletal muscle breakdown and increased circulating amino acids to support tumor growth. Pancreatic cancer-associated diabetes is a metabolic strategy by PDAC to fuel tumor growth. PDAC cells have a high demand for glucose (termed "glucose addiction"); hyperglycemia promotes invasion and migration of PDAC cells. PDAC-induced cachexia and pancreatic cancer-associated diabetes are distinct metabolic reprogramming induced by PDAC cells to secure amino acids and glucose for tumor growth [47].

Unexplained weight loss/cachexia is a clue to occult PDAC, but a modality that can identify PDAC-induced cachexia is needed to take advantage of this screening opportunity [47]. Optimizing glycemic control may not alleviate weight loss or muscle wasting, and therapies targeting mediators of pancreatic cancer-associated diabetes may not protect against the development of cachexia [47]. Management of cachexia in patients with PDAC is discussed in detail later in this course.

3. PATHOPHYSIOLOGY

PDAC is caused by somatic (acquired) and germline (inherited) mutations in specific cancer-associated genes. In PDAC, the accumulation of multiple combinations of gene mutations significantly perturbs major signaling pathways, leading to a malignant phenotype [13,48,49,50].

Like most solid tumors, PDACs are driven by mutations that disrupt intra- and extracellular networks that normally restrain abnormal growth, proliferation, survival, and invasion [51]. Four major genetic drivers are fundamental in nearly all PDACs. These involve mutational activation of the oncogene KRAS, and mutational inactivation of the tumor suppressor genes CDKN2A, TP53, and SMAD4 [3,50,52,53]. Inactivation of genome maintenance genes that repair DNA damage is a third broad type of mutation in PDAC.

PRIMARY MUTATIONAL DRIVERS IN PDAC

KRAS encodes a GTPase molecule that acts as a transducer for growth factor receptors on the cell surface. KRAS mutations dysregulate intrinsic GTPase activity, stimulating downstream pathways that drive uncontrolled cellular proliferation, angiogenesis, suppression of apoptosis, and evasion of immune response [54].

CDKN2A encodes the proteins p16 and p14ARF, which are both cell-cycle regulators. With loss of CDKN2A gene function, inactivation of p16 results in unchecked cell cycle progression and enhanced tumor cell proliferation [3,49]. TP53 encodes the protein p53, called the "guardian of the genome," which plays a central role in DNA repair, cell cycle arrest, and induction of apoptosis in response to DNA damage or cellular stress [55].

Inactivation of p53 (loss of function mutation) allows DNA damage to go unchecked with failed apoptosis and unregulated G1/S cell cycle transition. Mutant p53 can also gain pro-oncogenic activities (gain-of-function mutation), promoting cell proliferation, survival, angiogenesis, and metastases [54].

SMAD4 encodes the protein Smad4, a downstream effector of transforming growth factor-beta (TGF-b) signaling pathway. SMAD4 inactivation and loss of Smad4 promotes cancer progression by removing the early growth inhibitory effect of the TGF-b pathway and is associated with higher rates of distant metastasis and poorer prognosis [54].

MUTATIONAL SEQUENCE OF PDAC DEVELOPMENT

Through pathways and somatic mutations that differ modestly in each lesion, PDAC develops from precancerous precursor lesions: pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasms (MCNs). The most common are PanINs (approximately 90%), and the least common are MCNs. However, all precursor lesions have key similarities [4,48,50]:

- Early oncogene mutations initiate tumorigenesis.

- Later loss of tumor suppressor genes drive tumor progression, high-grade dysplasia, and invasive cancer.

- Increasing grades of dysplasia are associated with accumulation of somatic mutations in key driver genes.

Pancreatic Intraepithelial Neoplasia (PanIN)

PDAC develops in PanINs through a specific process [56]. First, mutational KRAS activation initiates pancreatic carcinogenesis. With tumor suppressor inactivation, cancer progresses. CDKN2A or SMAD4 are implicated in locally destructive disease; TP53 is involved in metastatic seeding; and concurrent SMAD4 and TP53 are often present in locally or metastatic dominant disease. IPMNs and MCNs often share the driver gene mutations and sequence of PanINs, but also show specific patterns.

Intraductal Papillary Mucinous Neoplasms (IPMN)

More than 90% of IPMNs are marked by activating mutations in the oncogene GNAS and/or inactivating mutations in the tumor suppressor gene RNF43 [48,53,54]. GNAS mutation causes constitutive activation of adenylyl cyclase, with downstream effects driving proliferation. RNF43 encodes E3 ubiquitin-protein ligase, which functions as a tumor suppressor in the Wnt-signaling pathway. After the initiating oncogene mutation, the progression of IPMN resembles PanIN.

Mucinous Cystic Neoplasms (MCN)

RNF43 mutation is also a prevalent event in MCNs (50%). As in PanINs, genetic changes accumulate with higher grade of dysplasia and invasiveness [48,53,54].

NATURAL HISTORY OF PDAC ONCOGENESIS

The PanIN Progression Model has been critical in shaping the perspective of how PDAC develops and progresses over the past two decades. PDAC arises through a specific sequence of genetic alterations over a gradual progression from early PanIN to late-stage metastatic disease [57,58,59].

The timeframe of PanIN progression has also been established. Based on computational modeling using autopsy cases, the estimated average time interval from initiation in normal cells to invasive ability (11.7 years), metastatic dissemination (6.8 years) and death (2.7 years) corresponds to an average of about 21 years from the initiating mutation until a patient's death [17].

Most cases with PDAC are diagnosed toward the end of this lifetime span, suggesting that poor prognosis is a result of late diagnosis in the natural history of PDAC, and that a golden opportunity of two or three years exists to diagnose "early" pancreatic cancer (i.e., Stage 0 or I) [60].

Chromothripsis, a recently identified phenomenon, is a catastrophic event causing tens to thousands of chromosomal rearrangements. Faced with hundreds of DNA breaks, the cell's DNA repair machinery attempts to rescue the genome, but the result bears little resemblance to its original structure [61,62]. This genomic disruption can drive the development of cancer through DNA copy number changes, including deletion of tumor suppressor genes and increased copy number (amplification) of oncogenes [61].

A 2016 study of more than 100 whole genomes from pancreatic cancer tumors found evidence of at least one chromothripsis event in 65% of tumors, and most copy-number changes seemed to occur after such catastrophic genetic events. With evidence of chromothripsis in some PDACs and nongradual tumorigenesis that defies the established mutational sequence, a punctuated equilibrium model was proposed, dividing tumor development into two major events [63]:

- A cancer-initiating event: PDAC pre-neoplasms acquire extensive mutation burden but remain non-invasive over a prolonged preneoplastic phase.

- A cataclysmic cancer-transforming event: Chromothripsis induces DNA copy number changes, creating genomic instability and generating invasive clones with rapid dissemination and colonization of distant sites. Why chromothripsis occurs in PDAC is not yet understood.

Non-Genetic Mechanisms

Rather than being uniformly aggressive, PDAC demonstrates clinical (e.g., variable patient survival) and disease (e.g., variable chemotherapy sensitivity) heterogeneity [64,65]. The first whole-genome description of PDAC in 2008 prompted great effort to advance a patient-tailored precision medicine approach that could better address this heterogeneity. Genetic alterations and molecular subtypes in PDAC were characterized and published. PDAC was shown mutationally dominated by the four driver genes and homogeneous. In general, the findings importantly informed the biology and familial predisposition of PDAC.

However, by 2019 it was apparent that PDAC disease heterogeneity cannot be explained by genetic mutations alone, and non-genetic mechanisms, including epigenetics and the tumorigenic microenvironment, were the path forward [21,56,59,62,64,65,66,67].

Epigenetic Factors

Broadly speaking, epigenetic changes influence gene expression, without altering the DNA sequence, through modifications of DNA or chromatin structures [4]. In PDAC, these include: DNA methylation and non-coding RNAs (ncRNAs).

Gene expression in PDAC can be silenced through non-mutational inactivation by aberrant promoter methylation, including the driver gene p16/CDKN2A [49]. Aberrant ncRNA expression plays a considerable role in initiation, proliferation, and chemo-resistance of PDAC. Oncogenic microRNA-21 promotes both cell proliferation and apoptosis and targets negative regulators of KRAS, which further enhances signaling by this oncogene [50,54].

Pancreatic Tumor Microenvironment

Pancreatic cancer tissue is comprised of PDAC cells and dense fibrotic stromal (stellate) cells. The stroma consists of extracellular matrix and non-neoplastic (e.g., fibroblastic, vascular, immune) cells [3]. Also described as PDAC fibrosis, the stroma makes up most of the tumor mass. Its importance beyond a physical barrier to drug penetration was not historically considered. Recognized only recently, the entire neoplastic tissue, both tumor cells and stroma, create a pancreatic tumor microenvironment that crucially facilitates PDAC growth, survival, and treatment failure [21,51,68].

Pancreatic cancer progresses in tandem with a stromal reaction, characterized by extensive deposition of extracellular matrix, recruitment and activation of cancer-associated fibroblasts, and high interstitial fluid pressures that compress blood vessels, causing hypoperfusion, hypovascularity, and hypoxia [21,69]. Extracellular matrix remodeling biomechanically induces intracellular signaling and tumor-stellate cell crosstalk. PDAC cells signal to stellate cells and recruit macrophages and immune suppressor cells. In turn, stellate cells secrete factors that promote PDAC cell proliferation and migration and suppress apoptosis [51]. Biochemical activation of signaling pathways that regulate PDAC cell survival and metastasis promotes tumor growth, immunosuppression, disease progression, epithelial-mesenchymal transition (a key step of the metastatic cascade) and invasive potential, and chemotherapy resistance [3,21,69].

Exosomes (a macromolecule involved in RNA degradation) released by PDAC cells accumulate in other tissues to create a premetastatic niche by activating stellate cells and inducing remodeling of the host extracellular matrix, which facilitates cancer cell invasion and growth [59,69].

HEREDITARY PDAC

In addition to the somatic mutations driving pancreatic tumorigenesis in all PDACs, specific germline variants also contribute to PDAC in some patients [48]. In many of these germline mutations, the oncogenic mechanism involves inactivation of DNA damage repair genes [49].

There are two broad categories of inherited risk for PDAC [26,70,71]:

- Genetic predisposition or hereditary pancreatic cancer: Germline mutations in PDAC susceptibility genes are present.

- Familial pancreatic cancer: Familial clustering of PDAC (i.e., at least one pair of affected first-degree relatives) without known germline mutations

Sporadic PDAC is when both factors are absent. However, mutations in known pancreatic cancer susceptibility genes are found in 5% to 10% of patients with apparently sporadic pancreatic cancer.

Inherited Cancer Susceptibility Syndromes and Germline Mutations

Several genetic syndromes are associated with specific genetic alterations with an increased risk for pancreatic cancer (Table 3) [48,54]. Germline mutations in familial atypical multiple mole melanoma syndrome (CDKN2A) and Li-Fraumeni syndrome (TP53) are core gene drivers in sporadic PDAC. Peutz-Jeghers syndrome is caused by germline inactivation of STK11, a tumor suppressor gene. Somatic STK11 mutations are observed in approximately 4% of pancreatic cancers, suggesting STK11 inactivation plays a role in both sporadic and familial forms [49].

Table 3: PANCREATIC CANCER SUSCEPTIBILITY SYNDROMES AND MUTATIONS

Category

Specific Syndromes and Germline Mutations

Gastrointestinal tract cancers

Lynch syndrome, also termed hereditary nonpolyposis colorectal cancer (MLH1, MSH2, MSH6, PMS2)

Peutz-Jeghers syndrome (STK11/LKB1)

Familial adenomatous polyposis (APC)

Solid tumor cancers

Hereditary breast/ovarian syndrome (BRCA1/2, PALB2)

Familial atypical multiple mole melanoma syndrome (CDKN2A)

Li-Fraumeni syndrome (TP53)

Chronic pancreatitis-associated syndromes

Hereditary pancreatitis (PRSS1, SPINK1)

Cystic fibrosis (CFTR)

Neurodegenerative disease

Ataxia-telangiectasia (ATM)

Source: [48,54]

Familial Pancreatic Cancer

An estimated 10% to 15% of all pancreatic cancers are attributable to genetic causes. Pancreatic cancer aggregates in some families; 5% to 10% of individuals with pancreatic cancer have a family history of the disease [26,70,72]. Familial pancreatic cancer represents 90% of all hereditary PDAC cases. The relative risk of PDAC increases with the number of affected first-degree relatives.

A specific gene defect responsible for familial pancreatic cancer has not been identified, but a rare autosomal-dominant gene may be responsible, putting 0.4% to 0.7% of the population at risk for developing PDAC [26,70,72]. Details about the relative and lifetime risks of PDAC, and the other prevalent cancers associated with specific germline mutations in cancer susceptibility syndromes and familial pancreatic cancer, are summarized in Table 4.

Table 4: PANCREATIC CANCER RISK IN PREDISPOSITION AND INHERITED CANCER SYNDROMES

Syndrome

Gene(s)

Risk of PDAC

Other Cancers

Relative

Lifetime

General population

–

1

0.5%

–

Hereditary breast/ovarian cancer

BRCA1

2 to 3

1.2% to 2%

Breast, ovarian, prostate

BRCA2

3.5 to 10

2% to 10%

PALB2

15

5% to 10%

Familial atypical multiple mole melanoma

CKDN2A

13 to 36

10% to 30%

Melanoma

Peutz-Jeghers

STK11

75 to 125

11% to 66%

GI, lung, breast, reproductive

Hereditary nonpolyposis colon cancer (Lynch II)

MLH1, MSH2, MSH6

8 to 10

3.7% to 10%

Colorectal, ovary, uterine, upper GI, urinary tract

Li-Fraumeni

TP53

7

unknown

Breast, brain, adrenal

Familial adenomatous polyposis

APC

4.5

Less than 5%

Colon, upper GI, thyroid, brain

Ataxia telangiectasia

ATM

8 to 9

1% to 5%

Breast, prostate

Hereditary pancreatitis

PRSS1, SPINK1

50 to 82

25% to 44%

–

Cystic fibrosis

CFTR

5

Less than 5%

–

Familial pancreatic cancera

1 first-degree relative

4.6

–

–

2 first-degree relatives

6.4

–

–

3 first-degree relatives

32

–

–

aRisk determined by number of affected first-degree relatives rather than specific gene.

Source: [49,54,70,73]

4. PANCREATIC CANCER SCREENING

With the low population incidence of PDAC (lifetime risk: 1.3%), absence of biomarker screening targets, and high cost of sensitive imaging methods, the U.S. Preventive Services Task Force recommended against screening for pancreatic cancer in asymptomatic adults in 2019, reaffirming its previous conclusion in 2004 [74]. As population screening to achieve earlier detection and intervention of PDAC is not currently feasible, other approaches for this objective have been identified.

In Australia, public awareness campaigns have highlighted the often vague symptoms of PDAC and encouraged individuals to seek medical attention early. Underscoring this point, one study found that many people who were ultimately diagnosed with PDAC were falsely reassured by the subtle, intermittent nature of their symptoms over the preceding months [75,76].

As a relatively rare cancer, many primary care providers will only see a PDAC case every few years, making it imperative to elevate awareness of early PDAC signs and symptoms among these professionals. A retrospective case-control study in primary care found that patients sought medical attention 18 times on average in the period preceding their pancreatic cancer diagnosis. PDAC was associated with 11 alarm symptoms; back pain, lethargy, and new-onset diabetes were unique features of PDAC [75,77].

Specific screening efforts in PDAC have focused on identifying high-risk individuals [48]. In 2020, the International Cancer of the Pancreas Screening (CAPS) Consortium updated its consensus recommendations for the management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status [71]. For selected high-risk individuals, pancreatic surveillance is recommended to detect and resect early pancreatic cancer and its high-grade precursors (Table 5). No consensus was reached on whether surveillance should be performed for hereditary pancreatitis.

Table 5: INTERNATIONAL CANCER OF THE PANCREAS SCREENING (CAPS) CONSORTIUM CONSENSUS ON SCREENING FOR PANCREATIC CANCER IN PATIENTS WITH INCREASED RISK FOR FAMILIAL PANCREATIC CANCER

What is the goal of pancreatic surveillance?

The primary goal is to prevent the emergence of and death from pancreatic cancer by identifying and treating stage I pancreatic cancer (resected with negative margins) and pancreatic cancer precursor lesions with high-grade dysplasia (PanIN or IPMN).

Who should be screened?

All patients with Peutz-Jeghers syndrome (carriers of a germline LKB1/STK11 mutation)

All carriers of a germline CDKN2A(p16) mutation

Carriers of a germline BRCA2, BRCA1, PALB2, ATM, MLH1, MSH2, or MSH6 gene mutation with at least one affected first-degree relative

Individuals with at least one first-degree relative with pancreatic cancer who in turn also has a first-degree relative with pancreatic cancer (familial pancreatic cancer kindred)

At what agea should pancreatic surveillance begin?

Familial pancreatic cancer kindred

Start at 50 or 55 years of age, or 10 years younger than the youngest affected blood relative

Mutation carriers

For CDKN2A and Peutz-Jeghers syndrome, start at 40 years of age

For BRCA2, ATM, PALB2, BRCA1, and MLH1/MSH2, start at 45 or 50 years of age, or 10 years younger than the youngest affected first-degree relative

What tests and indications?

Indication

Interval

Test(s)

Routine

At baseline and during follow-up

MRI/MRCP and endoscopic ultrasound

Fasting blood glucose and/or HbA1c

Concerning abnormalities for which immediate surgery is not indicated

After 3 to 6 months

Repeat follow-up testing

No abnormalities or only non-concerning abnormalities (e.g., pancreatic cysts without worrisome features)

After 12 months

Repeat follow-up testing

If concerning features on imaging

Upon indication

Serum CA 19-9

Solid lesions of ≥5 mm

Cystic lesions with worrisome features

Asymptomatic main pancreatic duct strictures (with or without mass)

Upon indication

Endoscopic ultrasound-guided FNA

Solid lesions, regardless of size

Asymptomatic main pancreatic duct strictures of unknown etiology (without mass)

Upon indication

CT

Positive FNA and/or a high suspicion of malignancy on imaging

Upon indication

Surgeryb

aAge to initiate surveillance depends on gene mutation status and family history. There is no consensus on the age to end surveillance.

bWhen surgery is indicated, it should be oncologic radical resection at a specialty center.

CA 19-9 = carbohydrate antigen 19-9; CT = computed tomography; FNA = fine-needle aspiration; HbA1c = hemoglobin A1c; IPMN = intraductal papillary mucinous neoplasm; MRI/MRCP = magnetic resonance imaging/magnetic retrograde cholangiopancreatography = PanIN: pancreatic intraepithelial neoplasia.

Source: [70,71]

However, it is important to remember that among patients with PDAC unselected for their family history of pancreatic cancer who had a germline susceptibility gene mutation, only 10% of these patients had a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Because family history remains one of the best predictors of future pancreatic cancer risk, routine gene testing of patients with newly diagnosed PDAC and their families may yield significant clinical benefits [78].

Genetic counseling of patients before and after any genetic testing is essential, to provide understanding and reassurance and to avoid harm. A challenge to less restrictive testing of patients with new PDAC is there are not enough genetic counselors to provide this service; this shortage of expertise applies to other cancers as well [78].

GERMLINE AND SOMATIC TESTING AND MOLECULAR ANALYSIS

With strong consensus that benefits outweigh harms, in 2018 the ASCO recommended germline genetic testing for patients with PDAC, even if family history is unremarkable, if an informative result could directly benefit the patient or their family members [73]. This stance was adopted in 2020 by the NCCN. Consensus has subsequently expanded.

All patients with pancreatic cancer should have germline testing and gene profiling offered as quickly as possible after diagnosis; the implications for first-line therapy and beyond are significant [79,80]. The 2020–2021 ASCO and NCCN recommendations are for all patients with PDAC to receive germline genomic testing using comprehensive gene panels for hereditary cancer syndromes, and targeted (somatic) profiling of tumor tissue using next-generation sequencing [10,11]. Patients with locally advanced or metastatic PDAC should have available tumor tissue tested for DNA mismatch repair deficiency (dMMR) and microsatellite instability–high (MSI-H) status. It is also recommended that these patients undergo testing for actionable somatic mutations, including fusions (ALK, NRG1, NTRK, ROS1), mutations (BRAF, BRCA1/2, HER2, KRAS, PALB2), and mismatch repair deficiency (dMMR).

5. CLINICAL EVALUATION OF PANCREATIC CANCER

Most pancreatic cancers (approximately 75%) originate in the head of the pancreas and typically metastasize to regional lymph nodes first, then to the liver. PDAC can also directly invade surrounding visceral organs (e.g., duodenum, stomach, colon); metastasize to any surface in the abdominal cavity via peritoneal spread where development of ascites carries an ominous prognosis; or spread to the skin as painful nodular metastases. By the time of diagnosis, 85% to 90% of patients have locally advanced tumors that have involved retroperitoneal structures, spread to regional lymph nodes, or metastasized to the liver or lung [2,13,24,81].

Early-stage pancreatic cancer is notoriously difficult to diagnose. The most common symptoms in a series of patients diagnosed with PDAC were fatigue (86%), weight loss (85%), anorexia (83%), abdominal pain (79%), epigastric pain (71%), jaundice (56%), nausea (51%), diarrhea (44%), pruritus (32%), and steatorrhea (25%) [82].

Abdominal pain, jaundice, and weight loss are nonspecific, subtle in onset, and easily attributed to other processes. Unless the healthcare provider has a high index of suspicion for the possibility of underlying pancreatic carcinoma, this can make it difficult to know when to escalate a workup, as PDAC lacks a specified diagnostic algorithm [2,24].

Development of abdominal pain, jaundice, or weight loss in the context of newly diagnosed diabetes, family history of PDAC, or history of pancreatitis should trigger inclusion of PDAC in the differential diagnosis [2]. Furthermore, past three-year onset of diabetes or ongoing hyperglycemia with significant weight loss and decreasing serum lipids should be considered a potential PDAC, even if abdominal pain or jaundice are absent, with urgent referral a priority.

As noted, pancreatic cancer-associated diabetes and pancreatic cancer cachexia are distinct paraneoplastic syndromes with clinical parameters that may alert attentive clinicians to pursue an appropriately aggressive workup [47]. The lethality of pancreatic cancer merits such an approach despite the absence of formal diagnostic guidelines in this area.

NEUROPSYCHIATRIC SYMPTOMS AND PANCREATIC CANCER

Depression is reported to be more common in patients with pancreatic cancer than with other abdominal tumors. In some patients, depression may be the most prominent presenting symptom, possibly secondary to delayed diagnosis. In addition, although patients may not communicate it to their families, they are often aware that a serious illness of some kind is occurring in them [24]. The risk of suicide among male patients with PDAC is almost 11 times higher than the general male population. Patients who underwent resection are more likely to commit suicide, specifically in the early postoperative period [83].

The association between mood disorders, fatigue, and PDAC has been assumed secondary to the psychosocial impact of diagnosis, loss of independence, and treatment toxicity [2]. However, it is now clear that PDAC has independent detrimental effects on the brain. These symptoms, often present before a diagnosis, are collectively the greatest drivers of declines in health-related quality of life and are independently predictive of survival. Evidence points to neuroinflammatory processes and the need to rethink PDAC as a systemic disease [2].

FAMILY HISTORY

The importance is emphasized of taking a thorough family history when seeing a new patient with pancreatic cancer. A family history of pancreatitis, melanoma, and pancreatic, colorectal, breast and ovarian cancers should be noted [11].

If a cancer syndrome is identified, at-risk relatives should be offered genetic counseling. With or without a known syndrome, individuals with a suspicious family history should be advised on risk-reducing strategies, including smoking cessation and weight loss. The possibility of screening for pancreatic and other cancers should be discussed.

Referral for genetic counseling should be considered for patients diagnosed with pancreatic cancer, especially those with a family history of cancer or who are young, those of Ashkenazi Jewish ancestry, or for whom a hereditary cancer syndrome is suspect. A free pancreatic cancer risk prediction tool, PancPRO, is available and may help determine risk [11].

COMMON PRESENTING SYMPTOMS AND SIGNS

Some, but not all, initial symptoms of PDAC result from a mass effect, such that pancreatic tumor location influences the stage of disease progression when symptoms appear [13].

Abdominal Pain

Abdominal pain is the most common symptom, usually insidious in onset and often present for one to two months at the time of presentation, the pain is often severe, and unrelenting in nature. The typical gnawing, visceral quality of pain is generally epigastric, radiating to the sides and/or straight through to the back; some patients may describe the pain as originating in the back. Nighttime pain is often the predominant complaint. Some patients note increased pain after eating and worsened pain when lying flat [24,81]. Rarely, acute pain develops when an episode of acute pancreatitis results in tumor occlusion of the main pancreatic duct [84].

While roughly one-third of patients may not have pain at the time of initial presentation, all patients will develop pain at some point [24]. Pancreatic cancer is one of the most painful malignancies, and effective pain control is extremely important [85]. This issue will be discussed in detail later in this course.

Jaundice

The most characteristic sign of tumor in the pancreatic head is obstructive jaundice, for which patients may seek medical attention before their tumor grows large enough to cause abdominal pain (and thus, a somewhat better prognosis). These patients usually notice a darkening of their urine and/or lightening of their stools before they or their families notice the change in skin pigmentation. Jaundice secondary to a tumor in the body or tail of the pancreas typically occurs at a later stage and may be secondary to liver metastases of PDAC [2,84].

Pruritus can accompany and often precedes obstructive jaundice. If present, it is often the patient's most distressing symptom [24].

Significant Weight Loss

A characteristic feature of pancreatic cancer, significant weight loss may be related to cancer-associated anorexia and/or subclinical malabsorption from pancreatic exocrine insufficiency caused by pancreatic duct obstruction. Nausea and early satiety from gastric outlet obstruction and delayed gastric emptying from the tumor can contribute to weight loss [24]. Significant weight loss is a symptom of cachexia.

Cachexia

Pancreatic cancer cachexia is a multifactorial paraneoplastic syndrome characterized by a loss of skeletal muscle mass, commonly associated with adipose tissue wasting and anorexia, fatigue, and reduced exercise tolerance. Cachexia develops in approximately 80% of patients with PDAC, in whom the syndrome is typically present at diagnosis and responds poorly to therapeutic interventions [47,86].

Pancreatic cancer leads to the development of cachexia through a combination of distinct factors that explain its high prevalence and clinical importance in this disease [86]:

- Systemic factors, including metabolic changes and pathogenic signals related to PDAC tumor biology

- Factors resulting from the disruption of the digestive and endocrine functions of the pancreas

- Factors related to the close anatomic and functional connection of the pancreas with the gut

Additional Symptoms

The initial assessment can uncover additional diagnostic clues. Undiagnosed diabetes leads to symptoms of glucose intolerance (e.g., polyuria, polydipsia). PDAC can interfere with production of digestive enzymes by the pancreas (pancreatic exocrine insufficiency) and with the ability to break down food and absorb nutrients (malabsorption) in some patients. This malabsorption causes bloating, gas, and a watery, greasy, and/or foul-smelling diarrhea, leading to weight loss and vitamin deficiencies [81].

While long-standing diabetes is a risk factor for later development of PDAC, new-onset hyperglycemia or diabetes has been identified in the majority of patients at diagnosis of otherwise asymptomatic PDAC. Deregulation in glucose homeostasis is often accompanied by changes in subcutaneous adipose tissue. Both represent paraneoplastic syndromes caused by the underlying PDAC [2].

This research is among the most important knowledge advances in PDAC in the past decade. In addition to metabolic deregulation, the pre-diagnostic soft tissue changes and symptoms of cachexia have profound implications for screening, early diagnosis, treatment selection, and patient prognosis [2].

Tumors can also grow locally into the duodenum (proximal for the head of the pancreas, distal for the body and tail of the pancreas) and result in an upper gastroduodenal obstruction [13]. Tumor in the body or tail of the pancreas may cause splenic vein obstruction, resulting in splenomegaly, gastric and esophageal varices, and gastrointestinal hemorrhage [81].

PHYSICAL EXAMINATION

Clinical signs of PDAC during physical examination include jaundice, pruritus, steatorrhea, and vascular issues [2,24,82,84]. Healthcare professionals can usually recognize clinical jaundice when total bilirubin reaches 2.5–3 mg/dL. Patients and their families do not usually notice clinical jaundice until total bilirubin reaches 6–8 mg/dL. Patients with jaundice may have a palpable gallbladder (i.e., Courvoisier sign). As noted, patients with clinical jaundice may have skin excoriations from unrelenting pruritus. If the pancreas has lost the ability to secrete fat-digesting enzymes or if the main pancreatic duct is blocked, steatorrhea will develop.

Migratory thrombophlebitis (i.e., Trousseau syndrome) and venous thrombosis may be present, reflecting the hypercoagulable state that frequently accompanies pancreatic cancer. Thromboembolic events (both venous and arterial) are especially prevalent in advanced disease, and thromboembolic complications occur more commonly with tumors in the pancreatic tail or body.

Multiple arterial emboli resulting from nonbacterial thrombotic endocarditis may be the presenting sign of PDAC. Marantic endocarditis (also known as nonbacterial thrombotic endocarditis) may develop in patients with pancreatic cancer and possibly mimic subacute bacterial endocarditis.

METASTATIC DISEASE

Metastatic disease most commonly affects the liver, peritoneum, lungs, and less frequently, bone [24,84]. Patients presenting with or developing advanced intra-abdominal disease may have ascites, a palpable abdominal mass, hepatomegaly from liver metastases, or splenomegaly from portal vein obstruction. Subcutaneous metastases (termed Sister Mary Joseph nodules) in the paraumbilical area signify advanced disease; pancreatic cancer is the origin of a cutaneous metastasis to the umbilicus in 7% to 9% of cases [24,84]. A metastatic mass in the rectal pouch may be palpable on rectal examination (Blumer shelf). As a metastatic node, left supraclavicular lymphadenopathy may be palpable, while other nodes in the cervical area may also be involved.

LABORATORY TESTING

Routine laboratory tests are often abnormal but nonspecific for PDAC. Common abnormalities include an elevated serum bilirubin and alkaline phosphatase levels, and presence of mild anemia [84].

Patients presenting with jaundice or epigastric pain should be evaluated with complete blood count, blood chemistry panel, and liver function tests to help assess the extent of cholestasis (bilirubin), liver metastasis (alkaline phosphatase), hepatitis (aminotransferases), and nutritional status (albumin, prealbumin). With epigastric pain, serum lipase should be measured to evaluate for acute pancreatitis [2].

DIFFERENTIAL DIAGNOSIS

Differential diagnosis before imaging and biopsy includes acute/chronic pancreatitis, cholangitis, cholecystitis, choledochal cyst, peptic ulcer disease, cholangiocarcinoma, and gastric cancer [85]. Unlike pancreatic exocrine tumors, the symptoms of pancreatic neuroendocrine tumors are distinctly related to excessive secretion of hormones such as insulin, glucagon, gastrin, somatostatin, and vasoactive peptide, resulting in hypoglycemia, hyperglycemia, and GI disturbances such as peptic ulcer and diarrhea.

6. THE DIAGNOSTIC AND STAGING WORKUP

It is not possible to reliably diagnose a patient with pancreatic cancer based on symptoms and signs alone. Abdominal imaging is used in the diagnostic and staging workup of a patient with suspected PDAC. Additional testing is based on the initial findings, the patient's clinical presentation and risk factors [2].

Accurate PDAC detection and staging at the time of presentation carries substantial implications for appropriate recommendation to patients of the most suitable treatment option, thus maximizing the survival benefit for patients in whom complete resection can be achieved and minimizing the morbidity from unnecessary laparotomy or major surgery in patients with high risk of residual disease following resection. The accuracy critically depends on the appropriate imaging protocol and radiologist experience [2,87]. As such, decisions about diagnosis, resectability, and management of pancreatic cancer should involve multidisciplinary consultation at high-volume centers [11].

IMAGING

Multidetector Computed Tomography

Evidence Based Practice Recommendation

The American Society of Clinical Oncology recommends a multiphase computed tomography (CT) scan of the abdomen and pelvis using a pancreatic protocol or magnetic resonance imaging (MRI) be performed for all patients with pancreatic cancer to assess the anatomic relationships of the primary tumor and to assess for the presence of intra-abdominal metastases.

https://ascopubs.org/doi/10.1200/JCO.19.00946

Last Accessed: August 19, 2021

Strength of Recommendation/Level of Evidence: Strong/high

Multidetector computed tomography (MDCT) angiography with intravenous (IV) contrast is the preferred imaging for initial evaluation of suspected PDAC. The Pancreatic CT Protocol standardizes its use, making MDCT highly accurate for assessing tumor extent, vascular invasion, and distant metastases [11,16,88,89]. The NCCN recommends that MDCT angiography should also cover the chest and pelvis for complete staging [11].

MDCT is 77% accurate in predicting resectability and 93% accurate in predicting unresectability [85]. MDCT may be superior to magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP) in vascular enhancement of a PDAC, the most important parameter of resectability. However, MDCT is inferior to MRI/MRCP in depicting isodense tumors or tumors smaller than 1.5 cm in size [54].

Magnetic Resonance Imaging/Magnetic Resonance Cholangiopancreatography (MRI/MRCP)

Abdominal MRI/MRCP with IV contrast also employs a standard multiphase protocol in PDAC, with efficacy comparable to MDCT in preoperative evaluation and assessment of vascular invasion. The sensitivity of MRI/MRCP in detecting liver metastases is nearly 100% (vs. 80% with MDCT) [81,85].

Selection of initial MDCT or MRI/MRCP is typically based on local availability and expertise [81,85]. Following initial MDCT, MRI/MRCP is used when PDAC is highly suspected but negative on MDCT, for characterizing small or indeterminate pancreatic and hepatic tumors, and in patients with severe allergy to iodinated IV contrast material used in MDCT [54,81,85].

Endoscopic Retrograde Cholangiopancreatography (ERCP)

With endoscopic retrograde cholangiopancreatography (ERCP), contrast dye is injected into the biliary ducts and pancreatic duct with an endoscope, and the level of obstruction is delineated. In some case, placement of a biliary stent can help relieve symptoms of jaundice [85]. Patients with obstructive jaundice may have ERCP as the first diagnostic procedure [81].

Ultrasonography

Transabdominal ultrasonography is useful in initial screening of patients who present with possible obstructive jaundice and can rapidly and accurately assess for biliary obstruction. However, definitive diagnosis requires other imaging [24].

Endoscopic ultrasonography is superior to MDCT in detecting solid pancreatic lesions less than 2 cm in size, with accuracy of about 92% [54]. Endoscopic ultrasonography-guided fine-needle aspiration (FNA) also allows for tissue sampling at the time of endoscopic ultrasonography diagnosis [24].

With the restricted field of view, endoscopic ultrasonography is complimentary to MDCT, but it should be used before other imaging options if no pancreatic mass is evident on MDCT. Endoscopic ultrasonography is also valuable in detecting tumor involvement of blood vessels or lymph nodes [11,89].

Positron-Emission Tomography (PET)

Positron-emission tomography (PET) imaging alone does not offer added advantages to MDCT. Combining PET with CT (PET/CT) is a more recent development that may enhance the detection of occult metastases in pancreatic cancer. The NCCN guidelines consider PET/CT an evolving technology; its role in the diagnosis of PDAC is not yet established [11].

BIOPSY

A positive biopsy is not needed in patients with resectable PDAC before undergoing surgery; biopsy may result in seeding, interfere with definitive surgery, and needlessly delay surgical resection if nondiagnostic [11]. However, histologic confirmation of a pancreatic cancer diagnosis is required in some situations, and endoscopic ultrasonography-guided FNA biopsy is the best modality for obtaining a tissue diagnosis [84].

A pathologic diagnosis is indicated to confirm PDAC in locally advanced or metastatic disease, before neoadjuvant therapy, and in atypical presentations in which differential diagnosis is needed with other pancreatic masses (e.g., pancreatitis, lymphoma, tuberculosis). If a biopsy does not confirm malignancy, it should be repeated at least once [16].

The difficulty of diagnosing PDAC in patients with underlying chronic pancreatitis is noteworthy. In such cases, all typical imaging methods may show abnormalities that do not differentiate between PDAC and chronic pancreatitis, and carbohydrate antigen 19-9 (CA19-9) may be similarly elevated in pancreatitis. These patients may require combined multiple imaging modalities, close follow-up, serial imaging studies, and in some cases, empiric resection to diagnose an underlying pancreatic carcinoma [24].

CARBOHYDRATE ANTIGEN 19-9 (CA19-9)

CA19-9 is a sialylated Lewis A blood group antigen, commonly expressed and shed in benign and malignant pancreatic and biliary disease. Although unsuitable for asymptomatic screening, CA19-9 is the most clinically useful biomarker in PDAC, with good sensitivity (79% to 81%) and specificity (82% to 90%) in symptomatic patients. A normal serum level is 37 U/mL [90].

Preoperative CA19-9 provides important prognostic information. Levels <100 U/mL imply likely resectable disease, while levels >100 U/mL suggest unresectablity or metastatic disease. Fewer than 4% of patients with levels >300 U/mL have resectable tumors [24,90].

In one study, patients with preoperative CA19-9 levels <37 U/mL showed longer median survival (22 to 40 months) than patients with levels >37 U/mL (7 to 30 months). Post-treatment changes (two to five weeks post-resection; six to eight weeks post-chemotherapy) from baseline may predict overall survival [90,91].

Post-operative CA19-9 levels of <37 U/mL, <200 U/mL, and >500 U/mL were associated with three-year survival rates of 49%, 38%, and 0%, respectively. Post-chemotherapy CA19-9 decreases of ≥20% predicted prolonged disease-free survival and overall survival [90,91].

Limitations

Around 5% to 10% of the population lacks the enzyme necessary to produce CA19-9; monitoring pancreatic cancer with this marker will not be possible in these individuals [24]. Biliary obstruction also stimulates the secretion of CA19-9. Hyperbilirubinemia is associated with elevated CA19-9 and false positivity in patients with obstructive jaundice. Following the treatment of obstruction, re-evaluation of CA19-9 should improve its diagnostic utility [92].

The NCCN recommends measurement of serum CA19-9 levels after neoadjuvant treatment, prior to and immediately following surgery before adjuvant therapy, and in surveillance. The importance is stressed of obtaining CA19-9 immediately before a therapeutic intervention to have an accurate baseline from which to follow response [11].

THE STAGING WORKUP

When a mass lesion of the pancreas is detected on MDCT (with or without additional imaging), it is reasonable to conclude that a neoplasm is present and is most likely malignant PDAC. After a probable diagnosis of pancreatic cancer is made, the next step is the staging evaluation to establish disease extent and resectability. Unlike many other cancers, imaging is the primary means through which the stage of pancreatic cancer is determined [11].

Using initial MDCT (with or without additional imaging), two different systems are involved [11,93]:

- American Joint Committee on Cancer (AJCC) TNM staging system, to assess tumor status/extent (T), lymph nodes (N), and metastasis (M)

- NCCN guideline to characterize resectable, borderline resectable, or locally advanced disease

TNM Staging

The AJCC system (Table 6) is used for staging PDAC in two contexts [16,94]:

- Clinical staging of all patients with imaging assessment of tumor size and extension, nodal involvement, and distant disease spread

- Pathologic staging of tissue specimens obtained during resection for presence of viable tumor cells

Table 6: AMERICAN JOINT COMMISSION ON CANCER EXOCRINE PANCREATIC CANCER TNM STAGING

Category

Criteria

Primary tumor (T)

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ, including high-grade PanIN (PanIN-3) and IPMN, ITPN, or MCN with high-grade dysplasia

T1

Tumor ≤2 cm in greatest dimension

T1a

Tumor ≤0.5 cm in greatest dimension

T1b

Tumor >0.5 and <1 cm in greatest dimension

T1c

Tumor 1–2 cm in greatest dimension

T2

Tumor >2 and ≤4 cm in greatest dimension

T3

Tumor >4 cm in greatest dimension

T4

Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery, regardless of size

Regional lymph nodes (N)

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in one to three regional lymph nodes

N2

Metastasis in four or more regional lymph nodes

Distant metastasis (M)

M0

No distant metastasis

M1

Distant metastasis

IPMN = intraductal papillary mucinous neoplasm; ITPN = intraductal tubulopapillary neoplasm; MCN = mucinous cystic neoplasm; PanIN = pancreatic intraepithelial neoplasia

Source: [93]

Clinical staging identifies the primary tumor and its vessel involvement, enlarged or suspicious lymph nodes, and metastatic disease sites. TNM staging provides important prognostic information (Table 7), but does not assess whether the PDAC tumor is amenable to surgical resection [54,94].

Table 7: AMERICAN JOINT COMMISSION ON CANCER ANATOMIC STAGE/PROGNOSTIC GROUPS FOR EXOCRINE PANCREATIC CANCER

Stage

T

N

M

A

T1

N0

M0

IB

T2

N0

M0

IIA

T3

N0

M0

IIB

T1–T3

N1

M0

III

Any T

N2

M0

T4

Any N

M0

IV

Any T

Any N

M1

Source: [93]

Resectability Assessment

Complete resection is the only potentially curative treatment for PDAC, but fewer than 20% of patients presenting with PDAC have localized and easily resectable tumors, and noncurative resections provide no survival benefit. Thus, accurate assessment of resectability is crucial [24,87,89].

The NCCN guideline classes PDAC resectability into the following clinical stages [11]:

- Stage 1: Resectable

- Stage 2: Borderline resectable (i.e., tumors that are involved with nearby structures so as to be neither clearly resectable nor clearly unresectable with a high chance of removal of all macroscopic disease)

- Stage 3: Locally advanced (i.e., tumors that are involved with nearby structures to an extent that renders them unresectable despite the absence of metastatic disease)

- Stage 4: Metastatic (i.e., non-resectable)

Localized PDAC falls on a spectrum from high to low resectability, determined by the extent of vessel contact and whether the involvement is arterial or venous (Figure 1) [11,54,84,87,89,95]. Major peripancreatic vessels include the superior mesenteric vein and artery, portal vein, common hepatic artery, and celiac artery. Tumor contact can be characterized as encasement (≥180 degrees of the vessel circumference), abutment (<180 degrees of the circumference), or direct involvement (absence of fat plane between tumor and vessel).

Figure 1: SPECTRUM OF PANCREATIC CANCER RESECTABILITY

Source [84,89,95]

In the past, vascular infiltration by PDAC was considered unresectable, but surgical advances have increased the number of patients with initial borderline resectable or locally advanced disease who can undergo resection. In general, venous abutment or encasement is usually borderline resectable as long as the venous segment is reconstructable. Arterial reconstruction is substantially more difficult and risky than venous reconstruction with comparable tumor contact.

Based on PDAC clinical status of resectable, borderline resectable, locally advanced, or metastatic disease, additional considerations and therapeutic approaches will be undertaken. The time-urgency between the first availability of full imaging findings, multidisciplinary evaluation, the diagnostic and staging workup, discussion with the patient of available treatment options, and treatment initiation cannot be overstated in this aggressive malignancy.

7. TREATMENT APPROACHES FOR PANCREATIC CANCER

As mentioned, the initial imaging workup of PDAC confirms the diagnosis, searches for evidence of metastases, and classifies nonmetastatic PDAC into resectable, borderline resectable, or locally advanced disease based on the involvement of surrounding arterial (superior mesenteric artery, common hepatic artery, and celiac axis) and venous (superior mesenteric vein or portal vein) structures, and other nearby organs and lymph nodes [96].

On average, 10% to 20% of patients initially present with "up-front" resectable PDAC. However, an increasing number of patients with initial borderline resectable or locally advanced disease are eligible for surgical resection as a result of neoadjuvant (i.e., before resection) therapies which may downstage the tumor, and advances in surgical technique, such as venous reconstruction in a vascular infiltration formerly considered unresectable [2].

In all therapeutic decisions, multidisciplinary collaboration to formulate treatment planning and disease management that incorporates patient preferences and available support, their comorbidity profile, symptom burden, and performance status should be the standard of care [6,7,10].

PATIENT FUNCTIONAL STATUS

Evidence Based Practice Recommendation

According to the ASCO, the baseline performance status, symptom burden, and comorbidity profile of a person diagnosed with potentially curable pancreatic cancer should be carefully evaluated.

https://ascopubs.org/doi/10.1200/JCO.19.00946

Last Accessed: August 19, 2021

Strength of Recommendation/Level of Evidence: Strong/high

Performance status is an important indicator of general well-being and the ability to perform activities of daily living in patients with cancer and is frequently assessed in both clinical and research settings. Performance status is repeatedly shown to predict important clinical outcomes, including quality of life, chemotherapy toxicity, response to chemotherapy, terminal illness, progression-free survival, and overall survival in patients with cancer [97].

The Karnofsky Performance Status tool has been used for this purpose, but PDAC guidelines and randomized controlled trials now solely employ the Eastern Cooperative Oncology Group Performance Status (ECOG) scale (Table 8) [97]. For instance, some chemotherapies are indicated solely for patients with good ECOG performance status (0 or 1).

Table 8: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS SCALE

Score

Definition

0

Fully active

No performance restrictions

1

Strenuous physical activity restricted

Fully ambulatory and able to carry out light work

2

Capable of all self-care but unable to carry out any work activities

Up and about >50% of waking hours

3

Capable of only limited self-care

Confined to bed or chair >50% of waking hours

4

Completely disabled

Cannot carry out any self-care

Totally confined to bed or chair

5

Deceased

Source: [98]

Baseline functional status and comorbidity profile should be carefully evaluated, because both have major implications for a person's ability to tolerate therapy. Performance status is consistently identified as a prognostic factor for people with pancreatic cancer. It is also an important determinant in treatment selection; some patients with up-front resectable PDAC may be physically weakened by weight loss and cachexia to an extent that places them at high risk of serious complications or mortality from definitive surgery. Performance status also helps predict chemotherapy toxicity, which can determine the treatment approach for patients with performance status 0 to 1 (multi-agent regimens) or performance status ≥2 (e.g., single-agent gemcitabine) [8].

Similarly, the comorbidity profile can influence the choice of chemotherapy, such as avoiding fluoropyrimidine-based regimens in patients with a known history of uncontrolled coronary artery disease. Nonetheless, performance status and comorbidities alone should not be used simply to rule in or out patients for treatment. For instance, disease control of comorbidities, such as controlled type 2 diabetes, can indicate that patient benefit from treatment may outweigh risks associated with poorly controlled comorbid diabetes [8].

RECOMMENDED TREATMENT OPTIONS BY CLINICAL STAGE

Treatment approaches for PDAC include surgical resection, chemotherapy, radiation therapy, and combined regimens (chemoradiation therapy). Chemotherapy is the backbone of pancreatic cancer treatment; most patients present with disease too advanced to benefit from surgery or resection alone may be insufficient to provide a substantive survival advantage over best supportive care. Chemotherapy and radiation therapy also have a role in palliation, as will be discussed in a later section [99].

Curative surgical approaches for resectable pancreatic cancer are well-established. In contrast, the pace of new U.S. Food and Drug Administration (FDA) approvals and/or phase III evidence continue to make chemotherapy, molecular-targeted therapy, radiation, and chemoradiotherapy approaches a fluid, evolving area, requiring frequent updating and revisions in multidisciplinary clinical practice guidelines for pancreatic cancer treatment. Many potential treatment approaches lacking phase III or prospective evidence are being addressed, with publication of trial results awaited [2].

Resectable or Borderline Resectable PDAC

For patients with resectable or borderline resectable PDAC, neoadjuvant therapy consists of chemotherapy with or without radiation therapy before radical pancreatic resection [99]. Radical pancreatic resection may include Whipple procedure (pancreaticoduodenal resection) or total pancreatectomy when necessary for adequate margins. Distal pancreatectomy is indicated for tumors of the body and tail of the pancreas.

Following resection, patients may receive postoperative chemotherapy or postoperative chemoradiation therapy (typically fluorouracil [5-FU] chemotherapy and radiation therapy) [99].

Locally Advanced PDAC

Chemotherapy with or without targeted therapy is recommended for patients with locally advanced PDAC [99]. For patients without metastatic disease, this should be followed by chemoradiation therapy. If removal is a possibility, radical pancreatic resection may be attempted. Palliative surgery options include surgical biliary and/or gastric bypass, percutaneous radiologic biliary stent placement, or endoscopic biliary stent placement.

Metastatic or Recurrent PDAC

Treatment of metastatic or recurrent PDAC is limited to chemotherapy with or without targeted therapy [99]. Palliative approaches should be used whenever available and feasible to improve patient comfort and quality of life.

RESECTION OF PANCREATIC CANCER

Selecting patients for surgery should be based on the probability of cure as determined by resection margins. Other factors include comorbidities, overall performance status, and age. Pancreaticoduodenectomy and distal and total pancreatectomy are curative resection options based on the location, size, and locally invasive aspects of the tumor. Each has its own set of perioperative complications and risks, which should be considered by the surgical team and discussed with the patient [24].

Mortality rates from resection have fallen significantly, but morbidity remains common and interferes the delivery of adjuvant therapy in up to 40% of patients. The NCCN recommends that patients seek out high-volume centers performing more than 15 to 20 resections annually, with multidisciplinary expertise to optimize their treatment plan and increase opportunities for clinical trial participation [2].

The only curative treatment for PDAC is radical surgery, but potential cure is only possible with a microscopically negative resection margin (R0). Macroscopic (R2) and microscopic (R1) margin infiltration have survival trends similar to patients without surgery. R0 is a minimum >1 mm distance of viable tumor cells from the resection margin, R1 is ≤1 mm distance. A retrospective analysis of 44,852 patients with PDAC reported median survival of 19.7 months following R0, 14.3 months following R1, and 9.8 months with R2 resections compared with 10.3 months without surgery [100]. An incomplete tumor resection imposes morbidity risks without benefit to the patient, and the aim of resection is to obtain microscopically negative margins (R0) [101].

Tissue specimens obtained during resection are examined. During resection, lymphadenectomy is performed, including at least 15 lymph nodes, which are likewise examined as part of pathologic staging [16].

With surgical advances and greater use of adjuvant therapies, long-term cancer survival outcomes following resection were anticipated to improve over time [102]. However, in 1,147 pancreatic resections performed over three decades at the Memorial Sloan Kettering Cancer Center, a lack of progress in long-term survival was reported. Although patients treated between 2000 and 2009 had lower rates of operative mortality and greater one-year survival, for patients treated in the 1980s, 1990s, and 2000s, the median survival was 23.2, 25.6, and 24.5 months, respectively [103]. The five-year survival rates were 17%, 20%, and 8%, respectively. These data underscore the need for earlier detection and more effective systemic therapies [102].

Approaches

Pancreaticoduodenectomy (Whipple Procedure)

Used for tumors in the pancreatic head or periampullary region, the conventional Whipple procedure involves removal of the pancreatic head, duodenum, gallbladder, and the antrum of the stomach, with surgical drainage of the distal pancreatic duct and biliary system, usually through anastomosis to the jejunum. The primary reason for removing so much of the intra-abdominal structures is that they all share a common blood supply [24,102].

The former high morbidity and mortality rates of Whipple have declined with the greater experience of a more limited number of surgeons who regularly perform the procedure in high-volume centers [102]. Common morbidities include delayed gastric emptying in roughly 25% of patients, which may require nasogastric decompression and a longer hospital stay. Pancreatic anastomotic leak can be treated with adequate drainage. Postoperative abscesses are not uncommon [24].

With operative mortality associated with Whipple decreasing from around 25% in the 1970s to less than 2% at high-volume centers in the 2010s, the focus has shifted from surviving the operation to surviving the cancer [104].

Distal Pancreatectomy

Distal pancreatectomy is a procedure for tumors in the pancreatic body or tail. It has a lower mortality than standard Whipple, but its use in curative resection is limited; with tumors in this location seldom causing bile duct obstruction, most patients present at a later stage with unresectable disease. The procedure involves resection of the distal pancreas containing the tumor with splenectomy and over-sewing of the distal pancreatic duct. Complications involve pancreatic stump leak, hemorrhage, and endocrine insufficiency. Laparoscopic exploration should precede attempted resection, because occult peritoneal metastases are common [16,24].

Total Pancreatectomy

Total pancreatectomy, the least commonly performed procedure with the highest associated mortality (8.3%), may be needed to achieve an R0 resection margin for tumors in the neck of the pancreas, especially with extension into the body or tail, and in multifocal PDAC. Total pancreatectomy may be an option to pancreatic anastomosis in highly selected patients with a high-risk pancreas (small pancreatic duct) and obese patients with pancreatic fat infiltration. The metabolic consequences of permanent exocrine insufficiency and diabetes have a detrimental impact on quality of life and long-term survival [16,24,102].

Vascular Resection

Vascular involvement has traditionally been a formal contraindication to resection. With recent advances, venous resection and reconstruction can achieve R0 resection with similar overall survival and morbidity compared to surgery without venous resection. However, arterial resection during Whipple is associated with increased mortality and morbidity (bowel ischemia, hemorrhage, thrombosis) and is generally not recommended [16].

Progress in neoadjuvant therapies may downstage some tumors with arterial invasion to borderline resectable or resectable disease, making resection more achievable. Despite these advancements, it is currently accepted that arterial reconstruction is only appropriate in highly selected patients in high-volume centers with surgeons who are familiar with the advanced techniques required for reconstruction [16].

Total pancreatectomy should be considered in patients with locally advanced tumors who undergo pancreatectomy with arterial resection and reconstruction [16].

Biliary Drainage

In most patients with jaundice, early resection without biliary drainage is preferred. Preoperative drainage is indicated in patients with cholangitis or with obstructive jaundice scheduled for neoadjuvant therapy. Endoscopic retrograde placement of a fully covered metal stent is preferred. Endoscopic ultrasonography-guided stent placement is an effective and safe alternative [16].

CHEMOTHERAPIES IN PANCREATIC CANCER

As mentioned, the backbone of PDAC treatment is chemotherapy. Most patients present with advanced disease, and even those who undergo resection will require adjuvant chemotherapy. Chemotherapy is also used as neoadjuvant therapy and in metastatic disease with first-line or second-line indications [11].

Until recently, chemotherapies found effective in other GI cancers were applied to patients with advanced PDAC; the few agents showing any response became adjuvant therapies in localized PDAC. The near-futility in effective chemotherapy and redundancy in agents used in localized and metastatic PDAC reflects the pathologic complexity of this cancer and its profound resistance to cytotoxic therapies [2].

Since 2010, chemotherapy effectiveness has improved with the introduction of combination regimens, the identification of patients in whom mutational status conferred improved response to existing chemotherapies, and the introduction of novel compounds explicitly targeting mutational-related advanced PDAC.

FDA-Approved Chemotherapies in PDAC

Evidence Based Practice Recommendation

According to the American Society of Clinical Oncology, all patients with resected pancreatic adenocarcinoma who did not receive preoperative therapy should be offered six months of adjuvant chemotherapy in the absence of medical or surgical contraindications. The mFOLFIRINOX regimen is preferred in the absence of concerns for toxicity or tolerance.

https://ascopubs.org/doi/10.1200/JCO.19.00946

Last Accessed: August 19, 2021

Strength of Recommendation/Level of Evidence: Strong/high

In addition to single chemotherapy agents, the FDA has approved regimens of these agents, including FOLFIRINOX (consisting of folinic acid [also referred to as leucovorin], fluorouracil [5-FU], irinotecan [IRN], and oxaliplatin [OX]) (Table 9) [3,24,80,99]. Available chemotherapies are associated with acute and delayed toxicities, some of which can be dose-limiting (Table 10). Table 11 summarizes the 2021 NCCN guideline for chemotherapy and chemoradiotherapy in PDAC.

Table 9: CHEMOTHERAPY PROTOCOLS IN PANCREATIC CANCER

Drug

Dose and route

Administration

Given on days

Gemcitabine

Indication: Nonmetastatic PDAC

Cycle length: 4 weeks (once weekly for 3 weeks, then 1 week off)

Gemcitabine

1,000 mg/m^2 IV

Dilute in 250 mL NS (concentration ≤40 mg/mL), administered over 30 minutes.

Days 1, 8, and 15

Gemcitabine and capecitabine (GemCap)

Indication: Adjuvant therapy

Cycle length: 28 days

Duration: 6 months

Gemcitabine

1,000 mg/m^2 IV

Dilute in 250 mL NS (concentration ≤40 mg/mL), administered over 30 minutes.

Days 1, 8, and 15

Capecitabinea

830 mg/m^2 per dose oral

Twice daily (total 1,660 mg/m^2 per day), 12 hours apart. Swallow with water within 30 minutes post-meal.

Days 1 through 21

Modified FOLFIRINOX

Cycle length: 14 days

Oxaliplatinb

85 mg/m^2 IV

Dilute in 500 mL D5W, administer over 2 hours (before leucovorin). Shorter schedules (e.g., 1 mg/m^2 per minute) appear safe.

Day 1

Leucovorin

400 mg/m^2 IV

Dilute in 250 mL normal saline or D5W, administer over 2 hours (after oxaliplatin).

Day 1

Irinotecanc

150 mg/m^2 IV

Dilute in 500 mL normal saline or D5W, administer over 90 minutes concurrent with the last 90 mins of leucovorin infusion, in separate bags, using Y-line connection.

Day 1

Fluorouracil

2,400 mg/m^2 IV

Dilute in 500–1,000 mL 0.9% normal saline or D5W, administered as continuous IV infusion over 46 hours.d

Day 1

FOLFIRINOX

Indication: Metastatic PDAC

Cycle length: 14 days

Oxaliplatinb

85 mg/m^2 IV

Dilute in 500 mL D5W, administer over 2 hours (before leucovorin). Shorter schedules (e.g., 1 mg/m^2 per minute) appear safe.

Day 1

Leucovorin

400 mg/m^2 IV

Dilute in 250 mL normal saline or D5W, administer over 2 hours (after oxaliplatin).

Day 1

Irinotecanc

150 mg/m^2 IV

Dilute in 500 mL normal saline or D5W, administer over 90 minutes concurrent with the last 90 mins of leucovorin infusion, in separate bags, using Y-line connection.

Day 1

Fluorouracil

400 mg/m^2 IV bolus

Give undiluted (50 mg/mL) as a slow IV push over 5 minutes (immediately after leucovorin).

Day 1

Fluorouracil

2400 mg/m^2 IV

Dilute in 500–1,000 mL 0.9% normal saline or D5W, administer as continuous IV infusion over 46 hours (immediately after IV bolus).d

Day 1

aCapecitabine is contraindicated in patients with known DPD deficiency.

bMany centers routinely infuse oxaliplatin via central venous line because of local pain with infusion into a peripheral vein

cConsider a lower dose of irinotecan with poor performance status.

dTo accommodate an ambulatory pump for outpatients, can be administered undiluted (50 mg/mL) or the total dose diluted in 100–150 mL normal saline.

Source: [98,105]

Table 10: ACUTE AND DELAYED CHEMOTHERAPY TOXICITIESa

Agent

Acute Toxicities

Delayed Toxicities

Fluorouracil

Nausea and vomiting

Diarrhea

Oral and GI ulcers

Bone marrow depression

Diarrhea (especially with leucovorin)

Neurologic defects, usually cerebellar

Cardiac arrhythmias

Palmar-plantar erythrodysesthesia (hand-foot syndrome)

Capecitabine

Nausea and vomiting

Hand-foot syndrome

Diarrhea

Stomatitis

Dermatitis

Bone marrow depression

Hyperbilirubinemia

Gemcitabine

Fatigue

Nausea and vomiting

Fever

Bone marrow depression

Edema

Pulmonary toxicity

Irinotecan

Diarrhea

Diarrhea

Leukopenia

Oxaliplatin

Peripheral sensory neuropathy

Pharyngolaryngeal dysesthesias

Paresthesias

Bone marrow depression

Diarrhea

Persistent neuropathy

Paclitaxel

Hypersensitivity reactions

Bone marrow depression

Peripheral neuropathy

Alopecia

Arthralgias

aDose-limiting toxicities are bold-faced.

Source: [106,107]

Table 11: NCCN TREATMENT SUMMARY FOR PDAC

Strength of Recommendation/Evidence

Regimen

Notesa

Adjuvant stage 1 (resectable)

Category 1

Gemcitabine

Gemcitabine/capecitabine

5-FU/leucovorin

–

Category 2a

5-FU continuous infusion

Chemoradiation

Chemoradiation should follow induction chemotherapy, with or without subsequent chemotherapy

Category 2B

Capecitabine

–

Neoadjuvant stage 1/2 (resectable or borderline resectable)

Category 2A

Gemcitabine/paclitaxel NAB

–

Category 2B

Gemcitabine/cisplatinb

FOLFIRINOX

Chemoradiation

–

Stage 3 (locally advanced)

Category 1

Gemcitabine

Preferred for patients with poor ECOG PS (≥2)

Category 2A

Gemcitabine/paclitaxel NAB

Gemcitabine/erlotinib

Gemcitabine/cisplatinb

Gemcitabine/capecitabine

Gemcitabine fixed-dose rate

FOLFIRINOX

Chemoradiation

Fixed-dose rate gemcitabine is a category 2B recommendation for patients with poor ECOG PS (≥2)

Chemoradiation should follow induction chemotherapy, with or without subsequent chemotherapy

Category 2B

Gemcitabine/docetaxel/capecitabine Capecitabine

5-FU continuous infusion

FOLFOX

–

Stage 4 (metastatic)

Category 1

Gemcitabine

Gemcitabine/paclitaxel NAB (preferred)

Gemcitabine/erlotinib

FOLFIRINOX (preferred)

–

Category 2A

Gemcitabine/cisplatinb

Gemcitabine/capecitabine

Gemcitabine fixed-dose rate

Olaparib

Pembrolizumab (for MSI-H or dMMR tumors only)

Larotrectinib (for NTRK-positive only)

Fixed-dose rate gemcitabine is a category 2B recommendation for patients with poor ECOG PS (≥2)

Olaparib for maintenance therapy only in BRCA1/2 or PALB2 mutated stage 4 disease without progression after 4 to 6 months of first-line platinum-based therapy

Category 2B

Gemcitabine/docetaxel/capecitabine

Capecitabinec

5-FU continuous infusionc

FOLFOX

Entrectinib (for NTRK-positive only)

–

Second-line therapy

Category 1

Gemcitabinec,d

5-FU/leucovorin/irinotecand

–

Category 2A

Gemcitabine fixed-dose rate

Fixed-dose rate gemcitabine is a category 2B recommendation for patients with poor ECOG PS (≥2)

Category 2B

Capecitabinec,e

5-FU continuous infusionc,e

–

Strength of Recommendation Definitions

Category

Definition

1

Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

2A

Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

2B

Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

aECOG performance status (PS) 0/1 only, unless noted.

bIn BRCA1/2 or PALB2 mutations only.

cPoor ECOG PS (≥2) only.

dIf prior non-gemcitabine-based therapy.

eIf prior gemcitabine-based therapy.

Source: [11]

Fluoropyrimidines

Fluorouracil is a fluorinated (fluoro)-pyrimidine antimetabolite that inhibits thymidylate synthase and interferes with RNA synthesis and function, with some effect on DNA.

Capecitabine is an oral fluoropyrimidine that undergoes hepatic hydrolysis to form fluorouracil. The final enzyme, thymidine phosphorylase, is present at higher levels in tumor tissue, providing better selectivity and tolerability.

Gemcitabine is a pyrimidine antimetabolite that inhibits DNA polymerase and ribonucleotide reductase, which in turn inhibit DNA synthesis, blocks DNA replication and several forms of DNA repair [3,24,80,99].

Erlotinib

Erlotinib is a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. EGFR is expressed on the cell surface of normal cells and cancer cells. Erlotinib inhibits intracellular phosphorylation, which prevents further downstream signaling, resulting in cell death [3,24,80,99].

Paclitaxel

Paclitaxel protein bound is a microtubular inhibitor (albumin-conjugated formulation) and a natural taxane that prevents depolymerization of cellular microtubules, which results in DNA, RNA, and protein synthesis inhibition [3,24,80,99].

Irinotecan Liposomal

Irinotecan and its active metabolite SN-38 bind reversibly to the topoisomerase-1 DNA complex and prevent re-ligation of the single-strand breaks, leading to exposure time-dependent double-strand DNA damage and cell death. Irinotecan liposomal is used in combination with fluorouracil and leucovorin [3,24,80,99].

DNA Damage Repair Mutational Status and Targeted Therapies

Platinum agents (e.g., cisplatin, oxaliplatin) and olaparib are recommended in patients with mutation in DNA damage repair (DDR) genes by the NCCN. DDR mutations are present in up to 24% of PDACs, most commonly BRCA1/2 and PALB2. Germline BRCA1/2 mutations (gBRCAm) affect approximately 7% of patients with PDAC [108]. DDR genes encode for proteins in the homologous repair pathway and DNA double-stranded break repair; thus, mutations may be more sensitive to further DNA damage [99].

Cisplatin inhibits DNA synthesis by the formation of DNA cross-links; denatures the double helix; covalently binds to DNA bases; and disrupts DNA function. Oxaliplatin is an alkylating agent. Following intracellular hydrolysis, the compound binds to DNA, forming cross-links that inhibit DNA replication and transcription, resulting in cell death [24,99].

PDACs with DDR mutations demonstrate improved responses to platinum-based therapies, and patients with advanced PDAC showed significantly improved median overall survival (22 months vs. 9 months) compared with nonplatinum therapy [96].

Poly (ADP-ribose) polymerase (PARP) inhibition has been posited to act synergistically with BRCA1/2 mutations by inhibiting single-stranded break repair, causing an accumulation of DNA damage and tumor-cell death [99,109]. Olaparib is a PARP inhibitor FDA-approved for PDAC with gBRCAm as maintenance therapy to sustain a progression-free state during platinum-based chemotherapy in metastatic PDAC [96].

The NCCN expands the use of olaparib to PDAC with gPALB2m. There are calls to expand these agents to PDACs with somatic DDR mutations [108].

Other FDA-Approved Targeted Therapies

The approved indications for the following agents are biomarker-defined, rather than by tumor site (e.g., pancreatic).

Pembrolizumab

Pembrolizumab is indicated in patients with microsatellite-instability-high (MSI-H) or dMMR mutations. Immune checkpoint inhibitors (ICIs) have efficacy in solid tumors with a high tumor mutational burden, and MSI-H or dMMR mutation solid tumors are associated with high tumor mutational burden. The ICI pembrolizumab is an anti-programmed death receptor-1 antibody that releases inhibition of the immune response, improving antitumor immunity [11,96].

Pembrolizumab is approved for any solid tumor with MSI-H or dMMR mutation that progresses during treatment without any satisfactory alternative treatment options [11,96]. This agent represented the first FDA approval (in 2017) with a biomarker-defined indication (i.e., agnostic of cancer site) [107]. Although this mutation is present in only about 1% of PDAC tumors, up to 83% of patients with dMMR PDAC respond to pembrolizumab [110].

Larotrectinib and Entrectinib

Larotrectinib and Entrectinib are neurotrophin receptor kinase (NTRK) inhibitors approved (in 2018 and 2019) for advanced, morbid, or unresectable solid tumors with NTRK fusion mutations, found in less than 1% of PDCAs [96].

The mutation product, TRK fusion protein, activates mitogen activated protein kinase-extracellular regulated kinase and phosphoinositide3 kinase-serine threonine signaling pathways, implicated in the oncogenesis of pancreatic cancer [96]. The NCCN recommends larotrectinib and entrectinib as first-line and subsequent treatment options for patients with NTRK gene fusion-positive locally advanced or metastatic PDAC [11].

Chemotherapy Efficacy: Localized Disease

A variety of data on chemotherapy efficacy are available, allowing for comparison of available agents in specific patient populations (Table 12). However, the terminology used can be confusing. Disease-free survival and progression-free survival are synonymous terms, and choice of the term used in this section will reflect the reference material. This is also the case with median survival and median overall survival. Unless noted otherwise, all patient outcomes are reported as median figures.

Table 12: ADJUVANT CHEMOTHERAPY TRIALS IN RESECTABLE PDAC

Phase III trial (Year)

Chemotherapy Comparison

Median Survival (months)

ESPAC-1 (2004)

5-FU vs. observation

21 vs. 15.5

CONKO-001 (2013)

Gemcitabine vs. observation

22.8 vs. 20.2

ESPAC-3 (2012)

Gemcitabine vs. 5-FU/leucovorin

46 vs. 39

ESPAC-4 (2017)

Gemcitabine/capecitabine vs. gemcitabine alone

28 vs. 25.5

PRODIGE 24 (2018)

Modified FOLFIRINOX vs. gemcitabine

54.4 vs. 35

APACT (2019)

Gemcitabine/paclitaxel vs. gemcitabine alone

40.5 vs. 36.2

5-FU = 5-fluorouracil.

Source: [2]

The CONKO-001 trial established gemcitabine as standard adjuvant chemotherapy. In this study, 354 patients were randomized to receive gemcitabine or observation after resection and followed a median 136 months. Gemcitabine led to a 24% improvement in overall survival, a 10.3% absolute improvement in 5-year survival (20.7% vs. 10.4%), and a 4.5% improvement in 10-year survival (12.2% vs. 7.7%), compared to observation [111,112].

The ESPAC-3 trial showed the importance of completing the full post-resection adjuvant chemotherapy course (six cycles) in extending median overall survival of these patients compared with those not completing chemotherapy (28.0 months vs. 14.6 months) [96].

A continuation, ESPAC-4, found adding another fluoropyrimidine-based agent (capecitabine) to gemcitabine was superior to gemcitabine alone in median survival (28.0 months vs. 25.5 months) and five-year survival (28.8% vs 16.3%). A synergistic effect between gemcitabine and capecitabine on the DNA thymidylate enzyme was suggested [96].

PRODIGE-24 randomized 493 patients (ECOG performance status ≤1) with resected PDAC to modified FOLFIRINOX or gemcitabine for 24 weeks. At median 33.6 month follow-up, the disease-free survival with modified FOLFIRINOX was 21.6 months, compared with 12.8 months with gemcitabine [113]. Grade 3/4 toxicities were more frequent with mFOLFIRINOX (75.9%) than gemcitabine (52.9%). Nonetheless, the median 54.4-month overall survival with resection followed by mFOLFIRINOX is the longest survival reported to date with phase III results [5,114].

Tolerance of adjuvant therapy remains a limitation, and patients commonly receive less than 50% of the planned dose, reflecting exposure to significant chemotherapy-related toxicity in patients experiencing substantial post-resection morbidity [2].

Chemotherapy Efficacy: Advanced/Metastatic Disease

First-Line Chemotherapy in Metastatic PDAC

5-FU has been used in pancreatic cancer treatment since the 1950s. Patients with advanced PDAC typically show response rates greater than 20% and median survival of 2.5 to 6 months [24,80].

In 1997, gemcitabine replaced 5-FU as first-line treatment in metastatic PDAC by improving one-year survival rates (18% vs. 2%) and median overall survival (5.65 months vs. 4.41 months) [32]. Subsequently, numerous attempts to improve gemcitabine efficacy in metastatic PDAC have involved adding another cytotoxic drug [2,96]. Some show marginal but statistically significant improvements in median survival over gemcitabine alone (Table 13).

Table 13: FIRST-LINE CHEMOTHERAPY TRIALS IN METASTATIC PDAC

Phase III Trial (Year)

Chemotherapy Comparison

Median Survival (Months)

Cullinan (1985)

5-FU vs. 5-FU/doxorubicin vs.

5-FU/doxorubicin/mitomycin

5.5 vs. 5.5 vs. 4.5

Burris (1997)

5-FU vs. gemcitabine

4.4 vs. 5.6

Tempero (2003)

Gemcitabine vs. gemcitabine fixed dose rate

5 vs. 8

Heinemann (2006)

Gemcitabine ± cisplatin

6.0 vs. 7.5

NCIC-CTG PA.3 (2007)

Gemcitabine ± erlotinib

5.9 vs. 6.2

Cunningham (2009)

Gemcitabine ± capecitabine

6.2 vs. 7.1

CALGB 80303 (2010)

Gemcitabine ± bevacizumab

5.9 vs. 5.8

SWOG S0205 (2010)

Gemcitabine ± cetuximab

5.9 vs. 6.3

PRODIGE 4 (2011)

Gemcitabine vs. FOLFIRINOX

6.8 vs. 11.1

MPACT (2013)

Gemcitabine ± nab-paclitaxel

6.7 vs. 8.5

Source: [2]

The NCIC CTG PA.3 trial found a nonmeaningful clinical improvement with gemcitabine/erlotinib over gemcitabine alone in median overall survival (6.24 months vs. 5.91 months). Despite FDA approval for locally advanced/metastatic PDAC, the clinical impact of this modest gain with increased toxicity can be questioned [32,96].

PRODIGE 4/ACCORD 11 demonstrated that patients with advanced PDAC and ECOG performance status ≤1 had better outcomes with FOLFIRINOX than gemcitabine in median overall survival (11.1 months vs. 6.8 months) and progression-free survival (6.4 months vs. 3.3 months). Following these findings, FOLFIRINOX became standard first-line therapy for candidate patients [2].

FOLFIRINOX was associated with more toxicities, but the six-month degradation in quality of life was better in FOLFIRINOX than gemcitabine (31% vs. 66%). Improved cancer control with FOLFIRINOX may be due to the inclusion of irinotecan, which has activity against PDAC and synergistic activity when given prior to 5-FU [96].

Finally, the MPACT study demonstrated an improvement of 1.8 months in both median overall survival and median progression-free survival with gemcitabine plus nab-paclitaxel versus gemcitabine alone, leading to another first-line option for metastatic PDAC [96].

Second-Line Chemotherapy in Metastatic PDAC

Second-line therapy primarily consists of doublet therapy using the alternative pyrimidine backbone to what was used in the first-line setting. In 2016, the NAPOLI-1 trial demonstrated that after progression on a first-line gemcitabine-containing regimen for metastatic PDAC, 5-FU/leucovorin plus nanoliposomal irinotecan improved overall survival from 4.2 months (with 5-FU/leucovorin alone) to 6.1 months. As with nab-paclitaxel, improving the delivery of traditional chemotherapies may lead to more effective treatments for individuals with pancreatic cancer [32].

The POLO trial examined targeted maintenance therapy in a biomarker-selected population. In patients with metastatic PDAC harboring germline BRCA1/2 mutations who had not progressed on first-line platinum-based chemotherapy, those randomized to olaparib had improved median progression-free survival (7.4 months compared with 3.8 months with placebo), but olaparib did not improve median overall survival [109]. The median duration of response to olaparib was 6 months, but was more than 24 months in a subset of patients (23%), which is exceptional in metastatic PDAC [108].

In second-line chemotherapy after progression on a first-line regimen, there is considerable heterogeneity in the survival of patients, and predicting which patients will benefit is not established. The decision to pursue second-line chemotherapy should be individualized and based on the patient's goals and preferences. Factors influencing the choice of second-line therapy include the regimen used for first-line therapy, performance status and comorbidity, and mutation status [106].

RADIATION THERAPY FOR PANCREATIC CANCER

In addition to resection and chemotherapy, treatment of patients with PDAC may include radiation therapy or chemoradiotherapy. Unlike chemotherapy, the role of radiation therapy in the treatment of PDAC is uncertain. Radiation therapy is not a stand-alone treatment in local PDAC but is sequenced with chemotherapy as chemoradiotherapy.

Earlier adjuvant radiation therapy trials demonstrated an overall survival and disease-free survival benefit, but subsequent European chemoradiation studies showed negative findings [12]. Technical advances suggest increasing promise with radiation therapy, but multi-institutional randomized trials in PDAC have lagged [12].

Stereotactic body radiation therapy has promising local control and quality of life, and is being evaluated for locally advanced and borderline resectable PDAC. However, adjuvant stereotactic body radiation therapy remains investigational with high toxicity risk and is only recommended as part of a clinical trial [12].

Evidence Based Practice Recommendation

Following surgical resection of pancreatic cancer, adjuvant conventionally fractionated radiotherapy with chemotherapy in select high-risk patients (i.e., positive lymph nodes and margins regardless of tumor location within the pancreas) is conditionally recommended by the American Society for Radiation Oncology.

https://www.practicalradonc.org/cms/10.1016/j.prro.2019.06.016/attachment/0e8abbe7-fcc6-4c5d-8b46-e81e636ce080/mmc1.pdf

Last Accessed: August 19, 2021

Strength of Recommendation/Level of Evidence: Conditional/low

In the absence of phase 3 trials directly comparing neoadjuvant treatment approaches with or without radiation, adjuvant and neoadjuvant chemoradiation in PDAC awaits definitive evidence. Several such trials are in progress [2,12]. In particular, RTOG 0848 is expected to definitively clarify the role of post-resection radiotherapy [115].

Nonetheless, the prospective cohort and retrospective evidence suggestive of decreased local recurrence and disease progression is sufficient for ASTRO, the NCCN and ASCO to recommend radiation therapy. Standard radiation prescriptions in the neoadjuvant setting consist of daily treatments over the course of five or six weeks to a total dose of 50–54 gray (Gy) [2].

The type and duration of chemotherapy given with radiation therapy for pancreatic cancer depends on the clinical stage, setting (neoadjuvant or adjuvant), performance status, and comorbidities. Patients with favorable performance status (0 or 1) are typically offered FOLFIRINOX prior to radiation therapy. Patients who are elderly or have a poor performance status (≥2) are typically offered gemcitabine or gemcitabine/nab-paclitaxel prior to radiation therapy. The duration (two to six months or longer) depends on patient tolerance and tumor response (i.e., no evidence of progression on chemotherapy). Common dose-limiting toxicities are diarrhea, neuropathy, and hematologic [12].

NEOADJUVANT THERAPY

Preoperative, or neoadjuvant, therapy is a major paradigm shift in treatment for patients with localized PDAC that offers the potential to lengthen survival while sparing patients unnecessary treatment-related morbidity using available treatments [116]. The rationale for neoadjuvant therapy differs somewhat by disease stage and clinical features.

Neoadjuvant therapy is recommended in upfront resectable disease with high-risk features of dissemination. This includes tumors in pancreas body and tail or >3–4 cm, ascites, large regional lymph nodes, CA19-9 levels >1,000 U/mL, severe weight loss, and extreme pain. For these patients, staging laparoscopy is recommended to identify liver and peritoneal metastases missed by MDCT in assessing resectability, with endoscopic ultrasonography-guided biopsy [7,11,15]. The next step is systemic neoadjuvant therapy (i.e., chemotherapy), post-neoadjuvant therapy CA19-9, and MDCT with contrast to reassess resectability (with some limitations). If R0 resection is feasible and there is no evidence of metastatic disease, surgery should be attempted [7,11,15].

In general, neoadjuvant therapy for patients who are candidates for resection is controversial [116]. Some oncology groups do not recommend neoadjuvant therapy in upfront resectable disease (except with high-risk features) until better evidence is available, but this stance has become less tenable as additional evidence supporting efficacy becomes available [7,13,15].

Even in patients with anatomically localized disease based on imaging and after complete resection with R0 margins, the high rates of distant failure after surgery for resectable PDAC indicates most patients already have systemic disease at the time of diagnosis. Current imaging fails to accurately assess the true burden of disease, missing occult metastases and under-staging patients [116].

Given this reality, systemic therapy is crucial, but many patients do not receive adjuvant therapy after resection. The high complication rates and potentially prolonged recovery with resection results in 25% to 50% of patients not receiving postoperative therapy [116]. However, systemic neoadjuvant therapy allows patients to receive therapy when they have better performance status and before the potential development of postoperative complications [116].

Neoadjuvant therapy also tests the tumor biology. Patients with aggressive tumors that progress and/or metastasize during neoadjuvant therapy are spared a futile operation. Due to their performance status, patients who do poorly on systemic neoadjuvant therapy would likely do poorly with surgery, resulting in mortality or serious perioperative morbidity precluding adjuvant therapy. Neoadjuvant therapy allows patients with resectable tumors who are poor surgical candidates time to medically and/or physically optimize before surgery.

Neoadjuvant therapy is not without its drawbacks. Eligibility for neoadjuvant therapy requires a tissue diagnosis, but the dense PDAC tumor stroma impedes tissue confirmation in approximately 15% of patients [116]. Further, neoadjuvant therapy means delaying surgery, with the possibility for local progression during neoadjuvant therapy into unresectable PDAC [15]. However, local progression almost always occurs concomitantly with development of systemic disease [116]. Essentially, better evidence is needed. Until phase III results are available, the poor outcomes of conventional treatment sequencing argue for the need for neoadjuvant therapy.

Borderline resectable pancreatic cancer is a recognized indication for neoadjuvant therapy, as this approach may shrink and make tumors more amenable for surgical resection with fewer complications and increased chance of R0 resection. Neoadjuvant therapy may minimize early non-detectable microscopic metastases, decrease lymph node involvement, and improve overall survival and outcomes [96].

Upfront Resectable/Borderline Resectable Tumor and Neoadjuvant Therapy

The NCCN recommends neoadjuvant therapy for patients with resectable or borderline resectable tumors. Treatment at or coordinated through a high-volume center is preferred, when feasible, and participation in a clinical trial is encouraged. The preferred neoadjuvant options are FOLFIRINOX with or without subsequent chemoradiation, or gemcitabine plus albumin-bound paclitaxel with or without subsequent chemoradiation [11]. For patients with BRCA/PALB2 mutations, the preferred regimen is gemcitabine plus cisplatin (two to six cycles) with or without subsequent chemoradiation [11].

ASTRO guidelines for neoadjuvant chemoradiation specify a radiation dose of 4,500–5,040 cGy in 180–200 cGy fractions [12]. They recommend delivery of radiation therapy following two to six months of chemotherapy.

Locally Advanced Pancreatic Cancer and Neoadjuvant Therapy

Locally advanced pancreatic cancer accounts for 30% of newly diagnosed cases. With local involvement of adjacent critical blood vessels and presence of occult micrometastatic disease, locally advanced pancreatic cancer is generally considered surgically unresectable and incurable, and the standard of care is similar to metastatic disease [2].

However, the increased use of preoperative multiagent chemotherapy followed by chemoradiation has significantly expanded the pool of patients with locally advanced pancreatic cancer eligible for resection with curative intent, significantly improving the resectability and overall survival of these patients [117].

In a single-institution phase II trial, 49 patients with locally advanced pancreatic cancer received eight cycles of FOLFIRINOX followed by 50.4 Gy of photon radiation with capecitabine and losartan. Of these patients, 39 were brought to the operating room, 34 (69%) had their cancer removed, and of these, 30 patients (88%) had an R0 resection. Among patients who underwent resection, median progression-free survival and overall survival were 21.3 and 33 months, respectively, versus the 11- to 12-month historical overall survival [118].

Neoadjuvant therapy is associated with a downstaging-to-resection rate of greater than 30% in selected patients with locally advanced pancreatic cancer, with survival comparable to or better than initially resectable disease. For patients with arterial involvement, arterial divestment shows a lower morbidity and mortality rate than arterial resection and reconstruction [117].

Post-Neoadjuvant Therapy Restaging Evaluation of Resectability

Following neoadjuvant therapy, a restaging evaluation with pancreatic protocol MDCT is required to image tumor shrinkage and rule out local progression for resectability. However, post-neoadjuvant therapy imaging is not a reliable indicator of resectability due to its inability to distinguish post-treatment fibrosis from residual viable tumor [117]. Post-neoadjuvant therapy CA19-9 levels are predictive of tumor regression and should be used to guide decisions about suitability for surgical exploration for resection. Diagnostic laparoscopy should be routinely used to minimize nontherapeutic surgery rates [117].

Adjuvant Chemotherapy in Patients with Resected PDAC After Neoadjuvant Therapy

After resection of pancreatic cancer following neoadjuvant FOLFIRINOX, the benefit of adjuvant chemotherapy on overall survival is unclear. Although randomized controlled trial confirmation is needed, a 2020 multicenter, retrospective study provided informative results [119]. Of 520 patients (median age: 61 years; 53.7% male) who received a median of six neoadjuvant cycles of FOLFIRINOX, 343 (66.0%) received adjuvant chemotherapy. Adjuvant chemotherapy was FOLFIRINOX for 68 patients (19.8%), gemcitabine-based chemotherapy for 201 (58.6%), capecitabine for 14 (4.1%), a combination or other agents for 45 (13.1%), and unknown for 15 patients (4.4%). The median overall survival was 38 months after diagnosis and 31 months after surgery. No survival difference was found for patients who received adjuvant chemotherapy compared with those who did not (29 months in both groups).

In multivariable analysis, the interaction of lymph node stage with adjuvant therapy was statistically significant. In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved overall survival (26 months vs. 13 months). For those with node-negative disease, adjuvant chemotherapy was not associated with improved survival (38 months vs. 54 months). These results suggest that adjuvant chemotherapy after neoadjuvant therapy FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease [119].

LOCALLY ADVANCED PANCREATIC CANCER

Neoadjuvant therapy increasingly shows the ability to downstage locally advanced pancreatic cancer into resectable tumor, but until such approaches are employed beyond specialized PDAC research centers, most of these patients will remain unresectable [2].

Chemotherapy selection for patients with locally advanced pancreatic cancer is largely based on extrapolation from studies in metastatic PDAC. However, the natural history of locally advanced pancreatic cancer is less predictable than metastatic disease [120]. In an important autopsy study, 28% of patients with locally advanced pancreatic cancer at initial diagnosis died with localized disease only, from complications of locally destructive tumor growth [120]. Also noted, not all isolated metastases at initial diagnosis are harbingers of widespread metastatic disease, nor the greatest threat to patient survival compared with the primary tumor or cachexia [17].

In patients with locally advanced pancreatic cancer, even with progression, treatment should not simply mirror that in metastatic disease. Rather, it should be based on the pattern of progression (locoregional vs. disseminated), prior chemotherapy and/or radiation, and sequence of therapy (as well as performance status and comorbidity). For example, if a patient with locally advanced pancreatic cancer and a history of only chemotherapy as prior treatment later develops locoregional progression, radiation may be the appropriate modality [8].

Fluoropyrimidines and gemcitabine are the most commonly used agents in adjuvant chemoradiotherapy trials of locally advanced pancreatic cancer. These studies suggest that as a radiosensitizer, capecitabine is a well-tolerated regimen with comparable or superior outcomes compared with low-dose gemcitabine [8].

There is a potential role for maintenance capecitabine or gemcitabine-based chemoradiotherapy in improving quality of life for patients with locally advanced pancreatic cancer and stable disease after 12 weeks of induction gemcitabine/capecitabine chemotherapy [8].

In contrast to conventionally fractionated chemoradiotherapy, there is growing interest in using induction chemotherapy for systemic control, followed by a short course of stereotactic body radiotherapy early during treatment with minimum disruption to systemic therapy. This could be particularly beneficial to patients with predominant local symptoms [8].

The ASCO guidelines for patients with locally advanced pancreatic cancer include several strong recommendations related to chemoradiotherapy or stereotactic body radiation therapy [2,8]. Specifically, it states that chemoradiotherapy or stereotactic body radiation therapy may be offered upfront rather than chemotherapy [8]. This approach is recommended for patients with local progression but no metastases, performance status ≤2, and favorable comorbid profile. It should also be offered to patients with response to an initial six months of chemotherapy or with stable disease who develop chemotherapy toxicities that are intolerable or cause a decline in performance status [8]. If patients respond or their disease has at least stabilized after six months of induction chemotherapy, chemoradiotherapy or stereotactic body radiation therapy may be offered as an alternative to continuing chemotherapy alone [8].

For patients with unresectable or locally advanced pancreatic cancer, definitive conventionally fractionated or dose-escalated radiation therapy with chemotherapy is used. For patients without systemic progression after four to six months (or longer) of chemotherapy, ASTRO recommends definitive radiation therapy [12]. The preferred dose is 5,040–5,600 cGy in 175–220 cGy fractions.

Local Ablative Radiation

With surgical resection considered the only potentially curative option but most patients harboring unresectable PDAC tumor, nonoperative local treatment options that can provide a similar benefit are needed. Emerging radiation techniques that address organ motion have enabled curative radiation doses delivered in patients with inoperable disease [121].

In one 2021 report, patients with locally advanced pancreatic cancer were treated with hypofractionated ablative radiation therapy, using respiratory gating, soft tissue image guidance, and other methods to address organ motion and limit the dose to surrounding luminal organs [121]. At baseline, 119 patients with locally advanced pancreatic cancer and median CA19-9 level >167 U/mL received four months of induction chemotherapy, followed by ablative radiation therapy. The median overall survival from diagnosis and ablative radiation therapy were 26.8 and 18.4 months. The 12- and 24-month overall survival following therapy were 74% and 38%, and the 12- and 24-month cumulative incidence of locoregional failure were 17.6% and 32.8% [121]. Postinduction CA19-9 decline was associated with improved locoregional control and survival. Grade 3 upper GI bleeding occurred in 10 patients (8%), with no grade 4 to 5 events. This cohort study of patients with inoperable locally advanced pancreatic cancer found that ablative radiation therapy following multiagent induction therapy was associated with durable locoregional tumor control and favorable survival [121].

METASTATIC DISEASE

Systemic chemotherapy can benefit patients with metastatic PDAC by improving disease-related symptoms and survival compared with best supportive care alone, but patients should understand that chemotherapy is palliative and not curative [80].

First-line chemotherapy in metastatic PDAC is highly consistent in clinical practice guidelines from ASCO, NCCN and ESMO. Treatment selection is based on PDAC mutation status, serum total bilirubin level, ECOG performance status, comorbidity profile, patient preference and a support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services for FOLFIRINOX or mFOLFIRINOX.

The initial chemotherapy selection for germline or somatic HRR gene mutation is a platinum-based chemotherapy regimen. For those with performance status ≤1 and serum bilirubin less than 1.5 times upper limit of normal, FOLFIRINOX or mFOLFIRINOX is preferred. Gemcitabine plus cisplatin can be used and probably has similar benefit. For patients with performance status 2, comorbidity that precludes intensive therapy, or a serum bilirubin more than 1.5 times upper limit of normal despite stenting, FOLFOX is preferred over FOLFIRINOX.

After at least 16 weeks of initial platinum-based chemotherapy without disease progression, chemotherapy should be discontinued and maintenance therapy with olaparib initiated for those with germline BRCA or PALB2 mutation. For advanced PDAC with somatic (i.e., non-germline) BRCA or PALB2 mutation, the benefit of olaparib maintenance therapy is not known and is under investigation.

For patients with an unknown (pending) HRR status, waiting until the germline or somatic mutation status is known is not recommend, given the rapidity of progression in most patients with newly diagnosed metastatic PDAC. These patients should be treated like HRR mutation carriers until results of genetic testing are available [80].

Patients with performance status ≤1, serum bilirubin less than 1.5 times upper limit of normal, and favorable comorbidity, FOLFIRINOX is preferred, with gemcitabine plus nabpaclitaxel a potentially less toxic alternative. Patients with serum bilirubin more than 1.5 times upper limit of normal despite placement of a stent should receive FOLFOX rather than a gemcitabine-containing regimen, because gemcitabine is hepatically metabolized and associated with greater toxicity with hepatic impairment. For patients with performance status 2, favorable/adequate comorbidity, and serum bilirubin level less than 1.5 times upper limit of normal, gemcitabine monotherapy is suggested; gemcitabine/capecitabine is another option.

Highly selected patients with performance status 2 due to heavy tumor burden should be treated with gemcitabine plus nabpaclitaxel, owing to its higher response rate. Dose and schedule adjustments should be made to minimize toxicities. In patients with performance status ≥3 or poorly controlled comorbidity (regardless of histology or BRCA/PALB2 mutation status), systemic chemotherapy should only be offered on an individualized, case-by-case basis; supportive care should be emphasized.

8. PALLIATION AND SYMPTOMATIC MANAGEMENT

At diagnosis, the median survival for patients with locally advanced, unresectable pancreatic cancer is 8 to 12 months; with metastatic disease, this decreases to 3 to 6 months. For patients with locally advanced and metastatic disease, systemic chemotherapy can improve survival. In the best outcomes to date, FOLFIRINOX demonstrated an 11.1-month median survival [122].

Patients receiving chemotherapy often report better overall quality of life, but extended survival with chemotherapy may not reduce symptom burden. Because the pancreas is located in the central abdomen at the root of the mesentery, most patients suffer from a significant symptom burden and frequently require medical attention and hospitalization for symptom management. Typical patients will require numerous interventions targeting pain, anorexia and weight loss, depression and anxiety, biliary obstruction, gastric outlet obstruction, ascites, and venous thromboembolism [122].

All patients with newly diagnosed PDAC should have a full assessment of symptom burden, psychological status, and social supports as early as possible. Regardless of cancer stage and patient prognosis, early introduction to expert palliative and supportive care improves the social, psychological, and physical well-being of patients; decreases the intensity of medical interventions at the end of life; and ultimately improves survival [2].

Palliative care is an interdisciplinary specialty that is focused on preventing and relieving suffering, and supporting the best possible quality of life for patients and their families facing serious illness, such as pancreatic cancer. Palliative care specialist clinicians provide in-depth pain and symptom management, communication regarding goals of care, and coordinated care across settings and over time. Palliative care aims to relieve suffering in all stages of disease and can be provided in tandem with curative or life-prolonging treatments [122].

When initiated early in the disease course, palliative care improves clinical, quality of care, and survival outcomes. Furthermore, multiple studies have shown that palliative care services improve patients' symptoms, allow patients to avoid hospitalization and to remain safely and adequately cared for at home, lead to better patient and family satisfaction, and significantly reduce prolonged grief and post-traumatic stress disorder among bereaved family members. Palliative care also lowers costs and reduces rates of unnecessary hospitalizations, diagnostic and treatment interventions, and nonbeneficial intensive care when patients are near the end of life [122].

VENOUS THROMBOEMBOLISM PROPHYLAXIS

Pancreatic cancer is one of the highest-risk malignancies for venous thromboembolism (VTE), which includes deep venous thrombosis (DVT), pulmonary embolism, and visceral portal or superior mesenteric vein thrombi. The incidence of VTE is four- to seven-fold higher in PDAC. The risk is highest in the first three months after diagnosis; chemotherapy further increases the risk. In PDAC, VTE is strongly associated with higher short- and long-term mortality and high risk of recurrent VTE [122].

All patients should be educated about warning signs and symptoms of VTE. Physical examination of the legs for asymmetric pitting edema, erythema, and warmth is crucial in each office visit, and the threshold to perform a CT angiogram with tachycardia or pleuritic chest pain present should be extremely low [122].

Routine anticoagulation for primary VTE prevention is not indicated in ambulatory outpatients with pancreatic cancer and no other VTE risk factors [122]. In a patient with PDAC and documented VTE (symptomatic or incidentally found), early initiation of anticoagulation is the standard approach, and lifelong therapy should be considered. The decision to continue anticoagulation should be balanced against bleeding risk, cost of therapy, quality of life, life expectancy, and patient preference. Low-molecular-weight heparin or oral rivaroxaban, apixaban, or edoxaban is preferred to vitamin K antagonist or unfractionated heparin for long-term anticoagulation [122].

PERI-PANCREATIC COMPLICATIONS

Bile Duct Obstruction

Endoscopic retrograde stenting is superior to surgical or percutaneous approaches to address bile duct obstruction because of a more favorable adverse event rate. Self-expandable metal stents are preferred over plastic stents in patients with a life expectancy of more than three months in terms of patency duration, less therapeutic failure and need for reintervention, lower cholangitis incidence, and better patient quality of life. Patency rates between covered and uncovered metal stents are not significantly different [16]. Endoscopic ultrasonography-guided biliary drainage is an alternative if endoscopic biliary stent placement is unsuccessful or technically not feasible.

Gastric Outlet Obstruction

In patients with gastric outlet obstruction, endoscopic duodenal stenting allows a quick resumption of oral intake, with a low complication rate and a short recovery period. However, the need for reintervention is higher after duodenal stenting compared with that of palliative surgery. Endoscopic ultrasonography-guided gastrojejunostomy is an effective and safe alternative to surgery [16].

Ascites

Ascites in patients with metastatic PDAC may be due to peritoneal metastases. In patients with locally advanced tumors, ascites may be caused by portal vein thrombus if the tumor compresses the portal vein locally [122].

Patients with malignant ascites from pancreatic cancer can experience abdominal discomfort, nausea, vomiting, and dyspnea from the pressure of the fluid against the anterior abdominal wall and diaphragm. For most patients, survival is short, and the focus is symptom control. Symptom relief from intermittent paracentesis tends to be short-lived, and the procedure must be repeated for symptom relief. If reaccumulation requires more than once-weekly paracentesis, placement of a long-term drainage catheter is an option; complication rates are higher with indwelling catheters. Diuretics such as spironolactone and furosemide decrease the absorption of water and sodium in the kidneys and may provide some symptomatic relief [122].

PAIN CONTROL INTERVENTIONS

Evidence Based Practice Recommendation

The ASCO recommends that patients with metastatic pancreatic cancer should be offered aggressive treatment of the pain and symptoms of the cancer and/or the cancer-directed therapy.

https://ascopubs.org/doi/10.1200/JCO.20.01364

Last Accessed: August 19, 2021

Strength of Recommendation/Level of Evidence: Strong/intermediate

Pancreatic cancer is one of the most painful malignancies [85]. All patients with locally advanced and metastatic pancreatic cancer should be offered aggressive treatment of pain [8]. Adequate control of pain may be unsatisfactory due to significant variation in local practice [123].

Pain is often the major presenting symptom of the disease and can be a significant feature of advanced pancreatic cancer. Patients describe a gnawing mid-epigastric pain, which radiates bilaterally under the ribs and into the mid-back, owing to the proximity of pancreatic tumors to the celiac plexus. All patients should have the level of pain and degree of pain relief from analgesics addressed at every visit [122].

Pharmacotherapy

The mainstay of pain management is opioid therapy, and palliation of pain can often be successfully achieved by opioid analgesics alone [122]. Patients with moderate-to-severe pain should receive doses adequate to provide relief. Concern about addiction should not be a barrier to effective pain control; even with dose escalation, addiction is seldom a problem in patients with PDAC and the risk is lower than generally assumed in non-malignant pain [81,123]. Given the ongoing concerns regarding opioid misuse in the United States, drug diversion may be a consideration.

For patients with persistent nausea and vomiting for whom taking oral medications is difficult, pain control may be achieved using transdermal patches when adipose tissue is sufficient for transdermal absorption [122]. When pain is constant rather than intermittent, long-acting oral (e.g., morphine, oxycodone, oxymorphone) or transdermal (e.g., fentanyl, buprenorphine) preparations may work better [81]. Breakthrough pain can be treated with rapid-onset transmucosal or intranasal fentanyl formulations. Methadone may be advantageous in many patients and can be used in small doses as add-on to existing opioid treatment. Methadone should only by prescribed by clinicians who are familiar with the complex pharmacology and adverse effect profile of this opioid [123].

Laxatives should be considered for all patients on opioid analgesia for PDAC pain, because constipation is a nearly universal side effect. There is considerable individual variation in both efficacy and side effects. Not all patients benefit from or tolerate opioids. A trial of an alternative opioid may also be indicated. Cases of poor pain control or intolerable pain may benefit from continuous opioid infusion via epidural or intrathecal catheters [81,123]. Adjunctive treatments, such as cannabinoids, ketamine, clonidine, benzodiazepines, anti-psychotics, gabapentin, pregabalin, nortriptyline, or duloxetine, warrant consideration [122].

Near the end of life, pain management for advanced and terminal PDAC can become very challenging, and an interdisciplinary approach including palliative care specialists is needed. It is important wherever possible to consider the preferences of the patient. A range of supportive care measures can be offered, including intensive home support, home care with parenteral opioids, patient-controlled analgesia, and palliative sedation [123].

Celiac plexus neurolysis offers medium-term relief, but other procedures (e.g., splanchnicectomy) are also available. Adjunctive treatments for pain, depression, and anxiety as well as radiotherapy, endoscopic therapy, and neuromodulation may be required. Palliative chemotherapy may provide pain relief as a collateral benefit [123].

Celiac Plexus Neurolysis

Neurolytic procedures reduce pain by destruction of the afferent pathways from the pancreas to the brain. One of the most commonly used procedures is celiac plexus neurolysis.

The celiac plexus is a dense network of nerves that innervates the upper abdominal organs. Pain may be relieved by inhibiting synaptic pathways within the plexus by chemical destruction of the pathways and ganglia using dehydrated alcohol. Celiac plexus neurolysis is performed under endoscopic ultrasonography guidance [122].

Celiac plexus neurolysis improves analgesia and quality of life and decreases opioid requirements. The analgesic effect seems to vanish after eight weeks, and in most patients, pain recurs after three months. Repeated celiac plexus neurolysis benefits about 30% of patients and is normally not offered [123].

Splanchnic Nerve Neurolysis

Splanchnicectomy may disrupt more nerve pathways than celiac plexus neurolysis and is a better option when there is a large mass in the region of the celiac plexus. Splanchnicectomy is seldom performed in patients with PDAC despite some evidence of long-lasting pain relief and few complications in observational series, possibly because the expertise is not widely available [123].

Radiation Therapy

External beam radiation therapy with or without concomitant chemotherapy may also significantly alleviate pain due to local invasion of pancreatic cancer, frequently with improvement in cachexia and obstructive symptoms. However, it may take several weeks to achieve its maximal effect. When pain is caused by liver or bone metastases, patients may benefit from radiation therapy [16,122].

CACHEXIA, WEIGHT LOSS, AND NUTRITIONAL COMPROMISE

Nutritional compromise in PDAC is common, but the underlying pathologies are diverse [2]. Nausea, caused both by the primary disease process and its associated chemotherapy, is most effectively treated with serotonin-3 receptor antagonists and atypical antipsychotics (e.g., olanzapine), with some emerging evidence suggesting efficacy with cannabinoids. Loss of appetite, even in the absence of overt nausea, is frequently reported by patients, and this symptom is driven by central pathways that are largely distinct from those that produce nausea.

Malabsorption secondary to pancreatic exocrine deficiency degrades nutritional status. Pancreatic enzyme-replacement therapy helps to stabilize weight loss and also improves quality of life by decreasing gastrointestinal symptoms. Malabsorption from biliary obstruction is a complication found in up to 90% of patients with PDAC. Similar to the replacement of pancreatic enzymes, the treatment of biliary obstruction improves symptoms beyond its effects on digestion, including anorexia, pruritus, and fatigue.

Collectively, careful attention to the nutritional status of patients with PDAC improves both their survival and quality of life. Early and regular involvement of nutrition experts in their care is recommended [2,124].

Cancer-Related Anorexia/Cachexia Syndrome (CACS)

A constellation of disproportionate loss of lean body mass, weight loss, muscle wasting, adipose tissue reprogramming, and anorexia, cancer-related anorexia/cachexia syndrome (CACS) is more frequent in patients with PDAC than in any other malignancy due to the complex metabolic profile of pancreatic cancer [2]. In a study of 390 patients with advanced cancers, the rate of cachexia was highest in PDAC (89%), followed by gastric cancer (76%) and esophageal cancer (53%) [125].

Unlike simple starvation, which is characterized by a caloric deficiency that can be reversed with appropriate feeding, the weight loss of cachexia cannot be adequately treated with aggressive feeding [126]. The physical impact of CACS contributes to decreased patient quality of life, treatment response, and survival due to gross alterations in protein metabolism, increased oxidative stress, and systemic inflammation. The psychological impact also contributes to decreased quality of life for both patients and their families [125].

In CACS, an abnormally accelerated resting energy expenditure increases muscle protein breakdown and lipolysis, which seems related to activation of cytokines (e.g., tumor necrosis factor-alpha, interleukin 6 and 1 beta), and tumor-derived, potentially cachexia-inducing factors that target skeletal muscle gene products [122,126].

Potentially Beneficial Agents

Cachexia in itself does not respond to nutritional support. There are no FDA-approved medications for treatment of CACS, and positive pharmacotherapy response in patients with anorexia associated with non-malignant disease has been difficult to translate into benefit for patients with cancer [127,128].

Many agents have been evaluated for the treatment of CACS, but only corticosteroids (e.g., dexamethasone) and progesterone analogs (e.g., megestrol acetate) have a proven benefit in the anorexia associated with this syndrome [122]. Selection is based on life expectancy and assessment of risks versus benefits. Dexamethasone is suggested for patients for whom only weeks of therapy are anticipated, while megestrol acetate or medroxyprogesterone acetate (another progesterone analog) are suggested for patients with longer life expectancies [126].

A phase III study randomized 190 patients with advanced cancer and anorexia to megestrol acetate (480 mg/day), dexamethasone (4 mg/day), or placebo for up to four weeks. Differences in primary endpoint (at least 25% improvement in appetite) between megestrol (79.3%), dexamethasone (65.5%), and placebo (58.5%) were non-significant. Hyperglycemia and deep vein thromboses were more frequent with dexamethasone than megestrol or placebo. No other differences from placebo were found [127].

In this trial, the higher rate of deep vein thromboses with dexamethasone was unexpected. Megestrol acetate is associated with thromboembolic events and is contraindicated in patients with VTE. Dexamethasone has the potential to reduce cancer-related fatigue and elevate mood, at the significant cost of accelerating catabolic effects on muscle [127]. The primary benefits associated with these drugs are increased appetite and weight gain, not improved survival, and both drugs are associated with potential harms [122].

Mirtazapine is well-known for promoting weight gain. A placebo-controlled randomized trial found that appetite scores increased similarly with mirtazapine (15 mg at night) and placebo during the 28-day study. Mirtazapine was associated with significantly less increase in depressive symptoms and higher prevalence of somnolence than placebo, but no other differences were found [128].

The evidence of benefit in patients with CACS is inconclusive for androgens and selective androgen receptor modulators, anamorelin, cyproheptadine, long-chain omega-3 fatty acids, vitamins, minerals, and other dietary supplements, nonsteroidal anti-inflammatory drugs (NSAIDs), thalidomide, and combination approaches [126]. However, a trial of low-dose olanzapine (5 mg/day) is reasonable, particularly for patients who have concurrent nausea and/or vomiting unrelated to chemotherapy or radiation therapy [126].

Cannabis and Cannabinoids

In the cannabis plant, delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best-characterized therapeutic constituents. Pharmaceutical cannabinoid products containing THC (dronabinol), a THC analog (nabilone), or THC:CBD in an oromucosal spray (nabiximols, investigational) were examined for efficacy in CACS and palliative care in two meta-analyses [126].

Unfortunately, no benefit beyond placebo was found for pharmaceutical cannabinoid products in CACS, despite their superior weight gain and appetite effects in patients with advanced HIV [129]. Cancer patients with more than 30% decrease in pain with cannabinoids compared with placebo approached significance [129].

In both meta-analyses, available studies of smoked cannabis in CACS did not meet evidence thresholds and were excluded. This limits the ability to inform real-world clinical practice, where patient preference, self-titration to tolerability/effect, access, and other factors favor smoked/vaped cannabis over single-molecule pharmaceutical cannabinoids [130].

Counseling and Support

The substantial loss of body mass can cause significant distress to patients. Although advanced cachexia is irreversible, palliating anorexia in patients with advanced cancer is best approached by focusing on stimulating appetite, supporting each person's food preferences, and avoiding prescriptive dietary advice [127].

Providing education to patients and their caregivers is crucial. The objective is to promote a shared understanding about changed goals of care, and to help reduce the distress caused by reduced oral intake [127].

Family members in particular can require educational intervention, as their distress may manifest in attempts to pressure or coerce the patient into increased feeding. Key points to discuss with patients and their family members, related to interactions about nutrition and eating near the end of life, include the following [131]:

- Loss of appetite is common in patients with advanced cancer and may be the result of the cancer process itself.

- Trying to force a patient to eat is usually counterproductive, potentially leading to increased nausea/vomiting.

- In most patients with advanced cancer and cachexia, providing additional calories by feeding tubes and/or intravenously does not improve outcomes.

- Trying to make a patient eat, when they have marked appetite loss, can lead to decreased social interactions and increased patient distress regarding interactions with caregivers (including stories of patients, in their dying days, pretending to be asleep when relatives visit, so that the relatives do not try to make them eat something).

Caregivers should be advised that it may be best to listen to and support the patient in a variety of other ways (such as giving the patient a massage or applying a lip moisturizer) instead of trying to talk them into eating more. Referral to a registered dietitian may provide patients and caregivers with additional opportunities to discuss concerns and challenges related to nutrition, appetite, and meal planning.

Diabetes Mellitus in PDAC

The presence of diabetes has been associated with higher mortality in patients with PDAC; corticosteroids can induce or exacerbate diabetes in these patients. For patients with PDAC-related diabetes, nutritional management by an experienced dietitian is essential [16]. Metformin or insulin is used as a first-line therapy. Insulin is often the preferred agent because of its efficacy, flexibility, and safety.

Careful monitoring of plasma glucose levels two hours after meals is widely recommended. The limited literature on this topic recommends maintaining blood glucose levels to avoid hypoglycemia and reduce symptoms of hyperglycemia.

Pancreatic Exocrine Insufficiency and Pancreatic Enzyme Replacement Therapy (PERT)

A contributory factor to extreme weight loss may be pancreatic exocrine insufficiency, which leads to maldigestion, fat malabsorption, and steatorrhea. The main clinical manifestation is weight loss and malnutrition, and nonspecific symptoms such as abdominal cramping, flatulence, and urgency to defecate. Fat malabsorption does not become evident until pancreatic lipase secretion falls below 10% of normal levels [122].

Pancreatic exocrine insufficiency results from loss of pancreatic parenchyma and/or tumor obstruction of the main pancreatic duct, and can occur after surgery or irradiation. The characteristic fatty stools associated with steatorrhea (loose, greasy, foul-smelling) may not be evident because patients tend to limit fat ingestion [122].

Pancreatic exocrine insufficiency is very frequent (>90% with tumors in the pancreatic head), and is associated with higher mortality in patients with unresectable PDAC. Pancreatic enzyme replacement therapy (PERT) improves survival in these patients [16]. Given its high incidence, diagnostic testing is not necessary. Patients suspected of fat malabsorption should be treated empirically with oral PERT [122].

The classical approach to patients with pancreatic exocrine insufficiency was restricting fat intake (<20 gm/day) in an attempt to reduce steatorrhea. However, this further restricts the intake of fat-soluble vitamins, which are already malabsorbed in patients with pancreatic exocrine insufficiency, and is not recommended. Frequent low-volume meals and avoidance of foods that are difficult to digest (e.g., legumes) are generally recommended [122].

Pancreatic exocrine insufficiency is treated with capsules of porcine pancreatic enzymes (pancrelipase). There are a number of commercial products available, and the amount of enzyme per capsule varies [81]. Doses are in United States Pharmacopeia (USP) units or International Units (IU); 90,000 USP is equivalent to 30,000 IU [122]. A healthy pancreas produces about 900,000 USP of lipase in response to a meal. Sufficient fat absorption can be maintained at around 10% of normal capacity; thus, roughly 90,000 USP per meal is needed. Because non-resected patients retain some pancreatic function, a starting dose of 75,000 USP with main meals and 25,000 with snacks should suffice in reducing steatorrhea and preventing weight loss. Enzymes are most effective when taken across the course of a meal. Following Whipple, patients will require 90,000 USP with meals and 45,000 USP with snacks [124].

Acidic gastric pH is normally neutralized by pancreatic bicarbonate secretion, which is absent in many patients with PDAC, especially following Whipple resection. Acid-suppressing therapy with a proton pump inhibitor is often required, as failure to neutralize gastric acid inactivates the enzymes [16,124].

Despite recommendation from expert groups, including the NCCN, evidence suggests PERT is underutilized. This was examined in a large commercially insured U.S. population from 2001–2013. Among patients with PDAC (32,461), 1.9% had diagnostic testing for exocrine insufficiency, 21.9% filled a prescription for PERT, and 5.5% were prescribed an adequate dose (defined as ≥120,000 USP lipase daily) [132].

Testing and appropriate dosing is infrequent and inconsistent in an insured U.S. population. Efforts are needed to educate medical providers on the best practices for managing exocrine pancreatic insufficiency in these patients [132].

9. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

For patients who are not proficient in English, it is important that information regarding all aspects of their care (including diagnostic procedures and treatment options) and palliative care 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.

10. CONCLUSION

PDAC is the most lethal solid malignancy, predicted to become the second leading cause of cancer death in the United States by 2030. The complexity of this aggressive cancer has been vexing to investigators and tragic for patients and their families. Major research efforts over the past 50 years have only marginally improved the five-year survival rate from 6% to 10.8%. The greatest gains—from resection of early-stage tumors—are the least likely to present at diagnosis. There is an urgent need to reduce PDAC incidence through primary and secondary prevention, and mortality by accelerating therapeutic development [133].

Until diagnostic or therapeutics breakthroughs arrive, novel uses of standard treatments (i.e., neoadjuvant therapy) show survival advantages for a greater number of patients. The longest survival reported by a phase III trial was published in 2018—a median 54.4 months in patients who received resection followed by mFOLFIRINOX [113]. Many novel treatments are in phase III trials. Additional approaches to manage morbidities and provide better palliative care are also needed. Cancer anorexia/cachexia is a high-priority area.

It is now clear that even early-stage PDAC is a systemic disease and that new-onset metabolic (e.g., diabetes, anorexia/cachexia, hyperglycemia) and neuropsychiatric (e.g., depression, fatigue) symptoms/syndromes are prodromal rather than comorbid or secondary. This recognition has also called for a re-thinking of pancreatic cancer from a more integrative, multi-system perspective [2].

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113. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379(25):2395-2406.

114. Fromer MW, Hawthorne J, Philips P, et al. An improved staging system for locally advanced pancreatic cancer: a critical need in the multidisciplinary era. Ann Surg Oncol. 2021;[Epub ahead of print].

115. Abrams RA, Winter KA, Safran H, et al. Results of the NRG Oncology/RTOG 0848 adjuvant chemotherapy question: erlotinib+gemcitabine for resected cancer of the pancreatic head: a phase II randomized clinical trial. Am J Clin Oncol. 2020;43(3):173-179.

116. Patel SH, Katz MHG, Ahmad SA. The landmark series: preoperative therapy for pancreatic cancer. Ann Surg Oncol. 2021;28(8):4104-4129.

117. Fong ZV, Ferrone CR. Surgery after response to chemotherapy for locally advanced pancreatic ductal adenocarcinoma: a guide for management. J Natl Compr Canc Netw. 2021;19(4):459-467.

118. Murphy JE, Wo JY, Ryan DP, et al. Total neoadjuvant therapy with FOLFIRINOX in combination with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: a phase 2 clinical trial. JAMA Oncol. 2019;5:1020-1027.

119. van Roessel S, van Veldhuisen E, Klompmaker S, et al. Evaluation of adjuvant chemotherapy in patients with resected pancreatic cancer after neoadjuvant FOLFIRINOX treatment. JAMA Oncol. 2020;6(11):1733-1740.

120. White RR, Murphy JD, Martin RCG. The landmark series: locally advanced pancreatic cancer and ablative therapy options.Ann Surg Oncol. 2021;28(8):4173-4180.

121. Reyngold M, O'Reilly EM, Varghese AM, et al. Association of ablative radiation therapy with survival among patients with inoperable pancreatic cancer. JAMA Oncol. 2021;7(5):735-738.

122. Fernandez-del Castillo C, Jimenez RE, Murphy JE. Supportive Care of the Patient with Locally Advanced or Metastatic Exocrine Pancreatic Cancer. Available at https://www.uptodate.com/contents/supportive-care-of-the-patient-with-locally-advanced-or-metastatic-exocrine-pancreatic-cancer. Last accessed July 14, 2021.

123. Drewes AM, Campbell CM, Ceyhan GO, et al. Pain in pancreatic ductal adenocarcinoma: a multidisciplinary, international guideline for optimized management. Pancreatology. 2018;18:446-457.

124. Powell-Brett S, Pande R, Roberts KJ. Achieving "marginal gains" to optimise outcomes in resectable pancreatic cancer. Cancers. 2021;13:1669.

125. Society on Sarcopenia, Cachexia and Wasting Disorders. Cachexia. Available at https://society-scwd.org/cachexia. Last accessed August 13, 2021.

126. Loprinzi CL, Jatoi A. Management of Cancer Anorexia/Cachexia. Available at https://www.uptodate.com/contents/management-of-cancer-anorexia-cachexia. Last accessed August 13, 2021.

127. Currow DC, Glare P, Louw S, et al. A randomised, double blind, placebo-controlled trial of megestrol acetate or dexamethasone in treating symptomatic anorexia in people with advanced cancer. Sci Rep. 2021;11(1):2421.

128. Hunter CN, Abdel-Aal HH, Elsherief WA, et al. Mirtazapine in cancer-associated anorexia and cachexia: a double-blind placebo-controlled randomized trial. J Pain Symptom Manage. 2021:3924(21):00369.

129. Mücke M, Weier M, Carter C, et al. Systematic review and meta-analysis of cannabinoids in palliative medicine. J Cachexia Sarcopenia Muscle. 2018;9(2):220-234.

130. Bonn-Miller MO, Sisley S, Riggs P, et al. The short-term impact of 3 smoked cannabis preparations versus placebo on PTSD symptoms: a randomized cross-over clinical trial. PLoS ONE. 2021;16(3):e0246990.

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Evidence-Based Practice Recommendations Citations

1. Khorana AA, McKernin SE, Berlin J, et al. Potentially curable pancreatic adenocarcinoma: ASCO clinical practice guideline update.J Clin Oncol. 2019;37(23):2082-2088. Available at https://ascopubs.org/doi/10.1200/JCO.19.00946. Last accessed August 19, 2021.

2. Palta M, Godfrey D, Goodman KA, et al. Radiation therapy for pancreatic cancer: an ASTRO clinical practice guideline. Pract Radiat Oncol. 2019;9(5):322-332. Available at https://www.practicalradonc.org/cms/10.1016/j.prro.2019.06.016/attachment/0e8abbe7-fcc6-4c5d-8b46-e81e636ce080/mmc1.pdf. Last accessed August 19, 2021.

3. Sohal DPS, Kennedy EB, Cinar P, et al. Metastatic pancreatic cancer: ASCO guideline update. J Clin Oncol. 2020;38(27):3217-3230. Available at https://ascopubs.org/doi/10.1200/JCO.20.01364. Last accessed August 19, 2021.

96963 • Opioid Use Disorder

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2021 NetCE, All rights reserved.

Morphine and heroin were first synthesized and used medicinally in the nineteenth century, and recreational and illicit use followed. Historically, heroin dependence has been difficult to treat successfully, with poor outcome being attributed to patient characteristics, environmental factors, and the powerful reinforcing effects of the drug. Agonist-replacement therapy was introduced 40 years ago and represented a breakthrough in the management of heroin addiction. Advances in treatment have included newer pharmacotherapies, psychosocial therapy, and the growth and accessibility of 12-step programs such as Narcotics Anonymous. This course will provide the most pertinent, up-to-date information regarding the characteristics of the patients with opioid use disorder; the mechanism of opioid action and the neurobiology of opioid addiction; the epidemiology, diagnosis and risk factors of opioid abuse and dependence; and pharmacologic, psychosocial, 12-step/self-help, and alternative therapies that are effective in treating opioid use disorders. Additionally, the demographics, characteristics, comorbidity and treatment of synthetic and prescription opioid use disorder will be addressed.

Table of Contents

96963 • Opioid Use Disorder

Course Overview

Audience

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. DEFINITIONS

3. BACKGROUND

4. EPIDEMIOLOGY OF OPIOID USE DISORDER

DEMOGRAPHICS OF ILLICIT OPIOID USERS

GEOGRAPHIC PATTERNS OF MISUSE

RISK FACTORS FOR OPIOID USE DISORDER

EPIDEMIOLOGY OF OVERDOSE

5. CLASSIFICATION

6. OPIOID SYNTHESIS

7. PHARMACOLOGY

ENDOGENOUS OPIOID PEPTIDES

OPIOID RECEPTORS

ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION

8. CLINICAL EFFECTS

ANALGESIA

EFFECT ON MOOD AND REWARD

NEUROENDOCRINE SYSTEM

RESPIRATION

GASTROINTESTINAL TRACT

CARDIOVASCULAR SYSTEM

OTHER EFFECTS

9. SPECIFIC OPIOID DRUGS

FULL AGONISTS

MIXED AGONISTS/ANTAGONISTS

OPIOID ANTAGONISTS

10. NATURAL HISTORY OF OPIOID DEPENDENCE

INITIATION

CONTINUATION

DETOXIFICATION AND WITHDRAWAL

RELAPSE FOLLOWING SUSTAINED ABSENCE

11. PATHOPHYSIOLOGY

OPIOID TOLERANCE

OPIOID DEPENDENCE

12. EFFECTS OF OPIOID USE DISORDER

INFECTIOUS DISEASE

ENDOCRINE/METABOLIC EFFECTS

NEUROCOGNITIVE EFFECTS

13. OPIOID OVERDOSE

RISK FACTORS

SYMPTOMS

14. OPIOID WITHDRAWAL

ACUTE OPIOID WITHDRAWAL

PROTRACTED WITHDRAWAL

PERSISTENT NEUROADAPTATION AND RELAPSE VULNERABILITY

15. LIABILITY OF MISUSE OF LEGITIMATELY PRESCRIBED OPIOID DRUGS

DEVELOPMENT OF DEPENDENCE

16. MANAGEMENT OF OPIOID USE DISORDER

CRISIS INTERVENTION

HARM REDUCTION

DETOXIFICATION AND WITHDRAWAL

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

ACUPUNCTURE

INTERVENTIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

17. MANAGEMENT OF COMORBID PSYCHOPATHOLOGY

ASSESSMENT

TREATMENT APPROACH

TREATING POLYSUBSTANCE ABUSE/DEPENDENCE

18. OPIOID USE DURING PREGNANCY

HEROIN

METHADONE

BUPRENORPHINE

OXYCODONE

NALTREXONE

19. PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

20. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

96963 • Opioid Use Disorder

Education Category. Psychiatric / Mental Health

Release Date. 04/01/2021

Expiration Date. 03/31/2024

Course Overview

Morphine and heroin were first synthesized and used medicinally in the nineteenth century, and recreational and illicit use followed. Historically, heroin dependence has been difficult to treat successfully, with poor outcome being attributed to patient characteristics, environmental factors, and the powerful reinforcing effects of the drug. Agonist-replacement therapy was introduced 40 years ago and represented a breakthrough in the management of heroin addiction. Advances in treatment have included newer pharmacotherapies, psychosocial therapy, and the growth and accessibility of 12-step programs such as Narcotics Anonymous. This course will provide the most pertinent, up-to-date information regarding the characteristics of the patients with opioid use disorder; the mechanism of opioid action and the neurobiology of opioid addiction; the epidemiology, diagnosis and risk factors of opioid abuse and dependence; and pharmacologic, psychosocial, 12-step/self-help, and alternative therapies that are effective in treating opioid use disorders. Additionally, the demographics, characteristics, comorbidity and treatment of synthetic and prescription opioid use disorder will be addressed.

Audience

This course is designed for medical and mental healthcare providers, including physicians, nurses, pharmacy professionals, social workers, and counselors/therapists who may be involved in identifying or treating opioid use disorder.

Course Objective

Practice guidance for opioid use disorder in primary care has not kept pace with rapid, profound changes in this area, leaving healthcare professionals with outdated and incomplete information to guide the clinical management of opioid use disorder and related morbidity. The purpose of this course is to close this gap to allow healthcare professionals to provide the best, evidence-based care to patients with opioid use disorder.

Learning Objectives

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

1. Define key terms associated with opioid abuse and dependence.

2. Outline the background and epidemiology of opioid use and abuse, including risk factors for misuse and dependence.

3. Describe the pharmacology and clinical effects of opioids.

4. Discuss characteristics of specific opioid drugs and opioid antagonists.

5. Review the natural history, pathophysiology, and effects of opioid abuse and dependence.

6. Identify signs and symptoms of opioid overdose and withdrawal.

7. List the issues associated with the abuse of or dependence on legitimately prescribed opioids.

8. Discuss the role of crisis intervention and harm reduction in the management of opioid abuse and dependence.

9. Identify methods of managing the detoxification and withdrawal associated with cessation of opioid abuse or dependence.

10. Discuss therapies used to maintain extended abstinence from opioids, including agonist replacement and abstinence therapies.

11. Identify common psychologic comorbidities present in opioid-dependent patients and implications for treatment.

12. Outline the effects of opioid use on fetuses and neonates and appropriate interventions for opioid-dependent pregnant women.

13. Identify factors associated with favorable/unfavorable treatment outcome.

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 V. Jurica, MD, MPH

Jane C. Norman, RN, MSN, CNE, PhD

Alice Yick Flanagan, PhD, MSW

James Trent, PhD

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

The purpose of this course is to provide the reader with a current, evidence-based overview of opioid use disorder and its treatment. Topics covered in this review include the history and demographics of illicit and prescription opioid abuse; risk factors, background characteristics, and comorbid conditions of opioid abusers; the pharmacology of opioid drugs; the biologic and behavioral characteristics of opioid dependence; and management of opioid dependence, including treatment of overdose, detoxification and withdrawal, agonist replacement therapy, and drug-free approaches. Additional areas of the course will be devoted to the abuse liability of prescription opioids and the impact of opioids on the fetus.

2. DEFINITIONS

The definitions and terminology used to describe opioids, addiction, and pain vary in meaning to different stakeholders, and while periodically revised, previous iterations circulate. Some terminology perpetuates misinformation or myths. A few widely used updated definitions include [1,2,3,4,5,6]:

- Misuse, nonmedical use: Any use of a drug prescribed to someone else or of one's own prescription departing from the authorized directions.

- Abuse: This term from older DSMs has been largely replaced by misuse. Definition varies widely depending on the context, but generally means a maladaptive pattern of use with the primary intent of achieving euphoria or getting high. The Drug Enforcement Agency (DEA) defines abuse as the use of a schedule II through V drug in a manner or amount inconsistent with the medical or social pattern of a culture. The American Psychiatric Association defines abuse as "a maladaptive pattern of substance use, leading to clinically significant impairment or distress as manifested by one or more behaviorally based criteria."

- Addiction: Defined by the American Society of Addiction Medicine (ASAM) as "a primary chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing the development and manifestations." It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Addiction has been referred to as psychologic dependence, but this terminology is incorrect as persons with addiction have become psychologically dependent on the substance, but not all persons with psychologic dependence develop addiction.

- Dependence: Introduced by the APA to replace the term "addiction," opioid dependence described both psychologic dependence (a symptom of addiction) and physical dependence (a process of neurobiologic adaptation that can manifest as tolerance and withdrawal symptoms reflecting uninterrupted exposure to the opioid independent of addiction). This terminology is largely abandoned as imprecise and obsolete.

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines opioid use disorder as a problematic pattern of opioid use, leading to clinically significant impairment or distress. The diagnosis of OUD is made by meeting two or more criteria in a one-year period [2,7]:

- Opioids taken in larger amounts or over a longer period than was intended

- A persistent desire or unsuccessful efforts to cut down or control use

- Excessive time spent to obtain, use, or recover from using the opioid

- Craving, an intense urge to use

- Opioid use interferes with obligations

- Continued use despite life disruption

- Reduction or elimination of important activities due to use

- Recurrent use in physically hazardous situations

- Continued use despite physical or psychologic problems

- Tolerance

- Need for increased doses of the opioid for the desired effect

- A markedly diminished effect with continued use of the same amount

- Withdrawal

Note: The criteria for tolerance and withdrawal are not considered to be met for those taking opioids solely under appropriate medical supervision.

In summary, the term dependence is used to describe two separate phenomena. Pharmacologically, drug dependence is characterized by the presence of tolerance and a withdrawal syndrome. Psychiatrically, drug dependence is characterized by compulsive use, inability to reduce use, preoccupation, drug-seeking behaviors, and a heightened vulnerability to relapse after abstinence [8]. Despite replacement of "opioid dependence" with opioid use disorder in the DSM-5, use of this term persists, along with conflation of tolerance with opioid addiction and exposure to medically indicated opioid analgesics with opioid dependence with opioid addiction.

Pseudoaddiction describes drug-seeking behaviors iatrogenically produced in pain patients by inadequate pain treatment. This is manifested as preoccupation with and pursuit of opioid medication driven by a desire for pain relief, not the drug's mood-altering effects. Pseudoaddiction develops in three phases. Initially, the patient receives an inadequate level of analgesia, which leads to the patient's escalation of analgesic demands and behavioral changes. This may be exaggerated to convince others of the pain severity and need for more medication, which results in a crisis of mistrust between the patient and the healthcare team. Pseudoaddiction is preventable when the patient's report of pain is accepted as valid [1,3,4,5].

3. BACKGROUND

The first reference to opium is found in the 3rd century BCE. The use of opium was well-understood by Arab physicians, and Arab traders introduced the drug to Asia, where it was utilized primarily for the control of dysentery [9].

The isolation of morphine from opium was achieved in 1806 and was named for Morpheus, the Greek god of dreams [9]. The discovery of other alkaloids in opium followed: codeine in 1832 and papaverine in 1848. By the mid-nineteenth century, pure alkaloids were used in medical practice in place of crude opium preparations [9].

In addition to the highly beneficial therapeutic effects, the toxic side effects and addictive potential of opioids have been known for centuries. These undesired effects have prompted a search for a potent synthetic opioid analgesic free of addictive potential and other complications. However, all synthetic opioids introduced into medical use share the same liabilities of the classical opioids. The search for new opioid therapeutics has resulted in the synthesis of opioid antagonists and compounds with mixed agonist-antagonist properties, such as buprenorphine, which has expanded therapeutic options and provided the basis of expanded knowledge of opioid mechanisms [9].

Nonmedical use of prescription opioids was reported in literature as early as 1880. A report in 1928 documented that injection of opioids contributed to the development of nonmedical use and misuses of prescription opioids. Before 1930, the prevalence of nonmedical opioid injecting in the United States was low. But by the mid-1940s, more than one-half the admissions to the National Institute of Mental Health's Lexington Hospital were for the misuse of prescription opioids [10].

4. EPIDEMIOLOGY OF OPIOID USE DISORDER

As of 2018, the estimated worldwide prevalence of past-year opioid use was 58 million people [11]. In 2018, an estimated 10.3 million people in the United States had misused prescription opioids in the past year, and of those people, 9.9 million reported the non-medical use of prescription opioids while nearly 800,000 reported past-year use of heroin [11]. With only 4.5% of the world's population, the United States annually consumes more than 80% of all opioid supplies, including [12]:

- 99% of all hydrocodone

- 78% of all oxycodone

- 57% of all methadone

- 51% of all hydromorphone

- 43% of all meperidine

- 31.5% of all fentanyl

Substantial regional differences in abuse patterns exist. In the majority of Europe, Africa, and Asia, heroin is the most prevalent illegally consumed opioid. In the Americas and Oceania (Australia and New Zealand), illegally diverted or misused prescription opioids (e.g., codeine, hydrocodone, morphine, hydromorphone, oxycodone, meperidine) are the primary opioids of abuse. However, some African and European nations have reported a surge in prescription opioid abuse in the last decade, and there is growing evidence of the nonmedical use of opioids in India [11,13]. Traditional opium-cultivating countries and their neighbors contain the majority of raw opium users. Although comprising less than 5% of the world population, Americans consume roughly 80% of the global opioid supply [14,15].

The Drug Abuse Warning Network (DAWN) was established in 1972 by the DEA to track and publish data collected from participating states on emergency department (ED) visits resulting from substance misuse or abuse, adverse reactions, drug-related suicide attempts, and substance abuse treatment [16]. By its final year in 2011, DAWN had collected data from metropolitan areas in 37 states, with complete coverage in 13 states. Although their total figures did not capture all 50 states, the population rates were representative and able to be extrapolated to the United States as a whole [16].

Data from the DAWN network indicates that opioid abuse is a growing problem in the United States. In 2011, the overall admission rate for misuse or abuse of opioid analgesics (excluding adverse reactions) was 134.8 per 100,000, an increase of 153% compared with 2004. In the 13 states involved in the DAWN network, the top four opioid analgesics involved in drug-related ED visits for 2011 were various formulations of oxycodone (175,229), hydrocodone (97,183), methadone (75,693), and morphine (38,416). Between 2004 and 2011, ED admissions increased 74% for methadone, 220% for oxycodone, 96% for hydrocodone, and 144% for morphine. Heroin-related ED episodes increased from 213,118 in 2009 to 258,482 in 2011 [17]. There was no meaningful change in ED admission rates involving opioid analgesics between 2009 and 2011 [16]. However, more than 81,000 drug overdose deaths occurred in the United States in the 12 months ending in May 2020, the highest number of overdose deaths ever recorded in a 12-month period, and the rise was mainly attributed to synthetic opioids [18]. From 2013 to 2019, the age-adjusted rate of deaths involving synthetic opioids other than methadone increased 1,040% [23].

Although prescription opioid abuse decreased by approximately 12% between 2010 and 2011, heroin use increased. There were 119,000 total users in 2003, but 281,000 by 2011 and 948,000 by 2016 [19]. In addition, first-time past-year use increased significantly between 2006 (90,000) and 2016 (170,000), with the greatest increases among young adults 18 to 25 years of age [19]. In 2016, an estimated 11.8 million people in the United States 12 years of age or older reported past-year use of heroin and 3.6 million reported past-month use [20]. According to the National Survey on Drug Use and Health, there were 50,000 new heroin users older than 12 years of age in 2019 [20]. Most new users are male and older than 18 years of age. In 2019, an estimated 438,000 persons received treatment for heroin abuse [20]. It is important to note that this survey underestimates heroin use, possibly to a substantial extent, as obtaining accurate statistics on illicit drug use is difficult [20].

According to the Monitoring the Future survey, NIDA's nationwide annual survey of drug use among the nation's 8th-, 10th-, and 12th-graders, heroin use declined slightly from 2017 to 2020 [21]. Lifetime heroin use (at least one use in an individual's lifetime) measured 0.5% among 8th-graders, 0.3% among 10th-graders, and 0.4% among 12th-graders; past-month use measured 0.2% among 8th-graders, 0.1% among 10th-graders, and 0.3% among 12th-graders. The survey also monitors the use of diverted opioids and shows past year oxycodone use rates at 0.9%, 1.0%, and 2.4%, respectively [21].

Nonmedical use of prescription opioids has caused increasing concern among law enforcement officials and regulatory, pain relief advocacy, and drug abuse organizations [22]. Between 1992 and 2003, the U.S. population increased 14%, while persons abusing opioid analgesics increased 94% and first-time nonmedical opioid analgesic users 12 to 17 years of age increased 542% [12]. The prevalence of past-year nonmedical oxycodone use decreased from 9.6% in 2018 to 8.9% in 2019 [20]. During 2019 in the United States, an estimated 9.7 million (3.5%) individuals misused prescription pain relievers; 1.6 million (0.6%) initiated misuse of prescription pain relievers; and almost 1.4 million (0.5%) had a substance use disorder involving prescription pain relievers [20]. ED visits involving acute harm from prescription opioids were estimated to be 267,020 in 2017 [25].

Among high school seniors, 1.2% used hydrocodone/acetaminophen (Vicodin) nonmedically in 2020, while rates were 0.5% and 0.9% among 8th- and 10th-graders, respectively [21]. More than 40 million prescriptions were written for acetaminophen/hydrocodone in 2020, making it the twelfth most prescribed drug in the United States [26]. At least 24 million Americans have ever used a hydrocodone product illicitly. In 2014, the DEA reclassified hydrocodone-containing products from Schedule III to Schedule II of the Controlled Substances Act. Following the rescheduling, prescriptions dropped from 120 million in 2014 to 93.5 million in 2015 [27,28].

Some studies estimate that as many as 20% of individuals in the United States have used a prescription opioid for nonmedical purposes at least once during their lifetime [29,30]. In 2018, 9.2 million young adults had used an prescription pain reliever for nonmedical purposes in the past year. This number dropped to 9.1 million in 2019 [20]. The greatest misuse was among individuals 18 to 25 years of age, and the incidence was higher in women than men of all age groups, except among those 12 to 17 years of age where the rates were similar [20]. Among persons 12 years of age or older, treatment admissions for prescribed opioid abuse have more than doubled between 2000 and 2010. In 2018, 735,000 people received past-year substance use treatment for prescription pain relievers. This number decreased slightly to 731,000 in 2019 [20].

The number of new nonmedical users of the four major classes of prescription-type drugs (pain relievers, tranquilizers, stimulants, and sedatives) increased between 1991 and 2019; the largest increase occurred with pain relievers. In 1990, there were 628,000 initiates compared with 1.6 million in 2019 [20]. As of 2019, it is conservatively estimated that 1.3 million individuals have a substance use disorder related to prescription pain medication [20]. The number of primary treatment admissions for pain medication use disorder was 731,000 in 2019 [20].

In 2019, 1.6 million individuals reported using prescription pain relievers nonmedically for the first time within the last year—nearly 4,400 per day [20]. Approximately 82.5 million individuals 12 years of age or older were past-year users of prescription pain relievers in 2019 [20].

DEMOGRAPHICS OF ILLICIT OPIOID USERS

Male-to-female ratios for lifetime heroin-only users and lifetime heroin and oxycodone users show that use is higher for men than for women [20]. However, within the 65 or older age group, the proportion of female admissions reporting primary abuse of oxycodone was nearly three times that of men (7.2% vs. 2.8%) [31]. Male opioid users are more likely to also use other illicit drugs; female opioid users are more likely to also abuse other prescription drugs [32]. There is a high incidence of mood/anxiety disorders among opioid users, and this incidence is significantly greater among women than men.

In 2019, the percentages of past-year nonmedical use of pain relievers among the predominant racial and ethnic groups were [20]:

- White: 3.7%

- Hispanic or Latino: 3.7%

- Native Hawaiian or Pacific Islander: 2.1%

- American Indian/Alaska Native: 5.0%

- Black or African American: 3.2%

- Asian: 1.6%

Lifetime oxycodone-only users and lifetime heroin and oxycodone users are similarly distributed racially and ethnically, with both groups being predominantly white (66.9% and 67.8%, respectively) [20]. A small percentage of these users are black or African American, and an even smaller proportion are other minority races/ethnicities.

Past-year heroin-only users and past-year heroin and oxycodone users are predominantly 18 to 34 years of age (7% and 7.3%, respectively) [20]. Past year oxycodone-only users are more likely to be 26 years of age or older (11.2%) [20]. As of 2019, individuals 18 to 34 years of age have the highest percentage of past year (5.2%) and past month (1.2%) illicit pain medication use [20].

The increase in opioid analgesic abuse is particularly troubling because respiratory depression and death can result from the doses at which these agents are frequently abused, especially when mixed with other central nervous system depressants [33]. The two populations for whom prescription opioid abuse is especially problematic are adolescents, due to the uncertain implication of future dependence, and the elderly, due to the increased vulnerability to toxicity. Early exposure to opioids in adolescent users may cause neurobiologic changes and behavioral consequences that differ from adults [33].

GEOGRAPHIC PATTERNS OF MISUSE

Nonmedical use of opioid analgesics has been observed in both rural and urban areas. Small metro (4.0%), large metro (3.4%), and urbanized nonmetro (3.4%) areas have the highest percentage of past-year illicit pain medication users; however, less urbanized (2.8%) and completely rural areas (2.9%) have significant rates as well [20]. Research data also suggest a problem with injecting among rural opioid users, a problem more typically associated with urban drug users [10]. The West (4.0%) and Midwest (3.6%) areas have the highest percentage of past-year users, followed by the South (3.5%) and Northeast (2.8%) [20].

RISK FACTORS FOR OPIOID USE DISORDER

Persons at heightened risk for heroin experimentation include those who abuse alcohol or marijuana, those with first-degree relatives addicted to alcohol or other drugs, and those with friends and associates addicted to heroin or at high risk of heroin experimentation [8]. Of course, not all persons who use drugs regarded as having a high liability of misuse end up becoming addicted to the drug. Among persons who try heroin, an estimated 23% develop heroin dependence, a rate comparable to cocaine but greater than marijuana [34].

The expected drug effect and the setting of use (context of administration) play important roles in the social learning of drug use. Because opioids, like other drugs that increase dopamine turnover, lead to conditional responses, the use of opioids may become conditioned to the activities of daily living. As a result, environmental stimuli become powerfully associated with opioid use, which can trigger cravings for the drug [33]. The visibility of pharmaceutical marketing and advertising of medications may also play a role by changing the attitudes toward ingestion of these agents [33]. For youth, a social learning aspect to drug use is likely, based on the modeling of drug use by adults in their families and social networks [33].

Individuals who use nonmedical prescription opioids before 13 years of age are more likely to become addicts than those who initiate use at 21 years of age or older. The odds of becoming an addict are reduced 5% each year after 13 years of age [35]. Additionally, it is a commonly held view among adolescents (27%) that prescription drugs are "much safer" than street drugs [36]. This belief is undoubtedly shared with much of the adult population and has led to the extraordinary rise in recreational prescription drug users.

Evidence Based Practice Recommendation

The Institute for Clinical Systems Improvement recommends considering screening patients for substance use disorders when there is an unclear etiology of pain.

https://www.icsi.org/wp-content/uploads/2019/10/Pain-Interactive-7th-V2-Ed-8.17.pdf

Last Accessed: March 30, 2021

Level of Evidence: Expert Opinion/Consensus Statement

Marked increases in prescriptions written for opioids in the United States and Internet access to prescription drugs may explain a portion of the increase in opioid use disorder. However, although Internet access is a major problem and accounts for some of the increase in opioid drug abuse, the same rate of increase has not been observed for other prescription drugs, such as stimulants, suggesting that other factors are involved [33]. Changes in the way medicine is practiced also influence prescription practices. Primary care physicians provide a greater proportion of care for pain patients rather than pain specialists, increasing the potential of diversion and misuse [33].

The increase in emergency department mentions is not solely accounted for by an increase in prescriptions; for example, from 1994–2002, fentanyl mentions increased more than 50-fold while the number of prescriptions increased only 7.2-fold. This is now clearly known to be the result of increases in illicitly manufactured formulations. Similar excessive increases in emergency department mentions relative to prescriptions have been observed with oxycodone but not morphine or hydrocodone [33].

Risk Factors for Prescription Opioid Abuse Among Pain Patients

Long-term use of prescription opioids for chronic pain results in abuse or dependence in 2.8% to 18.9% of patients [33]. Predictors of dependence on opioid medications among pain patients include substance abuse-related diagnoses, positive toxicology for opioids, and other medical diagnoses, including diagnosis of comorbid psychiatric conditions [37]. Other patients at risk include those with idiopathic pain (no clear etiology) or high levels of psychologic distress or disability [7]. Alcoholism and other drug dependence are often viewed as contraindications for opioid medications in chronic noncancer pain.

EPIDEMIOLOGY OF OVERDOSE

Overdose is a major cause of premature death among opioid drug users. Nonfatal overdoses (defined as instances in which loss of consciousness and respiratory depression occur but are not fatal) are highly prevalent among heroin users, occurring in 50% to 70% of this population [38]. As noted, the Centers for Disease Control and Prevention (CDC) reported the highest overdose rate in the year ending May 2020, primarily driven by rapid increases in overdose deaths involving synthetic opioids excluding methadone [18]. There were approximately 46,000 overdose fatalities attributable to synthetic opioids between May 2019 and May 2020. In 2018, men 25 to 44 years of age had the highest opioid death rate at 39.4 per 100,000, which was a decrease of 0.6% from 2017 [40]. While the overall opioid death rate decreased between 2017 and 2018, the rate increased for synthetic opioids.

Regional differences have been found in fatal drug overdose involving opioids. In 2018, the five states with the highest rates of death per 100,000 population due to overdose were West Virginia (51.5), Delaware (43.8), Maryland (37.2), Pennsylvania (36.1), Ohio (35.9), and New Hampshire (35.8) [41]. Significant increases from 2017 to 2018 were seen in the West. Only five states reported statistically significant increases in drug overdose death rates from 2017 to 2018 [41].

The opioid overdose rate among women has increased faster than it has in men. From 1999 to 2015, overdose fatality increased 471% in women, compared with 218% for men. There has been an alarming increase in the rates of synthetic opioid-related deaths, which increased 850% in women between 1999 and 2015 [42]. In aggregate, women tend to possess background characteristics and opioid analgesic use patterns that may contribute to overdose vulnerability. Women are more likely to experience chronic pain, receive prescriptions for opioid analgesics, receive higher doses of opioids, and use opioids for longer periods than men. Substance use disorders involving opioid analgesics are thought to develop more rapidly in women, and women may be more likely to obtain opioid prescriptions from multiple prescribers than men [39].

Risk Factors for Heroin/Opioid Overdose

Identified risk factors for fatal heroin overdose include male gender, single status, unemployment, history of heroin dependence, no current treatment for heroin dependence, intravenous (IV) use, and concomitant use of alcohol or benzodiazepines. An unexplained and consistent finding is that victims of fatal heroin overdose are generally older, experienced users. Also, at autopsy, a large proportion of overdose fatalities have relatively low blood morphine concentrations [38]. (Heroin is rapidly metabolized into morphine once administered.) Demographic patterns among overdose fatalities suggest that polydrug use and loss of tolerance are key factors, which partially explains low blood opioid concentrations. However, this does not explain the strong association of fatal overdose with age [38].

Risk factors for prescription opioid overdose are similar to those for heroin overdose, but also include obtaining overlapping prescriptions from multiple providers/pharmacies, taking high daily doses of prescription pain relievers, self-medication, polypharmacy, living in a rural area, and mental illness [43]. Most people who abuse prescription opioids get them free from a friend or relative. However, those at highest risk of overdose (i.e., those who use the drugs nonmedically 200 or more days per year) obtain them differently. Twenty-seven percent of those at highest risk of overdose obtain opioids using their own prescriptions; 26% obtain them from friends or relatives for free; 23% purchase the drugs from friends or relatives; and 15% purchase them from a drug dealer. Individuals at highest risk of overdose are four times more likely than the average user to buy the drugs from a dealer or other stranger [44].

Risk Factors for Methadone Overdose

Historically, methadone was used primarily as pharmacotherapy for heroin addiction. During the 1990s, however, methadone gained increased acceptance for use as an analgesic, and methadone began to be prescribed to outpatients with moderate-to-severe noncancer pain. Prescribing rates soared over the next decade; comparison of methadone sales quantity between 1997 and 2007 shows an increase of 1,293% [45,46]. This rising use of methadone occurred simultaneously with concerns over the abuse potential of other opioids and the search for a relatively inexpensive long-acting opioid analgesic alternative [47,48].

Since the mid-2000s, methadone has become disproportionately represented in cases of opioid analgesic fatality. Based on data showing that 70% of fatalities among those prescribed methadone occurred in the first seven days of treatment, the FDA changed the methadone labeling in 2006 to lengthen dosing intervals from every 3 to 4 hours to every 8 to 12 hours; the initial recommended dose of 2.5–10 mg was unchanged [49]. In 2008, use of the highest oral dose (40 mg) preparations was prohibited from use in pain treatment and restricted to addiction therapy [50].

In addition to the general risk factors for opioid overdose, specific factors that contribute to methadone fatality include [50]:

- Payer policies that encourage or mandate methadone as first-line therapy

- Methadone prescribing in opioid-naïve patients

- Lack of prescriber knowledge of methadone pharmacology

5. CLASSIFICATION

Opioid broadly refers to all compounds related to opium. The term opium is derived from opos, the Greek word for "juice," as the drug is derived from the latex sap of the opium poppy Papaver somniferum. Drugs derived from opium, including the natural products morphine, codeine, and thebaine, may be referred to as opiates [9]. However, for the purposes of simplification, all compounds will be referred to as opioids throughout this course.

The narcotic analgesics can be categorized into three groups. The first group includes the natural opium derivatives (heroin, morphine, and codeine) and the semisynthetic derivatives from this group, including hydromorphone, oxymorphone, hydrocodone, oxycodone, dihydrocodeine, and buprenorphine. The two other groups are synthetic chemicals: the phenylpiperidines, including meperidine and fentanyl, and the pseudo-piperidines, including methadone and propoxyphene [51].

6. OPIOID SYNTHESIS

As noted, opium is obtained from the unripe seed capsules of the poppy plant P. somniferum. The sides of the unripe seed pod are slit, and the milky sap that emerges is dried to make powdered opium. Although raw opium contains numerous alkaloids, only a few, such as morphine, codeine, thebaine, and papaverine, have clinical utility. Because morphine synthesis is difficult, the drug is still primarily obtained from opium or extracted from poppy straw [9].

Heroin, or diacetylmorphine, is synthesized by collecting and converting powdered opium to heroin hydrochloride in clandestine laboratories [8]. Impurities in the processing, particularly in heroin from Mexico, result in some street heroin being brown in color. This type of heroin, often referred to as "black tar," is the predominant type available in the western United States. The purity of Colombian and Mexican heroin powder averages 40% to 60% [8]. From the point of entry in the United States to the consumer, heroin hydrochloride is adulterated by the addition of quinine, lactose, mannitol, dextrose, or talc at each level of distribution, to the point that bags costing $10 ("dime bags") may contain only 6% heroin hydrochloride [8].

The numerous synthetic derivatives of morphine and thebaine are made by relatively simple modifications of the molecule. Examples of this include the transformation of morphine to diacetylmorphine by acetylation at the 3 and 6 positions. The main goals of opioid structural modification are to increase the affinity for various species of opioid receptors, alter the activity of the drug from agonist to antagonist, change the lipid solubility, and alter the resistance to metabolic breakdown [9].

7. PHARMACOLOGY

Opioids have been the mainstay of pain treatment for thousands of years, exerting their effects by mimicking naturally occurring endogenous opioid peptides or endorphins [9]. Although many new opioids have been developed with pharmacologic properties similar to morphine, morphine remains the standard against which new analgesics are measured [9].

ENDOGENOUS OPIOID PEPTIDES

The endogenous opioid system is complex and subtle, with diverse functions. The system plays a sensory role, which is prominent in inhibiting response to painful stimuli; a modulatory role in gastrointestinal, endocrine, and autonomic functions; an emotional role evidenced by the powerful rewarding and addicting properties of opioids; and a cognitive role involving modulation of learning and memory [9].

There are three distinct families of classical opioid peptides: enkephalins, endorphins, and dynorphins. Each of these families is derived from a distinct precursor protein and has a characteristic anatomical distribution. The precursor proteins, preproenkephalin, prepro-opiomelanocortin (POMC), and preprodynorphin are encoded by three corresponding genes. The primary opioid peptide derived from POMC is beta-endorphin. The POMC precursor is also processed into the non-opioid peptides adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (alpha-MSH), and beta-lipotropin (beta-LPH), suggesting a common precursor for the stress hormone ACTH and the opioid peptide beta-endorphin. This association indicates a shared physiologic linkage between the stress axis and opioid systems, which has been validated by the observation of stress-induced analgesia [9].

OPIOID RECEPTORS

Opioids produce their effects through activity at three major receptor subtypes: mu, kappa, and delta. These G-protein-coupled receptors are linked to adenylate cyclase. The endogenous ligands for these receptors, beta-endorphin, enkephalin, and dynorphin, are expressed heterogeneously throughout the central and peripheral nervous systems, with a distribution pattern parallel with that of opioid receptors. Opioid receptors are also found in the central respiratory centers. Functional studies have revealed substantial parallels between mu and delta receptors and dramatic contrasts between mu/delta and kappa receptors [52].

Most opioid therapeutics, and all opioids with abuse potential, are selective for mu receptors, reflecting their similarity to morphine. However, drugs that are relatively selective at standard doses can interact with additional receptor subtypes at higher doses, resulting in divergent pharmacologic profiles [9]. A large number of endogenous ligands activate a small number of opioid receptors, a pattern strikingly different from most other neurotransmitter systems, in which a single ligand interacts with a large number of receptors that have different structures and second messengers [9].

ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION

Typically, opioids are readily absorbed from the gastrointestinal tract. The more lipophilic opioids are easily absorbed through the nasal or buccal mucosa. The most lipophilic opioids can be absorbed transdermally [9]. Most opioids, including morphine, undergo variable but significant hepatic first-pass metabolism, limiting oral bioavailability relative to parenteral administration. Most opioids act quickly when given intravenously. Compared with more lipid-soluble opioids, such as codeine, heroin, and methadone, morphine crosses the blood-brain barrier at a considerably lower rate [9].

8. CLINICAL EFFECTS

Morphine and most other opioid agonists share in common the following physiologic effects [9]:

- Analgesia

- Changes in mood and reward behavior

- Disruption of neuroendocrine function

- Alteration of respiration

- Changes in gastrointestinal and cardiovascular function

ANALGESIA

Morphine-like drugs produce analgesia, drowsiness, changes in mood, and mental clouding, all without loss of consciousness. Patients in pain report that the pain is less intense, less discomforting, or entirely gone when given therapeutic doses of these drugs. The pain relief is fairly selective, and other sensory modalities are not affected. Some patients experience euphoria. When morphine in the same dose is given to a pain-free individual, the experience may be unpleasant. Nausea and vomiting is common, and drowsiness, difficulty in mentation, apathy, and decreased physical activity may occur. The subjective analgesic and toxic effects, including respiratory depression, become more pronounced as the dose is increased. Morphine-class drugs seldom cause slurred speech, emotional lability, or significant motor incoordination [9].

EFFECT ON MOOD AND REWARD

Although the mechanisms by which opioids induce euphoria, tranquility, and other alterations of mood (including rewarding properties) have not been entirely determined, the neural systems mediating opioid reinforcement are distinct from those involved in physical dependence and analgesia [53]. Behavioral and pharmacologic data point to the probable role of dopaminergic pathways, with interactions between opioids and dopamine mediating the opioid-induced reinforcement [9].

NEUROENDOCRINE SYSTEM

Morphine acts in the hypothalamus to inhibit the release of gonadotropin-releasing hormone and corticotropin-releasing hormone (CRH), which decrease circulating luteinizing hormone (LH), follicle-stimulating hormone (FSH), ACTH, and beta-endorphin. This in turn reduces the plasma concentrations of testosterone and cortisol [9].

RESPIRATION

Morphine-like opioids depress respiration in part through a direct effect on the brainstem respiratory centers. Therapeutic doses of morphine depress all phases of respiratory activity and possibly induce irregular and periodic breathing. Clinically significant respiratory depression seldom occurs at standard therapeutic doses. The primary mechanism of respiratory depression involves a diminished responsiveness of the brainstem respiratory centers to carbon dioxide [9].

GASTROINTESTINAL TRACT

Morphine-like drugs directly stimulate the chemoreceptor trigger zone for emesis in the area postrema of the medulla, resulting in the nausea and vomiting experienced by some patients [9]. Morphine also decreases gastric motility; diminishes biliary, pancreatic, and intestinal secretions; and delays digestion of food in the small intestine. In the colon, peristaltic waves are diminished or abolished and tone is increased to the point of spasm, delaying the passage of bowel contents [9].

CARDIOVASCULAR SYSTEM

There are no opioid receptors on the heart, so morphine does not act directly on the heart muscle. However, opioid agonists indirectly affect cardiovascular processes through suppression of reflex vasoconstriction, which may result in bradycardia and hypotension [54]. In cases of injecting use, bacterial endocarditis can develop [54].

OTHER EFFECTS

Opioid agonists may also affect reflexes, particularly swallow/cough reflexes and pupillary dilation. Morphine and related opioids depress the cough reflex by direct action on the cough center in the medulla [9]. Morphine and most mu and kappa agonists also constrict the pupils through excitation of the parasympathetic nerve stimulating the pupil [9].

9. SPECIFIC OPIOID DRUGS

FULL AGONISTS

Heroin

Heroin, or diacetylmorphine, is a highly potent, semisynthetic analgesic produced by the anhydrous acetylation of morphine. Heroin is generally believed to have no significant opioid receptor activity; however, heroin is rapidly metabolized to 6-monoacetylmorphine (6-MAM) and then to morphine. While diacetylmorphine and 6-monoacetylmorphine readily cross the blood-brain barrier, morphine itself is much slower to do so; thus, heroin can be considered a prodrug that facilitates the brain entry of morphine [52]. The drug rapidly enters the brain after IV administration, where it binds to mu, kappa, and other stereospecific opioid-receptor binding sites in the locus coeruleus [8]. The onset of euphorigenic action is approximately 30 minutes after intranasal ingestion, 15 minutes after subcutaneous injection, and almost instantaneously after IV injection, with a duration of about three to four hours [8]. As with many other opioids, heroin reduces the anticipatory anxiety associated with emotional or physical pain and alters the perception of pain [8].

Heroin is rapidly deacetylated in the microsomes of the endoplasmic reticulum in the liver to 6-MAM, which is further deacetylated to morphine. It is excreted in the urine over a 30- to 40-hour period as free morphine and morphine 3-glucuronide [8]. Other drugs, including tricyclic antidepressants (TCAs), can inhibit the metabolism of heroin. Genetic variation in the expression of the enzymes involved in opioid metabolism and the potential for drug interactions at these sites may contribute to variation in response to heroin administration both among various individuals and within one individual [52].

The sought-after effects of heroin include intense tranquility, euphoria, analgesia, and a clouding of the sensorium, with the state of ecstasy and contentment immediately following IV injection being the most desired. Many novice heroin users experience adverse effects, such as mild nausea and vomiting. However, tolerance to these effects is soon achieved [8].

The lifestyle of the heroin addict seriously decreases life expectancy. Age-adjusted mortality rates have been found to be least seven times greater than that of the general population, adjusting for age, with death usually attributable to violence or drug effects. Also, the desire to replicate the most intense rush may compel the heroin addict to escalate the dose, resulting in acute heroin overdoses [8].

Codeine

Codeine is approximately 60% as effective orally versus parenterally as an analgesic and respiratory depressant. Several codeine analogs, such as levorphanol, oxycodone, and methadone, have a high ratio of oral-to-parenteral potency, with the greater oral bioavailability reflecting lower hepatic first-pass metabolism [9].

Approximately 10% of ingested codeine is O-demethylated to morphine. Free and conjugated morphine can be found in the urine after therapeutic doses of codeine. Codeine has an exceptionally low affinity for opioid receptors, and the analgesic effect of codeine is due to its conversion to morphine. However, the antitussive effects of this drug may involve distinct receptors that bind codeine itself. The plasma half-life of codeine is two to four hours [9].

Codeine and promethazine syrup is the active component of the recreational drug "purple drank;" other common names include "syrup" and "lean" [55]. The combination of the purple antitussive, soft drinks, and in some cases candy has been mentioned in hip-hop music since the late 1990s and has been particularly popular in the South [55]. All opioid/soft drink concoctions may colloquially be referred to as "sizzurp."

Tramadol

Tramadol is a synthetic codeine analog and a weak mu-opioid receptor agonist. Tramadol is unusual among opioids in that a portion of its analgesic effect is produced by norepinephrine and serotonin uptake inhibition [9]. Tramadol is as effective as morphine or meperidine in the treatment of mild-to-moderate pain. It is 68% bioavailable following a single oral dose and 100% available following intramuscular administration. The affinity of tramadol for the mu-opioid receptor is only 1/6,000th that of morphine. However, the primary O-demethylated metabolite of tramadol is two to four times as potent as the parent drug and may partially explain the analgesic effect. Physical dependence with tramadol has been reported [9].

Levorphanol

Levorphanol (brand name Levo-Dromoran) is the only commercially available opioid agonist of the morphinan series, and it possesses pharmacologic effects very similar to those of morphine. Levorphanol is metabolized less rapidly than morphine and has a half-life of 12 to 16 hours [9,56].

Meperidine

Meperidine is predominantly a mu-receptor agonist. This agent, available under the brand name Demerol, is no longer recommended for treatment of chronic pain due to concerns of metabolic toxicity. Meperidine should not be used for longer than 48 hours or in doses greater than 600 mg/day [56]. The central nervous system effects are similar but not identical to that of morphine. In equianalgesic doses, meperidine produces comparable sedation, respiratory depression, and euphoria as morphine. Some patients may experience dysphoria. Meperidine can cause central nervous system excitation, characterized by tremors, muscle twitches, and seizures, primarily due to accumulation of the metabolite normeperidine [1]. Large doses repeated at short intervals by addicts who have developed a tolerance to the sedative effects can produce an excitatory syndrome characterized by hallucinations, tremors, muscle twitches, dilated pupils, hyperactive reflexes, and convulsions [9]. Meperidine is primarily abused by healthcare professionals [9].

Diphenoxylate and Loperamide

Diphenoxylate (in combination with atropine as Lomotil) and loperamide (Imodium) are meperidine congeners that are approved by the U.S. Food and Drug Administration (FDA) for the treatment of diarrhea [56]. These drugs slow gastrointestinal motility by affecting the circular and longitudinal muscles of the intestine, presumably through interaction with opioid receptors in the intestine [9].

Fentanyl and Congeners

Fentanyl is a synthetic opioid related to the phenylpiperidines. The actions of fentanyl and its congeners (sufentanil, remifentanil, and alfentanil) are similar to those of other mu-receptor agonists. Fentanyl is a popular drug in anesthesia practice because of its relatively short time to peak analgesic effect, rapid termination of effect after small bolus doses, and relative cardiovascular stability. Fentanyl is approximately 100 times more potent than morphine, and sufentanil is approximately 10 times more potent than fentanyl. These drugs are usually administered intravenously and are substantially more lipophilic than morphine. Time to peak analgesia is rapid, usually within five minutes. Respiratory depression potential is similar to other mu-receptor agonists with a more rapid onset. Fentanyl and sufentanil treatment of chronic pain has become more widespread, and transdermal patches that provide sustained release for 48 hours or more are available [9].

Fentanyl is delivered via the transdermal route for up to 72 hours, with patches containing 2.5, 5, 7.5, or 10 mg of fentanyl. Abuse of both the injectable formulation of fentanyl (Sublimaze) and the transdermal patch is primarily, but not exclusively, a problem among healthcare professionals due to availability and proximity. Fentanyl may be extracted from the patch and injected, or the patch contents may be chewed, ingested, or inhaled. Even a patch that has been used for three days contains sufficient fentanyl to be abused [1].

Methadone

Methadone was first synthesized as an analgesic in Germany during World War II as a response to the difficulty in obtaining raw opium [57]. Methadone is a long-acting mu-receptor agonist with pharmacologic properties quantitatively similar to those of morphine [9]. Methadone is well-absorbed from the gastrointestinal tract and can be detected in plasma within 30 minutes of oral ingestion. Peak concentrations occur in the brain within one or two hours of subcutaneous or intramuscular administration [9]. Oral bioavailability approaches 90% [56,57].

In contrast to heroin, the activity of methadone is due almost exclusively to the parent drug rather than its metabolites. The drug is characterized by a long, but highly variable, half-life. One of the primary elimination pathways of methadone is N-demethylation, with cytochrome P450 3A4 (CYP 3A4) the major enzyme involved [56]. Inhibition of CYP 3A4 with drugs such as ketoconazole and erythromycin may enhance and prolong the effect of methadone. Its induction with drugs such as rifampin, carbamazepine, and phenytoin will have the opposite effect [52,56]. Liver disease can increase the half-life of methadone, but renal failure will not [57]. Additionally, CYP 2D6 may be involved in the metabolism of the active enantiomer of methadone; less than 7% of white persons and more than 25% of Ethiopian persons are ultrarapid metabolizers at CYP 2D6. Individuals with this polymorphism may be more likely to experience methadone overdose [52,58].

Following absorption, methadone is distributed to the brain, liver, kidneys, muscles, and lungs. Tissue binding predominates over binding to plasma proteins, and accumulation of the drug occurs in these tissues with repeated dosing. Plasma concentrations are maintained by this peripheral reservoir. Methadone reabsorption from the tissues may continue for weeks after administration has ceased. It has an elimination half-life of about 22 hours, but metabolism varies in each person [59].

One of the most significant advantages of methadone is that it alleviates cravings for opioids (a primary reason for relapse) and blocks many of the pleasurable effects of heroin, which helps reinforce abstinence [57]. Some of the characteristic properties of methadone are its analgesic activity, its efficacy by the oral route, its extended duration of action in suppressing withdrawal symptoms in physically dependent individuals, and its ability to demonstrate persistent effects with repeated administration [9]. Accidental overdose fatalities can occur when pain patients re-administer methadone when the analgesia wears off and pain returns, potentially elevating plasma concentrations to life-threatening levels. These same pharmacologic properties also imperil those who use it illicitly. Opioid abusers often co-administer benzodiazepines, which greatly elevates lethality risk with methadone. Concurrent use of alcohol poses the same risk [47,48].

In methadone clinics, methadone is usually dispensed in prepared individual doses mixed with fruit juice to discourage IV use. Methadone is also prescribed for pain. Until recently, there had been little evidence that diversion of methadone from pain management was occurring on any substantial scale. The majority of diverted methadone is used by heroin addicts to self-medicate symptoms of opioid withdrawal. To date, there is no evidence that diversion of methadone from methadone clinics has resulted in significant numbers of new opioid addicts [1].

More frequent adverse effects associated with methadone use include sweating, decreased libido, weight gain, constipation, and irregular menstrual periods, all occurring primarily during the initial stabilization process. Uncommon side effects include facial flushing, pruritus, euphoria or dysphoria, insomnia, urinary retention, and bradycardia [56]. Rarely observed side effects include biliary spasm, urticaria, syncope, overdose death, and torsades de pointes [57]. These effects are more common at higher doses and when methadone is combined with certain other drugs [60]. Risk of QTc prolongation and arrhythmia led to a 2006 black box warning [56].

Tolerance to the opioid properties of methadone develops within four weeks. The minimal effective dose is regarded as 40 mg, but some patients require much greater doses [56,57]. Subcutaneous administration of 10-20 mg methadone to former opioid addicts unambiguously produces euphoria similar in duration and magnitude to that of morphine. Methadone's overall abuse potential is comparable to that of morphine [9].

Hydrocodone

Hydrocodone is a semi-synthetic codeine derivative first used clinically as an antitussive and analgesic in the 1920s. Following a 10-mg oral dose, maximum serum level is observed in 1.3 hours [61]. Hydrocodone exhibits a complex pattern of metabolism, including O-demethylation, N-demethylation, and 6-keto reduction to the corresponding 6-a- and 6-b-hydroxymetabolites. The 2D6 enzyme demethylates hydrocodone at the 3-carbon position into hydromorphone, which has much stronger mu binding than hydrocodone. Similar to codeine, it has been proposed that hydrocodone is a prodrug. Its analgesic properties are generally considered equipotent to codeine [63].

Oxycodone

Oxycodone is similar in structure to hydrocodone, with the addition of a hydroxyl group at the 14-carbon. Oxycodone, as a hydrochloride salt, is a pure agonist opioid that has been in clinical use since 1917. Unlike codeine and hydrocodone, oxycodone is a potent analgesic in its own right and not a prodrug, although 2D6 activity creates the active opioid analgesic metabolite oxymorphone (synthesized and marketed as the analgesic Opana). Oxycodone is suitable for oral administration due to high bioavailability (60%) but may also be taken intramuscularly, intravenously, subcutaneously, or rectally; however, oxycodone is only commercially available in oral preparations [56]. In terms of analgesic potency and lipophilicity, oxycodone is comparable to morphine, and both drugs possess similar abuse potential. With the exception of hallucinations, which occur more rarely with oxycodone than with morphine, the side effects of these drugs are highly similar [64].

Oxycodone is metabolized by demethylation to noroxycodone and oxymorphone followed by glucuronidation [56]. A urine screen may reveal oxycodone alone, oxycodone and oxymorphone, or oxymorphone alone [65].

Since 1995, oxycodone has been marketed in the United States as OxyContin, a Schedule II controlled-release oral tablet formulation. Oxycodone is also available in immediate-release tablets in combination with aspirin or acetaminophen under various trade names, including Percodan and Percocet, which contain 2.5–10 mg of oxycodone [56]. The oxycodone content of OxyContin ranges from 10 mg to 80 mg. When taken orally, OxyContin tablets release oxycodone over a 12-hour period. However, when the controlled-release mechanism is destroyed by crushing the tablet, the oxycodone can be snorted, ingested, or injected. It is this delivery of a large amount of the active drug in a relatively brief time period (compared to the intact tablet and the low-dose immediate-release form) that underlies addicts' interest in OxyContin [1].

In 2014, the FDA approved an extended-release version of oxycodone that is formulated to include naloxone in order to deter misuse [66]. If crushed and snorted or crushed, dissolved, and injected, the naloxone will block the euphoric effects of oxycodone, potentially deterring this type of abuse. This combination drug is intended for patients for whom alternative treatment options for chronic pain are ineffective or not tolerated [66]. The drug is no longer available in the United States [56].

Hydromorphone

Hydromorphone is a semi-synthetic hydrogenated ketone of morphine and shares the pharmacologic properties typical of mu-opioid agonists. Hydromorphone is a more potent analgesic than morphine; on a milligram basis, hydromorphone is 5 times as potent orally and 8.5 times as potent intravenously. Hydromorphone can be administered by infusion, intramuscularly, orally, or rectally [67].

Following oral administration of conventional-release hydromorphone, the drug is rapidly absorbed and undergoes hepatic first-pass elimination of approximately 50%. The terminal elimination half-life after IV administration is 2.5 to 3 hours. The primary mode of elimination is by urinary excretion as hydromorphone-3-glucuronide, the primary metabolite. Some metabolites may have greater analgesic activity than hydromorphone itself but are unlikely to contribute to the pharmacologic activity. Side effects are comparable to morphine [67].

MIXED AGONISTS/ANTAGONISTS

Discovery of an opioid analgesic with the efficacy but not the side effects or abuse potential of mu-agonists has been the ultimate goal of analgesic research for the past 60 years [29]. Mixed agonist-antagonist compounds have been developed with the hope that they would have less addictive potential and create less respiratory depression than morphine and related drugs. However, achieving the same degree of analgesia produces a similar magnitude of side effects, and a "ceiling effect," limiting the amount of analgesia attainable, is often seen with these drugs. Also, mixed agonist-antagonist drugs (e.g., pentazocine) can produce side effects not often seen with pure agonists, including severe, irreversible psychotomimetic effects [9].

Drugs such as nalbuphine and butorphanol are competitive mu-receptor antagonists, with their kappa receptor agonist action mediating the analgesic effect. Pentazocine qualitatively resembles these drugs but is a weaker mu-receptor antagonist or partial agonist while retaining its kappa-agonist activity. Buprenorphine is a partial mu-receptor agonist [9].

Pentazocine

Pentazocine was developed in an effort to synthesize an effective analgesic with little or no abuse potential. With agonistic actions and weak opioid antagonistic activity, the pattern of central nervous system effects is similar to that of morphine-like opioids, including analgesia, sedation, and respiratory depression. Dysphoric and psychotomimetic effects can be precipitated by higher doses (60 to 90 mg) [9].

In the 1970s and early 1980s, pentazocine (Talwin) was combined with the crushed, blue-colored antihistamine tablet tripelennamine and used intravenously, known as "Ts and Blues." Factors contributing to its widespread abuse included placement outside Schedule II and the erroneous belief that the drug was not abusable. Pentazocine was also widely abused by physicians because it could be prescribed in large quantities outside the stringent Schedule II monitoring system. At one point, pentazocine abuse became so prevalent that the manufacturer contemplated removing the drug from the market. Pentazocine was ultimately reformulated by the inclusion of the opioid antagonist naloxone. Similar to buprenorphine formulations containing naltrexone, when this formulation is taken as directed, the user experiences only the pentazocine effect because of poor oral naloxone absorption. However, if the tablet is dissolved and injected, the naloxone blocks the opioid effects of the pentazocine and precipitates acute opioid withdrawal [1].

Nalbuphine

Nalbuphine is an agonist-antagonist opioid related to naloxone and oxymorphone, with a spectrum of effects that qualitatively resembles that of pentazocine but with a lower potential to produce dysphoric side effects. Although doses of 10 mg or less produce few side effects, much higher doses (70 mg) can produce psychotomimetic side effects such as dysphoria, racing thoughts, and distorted body image. Prolonged administration of nalbuphine can produce physical dependence and withdrawal [9].

Butorphanol

Butorphanol is a morphinan congener with a profile of actions similar to those of pentazocine. It is generally more suitable for the relief of acute pain than chronic pain. Major side effects include drowsiness, weakness, sweating, feelings of floating, and nausea. Although the incidence of psychotomimetic side effects is lower than that with equianalgesic doses of pentazocine, they are qualitatively similar. Physical dependence to butorphanol can develop from regular use [9,56].

Buprenorphine

Buprenorphine was initially suggested in 1978 as an alternative oral opioid substitution therapy for opioid addicts. Buprenorphine and methadone are the two most widely used and effective pharmacotherapies for opioid use disorder, and both have regulatory approval in the United States for this indication [68]. Buprenorphine is a semi-synthetic opioid derivative made from thebaine, one of the naturally-occurring alkaloids in opium [69]. Buprenorphine, sold as Buprenex, Subutex, Belbuca, or Sublocade, is a long-acting partial opioid agonist that is classified as a Schedule III narcotic, in contrast to methadone and LAAM, which are Schedule II [56,57,70].

Buprenorphine has a very low oral bioavailability due to substantial intestinal and hepatic metabolism. The sublingual formulation used to treat opioid dependence is well-absorbed and produces opioid agonistic effects comparable to subcutaneous administration. Maximum plasma level is achieved 70 to 90 minutes after sublingual administration, and absolute bioavailability is 35% to 50% [69]. Following absorption, buprenorphine initially accumulates in the liver, kidneys, muscular tissue, and fatty tissue. It is released from fatty tissue when the plasma level drops and is then available at the opioid receptor. The slow dissociation kinetics explains the prolonged period of effectiveness. Buprenorphine is metabolized through the hepatic cytochrome P450 pathway. Approximately 80% is eliminated through binary excretion of the glucuronidated metabolites and 20% via the urinary route [69].

The minimum daily dose needed to suppress opioid use is about 4 mg. Larger doses of buprenorphine (32 mg) result less in an increase in therapeutic effect but more in an extension of the effect, which can last for up to 48 hours [69].

In 2014, the FDA approved a buccal film containing both buprenorphine and naloxone [71]. This combination therapy is applied once daily to suppress signs and symptoms of opioid withdrawal [56]. In 2016, the FDA approved the first buprenorphine implant (Probuphine) for opioid dependence [72]. The implant provides a constant, low-level dose of buprenorphine for six months. It is designed for use in patients who are already stable on a low dose of other forms of buprenorphine, as part of a complete treatment program. Because Probuphine must be inserted and removed surgically, healthcare providers are required to complete training and certification through the Probuphine Risk Evaluation and Mitigation Strategy (REMS) program [72]. In 2017, the FDA approved a once-monthly subcutaneous injection (Sublocade) for opioid use disorder [73]. Sublocade is intended for use in adult patients with moderate-to-severe opioid use disorder who have been on a stable dose of buprenorphine treatment for a minimum of seven days. The drug must be administered in a healthcare setting to avoid inadvertent IV administration that could result in death [73].Buprenorphine use is contraindicated for patients with alcohol intoxication, delirium tremens, and treatment with monoamine oxidase inhibitors. Cases of lethal buprenorphine intoxication almost always involve polyintoxication [69]. Buprenorphine contains a black box warning regarding the potential for serious, life-threatening, or fatal respiratory depression, especially during initiation or dose escalation [56]. Upon discontinuation, a withdrawal syndrome develops, with a delayed emergence in two days to two weeks. Signs and symptoms of buprenorphine withdrawal are typical of a milder morphine-type withdrawal and last roughly one to two weeks [9]. The more benign withdrawal syndrome is due to its partial agonist property at the mu receptor and weak antagonist property at the kappa receptor [57].

OPIOID ANTAGONISTS

Opioid antagonists have obvious therapeutic value in the treatment of opioid overdose. Relatively minor changes in the structure of an opioid can convert an agonist drug into one with antagonistic actions at one or more opioid receptor types. Opioid antagonists include naloxone, naltrexone, and nalmefene. Nalmefene is not approved in the United States [56]. Interestingly, naloxone also appears to block the analgesic effects of placebo medications and acupuncture. Naltrexone and naloxone have little or no potential for abuse [9].

10. NATURAL HISTORY OF OPIOID DEPENDENCE

Although the time from initiation to daily use and serious physiologic and psychologic dependence is highly variable, the different stages of opioid dependence are clearly delineated [8]. These stages include initiation, continuation, withdrawal, and relapse. Each stage is characterized by specific neurotransmitter action, involvement of specific brain structures, and activation of specific neural circuits. An understanding of these different processes is crucial to develop an understanding of the therapeutic strategies [13].

INITIATION

During the initiation phase, acute reinforcement of the initial drug effect is mediated by mu-opioid receptors and dopamine that inhabit the ventral tegmental area and nucleus accumbens. This results in conditioned responses and drug craving [13].

CONTINUATION

The second phase of continued drug use is characterized by diverse neurotransmitter involvement, including dopamine in the nucleus accumbens, corticotrophin-releasing hormone in the amygdala, and glutamate in the frontal-cingulate circuit. As tolerance develops, the dose and route of administration often change, with progression to IV use a frequent outcome [8].

DETOXIFICATION AND WITHDRAWAL

During detoxification and withdrawal from opioids and other central nervous system depressants, glutamate and norepinephrine in the locus coeruleus are primarily involved in causing the associated symptoms [13].

RELAPSE FOLLOWING SUSTAINED ABSENCE

Brain regions implicated in relapse to opioid use include the orbitofrontal cortex, anterior cingulate gyrus, and amygdala. Norepinephrine and corticotrophin-releasing hormones are involved in stress-induced relapse. Gamma-aminobutyric acid (GABA) and glutamate mediate brain systems that are involved in compulsive and habitual behavior and mediate cue-induced relapse [13].

11. PATHOPHYSIOLOGY

OPIOID TOLERANCE

Tolerance refers to a decrease in effectiveness of a drug with repeated administration. Tolerance to opioid effects is encountered in both the clinical use of opioids for pain relief and in recreational use of heroin [52]. Tolerance (as well as withdrawal and physiologic dependence) are expected responses to opioids and other controlled substances when given in sufficient doses over time and are not, by themselves, indicative of addiction [74,75]. Acute tolerance stems from transient administration of opioids; sustained administration leads to the development of classical or chronic tolerance. Short-term receptor desensitization may underlie the development of tolerance, probably involving phosphorylation of the mu and delta receptors by protein kinase C, protein kinase A, and beta-adrenergic receptor kinase (beta ARK). Long-term tolerance is believed to be associated with increases in adenylyl cyclase activity, a counter-regulation to the decrease in cyclic adenosine monophosphate levels [9].

The degree of tolerance can be influenced by changes in the environment in which drug use occurs. In the presence of cues previously associated with drug ingestion, tolerance is markedly enhanced, compared to the tolerance observed in a novel environment. Thus, administration of an opioid in an environment not previously associated with administration of the drug will be associated with lower tolerance and therefore a higher risk of overdose [52].

OPIOID DEPENDENCE

Opioid dependence is best described as a central nervous system disorder characterized by neurobiologic changes leading to compulsive drug-taking behaviors. As the result of chronic use, the cells producing endogenous opioids cease to function and degenerate, causing the user to become physically dependent on exogenous opioids [76].

According to the classical theory of addiction, opioid dependence results from the need to reduce distress, as withdrawal is a physical expression of distress. This is referred to as negatively reinforced behavior. This hypothesis has been challenged by the finding that the degree of physical dependence does not predict the intensity of subsequent craving, nor does detoxification and recovery from physical dependence prevent recidivism. Additionally, the motivational aspects of withdrawal are independent of the intensity and pattern of the physical symptoms of withdrawal [77].

Alternative hypotheses focus on the role of the mesocorticolimbic dopamine system, an anatomical pathway that originates from the ventral tegmental area in the midbrain and projects to several forebrain regions, including the nucleus accumbens and medial prefrontal cortex [77]. Dependence on most drugs of abuse is characterized by an altered physiologic state inferred from the emergence of a withdrawal syndrome following cessation of drug administration. Alleviation of an increasingly severe, withdrawal-induced negative affective state may reinforce continued drug taking and directly contribute to the development of dependence [78].

Molecular Basis

The diverse biologic effects of opioids are manifested through specific opioid receptors distributed throughout the central and peripheral nervous system. Opioid receptors, upon the binding of opioid drugs (or endogenous opioid peptides), regulate a multitude of intracellular signaling pathways. Involvement of opioid receptors in opioid dependence is unequivocal. This is reliably demonstrated by the rapid precipitation of withdrawal syndromes in opioid addicts by opioid receptor antagonists such as naloxone [79].

Repeated exposure to short-acting opioids can result in durable alterations in opioid receptor kinetics, transmembrane signaling, and postreceptor signal transduction [80]. Opioid dependence requires sustained activation of opioid receptors, and this chronic signaling process ultimately leads to changes in protein functions of gene transcription [79].

Opioid receptors are members of the G-protein receptor family, and each opioid receptor uses inhibitory G-proteins for signal transduction. Opioid receptors have the capacity to interact with five different forms of G-proteins, regulating a diverse spectrum of effectors ranging from adenylyl cyclases and ion channels to mitogen-activated protein kinases. These isoform-specific and differential regulations of various classes of effectors are combined into a sophisticated signaling network that mediates opioid actions. The enormous diversity in opioid signaling stems from the array of effectors and signaling molecules that functionally interact with the G-protein beta gamma complex [79].

Prolonged administration of opioids causes molecular and cellular adaptations that rapidly develop into tolerance and dependence. An upregulation of adenylyl cyclase responsiveness, referred to as adenylyl cyclases superactivation, is a classic sign of this tissue adaptation [79].

G-protein signals lead to changes in gene expression, and opioid-induced, long-term functional alterations of the nervous system involve changes in gene expression. Many opioid-induced signals converge at the level of transcription factors, although little is known about the exact mechanisms of gene transcription in the development of opioid tolerance and dependence [79].

Mechanism of Reinforcement

Drugs with an abuse liability have habit-forming actions that can be localized in a variety of brain regions. Drugs of abuse mimic or enhance the actions of endogenous chemical messengers in the brain [81]. The mesolimbic dopamine system is the likely substrate upon which opioids act to produce their reinforcing effects. Both the positive (rewarding) and negative (aversive) reinforcement of opioid mu- and kappa-receptor agonists are mediated by the mesolimbic dopamine system [77].

Opioids produce reinforcement by inhibition of the GABA neurons that normally inhibit dopaminergic neurons in the ventral tegmental area. This results in a surge of dopamine in the nucleus accumbens and other mesolimbic-mesocortical brain regions [82]. The neurochemical cascade begins with activation of mu- or kappa-opioid receptors differentially distributed on GABAergic cells in the ventral tegmental area and nucleus accumbens and dopamine terminals in the nucleus accumbens. This activation produces rewarding and aversive effects by increasing or decreasing dopamine release in the nucleus accumbens. Inhibition of medium spiny GABAergic neurons in the nucleus accumbens by dopamine and opioids can synergistically facilitate opioid reinforcement. Increases in glutamatergic afferents into the ventral tegmental area may facilitate opioid reinforcement by activating dopamine neurons. An increase in glutamate activity in the nucleus accumbens may decrease opioid action by activating nucleus accumbens GABAergic cells. Also, an increase in nucleus accumbens 5-HT by opioids modulates opioid reinforcement by activation of 5-HT1 and/or 5-HT3 receptors [77].

12. EFFECTS OF OPIOID USE DISORDER

The misuse of opioids results in several acute and long-term effects. Signs and symptoms of acute opioid intoxication include drowsiness, decreased respiration, euphoria, and impaired judgment (Table 1).

Table 1: SIGNS AND SYMPTOMS OF ACUTE OPIOID INTOXICATION

Constricted pupils (or dilated pupils with meperidine)

Euphoria

Apathy

Dysphoria

Drowsiness

Loss of consciousness

Coma

Psychomotor agitation or retardation

Decreased respiration

Decreased heart rate

Pulmonary edema

Impaired social judgment

Slurred speech

Impaired attention and memory

Impaired occupational functioning

Source: [83]

INFECTIOUS DISEASE

Infectious complications from opioid use generally stem from injection use, primarily of heroin, in which bloodborne pathogens are transmitted via contaminated needles. An estimated 60% to 90% of injection users have hepatitis C virus infection [84,85]. Other common infectious diseases include human immunodeficiency virus (HIV) and hepatitis B [8]. Common bacterial infections include Staphylococcus aureus, cellulitis and abscesses around the injection site, pneumonia, bacteremia, and endocarditis. Of HIV-positive persons in the United States, more than 33% have injected opioids and more than 25% report sharing needles with other users [10]. Injection drug users represented 6.6% of new HIV infections in 2018 and 11.5% of those living with HIV in 2018 [86].

ENDOCRINE/METABOLIC EFFECTS

Opioid use affects multiple endocrine functions and is associated with hypogonadism, adrenal dysfunction, reduced bone mineral density, and growth hormone abnormalities [87].

Hypothalamic-Pituitary-Gonadal (HPG) Axis

Opioid use has been implicated in gonadal dysfunction [88]. Central hypogonadism can result from opioid receptor activation in the vicinity of the hypothalamus. Resultant diminished secretion of gonadotropin-releasing hormone can lead to decreases in gonadotropin and testosterone levels. This effect may decrease over time secondary to the development of tolerance [87].

Metabolic Effects

Heroin use has been associated with abnormalities in glucose metabolism by multiple mechanisms. Fasting insulin levels can be substantially higher in heroin addicts than in control subjects, and insulin resistance stemming from opioid use may be coupled with beta cell dysfunction [89]. Heroin addicts often have lower acute insulin response than control patients evaluated by oral glucose tests and response to a standard meal. This blunted glucose response suggests an association between opioid use and abnormal glucose metabolism [87]. The use of highly active anti-retroviral therapy (HAART) for the treatment of HIV infection is also associated with a number of metabolic problems, including increased prevalence of insulin resistance, dyslipidemia, and changes in fat distribution. Because opioid use can also result in metabolic abnormalities, the presentation of patients who are both HIV-positive and opioid dependent may be complicated.

Chronic heroin use may also complicate dyslipidemia, evidenced by elevated total cholesterol levels, hypertriglyceridemia, decreased total cholesterol and high-density lipoprotein, and elevated triglyceride levels relative to controls [87].

Hypothalamic-Pituitary-Adrenal (HPA) Axis

Opioid addicts may also have impaired adrenal function, documented by a high prevalence of adrenal insufficiency and abnormal response to the cosyntropin test [88]. The action of heroin on neurotransmitters that regulate the secretion of corticotrophin-releasing factor, leading to disturbances in cortisol levels, has been hypothesized as the underlying pathophysiology. This is supported by the observation of lower plasma cortisol levels concurrent with depressed ACTH levels in heroin addicts [87].

In addition, chronic opioid use may contribute to low bone mineral density through reduction in lumbar bone mineral density. Growth hormone axis abnormalities are also seen in heroin addicts [87].

NEUROCOGNITIVE EFFECTS

Cognitive impairment resulting from chronic drug use may contribute to abuse and dependence in at least two ways. The first involves increasing the likelihood of drug-seeking behavior through various induced cognitive deficits, such as failure of impulse control mechanisms. The second involves the interference with users' ability to assimilate and participate in rehabilitation programs that have an educative and cognitive emphasis [90,91].

The chronic use of illicit drugs is often associated with a generalized profile of neuropsychologic deficit. However, it is thought that important differences in the patterns of interaction associated with various neurotransmitter systems, coupled with corresponding differences in the distributions of receptor subtypes, are responsible for the distinct neurocognitive effects of specific drugs of abuse [90].

Compared with marijuana and stimulants, there has been substantially less research into neuropsychologic deficits in chronic opioid abusers. Early studies found relatively little impairment in tasks involving abstraction and reasoning, leading investigators to conclude that chronic opioid use was not associated with deficient frontal lobe functioning. However, newer studies, utilizing more sensitive measures, have demonstrated that opioid abusers do possess marked deficits in frontal lobe functioning relative to healthy control subjects. These deficits may include problems with altered attentional control, altered decision making, or problems with choices involving motivationally significant outcomes [90]. Additional research is needed to establish whether this pattern reflects increased impulsivity. It should be noted that determining causation in studies involving drug users is difficult due to comorbid psychiatric disorders and polysubstance abuse [90].

Cognitive-Motor Effects of Methadone Maintenance

While under the influence of acute opioid ingestion, the ability to work safely or drive a car can be impaired. This does not appear to be the case with methadone patients who have adapted to the effects of opioids for months or even years, a reflection of the substantial tolerance to the central depressing effect when opioids are taken regularly on a long-term basis [92].

A review of the cognitive functioning of methadone patients found that [92]:

- On measures of concentration and attention, methadone patients tended to perform less well than controls.

- Methadone patients performed equally or slightly faster in speed of information processing and equally or slightly worse in motor reaction on measures of simple reactions and simple-choice reactions.

- Performance was inconsistent on complex-choice reactions under reactive stress.

- No evidence for inferior performance of methadone patients in vigilance tasks has been found.

- Methadone patients have performed worse than control groups in visual orientation.

- In tests combining tracking with a reaction task, slower reaction to peripheral signals have been observed in methadone patients together with equal accuracy and greater tracking deviation or smaller number of correct responses and equal tracking deviation.

Researchers concluded that among methadone-maintained patients without complicating comorbidity, visual structuring and reaction are not impaired [92]. Performance of attention, visual orientation, and eye-hand coordination are worsened. In general, performance of methadone patients and comparable healthy subjects overlap to a substantial degree. The study results may be better explained by sociodemographic factors than by the grouping factor; age, gender, and educational attainment showed a greater influence than methadone use. The authors concluded that being a methadone patient does not necessarily mean that impairment of cognitive-motor skills performance is inevitable [92]. Authors of more recent studies have reported similar findings [93,94].

The practical application of these findings suggests that methadone-maintained patients may be as capable as healthy persons in job performance. If job demands encompass skills with no differences found between healthy subjects and methadone patients, if minimum prerequisites are not extraordinarily high, or if patients exhibit favorable features exclusive of their methadone dependence, job performance is unlikely to be affected [92].

13. OPIOID OVERDOSE

As discussed, there were approximately 81,230 drug-overdose deaths in the United States in the 12-month period ending in May 2020 [18]. This was 18.2% higher than the rate in the year ending in June 2019, including approximately 46,000 deaths that involved synthetic opioid analgesics other than methadone, compared with 20,032 in 2015. Between 1999 and 2018, the age-adjusted death rate from drug overdose more than tripled (from 6.1 per 100,000 in 1999 to 20.7 in 2018) [95]. Overdose death rates from synthetic opioids other than methadone (e.g., fentanyl/fentanyl analogs, tramadol) increased from 0.3 per 100,000 in 1999 to 9.9 in 2018. The heroin overdose death rate increased from 0.7 per 100,000 in 1999 to 4.7 per 100,000 in 2018, a slight decrease compared with 2017 [95].

Overdose death rates involving natural and semisynthetic opioids (e.g., oxycodone, hydrocodone) increased from 1.0 per 100,000 in 1999 to 4.4 per 100,000 in 2016 then decreased to 3.6 per 100,000 in 2018 [95]. Overdose deaths involving methadone increased from 0.3 per 100,000 in 1999 to a peak of 1.8 in 2006, then declined to 0.9 in 2018 [95]. Most methadone fatalities occur when the drug is prescribed for pain rather than for addiction treatment [60].

RISK FACTORS

Heroin purity has only a moderate relationship to heroin-related fatalities, and despite the increasing incidence of heroin ingestion by smoking, almost all overdose deaths remain the result of injection. In fatal overdoses, instantaneous death is uncommon, indicating that there is time to intervene in the majority of cases. However, public responsiveness to overdoses is often poor, with the most common reason for delayed response being fear of police involvement [96]. The time following release from prison has also been identified as a very-high-risk period for both fatal and nonfatal overdose [96].

Methadone overdose decedents are more likely than other pharmaceutical opioid abusers to not have had a prescription for the overdose drug. They are also significantly more likely to be male [97,98].

Tolerance in Overdose

Variation has been found in the acquisition of tolerance to different opioid effects, including respiratory depression [38]. The role of tolerance in heroin overdose is suggested by the rigors of the heroin lifestyle, which often results in a reduction in use after a decade or more of use. Often, heroin addicts increase the use of other drugs, such as alcohol, to compensate for reduced heroin use. Both of these factors increase the risk for overdose.

Polysubstance Use

Polysubstance use in cases of fatal heroin overdose is so frequent that polydrug toxicity is often a better description of the cause of death. The primary drugs associated with fatal and nonfatal overdose are alcohol, benzodiazepines, and TCAs. The risk of nonfatal heroin overdose is increased significantly by TCA use but not by selective serotonin reuptake inhibitor (SSRI) use [17].

Alcohol and benzodiazepines are relatively weak respiratory depressants but can act synergistically with opioid agonists to produce substantial respiratory depression. Stimulants act as functional or physiologic opioid antagonists and may therefore minimize the respiratory depressant effects of opioids [52].

SYMPTOMS

In the case of opioid overdose, symptoms include mental clouding, stupor or coma, miotic pupils, bradypnea, diminished response to painful stimuli, and mottled, cooled skin. Respiratory depression is the most feared acute adverse effect. Direct suppression of the brain stem respiratory center leads to bradypnea, shallow respirations, and a significant overall reduction of tidal volume. Death from opioid overdose is almost always caused by respiratory depression [8,99].

Sequelae of nonfatal overdose include [38]:

- Pulmonary conditions, most frequently edema

- Pneumonia

- Cardiac complications such as arrhythmia, acute cardiomyopathy, and hemoglobinemia

- Rhabdomyolysis (disintegration or dissolution of muscle cells leading to myoglobinuria)

- Neurologic damage through prolonged hypoxia

14. OPIOID WITHDRAWAL

A withdrawal syndrome can be precipitated in humans after even a single dose of morphine. Physical dependence to opioids is assessed by observing the emergence of a withdrawal syndrome following discontinuation of opioid administration or through the administration of a competitive opioid antagonist, such as naloxone [100]. Signs and symptoms of opioid withdrawal include [83,101]:

- Dilated pupils

- Rhinorrhea

- Epiphora/lacrimation

- Piloerection

- Nausea

- Vomiting

- Diarrhea

- Yawning

- Muscle cramps

- Restlessness

- Elevated vital signs

Although the neurophysiology underlying opioid withdrawal is incompletely understood, several neurotransmitter systems are believed to play a role, including dopaminergic, cholinergic, noradrenergic, and glutamatergic systems [100]. The extended amygdala is robustly implicated in affective signs of withdrawal from chronic exposure to opioids. Less is known about the cellular mechanisms underlying acute dependence [78]. The progressive escalation of withdrawal severity that occurs across repeated acute opioid exposure separated by prolonged intervals suggests the involvement of long-term cellular plasticity in acute dependence [78]. The involvement of central mechanisms of the endothelin system in opioid withdrawal is also being investigated [102,103].

There are a number of useful opioid withdrawal scales that can assist the clinician's evaluation of patients by identifying and quantitating the severity of opioid withdrawal symptoms. These include the Objective Opioid Withdrawal Scale (OOWS), the Subjective Opioid Withdrawal Scale (SOWS), and the Clinical Opioid Withdrawal Scale (COWS). The OOWS is useful for measuring and documenting measurable symptoms of opioid withdrawal. The SOWS records the patient's rating of withdrawal on a 16-item scale. The COWS includes 11 items and contains signs and symptoms (both objective and subjective) of withdrawal [104].

In 2014, the FDA cleared the Bridge Neurostimulation System (an electroauricular device) for use in acupuncture. In 2017, the FDA approved a new indication for the device for use in helping to reduce the symptoms of opioid withdrawal [105]. The NSS-2 Bridge is placed behind the patient's ear and emits electrical pulses to stimulate branches of certain cranial nerves. It can be used for up to five days during the acute phase of withdrawal. In one study, within 30 minutes of using the device, all patients showed a reduction in COWS score of nearly 31% [105].

In 2018, the FDA approved lofexidine for the management of opioid withdrawal symptoms [24]. This agent may be incorporated into the treatment of adults with opioid withdrawal symptoms for up to 14 days.

ACUTE OPIOID WITHDRAWAL

Most research regarding acute withdrawal from an opioid has been conducted with heroin users. Withdrawal symptoms are the result of mu-agonist withdrawal in the case of heroin and begin approximately eight hours after the last dose. The symptoms begin slowly, peak at 48 to 72 hours, and then gradually taper during the next four to seven days [101]. As noted, typical symptoms of withdrawal include agitation, anxiety, piloerection, tachycardia, mild hypertension, and pupillary mydriasis. Approximately 8 to 12 hours after the last dose, increases in vital signs, pulse, blood pressure, and respiratory vital rate are observed. At the peak, pronounced anxiety, tremors, shakes, smooth and skeletal muscle cramps, and joint and deep bone pain begin to manifest [8].

PROTRACTED WITHDRAWAL

Withdrawal symptoms may persist long after elimination of the opioid agent. Such persistent behavioral change suggests plastic alternation within the nervous system, some of which may be mediated by the regulation of gene expression [100]. Chronic exposure to opioids may be associated with changes to the mu receptor, resulting in the propagation of signal transduction in the absence of an agonist. The withdrawal phase can be extended due to the cellular changes that occur after long-term opioid exposure [76].

PERSISTENT NEUROADAPTATION AND RELAPSE VULNERABILITY

Opioid dependence is a chronic relapsing disorder characterized by compulsive drug seeking and use. More than 80% of addicts relapse to drug seeking and use after a period of abstinence during the protracted withdrawal phase, underscoring the long-standing nature of the compulsion and high rates of recidivism [106]. Two important brain alterations occur following dependence and withdrawal that are believed to underlie the heightened vulnerability to relapse: conditioned responses of norepinephrine A1/A2 neuron release in the extended amygdala and changes in the mesocorticolimbic dopamine system and its afferents that alter hedonic processing. At the same time, motivation or learning for drug reward and drug-associated cues is increased [106].

Abstinence from chronic drug use unmasks neuroadaptation in brain function that contributes to an ill-defined feeling of dysphoria, anxiety, or malaise that can only be alleviated by renewed administration of the drug. Continued drug use is rewarding because it stimulates the natural reward circuitry and also because the action offsetting the anti-reward response (stress hypersensitivity and anxiety) produces an additional reinforcing effect that increases the sum of positive reinforcement. The protracted withdrawal period is often characterized by elevated anxiety involving alterations in the noradrenergic input to the bed nucleus of the stria terminalis or amygdala. Drug-associated stimuli activate noradrenergic A1/A2 neurons during protracted withdrawal, leading to elevated anxiety through the ensuing release of noradrenergic neurons in the extended amygdala. In turn, additional reinforcing properties are produced via the alleviation of anxiety when these noradrenergic neurons are inhibited, reflecting negative reinforcement [106,107].

Additionally, chronic drug exposure results in a generalized hedonic deficit for natural rewards and an incentive value for drugs. This deficit in the capacity for obtaining reinforcement from non-drug sources generates symptoms such as anhedonia and depression [107]. The sensitized hedonic drug value is also believed to increase motivation for drug use. Furthermore, the changes that occur in hedonic processing mechanisms following chronic opioid exposure may involve multiple systems that recover at different rates. Changes in the afferents to the ventral tegmental area or in plasticity within the ventral tegmental area itself could play a vital role in altered hedonic processing during protracted withdrawal [106,107].

Taken together, these findings suggest that elevated drug seeking during protracted withdrawal may involve two processes: prolonged and elevated anxiety leading to a negative reinforcement mechanism for opioids and increased incentive motivation for drug reward through a sensitization mechanism [106,107].

15. LIABILITY OF MISUSE OF LEGITIMATELY PRESCRIBED OPIOID DRUGS

There is broad consensus that patients with acute and chronic pain have often received inadequate pain control out of a fear of creating dependence. This is typified by the results of a survey in which 35% of Canadian family physicians reported they would never prescribe opioids for moderate-to-severe chronic pain and 37% identified dependence as a major barrier to prescribing opioids [108]. Prescriber knowledge deficit has been identified as a key obstacle to appropriate opioid prescribing and, along with gaps in policy, treatment, attitudes, and research, contributes to widespread inadequate treatment of pain [109]. A 2013 survey measured primary care physician understanding of opioids and addiction. Of the 200 participants, [110]:

- 35% admitted knowing little about opioid addiction.

- 66% and 57% viewed low levels of education and income, respectively, as causal or highly contributory to opioid addiction.

- 30% believed opioid addiction "is more of a psychologic problem," akin to poor lifestyle choices rather than a chronic illness or disease.

- 92% associated prescription analgesics with opioid addiction, but only 69% associated heroin with opioid addiction.

- 43% regarded opioid dependence and addiction as synonymous.

These statistics reflect knowledge and attitude gaps among physicians that lead to undertreatment of pain and unnecessary suffering among patients experiencing pain [108]. In response to this, the Joint Commission and other organizations have enacted accreditation standards that consider pain to be the fifth vital sign, assessed whenever other vital signs are measured [1].

However, with the growing concern about the undertreatment of pain and the underuse of opioids in pain treatment, there is also a renewed concern about prescription opioid dependence and overdose deaths [1]. The disparate concerns regarding undertreatment of pain and facilitation of dependence is underscored by the fact that, until recently, pain management and addiction specialists rarely communicated. Pain management physicians rightly concern themselves with alleviation of pain and have traditionally underestimated dependence among their patients, with such patients often simply dismissed from further care. Addiction specialists, on the other hand, seldom encounter pain patients whose quality of life is vastly improved by opioids, but instead see failed patients from pain treatment programs [1]. Additionally, there is a shortage of pain specialist physicians in the United States that is expected to worsen. This has resulted in most of the medical care for patients with chronic pain being delivered by primary care physicians, despite, as stated, significant and widespread knowledge deficits among these practitioners in the medical skills necessary for providing optimal pain management, managing drug abuse and addiction, and utilizing risk evaluation and mitigation strategies when prescribing opioids [111].

It is important to note that prescription opioid abuse has been tempered by improvements in opioid prescribing, community intervention, and improved awareness. Following a peak in opioid prescribing in 2011, numbers have consistently fallen. However, opioid use disorder rates and overdose fatalities continue to rise. This reinforces the need for appropriate opioid prescribing practices, patient assessment and referral, and optimal opioid use disorder treatment in patients with suspected addiction.

Abuse liability is related to the ease of extraction and modification to produce the desired psychologic effect. Medication tends to be more readily abusable if it has a rapid onset and short duration of action, is highly potent, and is smokable or easily ingested. Examples of opioids with high abuse liability include hydromorphone (Dilaudid) tablets, which can be easily dissolved in water and injected, and OxyContin tablets, which can be crushed to disable the controlled-release properties and then snorted or dissolved in solution and injected. A specific black box warning on the labeling of a medication can alert potential substance abusers of the abuse liability. Also, brand name drugs, which carry a higher street value, are more likely to be abused and diverted than generic equivalents [1].

In studies of trends in medical use and abuse of opioid analgesics, a corresponding increase in the rate of abuse with prescription rates has been apparent [15,112,113]. Thus, the increased medical use of opioid analgesics for the treatment of pain has contributed to an increase in opioid analgesic abuse and overdose fatalities. The abuse of hydrocodone and oxycodone products, which increased disproportionately to their availability between 2000 and 2011, is an extreme example of this trend [1]. Results of epidemiologic studies indicate a high prevalence of lifetime abuse of other substances and of substance-related disorders in patients with OxyContin dependence, suggesting that substance abuse predated the use of OxyContin [114].

Legitimate pain clinics offer large amounts of drugs with a high potential for abuse, often with little evaluation and follow-up [112]. In some states (e.g., Florida, Texas), increasingly liberal prescribing practices were linked to rising overdose death rates. Since 2011, misuse of prescription opioids has decreased; however, abuse of synthetic opioids (including illicitly manufactured fentanyl) has increased precipitously.

DEVELOPMENT OF DEPENDENCE

The dependence of a patient to a drug initially prescribed for a medical condition is referred to as iatrogenic dependence. Opioid prescriptions fall into two major subgroups: treatment of acute pain with short-term opioids and treatment of chronic pain with long-term opioids. In contrast to the rare association of dependence with short-term use, long-term administration of opioids is estimated to result in opioid abuse or dependence in 2.8% to 18.9% of patients, which typically parallels the rate of abuse or dependence among opioid users in the general population [33].

There is no adequately validated instrument to differentiate pain patients who are at risk of dependence from those who are not. Research suggests that patients, even alcoholics, with no history of opioid dependence are not at heightened risk of becoming addicted with short-term opioid exposure. However, those with a positive history of dependence would benefit from active recovery efforts while receiving such medications [1].

One way to gauge the adequacy of pain control is to consider whether the use of added opioids has resulted in improvements in the functional restoration, physical capacity, psychologic well-being, family/social interactions, and healthcare resource use, which are weighed against unwanted effects, such as daytime sedation, mental confusion, constipation, and other side effects.

Despite the rise in the prescribing and abuse of opioid analgesics, definitive data on the rate of dependence among patients administered opioids for acute pain does not yet exist. There is, however, agreement on how to minimize the risk of iatrogenic dependence. These steps include screening for dependence risk potential based on a family history of substance abuse and the exploration of different delivery systems that adequately treat pain but minimize abuse potential [34]. Although a pattern of aberrant behavior may be grounds for caution, a history of opioid abuse does not necessarily preclude a patient from successful treatment with an opioid [1]. Screening for psychologic disorders is also advisable, including psychosomatic causes of pain.

The final word on the dilemma of balancing the desire for patient pain relief with the desire to minimize the chance of iatrogenic abuse or dependence comes from the authoritative pharmacology textbook The Pharmacological Basis of Therapeutics, which states, "neither the presence of tolerance and dependence nor the fear that they may develop should ever interfere with the appropriate use of opioids for pain relief" [9].

16. MANAGEMENT OF OPIOID USE DISORDER

In 1914, the Harrison Act was passed, which had the effect of criminalizing addiction and led to significant apprehension among physicians in treating narcotic addicts. Treatment for opioid dependence was basically non-existent until 1935, when U.S. Public Health Services opened a hospital in Lexington, Kentucky, devoted to the treatment of opioid dependence. However, treatment was entirely detoxification-based at that time. In 1963, the New York Academy of Sciences recommended that clinics be established to dispense narcotics to opioid-dependent patients. During this time, research identified methadone as a possibly efficacious agent because of its long half-life, which allowed once-daily dosing. In 1972, the FDA created stringent regulations governing methadone, reducing the flexibility of practitioners caring for opioid-dependent patients. The Office of National Drug Control Policy subsequently made changes in the 1995 Federal Regulations of Methadone Treatment to encourage the development of a less restrictive approach and to give physicians more latitude in prescribing methadone [57].

Today, management of opioid dependence entails different methods to achieve different goals, depending on the health situation and treatment history of the patient. These treatment approaches include [13]:

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

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

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

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

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

All treatment approaches share the common goal of improving health outcomes and reducing drug-related criminality and public nuisance [13].

CRISIS INTERVENTION

Evidence Based Practice Recommendation

According to the World Health Organization, people likely to witness an opioid overdose should have access to naloxone and be instructed in its administration to enable them to use it for the emergency management of suspected opioid overdose.

https://www.who.int/publications/i/item/9789241548816

Last Accessed: March 30, 2021

Strength of Recommendation/Level of Evidence: Strong/very low

In response to acute overdose, the short-acting opioid antagonist naloxone is considered the criterion standard. Naloxone is effective in reversing respiratory depression and coma in overdose patients. There is no evidence that subcutaneous or intramuscular use is inferior to intravenous naloxone. This prompted discussion of making naloxone available to the general public for administration outside the healthcare setting to treat acute opioid overdose, and in April 2014, the FDA approved naloxone as an autoinjector dosage form for home use by family members or caregivers [116]. The autoinjector delivers 0.4 mg naloxone intramuscularly or subcutaneously. The autoinjector comes with visual and voice instruction, including directs to seek emergency medical care after use [116]. In November 2015, the FDA approved intranasal naloxone after a fast-track designation and priority review. Intranasal naloxone is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or CNS depression. It is available in a ready-to-use 4-mg or 2-mg single-dose sprayer [115,117,118].

HARM REDUCTION

Harm reduction measures are primarily employed to minimize the morbidity and mortality from opioid abuse and to reduce public nuisance [96]. As a part of this effort, measures to prevent and minimize the frequency and severity of overdoses have been identified. Enrollment in opioid substitution therapy, with agents such as methadone and buprenorphine, substantially reduces the risk of overdose as well as the risk for infection and other sequelae of illicit opioid use [96].

Education

Reducing the risk for harm involves education on polydrug use and needle-exchange programs [96]. The authors of one review noted that there was positive evidence, though limited, to support education regarding noninjecting routes of administration, brief interventions, and supervised injecting facilities [119]. Given that a harm-reduction approach can address risk behaviors that may occur alongside drug use, the authors of one paper suggest that risk-reduction education be based on harm reduction philosophy as a whole rather than on the specific harms of drug use and harm reduction strategies (e.g., needle-exchange programs) [120]. The authors defined six principles—humanism, pragmatism, individualism, autonomy, incrementalism, and accountability without termination—and generalized them for use in healthcare settings with patients beyond those who use illicit substances. Each principle was defined and providers were given descriptions of how to deliver interventions informed by the principles as well as examples of how to apply each principle in the healthcare setting [120].

To improve response to overdoses, opioid abusers and their friends and families should be taught simple cardiopulmonary resuscitation skills to keep comatose users alive until emergency medical personnel arrive. Associates of users should be encouraged to call an ambulance when overdose occurs. The provision of naloxone to opioid users should be tested and evaluated; naloxone could be distributed through existing outlets, such as needle and syringe exchanges, pharmacies, urgent care facilities, or treatment agencies. Heroin users should also be encouraged to switch to noninjecting routes of administration to reduce related morbidity and mortality [96].

Needle-Exchange Programs

Needle-exchange programs, also referred to as syringe services programs, have been shown to be effective in reducing drug-related health problems, reducing injection frequency, and increasing entry and retention in drug treatment [13]. According to one review, there is sufficient evidence of efficacy, effectiveness, and financial benefit to recommend needle-exchange and outreach programs [119]. It is important to note that information regarding infection prevention strategies be provided to all participants in needle-exchange programs, as increased incidences of HIV and other bloodborne pathogens have been noted in this population [121]. The Consolidated Appropriations Act of 2016 gives states and local communities, under limited circumstances, the opportunity to use federal funds to support certain components of needle-exchange programs. Although federal funds cannot be used to purchase sterile needles or syringes for illegal drug injection, these funds can be used to support a comprehensive set of services as part of a needle-exchange program [122].

Injection Rooms

Medically supervised injecting rooms are officially designated areas where injecting opioid users, often persons who use heroin, can inject without fear of arrest and with knowledge that medical assistance is available if overdose occurs. Such facilities have existed in Switzerland since 1986, in Germany since 1994, and in the Netherlands since 1996. The goal of user rooms is to promote health and reduce risk behaviors and public nuisance, with a specific focus on overdose reduction and hygiene [123]. Several descriptive studies have shown significant effects on harm reduction and reduction of public nuisance [13].

Heroin Maintenance

Heroin maintenance, also referred to as heroin-assisted treatment, is the implementation of heroin prescriptions under medical supervision. This option may improve health and reduce heroin overdoses, illicit opioid use, and crime. However, formidable barriers to heroin maintenance exist in the United States [96].

One systematic review compared heroin maintenance to methadone or other substitution treatments of opioid dependence for efficacy and acceptability; retaining patients in treatment; reducing the use of illicit substances; and improving health and social functioning [124]. Eight studies involving 2,007 patients met the inclusion criteria. Five studies compared supervised injected heroin plus flexible dosages of methadone to oral methadone alone. Results suggest an added value of heroin prescribed alongside flexible doses of methadone for long-term, treatment-refractory, opioid users to reduce use of illicit substances and sustain treatment [124].

DETOXIFICATION AND WITHDRAWAL

The process of tapering opioid-dependent patients from agonist therapy is often referred to as detoxification, or more accurately, medically supervised withdrawal [57,125]. Its purpose is to eliminate physical dependence on opioid medications. It can be considered the medically supported transition to a medication-free state or to antagonist therapy. A careful and thorough review of the risks and benefits of detoxification should be provided and informed consent obtained from patients prior to choosing this option [125,126]. Detoxification alone should not be considered a treatment and should only be promoted in the context of a well-planned relapse-prevention program [13,125].

Discontinuation of opioid use must be implemented slowly and cautiously to avoid a marked abstinence syndrome. Withdrawal symptoms may not begin for days after abrupt discontinuation of methadone or buprenorphine given their longer half-lives. Protracted abstinence, or post-acute withdrawal, may last for several months and is characterized by asthenia, depression, and hypotension. Post-acute withdrawal is more likely to occur with methadone than other opioids [57].

The three primary treatment modalities used for detoxification are opioid agonists, non-opioid medications, and rapid and ultra-rapid opioid detoxification [57]. The most frequently employed method of opioid withdrawal is a slow, supervised detoxification during which an opioid agonist, usually methadone, is substituted for the abused opioid [76]. Methadone is the most frequently used opioid agonist due to the convenience of its once-a-day dosing [57]. Methadone is highly bound to plasma proteins and accumulates more readily than heroin in all body tissues. Methadone also has a longer half-life, approximately 22 hours, which makes withdrawal more difficult than from heroin. Substitution therapy with methadone has a high initial dropout rate (30% to 90%) and an early relapse rate. Alternative pharmacologic detoxification choices include clonidine (with or without methadone), midazolam, trazodone, or buprenorphine [76].

Many opioid withdrawal symptoms, such as restlessness, rhinorrhea, lacrimation, diaphoresis, myosis, piloerection, and cardiovascular changes, are mediated through increased sympathetic activation, the result of increased neuron activity in the locus coeruleus. Non-opioid agents (such as clonidine), which inhibit hyperactivation of noradrenergic pathways stemming from the locus coeruleus nucleus, have been used to manage acute withdrawal [76,104]. The first non-opioid treatment approved for the management of opioid withdarawl symptoms is lofexidine [24]. In studies, patients treated with lofexidine reported less severe withdrawal symptoms and were more likely to complete treatment.

However, some withdrawal symptoms, including anxiety and myalgias, are resistant to clonidine; benzodiazepines and nonsteroidal anti-inflammatory agents may be necessary to treat these symptoms. To mitigate withdrawal symptoms and assist in detoxification, alpha2-agonists, opioid agonist-antagonists, benzodiazepines, and antidepressants have been used [76].

Following detoxification, patients may feel exhausted and weak. Other complications, such as slight variations in hemodynamic status and gastrointestinal tract symptoms, follow quickly and may take several days to resolve. Muscle cramps and low back pain can be treated with nonsteroidal anti-inflammatory drugs. However, the newer cyclooxygenase-2 (COX-2) inhibitors may be advantageous because they produce fewer gastrointestinal side effects [76]. Insomnia is a frequent aspect of acute and protracted withdrawal, as opioids disrupt the normal sleep-wake cycle and many addicts require narcotics to sleep. Although long-term disruption of the normal sleep-wake cycle cannot be corrected rapidly, melatonin (3 mg), benzodiazepines, or antihistamines can be used with beneficial effects. Hypnosis and relaxation techniques are nonpharmacologic methods that may also be used [76]. Psychosocial treatments offered in addition to pharmacologic detoxification treatments positively impact treatment retention and completion, results at follow-up, and compliance [127,128].

Ultra-Rapid Opioid Detoxification

Ultra-rapid opioid detoxification (UROD) has been developed as a means of avoiding the physical symptoms of withdrawal from opioids through the use of general anesthesia. UROD consists of naltrexone-assisted detoxification under heavy sedation or full anesthesia. Chemical sedation has been used since the early 1940s in the management of drug withdrawal. The major breakthrough in the management of opioid withdrawal occurred with the addition of an opioid antagonist during chemical sedation [129]. UROD was introduced in 1990 primarily by private practitioners in a for-profit setting [130].

Traditional withdrawal management utilizes the substitution of the short-acting opioid with a long-acting opioid and subsequent tapering or use of non-opioids. This may involve substantial discomfort to patients, who often terminate the detoxification process and return to opioid use. Some may not even attempt to quit due to fears of the discomfort of the withdrawal process. Thus, attempts have been made to induce and shorten opioid withdrawal through the use of UROD [130].

UROD is also referred to as rapid or anesthesia-assisted detoxification. One reason for the proliferation of terms is that the anesthesia-assisted procedure was commercially used and was submitted as a registered trademark or patent. Therefore, other researchers had to devise novel names for the process. Suggested classification is [130]:

- Ultra-rapid opioid detoxification (UROD): General anesthesia; duration <6 hours

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

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

The common underlying themes in all UROD techniques are a desire to condense the detoxification process into a shorter period to blunt the awareness of physical discomfort and to shorten the time lag between a patient's last dose of opioid and transfer to naltrexone maintenance [130]. This is accomplished by precipitating withdrawal following the administration of opioid antagonists under deep sedation or anesthesia.

A highly specific subgroup of patients may benefit more from UROD. This includes patients unable to abstain with methadone substitution despite adequate motivation, patients unable to stop methadone, and patients who are socially and occupationally active and cannot go through a lengthy detoxification. Patient preference is also an important variable [130].

Absolute contraindications include pregnancy; a history or clinical suspicion of cardiac disease; chronic renal impairment; liver disease; current dependence on benzodiazepines, alcohol, or stimulants; and history of psychotic illness [130]. Relative contraindications include a history of treatment for depression and unstable social circumstances. A comprehensive plan to stabilize such patients should be undertaken before the procedure [130]. Patients with chronic pain syndromes requiring opioid medication are not good candidates unless their pain can be controlled by alternative methods [76].

UROD is best performed in an intensive care unit with full resuscitative equipment and monitoring available [76]. Initiation of opioid withdrawal is precipitated by IV injection of a high-dose antagonist, usually naloxone. Antagonists are chosen that have high binding coefficients relative to agonists (naltrexone binds at the mu receptor 34 times more than morphine) [76]. Parameters that indicate adequacy of withdrawal include a 20% decrease of ventilation below the maximum minute ventilation, an electrocardiogram (ECG) detection of decreased QQ variability, and electroencephalogram (EEG) normalization [76].

Detoxification and withdrawal are rarely complete following UROD, and residual withdrawal symptoms can include drug craving, sympathetic hyperactivity, muscle pain, bone pain, nausea, vomiting, diarrhea, and insomnia. UROD does little to prevent protracted abstinence syndrome, which can last 3 to 10 weeks. Naltrexone may reduce opioid craving during the post-UROD period, with 50 mg per day recommended for relapse prevention [76]. However, patients undergoing long-term naltrexone therapy can become sensitized to opioid drugs, heightening the risk of fatal overdose if opioid use is resumed. Patients with a history of pre-existing liver dysfunction should undergo naltrexone maintenance therapy only under careful supervision. Clonidine may diminish sympathetic hyperactivity and should be continued through the protracted abstinence syndrome [76].

The withdrawal syndrome observed in many of the published studies on UROD was protracted, as reflected in the duration of inpatient stay, which varied from 24 hours to eight days, with a mean duration of three to four days. Therefore, alternatives to UROD are considered to be more cost-effective [130]. Krabbe et al. compared abstinence rates and withdrawal effects of UROD with standard methadone tapering in a prospective three-month trial [131]. They found significantly higher abstinence rates and fewer withdrawal symptoms in UROD patients versus methadone patients at one and two months, with no differences at three months.

A major shortcoming of UROD is the lack of evidence that an opioid antagonist can accelerate the restoration of neurobiologic homeostasis following opioid withdrawal [130]. Although significant drawbacks and questionable long-term efficacy exist with UROD, popular demand has proven difficult to restrain, in part due to the marketing of the procedure as a painless cure for opioid dependence. Marketing and the media have also blurred the fact that the original purpose of the procedure was to induce patients as rapidly as possible onto naltrexone and not to magically and permanently terminate years of opioid dependence [129].

There are a number of drawbacks to UROD relative to other detoxification methods. For example, one study found that, when used alone, naloxone has a high relapse rate in the long term [132]. The study included 64 opioid-dependent men 18 years of age and older (mean age: 31.1 years) at the time of UROD. One month after UROD, 48 patients (75%) reported relapse and 16 patients (25%) reported abstinence. There was no significant difference between the two groups regarding marital status, level of education, and family history of opioid dependence. Four patients from the nonrelapsed group reported on episode of opiate use [132]. Another study was conducted to assess UROD efficacy with naltrexone and estimate the relapse rate in a two-year follow-up period [133]. A total of 424 opioid-addicted self-reporting patients were enrolled in the study and entered the UROD program; 400 patients completed the program. Of the total patients, 303 (75.75%) were successful and 97 (24.25%) relapsed. No patients in the relapse group continued naltrexone maintenance at six-month follow-up. The relapse rate was 14% at the first month visit and 24% at the six-month visit and thereafter. All relapsed patients had discontinued use of naltrexone before relapse occurred [133].

Serious adverse events related to the anesthetic procedure also have been reported. A randomized, controlled trial directly comparing naltrexone-assisted detoxification with and without full anesthesia clearly stated that heavy sedation or full anesthesia should not be used because it does not confer any advantages in withdrawal symptom severity or increased rates of initiation or maintenance and it increases the potential for life-threatening adverse events [13]. A trial comparing naltrexone-induced, anesthesia-assisted detoxification with buprenorphine- or clonidine-assisted detoxification found no difference in withdrawal severity and rates of completion. However, potentially life-threatening adverse events associated with the UROD anesthesia were observed. The authors concluded that the data do not support use of anesthesia for detoxification [134]. Heavy sedation compared to light sedation does not confer additional benefits in terms of less severe withdrawal or increased rates of initiation and retention on naltrexone maintenance treatment. The risk for adverse events, the high monetary cost, and use of scarce intensive care resources suggest that this form of treatment should not be pursued [135,136]. Additionally, UROD has not undergone the processes of therapeutic protocols, which are recognized as essential in scientific medicine, and no animal studies have been conducted with the procedure [129].

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

Two principle treatment modalities are offered for opioid-dependent patients: agonist maintenance or detoxification followed by outpatient or residential drug-free treatment. Both can be effective, with no clear indication for each, although agonist maintenance leads to greater treatment retention [137]. A reasonable approach is initial outpatient or residential treatment referral for patients relatively new to treatment, with agonist maintenance appropriate for patients with history of treatment failures, greater disease severity, or a history of drug overdoses. Naltrexone is best reserved for patients with strong legal incentives to abstain, family involvement to monitor treatment, or concurrent enrollment and involvement in a psychosocial intervention [138].

At present, there are no direct interventions that are capable of reversing the effects of drugs of dependence on learning and motivation systems [34]. Instead, the management of opioid dependence often consists of pharmacotherapy with methadone and buprenorphine, which do not eliminate physical dependence on opioids. These medications instead reduce the use of illicit opioids and produce very strong positive health outcomes as measured by decreased mortality, improved mental and physical health, and reduced risk of disease transmission [34]. Considering the high rate of relapse after detoxification, maintenance therapy with methadone or buprenorphine is currently considered to be the first-line treatment for opioid-dependent patients [13].

Any treatment for opioid dependence must take into consideration the chronic relapsing nature of opioid dependence, characterized by a variable course of relapse and remission in many patients. Treatments should emphasize patient motivation, psychoeducation, continuity of care, integration of pharmacotherapy and psychosocial support, and improved liaison between the treatment staff and the judicial system. Pharmacotherapy must be offered in a comprehensive healthcare context that also addresses the psychosocial aspects of dependence [13]. Opioid-dependent patients frequently suffer from physical and psychiatric disorders, and targeted interventions of psychiatric comorbidity are essential in improving treatment outcome for these patients [13]. Polysubstance abuse is the rule rather than the exception in opioid dependence, and concurrent use of other substances should be carefully monitored and treated when necessary [13]. Incarceration should never automatically result in discontinuation of an existing treatment; imprisonment offers a window of opportunity to initiate or restart treatment with a necessary continuation after release [13].

Agonist Replacement Therapy

The goal of opioid replacement therapy is to reduce illicit drug use and associated health risks, with secondary goals of reducing unsafe sexual practices, improving vocational and psychosocial functioning, and enhancing quality of life [57]. The theoretical basis of opioid replacement stems from the finding that chronic opioid use results in an endogenous opioid deficiency as a result of the down-regulation of opioid production. This creates overwhelming cravings and necessitates interventions that shift the dependent patient's attention and drive from obsessive preoccupation with the next use of opioids to more adaptive areas of focus, such as work, relationships, and non-drug leisure activities [57].

The neurobiologic changes resulting from prolonged opioid exposure provide a rationale for specific pharmacotherapies, such as long-acting opioid agonists, that are aimed at stabilizing these complex systems [80]. Opioid agonist maintenance treatment stabilizes brain neurochemistry by replacing short-acting opioids, which can create rapid changes in opioid levels in the serum and brain, with a long-acting opioid that has relative steady-state pharmacokinetics. Opioid agonist maintenance treatment is designed to have minimal euphoric effect, block the euphoria associated with administration of exogenous opioids (competitive antagonism), eliminate the risk of infectious disease and health consequences associated with injection drug use, and prevent opioid withdrawal [80].

Successful maintenance treatment entails stabilization of opioid dependence through opioid receptor occupation. Positron emission tomography studies have revealed that only 25% to 35% of brain opioid receptors are occupied during steady-state methadone maintenance, suggesting that unoccupied opioid receptors disrupted during cycles of opioid abuse could normalize during methadone maintenance [57]. Additionally, opioid replacement therapy blocks much of the euphoria from illicit heroin use. Long-term opioid agonist treatment also has a positive impact on public health, through significantly reducing overdose deaths, criminal activity, and the spread of infectious disease [57].

As of 2019, 607,372 patients in the United States were enrolled in opioid replacement therapy in 1,691 opioid treatment programs [139]. However, this represents only an estimated 19% of all opioid-dependent patients. Although some have criticized the practice of methadone and buprenorphine therapy on the grounds that one opioid is merely being substituted for another, the clinical benefits strongly support this treatment modality [57]. When compared to active street heroin users, these benefits include a four-times lower HIV seroprevalence rates, 70% fewer crime-days per year, and a one-year mortality rate of 1% (versus 8%) [60].

Methadone

The first demonstrated efficacy of methadone treatment for opioid dependence was published in 1965. Methadone is now the most inexpensive and empirically validated agent available for use in opioid replacement therapy. Studies have shown one-year treatment retention rates of 80%, with significant reductions in illicit opioid use [57]. Individual and group counseling are the main ancillary therapies and consist primarily of cognitive-behavioral and supportive-expressive approaches. There is some evidence that augmentation of methadone with intensive psychosocial therapy significantly improves outcomes [57]. Efforts to provide methadone in an office-based setting have been successful, although federal regulation has limited the flexibility of providers [80,104].

Evidence Based Practice Recommendation

When considering initiation of methadone, the American Pain Society recommends that clinicians perform an individualized medical and behavioral risk evaluation to assess risks and benefits of methadone, given methadone's specific pharmacologic properties and adverse effect profile.

https://www.jpain.org/article/S1526-5900(14)00522-7/fulltext

Last Accessed: March 30, 2021

Strength of Recommendation/Level of Evidence: Strong/low

As noted, methadone maintenance treatment offers substantial benefits over no treatment, including reduced risk of death and disease, reduced heroin use, reduced criminal involvement, and improved well-being. However, the benefits are less with poor-quality or under-funded programs. The quality of the staff-patient interaction, attitudes of staff, good management of clinics, and good record-keeping characterize higher-quality programs [140].

Methadone maintenance is also cost-effective [57]. A 1997 study of Veterans' Affairs patients showed that the estimated six-month costs are about $21,000 for an untreated drug abuser, $20,000 for an incarcerated drug abuser, and $1,750 for a patient enrolled in a methadone maintenance program [141]. A study using data from one healthcare plan reached a similar conclusion regarding cost-effectiveness (albeit with differing cost estimates) [142]. The annual costs (in 2004 dollars) were $18,694 for patients receiving no methadone with 0 or 1 outpatient addiction treatment visits; $14,157 for patients receiving no methadone with 2 or more visits; and $7,163 for patients receiving methadone.

There is an unrealistic expectation that opioid users should be able to stop using all drugs. Although some do successfully stop, dependence is a chronic problem for most patients, associated with frequent relapses, serious health risks, and psychosocial impairment [140]. Unfortunately, a serious stigma surrounds methadone treatment, which is experienced most acutely by patients but also by professionals. This may pose a barrier to treatment support [140].

Treatment is initiated with a dose of 25–30 mg and is gradually titrated in 5- to 10-mg increments per day to a desired range of 60–120 mg. Low-dose treatment is associated with less positive outcomes than doses of 60–120 mg/day or greater [57,60]. One published review of efficacy literature concluded that high doses of methadone (>50 mg daily) are more effective than low doses (<50 mg daily) in reducing illicit opioid use. This may be due to the increased availability of highly pure heroin [60]. Additionally, high doses of methadone are more effective than low doses of buprenorphine (<8 mg daily). High dosages of methadone are comparable to high dosages of buprenorphine (>8 mg daily) on measures of treatment retention and reduction of illicit opioid use [13]. Methadone is contraindicated for the following patients [104]:

- Those with known hypersensitivity to methadone hydrochloride

- Those experiencing respiratory depression

- Those with acute bronchial asthma or hypercapnia

- Those with known or suspected paralytic ileus

Buprenorphine

Buprenorphine offers several advantages over methadone, including lower cost, milder withdrawal symptoms following abrupt cessation, lower risk of overdose, and longer duration of action, allowing alternate-day dosing [57,143]. Identifying subpopulations of opioid addicts who differentially respond to buprenorphine versus methadone has not been clearly established. However, patients with less chronic and less severe heroin dependence benefit more fully from buprenorphine than from a pure opioid agonist like methadone [57].

Studies support buprenorphine as a viable alternative for opioid maintenance therapy. However, its mixed agonist/antagonist action entails special considerations. Buprenorphine may precipitate opioid withdrawal, and patients being switched from short-acting opioids must abstain from illicit opioid use for at least 24 hours before initiating buprenorphine therapy [57,104]. Another drawback is associated with the sublingual route of administration. This administration presents some difficulties because the tablet is relatively large and slow to dissolve under the tongue and swallowing diminishes its effectiveness. Also, the transition to buprenorphine from long-acting opioids is difficult [34]. The ASAM warns that diversion and misuse are possible with buprenorphine, as is physical dependence. Respiratory depression may occur if buprenorphine is used with CNS depressants including alcohol, other opioids, and illicit drugs. Neonatal withdrawal has also been reported after use of buprenorphine during pregnancy. Buprenorphine is not recommended for patients with severe hepatic impairment [104].

Higher doses of buprenorphine (12 mg or greater) are more effective than lower doses in reducing illicit opioid use, with some studies reporting similar efficacy to methadone on major treatment-outcome measures. One systematic review was conducted to evaluate buprenorphine maintenance compared to placebo and methadone maintenance in the management of opioid dependence [144]. Outcomes considered were treatment retention, suppression of illicit drug use, and reduction in criminal activity and mortality. A total of 31 trials involving 5,430 participants with moderate- to high-quality evidence were included in the review. According to the data reviewed, buprenorphine retained participants better than placebo at low doses (2–6 mg), at medium doses (7–15 mg), and at high doses (≥16 mg). Only high-dose (≥16 mg) buprenorphine was more effective than placebo at suppressing illicit opioid use (as measured by urinanalysis). Buprenorphine in flexible doses (i.e., adjusted to participant need) was less effective than methadone in retaining participants, and for those retained in treatment, no difference was observed in suppression of illicit opioid use. In low fixed-dose studies, methadone (≤40 mg) was more likely to retain participants than low-dose (2–6 mg) buprenorphine. However, there was no difference between medium-dose (7–15 mg) buprenorphine and medium-dose (40–85 mg) methadone in retention or in suppression of illicit opioid use. Similarly, there was no difference between high-dose (≥16 mg) buprenorphine and high-dose (≥85 mg) methadone in retention or suppression of self-reported heroin use [144]. In a study of 34,000 Massachusetts Medicaid beneficiaries, the incidence of relapse was greater with buprenorphine than with methadone [143]. The primary advantage of buprenorphine over methadone is its superior safety profile [34].

Slow-Release Oral Morphine

Slow-release formulations of morphine that are effective with once-daily dosing are a viable alternative in the treatment of opioid dependence. These formulations considerably delay time to peak concentration after oral administration, resulting in delayed onset of action and making the reinforcing effects very weak when it is administered orally. Several trials have suggested that slow-release morphine has approximately equal efficacy with methadone; however, there is no definitive evidence of this effect [34,145,146]. Slow-release oral morphine may be a viable alternative for patients who are intolerant to methadone [147].

Diacetylmorphine (Heroin)

The pharmacokinetic properties of heroin make it less than ideal for use as a maintenance drug, and the main rationale for heroin maintenance has been the treatment of patients who simply do not respond to any other treatment modality. Although preliminary results seem to be positive, before suggesting that heroin treatment may have a place with a subpopulation of patients, further studies using standardized protocols are needed. Significantly, studies so far clearly indicate that heroin maintenance, with or without methadone, can be implemented safely. The relatively high cost of heroin maintenance compared with standard methadone or buprenorphine treatment is a drawback of this approach. However, at least one study suggests that heroin combined with methadone may be more cost-effective than methadone alone [34].

The results of medically prescribed heroin administration to chronic, treatment-refractory, heroin-dependent patients have been detailed in two reports. One report from Switzerland concluded that supervised medical prescription of heroin was associated with favorable treatment retention, reduced illicit drug use, reduced criminality, and improved health outcomes and social functioning. These findings were also reported in a controlled trial from Spain and Germany [13]. Research projects were also performed in the Netherlands, Canada, and England, and others are planned in Belgium and Denmark. Based on the positive outcomes thus far, heroin maintenance has become routine treatment for otherwise untreatable heroin addicts in Switzerland, the Netherlands, Germany, and England and is being recommended in Canada [148,149].

Agonist Replacement and Psychosocial Therapy

The addition of any psychosocial support modality to agonist replacement therapy significantly reduces illicit use during treatment, and treatment retention and results at follow-up are also improved [127,128]. There are two general types of psychosocial therapy used for treating addictive disorders. The first includes therapies developed for treating depression and anxiety that were later adapted for treating persons with addictive disorders, examples of which include cognitive behavioral therapy, supportive expressive therapy, and interpersonal therapy. The second type includes therapies developed specifically for persons with addictive disorders, such as the closely-related motivational interviewing and motivational enhancement therapy [150].

Drug counseling, another approach specific to addictive disorders, emphasizes abstinence, involvement in 12-step programs, and assistance with social, family, and legal problems. Drug counseling is not considered psychotherapy because it focuses on behaviors and external events rather than the intrapsychic processes [150].

Most studies of psychotherapy with opioid-dependent patients have been conducted in methadone programs and are actually pharmacotherapy/psychotherapy studies. In addition to pharmacologic intervention, methadone programs typically use behavioral contingencies that are based on cessation of illicit drug use and other improvements [150].

A review of the literature on psychosocial therapy outcomes with opioid-dependent patients receiving methadone has found evidence of an interaction between measures of psychiatric symptoms, therapy assignment, and outcomes [150]. Patients with minimal psychiatric symptoms did equally well with drug counseling alone or with drug counseling plus supportive expressive therapy or cognitive-behavioral therapy. Patients with moderate-level symptoms did somewhat better if they received additional psychotherapy, and patients with more severe psychiatric symptoms had substantially better outcomes with additional psychotherapy than with drug counseling alone. Improvements were observed in employment, legal, psychiatric, and drug use indices. Patients with opioid dependence and antisocial personality disorder did not benefit from additional psychosocial therapy beyond drug use reduction, but patients with opioid dependence, antisocial personality, and depression exhibited improvement in multiple areas [150].

Therapist variables played an important role in outcome, with better results associated with therapists who formed a positive, helping relationship with the patient. There is also some evidence that the best patient outcomes come from methadone programs with a higher level of services that include counseling, medical, and psychiatric services [150].

Abstinence-Oriented Therapies

The primary goal of abstinence-oriented interventions is cure, which is defined as long-term, stable abstinence from all opioids. Abstinence is achieved in two phases: detoxification and relapse prevention. Outcomes in abstinence-oriented programs are generally poor [13].

The primary goal of pharmacotherapy during detoxification is to alleviate opioid withdrawal severity and associated distress/medical complications and to enhance patient motivation to continue treatment. Withdrawal can also be reduced by psychosocial measures, such as contingency management or counseling, and as discussed, the addition of psychosocial therapy to pharmacologic treatment increases efficacy. Buprenorphine and clonidine are both used to manage withdrawal symptoms, but buprenorphine's advantages, compared with clonidine, are related to its favorable side effect profile and positive effects on well-being and psychosocial variables [13].

Opioid Antagonist Therapy

Relapse-prevention programs have traditionally involved long-term residential placement of nine months or more, often using the therapeutic community format. More recently, pharmacotherapeutic agents, such as naltrexone, have been added to reduce relapse risk. A drawback with opioid antagonist therapy is the high dropout rate during detoxification, which results in highly selective patient samples in most of the naltrexone maintenance studies. Naltrexone maintenance or relapse-prevention treatment should be reserved only for those patients who are highly motivated for long-term total abstinence and who are otherwise psychosocially stable [104]. Relapse prevention with naltrexone may also be suitable for pregnant women who are unable to stabilize on methadone or buprenorphine. Patients should be warned that reduced tolerance following naltrexone treatment may increase the risk of overdose [13].

The primary problem with naltrexone treatment is low compliance, with retention in treatment ranging from 6% to 45% [34,104]. Strategies to improve treatment compliance include combining naltrexone maintenance with contingency management, involving the provision of vouchers redeemable for goods and services contingent on naltrexone intake and drug-free urines [82]. The authors of one investigation evaluated prescribing patterns for opioid use disorder medications among a commercially insured population in the United States from 2010 to 2014. The evaluation revealed consistently low treatment completion rates for two forms (e.g., injectable, oral) of naltrexone. At 30 days post-initiation, 52% of individuals treated with injectable naltrexone had discontinued treatment, and 70% of individuals treated with oral naltrexone had discontinued treatment. The proportion of patients treated with either form of naltrexone grew over time, but the discontinuation rates were significantly higher compared with individuals treated with sublingual or oral-mucosal buprenorphine/naloxone [151]. Although the focus of this investigation was not on the reasons for treatment discontinuation, it did highlight the poor treatment compliance with naltrexone. The extended-release injectable naltrexone formulation may help overcome the compliance issues associated with the oral formulation [104].

Naltrexone is contraindicated in patients with hypersensitivity reactions to the agent, in patients with current physical and physiologic dependence on opioids, and in patients in acute opioid withdrawal [104]. At present, reviewers conclude "there is no sufficient evidence of efficacy of naltrexone to justify its use in the maintenance treatment of opioid dependence" [152].

Psychosocial Monotherapy

Evidence Based Practice Recommendation

In opioid treatment program settings, the Department of Veterans Affairs Work Group suggests offering individual counseling and/or contingency management, with consideration of patient preferences and provider training/competence.

https://www.healthquality.va.gov/guidelines/MH/sud/VADoDSUDCPGRevised22216.pdf

Last Accessed: March 30, 2021

Strength of Recommendation: Weak for

There is no data to support psychosocial interventions as a sole intervention for opioid dependence [127,128]. Psychosocial treatments alone are not adequately proven treatment modalities, nor are they superior to any other type of treatment for opioid dependence [153]. However, psychosocial treatments offered in addition to pharmacologic detoxification treatments are effective in terms of treatment completion, opioid use, and participant abstinence at follow-up [128].

12-Step/Self-Help Programs

Twelve-step programs for opioid use disorder include Narcotics Anonymous (NA) and Methadone Anonymous (MA) and are modeled after Alcoholics Anonymous (AA), an abstinence-based support and self-improvement program that is based on the 12-step model of recovery. AA is widely considered the most successful treatment for alcoholism and has helped hundreds of thousands of alcoholics achieve sobriety [154]. The 12-step model emphasizes acceptance of dependence as a chronic, progressive disease that can be arrested through abstinence but not cured. Additional elements include spiritual growth, personal responsibility, and helping other addicted persons. By inducing a shift in the consciousness of the addict, 12-step programs offer a holistic solution and are a resource for emotional support [154]. Although research on efficacy and patient outcomes in NA and MA is very limited, many prominent researchers emphasize the important role ongoing involvement in 12-step programs plays in recovery from substance abuse [155].

The understanding of drug dependence as a chronic and relapsing disorder has helped professionals gain a better comprehension of the vital role played by 12-step programs. Every patient attempting to recover from a substance use disorder will encounter a time when he or she faces urges to use without the resources or assistance of healthcare professionals. Twelve-step programs are not considered treatment, nor are they intended as substitutes for treatment. Instead, they are organizations that provide ongoing and indefinite support in the achievement and maintenance of abstinence and in personal growth and character development [155].

Part of the effectiveness of NA and MA is related to their ability to provide a competing and alternative reinforcer to drug use. Involvement in 12-step programs can enhance the quality of social support and the social network of the member, a potentially highly reinforcing aspect the person stands to forfeit if they resume drug using. Other reinforcing elements of 12-step involvement include recognition for increasingly durable periods of abstinence and frequent awareness of the consequences of drug and alcohol use through attendance of meetings [156]. Research shows that establishing a pattern of 12-step program attendance early in treatment predicts the level of ongoing involvement. Emphasis and facilitation of early engagement in a 12-step program involvement are key [157].

Narcotics Anonymous

Relative to the more established AA, there are few studies published on NA. However, some research has revealed important information about how NA functions to help both new and long-term members abstain from opioids and other drugs. Being active as an NA sponsor over a one-year period was found to be strongly associated with substantial improvements in sustained abstinence rates for the sponsors. This suggests that providing direction and support to other newer addicts is a way to enhance the likelihood of one's own abstinence [158]. In addition to being a sponsor, having a sponsor also is associated with positive outcomes. One analysis explored the predictors and outcomes of having a 12-step sponsor among individuals receiving treatment for stimulant use disorders [159]. Four types of 12-step groups were evaluated: NA, AA, Cocaine Anonymous, and Crystal Meth Anonymous. Factors evaluated were the extent to which participants obtained sponsors, the extent to which other predictors (e.g., beliefs, expectations) were associated with having a sponsor, and the effect of sponsorship at the end of treatment. Participants in the 12-step facilitation intervention had higher sponsorship rates at the end of treatment and at three-month follow-up, and end-of-treatment sponsorship predicted a higher likelihood of abstinence and no drug-related problems at follow-up [159].

Improvement in psychologic functioning as a result of NA involvement has been observed by Christo and Sutton [160]. Among the 200 NA members in their study, those who had been off drugs and involved with NA for longer periods tended to have lower trait anxiety and higher self-esteem scores, with those abstinent for more than three years exhibiting levels of anxiety and self-esteem similar to those of a comparison group of 60 students from a vocational training college [160].

Methadone Anonymous

MA was begun in 1991 when a staff member of a methadone maintenance treatment clinic in Baltimore attended an NA meeting and observed a woman receiving an "Anniversary Chip" in recognition of abstinence from heroin, only to be told to return the chip when she shared that methadone maintenance helped make it possible. This staff person went on to develop a 12-step program for methadone patients [161].

MA is based on the belief that "methadone is a therapeutic tool of recovery that may or may not be discontinued in time, dependent upon the needs of the individual," and that continued abstinence from drugs of abuse, including alcohol, is the foremost goal of recovery [162]. Most MA meetings are hosted by methadone clinics, and there are more than 1,000 MA clinics worldwide [163].

There are very few published studies involving MA. One study found that, similar to other 12-step programs, MA members undergo a spiritually-mediated transformation in their recovery process, with members describing methadone as the core of the group experience and an aid to spiritual transformation [164]. Length of time in MA has been found to be associated with reductions in the use of other substances as well, including alcohol, cocaine, and marijuana. Clients in methadone maintenance programs have rated components of MA to be significantly more helpful to recovery than methadone treatment components, suggesting that MA participation has benefits not available in professionally-driven methadone therapy programs [161].

ACUPUNCTURE

Auricular acupuncture is the most common acupuncture approach for substance abuse, including opioid abuse and dependence, in the United States and the United Kingdom. This technique consists of bilateral insertion of acupuncture needles in the outer ears [165]. There is controversy surrounding the presumed mechanism of action of acupuncture. Western scientists attempt to explain its action on the body's electromagnetic system, with the acupuncture needle creating a difference in electrical potential that stimulates extracellular ion flow. Chinese practitioners, who have been using acupuncture for several thousand years to treat a wide range of maladies, attribute its effects to unblocking or removing an excess of qi, or life energy, along key channels referred to as meridians [166].

Results from well-designed studies indicate that auricular acupuncture treatment is not sufficient in efficacy as a stand-alone treatment for opioid dependence. The placebo response rate is substantial, and the body of evidence does not demonstrate the type of qualitative and quantitative rigor needed to validate acupuncture efficacy in the treatment of opioid-addicted patients. Common adverse events from acupuncture include needle pain, fatigue, and bleeding; fainting and syncope are uncommon. Feelings of relaxation are reported by as many as 86% of patients [165]. There is some evidence that differences in efficacy may be influenced by racial physiologic differences among persons of European and Asian descent [165].

A 2016 review of 199 studies found that contradictory results, intergroup differences, and acupuncture placebo effects made it difficult to evaluate the effectiveness of acupuncture for drug addiction treatment [167]. The authors of another review looked at clinical trials of 100-Hz electroacupuncture for detoxification treatment. They found a potential for the treatment to allay opioid-associated depression and anxiety but no effect for opioid craving [168].

INTERVENTIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

For those 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.

17. MANAGEMENT OF COMORBID PSYCHOPATHOLOGY

Psychiatric comorbidity often accompanies opioid dependence and plays an important role in treatment outcome. Multiple national population surveys have found that roughly 50% of those who experience mental illness during their lives will also experience a substance use disorder and vice versa [169,170]. More than 60% of adolescents in community-based substance abuse treatment programs also meet diagnostic criteria for another mental illness [171]. An estimated 43% of individuals in treatment for nonmedical use of prescription opioids have a diagnosis or symptoms of a mental health disorder, particularly depression and anxiety [172].

Major depression prevalence among opioid-dependent patients is estimated to be 20% to 30% lifetime and 10% to 20% at enrollment in treatment. Depression is also associated with the use of prescription opioids for chronic pain and worse treatment outcomes. Approximately 50% of patients with chronic pain have a comorbid psychiatric condition, and 35% of patients with chronic back and neck pain have a comorbid depression or anxiety disorder [37,138,173,174]. The prevalence of depression is lower in out-of-treatment patients than in those seeking treatment and is associated with increased retention in methadone treatment. Thus, depression has a mixed effect on prognosis. It appears to be a motivating factor in treatment-seeking while at the same time interfering with treatment effectiveness [37,138,173,174]. In addition, opioid-dependent patients with Axis I psychiatric comorbidity often require significantly higher methadone doses [57].

Psychiatric comorbidity is especially pronounced with serious mental illness, which is defined by the Substance Abuse and Mental Health Services Administration as individuals 18 years of age or older having, at any time during the past year, a diagnosable mental, behavior, or emotional disorder that causes serious functional impairment that substantially interferes with or limits one or more major life activities [175]. Approximately one in four individuals with a serious mental illness (e.g., major depression, schizophrenia, bipolar disorder) have a comorbid substance use disorder [176].

A main issue in managing comorbid conditions is the differentiation of independent versus substance-induced disorders, as therapeutic plans differ for the two conditions [173]. Substance abuse can result in changes in mood, appetite, sleep patterns, beliefs, and perceptual experiences, all of which may present as psychiatric disorders but resolve with stabilization of drug use. Treatment should not focus solely on the non-substance-use psychiatric diagnosis, as symptom reduction will not translate into reduced drug use. Active substance use can also alter the presentation of personality and diagnosis of a personality disorder [177].

ASSESSMENT

It is important to assess dependent opioid users for other psychiatric and substance use disorders, especially alcohol and cocaine dependence because they are frequent comorbidities in opioid-dependent patients and can aggravate depressive symptoms [104,176]. Bipolar illness is rare but has substantial treatment implications. Anxiety disorders frequently co-occur with depression, and traumatic experiences and post-traumatic stress disorder are common and should be thoroughly evaluated and treated [138,176]. Independent disorders are psychiatric conditions occurring during periods of sustained abstinence or having an onset before the substance-use disorder. A positive family history can aid in identifying an independent psychiatric disorder.

Comprehensive assessment tools can reduce the chance of a missed or incorrect diagnosis. Patients with psychiatric comorbidities often exhibit symptoms that are more persistent, severe, and resistant to treatment compared to patients who have either disorder alone [178,179,180,181]. Assessment is critical to identify concomitant medical and psychiatric conditions that may need immediate attention and require transfer to a higher level of care [104]. The ASAM recommends that clinicians also assess social and environmental factors to identify facilitators and barriers to treatment, specifically to pharmacotherapy [104].

TREATMENT APPROACH

Treatment should initially focus on stabilization of the patient's substance use disorder, with an initial goal of two to four weeks abstinence before addressing comorbidities. Patients who persistently display symptoms of a psychiatric disorder during abstinence should be considered as having an independent disorder and should receive prompt psychiatric treatment [177].

Although depressive symptoms often improve following treatment admission, significant symptoms will persist in some patients [138]. Antidepressant medications can be effective in patients dually diagnosed with opioid dependence and depression when used at adequate doses for at least six weeks [182]. Factors emphasizing prompt antidepressant treatment include greater severity of depression, suicide risk, and co-occurring anxiety disorders [138].

SSRIs are generally safe and well-tolerated, but clinical trials with these agents in methadone patients have been negative [138]. Therefore, SSRIs may be considered first-line treatment based on their safety profile, but if the patient does not respond, then TCAs or newer generation agents should be considered. SSRIs in combination with cognitive-behavioral therapy have been found to be highly effective for treating clients with comorbid depression [170]. More stimulating antidepressants, such as venlafaxine and bupropion, may be suitable in patients with prominent low energy or past or current symptoms consistent with attention deficit hyperactivity disorder (ADHD) [138]. The utility of nonpharmacologic treatments should be emphasized. Psychosocial therapies are as effective as pharmacotherapy in the treatment of mild-to-moderate depressive and anxiety symptoms. Treatment of personality disorders is nonpharmacologic [177]. If depression persists, psychosocial modalities, such as cognitive therapy, supportive therapy, or contingency management, have some evidence to support their efficacy in opioid-dependent patients [138,170].

In the treatment of insomnia and anxiety, trazodone and nefazodone are helpful agents, although nefazodone should be used with caution because of reports of liver toxicity. Mirtazapine, a sedating antidepressant, is a logical alternative. A baseline ECG is recommended prior to a TCA trial in opioid users [138]. Benzodiazepines for anxiety should be avoided due to the liability of abuse and the potential of drug-seeking behavior, which is detrimental to treatment. Effective alternatives to benzodiazepines include antidepressants and anticonvulsant mood stabilizers. Sedating atypical antipsychotics may also be useful but should be used with caution due to potential side effects [138].

Medical comorbidities that may impact mental status and treatment response include [138]:

- Hypothyroidism

- HIV infection

- Hepatitis C and B

- Chronic lung disease

- Hypertension

- Diabetes

- Cardiovascular disease

The presence of comorbid conditions increases severity and complicates recovery. Patients with comorbid disorders demonstrate poorer treatment adherence and higher rates of treatment dropout [180,183]. A natural outgrowth of increased severity has been greater interest in and use of integrated treatment, compared with separate treatment of combined conditions [170]. Integrated treatment refers to a treatment focus on two or more conditions and the use of multiple treatments (e.g., combination of psychotherapy and pharmacotherapy). It is an approach supported by research that demonstrates the superiority of an integrated approach [184,185,186,187,188].

TREATING POLYSUBSTANCE ABUSE/DEPENDENCE

As noted, polysubstance use is the norm rather than the exception among opioid-dependent patients. The optimal approach to treating multiple substance abuse depends on the substances being used, the severity of the abuse, the treatment setting, familiarity of the clinician with treatment of the substance problem, and available resources for treatment. Optimal patient outcomes occur with pharmacologic and psychosocial combination therapy [177].

18. OPIOID USE DURING PREGNANCY

A portion of pregnant women with substance dependence continue using addictive substances despite awareness of the potential harm to the fetus [189]. Infants can sustain adverse effects from maternal opioid use, although it is difficult to separate factors due to opioid use from those due to the abuse of other drugs, poor prenatal care, poor nutrition, or other complications [100,190]. Reports of adverse effects of opioid use on fetuses and neonates include [189]:

- Fetal growth restriction

- Intrauterine withdrawal with increased fetal activity

- Depressed breathing movement

- Preterm delivery

- Preterm rupture of the membranes

- Meconium-stained amniotic fluid

- Perinatal death

- Neonatal abstinence syndrome (NAS)

Opioid withdrawal is a physiologic rebound from the chronic drug effects on brain function. In pregnant women, rapid opioid withdrawal may precipitate preterm labor; in neonates, it may be fatal [189]. NAS occurs when an infant becomes dependent on opioids or other drugs used by the mother during pregnancy [191]. It is an expected and treatable condition seen in 30% to 80% of infants born to women taking opioid agonist therapies [190]. NAS increased fivefold nationally between 2000 to 2012, coinciding with rising rates of opioid prescribing to pregnant women [192]. NAS may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, and seizures [191,193]. Withdrawal symptoms in neonates can include tremors, diarrhea, fever, irritability, jitteriness, sweating, fever, vomiting, and generalized convulsions [191,194].

The optimal treatment for NAS has not been established. Opioids are considered the first-line therapy [194]. Opioid treatment of NAS reduces the time to regain birth weight, reduces the duration of supportive care, and increases the length of hospital stay. There is no evidence of effect on treatment failure [195]. Treatment with long-acting opioids has been shown to be superior to phenobarbital and diazepam in infants with NAS [195].

Evidence Based Practice Recommendation

The World Health Organization recommends that healthcare providers should, at the earliest opportunity, advise pregnant women dependent on opioids to cease their use and offer, or refer to, detoxification services under medical supervision where necessary and applicable. Detoxification can be undertaken at any stage in pregnancy, but at no stage should antagonists (e.g., naloxone, naltrexone) be used to accelerate the detoxification process.

https://www.who.int/publications/i/item/9789241548731

Last Accessed: March 30, 2021

Strength of Recommendation/Level of Evidence: Strong/very low

Phenobarbital is generally considered a second-line agent and is effective for the treatment of withdrawal and polydrug exposure. Clonidine is also a safe second-line option for treatment of NAS symptoms that are refractory to opioid therapy [194,196]. Buprenorphine and methadone have both been shown to be safe and effective treatments for opioid use disorder during pregnancy [197]. A meta-analysis showed that methadone was associated with higher treatment retention and buprenorphine resulted in a 10% lower incidence of NAS, decreased neonatal treatment time of 8.46 days, and less morphine (3.6 mg) needed [198]. Infants whose mothers receive these medications may still experience NAS; however, it is less severe than in the absence of treatment [198].

In treating pregnant women with substance dependence, psychologic and pharmacologic treatments are often combined. Psychosocial treatments include contingency treatment, community reinforcement, behavioral marital therapy, cognitive-behavioral skills training, motivational enhancement therapy, and 12-step approaches [189].

HEROIN

Heroin rapidly crosses the placental blood barrier. Between 55% and 94% of infants born to IV heroin users exhibit signs of neonatal withdrawal, with a small minority showing neonatal seizure activity [199]. Methadone maintenance has been found to be an effective harm-reduction strategy and can reduce acute neonatal withdrawal problems, including seizures [200].

METHADONE

Pregnant women who are opioid dependent should be maintained on the lowest effective dose of methadone; detoxification, if attempted, should be done in the second trimester [189]. Outcomes are poor for patients who leave treatment. Fetal exposure can result in lower birth weight, smaller head circumference, jaundice, and thrombocytosis, although the cause of these conditions is difficult to distinguish between methadone and other concurrently-used substances. Methadone in the newborn infant will produce physical dependence and subsequent withdrawal symptoms that may not emerge until 48 hours after birth, regardless of maternal dose. Methadone-exposed infants function within a normal range of cognition at one- and two-year evaluations [189]. Methadone levels in breast milk appear to be small [201].

BUPRENORPHINE

Buprenorphine has been administered successfully to opioid-dependent pregnant women as a maintenance replacement opioid. Placental transfer may be less than methadone, reducing fetal exposure and subsequent dependence and withdrawal. Buprenorphine has a low incidence of labor and delivery complications and of neonatal abstinence syndrome [189]. Multiple small case series have examined maternal buprenorphine concentrations in breast milk and all concur that the amounts are small and unlikely to have short-term negative effects on the developing infant [202].

OXYCODONE

Oxycodone is metabolized to noroxycodone, oxymorphone, and their glucuronides and primarily excreted through urine. Oxycodone has been detected in breast milk, and although not found to be a teratogenic in experimental animals, it is not recommended for use in pregnancy [56]. Management of infants born to mothers abusing oxycodone is of particular concern because the drug and its metabolites are difficult to detect by the enzyme immunoassay methods typically used for urine and meconium opioid screens [203].

NALTREXONE

The literature is limited and equivocal regarding naltrexone and pregnancy. The substantial drop-out rates due to the reward-blocking and dysphoric effects of this drug have resulted in limited reports on pre- and perinatal complications. One Australian study showed no obstetric complications and healthy-appearing infants, leading the authors to conclude naltrexone is a safe alternative in select pregnant patients [189]. However, other authors have found that naltrexone can cause premature labor and fetal death, and it is considered to be pregnancy category C [8,56]. The manufacturer recommends that nursing mothers either discontinue the drug or discontinue nursing [56].

19. PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

The relapse rate among patients receiving treatment for opioid dependence and other substance abuse is high (25% to 97%), comparable to that of other patients with chronic relapsing conditions, including hypertension and asthma [62]. Many cases of relapse are attributable to treatment noncompliance and lack of lifestyle modification [83].

Duration of agonist replacement therapy is usually recommended as a minimum of one year, and some patients will receive agonist replacement therapy indefinitely. Longer durations of treatment are associated with higher rates of abstinence from illicit opioids [34].

Much remains unknown about patient outcomes following termination of long-term opioid replacement therapy. Some patients aim to achieve total abstinence from all opioids, but little is known about patient characteristics and strategies used among those who remain abstinent. It is likely that at least some of the patients who remain abstinent from all opioids do so with the help of a 12-step support program, such as NA [34].

20. CONCLUSION

Dependence on opioids is associated with serious morbidity and mortality, and advances in the understanding of the dependence have led to the development of effective treatments. More recently, the abuse of prescription opioids has become considerably more widespread, fueled in part by the availability of such drugs over the Internet. This has resulted in opioid abuse and dependence in populations seldom afflicted in the past. Thus, medical, mental health, and other healthcare professionals in a variety of settings may encounter patients with an opioid use disorder. The knowledge gained from the contents of this course can greatly assist the healthcare professional in identifying, treating, and providing an appropriate referral to patients with opioid use disorders.

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