FLPA26 • Florida Physician Assistants 2025-2026

Table of Contents

FLPA26 • Florida Physician Assistants 2025-2026

How to Receive Credit

NetCE 2 Hour Course #91334 • Medical Error Prevention and Root Cause Analysis

91334 • Medical Error Prevention and Root Cause Analysis

1. INTRODUCTION

2. DEFINING "MEDICAL ERROR"

3. ROOT CAUSE ANALYSIS PROCESS

4. ERROR REDUCTION AND PREVENTION

5. OTHER CONSIDERATIONS FOR PATIENT SAFETY

6. CONCLUSION

Works Cited

NetCE 2 Hour Course #97144 • Assessment and Management of Pain at the End of Life

97144 • Assessment and Management of Pain at the End of Life

1. INTRODUCTION

2. ISSUES IN EFFECTIVE PAIN MANAGEMENT

3. ETIOLOGY

4. ASSESSMENT

5. MANAGEMENT

6. LEGAL AND ETHICAL ISSUES RELATED TO THE TREATMENT OF PAIN

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

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

90350 • Neuromodulation for Refractory Neuropsychiatric and Pain Disorders

1. INTRODUCTION

2. OVERVIEW OF BRAIN MODULATION APPROACHES

3. NEUROMODULATION IN SPECIFIC PSYCHIATRIC DISORDERS

4. ELECTROCONVULSIVE THERAPY

5. TRANSCRANIAL MAGNETIC AND ELECTRIC STIMULATION IN PSYCHIATRIC DISORDERS

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

7. NEUROMODULATION FOR OTHER MENTAL HEALTH DISORDERS

8. INVASIVE NEUROSTIMULATION

9. NEUROMODULATION IN CHRONIC PAIN

10. INVASIVE NEUROSTIMULATION IN CHRONIC PAIN

11. SOCIAL ISSUES WITH NEUROSTIMULATORS

12. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

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

48854 • Pressure Injuries: Prevention and Management

1. INTRODUCTION

2. EPIDEMIOLOGY

3. PATHOGENESIS

4. RISK FACTORS

5. STAGING OF PRESSURE INJURIES

6. PHASES OF WOUND HEALING: AN OVERVIEW

7. DIAGNOSIS

8. PREVENTION AND TREATMENT

9. WOUND MONITORING

10. COMPLICATIONS

11. TREATMENT OF COMORBIDITIES

12. ADVANCES IN PRESSURE INJURY CARE

13. MEDICO-LEGAL ASPECTS OF INJURY CARE

14. EDUCATING PATIENTS

15. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 2 Hour Course #97924 • Domestic Violence: The Florida Requirement

97924 • Domestic Violence: The Florida Requirement

1. INTRODUCTION

2. DEFINING DOMESTIC VIOLENCE

3. NATIONAL AND STATE STATISTICS AND LEGISLATION

4. IDENTIFYING GROUPS AT RISK FOR DOMESTIC VIOLENCE

5. CHARACTERISTICS OF PERPETRATORS OF DOMESTIC VIOLENCE

6. SCREENING FOR DOMESTIC VIOLENCE AND ABUSE

7. ASSESSING DOMESTIC VIOLENCE AND ABUSE

8. INTERVENTIONS FOR DOMESTIC VIOLENCE AND ABUSE

9. DOCUMENTATION AND FOLLOW-UP

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 3 Hour Course #91153 • Strategies for Appropriate Opioid Prescribing: The Florida APRN/PA Requirement

91153 • Strategies for Appropriate Opioid Prescribing: The Florida APRN/PA Requirement

1. INTRODUCTION

2. DEFINITIONS

3. EPIDEMIOLOGY OF CHRONIC PAIN AND OPIOID MISUSE

4. INITIATION AND MANAGEMENT OF THE PATIENT WITH PAIN

5. CRISIS INTERVENTION: MANAGEMENT OF OVERDOSE

6. COMPLIANCE WITH STATE AND FEDERAL LAWS

7. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

8. INTERVENTIONS FOR SUSPECTED OR KNOWN DRUG DIVERSION

9. CASE STUDY

10. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

FLPA26 • Florida Physician Assistants 2025-2026

Marjorie Conner Allen, BSN, JD

Mark Rose, BS, MA, LP

Alice Yick Flanagan, PhD, MSW

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

FLPA26 • Florida Physician Assistants 2025-2026

Expiration Date: 08/31/2026

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.

91334 • Medical Error Prevention and Root Cause Analysis

Marjorie Conner Allen, BSN, JD

www.netce.com

Copyright © 2022 NetCE, All rights reserved.

The Institute of Medicine's (IOM) 1999 publication To Err is Human: Building a Safer Health System, illuminated the unfortunate reality of medical errors in the healthcare industry. The report reviewed the prevalence of medical errors in the United States and highlighted measures that should be taken to prevent them. Specifically, the authors of the report noted that at least 44,000 and perhaps as many as 98,000 Americans were dying in hospitals each year as a result of medical errors. A 2016 report stated that the average number of annual in-hospital deaths attributable to medical error might actually be much higher, at around 400,000. Certainly, these numbers must be balanced against the millions of admissions to hospitals in the United States, which is in excess of 35 million annually. Healthcare professionals should commit to continuing to pay attention to evaluating current approaches for reducing errors and to building new systems to reduce the incidence of medical errors.

Table of Contents

91334 • Medical Error Prevention and Root Cause Analysis

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. DEFINING "MEDICAL ERROR"

3. ROOT CAUSE ANALYSIS PROCESS

FLORIDA LAW

4. ERROR REDUCTION AND PREVENTION

PATIENT FALLS

DELAYS IN TREATMENT

UNINTENDED RETENTION OF A FOREIGN BODY

WRONG-SITE SURGERY

PATIENT SUICIDE

OPERATIVE AND POSTOPERATIVE COMPLICATIONS

MEDICATION ERRORS

COMMON MISDIAGNOSES

5. OTHER CONSIDERATIONS FOR PATIENT SAFETY

USE OF AN INTERPRETER

6. CONCLUSION

Works Cited

91334 • Medical Error Prevention and Root Cause Analysis

Education Category. Management

Release Date. 09/01/2022

Review Date. 04/15/2025

Expiration Date. 08/31/2026

Course Overview

The Institute of Medicine's (IOM) 1999 publication To Err is Human: Building a Safer Health System, illuminated the unfortunate reality of medical errors in the healthcare industry. The report reviewed the prevalence of medical errors in the United States and highlighted measures that should be taken to prevent them. Specifically, the authors of the report noted that at least 44,000 and perhaps as many as 98,000 Americans were dying in hospitals each year as a result of medical errors. A 2016 report stated that the average number of annual in-hospital deaths attributable to medical error might actually be much higher, at around 400,000. Certainly, these numbers must be balanced against the millions of admissions to hospitals in the United States, which is in excess of 35 million annually. Healthcare professionals should commit to continuing to pay attention to evaluating current approaches for reducing errors and to building new systems to reduce the incidence of medical errors.

Audience

This course is designed for all licensed healthcare professionals.

Accreditations & Approvals

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

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 2 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 2 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 2 ANCC contact hour(s). NetCE designates this continuing education activity for 2.4 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 2 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. Through the American Board of Medical Specialties ("ABMS") ongoing commitment to increase access to practice relevant Continuing Certification Activities through the ABMS Continuing Certification Directory, Medical Error Prevention and Root Cause Analysis has met the requirements as a Lifelong Learning CME Activity (apply toward general CME requirement) for the following ABMS Member Boards: Allergy and Immunology; Anesthesiology; Colon and Rectal Surgery; Family Medicine; Medical Genetics and Genomics; Nuclear Medicine; Ophthalmology; Physical Medicine and Rehabilitation; Plastic Surgery; Preventive Medicine; Psychiatry and Neurology; Radiology; Thoracic Surgery; Urology. Completion of this course satisfies one Improvement in Medical Practice activity for the American Board of Ophthalmology (ABO). 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 2 MOC points in the American Board of Pediatrics' (ABP) Maintenance of Certification (MOC) program. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABP MOC credit. This activity has been designated for 2 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 2 credit hour(s). AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 0.2 CEU(s) for this program.

Individual State Nursing Approvals

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

Special Approvals

This course fulfills the Florida requirement for 2 hours of education on the Prevention of Medical Errors. 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 satisfy the requirement of the Florida law and provide all licensed healthcare professionals with information regarding the root cause process, error reduction and prevention, and patient safety.

Learning Objectives

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

1. Describe how the Institute of Medicine defines "medical error."

2. Describe the types of sentinel events the Joint Commission has identified.

3. Discuss what factors must be included in a root cause analysis in order for the Joint Commission to consider it "thorough" and "credible."

4. Identify what types of adverse incidents must be reported to the Florida Agency for Healthcare Administration.

5. Identify the most common sentinel events reported to the Joint Commission.

6. Evaluate the most common misdiagnoses, as recognized by the Florida Board of Medicine, and outline the safety needs of special populations, including non-English-proficient patients.

Faculty

Marjorie Conner Allen, BSN, JD, received her Bachelor of Science in Nursing degree from the University of Florida, Gainesville, in 1984. She began her nursing career at Shands Teaching Hospital and Clinics at the University of Florida, Gainesville. While practicing nursing at Shands, she gave continuing education seminars regarding the nursing implications for dealing with adolescents with terminal illness. In 1988, Ms. Allen moved to Atlanta, Georgia where she worked at Egleston Children’s Hospital at Emory University in the bone marrow transplant unit. In the fall of 1989, she began law school at Florida State University. After graduating from law school in 1992, Ms. Allen took a two-year job as law clerk to the Honorable William Terrell Hodges, United States District Judge for the Middle District of Florida. After completing her clerkship, Ms. Allen began her employment with the law firm of Smith, Hulsey & Busey in Jacksonville, Florida where she has worked in the litigation department defending hospitals and nurses in medical malpractice actions. Ms. Allen resides in Jacksonville and is currently in-house counsel to the Mayo Clinic Jacksonville.

Faculty Disclosure

Contributing faculty, Marjorie Conner Allen, BSN, JD, 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

The Institute of Medicine's (IOM) 1999 publication To Err is Human: Building a Safer Health System, illuminated the unfortunate reality of medical errors in the healthcare industry. The report reviewed the prevalence of medical errors in the United States and highlighted measures that should be taken to prevent them. Specifically, the authors of the report noted that at least 44,000 and perhaps as many as 98,000 Americans were dying in hospitals each year as a result of medical errors and many more were being seriously injured [1]. They further noted that, even when using the lower estimate of 44,000, deaths in hospitals due to medical errors exceeded the annual deaths attributable to motor vehicle accidents (43,458), breast cancer (42,297), or AIDS (16,516) [1]. A 2016 report stated that the average number of annual in-hospital deaths attributable to medical error might actually be much higher, at around 400,000 [2]. This report places medical errors as the third leading cause of death in the United States. Certainly, these numbers must be balanced against the millions of admissions to hospitals in the United States, which is in excess of 33 million annually [1,3].

It does appear that some progress has been made in the past decade. The Agency for Healthcare Research and Quality found a 17% decline in hospital-acquired conditions between 2014 and 2017, or 910,000 fewer conditions and 20,500 fewer deaths than if the 2014 rate had remained steady [4]. Though the precise mechanism(s) responsible for this decline is not clear, it occurred following a concerted effort by federal agencies, organizations, and individual providers to curtail medical errors. However, the statistics indicate that medical errors continue to be an issue. Healthcare professionals should commit to continuing to pay greater attention to evaluating approaches for reducing errors and to building new systems to reduce the incidence of medical errors.

Spurred by a commitment to reducing medical error incidents, the Florida Legislature mandates that all healthcare professionals in Florida complete a two-hour course on the topic of prevention of medical errors [5]. This continuing education course is designed to satisfy the requirements of the Florida law and provide all licensed healthcare professionals with information regarding the root cause analysis process, error reduction and prevention, and patient safety, as well as information regarding the five most misdiagnosed conditions as determined by the Florida Board of Medicine.

2. DEFINING "MEDICAL ERROR"

The IOM Committee on Quality of Healthcare in America defines error as "the failure of a planned action to be completed as intended or the use of a wrong plan to achieve an aim" [1]. It is important to note that medical errors are not defined as intentional acts of wrongdoing and that not all medical errors rise to the level of medical malpractice or negligence. Errors depend on two kinds of failures: either the correct action does not proceed as intended, which is described as an "error of execution," or the original intended action is not correct, which is described as an "error of planning" [1]. A medical error can occur at any stage in the process of providing patient care, from diagnosis to treatment, and even while providing preventative care. Not all errors will result in harm to the patient. Medical errors that do result in injury are sometimes called preventable adverse events or sentinel events—sentinel because they signal the need for immediate investigation and response [6].

Preventable adverse events or sentinel events are defined as those events that cause an injury to a patient as a result of medical intervention or inaction on the part of the healthcare provider whereby the injury cannot reasonably be said to be related to the patient's underlying medical condition. Thus, for example, if a patient has a surgical procedure and dies postoperatively from pneumonia, the patient has suffered an adverse event. But was that adverse event preventable; was it caused by medical intervention or inaction? The specific facts of this case must be analyzed to determine whether the patient acquired the pneumonia as a result of poor handwashing techniques of the medical staff (i.e., an error of execution), which would indicate a preventable adverse event, or whether the patient acquired the pneumonia because of age and comorbidities, which would indicate a nonpreventable adverse event.

Healthcare professionals can learn much by closely scrutinizing and evaluating adverse events that lead to serious injury or death. The evaluation of such events would also enable healthcare professionals to improve the delivery of health care and reduce future mistakes. In addition, healthcare professionals should have a process in place to evaluate those instances in which a medical error occurred and did not cause harm to the patient. By reviewing these processes, healthcare professionals are afforded the unique opportunity to identify system improvements that have the potential to prevent future adverse events. The Joint Commission, recognizing the importance of analyzing both preventable adverse events and near-misses, has established guidelines for recognizing these events and requires healthcare facilities to conduct a root cause analysis to determine the underlying cause of the event [7].

3. ROOT CAUSE ANALYSIS PROCESS

The Joint Commission is a national organization with a mission to improve the quality of care provided at healthcare institutions in the United States. It accomplishes this mission by providing accredited status to healthcare facilities. Accreditors play an important role in encouraging and supporting actions within healthcare organizations by holding them accountable for ensuring a safe environment for patients. Healthcare organizations should actively engage in a cooperative relationship with the Joint Commission through this accreditation process and participate in the process to reduce risk and facilitate desired outcomes of care.

Root cause analysis, as defined by the Joint Commission, is "a process for identifying the basic or causal factors that underlie variation in performance, including the occurrence or possible occurrence of a sentinel event" [6]. In the 2022 update, the Joint Commission defines a sentinel event as a "patient safety event (not primarily related to the natural course of the illness or underlying condition) that reaches a patient and results in death, severe harm (regardless of duration of harm), or permanent harm (regardless of severity of harm)" [6,10]. Furthermore, the Joint Commission revision clarified the terms "severe" and "permanent" harm with regard to sentinel events. "Severe harm" is an event or condition that reaches the individual, resulting in life-threatening bodily injury (including pain or disfigurement) that interferes with or results in loss of functional ability or quality of life that requires continuous physiologic monitoring or a surgery, invasive procedure, or treatment to resolve the condition [6,10]."Permanent harm" is an event or condition that reaches the individual, resulting in any level of harm that permanently alters and/or affects an individual's baseline [6,10].

The following subsets of sentinel events are subject to review by the Joint Commission [6,11]:

- The event has resulted in an unanticipated death or major permanent loss of function, not related to the natural course of the patient's illness or underlying condition

or

- The event is one of the following (even if the outcome was not death or major permanent loss of function unrelated to the natural course of the patient's illness or underlying condition):

- Suicide of any patient receiving care, treatment, and services in a staffed around-the-clock care setting or within 72 hours of discharge

- Unanticipated death of a full-term infant

- Abduction of any patient receiving care, treatment, and services

- Any elopement (i.e., unauthorized departure) of a patient from a staffed around the-clock care setting (including the emergency department), leading to death, permanent harm, or severe temporary harm to the patient

- Discharge of an infant to the wrong family

- Rape, assault (leading to death or permanent loss of function), or homicide of any patient receiving care, treatment, and services

- Rape, assault (leading to death or permanent loss of function), or homicide of a staff member, licensed independent practitioner, visitor, or vendor while on site at the healthcare organization

- Hemolytic transfusion reaction involving administration of blood or blood products having major blood group incompatibilities (e.g., ABO, Rh, other blood groups)

- Invasive procedure, including surgery, on the wrong patient or wrong site

- Unintended retention of a foreign object in a patient after surgery or other invasive procedures

- Severe neonatal hyperbilirubinemia (bilirubin >30 mg/dL)

- Fluoroscopy resulting in permanent tissue injury when clinical and technical optimization were not implemented and/or recognized practice parameters were not followed

- Fire, flame, or unanticipated smoke, heat, or flashes occurring during an episode of patient care

- Any intrapartum (related to the birth process) maternal death

- Severe maternal morbidity

- Fall resulting in: any fracture; surgery, casting, or traction; required consult/management or comfort care for a neurological or internal injury; a patient with coagulopathy who receives blood products as a result of the fall; or death or permanent harm as a result of injuries sustained from the fall (not from physiologic events causing the fall)

Alternatively, the following examples are events that are NOT considered reviewable under the Joint Commission's sentinel event policy [6]:

- Any close call ("near miss")

- Full or expected return of limb or bodily function to the same level as prior to the adverse event by discharge or within two weeks of the initial loss of said function, whichever is the longer period

- Any sentinel event that has not affected a recipient of care (e.g., patient, individual, resident)

- Medication errors that do not result in death or major permanent loss of function

- Suicide other than in an around-the-clock care setting or following elopement from such a setting

- A death or loss of function following a discharge against medical advice

- Unsuccessful suicide attempts unless resulting in major permanent loss of function

- Minor degrees of hemolysis not caused by a major blood group incompatibility and with no clinical sequelae

For further definition of terms, please refer to the Joint Commission's Sentinel Event Policy and Procedures at https://www.jointcommission.org/resources/patient-safety-topics/sentinel-event/sentinel-event-policy-and-procedures.

As part of the accreditation requirement, the Joint Commission requires that healthcare organizations have a process in place to recognize these sentinel events, conduct thorough and credible root cause analyses that focus on process and system factors, and document a risk-reduction strategy and internal corrective action plan that includes measurement of the effectiveness of process and system improvements to reduce risk [6]. This process must be completed within 45 business days of the organization having become aware of the sentinel event.

The Joint Commission will consider a root cause analysis acceptable for accreditation purposes if it focuses primarily on systems and processes, not individual performance [6]. In other words, the healthcare organization should minimize the individual blame or retribution for involvement in a medical error. In addition, the root cause analysis should progress from special causes in clinical processes to common causes in organizational processes, and the analysis should repeatedly dig deeper by asking why, then, when answered, why again, and so on. The analysis should also identify changes that can be made in systems and processes, either through redesign or development of new systems or processes, which would reduce the risk of such events occurring in the future. The Joint Commission requires that the analysis be thorough and credible. To be considered thorough, the root cause analysis must include [6]:

- A determination of the human and other factors most directly associated with the sentinel event and the process(es) and systems related to its occurrence

- Analysis of the underlying systems and processes through a series of "why" questions to determine where redesign might reduce risk

- Inquiry into all areas appropriate to the specific type of event

- Identification of risk points and their potential contributions to this type of event

- A determination of potential improvement in processes or systems that would tend to decrease the likelihood of such events in the future, or a determination, after analysis, that no such improvement opportunities exist

To be considered credible, the root cause analysis must meet the following standards [6]:

- The organization's leadership and the individuals most closely involved in the process and systems under review must participate in the analysis.

- The analysis must be internally consistent; that is, it must not contradict itself or leave obvious questions unanswered.

- The analysis must provide an explanation for all findings of "not applicable" or "no problem."

- The analysis must include consideration of any relevant literature.

Finally, as previously discussed, after conducting this root cause analysis, the organization must prepare an internal corrective action plan. The Joint Commission will accept this action plan if it identifies changes that can be implemented to reduce risk or formulate a rationale for not undertaking such changes, and if, where improvement actions are planned, it identifies who is responsible for implementation, when the action will be implemented, and how the effectiveness of the actions will be evaluated [6].

FLORIDA LAW

Healthcare professionals have an obligation to report adverse events to leadership and ensure that organizations have processes in place to satisfy the Joint Commission requirement. In Florida, certain serious adverse incidents must also be reported to Florida's Agency for Health Care Administration (AHCA). Florida law requires that licensed facilities, such as hospitals, establish an internal risk management program. As part of that program, licensed facilities must develop and implement an incident reporting system, which requires the development of appropriate measures to minimize the risk of adverse incidents to patients, as well as imposes an affirmative duty on all healthcare providers and employees of the facility to report adverse incidents to the risk manager or to his or her designee. The risk manager must receive these incident reports within 3 business days of the incident, and depending on the type of incident, the risk manager may have to report the incident to AHCA within 15 days of receipt of the report.

Florida Statute 395.0197 specifically defines an adverse incident as [8]:

For purposes of reporting to the agency pursuant to this section, the term "adverse incident" means an event over which health care personnel could exercise control and which is associated in whole or in part with medical intervention, rather than the condition for which such intervention occurred, and which:

a) Results in one of the following injuries:

1. Death;

2. Brain or spinal damage;

3. Permanent disfigurement;

4. Fracture or dislocation of bones or joints;

5. A resulting limitation of neurological, physical, or sensory function which continues after discharge from the facility;

6. Any condition that required specialized medical attention or surgical intervention resulting from nonemergency medical intervention, other than an emergency medical condition, to which the patient has not given his or her informed consent; or

7. Any condition that required the transfer of the patient, within or outside the facility, to a unit providing a more acute level of care due to the adverse incident, rather than the patient's condition prior to the adverse incident

b) Was the performance of a surgical procedure on the wrong patient, a wrong surgical procedure, a wrong-site surgical procedure, or a surgical procedure otherwise unrelated to the patient's diagnosis or medical condition;

c) Required the surgical repair of damage resulting to a patient from a planned surgical procedure, where the damage was not a recognized specific risk, as disclosed to the patient and documented through informed-consent process; or

d) Was a procedure to remove unplanned foreign objects remaining from a surgical procedure.

In 2021, the Florida AHCA reported that a total of 184 deaths occurred as a result of hospital error, 21.4% of 859 adverse incidents reported for the year. The next most common incidents during this period were transfer of the patient to a unit providing a more acute level of care due to the adverse incident (18.7%), fracture or dislocation of bones or joints (17.0%), surgical procedures unrelated to the patient's diagnosis or medical needs (10.4%), surgical procedure to remove foreign object from a previous surgical procedure (10.2%), brain or spinal damage (5.0%), and surgical procedure performed on wrong site (4.3%) [9]. The following adverse incidents must be reported to the AHCA within 15 calendar days after their occurrence [8]:

- The death of a patient

- Brain or spinal damage to a patient

- The performance of a surgical procedure on the wrong patient

- The performance of a wrong-site surgical procedure

- The performance of a wrong surgical procedure

- The performance of a surgical procedure that is medically unnecessary or otherwise unrelated to the patient's diagnosis or medical condition

- The surgical repair of damage resulting to a patient from a planned surgical procedure, where the damage is not a recognized specific risk, as disclosed to the patient and documented through the informed-consent process

- The performance of procedures to remove unplanned foreign objects remaining from a surgical procedure

Each incident will be reviewed by the AHCA, who will then determine the penalty to be imposed upon the responsible party [8]. All Florida healthcare professionals who practice in licensed facilities should familiarize themselves with these requirements and ensure that the facility in which they practice has processes in place to ensure compliance.

Unlike Florida's mandatory reporting of serious adverse incidents, the Joint Commission recommends that healthcare organizations voluntarily report sentinel events, and it encourages the facilities to communicate the results of their root cause analyses and their corrective action plans. As a result of the sentinel events that have been reported, the Joint Commission has compiled Sentinel Event Alerts. These alerts are intended to provide healthcare organizations with important information regarding reported trends and, by doing so, highlight areas of potential concern so an organization may review its own internal processes to maximize error reduction and prevention with regard to a particular issue [7].

4. ERROR REDUCTION AND PREVENTION

Between 2005 and 2021, the Joint Commission reviewed 14,731 sentinel events [11]. Some events, such as fire, impacted multiple patients. Sentinel event reviews during this time period were frequently conducted for patient fall; delay in treatment; unintended retention of a foreign body; wrong-patient, wrong-site, wrong-procedure surgery; patient suicide; operative and postoperative complications; and medication error [11].

PATIENT FALLS

In 2021, the Joint Commission introduced a separate sentinel event line item for patient falls, making it the most frequently reported sentinel event that year. Patients who are at highest risk include the elderly, those who have an altered mental status due to chronic mental illness or acute intoxication, and those who have a history of prior falls. Additionally, the Joint Commission calls for an increased awareness to an under-recognized population at risk for falls. Newborns and infants are at risk for falls and/or drops, often due to maternal risk factors such as cesarean birth, use of pain medication within four hours, second or third postpartum night (specifically around midnight to early morning hours), and drowsiness associated with breastfeeding. It is obvious from these factors that a thorough and complete patient history may be the key to identifying those at risk.

The root causes of patient falls that healthcare facilities identified as sentinel events and reported to the Joint Commission included inadequate assessment; communication failures; lack of adherence to protocols and safety practices; inadequate staff orientation, supervision, staffing levels, or skill mix; deficiencies in the physical environment; and lack of leadership [19]. Risk reduction strategies to these root causes are fairly straightforward, although in practice, preventing falls is difficult. The most important are the use of a standardized assessment tool to identify fall and injury risk factors, assessing an individual patient's risks that may not have been captured through the tool, and interventions tailored to an individual patient's identified risks [19].

Because patient falls often result in morbidity, mortality, immobility, and early nursing home placement for patients, it is imperative that healthcare facilities initiate adequate fall prevention programs, which will ultimately reduce injuries. Failure to do so will result in a spiraling increase in the number of falls in healthcare facilities, particularly among the elderly who are at highest risk. As more Americans live beyond 65 years of age, the need to develop mobility protocols and programs to reduce the risk of falls and injuries for the older adult grows more urgent.

DELAYS IN TREATMENT

According to the Joint Commission, more than half of all reported delay in treatment sentinel events in 2010–2014 resulted in patient death [16]. It is important to keep in mind that delays in treatment can occur in any healthcare setting. The most common reason for a delay in treatment is misdiagnosis; however, delays can also result from delayed test results, lack of physician availability, delayed administration of ordered care, incomplete treatment, and even inability to get an initial appointment or follow-up appointment in a timely manner [16]. The main root causes contributing to delays in treatment are inadequate assessments, poor planning, communication failures, and human factors. Additionally, 48% of patients self-reported a delay in accessing healthcare during the COVID-19 pandemic. One study suggests that delays in treatment are likely due to widespread public health messages to avoid unnecessary visits, triage uncertainty, lack of providers, and lack of resources [36]. Recommendations from the Joint Commission include avoiding cognitive shortcuts, improving health information technology, incorporating diagnostic checklists into the electronic record, promoting provider-to-provider communication, engaging leadership in developing solutions, focusing organization attention on the scheduling process and on ordering tests and reporting test results, improving access to care, implementing a standardized communications method, maintaining adequate staffing levels, and increasing patient and family engagement/activation [16].

UNINTENDED RETENTION OF A FOREIGN BODY

In 2021, unintended retained foreign objects were the third most frequently reported sentinel event reported to the Joint Commission [11]. The prevalence of these events has remained relatively stable since 2009, indicating that preventing these errors remains difficult for practitioners and facilities. The most commonly retained items are sponges, followed by catheter guidewires and other (a broad category encompassing a wide variety of items) [11].

In addition to harming patients and contributing to distrust in the medical system, the unintended retention of foreign objects significantly contributes to patient care costs [13]. The average total cost of care related to unintended retained foreign objects is $166,000 to $200,000 [13].

According to the sentinel event data, the most common root causes of unintended retained foreign objects reported to the Joint Commission are [13]:

- The absence of policies and procedures

- Failure to comply with existing policies and procedures

- Problems with hierarchy and intimidation

- Failure in communication with physicians

- Failure of staff to communicate relevant patient information

- Inadequate or incomplete education of staff

WRONG-SITE SURGERY

Operating on the wrong part of a patient's body is an obvious sign that there is a problem in the operating room system. Interestingly, wrong-site surgery occurred more commonly in orthopedic procedures than in all other surgical specialties combined. The American Academy of Orthopaedic Surgeons takes this issue seriously, and it has taken special steps to eliminate the problem. For example, it recommends that a surgeon sign their initials at the correct site of surgery with an indelible pen. Unless the initials are visible, the surgeon should not make an incision [12]. Writing "NO" in large black letters on the side not to be operated on was suggested in the past, but this is discouraged due to possible confusion with the surgeon's initials. In spinal surgery, the Academy recommends that an intraoperative radiograph and radiopaque marker be used to determine the exact vertebral level of spinal surgery [12]. Whatever the mechanism used to prevent and reduce the incidence of this error, it is clear that this is not just the surgeon's problem. All operating room personnel, including physicians, nurses, technicians, anesthesiologists, and other preoperative allied health personnel, should monitor procedures to ensure verification procedures are followed, especially for high-risk procedures.

Due to the prevalence of wrong-site, wrong-procedure, and wrong-person surgeries, the Joint Commission, along with more than 50 professional healthcare organizations, convened two summits to help reduce the occurrence of these errors. The first summit, convened in 2003, developed a Universal Protocol that consisted of the following: a preprocedure verification process; marking the operative/procedure site with an indelible marker; taking a "time-out" with all team members immediately before starting the procedure; and adaptation of the requirements to all procedure settings, including bedside procedures. However, the incidence of wrong-site surgeries continued to increase, and in 2007 and 2010, additional summits were organized to pinpoint barriers in compliance and discover new strategies to eliminate these errors [14]. As of 2019, the Universal Protocol has been incorporated into the National Patient Safety Goal chapter of the Joint Commission accreditation manual [15].

PATIENT SUICIDE

It is estimated that between 48 and 65 hospital inpatient suicides occur per year in the United States. Most of these cases (31 to 52) occur in psychiatric units or involve psychiatric inpatients. The most common method is hanging [50]. Times of care transition are particularly risky, with a 200% increase in risk in the week after discharge from a psychiatric facility; the elevated risk continues for four years [18]. Other risk factors include previous suicide attempt or self-injury, mental or emotional disorders, history of trauma or loss, serious illness or chronic pain, substance use disorder, social isolation, and access to lethal means.

The most common root cause documented for patient suicide reported between 2010 and 2014 was shortcomings in assessment, most commonly psychiatric assessment [18]. In addition, nearly 25% of behavioral health facilities accredited by the Joint Commission were found noncompliant with the requirement to conduct an adequate suicide risk assessment in 2014.

The Joint Commission has recommended a number of suicide risk reduction strategies, including [18]:

- Review each patient's personal and family medical history for suicide risk factors.

- Screen all patients for suicide ideation, using a brief, standardized, evidence-based screening tool.

- Review screening questionnaires before the patient leaves the appointment or is discharged.

- Establish a collaborative, ongoing, and systematic assessment and treatment process with the patient involving the patient's other providers, family, and friends, as appropriate.

- To improve outcomes for at-risk patients, develop treatment and discharge plans that directly target suicidality.

- Educate all staff in patient care settings about how to identify and respond to patients with suicide ideation.

- Document decisions regarding the care and referral of patients with suicide risk.

A simple review of these measures demonstrates that healthcare providers can avoid the devastating impact of an inpatient suicide by implementing routine preventative strategies, such as removing harmful items and careful screening through the admission and discharge processes.

OPERATIVE AND POSTOPERATIVE COMPLICATIONS

Many of the sentinel events reported to the Joint Commission regarding operative and postoperative complications occurred in relation to nonemergent procedures, such as interventional imaging and/or endoscopy, tube or catheter insertion, open abdominal surgery, head and neck surgery, orthopedic surgery, and thoracic surgery [17]. The majority of the reporting healthcare facilities cited miscommunication as the primary root cause. Other identified causes include failure to follow established procedures, incomplete preoperative assessment, inconsistent postoperative monitoring procedures, and failure to question inappropriate orders. In order to reduce the risk, reporting facilities have identified a number of strategies, including improving staff orientation and training, increasing educational opportunities for physicians, clearly defining expected channels of communication, and monitoring consistency of compliance with procedures. Healthcare facilities should review postoperative patient monitoring procedures to ensure an adequate level appropriate to the needs of the patient, regardless of the setting (e.g., operating room, endoscopy suite, radiology department) [17]. Based upon these findings, it is clear that direct communication among healthcare providers is key to preventing operative and postoperative complications. Healthcare facilities should provide more staff education regarding preventative measures, and healthcare providers can do their part by engaging in a healthy and mutual respect for all of the members of the healthcare team [17].

MEDICATION ERRORS

Unquestionably, medication errors are one of the most common causes of avoidable harm to patients. These errors may occur at any of these critical points: when ordered or prescribed by a physician; during documentation; while transcribing; when dispensed by a pharmacist; when administered by a nurse; or during monitoring.

The National Coordinating Council for Medication Error Reporting and Prevention defines a medication error as [20]:

Any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient or consumer. Such events may be related to professional practice, healthcare products, procedures, and systems, including prescribing: order communication; product labeling; packaging, and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use.

It has been estimated that up to 50% of medication errors are caused by a provider writing the wrong medication, the wrong route or dose, or the wrong frequency, and nearly 75% of medication errors have been attributed to distraction of the care provider [24]. In addition, a number of medication errors can be linked to the prescriber who continually uses potentially dangerous abbreviations and dose expressions. Despite repeated warnings by the Institute for Safe Medication Practices about the dangers associated with using certain abbreviations when prescribing medications, this practice continues. To eliminate this factor, there are fairly simple steps that can eliminate much confusion. Prescribers should [21]:

- Avoid the use of the symbol "U" or "u" but rather spell "units" when ordering drugs, such as insulin.

- Spell out medication names completely rather than using abbreviations and acronyms.

- Avoid using abbreviations for "daily" (QD), "every other day" (QOD), or "four times daily" (QID), which are easily confused.

- Use leading zeros before a decimal point (e.g., 0.2 mg instead of .2 mg), and do not use trailing zeros (e.g., 2 mg instead of 2.0 mg).

- Write out "morphine sulfate" and "magnesium sulfate" instead of using the abbreviations (MS, MSO_4, MgSO_4).

The Institute for Safe Medication Practices publishes a list of error-prone abbreviations, symbols, and dose designations online at https://www.ismp.org/recommendations/error-prone-abbreviations-list.

Other factors contributing to prescriber errors are illegible or confusing handwriting and, a frequently cited cause of many adverse and sentinel events, the failure of healthcare providers to assess risk and prevent errors. Addressing illegibility may include developing appropriate policies and procedures, tracking and trending patterns, and evaluating results through peer review committees. Improving communication might include developing protocols for the use of verbal orders to assure that those from an onsite practitioner would be limited to an emergency situation only. No verbal orders should be taken for certain medications, such as for chemotherapy, and all verbal orders should be repeated for clarification and, whenever possible, reiterated to a third person. Another method of improving communication might involve reviewing the hospital formulary in collaboration with the Pharmacy and Therapeutics Committee of the medical staff to limit, where appropriate, the number of therapeutically and generically equivalent products [22].

It has been estimated that between 0.2% and 10% of prescriptions are dispensed incorrectly [23]. The three most common dispensing errors are: dispensing an incorrect medication, dosage strength, or dosage form; miscalculating a dose; and failing to identify drug interactions or contraindications [24]. Safe medication dispensing practices may include a number of risk reduction strategies to reduce the incidence of errors that may cause harm to patients [22,25,54,61]:

- Ensure that appropriate and current drug reference texts and/or online resources are immediately available to pharmacy personnel.

- Ensure that essential patient information, such as allergies, age, weight, current diagnoses, pertinent lab values, and current medication regimen, is available to the pharmacist prior to the dispensing of a new medication order.

- Require clarification of any order that is incomplete, illegible, or otherwise questionable using an established process for resolving questions.

- Whenever possible, dispense dosage units in a ready-to-administer form.

- Dispense single-dose vials and ampoules rather than multidose vials.

- Select oral rather than injectable routes, when possible.

- Require that a pharmacist double-check all mathematical calculations for neonatal and pediatric dilutions, parenteral nutrition solutions, and other compounded pharmaceutical products.

- Create an environment for the dispensing area that minimizes distractions and interruptions, provides appropriate lighting, air conditioning, and air flow, safe noise levels, and includes ergonomic consideration of equipment, fixtures, and technology.

- Require that a second pharmacist double-check the accuracy of order entry and dose calculations for all orders involving antineoplastic agents and other high-risk drugs dispensed by the pharmacy.

- Enhance the awareness of look-alike and sound-alike medications, and use warning signs to help differentiate medications from one another, especially when confusion exists between or among strengths, similar looking labels, or similar sounding names.

- Separate look-alike and sound-alike medications in pharmacy dispensing areas or consider repackaging or using different vendors.

- Follow-up and periodically evaluate the need for continued drug therapy for individual patients.

Once again, communication is likely the key to avoiding dispensing errors. Pharmacists should work closely with their staff to ensure that proper protocols are followed, and most importantly, when questions arise regarding a prescription, the pharmacist should take the time to contact the prescriber directly to obtain clarification.

The healthcare provider who has the responsibility to administer a medication has the final opportunity to avoid a mistake. In most cases, particularly in inpatient settings, this responsibility falls to the nurse. Nurses are often taught in nursing school to review the five "rights" prior to administering any medication: the right patient is given the right drug in the right dose by the right route at the right time [26]. Medication errors generally fall into four categories, which mimic these five "rights." The first is the failure to follow procedural safeguards, such as ensuring that essential patient information, including allergies, age, weight, and current medication regimen, is available. The second is unfamiliarity with a drug. In one case, a jury determined that a nurse was negligent for giving a drug without having reviewed the literature, which stated that the necessary precautions for the administration of the drug required the specialized skill of an anesthesiologist. The third category of drug administration is failure to use the correct mode of administration. A nurse in Delaware was held liable for administering a medication by injection after an order had been written to change the route to oral. The final category involves failure to obtain clarification if an order is incomplete, illegible, or otherwise questionable. In a case tried in Louisiana, a nurse was held liable for administering a medication that a physician ordered, notwithstanding that the dose was excessive. The nurse's administration of the drug led to the patient's death [27].

In addition, healthcare facilities should implement appropriate guidelines, policies, and procedures to ensure safe medication administration practice. These policies should require that staff members who administer medications [24,25,54,61]:

- Are knowledgeable about the drug's uses, precautions, contraindications, potential adverse reactions, interactions, and proper method of administration

- Resolve questions prior to medication administration

- Only administer medications that have been properly labeled with medication name, dose to be administered, dosage form, route, and expiration date

- Utilize a standard medication administration time schedule and receive education on how and when to incorporate newly started medication orders safely into the standardized schedule

- Have a second person verify a dosage calculation if a mathematical calculation of a dose is necessary

- Receive adequate education on the operation and use of devices and equipment used for medication administration (for example, patient-controlled anesthesia pumps and other types of infusion pumps)

- Have another person double-check infusion pump settings when critical, high-risk drugs are infused

- Document all medications immediately after administration

Finally, healthcare facilities should have proper quality assurance measures in place to monitor medication administration practices. Included among these would be protocols and guidelines for use with critical and problem-prone medications to help optimize therapies and minimize the possibility of adverse events and to integrate "triggers" to indicate the need for additional clinical monitoring [25].

It is important to note that the pediatric population is especially vulnerable to medication errors. When children are prescribed adult medications, care must be taken to adjust dosage according to weight, requiring the physician to use pediatric-specific calculations. Also, many healthcare settings are not trained to care for the pediatric patient. Intolerance due to physiologic immaturity is also a factor in adverse response to medications, and in many cases, this population cannot communicate their discomfort due to adverse reactions. Risk reduction strategies include standardizing and effectively identifying medications and processes for drug administration, ensuring pharmacy oversight, and using technology, such as medication dispensing programs, infusion pumps, and bar-coding, judiciously [28].

COMMON MISDIAGNOSES

As Florida healthcare professionals, it is important to be aware that in addition to wrong-site/wrong-procedure surgery, several medical conditions also continue to be misdiagnosed. As of 2024, the Florida Board of Medicine has determined the five most misdiagnosed conditions to be [29]:

- Oncology-related conditions

- Gastroenterology-related issues

- Cardiology-related issues

- Neurologic conditions

- Infectious disease-related conditions

It is important to be aware of the possibility of misdiagnosis and incorporate this knowledge into practice.

Oncology-Related Conditions

The early detection and diagnosis of cancers is crucial for selecting the appropriate treatment approach and to ensure an optimum outcome. However, an estimated 12% of cancer patients are initially misdiagnosed, and the missed or delayed diagnosis of cancers remains a significant cause of medical malpractice claims [30,31]. The causes of missed diagnoses vary widely among cancers in different parts of the body. In many cases, patients who do not fit the typical profile for a specific cancer (e.g., young age) may be underdiagnosed, and it is important that cancer is considered as part of the differential diagnosis in ambiguous cases [31,32,33]. In order to prevent missed or delayed cancer diagnosis, practitioners may take steps to ensure adherence to clinical guidelines for screening and diagnosis, use tools to facilitate communication, and engage strategies to ensure appropriate follow-up [55].

Gastroenterology-Related Conditions

Gasteroenterologic conditions may present with nonspecific complaints (e.g., abdominal pain, nausea) common to a variety of illnesses, complicating and delaying diagnosis. In one study of patients with pancreatic cancer, more than 30% were initially misdiagnosed, most commonly with gall bladder disease [58]. Diagnosis and screening for gastrointestinal disorders may be complicated by a lack of definitive test (e.g., irritable bowel syndrome) or by limits on screening recommendations (e.g., colorectal cancer). However, delayed diagnosis can lead to worsening conditions and poorer prognosis.

In general, gastrointestinal syndromes/symptoms may be classified into three general diagnostic categories: organic, motility, or functional disorders [59,60]. Functional GI disorders are idiopathic disorders of gut-brain interaction and, unlike organic and motility disorders, diagnosis involves identification of symptom clusters. As such, misdiagnosis is more common.

Another important consideration is GI symptom-specific anxiety, an important perpetuating factor that describes threatening interpretation and out-of-proportion behavioral response to GI sensations. This anxiety to real GI symptoms and the frequency of psychiatric comorbidity can lead to functional GI syndromes being dismissed as psychological or psychosomatic in nature.

Cardiology-Related Issues

The clinical presentation of chest pain has many possible etiologies, ranging from benign (e.g., panic/anxiety, pneumonia, peptic ulcer, gastroesophageal reflux disease, and pericarditis) to life-threatening (e.g., pulmonary embolism, acute coronary syndrome [ACS], aortic dissection, and pneumothorax). In many cases, it is best to rule out the more urgently threatening possibilities before testing for other causes.

Of the potentially life-threatening causes of chest pain, ACS is the most prevalent. Although a large percentage of individuals with suspected ACS will be seen initially in emergency departments, patients in any healthcare setting, regardless of other diagnoses, may abruptly develop chest pain suspicious for ACS. When a patient presents with clinical signs suspicious for myocardial infarction, immediate medical intervention is directed at confirming a diagnosis and stratifying the person's risk for adverse events such as cardiac arrest and severe/significant damage to the myocardium [41]. It is important to note that while some patients will present with classic ACS-related chest pain (tightness, sensation of pressure, heaviness, crushing, vise-like, aching pain in the substernal or upper left chest), many patients, particularly women and older patients, will present with "atypical" ACS-related chest pain [45,46]. Words commonly used to describe "atypical" chest pain associated with ACS include numbness, tingling, burning, stabbing, or pricking. Atypical chest pain location includes any area other than substernal or left sided, such as the back, area between shoulder blades, upper abdomen, shoulders, elbows, axillae, and ears [43,44,45,46]. Aside from atypical clinical presentation, other possible causes of missed ACS diagnosis include failure of interpretation of the history, failure to correctly interpret the electrocardiogram, failure to perform an electrocardiogram when necessary, and lack of proper use of cardiac enzyme test [47].

Neurologic-Related Conditions

Delayed or missed diagnoses of neurologic conditions may result in serious morbidity and mortality. Headaches are a common presenting condition in acute and primary care, and an estimated 5% of all patients admitted to emergency departments have neurologic symptoms [34]. Acute headache with neurologic symptoms may be misdiagnosed as stroke [35,64]. In addition, missed spinal fracture diagnoses are one of the leading causes of malpractice claims against radiologists [48].

One of the most common neurologic conditions is headache; however, it has been estimated that 50% of migraine patients remain undiagnosed or misdiagnosed, and only a small number (8% to 10%) of individuals with migraine take migraine-specific medications such as triptans or ergotamines [65,66]. Patients suffering from daily migraines may be misdiagnosed with chronic sinusitis or rhinitis and repeatedly and unsuccessfully treated with broad-spectrum antibiotics [62,63]. The diagnosis of migraine is based solely on a constellation of signs and symptoms, and a comprehensive medical and neurological examination is required to exclude secondary headache [56]. Useful evidence-based clinical guidelines for migraine screening have been developed and are summarized in the mnemonic POUND: pulsatile headache; one-day duration (4 to 72 hours); unilateral location; nausea or vomiting; and disabling intensity [57]. Competence of the clinician and effective communication with the patient play a crucial role in the diagnosis of migraine.

Infectious Disease-Related Conditions

Acute infection was the most commonly misdiagnosed disease in one study, with the potential adverse outcomes of sepsis, organ damage, and even death [37]. The presentation of infectious diseases may be atypical in certain populations (e.g., the elderly), making detection even more difficult. In one survey of physicians, delayed diagnoses were found to commonly occur with tuberculosis, nontuberculous mycobacterial infections, syphilis, epidural abscess, infective endocarditis, and endemic fungal infections (e.g., histoplasmosis, blastomycosis) [38]. Diseases with general symptoms and varied presentations (e.g., Lyme disease) also present complicated clinical pictures. Adherence to established guidelines for the diagnosis and treatment of specific infectious diseases and attentive patient assessment and history are recommended in order to improve diagnostic accuracy [39,40,42]. In addition, early consultation with an infectious disease specialist has been identified as potentially mitigating factor [38].

5. OTHER CONSIDERATIONS FOR PATIENT SAFETY

The most important issue to improving patient safety is being aware of the particular safety hazards that may exist for various patient populations and on particular specialty units. In addition, education of the patient and the family should be a priority.

Infants and young children are not developmentally or cognitively able to participate in care and decision making, thus putting them at higher risk, especially for medication errors. In addition, when a medication error occurs in this population, infants and young children are at higher risk because of their physical immaturity and increased sensitivity to the effects of drugs. The family or guardian of a pediatric patient should be encouraged to ask questions, especially if something seems wrong. In addition, a meta-analysis found that computerized provider order entry with clinical decision support reduced pediatric medication errors by 36% to 87% [51]. As such, the adoption of electronic support systems may help to reduce or eliminate these errors.

An estimated 30% of individuals 65 years of age or older who are living in the community fall each year [52]. Older patients may have poor vision, as a result of cataracts, glaucoma, and/or macular degeneration, and cardiovascular problems, which might result in syncope or postural hypotension. These conditions may affect patients' balance and stability. Bladder dysfunction, such as nocturia, may cause an elderly patient to have to ambulate more during the night in an unfamiliar environment, thereby increasing the risk of a fall. Lower extremity dysfunctions, such as arthritis, muscle weakness, or peripheral neuropathy, may make it more difficult to ambulate at any time. In addition to being at greater risk for falls, the elderly are also more prone to medication errors as their ability to understand instructions or to recognize an unfamiliar medication may be affected by dementia or other cognitive disorders. Interventions that can help prevent falls in the elderly include exercise programs, tai chi, vision improvement (e.g., first cataract surgery), and multifactorial assessment and intervention [52].

There are also unique factors that increase the risk of medical errors on specialty units. For instance, in critical care units, patients may be suffering from environmental psychosis, which could inhibit participation in their care. This is also true of lethargic and comatose patients. These patients are at particular risk because they cannot participate in the identification process. On psychiatric wards, patients may be suicidal or depressed, which may cause them to act out or attempt to harm themselves or others. Patients may also experience orthostatic side effects due to certain psychiatric medications, which may increase the incidence of falls. Obstetric patients are at higher risk for falls because they may have decreased sensation and mobility due to administration of epidural anesthesia, and they may also suffer from excessive blood loss, which could lead to postural hypotension [49]. Again, the key is identifying the unique needs of the particular population.

With regard to education, a number of organizations have developed guidelines to facilitate the role of patients as their own safety advocates. These guidelines are not intended to shift the burden of monitoring medical error to patients. Rather, they encourage patients to share responsibility for their own safety. As healthcare professionals, we should ensure that all of our patients are familiar with these guidelines. The Agency for Healthcare Research and Quality has developed a "Patient Fact Sheet" that outlines 20 tips for patients to help prevent medical errors [53]. Although some of these suggestions may seem extreme, many patients now desire to have a more active role in their care. Some of these items have become routine or are currently required, such as consultations by pharmacists when a patient picks up a prescribed medication.

USE OF AN INTERPRETER

As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because patient education is such a vital aspect of preventing medical errors, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient understanding. 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 are more than passive agents who translate and transmit information back and forth from party to party. They should be professionally trained in ethics, accuracy, completeness, and impartiality. Furthermore, it is the interpreter's role to negotiate cultural differences and promote culturally responsive communication and practice. 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 diagnostic procedures, treatment options, or medication/treatment measures is being provided, the use of an interpreter should be considered.

6. CONCLUSION

Although the United States has one of the top healthcare systems in the world, it is apparent that the numbers of medical errors are at unacceptably high levels. The consequences of medical errors are often more severe than the consequences of mistakes in other industries. They may lead to death or to serious and long-term disability, which underscores the need for aggressive action in this area. As a starting point, we should become an active part of the solution. This will only happen if all healthcare professionals voice their concerns when they identify problems in a system or process. In addition, we should actively participate in the root cause analysis process, understanding that the goal is not to assign blame, but rather to identify how we can improve the process to provide the best quality care to our patients. Medical errors are costly, not only because patients may lose their lives or livelihoods, but also because patients lose trust in the system and colleagues lose faith in each other. To preserve the integrity of our system, we must correct this problem, and the solution begins with each of us.

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97144 • Assessment and Management of Pain at the End of Life

John M. Leonard, MD

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

Because pain is frequently encountered in the palliative and hospice care environments, a knowledge of appropriate diagnosis and alleviation is vital to all members of the interdisciplinary team. A comprehensive discussion of these topics will provide the knowledge base necessary for all members of the interprofessional team to better understand the varied needs of their patients during the end-of-life period and to be better equipped to address those needs.

Table of Contents

97144 • Assessment and Management of Pain at the End of Life

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. ISSUES IN EFFECTIVE PAIN MANAGEMENT

3. ETIOLOGY

4. ASSESSMENT

5. MANAGEMENT

PHARMACOLOGIC INTERVENTIONS

NONPHARMACOLOGIC INTERVENTIONS

6. LEGAL AND ETHICAL ISSUES RELATED TO THE TREATMENT OF PAIN

PATIENTS WITH HISTORY OF SUBSTANCE ABUSE

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

97144 • Assessment and Management of Pain at the End of Life

Education Category. Ethics - Human Rights

Release Date. 11/01/2024

Expiration Date. 10/31/2027

Course Overview

Because pain is frequently encountered in the palliative and hospice care environments, a knowledge of appropriate diagnosis and alleviation is vital to all members of the interdisciplinary team. A comprehensive discussion of these topics will provide the knowledge base necessary for all members of the interprofessional team to better understand the varied needs of their patients during the end-of-life period and to be better equipped to address those needs.

Audience

This course is designed for physicians, physician assistants, nurses, social workers, and other members of the healthcare team seeking to enhance their knowledge of pain management.

Accreditations & Approvals

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

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 2 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 2 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 2 ANCC contact hour(s). NetCE designates this continuing education activity for 2 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 2 pharmacology hour(s) for physician assistants. NetCE designates this continuing education activity for 2.4 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 2 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. This activity has been designated for 2 Lifelong Learning (Part II) credits for the American Board of Pathology Continuing Certification Program. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. NetCE is authorized by IACET to offer 0.2 CEU(s) for this program. AACN Synergy CERP Category A.

Individual State Nursing Approvals

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

Special Approvals

This course fulfills the West Virginia requirement for 2 hours of continuing education in end-of-life care and pain management. This course meets the New Jersey requirement for 2 hours of end-of-life education. This course meets the Michigan requirement for 2 hours of continuing education in pain and pain symptom management. This course has been approved by the Kentucky Board of Medical Licensure to meet the requirement for continuing medical education relating to pain management and addiction disorders, as required by HB 1 of the Kentucky General Assembly. Course approval #0620-H2.0-NET4. This course meets the New Jersey requirement for 1 hour of continuing education in topics concerning opioid drugs, including the risks and signs of opioid abuse, addiction, and diversion. This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

Because pain is frequently encountered in the palliative and hospice care environments, a knowledge of appropriate diagnosis and alleviation is vital to all members of the interdisciplinary team. The purpose of this course is to provide an overview of the assessment and management of pain in the end of life, focusing on the components integral to providing optimum care.

Learning Objectives

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

1. Describe the etiology of pain at the end of life and issues in effective pain management.

2. Assess pain accurately through use of clinical tools and other strategies, including the use of an interpreter.

3. Select appropriate pharmacologic and/or nonpharmacologic therapies to manage pain in patients during the end-of-life period.

Faculty

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

Faculty Disclosure

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

Division Planners

John V. Jurica, MD, MPH

Mary Franks, MSN, APRN, FNP-C

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

Unrelieved pain is the greatest fear among people with a life-limiting disease, and the need for an increased understanding of effective pain management is well-documented[1]. Although experts have noted that 75% to 90% of end-of-life pain can be managed effectively, rates of pain are high, even among people receiving palliative care [1,2,3,4,5,6,7,8,9,10].

2. ISSUES IN EFFECTIVE PAIN MANAGEMENT

The inadequate management of pain is the result of several factors related to both patients and clinicians. In a survey of oncologists, patient reluctance to take opioids or to report pain were two of the most important barriers to effective pain relief [11]. This reluctance is related to a variety of attitudes and beliefs [1,11]:

- Fear of addiction to opioids

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

- Anxiety about unpleasant side effects from pain medications

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

- Desire to be a "good" patient

- Concern about the high cost of medications

Education and open communication are the keys to overcoming these barriers. Every member of the healthcare team should reinforce accurate information about pain management with patients and families. The clinician should initiate conversations about pain management, especially regarding the use of opioids, as few patients will raise the issue themselves or even express their concerns unless they are specifically asked [12]. It is important to acknowledge patients' fears individually and provide information to help them differentiate fact from fiction. For example, when discussing opioids with a patient who fears addiction, the clinician should explain that the risk of addiction is low [1]. It is also helpful to note the difference between addiction and physical dependence.

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

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

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

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

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

Clinicians' attitudes, beliefs, and experiences also influence pain management, with addiction, tolerance, side effects, and regulations being the most important concerns [1,8,11,13,14,15]. A lack of appropriate education and training in the assessment and management of pain has been noted to be a substantial contributor to ineffective pain management [11,13,15,16]. As a result, many clinicians, especially primary care physicians, do not feel confident about their ability to manage pain in their patients [11,13].

Cultural and demographic factors may also contribute to lack of effective pain management. Expression of pain and the use of pain medication differ across cultures. For example, Hispanic and Filipino patients have been shown to be reluctant to report pain because of fear of side effects or addiction [17]. Even when effective opioids have been prescribed, access may be difficult, as inadequate supplies of opioids are more likely in pharmacies in primarily nonwhite neighborhoods [18]. Communication with patients regarding level of pain is a vital aspect of caring for patients in the end of life. 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.

3. ETIOLOGY

The prevalence of pain at the end of life has been reported to range from 8% to 96%, occurring at higher rates among people with cancer than among adults with other life-limiting diseases [19,20]. Pain can be caused by a multitude of factors and is usually multidimensional, with pain frequently being exacerbated by other physical symptoms and by psychosocial factors, such as anxiety or depression [8].

4. ASSESSMENT

Pain should be assessed routinely, and frequent assessment has become the standard of care [8]. Pain is a subjective experience, and as such, the patient's self-report of pain is the most reliable indicator. Research has shown that pain is underestimated by healthcare professionals and overestimated by family members [8,21]. Therefore, it is essential to obtain a pain history directly from the patient, when possible, as a first step toward determining the cause of the pain and selecting appropriate treatment strategies. When the patient is unable to communicate verbally, other strategies must be used to determine the characteristics of the pain, as will be discussed.

Questions should be asked to elicit descriptions of the pain characteristics, including its location, distribution, quality, temporal aspect, and intensity. In addition, the patient should be asked about aggravating or alleviating factors. Pain is often felt in more than one area, and physicians should attempt to discern if the pain is focal, multifocal, or generalized. Focal or multifocal pain usually indicates an underlying tissue injury or lesion, whereas generalized pain could be associated with damage to the central nervous system. Pain can also be referred, usually an indicator of visceral pain.

The quality of the pain refers to the sensation experienced by the patient, and it often suggests the pathophysiology of the pain [8]. Pain that is well localized and described as aching, throbbing, sharp, or pressure-like is most likely somatic nociceptive pain. This type of pain is usually related to damage to bones and soft tissues. Diffuse pain that is described as squeezing, cramping, or gnawing is usually visceral nociceptive pain. Pain that is described as burning, tingling, shooting, or shock-like is neuropathic pain, which is generally a result of a lesion affecting the nervous system.

Temporal aspects of pain refer to its onset: acute, chronic, or "breakthrough." A recent onset characterizes acute pain, and there are accompanying signs of generalized hyperactivity of the sympathetic nervous system (diaphoresis and increased blood pressure and heart rate). Acute pain usually has an identifiable, precipitating cause, and appropriate treatment with analgesic agents will relieve the pain. When acute pain develops over several days with increasing intensity, it is said to be subacute. Episodic, or intermittent, pain occurs during defined periods of time, on a regular or irregular basis. Chronic pain is defined as pain that persists for at least three months beyond the usual course of an acute illness or injury. Such pain is not accompanied by overt pain behaviors (grimacing, moaning) or evidence of sympathetic hyperactivity.

"Breakthrough" is the term used to describe transitory exacerbations of severe pain over a baseline of moderate pain [22]. Breakthrough pain can be incident pain or pain that is precipitated by a voluntary act (such as movement or coughing) or can occur without a precipitating event. Breakthrough pain occurs in as many as 90% of people with cancer or in hospice settings and is often a consequence of inadequate pain management [1].

Documentation of pain intensity is key, as several treatment decisions depend on the intensity of the pain. For example, severe, intense pain requires urgent relief, which affects the choice of drug and the route of administration [8,23]. The numeric rating scale is the tool used most often to assess pain; with this tool, patients rate pain on a scale of 0 to 10 [8]. Visual analogue scales (patients rate pain on a line from 0 to 10) and verbal rating scales, which enable the patient to describe the pain as "mild," "moderate," or "severe," have also been found to be effective. Some patients, however, may have difficulty rating pain using even the simple scales. In an unpublished study involving 11 adults with cancer, the Wong-Baker FACES scale, developed for use in the pediatric setting, was found to be the easiest to use among three pain assessment tools that include faces to assess pain [24].

Functional assessment is important. The healthcare team should observe the patient to see how pain limits movements and should ask the patient or family how the pain interferes with normal activities. Determining functional limitations can help enhance patient compliance in reporting pain and adhering to pain-relieving measures, as clinicians can discuss compliance in terms of achieving established functional goals [12]. The Memorial Pain Assessment Card can be used to evaluate both the severity of pain and the effect of pain on function [8,25].

Physical examination can be valuable in determining an underlying cause of pain. Examination of painful areas can detect evidence of trauma, skin breakdown, or changes in osseous structures. Auscultation can detect abnormal breath or bowel sounds; percussion can detect fluid accumulation; and palpation can reveal tenderness. A neurologic examination should also be carried out to evaluate sensory and/or motor loss and changes in reflexes. During the examination, the clinician should watch closely for nonverbal cues that suggest pain, such as moaning, grimacing, and protective movements. These cues are especially important when examining patients who are unable to verbally communicate about pain.

5. MANAGEMENT

Strong evidence supports pain management approaches for people with cancer, but the evidence base for management of pain in people with other life-limiting diseases is weak [2,4,26,27,28,29,30]. Effective pain management involves a multidimensional approach involving pharmacologic and nonpharmacologic interventions that are individualized to the patient's specific situation [8].

PHARMACOLOGIC INTERVENTIONS

The WHO analgesic ladder, introduced in 1986 and disseminated worldwide, remains recognized as a useful educational tool but not as a strict protocol for the treatment of pain. It is intended to be used only as a general guide to pain management [31]. The three-step analgesic ladder designates the type of analgesic agent based on the severity of pain (Figure 1) [31]. Step 1 of the WHO ladder involves the use of nonopioid analgesics, with or without an adjuvant (co-analgesic) agent, for mild pain (pain that is rated 1 to 3 on a 10-point scale). Step 2 treatment, recommended for moderate pain (score of 4 to 6), calls for a weak opioid, which may be used in combination with a step 1 nonopioid analgesic for unrelieved pain. Step 3 treatment is reserved for severe pain (score of 7 to 10) or pain that persists after Step 2 treatment. Strong opioids are the optimum choice of drug at Step 3. At any step, nonopioids and/or adjuvant drugs may be helpful. Some consider this model to be outdated and/or simplistic, but most agree that it remains foundational. It can be modified or revised, as needed, to apply more accurately to different patient populations.

Figure 1: THE WORLD HEALTH ORGANIZATION'S THREE-STEP LADDER OF ANALGESIA

Source: [31]

The WHO ladder is also accompanied by five guiding principles [31]:

- Reduce pain to levels that allow an acceptable quality of life.

- Global assessment of the patient should guide treatment, recognizing that individuals experience and express pain differently.

- The safety of patients, carers, healthcare providers, communities, and society must be assured.

- A pain management plan includes pharmacologic treatments and may include psychosocial and spiritual care.

- Analgesics, including opioids, must be accessible: both available and affordable.

The pharmacologic treatment of pain involves selecting the right drug(s) at the right dose, frequency, and route, and managing side effects [8].

Nonopioid analgesics, such as aspirin, acetaminophen (Tylenol), and nonsteroidal anti-inflammatory drugs (NSAIDs), are primarily used for mild pain (Step 1 of the WHO ladder) and may also be helpful as coanalgesics at Steps 2 and 3. Acetaminophen is among the safest of analgesic agents, but it has essentially no anti-inflammatory effect. Toxicity is a concern at high doses, and the maximum recommended dose is 3–4 g per day [8]. Acetaminophen should be avoided or given at lower doses in people with a history of alcohol abuse or renal or hepatic insufficiency [8].

NSAIDs are most effective for pain associated with inflammation. Among the commonly used NSAIDs are ibuprofen (Motrin, Advil), naproxen (Aleve, Naprosyn), and indomethacin (Indocin). There are several classes of NSAIDs, and the response differs among patients; trials of drugs for an individual patient may be necessary to determine which drug is most effective [33]. NSAIDs inhibit platelet aggregation, increasing the risk of bleeding, and also can damage the mucosal lining of the stomach, leading to gastrointestinal bleeding. There is a ceiling effect to the nonopioid analgesics; that is, there is a dose beyond which there is no further analgesic effect. In addition, many side effects of nonopioids can be severe and may limit their use or dosing.

Moderate pain (Step 2) has often been treated with analgesic agents that are combinations of acetaminophen and an opioid, such as codeine, oxycodone, or hydrocodone. However, it is now recommended that these combination drugs be avoided, as limits on the maximum dose of acetaminophen limits the use of a combination drug [8,34]. Individual drugs in combination is preferred, allowing for increases in the dose of the opioid without increasing the dose of the co-analgesic.

Strong opioids are used for severe pain (Step 3). Guidelines suggest that the most appropriate opioid dose is the dose required to relieve the patient's pain throughout the dosing interval without causing unmanageable side effects [4,8,26,28,30,34,36]. Morphine, buprenorphine, oxycodone, hydromorphone, fentanyl, and methadone are the most widely used Step 3 opioids in the United States [35]. Unlike nonopioids, opioids do not have a ceiling effect, and the dose can be titrated until pain is relieved or side effects become unmanageable. For an opioid-naïve patient or a patient who has been receiving low doses of a weak opioid, the initial dose of a Step 3 opioid should be low, and, if pain persists, the dose may be titrated up daily until pain is controlled. Opioid-naïve patients are those who are not receiving opioid analgesic daily and therefore have not developed significant tolerance. Opioid-tolerant patients are those who have been taking an opioid analgesic daily for at least one week. The FDA identifies tolerance as receiving at least 60 mg of morphine daily, 30 mg of oral oxycodone daily, 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid for one week or longer [30]. Typical starting doses for patients who are opioid-naïve have been noted, but these doses should be used only as a guide, and the initial dose, as well as titrated dosing, should be done on an individual basis (Table 1).

Table 1: OPIOIDS FOR THE MANAGEMENT OF PAIN IN ADULTSa

Drug

Typical Starting Doseb

Onset of Action

Duration of Action

Codeine

15–60 mg

30 to 60 minutes

4 to 6 hours

Hydrocodone

2.5–10 mg

10 to 20 minutes

4 to 8 hours

Morphine, immediate release

15–30 mg

15 to 30 minutes (oral)

5 to 10 minutes (IV)

3 to 6 hours

Oxycodone, immediate release

5–10 mg

10 to 30 minutes

3 to 4 hours

Oxymorphone, sustained release

10 mg

5 to 10 minutes

8 to 12 hours

Hydromorphone

2–4 mg

15 to 30 minutes

4 to 5 hours

Methadone

5–10 mg

30 to 60 minutes

4 to 6 hours

Tapentadol

50–100 mg

<60 minutes

4 to 6 hours

Tapentadol, extended release

50–100 mg

—

—

Fentanyl (buccal tablet)

100–200 mcg

5 to 15 minutes

2 to 4 hours

Fentanyl (transdermal patch)

25 mcg/hour (worn for 3 days)

12 to 18 hours

48 to 72 hours

Buprenorphine (transdermal patch)

5–10 mcg/hour (worn for 7 days)

—

—

aAll information is given for oral formulations unless otherwise specified.

bDoses given are guidelines for opioid-naïve patients; actual doses should be determined on an individual basis.

Source: [4,8,30,37,38,39]

The most serious potential adverse effect following initiation of opioids for treatment of pain is oversedation followed by respiratory depression. To mitigate this risk, clinicians should discuss the role of naloxone administration by caregivers in the event of sedation/respiratory depression and make naloxone available as indicated or as required by local regulations [30]. When initiating morphine, or any opioid agent for treatment of moderate/severe pain, the prescribing clinician should consider lower starting dose titration in frail or older patients and in any patient with renal insufficiency (reduced creatinine clearance).

More than one route of opioid administration will be needed by many patients during end-of-life care, but in general, opioids should be given orally, as this route is the most convenient and least expensive. The transdermal route is preferred to the parenteral route, although dosing with a transdermal patch is less flexible and may not be appropriate for patients with unstable pain [8]. Intramuscular injections should be avoided because injections are painful, drug absorption is unreliable, and the time to peak concentration is long [8].

Morphine is considered to be the first-line treatment for a Step 3 opioid [34]. Morphine is available in both immediate-release and sustained-release forms, and the latter form can enhance patient compliance. The sustained-release tablets should not be cut, crushed, or chewed, as this counteracts the sustained-release properties. Morphine should be avoided in patients with severe renal failure [28].

Buprenorphine (Butrans) has the general structure of morphine but differs from it in several ways [35]. The transdermal formulation of the drug was approved in 2010 for moderate-to-severe chronic pain in patients requiring an around-the-clock opioid for an extended period [8]. It may be used for people with renal impairment but is contraindicated in patients who have substantial respiratory depression [35,37].

The sustained-release form of oxycodone (OxyContin) has been shown to be as safe and effective as morphine for cancer-related pain, and it may be associated with less common side effects, especially hallucinations and delirium [40]. Oxycodone is also available in an immediate-release form (Roxicodone). Oxycodone should be used in people with advanced chronic kidney disease only if alternative options are not available [28]. If the drug must be used, the intervals between doses should be increased, and the patient should be monitored closely [28].

Hydromorphone and fentanyl are the most potent opioids; neither drug should be given to an opioid-naïve patient. Hydromorphone, which is four times as potent as morphine, is available in immediate- and extended-release forms [41]. Fentanyl is the strongest opioid (approximately 80 times the potency of morphine) and is available as a transdermal drug-delivery system (Duragesic; Ionsys); a buccal film (Onsolis) and tablet (Fentora); a nasal spray (Lazanda); a sublingual spray (Subsys); a sublingual tablet (Abstral); and a lozenge (Actiq) [37,42]. Fentanyl preparations have a more rapid onset than other opioids given nonparenterally [8]. Because of its potency, fentanyl must be used with extreme care, as deaths have been associated with its use. Physicians must emphasize to patients and their families the importance of following prescribing information closely, and members of the healthcare team should monitor the use of the drug. Fentanyl, administered subcutaneously, is the recommended choice for patients with advanced chronic kidney disease [28].

The use of methadone to relieve pain has increased substantially over the past few years, moving from a second-line or third-line drug to a first-line medication for severe pain in people with life-limiting diseases [43]. A systematic review showed that methadone had efficacy similar to that of morphine [44]. However, the authors' conclusions were based on low-quality evidence. Other opioids (e.g., morphine, fentanyl) are easier to manage but may be more expensive than methadone in many economies [44]. Physicians must be well educated about the pharmacologic properties of methadone, as the risk for serious adverse events, including death, is high when the drug is not administered appropriately [44,45]. If the dose of methadone is increased too rapidly or administered too frequently, toxic accumulation of the drug can cause respiratory depression and death. Because of the unique nature of methadone, and its long and variable half-life, extreme care must be taken when titrating the drug, and frequent and careful evaluation of the patient is required. Practitioners are advised to consult with a pain or palliative care specialist if they are unfamiliar with methadone prescribing or if individual patient considerations necessitate rapid switching to or from methadone [4].

Meperidine (Demerol) should not be used in the palliative care setting because of limited efficacy and potential for severe toxicity [12,33]. Agonist-antagonist opioids (nalbuphine [Nubain], butorphanol [Stadol], and pentazocine [Talwin]) are not recommended for use with pure opioids, as they compete with them, leading to possible withdrawal symptoms.

Tapentadol (Nucynta) is a short-acting opioid approved for moderate to severe pain in adults; an extended release formulation (Nucynta ER) was approved in 2011 for moderate-to-severe chronic pain when an around-the-clock opioid is needed [46]. The drug is associated with a lower incidence of adverse effects than other opioids, and it has been shown to be highly effective for chronic pain conditions but has not been extensively studied in cancer-related pain or the palliative care setting [47]. A 2014 study of 123 patients that had previously received long-term analgesia for cancer-related pain showed tapentadol significantly reduced pain scores and was generally well tolerated; concomitant use of pain medications was also reduced [48].

The most appropriate option for breakthrough pain is an immediate-release opioid taken in addition to the around-the-clock regimen [8]. The fentanyl buccal tablet has been shown to be effective and safe for relieving breakthrough pain in people who are opioid tolerant [4,49,50]. Between January 2011 and January 2012, three forms of fentanyl were approved for breakthrough pain in people with cancer: fentanyl sublingual tablet (Abstral), fentanyl nasal spray (Lazanda), and fentanyl sublingual spray (Subsys) [37]. Abstral and Lazanda have since been discontinued [37,41]. As of 2021, the fentanyl lozenge (Actiq) and buccal tablet (Fentora) are also approved for breakthrough cancer pain [41]. For each formula, the initial dose may be repeated once if pain is not relieved adequately after 30 minutes. Patients must wait at least two hours before using the sublingual tablet, buccal film, or the nasal spray for another breakthrough pain episode; the interval is four hours for the sublingual spray, lozenge, or buccal tablet [37,41].

When pain responds poorly to escalated doses of an opioid, other approaches should be considered, including alternative routes of administration, use of alternate opioids (termed opioid rotation or opioid switching), use of adjuvant analgesics, and nonpharmacologic approaches. A process for opioid switching has been established; the first step is to calculate the equianalgesic dose of the new drug [4,8,34]. Additional care is needed when switching to methadone, and conversion ratios have been established [4]. Evidence suggests that the traditionally recommended equianalgesic doses for the fentanyl transdermal patch are subtherapeutic for patients with chronic cancer-related pain, and more aggressive approaches may be warranted [4,8,51].

Another approach that has been used for pain management in the cancer setting is combination opioid therapy, or the concurrent use of two strong opioids. The effectiveness of this approach has been evaluated in only two studies, and the combination was morphine and oxycodone or morphine with fentanyl or methadone [52]. The evidence to support a recommendation of combination opioid therapy is weak, and the side effects most likely outweigh the benefit [52].

Evidence Based Practice Recommendation

According to the Institute for Clinical Systems Improvement, there needs to be shared decision-making with the patient about reducing or eliminating opioids to avoid unnecessary complications from long-term opioid use. This involves following and re-evaluating the patient closely, with dose reduction or discontinuation as needed.

https://www.icsi.org/wp-content/uploads/2021/11/PalliativeCare_6th-Ed_2020_v2.pdf

Last Accessed: October 19, 2024

Level of Evidence: Expert Opinion/Consensus Statement

Opioids are associated with many side effects, the most notable of which is constipation, occurring in nearly 100% of patients. The universality of this side effect mandates that once extended treatment with an opioid begins, prophylactic treatment with laxatives must also be initiated. Tolerance to other side effects, such as nausea and sedation, usually develops within three to seven days. Some patients may state that they are "allergic" to an opioid. It is important for the physician to explore what the patient experienced when the drug was taken in the past, as many patients misinterpret side effects as an allergy. True allergy to an opioid is rare [8]. Opioid rotation may also be done to reduce adverse events.

When opioids are prescribed, careful documentation of the patient's history, examinations, treatments, progress, and plan of care are especially important from a legal perspective. This documentation must provide evidence that the patient is functionally better off with the medication than without [33]. In addition, physicians must note evidence of any dysfunction or abuse.

Adjuvant agents are often used in conjunction with opioids and are usually considered after the use of opioids has been optimized [33]. The primary indication for these drugs is adjunctive because they can provide relief in specific situations, especially neuropathic pain. Examples of adjuvant drugs are tricyclic antidepressants, anticonvulsants, muscle relaxants, and corticosteroids (Table 2) [4,8]. A systematic review found that there was limited evidence to support the use of selective serotonin reuptake inhibitors (SSRIs) for neuropathic pain, but one serotonin-norepinephrine reuptake inhibitor, venlafaxine (Effexor), was found to be effective [53].

Table 2: ORAL ADJUVANT ANALGESICS

Drug Class

Drug

Typical Starting Dose

Usual Effective Dose

Anticonvulsants

Gabapentin

100–300 mg once daily

300–1,200 mg (2 or 3 divided doses)

Pregabalin

25–75 mg twice daily

75–200 mg (3 divided doses)

Carbamazepine

50–100 mg twice daily

300–600 mg twice daily

Topiramate

25–50 mg daily

50–200 mg twice daily

Oxcarbazepine

150–300 mg twice daily

150–600 mg twice daily

Tiagabine

4 mg at bedtime

4–12 mg twice daily

Tricyclic antidepressants

Amitriptyline

Nortriptyline

Desipramine

10–25 mg at bedtime

50–150 mg at bedtime

Serotonin-norepinephrine reuptake inhibitors

Venlafaxine

37.5 mg daily

150–350 mg daily

Skeletal muscle relaxants

Baclofen

5 mg twice daily

10–20 mg 2 or 3 times daily

Cyclobenzaprine

5 mg 3 times daily

10–20 mg 3 times daily

Metaxalone

400 mg 3 times daily

Not defined

Corticosteroids

Dexamethasone

1–2 mg

Not defined

Source: [4,8,41]

NONPHARMACOLOGIC INTERVENTIONS

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

Palliative radiotherapy is effective for managing cancer-related pain, especially bone metastases [2,54,55]. Bone metastases are the most frequent cause of cancer-related pain; 50% to 75% of patients with bone metastases will have pain and impaired mobility [54]. External-beam radiotherapy is the mainstay of treatment for pain related to bone metastases. At least some response occurs in 70% to 80% of patients, and the median duration of pain relief has been reported to be 11 to 24 weeks [54]. It takes one to four weeks for optimal therapeutic results [54,55].

However, palliative radiotherapy has become a controversial issue. Although the benefits of palliative radiotherapy are well documented and most hospice and oncology professionals believe that palliative radiotherapy is important, this treatment approach is offered at approximately 24% of Medicare-certified freestanding hospices, with less than 3% of hospice patients being treated [56,57,58]. As previously noted, reimbursement issues present a primary barrier to the use of palliative radiotherapy [56,57,58]. Among other barriers are short life expectancy, transportation issues, patient inconvenience, and lack of knowledge about the benefits of palliative radiotherapy in the primary care community [55,56,57,59].

One study found that more than half (54%) of people use complementary/alternative medicine therapies at the end of life [60]. The most commonly used therapies are massage, music, relaxation techniques, and acupuncture [60,61,62,63,64].

Massage, which can be broadly defined as stroking, compression, or percussion, has led to significant and immediate improvement in pain in the hospice setting [65]. Both massage and vibration are primarily effective for muscle spasms related to tension or nerve injury, and massage can be carried out with simultaneous application of heat or cold. Massage may be harmful for patients with coagulation abnormalities or thrombophlebitis [12].

Focused relaxation and breathing can help decrease pain by easing muscle tension. Progressive muscle relaxation, in which patients follow a sequence of tensing and relaxing muscle groups, has enabled patients to feel more in control and to experience less pain and can also help provide distraction from pain [12]. This technique should be avoided if the muscle tensing will be too painful.

Acupuncture typically provides pain relief 15 to 40 minutes after stimulation. Relief seems to be related to the release of endorphins and a susceptibility to hypnosis [12]. The efficacy of acupuncture for relieving pain has not been proven, as study samples have been small. However, acupuncture has been found to be of some benefit for cancer-related pain when the therapy is given in conjunction with analgesic therapy [66].

Other nonpharmacologic interventions that have been helpful for some patients but lack a strong evidence base include manipulative and body-based methods (such as application of cold or heat, and positioning), yoga, distraction, and music or art therapy. The application of cold and heat are particularly useful for localized pain and have been found to be effective for cancer-related pain caused by bone metastases or nerve involvement, as well as for prevention of breakthrough incident pain [12]. Alternating application of heat and cold can be soothing for some patients, and it is often combined with other nonpharmacologic interventions.

Cold can be applied through wraps, gel packs, ice bags, and menthol. It provides relief for pain related to skeletal muscle spasms induced by nerve injury and inflamed joints. Cold application should not be used for patients with peripheral vascular disease. Heat can be applied as dry (heating pad) or moist (hot wrap, tub of water) and should be applied for no more than 20 minutes at a time, to avoid burning the skin. Heat should not be applied to areas of decreased sensation or with inadequate vascular supply, or for patients with bleeding disorders.

Changing the patient's position in the bed or chair may help relieve pain and also helps minimize complications such as decubitus ulcers, contractures, and frozen joints. Members of the healthcare team as well as family members and other informal caregivers can help reposition the patient for comfort and also perform range-of-motion exercises. Physical and occupational therapists can recommend materials, such as cushions, pillows, mattresses, splints, or support devices.

Hatha yoga is the branch of yoga most often used in the medical context, and it has been shown to provide pain relief for patients who have osteoarthritis and carpal tunnel syndrome but it has not been studied in patients at the end of life. Yoga may help relieve pain indirectly in some patients through its effects on reducing anxiety, increasing strength and flexibility, and enhancing breathing [67]. Yoga also helps patients feel a sense of control.

Methods to provide distraction from pain come in a wide variety of methods, including reciting poetry, meditating with a calm phrase, watching television or movies, playing cards, visiting with friends, or participating in crafts.

Music therapy and art therapy are also becoming more widely used as nonpharmacologic options for pain management. Listening to music has been shown to decrease the intensity of pain and reduce the amount of opioids needed, but the magnitude of the benefit was small [68]. Research suggests that art therapy contributes to a patient's sense of well-being [69]. Creating art helps patients and families to explore thoughts and fears during the end of life. An art therapist can help the creators reflect on the implications of the art work. Art therapy is especially helpful for patients who have difficulty expressing feelings with words, for physical or emotional reasons.

6. LEGAL AND ETHICAL ISSUES RELATED TO THE TREATMENT OF PAIN

Fear of license suspension for inappropriate prescribing of controlled substances is also prevalent, and a better understanding of pain medication will enable physicians to prescribe accurately, alleviating concern about regulatory oversight. Physicians must balance a fine line; on one side, strict federal regulations regarding the prescription of schedule II opioids (morphine, oxycodone, methadone, hydromorphone) raise fear of Drug Enforcement Agency investigation, criminal charges, and civil lawsuits [1,70]. Careful documentation on the patient's medical record regarding the rationale for opioid treatment is essential [70]. On the other side, clinicians must adhere to the American Medical Association's Code of Ethics, which states that failure to treat pain is unethical. The code states, in part: "Physicians have an obligation to relieve pain and suffering and to promote the dignity and autonomy of dying patients in their care. This includes providing effective palliative treatment even though it may foreseeably hasten death" [71]. In addition, the American Medical Association Statement on End-of-Life Care requires that physicians "reassure the patient and/or surrogate that all other medically appropriate care will be provided, including aggressive palliative care and appropriate symptom management, if that is what the patient wishes"[72].

Physicians should consider the legal ramifications of inadequate pain management and understand the liability risks associated with both inadequate treatment and treatment in excess. The undertreatment of pain carries a risk of malpractice liability, and this risk is set to increase as the general population becomes better educated about the availability of effective approaches to pain management at the end of life. Establishing malpractice requires evidence of breach of duty and proof of injury and damages. Before the development of various guidelines for pain management, it was difficult to establish a breach of duty, as this principle is defined by nonadherence to the standard of care in a designated specialty. With such standards now in existence, expert medical testimony can be used to demonstrate that a practitioner did not meet established standards of care for pain management. Another change in the analysis of malpractice liability involves injury and damages. Because pain management can be considered as separate from disease treatment and because untreated pain can lead to long-term physical and emotional damage, claims can be made for pain and suffering alone, without wrongful death or some other harm to the patient [73].

The proper storage and disposal of prescription pain medications should also be considered. Taking steps to ensure that medications are stored and destroyed securely and safely can help prevent unintended overdose and substance abuse. In 2010, the U.S. Senate passed the Secure and Responsible Drug Disposal Act, which amended the Controlled Substances Act to permit the take-back disposal of medications by authorized persons (rather than the patient with the prescription) [74]. As such, healthcare professionals may be required to dispose of drugs returned by patients in addition to drug samples that have expired or are not being dispensed. For best practice guidelines on the disposal of medications by patients or healthcare professionals, please visit the Drug Enforcement Administration Office of Diversion Control at https://www.deadiversion.usdoj.gov/drug_disposal/drug-disposal.html [32].

PATIENTS WITH HISTORY OF SUBSTANCE ABUSE

This population of people with a history of substance abuse presents challenges to the effective use of pain medication, with issues related to trust, the appropriate use of pain medications, interactions between illicit drugs and treatment, and compliance with treatment. The issues differ depending on whether substance abuse is a current or past behavior.

With active substance abusers, it is difficult to know if patients' self-reports of pain are valid or are drug-seeking behaviors. It has been recommended that, as with other patients at the end of life, self-reports of pain should be believed [12,33]. A multidisciplinary approach, involving psychiatric professionals, addiction specialists, and, perhaps, a pain specialist, is necessary. To decrease the potential for the patient to seek illicit drugs for pain, an appropriate pain management plan should be implemented and the patient should be reassured that pain can be managed effectively [12,33]. When planning treatment, the patient's tolerance must be considered; higher doses may be needed initially, and doses can be reduced once acute pain is under control. Long-acting pain medications are preferred for active substance abusers, and the use of nonopioids and coanalgesics can help minimize the use of opioids. Setting limits as well as realistic goals is essential and requires establishing trust and rapport with the patient and caregivers.

Establishing trust is also essential for patients with former substance abuse behavior, who often must be encouraged to adhere to a pain management program because of their fears of addiction. Involving the patient's drug counselor is beneficial, and other psychological clinicians may be helpful in assuring the patient that pain can be relieved without addiction. Recurrence of addiction is low, especially among people with cancer, but monitoring for signs of renewed abuse should be ongoing [12].

Patients who are following a methadone maintenance program may also fear effective pain management as a risk for recurrent abuse. Two approaches may be followed for these patients: they may receive an increased dose of methadone as the pain reliever or they may be given other opioids along with the same methadone dose, with the dose of the opioid titrated for effective pain relief [12,33]. Again, involvement of the drug counselor is important.

7. CONCLUSION

As many as 96% of people with a life-limiting disease have pain at the end of life, and unrelieved pain is a great fear in this population. However, experts estimate that 75% to 90% of end-of-life pain can be effectively managed. Healthcare professionals should strive to enhance their knowledge of key strategies to achieve high-quality pain management at the end of life through open communication, frequent assessment, and the use of evidence-based pharmacologic and nonpharmacologic interventions that are individualized to each patient's specific situation.

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

40. Lauretti GR, Oliveira GM, Pereira NL. Comparison of sustained-release morphine with sustained-release oxycodone in advanced cancer patients. Br J Cancer. 2003;89:2027-2030.

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42. McCleane G, Smith HS. Opioids for persistent noncancer pain. Anesthesiol Clin. 2007;25:787-807.

43. Shaiova L, Berger A, Blinderman CD, et al. Consensus guideline on parenteral methadone use in pain and palliative care. Palliat Support Care. 2008;6(2):165-176.

44. Nicholson AB, Watson GR, Derry S, Wiffen PJ. Methadone for cancer pain. Cochrane Database Syst Rev. 2017;(2):CD003971.

45. Dart RC, Woody GE, Kleber HD. Prescribing methadone as an analgesic [letter]. Ann Intern Med. 2005;143:620.

46. Drugs.com FDA Approves Nucynta ER (Tapentadol) Extended-Release Oral Tablets for the Management of Neuropathic Pain Associated with Diabetic Peripheral Neuropathy. Available at https://www.drugs.com/newdrugs/fda-approves-nucynta-er-tapentadol-extended-release-oral-management-neuropathic-pain-associated-3461.html. Last accessed October 16, 2024.

47. Vadivelu N, Timchenko A, Huang Y, Sinatra R. Tapentadol extended-release for treatment of chronic pain: a review. J Pain Res. 2011;4:211-218.

48. Schikowski A, Krings D, Schwenke K. Tapentadol prolonged release for severe chronic cancer-related pain: effectiveness, tolerability, and influence on quality of life of the patients. J Pain Res. 2014;8:1-8.

49. Blick SK, Wagstaff AJ. Fentanyl buccal tablet: in breakthrough pain in opioid-tolerant patients with cancer. Drugs. 2006;66(18):2387-2395.

50. Messina J, Darwish M, Fine PG. Fentanyl buccal tablet. Drugs Today (Barc). 2008;44(1):41-54.

51. Skaer T. Transdermal opioids for cancer pain. Health Qual Life Outcomes. 2006;4:24.

52. Fallon MT, Laird BJA. A systematic review of combination step III opioid therapy in cancer pain: an EPCRC opioid guideline project. Palliat Med. 2011;25(5):597-603.

53. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007;(4):CD005454.

54. Dolinsky C, Metz JM. Palliative radiation therapy in oncology. Anesthesiol Clin North Am. 2006;24:113-128.

55. Fine PG. Palliative radiation therapy in end-of-life care: evidence-based utilization. Am J Hospice Palliat Med. 2002;19(3):166-170.

56. Lutz S, Spence C, Chow E, et al. Survey on use of palliative radiotherapy in hospice care. J Clin Oncol. 2004;22:3581-3586.

57. McCloskey S, Tao ML, Rose CM, Fink A, Amadeo AM. National survey of perspectives of palliative radiation therapy: role, barriers, and needs. Cancer J. 2007;13(2):130-137.

58. Jarosek SL, Virnig BA, Feldman R. Palliative radiotherapy in Medicare-certified freestanding hospices. J Pain Symptom Manage. 2009;37(5):780-787.

59. Berrang T, Samant R. Palliative radiotherapy knowledge among community family physicians and nurses. J Cancer Educ. 2008;23(3):156-160.

60. Tilden VP, Drach LL, Tolle SW. Complementary and alternative therapy use at end-of-life in community settings. J Altern Complement Med. 2004;10(5):811-817.

61. Demmer C. A survey of complementary therapy services provided by hospices. J Palliat Med. 2004;7(4):510-516.

62. Kozak LE, Kayes L, McCarty R, et al. Use of complementary and alternative medicine (CAM) by Washington State hospices. Am J Hosp Palliat Care. 2008;25(6):463-468.

63. Dain AS, Bradley EH, Hurzeler R, Aldridge MD. Massage, Music, and Art Therapy in Hospice: Results of a National Survey. J Pain Symptom Manage. 2015;49(6):1035-1041.

64. Olotu BS, Brown CM, Lawson KA, Barner JC. Complementary and alternative medicine utilization in Texas hospices: prevalence, importance, and challenges. Am J Hosp Palliat Care. 2014;31(3):254-259.

65. Polubinski JP, West L. Implementation of a massage therapy program in the home hospice setting. J Pain Symptom Manage. 2005;30:104-106.

66. Choi TY, Lee MS, Kim TH, Zaslawski C, Ernst E. Acupuncture for the treatment of cancer pain: a systematic review of randomised clinical trials. Support Care Cancer. 2012;20(6):1147-1158.

67. Raub JA. Psychophysiologic effects of hatha yoga on musculoskeletal and cardiopulmonary function: a literature review. J Altern Complement Med. 2002;8:797-812.

68. Cepeda MS, Carr DB, Lau J, Alvarez H. WITHDRAWN: Music for pain relief. Cochrane Database Syst Rev. 2013;(10):CD004843.

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Evidence-Based Practice Recommendations Citations

1. McCusker M, Jolkvosky M, Ruff R, et al. Palliative Care for Adults. 6th ed. Bloomington, MN: Institute for Clinical Systems Improvement; 2020. Available at https://www.icsi.org/wp-content/uploads/2021/11/PalliativeCare_6th-Ed_2020_v2.pdf. Last accessed October 19, 2024.

90350 • Neuromodulation for Refractory Neuropsychiatric and Pain Disorders

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2025 NetCE, All rights reserved.

This course will provide an overview of neuromodulation therapy for neuropsychiatric diseases and conditions and will examine the potential short- and long-term benefits and risks; clinical indications; patient selection; and potential ethical issues associated with neuromodulation therapies, including their non-therapeutic use for cognitive and performance enhancement. Refractory psychiatric disorders are emphasized, as several psychiatric disorders are poorly responsive to standard therapies, leaving patients distressed and functionally impaired. Neuromodulation therapies (aside from ECT for refractory major depressive disorder) are a more recent option for psychiatric disorders, a rapidly growing indication for use. Refractory chronic pain is another therapeutic area discussed in this course.

Table of Contents

90350 • Neuromodulation for Refractory Neuropsychiatric and Pain Disorders

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. OVERVIEW OF BRAIN MODULATION APPROACHES

ELECTROCONVULSIVE THERAPY

NON-INVASIVE TRANSCRANIAL STIMULATION

OTHER MAGNETIC STIMULATION THERAPIES

OTHER ELECTRICAL STIMULATION THERAPIES

3. NEUROMODULATION IN SPECIFIC PSYCHIATRIC DISORDERS

MAJOR DEPRESSIVE DISORDER (MDD)

ANXIETY DISORDERS AND ANXIETY-RELATED DISORDERS

POST-TRAUMATIC STRESS DISORDER

OBSESSIVE-COMPULSIVE DISORDER

SCHIZOPHRENIA

SUBSTANCE USE DISORDERS

EATING DISORDERS

DEPERSONALIZATION/DEREALIZATION DISORDER

4. ELECTROCONVULSIVE THERAPY

CANDIDATES FOR ECT

TREATMENT PARAMETERS IN ECT

EFFICACY

PREDICTORS OF ECT RESPONSE AND RELAPSE

POST-ECT MAINTENANCE

ADVERSE EFFECTS OF ECT

5. TRANSCRANIAL MAGNETIC AND ELECTRIC STIMULATION IN PSYCHIATRIC DISORDERS

TRANSCRANIAL MAGNETIC STIMULATION (rTMS) IN PSYCHIATRY

TRANSCRANIAL DIRECT CURRENT STIMULATION (tDCS) IN PSYCHIATRY

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

REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION (rTMS)

TRANSCRANIAL DIRECT CURRENT STIMULATION IN MDD

7. NEUROMODULATION FOR OTHER MENTAL HEALTH DISORDERS

NEUROMODULATION FOR BIPOLAR II DEPRESSION AND BIPOLAR DISORDER

ANXIETY DISORDERS AND ANXIETY-RELATED DISORDERS

POST-TRAUMATIC STRESS DISORDER

OBSESSIVE-COMPULSIVE DISORDER (OCD)

TOURETTE SYNDROME

SCHIZOPHRENIA WITH AUDITORY VERBAL HALLUCINATIONS

SCHIZOPHRENIA, NEGATIVE SYMPTOMS

SUBSTANCE USE DISORDERS

EATING DISORDERS

DEPERSONALIZATION/DEREALIZATION DISORDER

EXTERNAL TRIGEMINAL NERVE STIMULATION (eTNS)

MAJOR DEPRESSIVE DISORDER

PTSD AND COMORBID MDD

PANIC DISORDER

8. INVASIVE NEUROSTIMULATION

VAGUS NERVE STIMULATION

DEEP BRAIN STIMULATION

9. NEUROMODULATION IN CHRONIC PAIN

OVERVIEW OF NONINVASIVE BRAIN STIMULATION IN PAIN

CHARACTERISTICS OF CHRONIC PAIN CONDITIONS

TRANSCRANIAL MAGNETIC AND ELECTRIC STIMULATION

TRANSCRANIAL DIRECT CURRENT STIMULATION

COMPARISONS OF rTMS AND tDCS IN PAIN TREATMENT

10. INVASIVE NEUROSTIMULATION IN CHRONIC PAIN

MOTOR CORTEX STIMULATION

DEEP BRAIN STIMULATION

THALAMIC DEEP BRAIN STIMULATION

NEUROMODULATION SAFETY IN PAIN TREATMENT

11. SOCIAL ISSUES WITH NEUROSTIMULATORS

RISING CONSUMER USE

REGULATORY CHALLENGES AND SAFETY CONCERNS

12. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

90350 • Neuromodulation for Refractory Neuropsychiatric and Pain Disorders

Education Category. Medical / Surgical

Release Date. 08/01/2025

Expiration Date. 07/31/2028

Course Overview

This course will provide an overview of neuromodulation therapy for neuropsychiatric diseases and conditions and will examine the potential short- and long-term benefits and risks; clinical indications; patient selection; and potential ethical issues associated with neuromodulation therapies, including their non-therapeutic use for cognitive and performance enhancement. Refractory psychiatric disorders are emphasized, as several psychiatric disorders are poorly responsive to standard therapies, leaving patients distressed and functionally impaired. Neuromodulation therapies (aside from ECT for refractory major depressive disorder) are a more recent option for psychiatric disorders, a rapidly growing indication for use. Refractory chronic pain is another therapeutic area discussed in this course.

Audience

This course is designed for physicians, PAs, and nurses involved in the care of patients with refractory pain or neuropsychiatric disorders.

Accreditations & Approvals

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

Designations of Credit

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

Individual State Nursing Approvals

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

Special Approvals

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

Course Objective

As the therapeutic landscape evolves beyond traditional pharmacologic and surgical approaches, neuromodulation offers a promising option for patients with refractory conditions who have not responded adequately to standard treatments. The purpose of this continuing education course is to enhance physician and nurse understanding of neuromodulation therapies for the treatment of neuropsychiatric and chronic pain disorders.

Learning Objectives

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

1. Outline the background and underlying concepts supporting neuromodulation therapy.

2. Describe the mechanisms, benefits, and risks of electroconvulsive therapy (ECT).

3. Review the implementation of transcranial magnetic and electric stimulation in psychiatric disorders.

4. Evaluate the use of neuromodulation approaches to the management of treatment-refractory major depression disorder (MDD).

5. Compare the efficacy of neuromodulation techniques for the treatment of other psychiatric disorders.

6. Analyze the efficacy and safety of invasive neurostimulation for the management of psychiatric disorders.

7. Formulate strategies for integrating neuromodulation therapies into comprehensive treatment plans for refractory pain conditions.

8. Discuss the potential role of invasive neurostimulation in patients with chronic pain.

Faculty

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

Faculty Disclosure

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

Division Planners

John M. Leonard, MD

Margo A. Halm, RN, PhD, NEA-BC, FAAN

Division Planners Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

Implicit Bias in Health Care

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

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

1. INTRODUCTION

Neuromodulation, neurostimulation, brain modulation, and brain stimulation are synonymous and describe noninvasive, minimally invasive or invasive techniques that deliver electrical or magnetic stimulation to specific brain region targets for the treatment of psychiatric and pain conditions.

Electroconvulsive therapy (ECT) is the oldest and most established brain stimulation mode in current use. Over the past decade, the most-studied brain stimulation modality in the treatment of psychiatric and pain conditions has been transcranial magnetic stimulation (TMS), followed by transcranial direct current stimulation (tDCS). Several recent modifications of TMS and tDCS are under development to improve efficacy or accelerate treatment response. External trigeminal nerve stimulation (eTNS) is a recent but highly promising approach. Minimally invasive vagus nerve stimulation (VNS) is modestly effective in refractory depression, and invasive stimulation requiring surgical implantation into brain targets has a limited yet highly valuable role in treatment of severe, refractory conditions.

In the context of this course, ECT is given its own section because the indicated use for ECT involves one condition (depression). The non-invasive modalities TMS and tDCS are the most extensively researched brain stimulation approaches and are combined in discussions of specific psychiatric disorders and pain conditions. Invasive brain stimulation is discussed in the last sections of psychiatric disorders and pain conditions.

2. OVERVIEW OF BRAIN MODULATION APPROACHES

Numerous brain stimulation modalities are in varying stages of research development or clinical use in the treatment of psychiatric and pain conditions. Their general characteristics are described in this section. Characteristics specific to treatment of psychiatric or pain disorders are discussed in later sections.

Therapeutic brain stimulation intends to induce durable treatment effects by exploiting brain capacity for plasticity. Neuroplasticity is the process where alterations in brain structure promote functional changes, and represents the process of normal brain functions during learning, adaptation to change, and recovery from brain injury. It is thought that early changes with brain stimulation involve alteration in synaptic strength, with longer exposures trigger longer-lasting anatomical changes such as neuronal sprouting and alterations of dendritic spines. Brain stimulation is best viewed as an intervention that targets specific brain circuits, rather than brain transmitter chemicals (neurotransmitters) [1,2]. Two processes that occur during brain stimulation-induced neuroplasticity [1]:

- Long-term potentiation: Reinforcement of synaptic strength

- Long-term depression: Weakening of synaptic strength

Parameters refers to the range of settings with stimulation devices, adjusted to manipulate energy output and desired treatment effects. Parameters include the location of electrode, magnet or lead placement; and the intensity, duration and pattern of delivered energy. Montage refers to configurations of externally placed or implanted electrode.

Brain stimulation therapy is not new to the 20th century. In the Roman era, electric torpedo fish were placed on the scalp to treat headache or epilepsy, and gouty arthritis was treated by placing painful extremities in pools with torpedo fish. In the mid-1700s, advances in electrophysiology inspired the use of transcranial electrical stimulation with direct currents to treat mental disorders [3,4]. Transcranial electrical stimulation machines for private use became widely available, and study of transcranial electrical stimulation intensified in the 1800s. Transcranial electrical stimulation was claimed to generate euphoria and improve mental performance by some patients and physicians, who advised that currents to the head not exceed 10 mA from risks of burning and shock. Common side effects were headaches, dizziness and nausea; Benjamin Franklin suffered retrograde amnesia after accidentally administering an electric shock to his head [3].

Erratic results and the advent of ECT led to waning interest in direct current brain stimulation [4]. ECT was introduced in 1938 to replace drug-induced convulsive therapy of severe psychosis; epilepsy was mistakenly believed antagonistic to schizophrenia. Depression was later known as a more suitable indication [5]. Psychosurgery using stereotactic lesioning in specific deep brain structures was introduced in 1947 to avoid the side effects of the widely used frontal lobotomy. Deep brain stimulation followed in the early 1950s as treatment for psychiatric illness, Parkinson disease, and pain [5,6]. Primitive forms of magnetic stimulation were first investigated in the 1890s, first shown to stimulate isolated nerves in 1959, and the first modern device was introduced in 1976, the precursor for the first TMS technique in 1985 [3].

These crude, earlier forms of brain stimulation were abandoned or curtailed with replacement by drug therapies, or stigma and rejection over unethical practices and side effects. All have been reintroduced in substantially safer and more effective forms with ethical safeguards; ECT is prohibited without full patient consent [5,6].

ELECTROCONVULSIVE THERAPY

Although not often considered non-invasive due to seizure induction, ECT remains established as a potent and rapidly acting treatment for severe or refractory major depressive disorder (MDD). ECT is considered unrivaled among all therapeutic options for rapidly inducing antidepressant effects, although multiple ECT treatments are usually required [7].

ECT generates electrical stimuli through electrodes applied to the scalp for seizure induction, with the patient in general anesthesia and pre-medicated with a muscle relaxant. Clinical outcomes are highly influenced by electrode placements, electrical intensity and pulse width, and these are described in a later section [8].

ECT is thought to work by generating seizure-induced changes in neurotransmitter activity, neuroplasticity, and functional connectivity. ECT increases levels of brain-derived neurotrophic factor (BDNF), which may promote neuroplasticity and contribute to the antidepressant effect [8,9].

Stigma surrounds this treatment mode and may interfere with patient acceptance of initiating ECT therapy.

NON-INVASIVE TRANSCRANIAL STIMULATION

The preponderance of research on non-invasive neuromodulation involves magnetic or electric stimulation using repetitive transcranial magnetic stimulation (rTMS) or tDCS. Both modalities allow external manipulation of the brain, performed safely without requiring neurosurgical procedures or general anesthesia [10].

Repetitive Transcranial Magnetic Stimulation

First demonstrated in 1985, TMS projects a fluctuating magnetic field (magnetic pulses) through the skull into the brain via an inductor coil placed against the scalp. This generates electrical currents in brain tissue (via electromagnetic induction) of sufficient strength to modulate neuronal firing. Multiple TMS pulses given consecutively are termed repetitive TMS. rTMS is noninvasive, and unlike ECT does not require anesthesia [2,8].

Frequency

Frequency is the intensity of stimulation energy [2]. High-frequency (5–20 Hz) rTMS (HF-rTMS) increases neuronal activity and cortical excitability and increases relative regional cerebral blood flow (with exceptions). Low-frequency (≤1 Hz) rTMS (LF-rTMS) reduces neuronal activity and cortical excitability. HF-rTMS and LF-rTMS, applied to the same brain site, can induce dissimilar effects on brain circuits.

Stimulation strength is tailored to the motor threshold of each patient that is determined by the amount of current, with single-pulse TMS applied to the primary motor cortex (M1), that produces a twitch in a peripheral muscle (a motor-evoked potential) [11,12]. rTMS is usually applied in "trains" of pulses interspersed with rest periods, because prolonged high-frequency stimulation increases seizure risk [13].

Coil Type

Most rTMS studies use a standard figure-8 coil, which has the drawback of poor brain penetration that limits the depth of stimulation delivery, although superficial areas of the prefrontal cortex (PFC) such as the dorsolateral PFC represent important targets fully amenable to rTMS stimulation. This partially explains the preponderance of rTMS studies in MDD, as the dorsolateral PFC is highly relevant in depression [12].

The deep (H) coil delivers pulses deeper than the figure-8 coil to stimulate broader and deeper frontal cortex regions such as the insula and ventrolateral prefrontal cortex, as well as the dorsolateral PFC. This may come at the expense of specificity, where deeper penetration expands the magnetic field to stimulate regions and circuits that interfere with therapeutic response or contribute to adverse effects [2,12].

Mechanism

Trains of magnetic pulses with rTMS temporarily summate to alter neural activity that can modulate cortical excitability. LF-rTMS mostly stimulates low-threshold inhibitory interneurons, and HF-rTMS excite projection neurons [13]. The effects of rTMS are not limited to the brain areas under the stimulation coil, and remote brain areas connected to the stimulated site are affected [14]. Because of synaptic connections, distal effects (cortical and subcortical, ipsilateral and contralateral) on neural activity, regional cerebral blood flow, and neurotransmitter activity may differ from proximal effects. rTMS can be viewed as targeting brain circuits instead of neurotransmitters, although behavioral effects depend on neurotransmitter systems within the manipulated brain circuit [2]. Long-lasting therapeutic effects with rTMS are related to long-term potentiation and long-term depression mediated through N-methyl-D-aspartate (NMDA) synaptic plasticity [15].

Transcranial Direct Current Stimulation (tDCS)

tDCS is a non-invasive, painless brain stimulation treatment in numerous psychiatric and chronic pain conditions. tDCS is delivered through a device that transfers low-intensity (0.5–3 mA) electrical current to the scalp surface with 2 large (20–35 cm^22) saline-soaked sponge-electrodes, an anode and a cathode. The anode and cathode are attached to distinct areas of the scalp with a rubber headband. The current penetrates the skull and enters the brain from the anode, travels through the tissue, and exits via the cathode [16].

In contrast to other non-invasive brain stimulation modes, tDCS does not induce neuron action potentials but instead modulates neuron membrane excitability [15]. Parameters that influence patient response and functional outcomes with tDCS are current polarity, delivered dose, and electrode positions.

Stimulation Types and Effects

The tDCS current is too weak to induce neuron firing, but alters neuron excitability by shifting the resting membrane potentials of neurons in a depolarizing or hyperpolarizing direction, making them more or less likely to re-fire. Changes in spontaneous neuron firing induced by stimulation type [4,10]:

- Anodal stimulation: Depolarizes (raises) neuron membrane potentials, which excites neuronal function and increases cortical excitability.

- Cathodal stimulation: Hyperpolarizes (lowers) neuron membrane potentials, which decreases neuronal function and cortical excitability.

Thus, effects of tDCS on cortical excitability are polarity-dependent (anodal or cathodal), and both cause changes in spontaneous firing.

Mechanisms

With repeated use, tDCS modulates synaptic connectivity by inducing long-term potentiation and depression, mediated in part by NMDA receptor-dependent mechanisms; neuroplastic changes regulated by neurotransmitters systems such as dopamine, acetylcholine, gamma-aminobutryic acid (GABA), serotonin and BDNF; and changes in neuronal membrane channels including sodium and calcium pumps [8,17,18]. tDCS can also upregulate and downregulate functional connectivity within brain networks, including those important for cognitive, motor, and pain processing [18].

OTHER MAGNETIC STIMULATION THERAPIES

While rTMS and tDCS are the dominant techniques, other novel or modified forms of non-invasive magnetic and electric current neuromodulation have been developed and are actively under investigation.

Theta-Burst Stimulation

Theta-burst stimulation is a form of rTMS that delivers a 50-Hz burst of three pulses every 200 ms [19]. Intermittent theta-burst stimulation delivers 600 pulses of stimulation for 2 seconds, followed by an 8-second rest, over two to three minutes. Intermittent theta-burst stimulation is considered excitatory. In contrast, continuous theta-burst stimulation is applied in 40 second trains to result in long-term depression-like decreases in motor cortex excitability. Continuous theta-burst stimulation is considered inhibitory [8].

Magnetic Seizure Therapy

Magnetic seizure therapy is a noninvasive convulsive neurostimulation therapy currently investigated as an alternative to ECT. A neurostimulator and coil are placed directly on the skull. Electrical current passing through the coil generates a strong focal magnetic field (2 Tesla). This passes unimpeded through the skull and soft tissue to reach brain tissue, where an electrical current is induced that causes neuronal depolarization triggering a generalized tonic-clonic seizure. Magnetic seizure therapy and ECT both induce seizures in patients under general anesthesia with assisted ventilation and EEG monitoring, but magnetic seizure therapy may have fewer side effects, particularly cognitive impairment [8,20].

OTHER ELECTRICAL STIMULATION THERAPIES

Transcranial Electrical Stimulation

An early approach to brain stimulation, transcranial electrical stimulation applied high-voltage electric stimuli through electrodes on the scalp. Most of the current travelled along the scalp between the electrodes, but a small portion penetrated the brain to activate neurons. This method was refined in 1980 and termed transcranial electrical stimulation. Transcranial electrical stimulation is credited as the pioneering neurophysiological approach for noninvasive brain stimulation, but interest in transcranial electrical stimulation declined rapidly with the introduction of TMS in 1985 [19].

Transcranial Alternating Current Stimulation (tACS)

Most published research on transcranial electrical stimulation efficacy has involved tDCS. Only recently has tACS attracted attention as a promising alternative approach to directly interact with ongoing oscillatory cortical activity. To date, evaluation of tACS has been primarily limited to possible cognitive enhancing effects in healthy adults, and in the elderly with normal, age-related cognitive declines [21].

Transcranial Random Noise Stimulation (tRNS)

tRNS is a variant of tACS that uses a constantly changing current. While tACS stimulates at a set frequency to entrain oscillatory activity, tRNS stimulates at a randomly changing frequency between 0.1–640 Hz. tRNS at higher frequencies (>100 Hz) may induce larger excitability changes than stimulation with a direct current such as tDCS, because the sodium channels of underlying neurons are repeatedly opened by stimulation. Neuronal homeostatic mechanisms are prevented because the underlying neurons cannot adjust to the constantly randomly changing electrical field. As a relatively new technique, the number of published reports on tRNS treatment in psychiatric and pain disorders is sparse [22].

External Trigeminal Nerve Stimulation (eTNS)

eTNS is an external neuromodulatory device originally developed for use in refractory seizures. The theoretical basis for eTNS is that bilateral electrical stimulation over the trigeminal cranial nerve may neuromodulate cortical and subcortical areas related to neuropsychiatric disorders, such as the amygdala, insular cortex, prefrontal cortex, hippocampus, thalamus, locus coeruleus, nucleus of the solitary tract, and the anterior cingulate cortex. eTNS involves a bottom-up mechanism where stimuli propagate from the cranial nerve in the direction of the brainstem and central brain regions. As such, this represents a novel approach that differs from transcranial stimulation involving top-down mechanisms [23,24].

Two eTNS protocols are described for psychiatric disorder treatment. Both protocols use stimulation frequencies of 120 Hz, asymmetrical alternate current, pulse duration of 0.25 ms and intensity based on patient sensitivity and pain threshold. Protocol I delivers eTNS in 8-hour sessions during sleep for 8 weeks, with a 30 seconds on/30 seconds off cycle, while Protocol II uses 30-minute sessions in 10 weekdays for 2 weeks, with continuous stimulation [24].

Low-Intensity Focused Ultrasound

The concept of using focused ultrasound beams deep in the brain to treat movement disorders was conceived in the 1950s, but the need to make a cranial window in the skull led to its development abandoned. Low-intensity focused ultrasound can be delivered through the intact skull, making ultrasound neuromodulation the focus of considerable interest [7]. An advantage is its ability for deep brain delivery without causing permanent damage or effects [25]. Potential indications include acute symptoms such as seizures, and chronic conditions such as depression where plasticity may be important. Ultrasound neuromodulation is at a much earlier stage of development than TMS or tDCS [7].

Vagus Nerve Stimulation (VNS)

VNS is a minimally invasive therapy, first approved in 1997 for refractory seizure disorders and in 2005 for treatment-refractory MDD. Vagus nerves are cranial nerve with fibers that transmit nerve impulses from the periphery to the brain. Electrical stimulation of the vagus nerve stimulates the nucleus tractus solitaries, enhancing its capacity to modulate brain areas through its neuronal connections distributed to subcortical and cortical brain regions [8].

With VNS, an implantable pulse generator is surgically inserted in the chest region. The lead from the device is attached to the left vagus nerve in the neck, where a small electrical current is delivered. Stimulation is around-the-clock, with typical stimulation periods or "trains" lasting 30 seconds, with 5 minutes of rest between trains. The device parameters (pulse width, frequency, duration of stimulation, and duty cycle) can be modified transcutaneously (as with cardiac pacemakers) using a wand attached to a small handheld programming computer [26].

Motor Cortex Stimulation

Motor cortex stimulation is an invasive procedure, with use in chronic refractory pain first documented in the early 1990s. With motor cortex stimulation, the skull is surgically opened and an electrode array is inserted [13]. In epidural motor cortex stimulation, the electrodes are attached to the dura directly above the motor cortex. In subdural motor cortex stimulation, the dural layer is penetrated for electrode placement.

Motor cortex stimulation affects structures involved in affective, cognitive, and emotional aspects of pain. The analgesic mechanisms of motor cortex stimulation involve extensive changes at various CNS levels, with a likely entry point at the thalamic level that triggers distant effects on limbic, cingulate and orbitofrontal cortices, and descending modulation that reaches the spinal horn. Activation of the endogenous opioid system or gamma-aminobutyric acid transmission in these areas is thought to underlie long-term pain relief with motor cortex stimulation [13,27].

Deep Brain Stimulation

Deep brain stimulation is an invasive neurosurgical procedure performed under MRI guidance, where electrodes are implanted through the skull and dura into discrete brain targets for stimulation. The electrodes are internalized and connected to an implantable pulse generator implanted into the chest below the right clavicle. The implantable pulse generator is accessible with a handheld device, which allows remote monitoring and/or programming of stimulation parameters. The deep brain stimulation parameters of pulse width, frequency, and amplitude (voltage or current) are programmed by the treating physician and titrated to clinical effect. Deep brain stimulation has been extensively developed and refined for use in later-stage Parkinson disease, where it is a standard of care. Deep brain stimulation is also used in other movement disorders, but severe refractory psychiatric and pain disorders represent a growing research field [8].

3. NEUROMODULATION IN SPECIFIC PSYCHIATRIC DISORDERS

Among psychiatric disorders, depression has been the most extensively researched condition, followed by schizophrenia and substance use disorders. The most extensively studied brain stimulation modality is rTMS, followed by tDCS. While non-invasive brain stimulation approaches were developed to provide the efficacy of ECT without the adverse effects, ECT remains established in treating severe or refractory depression. Aside from ECT, deep brain stimulation is its current form has been in clinical use longer than other brain stimulation modes, but its invasive nature and restricted use to severe, refractory patients partially accounts for fewer published deep brain stimulation studies compared to rTMS and tDCS.

With noninvasive neurostimulation in psychiatric disorders and especially rTMS and tDCS, the speed at which the knowledge base is expanding cannot be overstated. Important factors that influence patient response to rTMS or tDCS are absent from earlier studies. Among these factors, perhaps the greatest efficacy-disrupting effect is found with smoking or benzodiazepine user on tDCS response.

In neurostimulation studies of psychiatric disorders, the Clinical Global Impression-Severity (CGI-S) scale may be used to measure patient response and clinical outcomes. This is a clinician rating scale of general improvement. More specific scales may be used to measure response for specific conditions.

MAJOR DEPRESSIVE DISORDER (MDD)

MDD is a disorder of mood involving disturbances in emotional, cognitive, behavioral, and somatic regulation which manifest in depressed mood and feelings of worthlessness or guilt; social withdrawal and agitation; impairments in concentration or decision-making; and insomnia or fatigue [28]. MDD is highly prevalent and associated with serious personal suffering, societal costs, severe symptoms and functional impairment. An estimated 30% of MDD patients do not adequately respond to pharmacotherapy and psychotherapy. Treatment-resistant depression is loosely defined as failure to achieve remission despite therapeutic interventions [29].

The dorsolateral PFC functions to regulate affective states through cognitive control over stress and emotion responsive, and is hypoactive during depressive episodes [30]. The dorsolateral PFC and rostral anterior cingulate cortex areas are closely inter-connected; decreased neuronal activity in these frontal areas underlies apathy, psychomotor slowness, and impaired executive functioning common in MDD [31,32].

Two different scales may be used to assess patient response. The first is the Hamilton Depression Rating Scale (HDRS or HAM-D), a 21-item measure of depression symptoms. In clinical trials, remission is defined as HDRS score <8. The other is the Montgomery-Åsberg Depression Rating Scale (MADRS), a depression scale that measures affective, cognitive, and vegetative symptoms.

ANXIETY DISORDERS AND ANXIETY-RELATED DISORDERS

Generalized Anxiety Disorder (GAD)

Generalized anxiety disorder (GAD) is a chronic psychiatric condition defined by excessive and uncontrollable worry, with at least three of six hyperarousal symptoms (restlessness, muscle tension, fatigue, irritability, difficulty in sleeping, concentration problems). Lifetime prevalence is 5.7%, with higher rates in primary care and psychiatric outpatient samples. GAD is frequently comorbid with depression, complicating presentation, treatment and prognosis. At the individual level, GAD is associated with significant quality-of-life impairments and diminished physical health. At the systems level, GAD is associated with high use of health care services and high costs [33].

Pharmacotherapy (antidepressants, anxiolytics) and cognitive-behavioral therapy are standard treatments for GAD, but fail to achieve symptom remission in 33% to 50% of patients. The best existing treatments leave many patients with GAD without relief, and alternative treatments are needed [33].

GAD is characterized by abnormalities in frontal and limbic structures primarily involving the prefrontal cortex, anterior cingulate cortex, and amygdala; decreased structural and functional connectivity between frontal and limbic regions; and impairments in emotion regulation associated with abnormal functioning in neural circuits that encompass frontolimbic regions including the dorsolateral PFC [34].

Panic Disorder

Panic disorder is characterized by sudden unexpected panic attacks and apprehension about the possible causes and consequences of the attacks. Comorbid agoraphobia is characterized by behavioral avoidance of situations from which escape might be difficult if a panic attack occurred [35].

Patients with panic disorder with and without agoraphobia have shown PFC hypoactivity paired with fear-relevant brain structure (amygdala) hyperactivity, suggesting inadequate PFC inhibition of responses to anxiety-related stimuli [36]. Hypofrontality is shown in patients with panic disorder during cognitive tasks without emotional content, and in responses to emotional stimuli. Altered activation patterns in the left inferior PFC are associated with panic attacks, and altered right anterior PFC associated with severity of agoraphobic avoidance [35,36,37].

A variety of scales are available to assess response of patients with anxiety disorders to neuromodulation therapies, including:

- Generalized Anxiety Disorder 7-item (GAD-7) scale

- Hamilton Anxiety Rating Scale (HARS or HAM-A)

- Panic and Agoraphobia Scale (PAS)

- Panic Disorder Severity Scale (PDSS)

- Clinician-Administered PTSD Scale

- Yale-Brown obsessive-compulsive scale (Y-BOCS) (the standard obsessive-compulsive disorder [OCD] measure)

- Yale Global Tic Severity Scale (YGTSS) (the standard Tourette syndrome measure)

POST-TRAUMATIC STRESS DISORDER

Formerly classed as anxiety disorders, post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder are now separately classed in the fifth revised edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) [28]. PTSD is a severe, potentially chronic and disabling disorder that can develop following exposure to a traumatic event involving actual or threatened death, serious injury, or sexual assault. Common symptoms include intrusive thoughts, nightmares and flashbacks of the traumatic event, avoidance of trauma reminders, hypervigilance, and sleep disturbance. These symptoms can be highly distressing and substantially impair social, occupational, and interpersonal functioning [28].

PTSD becomes chronic in as many as 40% of cases [38]. An estimated 8% of Americans currently meet PTSD diagnostic criteria, but less than half receive minimally adequate treatment [39]. PTSD is often comorbid with depression, substance misuse, and suicidality, and often responds poorly to conventional treatments [40]. Few therapies target the trauma memories, considered the root cause of clinical expression, symptom chronicity and impairment in PTSD. The potential of neurostimulation to modulate dysfunctional brain regions led to clinical trials in PTSD [40].

OBSESSIVE-COMPULSIVE DISORDER

OCD has a lifetime prevalence of 2% to 3% and an early onset in adolescence or young adulthood. The core OCD symptoms are:

- Obsessions, which are unwanted, disturbing, and intrusive thoughts, images, or impulses generally perceived by the patient as excessive or irrational

- Compulsions, defined as repetitive behaviors and mental acts that serve to ameliorate obsessions and reduce emotional distress

The obsessions and compulsions are often highly distressing to the patient. OCD is a frequently debilitating and often severe [28].

Even with the currently available treatment options, OCD has a tendency to chronicity and can have a devastating effect on occupational functioning, relationships and social life. With standard therapies involving selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy plus exposure and response prevention, around half of patients achieve 40% to 60% symptom reduction. Roughly 10% of patients are refractory to standard therapies and may become profoundly disabled. OCD pathology is thought to involve dysfunction of the cortico-striato-pallido-thalamo-cortical pathway, failure of ventral striatum inhibition, and pathological hyper-connectivity between cortical and striatal structures [41].

SCHIZOPHRENIA

Schizophrenia is a chronic psychotic disorder characterized by disordered cognition, emotion and perception of reality, Patients may experience positive symptoms (hallucinations, delusions) and exhibit behaviors perceived as odd and bizarre. Negative symptoms may be present at any disease stage, and persistent symptoms can include affective flattening, attentional/motor impairment, alogia, avolition, asociality and anhedonia. These are grouped into the subdomains of diminished expression (affective flattening) and amotivation (avolition/apathy) [17].

Traditionally viewed as an illness defined by psychosis, successful schizophrenia treatment was defined as resolution of delusions and hallucinations. Recently recognized is the substantial impact of negative symptoms on functional impairment. Resolution of positive symptoms, even in early-stage schizophrenia, may not translate into functional recovery. Full functional/social recovery occurs in less than 15% of schizophrenics, largely due to negative symptoms [42].

Efforts have expanded the definition of successful treatment outcome beyond clinical recovery to incorporate functional recovery. This recent focus on the relevance of negative and cognitive symptom in functional recovery prompted research efforts into more broadly effective treatments, including brain stimulation. Neurostimulation targets were suggested by the results of modafinil treatment studies. Modafinil increases dorsolateral PFC activity, and in schizophrenic patients, improved working memory, emotion recognition, cognitive flexibility, motor activity, and quality of life [42].

To assess patient response to therapy, clinicians may use the Auditory Hallucinations Rating Scale (AHRS), a seven-item scale that assesses the number of voices experienced and voice frequency, loudness, vividness, attentional salience, length, and distress caused [22]. For schizophrenia with negative symptoms, the Positive and Negative Syndrome Scale (PANSS) may be useful. Using this measure, moderate-to-severe negative symptoms score ≥15 on the Negative Subscale [43].

SUBSTANCE USE DISORDERS

Substance use disorder is a chronic relapsing disorder even following optimal detoxification and treatment, and substance craving is an important contributor to relapse. The reward effects of alcohol and abused drugs are mediated by the mesocorticolimbic system, comprised of the ventral tegmental area (VTA), nucleus accumbens, amygdala, and prefrontal cortex [44]. Also involved in substance use disorder is abnormal reinforcement in brain reward circuitry, and inhibitory control mechanisms exerted by the dorsolateral PFC and other prefrontal cortical networks [17].

Nicotine dependence imposes significant morbidity, mortality, and socio-economic burdens. It remains among the leading causes of mortality worldwide, and of preventable deaths in developed countries. Despite availability of approved medications for nicotine dependence, only 6% of smokers who report wanting to quit each year are successful in doing so for longer than one month. This mostly results from poor abstinence rates, and therapeutic alternatives are urgently needed. Emerging positive evidence suggests that non-invasive brain stimulation with TMS or tDCS can reduce smoking-related behaviors [45].

EATING DISORDERS

Anorexia Nervosa

Anorexia nervosa is a disorder characterized by a pathological fear of food, eating and gaining weight, and sustained (more than three years) duration of significant underweight (body mass index [BMI] <18.5 kg/m^2) [46,47]. Onset is usually peri-pubertal and anorexia nervosa mainly affects girls and women. The lifetime prevalence of anorexia nervosa in women is 2% to 4%, median duration is 5 to 7 years, and illness duration is more than 15 years in 30% [47]. The disorder has a high mortality rate, and only 10% to 30% of adults with anorexia nervosa recover through the best available therapies [46].

Patients with anorexia nervosa have limited treatment options, especially with prior treatment nonresponse [47]. Pharmacotherapy is largely ineffective and poorly accepted [46]. Patients underweight for three to five years have worse treatment response and outcome, possibly from the neurotoxic effects of starvation and stress hormones (cortisol) to the brain. This makes the first years from onset critical for successful intervention [47].

Anorexia nervosa is associated with structural changes such as reduced grey matter in fronto-limbic-striatal areas; functional changes with over-active limbic drives from the insula and amygdala, and diminished prefrontal activity; and hypoactivity of PFC regions during response inhibition and set-shifting tasks, a marker of poor inhibitory control that promotes anorexia nervosa chronicity. Improved, neuroscience-based treatments are needed that target the neural substrates of anorexia nervosa [46].

The Eating Disorder Examination Questionnaire (EDE-Q) measures eating disorder symptoms and general psychopathology. This has been the most common measure of response to therapy in the literature.

Bulimia Nervosa

Bulimia nervosa is an eating disorder with recurrent episodes of binge eating characterized by eating large amounts of food in a discrete amount of time (i.e., within a two-hour period) and feeling of lack of control over eating during episodes; and recurrent inappropriate compensatory behavior to prevent weight gain (purging). The binge eating and compensatory behaviors both occur at least once a week, on average, for three months, and patient self-evaluation is unduly influenced by body shape and weight [28].

Similar to anorexia, reduced PFC activity may contribute to symptoms in bulimic patients through impaired inhibitory control of binge eating and purging; poor cognitive flexibility that perpetuates compulsive body checking and exercise; and obsessive pre-occupation with eating, weight and shape [46].

Binge-Eating Disorder

The lifetime prevalence of binge-eating disorder is roughly 5% of the U.S. adult population, and 1.2% to 4.5% are diagnosed with subthreshold binge-eating disorder and any binge eating. Compared to obese individuals who do not binge-eat, patients with binge-eating disorder are more prone to depression, anxiety, body dissatisfaction, low self-esteem, and social withdrawal [48].

Cognitive-behavioral therapy can reduce binge symptoms, but many patients lack response and treatment-related weight-loss is minimal. Effective and lasting treatments for binge-eating disorder are needed to alleviate symptoms of this psychological disorder and the medical consequences of obesity [48].

DEPERSONALIZATION/DEREALIZATION DISORDER

Depersonalization/derealization disorder is characterized by distressing feelings of unreality and alteration, with persistent or recurrent experiences of feeling detached from, as if an outside observer of, one's mental processes or body. The condition has an estimated prevalence of 1%, commonly begins in early adulthood and tends to become chronic [28]. Depersonalization/derealization disorder can appear as a symptom of other psychiatric disorders, including 12% of cases of panic disorder [49]. Depersonalization is a commonly described symptom in patients with temporal lobe epilepsy, and may occur with use of some illicit substances [50]. Several pharmacotherapies have been trialed but most have not led to sufficient symptom improvement [51,52]. The Cambridge Depersonalization Scale (CDS) may be used with these patients to assess response.

4. ELECTROCONVULSIVE THERAPY

CANDIDATES FOR ECT

During the course of its long history, ECT became stigmatized in the viewpoints of patients, most psychiatrists and the lay public. While not undeserved considering the past misuse and crude technique of this procedure, the persistence of stigma has outlived substantial refinements in method and established efficacy and represents a barrier to treatment.

ECT is reserved for use in complex and acutely severe clinical presentations of MDD; in these patients, ECT is considered unrivaled for rapid induction of antidepressant effects [7]. ECT is recommended as first-line treatment in the following patients: extremely severe melancholic depression; those who refuse to eat or drink; have a very high suicide risk; very high levels of distress; psychotic depression; refractory MDD; catatonia; or previous positive ECT response [53].

With psychotic depression, ECT is a first-line option, and highly effective; a large study of bitemporal ECT efficacy reported remission rates of 95% in study completers [53,54].

TREATMENT PARAMETERS IN ECT

ECT outcomes are highly influenced by electrode placements, electrical intensity, and pulse width. Electrode placements are generally right unilateral, bitemporal, or bifrontal [8].

Electrical intensity is the ECT "dose." The delivered electrical intensity dose is individualized and based on seizure threshold—the minimum intensity to induce a generalized seizure. Doses five to eight times seizure threshold maximize the efficacy of unilateral placement, while doses 50% to 100% above seizure threshold for bilateral placement are usually sufficient [53].

Pulse width in ECT includes brief pulse width and ultra-brief pulse width (≤0.5 ms) [8]. The recommended first-line parameter for ECT in MDD is right unilateral or bifrontal placement; second-line placement is ultra-brief pulse right unilateral or bifrontal, or brief pulse bitemporal placement [8]. If there is no response to right unilateral after four to six sessions, switch to bilateral bitemporal or bifrontal.

Twice/week ECT has similar efficacy to three times/week but requires longer treatment duration; more than three treatments/week are not recommended due to greater cognitive side effects [8].

Dose level above seizure threshold determines the relative efficacy of electrode placements but can increase cognitive side effects. Generally, bitemporal ECT is more effective than unilateral, but cognitive side effects are greater. At six times threshold, unilateral efficacy approaches bitemporal ECT, but cognitive impairment is greater than with lower doses. Bifrontal ECT is less studied, but appears as effective as high-dose unilateral and bitemporal placement. Research evidence is insufficient to conclude a cognitive benefit for bifrontal over bitemporal ECT, but clinical experience suggests bifrontal ECT may induce fewer cognitive side effects than bitemporal. Bifrontal ECT may be associated with lower rates of ECT-induced cardiac arrhythmia, suggesting a safety advantage over unilateral and bitemporal ECT in patients with cardiovascular comorbidity [53,55].

Ultra-brief pulse width unilateral ECT allows effective treatment with markedly fewer cognitive side effects. Ultra-brief pulse efficacy appears comparable to standard brief pulse unilateral ECT but may require more treatments to achieve remission. Ultra-brief pulse bifrontal ECT is effective in cognitive sparing but ultra-brief pulse bitemporal is ineffective and not recommended [53,56,57,58].

Efficacy is balanced against side effects. ECT for most patients should begin with ultra-brief pulse unilateral ECT, as this has fewer cognitive side effects but may require a longer treatment course. When speed and reliability of ECT response is crucial, as with patients who are dehydrated or at extreme risk for suicide, bifrontal or bitemporal ECT should be considered [53].

EFFICACY

ECT is one of the most rapidly effective treatments for MDD. Response rates can reach 70% to 80% and remission rates 40% to 50% or higher, depending on the patient population and electrode placements; remission rates of 55% for right unilateral, 61% for bifrontal, and 64% for bitemporal were reported in a population of patients with unipolar (77%) or bipolar (23%) depression [8,59].

After an acute course of ECT, relapse rates are high, and greatest in the first six months post-ECT (37.7%). Even patients receiving post-ECT maintenance showed high relapse rates at one year (51.1%) and two years (50.4%) [60].

PREDICTORS OF ECT RESPONSE AND RELAPSE

ECT nonresponse is strongly predicted by severity of previous treatment resistance. In highly treatment resistant patients, ECT response rates were roughly 50% versus 65% in patients without previous treatment failure [61,62].

Highest response rates are associated with older age, psychotic features, shorter MDD duration, less previous treatment non-response, and possibly lower depressive severity [8]. Lower relapse rates are found in MDD cohorts with higher proportions of psychotic patients and older patients. Pre-ECT medication resistance is not associated with relapse risk [8].

POST-ECT MAINTENANCE

Initial ECT response can be maintained with medication or ECT. Post-ECT antidepressant use reduces relapse rates by roughly 50% [60]. Strongest evidence supports the post-ECT relapse reduction efficacy of nortriptyline plus lithium or venlafaxine plus lithium, and both show comparable efficacy [63,64].

Patients continuing their antidepressants during ECT show lower relapse rates versus antidepressant initiation after ECT (29.2% vs 41.6%), suggesting concurrent instead of sequential use of ECT and medication improves long-term outcomes [60]. Lithium during ECT may increase risks of cognitive side effects, encephalopathy, and spontaneous seizures; benzodiazepines and anticonvulsants may raise seizure threshold and decrease seizure efficacy, but lamotrigine may be less problematic than other anticonvulsants [8,65].

Continuation/maintenance ECT is safe and effective for reducing relapse, and shows comparable efficacy to nortriptyline plus lithium in relapse rates at six months (37.2% vs 37.7%) [66,67]. The frequency of continuation/maintenance ECT should be tailored to the patient, but is typically weekly for four weeks, then biweekly for eight weeks, and then monthly. More frequent sessions can be added with signs of relapse [8].

There are few psychotherapy studies of post-ECT relapse prevention, but patients randomized to cognitive-behavioral group therapy plus continuation medication have shown lower relapse rates at 6 and 12 months compared to continuation/maintenance ECT plus medication or medication continuation alone [68,69].

ADVERSE EFFECTS OF ECT

The use of general anesthesia, muscle relaxants, oxygenation and monitoring has minimized ECT-related morbidity, and mortality is estimated at less than one death per 73,440 treatments. ECT-related damage to brain structures has not been found. Adverse effects of headaches (45%), muscle soreness (20%) and nausea (1% to 25%) during treatment are transient and treated symptomatically. Roughly 7% of patients with MDD switch into a manic or mixed state [8].

Cognitive impairment is the greatest concern, and includes transient post-ECT disorientation due to postictal confusion and general anesthesia; retrograde amnesia (difficulty recalling information learned pre-ECT), and anterograde amnesia (difficulty retaining information learned post-ECT) (Table 1). Mild, short-term impairment in memory and other cognitive domains often occur during, and just after, ECT [53].

Table 1: ECT-RELATED FACTORS WITH HIGHER VERSUS LOWER RISK OF SHORT-TERM COGNITIVE IMPAIRMENT

ECT-Related Factors

Short-Term Cognitive Impairment

Higher Risk

Lower Risk

Electrode placement

Bitemporal

Bifrontal, unilateral

Pulse width

Brief (1.0–1.5 ms)

Ultrabrief (0.3–0.5 ms)

Stimulation dose

Suprathreshold

Lower electrical dose

Treatment frequency

3 times/week

2 times/week

Concurrent medications

Lithium, agents with known cognitive side effects

Reducing or discontinuing these agents

Anesthesia

High–dose

Lower doses

Source: [8]

Anterograde and retrograde memory are variably affected. Within two to four weeks, impaired anterograde memory usually returns to normal or may improve versus pre-ECT levels [70]. Retrograde impairment can persist for prolonged periods [71]. Perhaps most distressing to some patients is loss of autobiographical memory recall. Patients have reported persistent retrograde amnesia beyond six months; researchers counter by stating these subjective complaints could not be confirmed with objective testing, concluding they reflect persistent depressive symptoms [72,73]. Patients and their immediate family/partner should be informed of the potential effects on memory before undergoing ECT [53].

Absolute contraindications to ECT have not been identified, but several factors are associated with increased safety risk, including [8,9]:

- Space-occupying cerebral lesion

- Increased intracranial pressure

- Recent myocardial infarction

- Recent cerebral hemorrhage

- Vascular malformation or unstable aneurysm

- Pheochromocytoma

- Class 4 or 5 anesthesia risk

5. TRANSCRANIAL MAGNETIC AND ELECTRIC STIMULATION IN PSYCHIATRIC DISORDERS

Important background information on rTMS and tDCS use that spans the range of psychiatric disorders is presented in this section, including factors that influence patient response, safety, and contraindications. Disorder-specific information is discussed further later in this course.

TRANSCRANIAL MAGNETIC STIMULATION (rTMS) IN PSYCHIATRY

Many psychiatric disorders have been evaluated in rTMS treatment, with the greatest evidence of efficacy in treatment-resistant depression [13]. Nicotine dependence is the most studied substance use disorder [12].

Concurrent Medications and rTMS Safety

Evidence Based Practice Recommendation

The safety guidelines for rTMS were determined in study participants who were largely free of antidepressant medications. While it is possible that psychotropic medication can affect the motor threshold, the National Network of Depression Centers and the American Psychiatric Association indicate there are no known absolute contraindications to psychotropic medication usage during rTMS. All medication use and change should be documented.

https://pmc.ncbi.nlm.nih.gov/articles/PMC5846193

Last Accessed: July 24, 2025

Level of Evidence: Expert Opinion/Consensus Statement

Potentially problematic medications commonly used in psychiatry and pain includes tricyclic antidepressants (nortriptyline, amitriptyline), antipsychotic drugs (chlorpromazine, clozapine), and antiviral medications. Abuse of alcohol or some illicit substances can increase cortical excitability and risk of a TMS-induced seizure. Withdrawal from CNS sedatives, including alcohol and benzodiazepines, increases seizure risk and patients must be asked about recent and current use. Recent substance abuse should be a contraindication to rTMS therapy [13]. The antidepressant bupropion is associated with increased seizure risk in some populations, raising concerns of its use during rTMS therapy. A systematic review found no evidence that supports excluding patients taking bupropion from rTMS [74].

Adverse Effects with rTMS

Seizure induction is the most serious adverse effects with rTMS, but fewer than 25 cases have been reported worldwide to date. The estimated incidence of spontaneous seizures is 0.01% to 0.1% with rTMS, 0.1% to 0.6% with antidepressant drugs, and 0.07% to 0.09% in the general population. HF-rTMS is contraindicated in patients with seizure history. Safety of LF-rTMS has been demonstrated in patients with epilepsy but is not established in patients with depression and seizures. Seizure history is usually considered an absolute contraindication [8].

Contraindications to rTMS

Evidence Based Practice Recommendation

According to the National Network of Depression Centers and the American Psychiatric Association, a comprehensive review of the patient's health status (including historical and current medical, surgical, neurologic, and psychiatric conditions and medications) and physical examination are evaluation components to determine the medical safety and necessity of rTMS.

https://pmc.ncbi.nlm.nih.gov/articles/PMC5846193

Last Accessed: July 24, 2025

Level of Evidence: Expert Opinion/Consensus Statement

Absolute contraindications to rTMS are ferromagnetic metal in the head (e.g., plates or pins, bullets, shrapnel) and metallic hardware anywhere in the head, except the mouth (e.g., Cochlear implants, brain stimulators or electrodes, aneurysm clip) [8,13]. Relative contraindications include [8,13]:

- Presence of a brain lesion (vascular, traumatic, neoplastic, infectious or metabolic) or major head trauma

- Ferromagnetic metal in neck or chest

- Microprocessor implants in the neck, such as vagus nerve stimulator

- History of epilepsy or induced seizures

- Microprocessor implants below the neck: Spinal pumps or stimulators, cardiac pacemaker, implantable defibrillator

- Medications that lower seizure threshold

- Recent withdrawal from CNS sedatives that raise seizure risk (e.g., alcohol, benzo-diazepines)

- Pregnancy

- Hearing loss, tinnitus

TRANSCRANIAL DIRECT CURRENT STIMULATION (tDCS) IN PSYCHIATRY

Compared with rTMS, tDCS is more recently introduced, with fewer published efficacy and safety studies in psychiatric disorders. Antagonist effects on tDCS treatment response from two drug agents were first identified in a 2016 review of tDCS in psychiatric disorders [16]. Nicotine inhibits schizophrenic patient response to tDCS. This effect is confirmed experimentally, and evident empirically in tDCS studies outcomes of schizophrenia; higher rates of current smokers repeatedly showed direct association with lower tDCS response rates [16]. In patients with MDD, co-use of benzodiazepines blunts therapeutic response to tDCS [16].

The efficacy-disrupting effects of concurrent benzodiazepine use in MDD trials and cigarette smoking in schizophrenia trials was not previously known, and throws reported outcomes of tDCS studies with negative or ambiguous findings into question (unless patient prevalence of benzodiazepine use or smoking was recorded) [16].

Serotonergic neurotransmission is enhanced by SSRI antidepressants, which facilitates neural excitation of anodal tDCS, but switches the inhibited excitability of cathodal tDCS to facilitated excitability. Similar effects are found with amphetamine, and the NMDA receptor agonist D-cycloserine [18].

Mood stabilizer antiepileptic agents interfere with tDCS-elicited excitability changes by blocking voltage-gated sodium and calcium channels [75].

Dopaminergic agents variously interact with tDCS to amplify or block the intended effects. Neuroleptics and other dopamine receptor antagonists suppress tDCS effects, while dopaminergic agonists have a non-linear synergistic effect on tDCS-induced excitability, and a prolonging effect on excitability inhibition. This may be relevant to the reduced tDCS effects in smokers during nicotine withdrawal [76].

Several biological, psychological, and lifestyle factors have been identified that influence tDCS response and contribute to the variable efficacy in tDCS trials [16]. COMT gene polymorphism moderated tDCS effects in patients with schizophrenia [77]. Prefrontal tDCS intensified cravings in patients with substance use disorder with drug-related cues present [78]. tDCS shows greater therapeutic effect in more severe MDD than in mild/moderate MDD [79]. Finally, severity of treatment-resistance in MDD negatively influences tDCS response, although attention should be paid to how treatment-resistance is defined [16].

Safety

Using conventional tDCS protocols (sessions ≤40 min, ≤2 times/day, ≤4 mA, electrodes that minimize skin burns), repeated sessions in more than 1,000 subjects receiving more than 33,200 sessions has not produced any reports of serious adverse events or irreversible injury to date. This includes diverse subject populations and patients from vulnerable populations [16,80]. Reports in the published evidence include patients receiving more than 100 tDCS sessions without adverse events from cumulative exposure; lack of unexpected or serious adverse events in more than 40 studies with more than 600 older adults; lack of decrements in behavior or mood in stroke populations; and no finding of drug agents that increase risk of serious adverse effects [80].

Seizure concerns with TMS have spread to tDCS, but evidence of increased seizure risk with tDCS is absent. tDCS produces static and not pulsed electric fields that are two orders of magnitude below those of rTMS, ECT and transcranial electrical stimulation, and thus, no apparent seizure risk [80].

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

REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION (rTMS)

As a medical intervention with seizure risk, rTMS should only be performed in a medical setting under physician guidance and supervision. The medical team should include a psychiatrist when used as treatment for acute depression, and psychiatrists who use TMS benefit from training in brain stimulation methods [19].

Clinical guidance regarding the recommended approach to administering rTMS and theta-burst stimulation has been established for patients with MDD [8]. The initial session should stimulate at 110% to 120% of resting motor threshold (or 70% to 80% for theta-burst stimulation). The stimulation frequency and site should be selected (Table 2). Stimulations should be performed five times per week. The initial course is usually 20 sessions over a four-week period; this may be extended to 30 sessions (over six weeks) in non-remitting partial responders. Patients may return to this therapy as needed to maintain response.

Table 2: RECOMMENDED rTMS AND TBS PROTOCOLS IN MDD

Approach

Intensity and Site

First-line

HF-rTMS to left DLPFC

LF-rTMS to right DLPFC

Second-line

Bilateral rTMS to DLPFC (left HF and right LF)

LF-rTMS to right DLPFC (if nonresponse to left DLPFC HF-rTMS)

HF-rTMS to left DLPFC (if nonresponse to right DLPFC LF-rTMS)

TBS protocols:

- Intermittent TBS to left DLPFC

- Left intermittent and right continuous TBS to DLPFC

- Intermittent TBS to bilateral DMPFC

Third-line

HF-rTMS to bilateral DMPFC

DLPFC = dorsolateral prefrontal cortex, DMPFC = dorsomedial prefrontal cortex HF-rTMS = high-frequency rTMS, LF-rTMS = low-frequency rTMS, MDD = major depressive disorder, rTMS = repetitive transcranial magnetic stimulation, TBS = theta-burst stimulation.

Source: [8]

Unless otherwise stated, in the studies discussed in this section, HF-rTMS is applied to the left dorsolateral PFC, and LF-rTMS to the right dorsolateral PFC.

Most studies of rTMS in MDD have involved patients with some degree of treatment resistance (at least one to two failed antidepressant trials). Overall, rTMS is considered a first-line treatment for patients with MDD and at least one failed antidepressant trial [8].

Efficacy is established with both HF-rTMS and LF-rTMS of the left and right dorsolateral PFC, respectively. Differences in outcome are few, although LF may require shorter treatment duration. Non-responders of HF may respond to LF, and vice versa. Bilateral stimulation combines HF left and LF right dorsolateral PFC, but requires intensive setup but is not superior to unilateral approaches [8].

Evidence Based Practice Recommendation

A European consortium of experts found definite antidepressant efficacy of deep HF-rTMS over the left DLPFC in major depression.

https://www.sciencedirect.com/science/article/pii/S1388245719312799

Last Accessed: July 24, 2025

Level of Evidence: A (Definitely effective or ineffective based on at least two Class I studies or one Class I study and at least two Class II studies)

rTMS efficacy is established in treatment-resistant depression using the most stringent criteria. A meta-analysis of HF-rTMS in patients with treatment-resistant depression found significantly greater efficacy and effect size over sham [81]. randomized sham-controlled trials of HF-rTMS using adequate sessions (20 to 30) and treatment durations (≥4 weeks) achieved 40% to 55% response and 25% to 35% remission rates, similar to results of uncontrolled trials showing 58% response and 37% remission rates [82]. A meta-analysis also found superior remission rates with LF-rTMS (35%) versus sham (10%) [83].

HF-rTMS of the dorsomedial PFC (DMPFC) produces antidepressant effects. A randomized controlled trial found slightly better outcomes for DMPFC rTMS, while an uncontrolled trial of DMPFC rTMS reported 50% response and 36% remission rates [84,85,86].

Post-rTMS Maintenance of Efficacy

Relapse is frequent after successful rTMS without maintenance treatment. An uncontrolled study reported a median 120 days until relapse, with 25%, 40%, 57%, and 77% relapsing at 2, 3, 4, and 6 months, respectively [87]. In contrast, rTMS maintenance as needed over 12 months in 257 patients was able to sustain remission in 71% of remitters, and response in 63% of responders [88]. Another study found 38% of rTMS responders relapsed within 24 weeks (mean: 109 days post-treatment). With reinstatement of as-needed rTMS, 73% met response and 60% met remission at 24 weeks [89].

A 20-week gradual taper of maintenance rTMS (from 3 sessions/week to 1 session/month) was compared to no maintenance, and relapse rates were 38% with maintenance versus 82% without maintenance. Five "clustered" maintenance sessions over three days every month extended the mean relapse to 10.8 months [8,90,91].

rTMS versus ECT

The available evidence suggests ECT is generally more rapid and effective in antidepression effects, with greater side effects and lower patient acceptance than rTMS. An open-label study compared efficacy and patient acceptance of ECT versus rTMS in outpatients with treatment-resistant depression. While both therapies significantly improved depression scores, benefits were greater with ECT than rTMS, and anxiety symptoms decreased with ECT but not rTMS. Patients who received ECT reported they would have chosen rTMS if it had been financially available, even when informed rTMS was less effective than ECT for treatment-resistant depression. The authors stated this reflects the level of stigma that surrounds ECT [29].

A meta-analysis compared the efficacy of ECT and rTMS in MDD. ECT was superior to HF-rTMS in response (64.4% vs 48.7%) and remission (52.9% vs 33.6%), and discontinuation was similar (8.3% vs 9.4%). ECT was superior in psychotic depression, but HF-rTMS and ECT were comparable in non-psychotic depression. ECT had a slight advantage over rTMS in overall improvement in HAM-D scores. Data on medium or long-term efficacy was insufficient. The same results were found with ECT versus LF-rTMS. ECT led to greater impairment in cognitive domains such as visual memory and verbal fluency. ECT and rTMS seemed comparably effective in patients with MDD without psychosis, but ECT was more effective with psychotic depression [92].

Other meta-analyses found larger differences favoring ECT for all outcomes, especially in MDD with psychotic features. rTMS response is poor in patients with ECT failure, and rTMS should be considered before pursuing ECT because patients lacking ECT response are unlikely to benefit from rTMS [8].

rTMS and Antidepressants

rTMS has mostly been evaluated as an add-on therapy to stable antidepressant regimens, and no evidence shows outcomes are improved by discontinuing antidepressants before rTMS. However, some evidence suggests that initiating antidepressants during rTMS promotes higher response and remission rates than rTMS alone [8,83].

In patients with treatment-resistant depression receiving LF-rTMS, responders showed lower psychomotor retardation at baseline than non-responders, and ex-smokers showed substantially higher response rates than current smokers [93].

Adverse Effects

The most frequent adverse effects were scalp pain during stimulation (40%) and transient headache after stimulation (30%). Both diminish with repeated treatment, respond to over-the-counter analgesics, and resulted in few study dropouts. The cognitive safety profile of rTMS appears benign; studies that assessed rTMS and cognitive performance found no differences between active and sham rTMS [8,94].

Unresolved Issues

Although published evidence suggests that daily prefrontal rTMS has a significantly greater antidepressant effect than sham, with a magnitude of effect at least as large as antidepressant drugs, some issues remain unresolved [19]. The optimal hemisphere and position of coil placement remains unclear in depression treatment. Whether coil placement using individualized location via neuronavigated methods is superior to general algorithms for probabilistic positioning is not clear. Also, duration of rTMS treatment and patient follow-up are inadequate in many older studies.

Deep rTMS

Personality traits such as extraversion and neuroticism have attracted increasing attention as characteristics in predicting MDD response to pharmacotherapy, psychotherapy, and more recently, neuromodulation. Deep rTMS allows stimulation of deeper cortical regions, and the influence of personality dimensions in antidepressant response to deep rTMS in treatment-resistant depression was evaluated. After four weeks of daily deep rTMS (20 Hz, 3,000 pulses/session) of the left dorsolateral FPC, clinical remission was associated with higher baseline levels of agreeableness and conscientiousness. Levels of agreeableness and extraversion were linearly associated with antidepressant response. Neuroticism was not associated with antidepressant effects. Five-factor personality assessment may have prognostic value in deep rTMS for treatment-resistant depression, as agreeableness, extraversion, and conscientiousness were associated with reductions in depressive symptoms during treatment [95].

Theta-Burst Stimulation

A variation of rTMS is theta-burst stimulation. In MDD, theta-burst stimulation is delivered at lower intensities than rTMS (70% to 80% of active motor threshold) and requires only one to three minutes of stimulation [8]. Studies of both theta-burst stimulation types suggest lasting effects on cortical excitability that exceed standard rTMS. Increased cortical excitability with intermittent theta-burst stimulation has persisted longer than HF-rTMS. With continuous theta-burst stimulation, persistence in reduction of cortical excitability has been less consistent. Enthusiasm over the promising rapid effects on synaptic plasticity with theta-burst stimulation should be tempered by the highly variable patient response [19].

Small randomized controlled trials of dorsolateral PFC theta-burst stimulation showed superiority over sham with left intermittent theta-burst stimulation but not right continuous theta-burst stimulation, with bilateral stimulation (left intermittent/right continuous) showing mixed results. Data on bilateral DMPFC theta-burst stimulation suggest similar outcomes between intermittent theta-burst stimulation and longer conventional 10-Hz rTMS. Randomized controlled trial of conventional rTMS and theta-burst stimulation are in progress [8].

A randomized sham-controlled trial of 20 sessions found intermittent theta-burst stimulation safe, and resulted in immediate statistically significant decreases in depressive symptoms versus sham. After the two-week double-blind protocol, only 28% of patients showed ≥50% reduction in depression scores, but response rates increased to 38% an extra two weeks later to indicate delayed clinical effects. Importantly, 30% of the responders were in clinical remission. The findings suggest that only four days of accelerated intermittent theta-burst stimulation treatment in treatment-resistant depression may lead to meaningful clinical responses within two weeks post-stimulation [96].

Intermittent theta-burst stimulation was examined in a crossover randomized sham-controlled trial of 50 suicidal, antidepressant-free patients with treatment-resistant depression. Patients received 20 intermittent theta-burst stimulation sessions over four days, and the alternate condition (active or sham) at study day 7. This study found a significant decrease in suicide risk, lasting up to one month, unrelated to active or sham stimulation and unrelated to depression response. A high placebo response to sham was noted in those receiving sham intermittent theta-burst stimulation before they crossed over to active intermittent theta-burst stimulation. None of the patients committed suicide until six months after intermittent theta-burst stimulation treatment [97].

Magnetic Seizure Therapy

A randomized controlled trial of magnetic seizure therapy versus unilateral ECT found similar rates of response (60% vs 40%) and remission (30% vs 40%). A large uncontrolled magnetic seizure therapy trial reported a 69% response rate and a 46% remission rate, similar to published ECT outcomes [98,99]. Studies evaluating magnetic seizure therapy versus sham stimulation, relapse following magnetic seizure therapy, or relapse prevention await publication [8].

Magnetic seizure therapy has shown lower rates of headaches and muscle aches than ECT, without noticeable anterograde or retrograde amnesia. Reorientation time (time from seizure and anesthesia emergence to fully oriented by person, place, and time) was briefer with magnetic seizure therapy (2 to 7 minutes) than ECT (7 to 26 minutes). The sole randomized controlled trial in magnetic seizure therapy (versus unilateral ECT) found comparable neuropsychological testing results after 12 treatments [98,100].

TRANSCRANIAL DIRECT CURRENT STIMULATION IN MDD

The first published trial of tDCS in depressive disorders appeared in 2006. Almost all affective disorder studies have evaluated tDCS treatment in unipolar MDD [17,101].

The number of sessions, and anode/cathode polarity are thought to influence tDCS efficacy [16]. Most MDD have trials consist of placement of the anode over the left dorsolateral PFC and cathode over a noncortical region, or left dorsolateral PFC anodal stimulation combined with right dorsolateral PFC cathodal stimulation (bilateral tDCS). Minimum stimulation with 2 mA for ≥30 minutes per day over two weeks is required for an antidepressant effect.

With these parameters, six-week remission rates were higher in tDCS plus sertraline (47%) versus tDCS (40%) or sertraline (30%) alone, suggesting tDCS may potentiate antidepressant effects [102,103]. tDCS may also enhance psychotherapy outcomes [8,9]. Data from randomized sham-controlled trials suggest that multiple session tDCS can induce durable benefit in patients with MDD [16].

Treatment of Acute MDD Episodes

A review of six randomized sham-controlled trials found active tDCS significantly superior to sham in response (34% vs 19%), remission (23.1% vs 12.7%), and improvement in depression. Treatment-resistant depression and higher tDCS "doses" were negative and positive predictors of tDCS efficacy, respectively. The authors concluded the tDCS treatment effect size was comparable to those of rTMS and antidepressant drug treatment in primary care [104].

A meta-analysis of tDCS in MDD evaluated improvement in HAM-D scores, and a moderate-large effect size was found that favored active tDCS over sham. Two additional randomized sham-controlled trials were added, effect sizes were calculated for response and remission, and active tDCS was found not superior to sham in response or remission. Closer examination of the involved studies indicated that tDCS showed negative results in studies with high treatment resistance samples, and positive results in studies where subjects were lower in treatment non-response. Concurrent use of antidepressants, mood stabilizers, or benzodiazepines hampered patient response to tDCS. As such, tDCS seems efficacious for the treatment of depression, but it is not recommended in treatment-resistant depression or as an add-on to medication [75].

Maintenance of Acute Response

Several studies have evaluated persistence of acute effects and relapse following initial tDCS treatment, and strategies to prevent relapse. In one study, three months after completion of acute tDCS treatment, antidepressant effects persisted in almost half (47.8%) of patients without maintenance tDCS, and the need to prolong acute tDCS efficacy was noted [105].

Following clinical response to acute treatment, subjects received continuation tDCS every week for three months, and then every two weeks the final three months. Cumulative relapse-free survival was 83.7% at three months and 51.1% at six months; with decreased continuation tDCS at three months, relapse increased from 16.3% to 48.9%. Medication resistance was the greatest predictor of relapse during continuation tDCS [106].

Another study of tDCS relapse followed subjects 24 weeks. After response to acute treatment, subjects received up to nine tDCS sessions every two weeks for three months, followed by one tDCS session/month for three months. The mean response duration was 11.7 weeks, and relapse-free survival rate at 24 weeks was 47%. Patients with treatment-resistant MDD showed substantially worse 24-week survival versus patients with non-depression (10% vs 77%) [107].

tDCS versus Antidepressants

In a double-blind trial, patients with MDD were randomized to active tDCS, sham tDCS and fluoxetine 20 mg. More rapid improvement in depressive symptoms occurred with active tDCS than with fluoxetine, and after six weeks, active tDCS and fluoxetine showed the same improvement in depression scores and were significantly superior to sham [108].

Another study randomized 120 patients with MDD to active or placebo sertraline 50 mg plus active or sham tDCS in a four-arm trial. The combined active sertraline plus active tDCS was superior to all other groups, both groups with one active agent (sertraline or tDCS) did not differ and were superior to the group with placebo plus sham. Of note is that sertraline and tDCS were started concurrently in non-resistant patients, which could account for the additive effect rather than blocked response seen with tDCS as an add-on to stable but marginally ineffective antidepressants [109].

Side Effects

At present, tDCS trials are reviewed and conducted in accordance with the Non-Significant Risk U.S. Food and Drug Administration (FDA) designation for medical devices [80]. tDCS is generally well-tolerated. Frequent adverse events (>50%) include reddening of the skin, itching, burning, heat, and tingling sensations at the site of electrode placement. Sporadically reported adverse events with similar rates between active tDCS and sham include nausea, euphoria, reduced concentration, and anxiety. Study dropout rates from adverse events are comparable for tDCS and sham (both 3%), but long-term data on safety and tolerability are lacking [8]. No post-acute side effects emerged during follow-up in the longer-term maintenance studies [105].

tDCS is recommended as a third-line treatment for MDD, with more research needed to establish optimal stimulation parameters [8]

7. NEUROMODULATION FOR OTHER MENTAL HEALTH DISORDERS

NEUROMODULATION FOR BIPOLAR II DEPRESSION AND BIPOLAR DISORDER

The depressive phase of bipolar disorder has few published studies, and treatment of manic symptoms in even fewer studies. Brain stimulation in bipolar disorder has used the parameters in unipolar depression treatment, but important differences between the two disorders require tailored stimulation for bipolar disorder [110].

In patients with bipolar II depression, quetiapine plus four weeks of HF-rTMS, LF-rTMS, or sham found quetiapine/active rTMS did not differ from quetiapine/sham on any outcome measure [111]. The few tDCS studies in bipolar depression or mania found some support but used small patient numbers [17,101].

ANXIETY DISORDERS AND ANXIETY-RELATED DISORDERS

Unless stated otherwise in this section, rTMS targets are HF-rTMS of the left dorsolateral PFC, and LF-rTMS of the right dorsolateral PFC. The efficacy of rTMS in anxiety symptom reduction was evaluated in 14 randomized sham-controlled trials, primarily involving patients with PTSD or OCD. Active TMS was not clinically or statistically superior to sham in reducing anxiety symptoms in patients with OCD, PTSD, or panic disorder [112]. It should be noted that while clinically relevant anxiety can be present in patients with PTSD or OCD, these conditions are no longer classified as anxiety disorders by the DSM-5-TR because their core features differ in pathological basis and clinical presentation from anxiety disorders (e.g., GAD, panic disorder) [28].

Few studies have evaluated tDCS in anxiety disorders. However, tDCS modulation of dorsolateral PFC activity led to significant reductions in fear vigilance to threatening stimuli, similar to that observed with anxiolytic treatments. This finding that tDCS acutely altered the processing of threatening information suggests a potential mechanism that could be harnessed for treatment of clinical populations. These results were obtained from healthy volunteers [113].

Generalized Anxiety Disorder

A randomized sham-controlled trial evaluated 30-session (over six weeks) LF-rTMS in 25 patients with GAD. Patients undergoing active rTMS (versus sham) experienced higher response rates (71% vs 25%) and significant reductions in anxiety, worry, and depressive symptoms. At three months post-rTMS, 43% of active rTMS patients showed remission, versus 8% with sham. Response rates with active rTMS were maintained during follow-up, with some additional gains in remission rates. At post-treatment, right dorsolateral PFC activation was increased for active rTMS only, and changes in neuroactivation significantly correlated with changes in worry symptoms. These findings provide preliminary evidence that rTMS may improve GAD symptoms by modifying neural activity in the stimulation site [114].

A secondary analysis study was performed to determine if dorsolateral PFC neuromodulation improved emotion regulation in patients with GAD [114]. Statistically significant improvements in self-reported emotion regulation difficulties were found at post-treatment and three-month follow-up with active rTMS only. Improvements primarily involved the domains of goal-directed behaviors and impulse control, and were significantly associated with global clinician ratings of improvement. These preliminary results support rTMS as a treatment for GAD and suggest improved emotion regulation as a possible mechanism of change [34].

Bilateral LF-rTMS was evaluated in 13 patients with comorbid GAD and MDD, who received 24 to 36 rTMS sessions over five to six weeks. Following the last treatment, 11 of 13 (84.6%) patients achieved remission in anxiety symptoms (<5 on the GAD-7), and 10 of 13 patients (76.9%) achieved remission in depressive symptoms (<8 on the HAM-D). In this small pilot study, most patients with comorbid GAD/MDD achieved significant improvement in anxiety and depressive symptoms after bilateral rTMS [115].

Panic Disorder

In two randomized sham-controlled trials of LF-rTMS, patients with panic disorder were treated for two or four weeks as augmentation therapy. Active rTMS was superior to sham in reducing panic symptoms in one trial, and all patients showed improvement with no differences between active and sham in the other trial. The available data were insufficient to draw conclusions about rTMS efficacy in panic disorder [14].

Deep rTMS and Anxiety Reduction

The anxiolytic effects of deep rTMS in MDD patients were reviewed. Data from six open-label studies found that relative to baseline, large anxiolytic and antidepressant outcomes were obtained after 20 daily sessions of high-frequency deep rTMS. Unlike the antidepressant effect, anxiolytic effects were more heterogeneous across studies, and unrelated to concurrent antidepressant treatment [116].

POST-TRAUMATIC STRESS DISORDER

In 20 veterans, LF-rTMS for 10 sessions led to significant improvement in core symptoms of PTSD and depression versus sham. Improvements persisted for two months post-rTMS, and declined over time [117].

A meta-analysis of five randomized sham-controlled trials found rTMS significantly superior to sham in reducing PTSD core symptom scores. No single stimulation frequency (1 Hz vs 20 Hz) target (left vs right dorsolateral PFC) or mode (rTMS vs deep TMS) differed markedly in effect [118].

In a chart review of 10 patients who received five treatments of 5-Hz rTMS for comorbid PTSD and MDD, significant reductions were observed in 80% patients for PTSD symptoms, and 60% patients for MDD symptoms. The intermediate pulse frequency of 5-Hz may be effective in patients with PTSD and serious comorbidity and was well-tolerated without serious adverse effects [119].

Deep rTMS in PTSD

Following three sessions per week for four weeks of deep rTMS or sham to the medial prefrontal cortex (mPFC) in 30 patients with PTSD, significant improvement in intrusive symptoms was observed (mean reduction: 31%) with active but not sham deep rTMS. This suggested the potential of deep rTMS to treat core PTSD symptoms and suggests a role of mPFC hypoactivity in presentation of the disorder [40,120].

OBSESSIVE-COMPULSIVE DISORDER (OCD)

rTMS and tDCS have been increasingly researched in OCD. In clinical trials, LF-rTMS of the supplementary motor area, orbital frontal cortex, or right dorsolateral PFC shows the most promising efficacy, while older studies targeting the prefrontal dorsal cortex were not as successful. Larger-scale investigations of tDCS have yet to be published in OCD [1].

Patients with OCD were randomized to rTMS frequencies of 1 Hz, 10 Hz, or sham of the right dorsolateral PFC for 10 sessions. Patients were assessed after the last session and three months later. Compared with 10 Hz or sham, 1 Hz led to significantly greater improvements in obsessive-compulsive and anxiety symptoms, greater clinical benefit, and significantly larger percentage change in global improvement. One Hz LF-rTMS of the right dorsolateral PFC is a promising treatment approach in OCD [121].

The efficacy of rTMS in OCD was evaluated by reviewing 15 randomized sham-controlled trials. rTMS was significantly superior to sham for OCD symptom reduction. The risk of publication bias was low, and between-study heterogeneity was low. Meta-regression showed no particular influence of any variable on the results. In all, rTMS was superior to sham for amelioration of OCD symptoms [122].

In two trials, patients with treatment-resistant OCD received rTMS or sham for two and four weeks. Compared with sham, active rTMS led to significantly greater improvements in symptom severity; and cognitive performance in auditory perception, visual perception, short-term memory, and processing speed [123,124].

TOURETTE SYNDROME

Open-label trials suggested LF-rTMS of the supplementary motor area in patients with Tourette syndrome may be effective, but a randomized sham-controlled trial found no benefit [125].

SCHIZOPHRENIA WITH AUDITORY VERBAL HALLUCINATIONS

In rTMS studies of patients with schizophrenia with auditory verbal hallucinations, evaluation of placebo response found a significant effect size of placebo response in parallel studies but not crossover studies. The authors suggest that placebo effect should be considered a source of bias in open-label trials and randomized sham-controlled trials without documented efforts to improve concealment of active rTMS [126].

Studies of rTMS treatment in schizophrenic symptoms such as auditory hallucinations have found contradictory results. A review of 10 randomized sham-controlled trials using LF-rTMS reported a positive effect size favoring rTMS over sham, with the left temporoparietal cortex appearing an effective target [127]. Studies published after 2013 were not available for this review. A study of HF-rTMS to the left temporoparietal cortex over 2 days found no difference between active rTMS or sham [128]. The overall sham-controlled outcomes of rTMS to the left temporoparietal cortex are mixed; even when rTMS was effective following 10 sessions, treatment effect began dissipating one month later [129].

Auditory verbal hallucinations are commonly observed persistent symptoms in schizophrenia, even when patients are stabilized by antipsychotic medication. The primary indication for tDCS in psychotic disorders is reduction of auditory verbal hallucinations. Eliminating or reducing these debilitating residual symptoms requires inhibition of neuronal activity of the left temporoparietal junction (TPJ) that mediates auditory verbal hallucinations [17].

Most tDCS treatment studies in schizophrenia have used anode placement over the l-dorsolateral PFC and the cathode over the left TPJ. After 10 twice-daily sessions, this placement has been consistently shown in sham-controlled randomized controlled trials to ameliorate symptoms of the illness, with robust reductions in auditory verbal hallucinations at acute and three-month follow-up, improvements in other schizophrenic symptoms, and substantive decreases in treatment-resistant auditory verbal hallucination frequency. Further support for this tDCS protocol comes from uncontrolled trials of schizophrenic patients with persistent auditory verbal hallucinations, with significant reductions in psychotic and auditory verbal hallucination symptoms reported. Several case reports described refractory schizophrenic patients who achieved responses ranging from significant reductions in psychotic and auditory verbal hallucinations, to full remission. Greater therapeutic response in nonsmokers was noted [16].

In a randomized sham-controlled trial of tDCS to the left TPJ in patients with schizophrenia with auditory verbal hallucination and negative symptoms, acute beneficial effects in negative symptoms and prolonged (up to three months) reductions in auditory verbal hallucination were observed with active tDCS [130].

Active vs sham frontotemporal tDCS was evaluated by functional MRI for effects on auditory verbal hallucinations and resting-state functional connectivity of the left temporo-parietal junction in schizophrenic patients. Reductions in hallucination severity following active tDCS correlated with decreased functional connectivity between the left TPJ, the left anterior insula and the right inferior frontal gyrus; and with increased functional connectivity between the left TPJ, the left angular gyrus, left dorsolateral PFC and the precuneus, regions that mediate language-related and self-other recognition networks [131].

A series of motor-evoked potential studies in schizophrenic patients found diminished excitability and enhanced neuroplasticity with anodal or cathodal tDCS [17].

SCHIZOPHRENIA, NEGATIVE SYMPTOMS

Earlier meta-analyses found rTMS benefitted negative symptoms, with effect sizes ranging from non-significant and small to very large. This large range reflected differences in study duration, stimulus frequency, outcome measures, and illness duration [42]. A randomized sham-controlled trial found treatment response with active rTMS was sustained over 24-week follow-up, but a large, randomized sham-controlled trial failed to show greater benefit with active versus sham rTMS [132,133]. Many factors known to influence rTMS response make it difficult to reconcile negative findings with those from numerous earlier reports [42].

In patients with schizophrenia with predominant negative symptoms, 15 sessions of 10-Hz rTMS to the left dorsolateral PFC for three weeks was not superior to sham for improving schizophrenic cognitive domains, in contrast to previous preliminary findings [134].

A randomized sham-controlled trial evaluated 2 mA tDCS of the bilateral dorsolateral PFC. After 10 daily sessions, statistically significant reductions in PANSS negative, general, and total scores occurred with active tDCS, but not sham [135].

tDCS-induced neural changes, measured by EEG oscillations, were assessed in patients with schizophrenia following tDCS to the left dorsolateral PFC. A significant increase in gamma synchronization in the dorsolateral PFC was found with 2-mA tDCS but not 1-mA or sham. Increased gamma synchronization correlated with improved working memory performance, suggesting that 2-mA tDCS may modulate neural synchrony, and restore neural and behavioral functioning in schizophrenia [136].

Building on this, 20 patients with schizophrenia with predominant negative symptoms were randomized to 10 sessions of active 2-mA or sham tDCS to the left dorsolateral PFC and received imaging by functional connectivity MRI (fcMRI). Negative symptom scores decreased 36% with tDCS (sham: 0.7%). Analysis of MRI indicated changes in subgenual cortex and dorsolateral PFC connectivity within frontal-thalamic-temporo-parietal networks in the active but not sham group [137].

Smoking Status and tDCS Response

The rate of current tobacco use disorder in clinical samples of patients with schizophrenia is 62%, significantly higher than in the general population and in other psychiatric disorders [138]. This high prevalence is thought to arise from nicotine-induced improvements in working memory, selective attention, and cognitive impairments in patients with schizophrenia. These nicotine effects are linked to stimulation of the alpha7-nicotinic acetlycholine receptor, which enhances thalamo-cortical functional connectivity and dopamine release regulation. Nicotine can modify neuroplasticity, and in contrast to nonsmokers, single-session, excitability-diminishing cathodal tDCS does not induce plasticity in patients with schizophrenia who smoke [139].

Neural plasticity induced by tDCS may differ between patients with schizophrenia who do and do not smoke. This was explicitly investigated in the first-ever study that evaluated the effects of cigarette smoking on tDCS response in patients with schizophrenia. Patients with schizophrenia with treatment-resistant auditory verbal hallucination received 10 sessions of frontotemporal tDCS (2 mA). Auditory verbal hallucinations symptoms decreased 20% in the entire sample, 46% in nonsmokers, and 6% in smokers. When response was defined as ≥25% symptom reduction, 83% of non-smokers vs 20% of smokers were responders. tDCS had no effect on cigarette use. This was the first published report to describe the impairing effect on tDCS response and efficacy in patients with hallucinatory schizophrenia who are actively smoking. Adjustment for age, medication use, and illness duration did not impact this effect [140].

Combined Therapies in Refractory Schizophrenia

Many (40% to 70%) patients with treatment-resistant schizophrenia remain symptomatic despite an adequate clozapine trial [141]. Brain stimulation approaches are promising for these patients, but clozapine co-administration has raised safety concerns. Studies have been reviewed to determine if this safety issue was resolved. While ECT is effective in clozapine-refractory schizophrenia, safety with the combination is not known. Until sufficient data accumulate, vigilance for adverse effects related to lowered seizure threshold, cognitive impairment, and cardiovascular events is required. In patients receiving clozapine, HF-rTMS over the dorsolateral PFC and LF-rTMS over the temporo-parietal cortex are safe, but efficacy is uncertain [141].

SUBSTANCE USE DISORDERS

The dorsolateral PFC plays a key role in self-regulatory control mechanisms and is a common brain stimulation target in disorders of fronto-limbic dysregulation. rTMS of the dorsolateral PFC has demonstrated potential in reducing addictive behaviors and craving for nicotine, alcohol, and cocaine [46].

Placement of right-anodal plus left-cathodal tDCS over the bilateral dorsolateral PFC has reduced a variety of substance cravings in patients with substance use disorders, and bilateral stimulation with both polarities may be equally effective [142]. tDCS can enhance patient ability to inhibit potent responses, a clinical important finding because impaired inhibitory control contributes to relapse in patients with substance use disorder [17].

Smoking Cessation/Tobacco Use Disorder

Relapse is common within days after smoking cessation, and combining the anti-craving effects of rTMS with nicotine replacement therapy (NRT) may attenuate withdrawal symptoms and craving to increase abstinence rates in smokers with severe nicotine dependence attempting to quit [143].

The day after quitting, smokers who failed to quit with standard treatments started NRT (21-mg patch) and received active 1-Hz rTMS or sham of the right dorsolateral PFC (10 sessions) for two weeks. Abstinence rates and craving were measured during combined treatment and up to 12 weeks after quitting. At the end of combined treatment, more participants were abstinent with active rTMS (89%) than sham (47%). Compulsive craving was significantly decreased with active rTMS but not sham, but no lasting effect was found [143].

Similar results were shown by an earlier randomized sham-controlled trial of 10-Hz rTMS to the left dorsolateral PFC for 10 daily sessions. Active rTMS, but not sham, led to significantly reduced cigarette consumption and blocked craving during treatment, but the effects dissipating after the rTMS sessions ended [144].

Deep rTMS was evaluated in 115 smokers randomized to 13 daily sessions of HF, LF, or sham deep rTMS to the lateral PFC and bilateral insula. HF (but not LF or sham) deep rTMS significantly reduced cigarette consumption and nicotine dependence. The combination of high-frequency deep rTMS and exposure to smoking cues enhanced cigarette reduction, with abstinence rates of 44% at the end of the treatment and 33% at six-month follow-up [145].

Results from two studies provided data to encourage larger trials in determining the clinical usefulness of this intervention. A single-session randomized sham-controlled trial of 1-mA anodal stimulation over the left dorsolateral PFC found that active tDCS (versus sham) significantly increased latency to smoking and decreased total number of cigarettes smoked [146].

Cathodal tDCS stimulation is a way to manipulate cortical excitability through inhibition. tDCS inhibition of the frontal-parietal-temporal association area (FPT) was examined for effects on attention bias to smoking-related cues and smoking behavior in a small short-term trial. Bilateral cathodal tDCS stimulation of the FPT area modestly decreased attention to smoking-related cues and significantly decreased daily cigarette use [147].

Alcohol Use Disorder

Most rTMS studies in alcohol use disorder have investigated craving but not drinking reduction. As with studies in nicotine dependence, most used HF-rTMS to target the dorsolateral PFC. The effect of rTMS on craving for alcohol was mixed, with some studies showing an effect while others do not [12].

More promising results came with using H-coil rTMS, but these were preliminary open trials. A small study of bilateral H coil stimulation of the PFC in patients with comorbid alcohol use disorder and dysthymic disorder found improvements in depressive symptoms and reductions in craving for alcohol. Another pilot study using H-coil stimulation of the medial PFC reported decreased alcohol intake by mean drinks per day and mean drinks on days of maximum alcohol use [12].

Four sessions of HF-rTMS was evaluated in a randomized sham-controlled trial of 17 residents of an alcohol detoxification program. At one-month follow-up, active (but not sham) HF-rTMS led to significantly decreased depressive symptoms and fast EEG frequencies, significantly increased inhibitory control and executive function, but no effect was found on craving or drinking reduction [148].

Published randomized controlled trials of tDCS in alcohol use disorder have shown mixed results. In 13 subjects with alcohol use disorder, one session of tDCS to the bilateral dorsolateral PFC significantly decreased alcohol craving (versus sham), which remained suppressed during exposure to alcohol cues [149].

In a relapse reduction study, 33 outpatients with severe alcohol use disorder received twice-daily 2 mA tDCS to the bilateral dorsolateral PFC for five days. At six-month follow-up, tDCS did not diminish craving, but 50% treated with active tDCS versus 11.8% with sham remained alcohol-abstinent. Active tDCS also led to improved perception of quality of life [150].

A disconnect between alcohol craving and alcohol use was also reported in a study of 13 patients with alcohol use disorder who received five weekly sessions of anodal tDCS to the left dorsolateral PFC. Active tDCS suppressed cravings but showed an unexpected trend for more frequent relapse; neither was found with sham [151].

Stimulant Use Disorders

Very promising results came from a pilot study in which 18 subjects with cocaine use disorder received 12 sessions of 10-Hz H-coil rTMS or sham to the bilateral PFC. After four weeks of stimulation, cocaine use in active and sham groups both decreased without difference, but decreases in cocaine use showed a significant difference at three months and six months post-baseline favoring the active rTMS group. Transient mild headaches were reported during stimulation [152].

Patients with addiction to crack cocaine received five sessions of active or sham bilateral dorsolateral PFC stimulation. The active tDCS group showed a higher percentage of abstinence at three-month follow-up versus sham [153]. This study protocol was replicated in a larger group of patients whose crack cocaine cravings were suppressed for at least one week by active versus sham tDCS. Effects on crack cocaine use were not studied [154].

Abstinent methamphetamine users received single-session anodal tDCS or sham to the right dorsolateral PFC. Active tDCS acutely reduced craving at rest, but significantly increased methamphetamine craving during methamphetamine-related cue exposure. Neither effect was found with sham [78].

Mixed Substance Abuse Disorders

The effect of rTMS on craving in substance addiction was evaluated in a review of eight randomized sham-controlled trials. Active TMS was significantly superior to sham, but only in studies targeting the right dorsolateral PFC with HF-rTMS. This finding was consistent throughout the reviewed studies [155].

EATING DISORDERS

Eating behavior and eating disorder treatment is an area of study in noninvasive neurostimulation, and the sole evaluated modalities are rTMS and tDCS. The dorsolateral PFC is a complex brain region involved in executive functions that support cognitive control of food intake. Enhanced dorsolateral PFC activity may alter the reward-cognition balance toward facilitation of cognitive control, and possible suppression of reward-related mechanisms that drive food craving and overeating [10].

Anorexia Nervosa

The dorsolateral PFC is implicated in emotion regulation. HF-rTMS may improve food restriction and other maladaptive emotion regulation strategies in anorexia nervosa by remediating prefrontal region hypoactivity associated with poor impulse control and impaired cognitive flexibility in anorexia nervosa [46].

In a uncontrolled trial, 10 patients with anorexia nervosa received single-session HF-rTMS to the left dorsolateral PFC, and showed short-term improvements in anxiety, feeling full, and feeling fat [156]. In patients with chronic anorexia nervosa receiving HF-rTMS to the left dorsolateral PFC, significant improvements in eating disorder symptoms and mood were found after six months in 60%, with 40% deemed "recovered" based on psychometric scores. However, most participants lost weight, and therapeutic effects on psychopathology waned by 12 months [157].

Bulimia Nervosa

Several single-session rTMS studies in small numbers of patients with bulimia were performed, and reported positive short-term effects of reduced binge-eating episodes and food craving [46]. Sham-controlled single-session studies of HF-rTMS of the left dorsolateral PFC reported inconsistent effects, with positive effects reported in one study of 38 patients and no effects in a study of 10 patients [158,159]. Randomized controlled trial with sham control using 20 rTMS sessions did not find benefit beyond sham [46,160].

Binge-Eating Disorder

A trial of 30 subjects with binge-eating disorder evaluated singles-session 2-mA tDCS or sham to the dorsolateral PFC. Compared with sham, tDCS decreased craving for sweets and savory proteins with greatest reductions in men; decreased total and preferred food intake by 11% and 17.5% regardless of sex; and reduced desire to binge eat in men on the day following active tDCS. Reductions in craving and food intake were predicted by eating less often for reward motives, and greater intent to restrict calories, respectively. The findings of enhanced cognitive control and/or decreased need for reward may reflect tDCS action on functional mechanisms, and should be further researched [48].

DEPERSONALIZATION/DEREALIZATION DISORDER

Patients with chronic refractory depersonalization/derealization disorder received 17 to 20 sessions of LF-rTMS to the right ventrolateral PFC (VLPFC) over 10 weeks. Mean depersonalization symptom scores decreased 44.4%. After one session, 71% of patients showed partial response (symptom reduction ≥25%). After trial completion, 28% of patients showed full response (symptom reduction ≥50%), 57% had partial response, and 14% had no response. Mean anxiety scores decreased 28.4% from baseline. Side effects were transient mild headache [52].

Several subjects showed transient disinhibitory behaviors immediately after rTMS, including wearing the physician's jacket, labile affect, spontaneous laughter without apparent origin, and spontaneous discussion of provocative subjects. None were persistent or clinically concerning. Patients commented the measuring scales that assessed treatment response did not capture the phenomenological changes they experienced [52].

EXTERNAL TRIGEMINAL NERVE STIMULATION (eTNS)

eTNS is an emerging external neuromodulation approach originally developed for refractory seizures. Early evidence of safety and improved mood led to trials in MDD. Brain projections of the trigeminal system suggest eTNS may alter activity in structures regulating mood, anxiety, and sleep [161].

MAJOR DEPRESSIVE DISORDER

Initial open-label trials showed response rates of 54.5%, 75%, and 100%, and remission rates of 63.6% and 90.9%. A randomized sham-controlled trial of 40 patients found high placebo response to sham, but active eTNS still led to a significant mean reduction of 6.36 points in HDRS scores versus sham. An open-label eTNS trial in older patients with MDD (mean age: 73 years) found 80% response and 40% remission rates [163].

PTSD AND COMORBID MDD

Patients with PTSD and comorbid MDD received eTNS eight hours nightly for eight weeks as a pharmacotherapy adjunct. After eight weeks, significant improvement was found in depression, core PTSD symptoms, and quality-of-life measures. eTNS was well-tolerated with few adverse events [161]. Another open-label eTNS trial in comorbid PTSD/MDD reported the same positive outcomes [162].

PANIC DISORDER

Seven patients with panic disorder received ten daily sessions of TNS. At day 10, panic disorder symptom severity showed a significant decrease from baseline, remaining stable at follow-up day 45. Significant global clinical gains were also reported at days 10 and 45. Cognitive function was unchanged. All patients reported mild paresthesia underneath the electrodes during stimulation. One patient dropped out after four sessions from stimulation-related headaches. No other adverse events were observed [164].

eTNS is well-tolerated, without reports of serious adverse events or changes in cognitive performance. These data, while impressive, mostly come from small, short-term uncontrolled trials [23,24,163].

8. INVASIVE NEUROSTIMULATION

Most invasive neurostimulation studies in psychiatric disorders have been performed in treatment-resistant MDD, but this is currently expanding into refractory Tourette syndrome, OCD, and addictive disorders.

VAGUS NERVE STIMULATION

The FDA approved VNS in 2005 as adjunctive therapy in refractory MDD with four or more failed adequate antidepressant trials. Some studies below also enrolled patients with treatment-resistant bipolar depression, and VNS outcomes were similar for both [165].

Worth noting in the VNS studies is the severity of MDD in the patient population, distinguished by chronicity (average duration of illness: >25 years, and current episode: 7 years), treatment-resistance (average of seven drug failures, and ECT failure in >50%), high rates of lifetime hospital admissions and suicide attempts [165]. However, VNS was found ineffective in patients with eating disorders or schizophrenia [10,166].

Dose Response

VNS "dose" is measured by electrical output, in mA of current. A comparison of low (0.25 mA), medium (0.5–1.0 mA) and high (1.25–1.5 mA) dose VNS found greater improvement in depressive symptoms with higher doses, greater sustained antidepressant response and less frequent suicide attempts with medium- and high-dose versus low-dose VNS [167].

Efficacy

Open-label studies found an average 31.8% response rate, but a randomized sham-controlled trial found no difference between VNS and sham at 12 weeks [168]. VNS efficacy may increase over time, and six trials comparing VNS to treatment as usual found at 12, 24, 48, and 96 weeks that VNS/treatment as usual remission rates were 3%, 5%, 10%, and 14% versus 1%, 1%, 2%, and 4% for treatment as usual alone [169]. Median time to VNS response was nine months in one study. In patients with response by 3 months (35%), response was maintained by 61.5% at 12 months, and 50% at 24 months [170,171].

High retention and low dropout rates suggest that patients without measurable response or remission gain therapeutic benefits undetected by depression rating scales [165]. Higher success rates with VNS in treatment-resistant depression were reported with careful patient selection to screen out comorbid personality disorders or active substance use disorders [26].

Adverse Effects

The most common adverse events after one year of VNS were voice alteration (69.3%), dyspnea (30.1%), pain (28.4%), and increased cough (26.4%), mostly from active VNS and resolved by halting stimulation. VNS tolerability improves over time, and adverse effect reports diminish. Compared to treatment as usual, patients with treatment-resistant depression receiving VNS showed lower all-cause mortality rates, including suicide [8].

DEEP BRAIN STIMULATION

Treatment-Resistant Depression

Deep brain stimulation treatment for treatment-resistant depression remains investigational. Deep brain stimulation is mostly used to augment antidepressants, and few patients are free of psychotropic drugs when implanted [8]. The main deep brain stimulation brain targets are [8]:

- Subcallosal cingulate white matter

- Ventral capsule/ventral striatum (VC/VS)

- Nucleus accumbens

- Medial forebrain bundle

The most common target in treatment-resistant depression is the subcallosal cingulate. Patients in deep brain stimulation trials are refractory to antidepressants, psychotherapy, and (often) ECT [8].

Short-term outcomes with deep brain stimulation show 30% to 60% response rates and 20% to 40% remission rates at three or six months, and medial forebrain bundle deep brain stimulation in seven patients reported response and remission rates of 85.7% and 57.1% [172,173].

As with VNS, two randomized sham-controlled trials of deep brain stimulation were halted early from lack of benefit, later seen as premature with recognition that efficacy increases with longer stimulation [8]. Outcomes of four studies showed depression severity was significantly reduced by 12 months. At 3, 6, and 12 months, response rates were 36.6%, 53.9%, and 39.9%, with remission rates 16.7%, 24.1%, and 26.3% [174].

Subcallosal cingulate deep brain stimulation studies of greater than one year duration reported response rates of 36% and 92% at one and two years, and a 58% remission rate at two years. A longer trial reported 62.5%, 46.2%, and 75% response rates at one, two, and three years, with 20% and 40% remission rates at two and three years. Long-term subcallosal cingulate and medial forebrain bundle deep brain stimulation led to improved health-related quality of life [173,175,176].

Maintaining Response

A small trial suggested that maintaining remission requires ongoing deep brain stimulation. Patients were treated to remission with subcallosal cingulate deep brain stimulation, and then randomized to on/off or off/on stimulation for three months. Most patients relapsed with deep brain stimulation turned off, and none with deep brain stimulation on [177].

Adverse Effects

Adverse events during long-term deep brain stimulation have been secondary to implantation (e.g., intracranial hemorrhage), perioperative risks (e.g., wound infection), effects of specific brain region stimulation, or deep brain stimulation parameters. Deep brain stimulation is generally well tolerated despite the risks of invasive neurosurgical procedures, and the pooled one-year dropout rate with subcallosal cingulate deep brain stimulation was 10.8%. Worsening neuropsychological performance has not been observed with any brain target, but improved cognitive performance has been reported [174].

Transient psychosis and hypomania have emerged when changing parameters during nucleus accumbens stimulation, resolved by switching parameters. No hypomania episodes were reported with subcallosal cingulate deep brain stimulation, including patients with bipolar disorder. Oculomotor adverse events of blurred vision and strabismus occurred in all patients receiving higher amplitude medial forebrain bundle deep brain stimulation. Reports of suicidality and completed suicide were deemed not device-related, but risk of suicidality may be increased by a history of pre-deep brain stimulation suicidality or major life stressors [8].

Tourette Syndrome

Deep brain stimulation is an emerging treatment option for patients with severe refractory Tourette syndrome. In 156 published cases, deep brain stimulation led to an overall 52.68% improvement of symptoms. Outcomes of controlled trials significantly favored stimulation versus sham. Significant symptom reductions were found across deep brain stimulation targets, with no differences in outcome indicating modulation of a common network. Despite the small patient numbers, deep brain stimulation for Tourette syndrome is a valid option for medically intractable patients [178].

Treatment-Resistant Obsessive-Compulsive Disorder

Deep brain stimulation efficacy in severe, refractory OCD was reviewed in 25 trials. Outcome was change in Y-BOCS scores; response was ≥35% improvement in Y-BOCS (Table 3) [41]. Reported adverse effects included serious events during surgery (i.e., two seizures, three intracerebral hemorrhages), device-related adverse events, and stimulation-related events. Device-related events included breaks in stimulation leads and battery failure resulting in acute psychiatric symptoms until replacement [41]. Stimulation-related adverse events were acute increases in anxiety and hypomania, induced by changing stimulation parameters or battery depletion. All cases resolved with parameter adjustment. Cognitive problems resolved with time or parameter adjustment. No personality changes during deep brain stimulation were observed.

Table 3: DEEP BRAIN STIMULATION (DBS) TARGET OUTCOMES IN OCD

Trial Characteristics

ALIC

Nucleus Accumbens

Ventral Capsule/Ventral Striatum

Subthalamic Nucleus

Inferior Thalamic Peduncle

Number of trials

5

8

4

5

1

Follow-up, months

23–51

3–24

12–36

3–6

36

Mean DBS response rate

75%

45.5%

50.0%

57.1%

100%

Mean reduction in Y-BOCS

46.5%

37.8%

41.5%

45.3%

82.5%

ALIC = anterior limb of the internal capsule.

Source: [41]

Neural circuits involved in OCD and depression include the VC/VS and anterior cingulate gyrus. VC/VS deep brain stimulation combined with anterior cingulotomy was evaluated in patients with refractory OCD and MDD. Mean baseline Y-BOCS scores were 34.7, decreasing to 23.0 at three months, and stable two years post-surgery at 19.0. These outcomes were comparable, but not superior, to published outcomes for VC/VS deep brain stimulation alone, and deep brain stimulation may be sufficient to control refractory OCD [179].

Substance Addiction

A few small deep brain stimulation studies have been performed in severely addicted patients. Five severely alcohol dependent patients received nucleus accumbens deep brain stimulation. Followed an average 38 months, all five showed significant craving reductions, two remained abstinent for more than four years, and three had truncated relapses [180]. Two patients with heroin dependence received nucleus accumbens deep brain stimulation; depressive and anxiety symptoms improved, with drug use reduced but not ceased [181].

9. NEUROMODULATION IN CHRONIC PAIN

Pain processing in the brain is not limited to one area or sensory system. The cerebral pain processing neural network is complex, and mediates the vegetative, sensory-discriminative, affective, and cognitive aspects of pain. The vegetative and neuroendocrine effects of pain perception are mainly linked to subcortical regions such as the amygdala and hypothalamus. The sensory-discriminative aspects of pain involve the spinothalamic tract, lateral thalamus, somatosensory areas, and the posterior insula with input from the descending corticothalamic pathways originating in the motor cortex. The affective/cognitive processing of pain involves the anterior insula, cingulate cortex, and prefrontal regions [18,182].

Brain stimulation is not usually considered for acute nociceptive/inflammatory pain, because the standard of care involves resolution of the underlying cause [13]. Brain stimulation is solely used in chronic pain, typically in patients for whom standard therapies have failed to relieve pain. In most forms of chronic pain, the mechanisms that generate pain have dissociated from the original peripheral tissue injury source. Instead, pain is perpetuated by alteration in CNS structures involved in transmitting, processing and response to pain signals. Alteration in these regions is termed central sensitization [183].

OVERVIEW OF NONINVASIVE BRAIN STIMULATION IN PAIN

In the early 1990s, epidural motor cortex stimulation (eMCS) showed repeated efficacy in pharmaco-resistant neuropathic pain. These methods were adopted by TMS researchers in chronic pain using stimulation to the primary motor cortex (M1) and precentral gyrus in the hemisphere contralateral to pain [27]. Stimulation parameters were refined over time to maximize efficacy. An early 10-day protocol of 5 Hz rTMS of M1 in patients with diverse chronic neuropathic pain reported minimal benefit, the result of using low frequency (5 Hz) stimulation and small number of pulses (500) per session. A subsequent five-day protocol of 20 Hz HF-rTMS of M1 led to durable pain reduction in patients with post-stroke pain, trigeminal neuropathic pain, and phantom limb pain [19].

Several rTMS targets have been evaluated in neuropathic pain, and M1 is preferable to premotor or primary somatosensory cortical regions. In refractory pain, dorsolateral PFC stimulation is less studied, despite efficacy of this target in depression and the established link between depression and chronic pain [19].

When used in pain treatment, a figure-8 coil delivering biphasic pulses should be placed over the precentral gyrus (M1) contralateral to the painful side with a posteroanterior orientation [13,27]. HF-rTMS (10–20 Hz) is used to activate projecting axons and local interneurons and applied below the motor activation threshold to avoid inducing muscle contractions. Focal neuropathic pain can be relieved by HF-rTMS (but not LF-rTMS) to the contralateral M1 area. Repeated rTMS sessions can induce cumulative pain reductions for at least several weeks following 10 consecutive sessions, but optimal timing for long-term efficacy and safety remain studied.

Investigation of tDCS in pain treatment began more recently than rTMS, and there are fewer published studies on treatment outcomes and parameter settings. However, the positive pain outcomes are found with using current intensities of 1–2 mA delivered for 15 to 20 minutes, and electrode size 25–35 cm^2. Treatment is given daily (consecutive or with breaks) over one or more weeks. Within these dose parameters, tDCS has extensive evidence of safety and tolerability [18,184].

The properties of tDCS make it a promising approach for pain treatment, including the potential to address pathological alterations in neural activity, excitability, and connectivity at multiple levels and sites of cerebral pain processing. Reversal of maladaptive plasticity in cerebral pain processing systems is associated with pain relief. The potential of tDCS to prevent or reverse such maladaptive changes, or enhance adaptive neuroplastic changes in pain processing networks is highly relevant in pain management [18]. Proposed mechanism of action in chronic pain include [27]:

- M1 stimulation reduces thalamic and brainstem nuclei hyperactivity that underlies pain.

- Dorsolateral PFC stimulation is thought to mediate analgesic effects by modulating pain-related affective-emotional networks

Higher stimulation intensity or duration to enhance efficacy has been examined, but prolonged M1 stimulation at higher intensities may reverse the intended effects on neural excitability [185].

CHARACTERISTICS OF CHRONIC PAIN CONDITIONS

Brain stimulation therapies have been evaluated for efficacy, safety, and tolerability in the following pain conditions.

Neuropathic Pain

Neuropathic pain is caused by abnormality, trauma, or disease of the somatosensory nervous system, resulting from various etiologies including traumatic or surgical injuries to peripheral nerves, infectious diseases (e.g., herpes zoster, postherpetic neuralgia), metabolic disorders (e.g., diabetic peripheral neuropathy), and injuries or diseases that affect the CNS such as stroke or spinal cord injury. Nearly 25% of people with chronic diabetes have neuropathic pain [186,187].

Among adults in the general population, an estimated 7% to 8% have chronic pain with neuropathic features, and 5% have moderate-to-severe pain with neuropathic features [188]. Neuropathic pain is associated with significant loss of productive time, withdrawal from the workforce, development of mood disorders, and disruption of family and social life [189]. Neuropathic pain is reported to be more severe than non-neuropathic pain and the management of chronic neuropathic pain is challenging; more than 50% of patients experience partial or no pain relief, and the adverse effects of medications used to manage the pain may limit their clinical utility in general and in elderly patients in particular [186,187].

Spinal Cord Injury Pain

In the United States, spinal cord injury occurs in 17,000 persons annually, and an estimated 282,000 patients are living with spinal cord injury. Six months after discharge, 27% of patients with spinal cord injury report pain that is severe enough to interfere with most daily activities. Spinal cord injury pain can develop at or below the level of spinal injury and does not correlate well with the magnitude or location of the lesion. Injury from gunshot is associated with more severe pain. Neuropathic, musculoskeletal, and/or visceral pain can contribute to spinal cord injury pain, and central neuropathic pain can develop weeks to months following injury [190,191].

Central Poststroke Pain

Pain is reported by 11% to 55% of stroke survivors, and can arise from muscles, joints or viscera, or from the peripheral or central nervous system. The most common types of poststroke pain include hemiplegic shoulder pain, pain due to spasticity, and central poststroke pain. Along with spinal cord injury pain, central poststroke pain is a central neuropathic pain condition with pain
arising from a cerebrovascular lesion in the central somatosensory nervous system. Sensory descriptors used in patients with central poststroke pain include burning, aching, pricking, lacerating, shooting, squeezing, throbbing, sharp, stabbing, painful pins and needles, dull, and cramping. Treatment of central poststroke pain is difficult, due to the limited efficacy and dose-limiting side effects of available drugs [192].

Failed Back Surgery Syndrome

In the United States, more than 300,000 spinal surgeries are performed annually, mainly in the lumbar spine, and as many as 100,000 result in failure where the patient experiences new-onset pain in addition to unresolved pain from the original problem. The level of pain is widely variable and may occur with neurologic deficits. Contributors to pain and the clinical features of failed back surgery syndrome include recurrent disk herniation, epidural abscess, scar tissue formation around the nerve root, facet joint syndrome, and muscle spasm. Patients with persistent radicular pain, usually from chronic nerve injury, greatly benefit from treatment that addresses the neuropathic pain [193].

Lumbosacral Radiculopathy Pain

Lumbosacral radiculopathy results from nerve root irritation and compression, resulting in a symptom distribution of the affected lumbar or sacral nerve root such as numbness, weakness, or paresthesia. Sciatica is the most common symptom of lumbar radiculopathy and refers to pain that radiates down the leg below the knee in the distribution of the sciatic nerve to indicate nerve root compromise from mechanical pressure or inflammation [194].

Chronic low back and neck pain are highly prevalent but largely unaddressed in brain stimulation trials because origin is usually multifactorial, psychosocial contribution is often prominent and the torso has less cortical representation [13].

Temporomandibular Disorders

Temporomandibular disorders (TMDs) involve persistent pain in the cheek and jaw area of the face and have an estimated 11% prevalence in community samples. TMD pain considerably impedes quality of life, with nearly 80% of patients with TMD reporting regular discomfort eating and more than 40% reporting difficulty performing their jobs. The importance of CNS factors in TMD etiology is established, and neuroimaging has revealed structural, functional, and neurochemical aberrations in TMD pain [195].

Phantom Limb Pain

Phantom limb pain is painful or unpleasant sensation in the distribution of the lost or deafferentated body part. Phantom limb pain can resemble neuropathic pain with descriptors such as sharp, shooting, or electrical-like; or resemble nociceptive pain with dull, squeezing, or cramping pain. The pain can be widespread throughout the missing limb or confined to a smaller limb area. The prevalence of phantom limb pain following amputation may be as high as 85%. Phantom limb pain remains an extremely difficult pain condition to treat, and most pharmacologic therapies are not successful [196].

Postherpetic Neuralgia

Postherpetic neuralgia is persistent neuropathic pain after the healing of herpes zoster infection. Risk of developing postherpetic neuralgia increases with age, and the duration can be months to years. Pain levels range from mild to excruciating, with pain severity placing the patient at risk for suicide. In the United States, postherpetic neuralgia is the most common cause of suicide in patients with chronic pain older than 70 years of age. In postherpetic neuralgia, peripheral and CNS sensitization generate pain characterized by severe or excruciating pain from light touch (allodynia) or severe spontaneous pain without allodynia. Postherpetic neuralgia pain is highly resistant to conventional pain treatment [197].

Complex Regional Pain Syndrome

Complex regional pain syndrome is thought to result from injury to autonomic, central, and peripheral nervous systems. It presents as pain affecting one or multiple limbs without following a dermatomal distribution. The pain is disproportionate to the inciting injury, and pain severity can be disabling. The affected limb(s) undergo marked changes in skin color, texture, and/or temperature. Absence of nerve injury is termed CRPS-I, with CRPS-II describing complex regional pain syndrome that develops after nerve damage. However, recent studies have shown nerve damage in patients classified as CRPS-I, suggesting a false dichotomy [198]. The pathophysiology of complex regional pain syndrome is multifactorial, and while multimodal conventional treatment is indicated, some patients with complex regional pain syndrome do not respond to standard approaches and develop refractory disease [199].

Migraine Headache Pain

Most patients with chronic refractory headaches have medication overuse headache, alleviated by detoxification from their headache medication. A subset remains with chronic refractory headache pain. Neuromodulation options can be considered in selected cases [200].

Migraine has a lifetime prevalence of 18%, and women experience higher past-year rates (13% to 18%) than men (5% to 10%). The main clinical feature of migraine is a unilateral or bilateral throbbing or pulsating headache of moderate-to-severe pain, often preceded by an aura. Other symptoms include gastrointestinal disturbances (nausea or vomiting) and intense sensitivity to light or sound. Medical treatment is particularly challenging, with non-response to high-dose preventive medications or side effects that complicate treatment course in many cases [200].

Cluster Headache

The main clinical feature of cluster headaches is severe, excruciating pain with unilateral distribution around and above the eye and along the side of the head or face; pain sensation described as sharp, boring, burning, throbbing, or tightening; and restlessness or agitation during the headache. Autonomic features associated with cluster headache include ipsilateral conjunctival injection and lacrimation, rhinorrhea or nasal blockage, and ptosis. The pain is more severe than any other headache type and ranks among the most severe known to humans, which has earned cluster headache the term "suicide headache" from reports of suicidal behavior in patients desperate to stop the pain [201]. Treatments for cluster headache are effective in some patients, but patients may not respond to medication, and ablative or destructive methods can be ineffective [200].

Fibromyalgia

Fibromyalgia afflicts an estimated 5 million adults in the United States, of whom 80% to 90% are women [202]. The cardinal features of fibromyalgia are widespread pain and tenderness in multiple regions of the body, not attributable to another condition. Abnormal reactivity to painful stimuli or discomfort is characteristic of fibromyalgia. Pain with fibromyalgia is described as a persistent, diffuse, deep, aching, throbbing sensation in muscles that is most often continuous. Patients with fibromyalgia suffer from a complex symptom spectrum that includes pain, as well as sleep problems, fatigue, cognition difficulties, and depression [203].

The pathophysiology of fibromyalgia involves CNS dysfunction and neurotransmitter dysregulation that results in central sensitization to pain, where disordered processing in central afferent neurons accounts for the dominant symptoms of pain and tenderness in fibromyalgia [204].

TRANSCRANIAL MAGNETIC AND ELECTRIC STIMULATION

Daily rTMS sessions for at least one week can produce durable cumulative effects, but maintenance of efficacy requires additional rTMS sessions at regular intervals [27]. Two systematic reviews synthesized the results of published rTMS studies in chronic pain. Both found rTMS effective, with strongest evidence in neuropathic pain. A consortium of European experts found definite efficacy for HF-rTMS of the M1 in neuropathic pain [129].

Neuropathic Pain

Evidence Based Practice Recommendation

According to a European consortium of experts, HF-rTMS of M1 contralateral to pain side displays definite analgesic efficacy for neuropathic pain; LF-rTMS is probably ineffective.

https://www.sciencedirect.com/science/article/pii/S1388245719312799

Last Accessed: July 24, 2025

Level of Evidence: A (Definitely effective or ineffective based on at least two Class I studies or one Class I study and at least two Class II studies)

Of nine randomized controlled trials evaluated, three had major limitations from using less than 1,000 pulses per session and studies used 5-day or 10-day stimulations. HF-rTMS (5–20 Hz) to M1 showed efficacy at short-term (≤1 week from last session) and mid-term (1 to 6 weeks from last session) follow-up. Pain scores were reduced by 20% to 45% following active stimulation, and 35% to 60% of patients were responders (>30% pain relief). These analgesic effects were obtained in neuropathic pain regardless of anatomical origin or whether the pain had central or peripheral nervous system involvement [27].

HF-rTMS to M1 contralateral to the pain side received a Level A recommendation for consistent analgesia in patients with neuropathic pain. This was based on results of 511 patients indicating significant efficacy, with pain relief >30% in 46% to 62% of patients, and >50% pain relief in 29% of patients [129]. There were also modest but significant analgesic long-term effects with repeated sessions.

In contrast, LF-rTMS to M1 contralateral to the pain side received a Level B recommendation (probably ineffective) in patients with neuropathic pain. This was based on results of 138 patients in six randomized sham-controlled trials, which consistently reported the absence of any significant analgesic effect of active rTMS versus sham [129].

Of the few rTMS studies targeting the dorsolateral PFC in neuropathic pain, the results were inconsistent and tended to show lack of efficacy [27].

Evidence Based Practice Recommendation

A European consortium of experts has found probable efficacy of HF-rTMS of the left M1 or the left DLPFC in improving quality of life of patients with fibromyalgia.

https://www.sciencedirect.com/science/article/pii/S1388245719312799

Last Accessed: July 24, 2025

Level of Evidence: B (Probably effective based on at least two Class II studies or the combination of one Class I or II study and at least two Class III studies)

Neuropathic pain syndromes tend to show greatest benefit from rTMS to the M1, but some nonneuropathic chronic pain syndromes, such as CRPS-I or fibromyalgia, may have a neuropathic component. Focal lesions with defined onset, such as pain from shingles or trauma, have advantages of known localization and time of onset, but early cases often improve spontaneously which complicates treatment outcomes in research; thus, established cases with pain duration of at least one year are preferable [13].

rTMS should be applied contralaterally for localized neuropathic pain, or to the left hemisphere for widespread neuropathic pain or fibromyalgia. HF-rTMS (≥5 Hz) stimulation should be used, delivered by a figure-8 coil oriented parallel to the midline over M1 for ≥1 week with ≥1,000 pulses per session. Increasing the total pulses per session and repeating the sessions over several days or weeks may enhance rTMS analgesia [27].

CRPS-I

One randomized controlled trial using 10 daily sessions of 10 Hz rTMS in patients with refractory CRPS-I pain found significantly greater analgesic effects with active than sham rTMS over the three-week treatment period [27,205].

HF-rTMS of M1 in patients with CRPS-I showed significant and rapid reductions in pain intensity, but persistence after stimulation was, on average, short-term. There was high variation in duration of treatment response, with total pain relief for three months post-rTMS reported [129].

Fibromyalgia

HF-rTMS to the left M1 was evaluated in several controlled trials. Significant reductions in global pain on a numerical scale, and improvements in quality of life up to one month following 10 daily sessions were found, as well as extension of these effects for several months with maintenance sessions after completion of the original treatment course [129].

HF-rTMS to M1 was effective in five randomized sham-controlled trials at short term but not at mid-term follow-up. Results of one trial were negative for pain intensity but positive for improvement in quality of life, and another study with 14 sessions of left M1 rTMS over 21 weeks reduced pain for only one month beyond stimulation [27].

HF-rTMS to the left dorsolateral PFC also showed analgesic efficacy, with a mean 29% difference in pain relief between active and sham conditions. This degree of analgesia was also found with LF-rTMS to the left dorsolateral PFC. LF-rTMS to the right dorsolateral PFC showed mixed results, with open-label trials showing positive effect that was not replicated by a sham-controlled trial [129].

Most studies conducted in fibromyalgia using LF-rTMS (1 Hz) to the right dorsolateral PFC or HF-rTMS (10–20 Hz) to the left dorsolateral PFC reported results suggesting that analgesic effects were independent of antidepressant effects. Outcomes with highest-quality evidence show durable and clinically relevant pain reduction preceding improvements in depression [27].

Migraine

HF-rTMS of the motor cortex, in contrast to the left dorsolateral PFC, has shown consistent efficacy in multiple trials that showed significant improvement in headache frequency, pain score and functional disability after active rTMS versus sham. LF-rTMS to M1 showed no benefit beyond placebo effect [129].

HF-rTMS of the left dorsolateral PFC showed mixed results in sham-controlled trials, with significant decreases in migraine attack frequency and intensity, and reductions in oral medication found up to 1 month after 12 sessions in one study, and 23 sessions of active rTMS over 8 weeks less effective than sham in decreasing the number of headache days in another trial [129].

Facial Pain and Cluster Headache

HF-rTMS to the M1 in 19 sessions over six months led to significant relief of refractory facial pain, including cluster headache, with a 40% response rate at six-month follow-up. The analgesic effect remained when session duration was shortened from 20 to 10 minutes while keeping pulses per session (2,000) constant [206].

The effectiveness of maintenance rTMS to prolong analgesia and increase long-term pain reduction was evaluated in 55 patients with chronic refractory facial pain, including cluster headache, trigeminal neuropathic pain, and atypical facial pain. Subjects received 10 HF-rTMS treatments of M1 over two weeks, two sessions in week 3, one session in weeks 4 and 6, and monthly sessions the next 5 months. Pain intensity was measured on a 0–10 scale. Significant decreases from baseline to day 15 were found in permanent pain (5.2 to 3.2) and paroxysmal pain (8.6 to 4.5) intensities, and daily number of pain attacks (5.6 to 2.3). At day 15, 73% had a pain reduction ≥30%, decreasing to 40% at day 180. The analgesic effect was similar for all pain types, but significantly lower when session duration was shortened [206].

Phantom Limb Pain

Land mine victims with phantom limb pain received 10-Hz rTMS or sham of the M1 contralateral to the amputated leg in 10 daily sessions. Follow-up, in days, began after the last session. Active rTMS led to significantly greater reduction in pain intensity scores at 15 days vs sham, but the difference was non-significant at 30 days. At 15 days, 70.3% with rTMS versus 40.7% with sham attained clinically significant pain reduction (≥30%). Traumatic amputees with phantom limb pain were able to experience clinically significant pain reduction following 10-session HF-rTMS without side effects, and further work will identify protocols to extend analgesia [207].

Postherpetic Neuralgia

A randomized controlled trial evaluated high-frequency rTMS in 40 patients with postherpetic neuralgia. After 10 sessions of active or sham rTMS of the M1, active rTMS led to an overall 16.89% greater pain reduction than sham at final stimulation, and one and three months post-stimulation. Analgesic effects were associated with long-term improvement in quality of life [208].

Postoperative Pain Secondary to Gastric Bypass Surgery

HF-rTMS of the left dorsolateral FPC led to immediate, short-term analgesic effects and significant reduction of morphine consumption in small open-label trials [129].

Concomitant Medications and Substances

Potentially problematic prescription medications used by some pain patients include tricyclics (e.g., nortriptyline, amitriptyline), antiviral medications, and antipsychotic medications (e.g., chlorpromazine, clozapine). Consuming or discontinuing commonly abused substances can increase cortical excitability and risk of a TMS-induced seizure. Withdrawal from sedatives (e.g., alcohol, benzodiazepines) increases seizure risk, so patients should be asked about recent and current use, and recent substance abuse should be an exclusion criterion [13].

TRANSCRANIAL DIRECT CURRENT STIMULATION

Pain outcomes with tDCS are highly influenced by the brain state of the chronic disorder, adjunct pharmacological interventions, and the number of tDCS treatment sessions is a critical factor for pain relief effectiveness [18,209]. tDCS has been evaluated in diverse pain conditions, including difficult-to-treat pain syndromes such as fibromyalgia, complex regional pain syndrome, central pain due to spinal cord injury or stroke, headaches, and acute post-operative pain. Published evidence ranges from case reports to randomized controlled trials [18].

A main drawback with tDCS is that it produces diffuse brain current flow. High-definition tDCS was introduced to increase the specificity of targeted brain stimulation. High-definition tDCS uses five electrodes. With the M1 target, the anode is placed over the left M1, with the four return cathodal electrodes placed 5 cm radially from the cathode [209].

Fibromyalgia

The efficacy of 2 mA tDCS over the M1 or dorsolateral PFC (10 sessions over 2 weeks) was evaluated in a randomized sham-controlled trial of patients with chronic medically refractory fibromyalgia. Both M1 and dorsolateral PFC stimulation (but not sham) resulted in significant decreases in pain intensity and a positive benefit on quality-of-life measures immediately following the sessions, but only the M1 stimulation produced longer-lasting pain relief thorough 60-day follow up. The analgesic effects of dorsolateral PFC stimulation dissipated by 30-day follow up [210].

Prefrontal areas are involved in the affective/cognitive processing of pain, and tDCS to the dorsolateral PFC may be more relevant to modulation of the emotional experience of pain than for the somatosensory aspect of pain or pain intensity [18].

An optimized protocol for fibromyalgia pain treatment with tDCS has been published. High-definition 2-mA tDCS of M1 led to clinically significant benefits of ≥50% pain reduction in 50% of patients, with both responders and nonresponders benefiting from a cumulative treatment effect of significant pain reduction and improved quality of life over time. An estimated 15 high-definition tDCS sessions (median) are needed for ≥50% pain reduction [209].

Temporomandibular Disorders

TMD has a high prevalence and in many patients, pain and masticatory dysfunction persist despite a range of treatments. Women with chronic myofascial TMD pain received five sessions of active or sham 2-mA high-definition tDCS to the M1. Compared with sham, active tDCS led to significantly higher number of subjects with ≥50% pain reduction at four weeks, pain-free mouth opening at one-week follow-up, and sectional pain area, intensity and their sum measures contralateral to M1 stimulation during the treatment week. There were no changes on emotional measures. high-definition tDCS M1 stimulation led to clinically meaningful improvement in sensory-discriminative pain and motor measures up to four weeks post-treatment in patients with chronic myofascial TMD pain [211].

Phantom Limb Pain

Eight subjects with unilateral lower or upper limb amputation and chronic phantom limb pain received active or sham 1.5 mA anodal tDCS to M1 daily for five days. Active but not sham tDCS decreased background pain and frequency of phantom limb pain paroxysms through one-week post-tDCS. Also, on each treatment day, active tDCS patients reported immediate pain relief and increased ability to move their phantom limb. Immediate patient response to sham was variable, with increased or decreased pain from baseline [212].

Burn Pain

Burn pain severity and anxiety are highly correlated in burn patients, and a randomized sham-controlled trial assessed the effect of single-session cathodal 1-mA tDCS to the sensory cortex on pain anxiety in 60 patients with severe burn. Following stimulation, pain anxiety scores were significantly reduced with tDCS compared to sham. Post-stimulation assessment was followed by burn dressing; afterwards, pain anxiety scores remained significantly lower with tDCS versus sham. Acute pain anxiety reduction in patients with burns may be attained with cathodal tDCS [213].

Interferon-Induced Pain

Interferon-alpha (IFN) is a standard treatment for chronic hepatitis C infection, and many patients develop painful symptoms during the three- to six-month treatment course. BDNF is a marker of inflammatory-mediated pain, and tDCS was evaluated for effects on pain and plasma BDNF in 28 patients with hepatitis C infection. Following five days of 2-mA anodal stimulation of M1, active tDCS (compared with sham) reduced pain scores with a mean 56% reduction, enhanced BDNF levels with a mean increase of 37.48%, reduced chronic pain scores and analgesic use. Multivariate regression identified a significant interaction between pain reduction and BDNF level increase with active tDCS only [214].

COMPARISONS OF rTMS AND tDCS IN PAIN TREATMENT

Lumbosacral Radiculopathy Pain

Patients with neuropathic pain due to lumbosacral radiculopathy received rTMS (10 Hz) and tDCS (anodal 2-mA) in a sham-controlled crossover trial. Active rTMS was superior to tDCS and sham in pain intensity reduction. tDCS was not superior to sham, but its analgesic effects correlated to rTMS, suggesting common mechanisms of action. Lowered cold pain thresholds with rTMS correlated to its analgesic efficacy, but had no effect on individual neuropathic symptoms. rTMS was more effective than tDCS and sham in patients with neuropathic pain due to lumbosacral radiculopathy, and may modulate sensory and affective dimensions of pain [215].

Fibromyalgia

The treatment efficacy of rTMS and tDCS of fibromyalgia was evaluated by reviewing 16 randomized sham-controlled trials. Significant improvements in fibromyalgia domains were found [204]. Overall treatment effect sizes were large for pain, sleep disturbance, fatigue, and tender points. Effect sizes were medium for depression and general health/function. rTMS showed a significantly greater effect size than tDCS. Primary motor cortex (M1) stimulation produced a subtle but greater effect size in pain reduction versus dorsolateral PFC, and dorsolateral PFC stimulation may be better for depression improvement. Clinically meaningful improvements in anxiety or cognition, or dose-response effect in fibromyalgia pain reduction, were not found for either modality.

Several studies delivered stimulation for two to four weeks, which possibly led to underestimated efficacy because rTMS in treatment-resistant MDD usually requires four to six weeks of daily treatment for durable response/remission.

Adverse events were generally minor, most commonly skin discomfort at the stimulation site, headache, neck pain, and dizziness. Many studies found no significant difference between active and sham stimulation. Some temporary neurobehavioral adverse effects were observed, including insomnia, sleepiness, restlessness, and worsening of depressive symptoms. Detrimental cognition effects or seizures were not observed [204].

10. INVASIVE NEUROSTIMULATION IN CHRONIC PAIN

Deep brain stimulation is more invasive than motor cortex stimulation because electrodes are implanted through the skull, dura, and brain to stimulate deep targets. Morbidity associated with motor cortex stimulation and deep brain stimulation have greatly improved over time since their introduction [13]. For intractable pain, patients selected for motor cortex stimulation/deep brain stimulation should have evidence of exhaustive but failed conservative management, screening for secondary gain, and receive a psychological evaluation. Trial stimulation is mandatory with deep brain stimulation, but is symptom dependent with motor cortex stimulation. Motor cortex stimulation/deep brain stimulation in chronic intractable pain are both proven effective in specific pain indications (>40% pain reduction for ≥12 months) [216].

MOTOR CORTEX STIMULATION

Motor cortex stimulation is based on observations in the 1990s that stimulation
of the precentral gyrus below motor thresholds relieved pain in patients with thalamic pain. Subsequent investigations have shown efficacy in trigeminal neuropathic pain, deafferentation syndromes such as post-stroke pain and spinal cord injury pain, and brachial plexus injuries [187].

Stimulation of central motor systems (e.g., cerebral cortex, pyramidal tracts) can influence descending inhibition of nociceptive spinal and thalamic transmission and induce analgesia. Motor cortex stimulation is increasingly used in chronic, refractory neuropathic pain, with efficacy supported by clinical trials that show response (≥30% pain reduction) in 55% to 64% of patients [27]. Few studies have evaluated long-term outcomes [217].

Refractory Neuropathic Pain

A review of 17 open-label trials reported mixed pain outcomes, but analgesic efficacy may have been underestimated by brief study durations. Motor cortex stimulation has shown delayed, fluctuating analgesic effects, and randomized sham-controlled trials have found substantial pain relief at one year with initial non-responders [27].

Some, but not all studies have strongly correlated preoperative M1 rTMS response with follow-up response to motor cortex stimulation. Other studies found improved motor cortex stimulation outcomes using (versus not using) preoperative rTMS. Positive preoperative rTMS response predicts better motor cortex stimulation outcomes and can improve patient selection [27]. In 20 patients with refractory neuropathic pain followed a mean 6.1 years after motor cortex stimulation, mean pain reduction at any time ranged from 28.9% to 37.2%, and immediate post-rTMS improvement predicted long-term pain reduction. Greatest long-term benefit occurred in physical pain and dependence (autonomy in daily activities); little changed were disability, anxiety, stress and depression [217].

Motor cortex stimulation is safe and effective in central and peripheral neuropathic pain (≥40% to 50% pain reduction in approximately 50% of patients), with best outcomes in central post-stroke pain and neuropathic facial pain [218]. Benefit is established in spinal cord injury pain. Multiple randomized sham-controlled trials with ≥12-month follow-up show sustained response rates in 60% of patients with central and peripheral neuropathic pain. Intracranial motor cortex stimulation is more effective than non-invasive stimulation, and partial rTMS responders should be considered for motor cortex stimulation [13,219,220].

DEEP BRAIN STIMULATION

Deep brain stimulation is effective in relieving diverse intractable pain, including chronic pain refractory to medication, conservative approaches, and TMS. Deep brain stimulation shows efficacy in failed back surgery syndrome, phantom limb pain and peripheral neuropathic pain, and possibly greater efficacy in nociceptive versus neuropathic pain. Deep brain stimulation shows superior outcomes in cluster headaches. Although deemed investigational by the FDA, deep brain stimulation has a clear role in chronic refractory pain [221].

Deep brain stimulation sites in pain treatment differ from those in refractory psychiatric disorders. Effective deep brain stimulation targets in pain control [27]:

- The sensory ventral posterior lateral and medial (VPL/VPM) thalamus

- Periventricular and periaqueductal gray (PVG, PAG) matter

- Internal capsule

- Anterior cingulate cortex

The PVG and VPL/VPM overlap in analgesic mechanisms; some deep brain stimulation studies target both for synergistic effects [8,222]. Greatest long-term deep brain stimulation efficacy is found with PVG/PAG, with/without sensory thalamus or internal capsule stimulation (87% or 79%). Less effective is thalamus stimulation alone (58%) [223]. Deep brain stimulation of the ventral PVG/PAG is thought to trigger non-opioid analgesia and acts through autonomic mechanisms, with dorsal PVG deep brain stimulation triggering endogenous opioid release [27].

The early excitement over deep brain stimulation for pain was dampened when two open-label studies sponsored by Medtronic failed to reach their defined efficacy targets. The first trial enrolled 196 chronic pain patients from 1989–1993 but did not achieve ≥50% pain reduction in ≥50% of patients. The second trial began in 1992 but failed from lack of accrual by 1998 [224].

Without this large-scale prospective data, the FDA has not approved deep brain stimulation for pain and only permits off label use [225]. Due to its off-label status for pain treatment in the United States, only a few surgeons publish their deep brain stimulation pain outcomes [222].

Subsequent large deep brain stimulation trials showed beneficial outcomes. Patients with diverse neuropathic pain syndromes were followed for one to eight years. The best long-term pain outcomes were found in failed back surgery syndrome, and CRPS-II (66% with ≥50% pain reduction). Central pain from spinal cord injury or post-stroke pain showed poor response [225,226].

Following deep brain stimulation of the PVG/PAG grey area or VPL/VPM/internal capsule, patients were followed a mean 78 months and ≥50% pain reduction was attained in patients with failed back surgery syndrome (74%), peripheral neuropathy (60%), thalamic pain (20%), and in patients with trigeminal neuropathy or phantom limb pain but not spinal cord injury or postherpetic neuralgia [227].

Consistent findings of earlier trials were deep brain stimulation efficacy in failed back surgery syndrome and neuropathic pain of peripheral origin; poor response in spinal cord injury or post-stroke pain; and initial benefit may be lost after several years [225].

Intractable Neuropathic Pain

Deep brain stimulation study reviews found long-term pain relief in more than 80% of patients with intractable failed back surgery syndrome, 58% with post-stroke pain, and higher rates in peripheral neuropathic pain (phantom limb pain, polyneuropathies) [13].

In 59 patients with long-term follow-up after deep brain stimulation of the PVG (53.8%), VPL/VPM (12.8%), or both (33.3%), ≥50% pain reduction was attained in patients with phantom limb pain (89%), brachial plexus injury (50%), post-stroke (69%) and spinal cord injury (57%) pain, and chronic headache (54%) [228]. Complications included implantable pulse generator changes (42%), lead revisions (18%), lead erosion requiring removal, and infection, with two treated by antibiotics and five requiring device removal [222].

In seven open-label studies in peripheral or central neuropathic pain, mean pain reduction approached 50%, although pain relief varied largely across studies. The best outcomes occurred with somatosensory thalamus deep brain stimulation in peripheral neuropathic pain [27]. The dorsal anterior cingulate cortex is a potential deep brain stimulation target in chronic neuropathic pain that warrants further study, given its central role in cognitive and affective processing [189].

Intractable Cluster Headache

The American Headache Society practice recommendation for unilateral hypothalamic deep brain stimulation was downgraded to Negative B, based on a study showing active deep brain stimulation no different from sham in pain reduction and serious adverse effects during deep brain stimulation treatment [201].

THALAMIC DEEP BRAIN STIMULATION

Thalamic deep brain stimulation of refractory pain was largely abandoned from inadequate efficacy. Diffusion tensor imaging-based segmentation is a new method to improve thalamic lead positioning and clinical outcome, and was evaluated in five intractable pain patients receiving sensory thalamus deep brain stimulation. Diffusion tensor imaging identified the narrowly specific lead placement shared by four patients with significant post-deep brain stimulation pain relief, and ineffective lead placement in one patient lacking deep brain stimulation response. Diffusion tensor imaging confirmed thalamic lead placement and may be useful for guiding the procedure in the future [229].

Deep brain stimulation is generally safe, with an overall frequency of adverse events of 8% to 9%. These include lead fractures, wound infections, intraoperative seizure and postoperative burr-hole site erosion. Contraindications to pain treatment include psychiatric disorders, coagulopathy, and ventriculomegaly that preclude direct electrode passage to the surgical target [27].

NEUROMODULATION SAFETY IN PAIN TREATMENT

A systematic review concluded all neurostimulation techniques, including invasive procedures, were found safe to very safe. Reports of deaths or serious adverse events after invasive procedures in thousands of patients are conspicuously few. By far the most common side effects of invasive neurostimulation involved stimulation device malfunction or electrode movement. However, due to the invasive nature, implanted neurostimulation should be reserved for patients in whom conventional pain management is ineffective, intolerable or contraindicated; with clearly defined pain conditions; and after an optimal selection process [27].

11. SOCIAL ISSUES WITH NEUROSTIMULATORS

Consumer use of neurostimulators is rapidly expanding, far outpacing regulatory oversight and known safety implications. While patients can obtain devices through purchase, assembly of parts, or clinician prescribing, direct-to-consumer tDCS devices with non-medical product use claims are increasingly available. tDCS is the dominant modality in product availability and consumer demand [7]. Fueling this tDCS 'home use' movement is perception of safety, low device cost, published benefit in some neuropsychiatric disorders, and popularized media accounts of enhancement in normal neuropsychological function.

RISING CONSUMER USE

tDCS may reduce the symptoms of several neuropsychiatric disorders. Patients with these conditions can be highly motivated to seek tDCS therapy, but access is limited to clinical trial enrollment because tDCS remains investigational. Access to clinical trials of tDCS is not pragmatic or possible for many. Even after completing a study, patients have few options for therapy continuity, and unable to access tDCS under medical care, are seeking alternative routes of access [230,231]. This increasingly involves the Internet-mediated "do-it-yourself" tDCS movement of individuals who stimulate their own brains with tDCS outside of research or medical settings for self-improvement goals [231,232].

Some tDCS trials suggest improved cognition, attention, memory, language, and learning ability in healthy subjects [4]. These interesting results began attracting media attention, such as a New York Times article titled "Jump-Starter Kits for the Mind" [233]. The popularized positive effects of neuromodulation have spurred a growth industry in tDCS devices for non-therapeutic enhancement [7].

REGULATORY CHALLENGES AND SAFETY CONCERNS

The FDA designates medical devices by risk level for illness or injury as Class I (low-risk; bandages, dental floss); Class II (medium-risk; breast pump kits, over-the-counter TENS devices for pain); or Class III (high-risk; heart replacement valves, deep-brain stimulating electrodes) devices [232]. The definition of "medical device" is based on intended use and not mechanism of action. A product is a medical device if it is intended for use in diagnosis or treatment, or intended to affect the structure or function of the body [232].

The FDA classifies a product as a medical device according to its representation by the manufacturer, and the level of product regulation is greatly impacted by the intended use claims. This is relevant to how consumer tDCS devices makers represent their product. The websites of most direct-to-consumer tDCS devices tend to imply that intended use was for enhancing or optimizing brain function. Other makers have used the term "kit" to distance their product from possible FDA device classing. "Wellness," but not therapeutic, claims generally place a product outside the definition of a medical device, avoiding FDA regulation. The FDA states this solely applies to low-risk consumer "wellness" devices, but risk level only defines the regulatory process once a device is deemed within FDA jurisdiction [232].

A strong contributor to consumer demand is perceived safety. Safety reviews of tDCS trials treating more than 1,000 subjects with more than 33,200 sessions found no reports of serious adverse effects, irreversible injury or cognitive impairment with standard tDCS protocols (sessions ≤40 min, ≤2 times/day, ≤4 mA, electrodes that minimize skin burns) [16,231]. Another review noted that adverse effects were mentioned in only 56% of 172 published trials, indicating that systematic assessment and reporting of adverse effects was absent from a large portion of the evidence base [235].

A case report described respiratory and motor paralysis, muscle cramping, and nausea in a patient who, during electrical stimulation therapy, was accidentally delivered a current 10 times higher than intended. This report was shown to underscore the risk of applying electrical stimulation outside of established parameters, with clinically unsupervised home use of tDCS increasing the risk of permanent injury [234,235]. The efficacy and high overall safety reported in tDCS trials is specific to the device and clinical protocol. Changing any aspect of the device, electrode placement, or delivered dose is likely to obviate the desired effect. Direct-to-consumer tDCS products cannot claim the benefits of illness treatment or enhancement of normal function found by tDCS trials because they deviate in these aspects [235].

Other concerns with home use of tDCS include data that suggest cognitive enhancement mediated by tDCS may occur at the expense of other cognitive functions; the lack of long-term safety data; and the innumerable scenarios of inept home use and potential harm that may arise. An ethical concern is the media "neuro-hype" surrounding tDCS can shape public risk-benefit perception, promote therapeutic misconceptions, and impact the uptake of this technology. This increases the potential for desperate and vulnerable patients to overestimate tDCS benefits and under-estimate the risks [16,234].

12. CONCLUSION

A diverse array of brain stimulation modalities are available or being evaluated for the treatment of chronic psychiatric and pain conditions. Noninvasive approaches include ECT, which remains established as the most reliable means for rapid antidepressant induction; the more recent rTMS and tDCS, introduced to rival ECT efficacy without cognitive adverse effects or need for general anesthesia; several very recent variants of rTMS and tDCS; and trigeminal nerve stimulation (eTNS). The most-studied non-invasive brain stimulation is rTMS, followed by tDCS.

Unlike ECT, use of rTMS and tDCS have expanded beyond MDD. Efficacy in MDD is established with rTMS and more modest with tDCS. rTMS shows greater efficacy in anxiety-related disorders, substance use and eating disorders, while tDCS shows greater efficacy in alleviating residual audio verbal hallucinations and negative symptoms in schizophrenia. In diverse chronic pain conditions, rTMS is somewhat more effective than tDCS. VNS may have a role in severely treatment-resistant MDD, and motor cortex stimulation is effective in central refractory neuropathic pain. Deep brain stimulation is the most invasive modality, and may provide long-term, clinically meaningful symptom reduction and improved quality of life in patients with a range of intractable psychiatric or chronic pain conditions.

The current rate of knowledge expansion and publication output involving rTMS and tDCS cannot be overstated. The continuous refinement and improvements in specificity of stimulation and duration of response is rapidly making non-recent publications obsolete.

Many brain stimulation devices show consistent and significant treatment responses in various psychiatric and pain conditions. From a rigid, evidence-based perspective, the strength of evidence for efficacy is considered weak in many stimulation-responsive conditions. This does not imply the therapy is ineffective, but instead reflects the small numbers of treated patients in many clinical conditions [187]. Compared to long-term efficacy, safety and adverse effects are much more established in rTMS and tDCS; with ECT and deep brain stimulation, all three dimensions of treatment outcome are established. However, in real world clinical care, decision-making weighs potential benefits against known risks across the range of options. Most patients evaluated for response to brain stimulation have multiple prior failed treatments. Brain stimulation offers the potential to offset patient non-response or intolerance to standard therapies.

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Evidence-Based Practice Recommendations Citations

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48854 • Pressure Injuries: Prevention and Management

John M. Leonard, MD

www.netce.com

Copyright © 2025 NetCE, All rights reserved.

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

Table of Contents

48854 • Pressure Injuries: Prevention and Management

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. EPIDEMIOLOGY

3. PATHOGENESIS

4. RISK FACTORS

EXTRINSIC FACTORS

INTRINSIC RISK FACTORS

RISK ASSESSMENT

5. STAGING OF PRESSURE INJURIES

DEEP TISSUE PRESSURE INJURY

STAGE 1: NONBLANCHABLE ERYTHEMA

STAGE 2: PARTIAL-THICKNESS SKIN LOSS WITH EXPOSED DERMIS

STAGE 3: FULL-THICKNESS SKIN LOSS

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

UNSTAGEABLE

MEDICAL DEVICE-RELATED PRESSURE INJURY

MUCOSAL MEMBRANE PRESSURE INJURY

6. PHASES OF WOUND HEALING: AN OVERVIEW

INFLAMMATORY PHASE

PROLIFERATION PHASE

MATURATION PHASE

7. DIAGNOSIS

8. PREVENTION AND TREATMENT

SKIN CARE AND PRESSURE-RELIEVING STRATEGIES

NUTRITIONAL SUPPORT

WOUND CLEANSING

DEBRIDEMENT

DRESSINGS

PAIN MANAGEMENT

SURGICAL CLOSURE

INFECTION MANAGEMENT

ADJUNCTIVE TREATMENTS

INDIVIDUAL STAGING TREATMENT PLANS

9. WOUND MONITORING

WOUND ASSESSMENT

WOUND EDGE AND SURROUNDING SKIN

PAIN

PRESENCE OF INFECTION

10. COMPLICATIONS

CELLULITIS

SEPSIS AND SEPTIC SHOCK

BONE AND JOINT INFECTIONS

MALIGNANCY

GAS GANGRENE

NECROTIZING FASCIITIS

RECURRENCE

11. TREATMENT OF COMORBIDITIES

DIABETES

URINARY AND FECAL INCONTINENCE

PERIPHERAL VASCULAR DISEASE

HYPOTENSION AND HYPOXIA

GASTROINTESTINAL DISORDERS AND MALABSORPTION

MALIGNANCY

END-STAGE RENAL DISEASE

DEPRESSION

COGNITIVE IMPAIRMENT

12. ADVANCES IN PRESSURE INJURY CARE

REPOSITIONING ALERTS

DETECTION

DOCUMENTATION

ULTRASOUND

SKIN SUBSTITUTES OR GRAFTS

GENE THERAPY

NEGATIVE PRESSURE WOUND DEVICES

GROWTH FACTORS AND BIOLOGIC WOUND PRODUCTS

OTHER TREATMENT MODALITIES

13. MEDICO-LEGAL ASPECTS OF INJURY CARE

AVOIDABLE VERSUS UNAVOIDABLE INJURIES

DETERMINATION OF NEGLECT

14. EDUCATING PATIENTS

PATHOGENESIS OF PRESSURE INJURIES

REDUCTION OF RISK

REDUCTION OF FRICTION AND SHEAR

SKIN INSPECTION AND PROTECTION

NUTRITION

PROCEDURE FOR RECURRENCES

MANAGEMENT OF PRESSURE INJURY

PROPER DRESSING CHANGE PROCEDURE

15. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

48854 • Pressure Injuries: Prevention and Management

Education Category. Infection Control / Internal Medicine

Release Date. 05/01/2025

Expiration Date. 04/30/2028

Course Overview

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

Audience

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

Accreditations & Approvals

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

Designations of Credit

NetCE designates this enduring material for a maximum of 10 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 10 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the activity with individual assessments of the participant and feedback to the participant, enables the participant to earn 10 MOC points in the American Board of Pediatrics' (ABP) Maintenance of Certification (MOC) program. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABP MOC credit. This activity has been designated for 10 Lifelong Learning (Part II) credits for the American Board of Pathology Continuing Certification Program. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. NetCE is authorized by IACET to offer 1 CEU(s) for this program.

Special Approvals

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

Course Objective

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

Learning Objectives

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

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

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

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

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

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

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

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

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

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

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

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

Faculty

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

Faculty Disclosure

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

Division Planners

John V. Jurica, MD, MPH

Ronald Runciman, MD

Division Planners Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

Implicit Bias in Health Care

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

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

1. INTRODUCTION

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

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

2. EPIDEMIOLOGY

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

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

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

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

3. PATHOGENESIS

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

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

4. RISK FACTORS

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

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

EXTRINSIC FACTORS

Pressure and Shear

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

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

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

Friction

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

Moisture

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

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

INTRINSIC RISK FACTORS

Age

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

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

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

Immobility

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

Sensory Loss

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

Poor Nutrition and/or Volume Depletion

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

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

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

Incontinence

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

Skin Perfusion Status

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

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

Smoking

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

Stress

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

Obesity

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

Comorbidities

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

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

- Diabetes

- End-stage renal disease (ESRD)

- Thyroid disease

- Congestive heart failure

- Peripheral vascular disease

- Collagen vascular disorders and vasculitis

- Immune deficiency states

- Malignancies

- Chronic obstructive pulmonary disease

- Depression and psychosis

- Drugs that delay healing

- Joint contractures

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

RISK ASSESSMENT

Evidence Based Practice Recommendation

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

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Last Accessed: April 28, 2025

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

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

- Populations at risk

- Level of risk

- Type of risk

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

The Braden Scale

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

- Sensory perception

- Moisture

- Activity

- Mobility

- Nutrition

- Friction and shear

Table 1: THE BRADEN SCALE FOR PREDICTING PRESSURE ULCER RISK

Domain

Scorea

1

2

3

4

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

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

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

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

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

Moisture: Degree to which skin is exposed to moisture

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

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

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

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

Activity: Degree of physical activity

Bedfast: Confined to bed

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

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

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

Mobility: Ability to change and control body position

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

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

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

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

Nutrition: Usual food intake pattern

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

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

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

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

Friction and shear

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

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

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

—

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

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

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

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

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

The Norton Scale

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

Table 2: THE NORTON SCALE FOR PREDICTING PRESSURE ULCER RISK

Score

Physical condition

Mental condition

Activity

Mobility

Incontinent

4

Good

Alert

Ambulant

Full

Not

3

Fair

Apathetic

Walk-help

Slightly limited

Occasional

2

Poor

Confused

Chair-bound

Very limited

Usually (urine)

1

Very bad

Stupor

Stupor

Immobile

Doubly

Source: [28]

5. STAGING OF PRESSURE INJURIES

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

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

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

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

- Medical device-related pressure injury

- Mucosal membrane pressure injury

DEEP TISSUE PRESSURE INJURY

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

Image 1: ILLUSTRATIONS OF DEEP TISSUE PRESSURE INJURY

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

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

STAGE 1: NONBLANCHABLE ERYTHEMA

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

Image 2: ILLUSTRATION OF A STAGE 1 PRESSURE INJURY

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

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

STAGE 2: PARTIAL-THICKNESS SKIN LOSS WITH EXPOSED DERMIS

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

Image 3: ILLUSTRATION OF A STAGE 2 PRESSURE INJURY

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

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

STAGE 3: FULL-THICKNESS SKIN LOSS

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

Image 4: ILLUSTRATION OF A STAGE 3 PRESSURE INJURY

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

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

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

Image 5: ILLUSTRATION OF A STAGE 4 PRESSURE INJURY

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

UNSTAGEABLE

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

Image 6: ILLUSTRATION OF AN UNSTAGEABLE PRESSURE INJURY

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

MEDICAL DEVICE-RELATED PRESSURE INJURY

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

MUCOSAL MEMBRANE PRESSURE INJURY

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

6. PHASES OF WOUND HEALING: AN OVERVIEW

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

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

INFLAMMATORY PHASE

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

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

PROLIFERATION PHASE

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

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

MATURATION PHASE

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

7. DIAGNOSIS

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

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

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

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

8. PREVENTION AND TREATMENT

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

The primary objectives for prevention and arrest of progression are:

- Preventive skin care

- Pressure reduction, minimizing or eliminating friction and shear forces

- Adequate nutrition

- Exudate management

- Prevention of wound infection

- Managing moist wound environments

- Decreasing the frequency of dressing changes

The general treatment of established injuries involves:

- Pressure-relieving strategies

- Optimal nutritional support, including protein and micronutrient supplementation

- Intense injury care

- Pain management

- Prevention/eradication of infection

- Adjunctive treatment or surgery

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

SKIN CARE AND PRESSURE-RELIEVING STRATEGIES

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

- Avoid positioning the patient over an area of erythema.

- Keep the skin clean and dry.

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

- Develop an individualized continence plan.

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

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

- Careful patient positioning

- Use of protective devices

- Judicious use of support surfaces

Positioning

Bedbound Patients

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

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

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

Chairbound Patients

Evidence Based Practice Recommendation

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

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

Last Accessed: April 28, 2025

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

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

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

Protective Devices

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

Support Surfaces

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

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

Table 3: THERAPEUTIC SUPPORT SURFACE SELECTION TOOL

Validated Risk Assessment Category or Pressure Ulcer Description

At risk

OR

Redness present that fades quickly when pressure is removed

Moderate risk

OR

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

High risk

OR

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

Very high risk

OR

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

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

Total assist to change position in bed.

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

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

Active support surface:

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

Active support surface:

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

Moderate assistance with bed mobility required.

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

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

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

Active support surface:

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

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

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

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

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

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

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

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

Types of Support Surfaces

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

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

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

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

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

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

NUTRITIONAL SUPPORT

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

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

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

- Loss of subcutaneous tissue

- Muscle wasting

- Generalized edema

- Dry, pluckable hair

- Dry, flaky, itchy skin

- Cracks in the mucous membranes

- Delayed wound healing/failure to granulate

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

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

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

Interventions to Promote Nutrition

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

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

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

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

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

WOUND CLEANSING

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

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

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

DEBRIDEMENT

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

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

Autolytic Debridement

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

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

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

Mechanical Debridement

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

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

Surgical Debridement

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

Maggot Debridement Therapy

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

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

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

Enzymatic Debridement

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

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

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

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

DRESSINGS

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

- Condition of the injury and wound bed

- Size and depth

- Necrosis/slough

- Dry/exudating

- Epithelializing

- Presence of tunneling

- Infection

- Over-granulating

- Malodorous

- Malignant

- Pain

- Aim of treatment

- Facilitate healing

- Promote debridement

- Combat infection

- Relieve pain

- Absorb exudates or add moisture

- Prevent or treat scarring

- Combat odor

- Cosmetic/provide concealment

- Condition of surrounding skin

- Fragile

- Macerated

- Anatomical location

- Difficult to dress

- Dressing affects use of normal clothing or shoes

- Etiology

- External compression

- Prospect of healing

- Palliation

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

- Economics/cost

- Availability (reimbursement issues)

Table 4: OVERVIEW OF DIFFERENT DRESSINGS FOR PRESSURE ULCERS

Dressing Type

Description

Indication

Advantages

Disadvantages

Transparent film

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

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

Retains moisture

Impermeable to bacteria and other contaminants

Facilitates autolytic debridement

Allows for wound observation

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

Not recommended for infected wounds or wounds with drainage

Requires border of intact skin for adhesion

May dislodge in high-friction areas

Not recommended on fragile skin

Hydrogel

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

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

Soothing, reduces pain

Rehydrates wound bed

Facilitates autolytic debridement

Fills dead tissue space

Easy to apply and remove

Can be used in infected wounds or to pack deep wounds

Not recommended for wounds with heavy exudate

Dehydrates easily if not covered

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

May cause maceration

Alginate

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

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

Absorbs up to 20 times its weight

Forms a gel within the wound

Conforms to the shape of the wound

Facilitates autolytic debridement

Fills in dead tissue space

Easy to apply and remove

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

May dehydrate the wound bed

Requires secondary dressing

Foam

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

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

Nonadherent, although some have adherent borders

Repels contaminants

Easy to apply and remove

Absorbs light-to-heavy exudate

May be used under compression

Recommended for fragile skin

Not effective for wounds with dry eschar

May require a secondary dressing

Hydrocolloid

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

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

Impermeable to bacteria and other contaminants

Facilitates autolytic debridement

Self-adherent, molds well

Allows observation, if transparent

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

May be applied over alginate dressing to control drainage

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

May curl at edges

May injure fragile skin upon removal

Contraindicated for wounds with packing

Moistened gauze

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

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

Accessible

Must be remoistened often

Time-consuming to apply

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

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

Transparent Films

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

Hydrogels

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

Hydrocolloids

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

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

Calcium Alginates

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

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

Foam Dressings

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

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

Silver-Impregnated Dressings

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

Cadexomer Iodine Dressings

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

Gauze

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

Composite Dressings

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

Collagen Dressings

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

PAIN MANAGEMENT

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

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

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

Evidence Based Practice Recommendation

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

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Last Accessed: April 28, 2025

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

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

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

SURGICAL CLOSURE

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

- Simple cutaneous: Includes skin and subcutaneous tissue only

- Fasciocutaneous: Includes skin, subcutaneous tissue, and fascia

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

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

INFECTION MANAGEMENT

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

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

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

ADJUNCTIVE TREATMENTS

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

Electrical Stimulation

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

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

Growth Factors

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

Hyperbaric Oxygen

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

Normothermic Infrared and Temperature Therapy

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

Therapeutic Ultrasound

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

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

Thermal

Non-Thermal

Increased collagen elasticity

Decreased muscle and joint stiffness

Decreased pain

Decreased muscle spasm

Increased oxygen transport

Hyperemia

Speeds up inflammatory process

Increases release of growth factors

Fibroblast and endothelial cell proliferation

Increased collagen production

Accelerated angiogenesis

Better organization of collagen matrix

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

Pulsed Electromagnetic Field Energy

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

Negative Pressure Wound Therapy (Vacuum-Assisted Closure)

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

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

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

INDIVIDUAL STAGING TREATMENT PLANS

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

Figure 1: ALGORITHM FOR THE TREATMENT OF PRESSURE ULCERS

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

Suspected Deep Tissue Pressure Injury

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

- Pressure redistribution

- Prevention of shear and friction

- Moisture maintenance

- Physical therapy and nutritional support

- Periodic assessment of the patient

- Pain management

- Prevention and treatment of infection

Stage 1

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

Stage 2

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

Stage 3

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

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

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

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

Stage 4

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

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

Unstageable

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

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

9. WOUND MONITORING

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

WOUND ASSESSMENT

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

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

- Maceration of the surrounding skin

- Inadequate control of wound drainage

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

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

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

Factor

Points

Size (surface area)

0 cm^2

0

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

1

0.3–0.6 cm^2

2

0.7–1.0 cm^2

3

1.1–2.0 cm^2

4

2.1–3.0 cm^2

5

3.1–4.0 cm^2

6

4.1–8.0 cm^2

7

8.1–12.0 cm^2

8

12.1–24.0 cm^2

9

>24.0 cm^2

10

Exudate amount

None

0

Light

1

Moderate

2

Heavy

3

Tissue in wound bed

Closed wound

0

Epithelial tissue

1

Granulation tissue

2

Slough

3

Necrotic tissue

4

Source: [87]

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

Location

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

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

Size and Depth

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

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

Undermining/Tunneling

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

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

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

Wound Bed

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

Table 7: WOUND BASE COLOR DESCRIPTIONS

Color

Description and Clinical Implications

Red

Clean and uniformly pink to red in color.

Usually heals by secondary intention.

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

Yellow

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

Caution: Tendon may appear as yellow or white.

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

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

Black or brown

Ranges in color from dark brown and gray to black.

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

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

Source: [13]

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

Exudates

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

- Large/copious: Extends beyond dressing

- Moderate: Contained within the dressing

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

- None: Absence of exudate

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

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

- Serosanguineous: Thin and pink or light red in color

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

- Hemorrhagic: Red and thick, consisting mainly of blood

- Fibrinous: Cloudy and thin with strands of fibrin

Odor

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

WOUND EDGE AND SURROUNDING SKIN

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

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

PAIN

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

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

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

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

- What kind of pain are you experiencing?

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

- What makes the pain better?

- What makes it worse?

- Where is the pain located?

- Does the pain radiate?

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

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

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

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

- When does it start and when does it stop?

PRESENCE OF INFECTION

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

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

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

- Unusual odor

- Friable or dysmorphic granulation

- Purulent exudates

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

10. COMPLICATIONS

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

CELLULITIS

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

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

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

SEPSIS AND SEPTIC SHOCK

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

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

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

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

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

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

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

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

- Bilirubin >2 mg/dL

- An acute alteration in mental status

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

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

- Respiratory rate ≥22/min

- Altered mentation (Glasgow Coma Scale <15)

- Systolic blood pressure ≤100 mm Hg

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

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

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

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

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

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

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

Antimicrobial Therapy

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

Proper support for organ failure is indicated for patients with severe sepsis, and sedation, mechanical ventilation, and analgesia are often required in late-stage disease. Adequate nutrition (usually administered parenterally) and glucose control are necessary. The patient should be stabilized prior to restarting injury treatments.

BONE AND JOINT INFECTIONS

When the infection from a full-thickness tissue injury, generally stage IV, spreads to bone and joints, periosteitis, septic or infectious arthritis, or osteomyelitis can result. If the injury crater can be probed to bone (i.e., one can see or palpate bone at the base of the crater), then the likelihood of bone infection approaches 80%. Confirmation of the diagnosis relies on imaging studies and needle aspiration or bone biopsy for histopathology and culture.

Plain bone radiographs are useful for diagnosing chronic osteomyelitis when infection has been present for many weeks; however, false-positive or false-negative results are common. Computed tomography scans are helpful for demonstrating fluid collections, bony erosion, and joint involvement. Radionuclide bone scanning (with technetium methylene-99m diphosphate) can be diagnostic, but it only has a moderate degree of sensitivity and specificity. Magnetic resonance imaging is the most sensitive and specific imaging modality for identifying the presence of osteomyelitis.

Bone biopsy is the definitive diagnostic test. Bone biopsy for histologic examination and culture not only verifies bone involvement but also helps to establish the bacterial etiology and antibiotic sensitivities upon which optimal treatment depends.

Treatment

In the presence of underlying osteomyelitis, satisfactory healing of the pressure injury is usually not possible unless the bone infection is eradicated. This requires parenteral followed by oral antimicrobial therapy for a minimum of six to eight weeks, combined, if necessary, with surgical debridement of necrotic bone. Any surgical approach to (presumed) infected bone, whether needle aspiration, biopsy, or debridement, should include submission of bone specimens for culture.

In the surgical management of stage 4 injury cases with little or no overt clinical or radiographic sign of bone infection, submission of bone specimens for culture is useful for identifying early, limited osteomyelitis and thus the need for post-operative antimicrobial treatment. Examples are cases requiring partial ostectomy or ablative surgery of stage 4 injuries with resection of bone from the base of the injury crater.

MALIGNANCY

Long-standing pressure injuries can develop into malignant tumors called Marjolin ulcers. These tumors were named for surgeon Jean-Nicolas Marjolin, who first described the condition in 1820 [98,99]. They are very aggressive ulcerating squamous cell carcinoma found in the area of injuries and other long-standing indolent wounds. It can develop many years after the initial trauma.

The first sign of Marjolin ulcer is a change in the character of the wound. Drainage increases, and the odor of the drainage becomes putrid. In some cases, there is frank bleeding. Diagnosis is made after histologic examination of a specimen removed from the injury, usually at the time of a flap closure. Confirmation of the diagnosis requires a preoperative tissue biopsy; wedge biopsy is the method of choice.

Excision of the lesion with 1-cm margin is required. Oncologic assistance is also necessary in the management of this condition, and extensive treatment is often necessary.

GAS GANGRENE

Gas gangrene is a rare but serious form of Clostridium perfringens infection. These obligate anaerobes release gas and harmful toxins that can result in gas gangrene, sepsis, and septic shock. The most common symptoms are severe pain and rapid swelling of the skin around or near the injury.

Surgical debridement is usually necessary [100]. In very serious cases, excision with amputation is required to prevent spread of the infection [101]. Penicillin is administered as adjuvant therapy. Hyperbaric oxygen therapy is effective in growth inhibition and killing C. perfringens [102,103]. However, results of a Cochrane review could not determine the efficacy and safety of hyperbaric oxygen therapy for the treatment of gas gangrene [101].

NECROTIZING FASCIITIS

People with stage 3 and 4 injuries are at a risk for contracting the rapidly progressive infection necrotizing fasciitis. Necrotizing fasciitis is defined as a group A streptococcal infection of the fascia with accompanying necrosis of the subcutaneous tissues. It is an uncommon consequence of pressure ulceration [104,105].

Initial signs of this condition are fever, pain, and massive swelling. Visual and microscopic evaluation of the tissues confirms the diagnosis. Emergency treatment is required, and aggressive surgical debridement is vital to prevent spreading [106]. In some cases, early amputation of affected tissues and maximum intensive care treatment (e.g., in case of sepsis) are required [106].

As soon as necrotizing fasciitis is suspected, antibiotics should be started. A combination of intravenous antibiotics, usually clindamycin, vancomycin, and penicillin, is administered. One review recommended aminopenicillin plus sulbactam in combination with clindamycin and/or metronidazole as initial treatment [106]. Hyperbaric oxygen therapy can also be effective.

RECURRENCE

Recurrence of a pressure injury is a common complication of treatment. As noted, as many as 90% of patients with a healed wound will experience a recurrence [6,9]. Compared to normal tissue, scar tissue has lower tensile strength, poor blood supply, and poor ability to withstand trauma, making it vulnerable to recurrent episodes. If an injury recurs at the same site within four months of the initial injury, it is likely due to incomplete healing rather than a true recurrence [107]. Risk factors for recurrence include male sex, younger age, African/black race, lower socioeconomic status, nursing home residence, and previous pressure injury surgery [107].

11. TREATMENT OF COMORBIDITIES

Comorbid conditions both increase susceptibility to pressure injuries and impair the healing process. Therefore, comorbid conditions should be addressed as part of the overall treatment plan. Common comorbid conditions in patients with pressure injuries include:

- Diabetes

- Incontinence

- Peripheral vascular disease (PVD)

- Hypotension and hypoxia

- Dehydration, poor nutritional status, or malnutrition

- Cancers

- ESRD

- Depression and cognitive impairment

Even with the best medical care and preventive measures, pressure injuries can occur [108]. It is unclear which combination of comorbid conditions can lead to injury formation, but changes in skin with comorbidities are believed to result in injuries. Recent acute illnesses or acute exacerbation of comorbid conditions may cause lethargy and reduced mobility, increasing the risk of pressure injuries. In patients with comorbid conditions, special attention to the drugs being used is necessary. Chemotherapeutic agents, systemic corticosteroids, and NSAIDs can impair healing.

DIABETES

In patients with long-standing diabetes, both macro- and microvasculature can be severely damaged, particularly if the disease is poorly controlled. Diabetes also causes neuropathy, and the resultant loss of sensation and protective reflexes is a risk factor for pressure injury progression. Patients with diabetes have elevated glucose levels that result in rigid blood cell walls and decreased blood flow through microvasculature. The disease also impairs oxygen release by the hemoglobin, resulting in hypoxia. Leukocytes have less effective chemotaxis and phagocytosis, which makes the patient susceptible to infection. Diabetics are prone to fungal rashes that can result in perineal irritation and skin breakdown. Impaired granulocyte function inhibits wound healing. All of these factors contribute to the increased risk of pressure injury development in a patient with diabetes.

The aim of diabetes management is to keep blood glucose levels close to normal (i.e., glycosylated hemoglobin less than 7%). Usually, pharmacotherapy and/or insulin therapy is necessary for optimum disease control. In addition, eating habits should be modified and physical activity should be increased.

URINARY AND FECAL INCONTINENCE

Approximately 10 to 13 million Americans have transient or chronic urinary incontinence [109]. It is also estimated that 50% to 70% of patients with urinary incontinence fail to seek medical intervention or treatment [109]. The high prevalence of incontinence among certain populations (e.g., nursing home residents) makes this an important factor in pressure injury development and healing.

Extended exposure of skin to urine and feces can result in breakdown, making the patient more susceptible to injuries [110]. Urinary incontinence results in maceration, which causes increased skin irritation and fragility. Coliform bacteria and C. difficile contamination of existing wounds can lead to severe infections.

The treatment of these patients is dependent on determining the incontinence etiology. General approaches include regular assessment of skin; hydration and infection should not be ignored. Patients should be checked for incontinence every two hours. For patients who are cooperative and aware of bladder filling, a toilet program should be instituted, including planned voiding every two hours. For patients who are uncooperative or unaware of bladder filling, consider the use of absorptive products or condom catheters for men. It is important to use diapers and underpads that wick moisture away from patients' skin. Incontinent patients should be cleaned as soon as possible after soiling using specialized incontinence skin cleansers or soaps.

For patients with severe diarrhea, all potential causative factors should be explored and addressed. A rectal pouch may be useful for these patients. In cases of chronic incontinence, an every other day suppository or enema may be considered. In addition, barrier ointments help protect the skin from incontinent episodes. If used, apply a thick coat of ointment, wipe off the soiled top layer, and apply another layer. Do not clean off the paste to skin level when bathing or cleaning.

PERIPHERAL VASCULAR DISEASE

PVD is an important contributory factor in the development of vascular injuries, particularly diabetic foot ulcerations (as the cause of 10% to 30% of all cases) [111]. The wounds of patients with severe PVD heal poorly as a result of inadequate blood supply, and minor trauma or pressure often leads to ulceration.

When conducting a thorough physical examination, signs and symptoms consistent with PVD should be documented and ankle-brachial index or pulse volume recordings should be recorded. The ankle-brachial index is not specific in patients with advanced calcific atherosclerotic disease, and for patients with this condition, photoplethysmography or magnetic resonance angiogram is more accurate [112,113].

Treatment of PVD first relies on assessment and management of modifiable risk factors (e.g., smoking, physical activity). Pharmacologic management with antiplatelets is the gold standard for patients whose disease is not well controlled with lifestyle changes [114]. In addition, comorbidities should be treated aggressively.

HYPOTENSION AND HYPOXIA

Prolonged hypotension and hypoxia can cause tissue hypoperfusion, especially in anatomical locations already at risk for developing injuries. Patients with septic shock have microvascular endothelial dysfunction, which results in tissue hypoxia despite adequate oxygenation [115,116]. Tissue hypoxia and hypoperfusion may also be caused by hemorrhagic shock. Anemia and low cardiac output limit the blood's oxygen-carrying capacity and perpetuate tissue hypoperfusion. It is necessary to check vital signs, CBC, blood gas, and echocardiogram and manage accordingly.

GASTROINTESTINAL DISORDERS AND MALABSORPTION

As discussed, optimal nutrition is important for the prevention and treatment of pressure injuries. Therefore, intestinal diseases and acquired disorders that adversely affect nutrient absorption should be identified and treated as part of a management plan. Conditions like celiac disease, Crohn disease, and gastrointestinal malignancy often lead to malabsorption and micronutrient deficiencies. C. difficile colitis can cause severe diarrhea and hypoalbuminemia, making patients nutritionally and hemodynamically compromised. Patients who have undergone surgical bowel resections and fecal diversion are also at risk for malabsorption, fluid depletion, and electrolyte deficiency.

In addition to correction of nutritional deficiencies, the primary cause of malabsorption should be identified and treated. The plan of care will include interventions to increase nutritional intake, keeping in mind that the patient's and family's preferences play an important role in establishing a diet plan.

MALIGNANCY

Malignancy often leads to cachexia, a syndrome characterized by weight loss, malnutrition, weakness, and anemia. However, there is limited research exploring the link between pressure injuries and cancer [117]. Radiation therapy can cause dermatitis and desquamation and increase the risk for skin breakdown. Both the malignancy and associated treatments may cause immunosuppression and increase the likelihood and severity of infections.

Patients with cancer who are also experiencing skin breakdown should be assessed for nutritional status, and medications may be prescribed to combat the anorexia associated with chemotherapy. Optimum skin care, particularly in areas affected by radiation therapy, is a necessity.

END-STAGE RENAL DISEASE

Severe uremia associated with ESRD necessitates the use of dialysis to remove uremic toxins and prevent or control complications, and pruritus and xerosis are common in these patients. Malnutrition and dehydration are also risks. Dietary management of patients with ESRD should be aimed at control of electrolytes (including calcium, phosphorus, and potassium), prevention of malnutrition, and maintenance of acceptable fluid volume status.

DEPRESSION

The National Institute of Mental Health estimates that 8.4% of adults in the United States are suffering from depression, and major depression is the leading cause of disability worldwide [118]. Depressed patients often have little interest in self-care and nutrition, both of which may predispose an individual to pressure injuries [15]. Pressure injuries have also been found to contribute to depressive symptoms [119]. Patients should be regularly assessed for depression or other psychologic illnesses and referred to mental health care.

COGNITIVE IMPAIRMENT

Loss of cognition is associated with increased risk for pressure injuries, and impaired mental status leads to a lack of awareness of discomfort or pressure and may be associated with incontinence. The ability to respond appropriately or to inform others of the need for assistance may be lost completely. As such, these patients often require intensive care.

12. ADVANCES IN PRESSURE INJURY CARE

Research and technical innovations are producing sophisticated technology and analytic devices to diagnose, prevent, and treat pressure injuries. These new innovations are changing the way injuries are cared for and prevented in a variety of settings.

REPOSITIONING ALERTS

Studies have shown that patients with less nocturnal periodic movements are at risk for pressure injuries, but sleeping patients may be unaware of their lack of movement [120]. Alert systems have been implemented to remind staff to reposition the patient every two hours. Because repositioning is one of the basic hallmarks of pressure injury prevention, alerts may help address this risk factor better.

DETECTION

Early detection is of utmost importance in pressure injury management. Advanced technology and devices can be used to achieve better sensitivity and specificity in the diagnosis of injuries. These techniques include laser Doppler, visible and near-infrared spectroscopy, ultrasound, and pulse oximetry [121]. Each of these approaches ascertains clinical parameters associated with blood flow and hemoglobin concentration, and combining such measures with clinical information allows for a high degree of sensitivity and specificity in identifying impending chronic wounds in patients with any skin color [121].

DOCUMENTATION

New methodologies for documenting and measuring wounds can help both with monitoring treatment and preventing legal complications. Highly advanced computerized documentation is being used by many organizations. Techniques are now available to thoroughly assess the geometric, physiologic (i.e., pressure and degree of wound perfusion), and biochemical (i.e., concentrations of various enzymes involved in tissue degradation and healing) aspects of the wound.

Electronic records and images are preferred by many institutions. The role of wound photography is growing and is a vital aspect of monitoring response to treatment and in defending against possible future litigation. Most home health agencies in the United States include wound photography as part of the patient's medical record [35].

ULTRASOUND

Ultrasound has been explored as a diagnostic and monitoring tool. High-frequency ultrasound provides greater resolution than other ultrasound techniques, but the depth of penetration of the sound waves is less. Therefore, it is ideal for imaging near-surface pathology. High-resolution ultrasound can easily detect the fluid content of tissue and measure skin thickness. More research is necessary to determine the efficacy and cost effectiveness of ultrasound for the routine care of pressure injuries.

SKIN SUBSTITUTES OR GRAFTS

Although the available skin substitutes are not perfect, they do offer benefits when treating pressure injuries, particularly those resistant to healing. Research in the field of skin tissue engineering focuses on improving the skin barrier properties and the structural interaction of the epidermal and dermal equivalent of composite grafts. There are two types of bioengineered skin replacements available: biosynthetic skin substitutes and skin grafts.

Biosynthetic skin substitutes are developed without allogenic cells and consist of a mesh coated with a dermal analogue (bilayer) or an acellular dressing (monolayer). They act as starting points to promote ingrowth of tissue in the wound. The bilayer options also include a removable silicone layer that functions as a protective dressing.

Skin grafts may be categorized as xenografts, autografts, or allografts. A xenograft is derived from a non-human source, usually porcine skin. An autograft is a graft taken from the patient, while an allograft is transplanted from a genetically non-identical individual, often from a cadaver donor. Grafts may be further identified as dermal or epithelial/epidermal (or both) and as cultured or processed. Within these categories, there are several specific options, each with their own benefits and drawbacks [122]. It has been suggested that the properties inherent to skin grafts, such as the presence of hair follicles, may make them a good option to accelerate wound healing [123]. Selection of the best option is dependent on the features of the wound, the goals of treatment, and patient preferences.

GENE THERAPY

Gene therapy has a tremendous potential, but use of the technology in the treatment of pressure injuries is still in its infancy. Gene therapy has been proposed to accelerate wound healing and also to reduce healing complications such as keloid formation or chronic ulceration.

Genetically modified skin grafts have a potential use for treatment of large wounds. Smaller wounds may be amenable to in vivo delivery of genetic material using a variety of approaches including gene injection, gene gun, microseeding, and liposomal gene delivery. The preclinical studies of genetically modified skin grafts are promising, but more tests are necessary to determine the effectiveness of this treatment option [124,125].

NEGATIVE PRESSURE WOUND DEVICES

Negative pressure wound devices provide an environment that resolves edema and hematoma and results in increased local perfusion. Newer negative pressure wound devices are smaller and more portable than earlier devices, and some deliver continuous subatmospheric pressure to the wound bed to promote healing. It should be noted that these devices have been associated with extensive bleeding, particularly in patients with blood vessel grafts in the leg, with breastbone or groin wounds, or who are receiving anticoagulant therapy [126]. Hemorrhage may also occur when dressings attached to the tissues are removed.

GROWTH FACTORS AND BIOLOGIC WOUND PRODUCTS

Biologic wound products accelerate healing by augmentation or modulation of inflammatory mediators. Growth factors that hold great promise in wound healing include eicosanoids, prostaglandin E1, cytokines, and interleukin-1.

OTHER TREATMENT MODALITIES

Lasers may also accelerate the process of tissue repairing [127]. The lasers appear to simulate fibroblastic activity, although the mechanism is not yet fully understood.

Nanoparticles containing chitosan have been shown to have effective antimicrobial activity against Staphylococcus saprophyticus and Escherichia coli [127]. These materials could be used to prevent infection and facilitate wound healing.

Researchers have shown that a novel peptide (UN3) created by the combination of two naturally occurring peptides found in platelet-rich plasma stimulates wound vascularization and promotes epithelial proliferation. This could lead to new treatments for pressure injuries [128]. The use of novel peptides derived from platelet-derived growth factor (PDGF-BB) also shows promise for wound healing and treatment [129]. PDGF stimulates bone cell replication and DNA synthesis.

Electrical stimulation may also accelerate healing in pressure injuries, but its effect on time to complete healing is uncertain compared with no electrical stimulation [130,131]. Free radical scavengers and special drug delivery systems can also be effective in prevention of injuries [132,133,134].

13. MEDICO-LEGAL ASPECTS OF INJURY CARE

Pressure injuries are the second most common medicolegal claim after wrongful death, resulting in more than 17,000 lawsuits annually in the United States [135]. Results of a retrospective study published in 2019 examined 141 cases related to pressure injuries over a 32-year period from 1987 to 2019 [136]. Of the 141 cases, 75.9% were for negligence and 22.7% were for malpractice. Hospitals were listed as the defendant 61.7% of the time, nursing homes 31.2% of the time, and individual providers 7.1% of the time. Hospitals lost 63% of the cases brought against them, nursing homes lost 75%, and individual providers lost 20%. Hospitals paid out approximately $1.6 million to plaintiffs, nursing homes $4 million, and individual providers an average of $400,000 [136].

As litigation is becoming more common, adherence to established standards of care is very important and has legal implications [137]. Some experts have suggested that if institutional neglect is responsible for development of pressure injuries, caregivers could be liable to criminal prosecution.

AVOIDABLE VERSUS UNAVOIDABLE INJURIES

Federal law establishes standards for long-term care facilities [138]. Based on the comprehensive assessment of a resident, the facility must ensure that 1) a resident who enters the facility without pressure sores does not develop pressure sores unless the individual's clinical condition demonstrates that they were unavoidable; and 2) a resident having pressure sores receives necessary treatment and services to promote healing, prevent infection, and prevent new sores from developing.

As noted, despite best patient care and treatment, not all pressure injuries are avoidable [139]. In long-term care, the NPIAP defines an unavoidable injury as one that occurs even though "the facility had evaluated the individual's clinical condition and pressure injury risk factors; defined and implemented interventions that are consistent with individual needs, goals, and recognized standards of practice; monitored and evaluated the impact of the interventions; and revised the approaches as appropriate" [140]. In addition to establishing the definition for long-term care facilities, in 2014 the NPIAP sought to establish consensus (80% agreement among conference delegates) on whether pressure injury development may be unavoidable in some individuals and whether there is a difference between pressure injuries and end-of-life skin changes. Unanimous consensus was reached for the following statements [141]:

- Most (but not all) pressure injuries are avoidable.

- Comorbid conditions can contribute to unavoidable pressure injuries.

- Some situations render pressure injury development unavoidable, including:

- Hemodynamic instability worsened by physical movement

- Poor nutrition/hydration status and/or advanced directive that prohibits artificial nutrition/hydration

- Pressure redistribution surfaces cannot replace turning/repositioning

- Skin cannot always survive even when pressure from external body skin is alleviated

In light of the significant changes to pressure injury prevention in acute care hospitals brought about by the COVID-19 pandemic, the NPIAP additionally published position statements on pressure injuries that develop during COVID-19 crisis situations in these healthcare settings [141].

Facilities should institute adequate measures to prevent wounds, and in the case an injury develops, staff should respond appropriately to prevent worsening of the wound. Wounds detected in the early stages have a greater chance of cure than later stage wounds that are infected or necrotic. Therefore, regular assessment and early intervention are required for all injuries, avoidable or not. The presence of risk factors, including comorbidities, inability to maintain adequate nutrition and hydration status (e.g., if an advance directive prohibits artificial feeding), certain drugs, and immobility, is an indicator of avoidability. After assessment of risk factors, the next step is to ascertain if the response was timely according to documentation of all interventions. If any skin ulceration develops in spite of timely, appropriate interventions, the injury may be considered unavoidable.

DETERMINATION OF NEGLECT

Suspicion that improper medical care resulting in the development and/or worsening of a pressure injury requires a full, document-intensive investigation. Because many factors can be indicative of medical neglect, each domain of care should be assessed (Table 8). Furthermore, the best defense against a claim of neglect is complete documentation of appropriate care.

Table 8: FACTORS LEADING TO A DETERMINATION OF NEGLECT

Inadequate prevention

Poor documentation

Inadequate nutrition

Inadequate medical care

No family notification

Poor care planning

Wound severity and outcome

Source: Compiled by Author

New or worsening pressure injuries are generally due to poor administrative organization, understaffing, and poor training. The medico-legal implications of proper care cannot be overlooked, as those injuries are responsible for a significant proportion of healthcare litigation.

Medical Record

The medical chart should be examined to determine the level of care planning, assessment, and interventions. Wound neglect is usually associated with improper treatment, inadequate nutrition, and/or poor survey results.

Family diaries, stage surveys, in-service records, complaint files, minutes of quality assurance meetings, and photographs can also be helpful for identification of deviations from standard injury care.

Wound Documentation

Documentation of pressure injury care must be timely and detailed. Regular and consistent descriptions of the injury should be documented, as should responses to treatment. Improper, irregular, or "late entries" are absolutely impermissible and unacceptable.

In patients with multiple injuries, progression of each wound should be documented and tracked. With the growing awareness of the possibility of litigation in wound care, many facilities have instigated a policy of photo documentation. Wounds present on admission are photographed, and some facilities require serial photographs to track wound progress and status at the time of discharge. Signed consent is required before wound photographs can be taken, and in most instances, the photographs become a permanent part of the patient's medical record.

Nutritional Assessments

It has been found that 30% to 85% of nursing home residents are malnourished and 30% to 50% are considered underweight [112]. Pressure injury treatment requires proper nutritional assessment and intervention during every stage. Weight loss, lab results, protein consumption, and vitamin levels should be documented, as should attempts to address abnormalities. If tube feeding is indicated, it should be discussed with the family prior to initiation.

Treatment Records

Treatment administration records should be examined to ensure that treatments were carried out per orders. Documentation should also include staffing records and time-sheets. Dates and times should always be included.

Minimum Data Sets and Care Plans

Minimum data sets are required for all residents of skilled nursing facilities. Improper and inaccurate entries in the minimum data sets indicate a facility with under-staffing and disorganized structure providing poor treatment to the resident. Scrutiny of this document can lead to litigation.

14. EDUCATING PATIENTS

A vital component of any pressure injury program is patient/family education, with an overall goal of decreasing the incidence of injury development or recurrence. If possible, pressure injury prevention should not be a passive process for the patient and his/her family members. Rather, it should be a dialogue in which the patient and family feel comfortable asking questions and discussing problems. Patients should have as much control as possible in the plan of care. Empowerment is very important in maintaining the patient's physical and emotional well-being, and the plan of care should be explained thoroughly to cognitively aware patients and/or their family. It is important for everyone involved to appreciate that the prevention of pressure injury formation is a lifelong process [142].

At the same time, it is necessary to evaluate the patient's/family's existing knowledge regarding pressure and pressure injuries. Healthcare professionals should show patients what they can do to facilitate pressure relief (e.g., how to make small position changes while in the chair). If possible, teach patients how to do simple range-of-motion exercises. Take time to train the patient as often as is appropriate; not everyone will absorb the information the first time they hear it [4]. It is important not to let noncompliance or a bad attitude from the patient or family discourage the teaching process. The subject should be approached as often as is reasonable. Include the family members and caregivers in the instructions; as well as assisting with care, they can encourage compliance. All efforts at patient and family/caregiver education should be documented, along with the patient's response (both verbal and behavioral).

Different methods of teaching, such as photographs, videos, charts, diagrams, and written materials in the patient's native language, should be used. Education should be reinforced regularly and consistently [143]. The information provided to patients and/or their families should be specific to the individual treatment plan and goals.

Patient education programs should include all of the following areas:

- Etiology of pressure injuries

- Reduction of risk

- Reduction of friction and shear

- Skin protection and inspection

- Importance of nutrition

- Proper and safe cleansing procedures and agents

- Procedure for recurrence(s)

- Management approaches

- Proper dressing change procedure

PATHOGENESIS OF PRESSURE INJURIES

Patients should be provided information about factors involved in pressure injury development. The role of pressure, friction, shear, and moisture in the development of injuries should be explained. Other conditions that can impact pressure injury development should be outlined, including:

- Immobility (partial or total)

- Excessive moisture and/or incontinence

- Poor local or systemic circulation

- Uncontrolled diabetes

- Severe trauma

- Dehydration

- Hypoxia

- Malnutrition

- Sepsis

- Previous history of pressure injury

REDUCTION OF RISK

Pressure reduction techniques should be thoroughly explained. Proper use of mattresses, cushions, and overlays and the placement of pillows, heel protectors, and wedges are essential. The role of repositioning and turning of the patient should be stressed. If the patient will be sitting in a chair for a long period of time, pressure release tactics should be included. Repositioning should be done every one to two hours, depending on the patient's condition [49].

REDUCTION OF FRICTION AND SHEAR

Patients and/or caregivers should have a clear understanding of measures to decrease friction and shear. Education should include the proper body alignments that should be maintained when sitting in a chair or lying on a bed. The importance of using lifting devices for repositioning or transferring should be stressed.

SKIN INSPECTION AND PROTECTION

Careful skin inspection is paramount in the care of pressure injuries. The patient or caregiver should carefully inspect the skin for new openings or breaks in the skin at every repositioning. Any discoloration or redness of the skin that does not resolve within 30 minutes after changing position should be reported.

Maintaining skin cleanliness and moisturizing frequently can protect skin integrity. The skin should be cleaned with water and a gentle soap, preferably a pH-balanced cleanser. Alkaline products remove skin lipids, which increases water loss and weakens the barrier function of the skin [2]. Avoid hot water for bathing and scrubbing or using harsh cleaning agents. A soft cloth should be used to pat rather than rub the skin dry. Thromboembolic deterrent hose should be removed when bathing, and the nurse or physician should be notified of any redness, discoloration, or skin breakdown.

It is important to individualize the frequency of skin cleansing based on the patient's age, skin texture, and dryness or excessive oiliness of the skin. A daily bath may not be needed for all patients.

The epidermis is about 30% water, but through a process called trans-epidermal water loss, skin can lose its natural moisture. Without sufficient moisture, skin can become dry, brittle, and vulnerable to breakdown [10]. Therefore, products should be used to keep the skin supple. Emollients, such as mineral oil, petrolatum, and lanolin, penetrate into the stratum corneum to increase the lipid component and add softness to the skin. The oil film on the skin surface also prevents water loss and helps to rehydrate the stratum corneum [10]. Moisture barriers such as dimethicone can prevent water loss and help to retain lipids and water within the skin cells [10].

Humectants, such as glycerin, urea, and lactic acid, increase the water content of the stratum corneum by pulling water from the environment. All moisturizers should be applied to clean, slightly moist skin. Special attention should be paid to bony prominences, heels, ears, and the back of the head.

NUTRITION

Adequate nutrition is an essential area of patient education, as malnutrition makes individuals susceptible to the development of pressure injuries and at increased risk for infections, including sepsis, necrotizing fasciitis, and gangrene. Patients must also understand that adequate hydration is essential to improve tissue perfusion and excreting waste products. Patients/caregivers should make sure they comply with dietitian recommendations for diet, adequate fluid intake, and nutritional supplements.

PROCEDURE FOR RECURRENCES

Patients should be advised to take the following actions should a pressure injury develop:

- Increase the frequency of repositioning and turning.

- Note the size, location, odor, color, and drainage of the wound and adjacent tissue.

- Notify the physician immediately about this new development.

- If the patient is receiving home care services, the home health nurse should be notified immediately.

MANAGEMENT OF PRESSURE INJURY

After a treatment plan is set, all aspects should be explained to the patient or caregiver again. Key education points include:

- Products being used for wound prevention or healing

- Where to procure dressings and pressure redistribution surfaces

- Signs and symptoms of pressure injury deterioration

- The importance of compliance to the established plan

Patients should be advised to look for new necrotic tissue in the wound bed, wound drainage with odor, and erythema and induration around the injury. If a clean wound enlarges or becomes deeper, the patient should be instructed to contact his or her physician immediately.

PROPER DRESSING CHANGE PROCEDURE

Proper dressing change technique should be demonstrated. The patient/caregiver should be able to change the dressing without any assistance from the supporting staff, and clean technique should be used. Hand washing, use of gloves, and infection prevention should all be a part of basic patient education.

15. CONCLUSION

Pressure injuries are a common but preventable condition frequently seen in elderly individuals and those with comorbid conditions. In the United States, the incidence of pressure injuries in critical care patients ranges from 12% to 33%, depending on treatment setting [2].

Pressure injuries are a major psychologic, physical, and social burden to patients and often result in significantly decreased quality of life. In addition, they are a major source of healthcare expenditures. The healthcare costs related to the care of patients with pressure injuries exceeds $11 billion annually in the United States [9].

Evolution of pressure injuries is multifactorial, and individuals with specific risk factors are more susceptible to injury development. Without proper care and treatment, superficial injuries progress to more serious deep tissue wounds, often with life-threatening complications. Satisfactory resolution of a well-established pressure injury is difficult, time-consuming, and costly; it is far better to prevent the injury in the first place. An interdisciplinary approach of creating a care plan that includes steps for the prevention of injuries is the best practice.

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141. NPIAP. Unavoidable Pressure Injury During COVID-19 Pandemic: A Position Paper from the National Pressure Injury Advisory Panel. Available at https://cdn.ymaws.com/npiap.com/resource/resmgr/white_papers/Unavoidable_in_COVID_Pandemi.pdf. Last accessed April 20, 2025.

142. Relander M, Palmer B. Recurrence of surgically treated pressure sores. Scand J Plast Reconstr Surg Hand Surg. 1988;22(1):89-92.

143. Oot-Giromini B, Bidwell FC, Heller NB, Parks ML, Wicks P, Williams PM. Evolution of skin care: pressure ulcer prevalence rates pre/post intervention. Decubitus. 1989;2(2):54-55.

Evidence-Based Practice Recommendations Citations

1. National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel, Pan Pacific Pressure Injury Alliance. Prevention and Treatment of Pressure Ulcers: Clinical Practice Guideline. 3rd ed. Washington, DC: National Pressure Ulcer Advisory Panel; 2019. Available at https://static1.squarespace.com/static/6479484083027f25a6246fcb/t/6553d3440e18d57a550c4e7e/1699992399539/CPG2019edition-digital-Nov2023version.pdf. Last accessed April 28, 2025.

2. National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel, Pan Pacific Pressure Injury Alliance. Prevention and Treatment of Pressure Ulcers: Clinical Practice Guideline. 4th ed. Washington, DC: National Pressure Ulcer Advisory Panel; 2025. Available at https://internationalguideline.com/the-international-guideline. Last accessed April 28, 2025.

97924 • Domestic Violence: The Florida Requirement

Marjorie Conner Allen, BSN, JD

Alice Yick Flanagan, PhD, MSW

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

Domestic violence continues to be a prevalent problem in the United States today. Because of the number of individuals affected, it is likely that most healthcare professionals will encounter patients in their practice who are victims. Accordingly, it is essential that healthcare professionals are taught to recognize and accurately interpret behaviors associated with domestic violence. It is incumbent upon the healthcare professional to establish and implement protocols for early identification of domestic violence victims and their abusers. In order to prevent domestic violence and promote the well-being of their patients, healthcare professionals in all settings must take the initiative to properly assess all women for abuse during each visit and, for those women who are or may be victims, to offer education, counseling, and referral information.

Table of Contents

97924 • Domestic Violence: The Florida Requirement

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Individual State Behavioral Health 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. DEFINING DOMESTIC VIOLENCE

3. NATIONAL AND STATE STATISTICS AND LEGISLATION

FLORIDA

4. IDENTIFYING GROUPS AT RISK FOR DOMESTIC VIOLENCE

PREGNANT WOMEN

CHILDREN

ELDERLY

MEN

LESBIAN, GAY, BISEXUAL, TRANSGENDER, AND QUEER/QUESTIONING VICTIMS

5. CHARACTERISTICS OF PERPETRATORS OF DOMESTIC VIOLENCE

6. SCREENING FOR DOMESTIC VIOLENCE AND ABUSE

7. ASSESSING DOMESTIC VIOLENCE AND ABUSE

CULTURALLY SENSITIVE ASSESSMENT

8. INTERVENTIONS FOR DOMESTIC VIOLENCE AND ABUSE

9. DOCUMENTATION AND FOLLOW-UP

Works Cited

Evidence-Based Practice Recommendations Citations

97924 • Domestic Violence: The Florida Requirement

Education Category. Ethics - Human Rights

Release Date. 08/01/2026

Expiration Date. 07/31/2029

Course Overview

Domestic violence continues to be a prevalent problem in the United States today. Because of the number of individuals affected, it is likely that most healthcare professionals will encounter patients in their practice who are victims. Accordingly, it is essential that healthcare professionals are taught to recognize and accurately interpret behaviors associated with domestic violence. It is incumbent upon the healthcare professional to establish and implement protocols for early identification of domestic violence victims and their abusers. In order to prevent domestic violence and promote the well-being of their patients, healthcare professionals in all settings must take the initiative to properly assess all women for abuse during each visit and, for those women who are or may be victims, to offer education, counseling, and referral information.

Audience

This course is designed for all Florida healthcare professionals required to complete domestic violence education.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE has been approved by NBCC as an Approved Continuing Education Provider, ACEP No. 6361. Programs that do not qualify for NBCC credit are clearly identified. NetCE is solely responsible for all aspects of the programs. NetCE is approved to offer continuing education through the Florida Board of Nursing Home Administrators, Provider #50-2405. As a Jointly Accredited Organization, NetCE is approved to offer social work continuing education by the Association of Social Work Boards (ASWB) Approved Continuing Education (ACE) program. Organizations, not individual courses, are approved under this program. Regulatory boards are the final authority on courses accepted for continuing education credit. Continuing Education (CE) credits for psychologists are provided through the co-sponsorship of the American Psychological Association (APA) Office of Continuing Education in Psychology (CEP). The APA CEP Office maintains responsibility for the content of the programs. 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 recognized by the New York State Education Department's State Board for Social Work as an approved provider of continuing education for licensed social workers #SW-0033. This course is considered self-study, as defined by the New York State Board for Social Work. NetCE is recognized by the New York State Education Department's State Board for Mental Health Practitioners as an approved provider of continuing education for licensed mental health counselors #MHC-0021. This course is considered self-study by the New York State Board of Mental Health Counseling. NetCE is recognized by the New York State Education Department's State Board for Mental Health Practitioners as an approved provider of continuing education for licensed marriage and family therapists. #MFT-0015.This course is considered self-study by the New York State Board of Marriage and Family Therapy. Materials that are included in this course may include interventions and modalities that are beyond the authorized practice of licensed master social work and licensed clinical social work in New York. As a licensed professional, you are responsible for reviewing the scope of practice, including activities that are defined in law as beyond the boundaries of practice for an LMSW and LCSW. A licensee who practices beyond the authorized scope of practice could be charged with unprofessional conduct under the Education Law and Regents Rules.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 2 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 2 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 2 ANCC contact hour(s). NetCE designates this continuing education activity for 2.4 hours for Alabama nurses. NetCE designates this continuing education activity for 1 NBCC clock hour(s). Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 2 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. Social workers participating in this intermediate to advanced course will receive 2 Clinical continuing education clock hours. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. 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 2 MOC points in the American Board of Pediatrics' (ABP) Maintenance of Certification (MOC) program. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABP MOC credit. This activity has been designated for 2 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 2 credit hour(s). NetCE is authorized by IACET to offer 0.2 CEU(s) for this program. AACN Synergy CERP Category B. NetCE designates this continuing education activity for 2 credit(s).

Individual State Nursing Approvals

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

Individual State Behavioral Health Approvals

In addition to states that accept ASWB, NetCE is approved as a provider of continuing education by the following state boards: Alabama State Board of Social Work Examiners, Provider #0515; Florida Board of Clinical Social Work, Marriage and Family Therapy and Mental Health Counseling, CE Broker Provider #50-2405; Illinois Division of Professional Regulation for Social Workers, License #159.001094; Illinois Division of Professional Regulation for Licensed Professional and Clinical Counselors, License #197.000185; Illinois Division of Professional Regulation for Marriage and Family Therapists, License #168.000190;

Special Approvals

This course fulfills the Florida requirement for 2 hours of Domestic Violence education every third renewal period. 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 enable healthcare professionals in all practice settings to define domestic violence and identify those who are affected by domestic violence in the United States. This course describes how a victim can be accurately diagnosed and identifies the community resources available in the state of Florida for domestic violence victims.

Learning Objectives

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

1. Define domestic violence and its impact on health care.

2. Cite the general prevalence of domestic violence on a national and state level and identify state laws pertaining to the issue.

3. Describe how to screen and assess individuals who may be victims or perpetrators of domestic violence, including the importance of conducting a culturally sensitive assessment.

4. Identify community resources presently available for domestic violence victims and their perpetrators throughout Florida concerning legal aid, shelter, victim and batterer counseling, and child protection services.

Faculty

Marjorie Conner Allen, BSN, JD, received her Bachelor of Science in Nursing degree from the University of Florida, Gainesville, in 1984. She began her nursing career at Shands Teaching Hospital and Clinics at the University of Florida, Gainesville. While practicing nursing at Shands, she gave continuing education seminars regarding the nursing implications for dealing with adolescents with terminal illness. In 1988, Ms. Allen moved to Atlanta, Georgia where she worked at Egleston Children’s Hospital at Emory University in the bone marrow transplant unit. In the fall of 1989, she began law school at Florida State University. After graduating from law school in 1992, Ms. Allen took a two-year job as law clerk to the Honorable William Terrell Hodges, United States District Judge for the Middle District of Florida. After completing her clerkship, Ms. Allen began her employment with the law firm of Smith, Hulsey & Busey in Jacksonville, Florida where she has worked in the litigation department defending hospitals and nurses in medical malpractice actions. Ms. Allen resides in Jacksonville and is currently in-house counsel to the Mayo Clinic Jacksonville.

Alice Yick Flanagan, PhD, MSW, received her Master’s in Social Work from Columbia University, School of Social Work. She has clinical experience in mental health in correctional settings, psychiatric hospitals, and community health centers. In 1997, she received her PhD from UCLA, School of Public Policy and Social Research. Dr. Yick Flanagan completed a year-long post-doctoral fellowship at Hunter College, School of Social Work in 1999. In that year she taught the course Research Methods and Violence Against Women to Masters degree students, as well as conducting qualitative research studies on death and dying in Chinese American families.

Previously acting as a faculty member at Capella University and Northcentral University, Dr. Yick Flanagan is currently a contributing faculty member at Walden University, School of Social Work, and a dissertation chair at Grand Canyon University, College of Doctoral Studies, working with Industrial Organizational Psychology doctoral students. She also serves as a consultant/subject matter expert for the New York City Board of Education and publishing companies for online curriculum development, developing practice MCAT questions in the area of psychology and sociology. Her research focus is on the area of culture and mental health in ethnic minority communities.

Faculty Disclosure

Contributing faculty, Marjorie Conner Allen, BSN, JD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Contributing faculty, Alice Yick Flanagan, PhD, MSW, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Mary Franks, MSN, APRN, FNP-C

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

Domestic violence continues to be a prevalent problem in the United States today. Because of the number of individuals affected, it is likely that most healthcare professionals will encounter patients in their practice who are victims. Accordingly, it is essential that healthcare professionals are taught to recognize and accurately interpret behaviors associated with domestic violence. It is incumbent upon the healthcare professional to establish and implement protocols for early identification of domestic violence victims and their abusers. In order to prevent domestic violence and promote the well-being of their patients, healthcare professionals in all settings should take the initiative to properly assess all women for abuse during each visit and, for those women who are or may be victims, to offer education, counseling, and referral information.

Victims of domestic violence suffer emotional, psychologic, and physical abuse, all of which can result in both acute and chronic signs and symptoms of physical and mental disease, illness, and injury. Frequently, the injuries sustained require abused victims to seek care from healthcare professionals immediately after their victimization. Subsequently, physicians and nurses are often the first healthcare providers that victims encounter and are in a critical position to identify domestic violence victims in a variety of clinical practice settings where victims receive care. Accordingly, each healthcare professional should educate himself or herself to enhance awareness of the presence of abuse victims in his or her particular practice or clinical setting.

Specifically, healthcare professionals should be aware of the signs and symptoms associated with domestic violence. In addition, when family violence cases are identified, there should be a plan of action that includes providing information on, and referral to, local community resources related to legal aid, sheltering, victim counseling, batterer counseling, advocacy groups, and child protection.

2. DEFINING DOMESTIC VIOLENCE

Domestic violence, which is sometimes also referred to as spousal abuse, battering, or intimate partner violence (IPV), refers to the victimization of an individual with whom the abuser has or has had an intimate or romantic relationship. Researchers in the field of domestic violence have not agreed on a uniform definition of what constitutes violence or an abusive relationship. The Centers for Disease Control and Prevention (CDC) defines IPV as, "abuse or aggression that occurs in a romantic relationship" [1]. According to the Florida Department of Children and Families, domestic violence is "a pattern of abusive behaviors that adults use to maintain power and control over their intimate partners or former partners. People who abuse their partners use a variety of tactics to coerce, intimidate, threaten, and frighten their victims" [2]. Domestic violence may include physical violence, sexual violence, emotional abuse, economic abuse, isolation, pet abuse, threats relating to children, and a variety of other behaviors meant to increase fear, intimidation, and power over the victim [2]. Florida law defines domestic violence as "any assault, aggravated assault, battery, aggravated battery, sexual assault, sexual battery, stalking, aggravated stalking, kidnapping, false imprisonment, or any criminal offense resulting in physical injury or death of one family or household member by another family or household member" [3]. Family or household members, according to Florida definition, must "be currently residing or have in the past resided together in the same single dwelling unit" [3]. Domestic violence knows no boundaries. It occurs in intimate relationships regardless of race, religion, culture, or socioeconomic status [2].

Whatever the definition, it is important for healthcare professionals to understand that domestic violence, in the form of emotional and psychologic abuse, sexual abuse, and physical violence, is prevalent in our society. Because of the similar nature of the definitions, this course will use the terms "domestic violence" and "IPV" interchangeably.

3. NATIONAL AND STATE STATISTICS AND LEGISLATION

Domestic violence is one of the most serious public health problems in the United States. More than 34.0 % of women and 17% of men have a lifetime history of IPV [4]. In Florida, the weighted lifetime prevalence of IPV (including rape, physical violence, and/or stalking) is 23.8% among women. The weighted lifetime prevalence of IPV among men in Florida is not well documented and not considered statistically stable. However, the national estimated lifetime prevalence of IPV among men is 11.9% [4]. Although many of these incidents consist of pushing, grabbing, shoving, slapping, and hitting, IPV resulted in the death of 11,466 individuals the United States between 2020–2024 (nearly 2,300 victims annually) [5]. The most recent data from Florida indicates approximately 192 IPV-related deaths occurred in Florida in 2021, accounting for nearly 9% of the nation's total annually [5,6]. One of the difficulties in addressing the problem is that abuse is prevalent in all demographics, regardless of age, ethnicity, race, religious denomination, education, or socioeconomic status [2].

Victims of abuse often suffer severe physical injuries and will likely seek care at a hospital or clinic. The health and economic consequences of domestic violence are significant, although difficult to accurately capture due to the vast number of variables associated with IPV. To first address the true economic burden of IPV, the U.S. Congress funded the CDC to conduct a study, which resulted in the 2003 CDC report Costs of Intimate Partner Violence Against Women in the United States [7]. The report relied on data from the National Violence Against Women Survey conducted in 1995 and estimated the costs of IPV by measuring how many female victims were nonfatally injured; how many women used medical and mental healthcare services; and how many women lost time from paid work and household chores. The estimated total annual cost of IPV against women in the 1995 survey was more than $5.8 billion [7]. However, there were several limitations to this study, and subsequent cost estimates were often based on this data, underestimating the true economic burden of domestic violence.

In 2018, an updated study that aimed to determine the lifetime economic burden of IPV per individual was published. This study used the 2012 U.S. National Intimate Partner and Sexual Violence Survey data and previous studies in a mathematical model. Costs included those attributable to impaired health, lost productivity, and criminal justice costs [8]. Analysis (conducted in 2017) found that the estimated IPV lifetime cost was $103,767 per female victim and $23,414 per male victim. Based on a reported 43 million U.S. adults with a history of IPV, the population economic burden equates to nearly $3.6 trillion (2014 US$) over the victims' lifetimes, including [8]:

- $2.1 trillion (59% of total) in medical costs

- $1.3 trillion (37%) in lost productivity among victims and perpetrators

- $73 billion (2%) in criminal justice activities

- $62 billion (2%) in other costs, including victim property loss or damage

It is estimated that government sources pay an estimated $1.3 trillion (37%) of the lifetime economic burden [4,8].

The national rate of nonfatal domestic violence against women declined 72% between 1993 and 2011 and continues to decline [9]. The rate of overall violent crime fell by nearly 60% in this same time period [9]. Studies reveal that several factors may have contributed to the reduction in violence, including a decline in the marriage rate and decrease of domesticity, better access to federally funded domestic violence shelters, improvements in women's economic status, and demographic trends, such as the aging of the population [10,11]. Of note, declines in the economy and stress associated with financial hardship and unemployment are significant contributors to IPV in the United States. Following the economic downturn in late 2008, there was a significant increase in the use of the National Domestic Violence Hotline in 2009, with more than half of victims reporting a change in household financial situation in the last year [12]. This trend continued with the COVID-19 pandemic, with stressors from lockdown orders, unemployment, financial insecurity, childcare and homeschool responsibilities, and poor coping strategies (e.g., substance abuse) increasing the rate of domestic violence. Reports showed a 9.7% increase in domestic violence calls for service in the first two months state-mandated lockdowns were imposed; furthermore, the National Commission on COVID-19 and Criminal Justice reported an increase of 8.1% in domestic violence incidents within the first months of mandated stay-at-home orders [10].

FLORIDA

In response to troubling domestic violence statistics, Governor Lawton Chiles appointed a Task Force on Domestic Violence on September 28, 1993, to investigate the problems associated with domestic violence in Florida and to compile recommendations as to how the problems should be approached and ultimately resolved. On January 31, 1994, the Task Force issued its first report on domestic violence. This report recommended standards to accurately measure the extent of domestic violence and strategies for increasing public awareness and education. It identified programs and resources that are available to victims in Florida, made legislative and budgetary suggestions for needed changes, provided a methodology for implementing these changes, and identified areas of domestic violence that require further study.

As a result of this report, Florida enacted legislation during the 1995 session implementing various suggestions of the Task Force. Specifically, the Legislature amended Section 455.222 of the Florida Statutes to require that all physicians, osteopaths, nurses, dentists, dental hygienists, midwives, psychologists, and psychotherapists obtain, as part of their biennial continuing education requirements, a one-hour continuing education course on domestic violence [14]. In June of 2006, Governor Jeb Bush signed into law House Bill 699. The bill, which went into effect July 1, 2006, changed the domestic violence continuing education requirement from one hour every renewal period to two hours every third renewal period.

In 1997, at the request of the Governor's Task Force, a workgroup was established by the Florida Department of Law Enforcement (FDLE) to evaluate the feasibility of tracking incidents of domestic violence in the state [15]. This resulted in the creation of the Domestic Violence Data Resource Center (DVDRC). The original mission of the DVDRC was to collect information related to domestic violence and to report and maintain the information in a statewide tracking system [16]. Domestic Violence Fatality Review Teams were established to examine those cases of domestic violence that resulted in a fatality and identify potential changes in policy or procedure that might prevent future deaths. The teams were comprised of representatives from law enforcement, the courts, social services, state attorneys, domestic violence centers, and others who may come into contact with domestic violence victims and perpetrators [17]. In 2000, the creation of Florida Statute 741.316 required the FDLE to annually publish a report based on the data gathered by the Fatality Review Teams [16]. Due to budgetary constraints, responsibility of compiling this data transferred to the Department of Children and Families in 2008 [18].

As part of Governor Jeb Bush's initiative, the "Family Protection Act" was signed into law in 2001. The act requires a 5-day mandatory jail term for any crime of domestic battery in which the perpetrator deliberately injures the victim. The law also makes a second battery crime a felony offense, treating offenders as serious criminals. Additional legislation, signed into law in 2002, includes Senate Bills 716 and 1974. Senate Bill 716 protects domestic violence victims by including dating relationships of six months in the definition of domestic violence laws. Senate Bill 1974 requires judges to inform victims of their rights, including the right to appear, be notified, seek restitution, and make a victim-impact statement. Governor Bush also created the Violence Free Florida campaign to increase public awareness of domestic violence issues [19].

In 2003, Governor Bush signed House Bill 1099, which transferred funding authority of the Florida Domestic Violence Trust Fund from the Department of Children and Families to the Florida Coalition Against Domestic Violence. According to the Domestic Violence in Florida 2010–2011 Annual Report to the Legislature, this has strengthened domestic violence services provided by streamlining the process of allocating funds [20].

In 2007, the Domestic Violence Leave Act was signed into law by Governor Charlie Crist [18]. This law requires employers with 50 or more employees to provide guaranteed leave for domestic violence issues.

In 2021, the FDLE reported 103,915 domestic violence offenses [6]. An estimated 19.1% of domestic violence incidents involved spouses and 28.3% involved cohabitants. Domestic violence offenses resulted in the death of 192 victims in Florida in 2021, a number that has been decreasing since 2014 [6]. Domestic violence accounted for 16.9% of the state's murders in 2020 [6].

In their 2026 Annual Report, Fatality Review Teams summarized 20 cases of domestic violence fatalities and near fatalities [21]. The most significant findings included the following observations [21]:

- The perpetrators were predominantly male (90%) with female victims (85%). Approximately 40% had prior domestic violence-related criminal histories, and 55% had non-domestic-violence-related criminal histories.

- In 35% of fatalities, the perpetrators had a known "do not contact" order filed against them, and 25% of perpetrators had a known permanent injunction for protection against them filed by someone other than the victim.

- History of substance abuse by the perpetrator was identified in 50% of the cases and diagnosed mental health disorders in 30%.

- In most cases, neither the decedent nor perpetrator sought help from the various intervention programs available to them.

4. IDENTIFYING GROUPS AT RISK FOR DOMESTIC VIOLENCE

Healthcare professionals are in a critical position to identify domestic violence victims in a variety of clinical practice settings. Nurses are often the first healthcare provider a victim of domestic violence will encounter in a healthcare setting and should therefore be prepared to provide care and support for these victims. Although women are most often the victims, domestic violence extends to others in the household as well. For example, domestic violence includes abused men, children abused by their parents or parents abused by their children, elder abuse, and abuse among siblings [3].

Many victims of abuse sustain injuries that lead them to present to hospital emergency departments. Research has found that up to 14% of female patients admitted to the emergency department are treated for IPV-related conditions, between 5% and 38% of women report IPV violence in the past year, and an estimated 40% of women seen in emergency departments reported a history of abuse in their lifetime [22]. These statistics demonstrate that healthcare professionals who work in acute care, such as hospital emergency rooms, should maintain a high index of suspicion for battering of the patients that they see. Healthcare professionals who work in these settings should work with hospital administrators to establish and institute assessment mechanisms to accurately detect these victims.

For every victim of abuse, there is also a perpetrator. Like their victims, perpetrators of domestic violence come from all socioeconomic backgrounds, races, religions, and walks of life [1,4]. Accordingly, healthcare professionals should likewise be aware that seemingly supportive family members may, in fact, be abusers.

PREGNANT WOMEN

Because a gynecologist or obstetrician is frequently a woman's primary care physician, the American College of Obstetricians and Gynecologists (ACOG) recommends that all women be routinely assessed for signs of IPV (i.e., physical and psychologic abuse, reproductive coercion, and progressive isolation), including during prenatal visits, and providers should offer support and referral information for those being abused [23]. According to the ACOG, IPV affects as many as 324,000 pregnant women each year [23]. The CDC reports that 6% of women with a recent live birth experienced IPV during pregnancy, with two-thirds of those individuals having experienced IPV before pregnancy [24]. Between 2018 and 2019, the homicide rate was 16% higher among women who were pregnant or one year post-pregnancy, compared with those who were not pregnant. In addition, nearly half (45.3%) of homicides during pregnancy/one-year post-pregnancy were found to involve IPV [24]. As with all domestic violence statistics, these estimates are presumed to be lower than the actual incidence as a result of under-reporting and lack of data on women whose pregnancies ended in fetal or maternal death. This makes IPV more prevalent among pregnant women than some of the health conditions included in prenatal screenings, including pre-eclampsia and gestational diabetes [23]. Because 96% of pregnant women receive prenatal care, this is an optimal time to assess for domestic violence and develop trusting relationships with the women. Possible factors that may predispose pregnant women to IPV include being unmarried, lower socioeconomic status, young maternal age, unintended pregnancy, delayed prenatal care, lack of social support, and use of tobacco, alcohol, or illegal drugs [23,25].

The overarching problem of violence against pregnant women cannot be ignored, especially as both mother and fetus are at risk. At this particularly vulnerable time in a woman's life, an organized clinical construct leading to immediate diagnosis and medical intervention will ensure that therapeutic opportunities are available to the pregnant woman and will reduce the potential negative outcomes [26]. Healthcare professionals should also be aware of the possible psychologic consequences of abuse during pregnancy. There is a higher risk of stress, depression, and addiction to alcohol and drugs in abused women. These conditions may result in damage to the fetus from tobacco, drugs, and alcohol and a loss of interest on the part of the mother in her or her baby's health [27,28]. Possible direct injuries to the fetus may result from maternal trauma [23].

Control of reproductive or sexual health is also a recognized trend in IPV. This type of abuse includes trying to impregnate or become pregnant against a partner's wishes, refusal to use birth control (e.g., condoms, oral contraceptives), or stopping a partner from using birth control [4].

CHILDREN

Children exposed to family violence are at high risk for abuse and for emotional damage that may affect them as they grow older. The Department of Justice estimates that of the 76 million children in the United States, 46 million will be exposed to some type of violence during their childhood [29]. Results of the National Survey of Children's Exposure to Violence indicated that 11% of children were exposed to IPV at home within the last year, and as many as 26% of children were exposed to at least one form of family violence during their lifetimes [30]. Of those children exposed to IPV, 90% were direct eyewitnesses of the violence; the remaining children were exposed by either hearing the violence or seeing or being told about injuries [30]. Of note, according to Florida criminal law, witnessing domestic violence is defined as "violence in the presence of a child if an offender is convicted of a primary offense of domestic violence, and that offense was committed in the presence of a child under age 16 who is a family or household member with the victim or perpetrator" [31].

A number of studies indicate that child witnesses are at increased risk for post-traumatic stress disorder, impaired development, aggressive behavior, anxiety, difficulties with peers, substance abuse, and academic problems than the average child [32,33,34]. Children exposed to violence may also be more prone to dating violence (as a perpetrator or a victim), and the ability to effectively cope with partnerships and parenting later in life may be affected, continuing the cycle of violence into the next generation [35,36].

In addition to witnessing violence, various studies have shown that these children may also become direct victims of violence, and children who both witness and experience violence are at the greatest risk for adverse psychosocial outcomes [37]. Research indicates that in 30% and 65% of families in which domestic violence is identified, some form of co-occurring child maltreatment is also present [38,39]. Moreover, victims of abuse will often turn on their children; statistics demonstrate that 85% of domestic violence victims abuse or neglect their children. The 2021 Crime in Florida report found that more than 19% of domestic homicide victims were children killed by a parent [6]. Adolescents are also victims of IPV, with an estimated 7.1% of females and 3.7% of males in the United States experiencing first IPV victimization before 18 years of age [40]. Globally, 24% of adolescent girls will have experienced physical and/or sexual intimate partner violence by the time they are 20 years of age [41]. Using data from 2003–2016, it was found that 6.9% of all homicides among individuals 11 to 18 years of age in the United States were classified as intimate partner-related homicide [42]. Abused teens often do not report abuse. Individuals 12 to 19 years of age report only 35.7% of crimes against them, compared with 54% in older age groups [43]. Accordingly, healthcare professionals who see young children and adolescents in their practice (e.g., pediatricians, family physicians, school nurses, pediatric nurse practitioners, community health nurses) should have the tools necessary to detect these "silent victims" of domestic violence and to intervene quickly to protect young children and adolescents from further abuse. Without such critical intervention, the cycle of violence will never end.

ELDERLY

Abused and neglected elders, who may be mistreated by their spouses, partners, children, or other relatives, are among the most isolated of all victims of family violence. In a national study conducted by the National Institute of Justice in 2010, 4.6% of participants (community dwelling adults 60 years of age or older) were victims of emotional abuse in the past year, 1.6% physical abuse, 0.6% sexual abuse, 5.1% potential neglect, and 5.2% current financial abuse by a family member [44]. A 2017 study found a self-reported incidence of 11.6% psychological abuse, 2.6% physical abuse, 6.8% financial abuse, 4.2% neglect, and 0.9% sexual abuse [45]. The estimated annual incidence of all elder abuse types is 2% to 10%, but it is believed to be severely under-measured. According to one study, only one in 24 cases of elder abuse are reported to the authorities [46].

The prevalence rate of elder abuse in institutional settings is not clear. However, in a 2019 review of nine studies, 64% of elder care facility staff disclosed to having perpetrated abuse against an elderly resident in the past year [47]. In a random sample survey, 24.3% of respondents reported at least one incident of elder physical abuse perpetrated by a nursing home staff member [48].

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for caregiver abuse and neglect in older or vulnerable adults.

https://jamanetwork.com/journals/jama/fullarticle/2835641

Last Accessed: July 24, 2026

Strength of Recommendation: I (Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.)

As healthcare professionals in Florida, which leads the nation in percentage of older residents, it is important to understand that the needs of older Floridians will increase as will the numbers of elder victims of domestic violence. Because elder abuse can occur in family homes, nursing homes, board and care facilities, and even medical facilities, healthcare professionals should remain keenly aware of the potential for abuse. When abuse occurs between elder partners, it is primarily manifested in one of two ways: either as a long-standing pattern of marital violence or as abuse originating in old age. In the latter case, abuse may be precipitated by issues related to advanced age, including the stress that accompanies disability and changing family relationships [46].

It is important to understand that the domestic violence dynamic involves not only a victim but a perpetrator as well. For example, an adult son or daughter who lives in the parents' home and depends on the parents for financial support may be in a position to inflict abuse. This abuse may not always manifest itself as violence but can lead to an environment in which the elder parent is controlled and isolated. The elder may be hesitant to seek help because the abuser's absence from the home may leave the elder without a caregiver [46]. Because these elderly victims are often isolated, dependent, infirm, or mentally impaired, it is easy for the abuse to remain undetected. Healthcare professionals in all settings should remain aware of the potential for abuse and keep a watchful eye on this particularly vulnerable group.

MEN

Statistics confirm that domestic violence is predominantly perpetrated by men against women; however, there is evidence that women also exhibit IPV-related behavior against their male partners [4,49]. Approximately one in six men (20.7 million individuals) in the United States experienced contact sexual violence, physical violence, and/or stalking by an intimate partner during their lifetime, compared with one in three women (nearly 43.5 million) [1,49]. Nearly 56% of first-time victimizations occurred by 25 years of age, with many occurring before 18 years of age. When further examined according to abuse and perpetrator characteristics, it was found that 48% of male victims of lifetime non-contact unwanted sexual experiences reported only male perpetrators and 52% reported female perpetrators. Among male victims of stalking, 46% of male victims were stalked by only female perpetrators and 43% by only male perpetrators [49]. In 2021, it was estimated that 34% of female victims of murder and non-negligent manslaughter were killed by an intimate partner, compared with 6% of males [50]. Although women are more often victims of IPV, healthcare professionals should help remove the stigma and always keep in mind that men can also be victimized and assess accordingly.

LESBIAN, GAY, BISEXUAL, TRANSGENDER, AND QUEER/QUESTIONING VICTIMS

Domestic violence exists in lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ+) communities, and the rates are thought to mirror those of heterosexual women—approximately 25% [51]. However, women living with female intimate partners experience less IPV than women living with men [6]. Conversely, men living with male intimate partners experience more IPV than do men who live with female intimate partners [6]. In addition, 78% of IPV homicide victims reported in 2017 were transgender women or cisgender men [52]. This supports other statistics indicating that IPV is perpetrated primarily by men. A form of abuse specific to the gay community is for an abuser to threaten or to proceed with "outing" a partner to others [51,53].

Transgender individuals appear to be at particular risk for violence. According to a large national report, transgender victims of IPV were 1.9 times more likely to experience physical violence and 3.9 times more likely to experience discrimination than other members of the LGBTQ+ community [52].

In 2017, an annual national report recorded 52 incidences of hate violence-related homicides of LGBTQ+ people, the highest incident number recorded in its 20-year history [52]. This increasing prevalence of anti-LGBTQ+ violence can exacerbate IPV in LGBTQ+ communities. For example, a person who loses their job because of anti-trans bias may be more financially reliant on an unhealthy relationship. An abusive partner may also use the violence that an LGBTQ+ person experiences from their family as a way of isolating that person further [52].

Because of the stigma of being LGBTQ+, victims may be reticent to report abuse and afraid that their sexual orientation or biologic sex will be revealed. In one study, the three major barriers to seeking help were a limited understanding of the problem of LGBTQ+ IPV, stigma, and systemic inequities [53]. Many in this community feel that support services (e.g., shelters, support groups, crisis hotlines) are not available to them due to homophobia of the service providers. Unfortunately, this results in the victim feeling isolated and unsupported. Healthcare professionals should strive to be sensitive and supportive when working with homosexual patients.

5. CHARACTERISTICS OF PERPETRATORS OF DOMESTIC VIOLENCE

Abuser characteristics have been studied far less frequently than victim characteristics. Some studies suggest a correlation between the occurrence of abuse and the consumption of alcohol. An individual who abuses alcohol is also likely to abuse their mate, although the abuser may not necessarily be inebriated at the time the abuse is inflicted [54]. Domestic violence assessment questionnaires should include questions that explore social drinking habits of both victims and their partners.

Other studies demonstrate that abusive mates are generally possessive and jealous. Another characteristic related to the abuser's dependency and jealousy is extreme suspiciousness. This characteristic may be so extreme as to border on paranoia [55]. Domestic violence victims frequently report that abusers are extremely controlling of the everyday activities of the family. This domination is generally all encompassing and often includes maintaining complete control of finances and activities of the victim (e.g., work, school, social interactions) [55].

In addition, abusers often suffer from low self-esteem and their sense of self and identity is directly connected to their partner [55]. Extreme dependence is common in both abusers and those being abused. Due to low self-esteem and self-worth, emotional dependence often occurs in both partners, but even more so in the abuser. Emotional dependence in the victim stems from both physical and psychologic abuse, which results in a negative self-image and lack of self-worth. Financial dependence is also very common, as the abuser often withholds or controls financial resources to maintain power over the victim [1,4].

6. SCREENING FOR DOMESTIC VIOLENCE AND ABUSE

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends that that clinicians screen for intimate partner violence (IPV) in women of reproductive age, including those who are pregnant and postpartum.

https://jamanetwork.com/journals/jama/fullarticle/2835641

Last Accessed: July 24, 2026

Strength of Recommendation: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

There is no universal guideline for identifying and responding to domestic violence, but it is universally accepted that a plan for screening, assessing, and referring patients of suspected abuse should be in place at every healthcare facility. Guidelines should review appropriate interview techniques for a given setting and should also include the utilization of assessment tools. Furthermore, protocols within each facility or healthcare setting should include referral, documentation, and follow-up. This section relies heavily on the guidelines outlined in the Family Violence Prevention Fund's National Consensus Guidelines on Identifying and Responding to Domestic Violence Victimization in Health Care Settings; however, protocols should be customized based on individual practice settings and resources available [39]. The Center for Justice Innovation has provided a compilation of commonly used IPV risk assessment tools and models for the interprofessional team to assist in determining the most appropriate assessment, available at https://dvrisc.org/domestic-violence-homicide-prevention-tools-strategies-assessments [56].

Several barriers to screening for domestic violence have been noted, including a lack of knowledge and training, time constraints, lack of privacy for asking appropriate questions, and the sensitive nature of the subject [39]. Although awareness and assessment for IPV has increased among healthcare providers, many are still hesitant to inquire about abuse [57]. At a minimum, those exhibiting signs of domestic violence should be screened. Although victims of IPV may not display typical signs and symptoms when they present to healthcare providers, there are certain cues that may be attributed to abuse. The obvious cues are physical. Injuries range from bruises, cuts, black eyes, concussions, broken bones, and miscarriages to permanent injuries such as damage to joints, partial loss of hearing or vision, and scars from burns, bites, or knife wounds. Typical injury patterns include contusions or minor lacerations to the head, face, neck, breast, or abdomen, and musculoskeletal injuries. These are often distinguishable from accidental injuries, which are more likely to involve the extremities of the body. Abuse victims are also more likely to have multiple injuries than accident victims. When this pattern of injuries is seen, particularly in combination with evidence of old injury, physical abuse should be suspected [54].

In addition to physical signs and symptoms, domestic violence victims also exhibit psychologic cues that resemble an agitated depression. As a result of prolonged stress, various psychosomatic symptoms that generally lack an organic basis often manifest. For example, complaints of backaches, headaches, and digestive problems are common. Often, there are reports of fatigue, restlessness, insomnia, or loss of appetite. Great amounts of anxiety, guilt, and depression or dysphoria are also typical. Women who experienced IPV are also more likely to report asthma, irritable bowel syndrome, and diabetes [4]. Healthcare professionals should look beyond the typical symptoms of a domestic violence victim and work within their respective practice settings to develop appropriate assessment mechanisms to detect victims who exhibit less obvious symptoms.

The unique relationship dynamics of the abuser and abused are not easily detected under the best of circumstances. They may be especially difficult to uncover in circumstances in which the parties are suspicious and frightened, as might be expected when a victim presents to the emergency department. The key to detection, however, is to establish a proper assessment tool that can be utilized in the particular setting and to maintain a keen awareness for the cues described in this course. Screening for IPV should be carried out at the entry points of contact between victims and medical care (e.g., primary care, emergency services, obstetric and gynecologic services, psychiatric services, and pediatric care) [39].

The key to an initial assessment is to obtain an adequate history. Establishing that a patient's injuries are secondary to abuse is the first task. Clearly, there will be times when a victim is injured so severely that treatment of these injuries becomes the first priority. After such treatment is rendered, however, it is important that healthcare professionals not ignore the reasons that brought the victim to the emergency department [39].

7. ASSESSING DOMESTIC VIOLENCE AND ABUSE

Healthcare providers have reported that even if routine screening and inquiry results in a positive identification of IPV, the next steps of assessing and referring are often difficult, and many feel that they are not adequately prepared [57]. According to the Family Violence Prevention Fund, the goals of the assessment are to create a supportive environment, gather information about health problems associated with the abuse, and assess the immediate and long-term health and safety needs for the patient to develop an intervention [39].

Assessment of domestic violence victims should occur immediately after disclosure of abuse and at any follow-up appointments. Assessing immediate safety is priority. Having a list of questions readily available and well-practiced can help alleviate the uncertainty of how to begin the assessment (Table 1). If the patient is in immediate danger, referral to an advocate, support system, hotline, or shelter is indicated [39].

Table 1: ASSESSMENT OF IMMEDIATE SAFETY FOR DOMESTIC VIOLENCE VICTIMS

Are you in immediate danger?

Is your partner at the health facility now?

Do you want to (or have to) go home with your partner?

Do you have somewhere safe to go?

Have there been threats or direct abuse of the child(ren) (if applicable)?

Are you afraid your life may be in danger?

Has the violence gotten worse or is it getting scarier? Is it happening more often?

Has your partner used weapons, alcohol, or drugs?

Has your partner ever held you or your child(ren) against your will?

Does your partner ever watch you closely, follow you or stalk you?

Has your partner ever threatened to kill you, him/herself or your child(ren)?

Source: [39]

If the patient is not in immediate danger, the assessment may continue with a focus on the impact of IPV on the patient's mental and physical health and the pattern of history and current abuse [39]. These responses will help formulate an appropriate intervention.

CULTURALLY SENSITIVE ASSESSMENT

During the assessment process, a practitioner should be open and sensitive to the patient's worldview, cultural belief systems and how he/she views the illness [58]. This may reduce the tendency to over-pathologize or minimize health concerns of ethnic minority patients.

Pachter proposed a dynamic model that involves several tiers and transactions [59]. The first component of Pachter's model calls for the practitioner to take responsibility for cultural awareness and knowledge. The professional should be willing to acknowledge that he/she does not possess enough or adequate knowledge in health beliefs and practices among the different ethnic and cultural groups he/she comes in contact with. Reading and becoming familiar with medical anthropology is a good first step.

The second component emphasizes the need for specifically tailored assessment [59]. Pachter advocates the notion that there is tremendous diversity within groups. For example, one cannot automatically assume that a Cuban immigrant adheres to traditional beliefs. Often, there are many variables, such as level of acculturation, age at immigration, educational level, and socioeconomic status, that influence health ideologies. Finally, the third component involves a negotiation process between the patient and the professional [59]. The negotiation consists of a dialogue that involves a genuine respect of beliefs. It is important to remember that these beliefs may affect symptoms or appropriate interventions in the case of domestic violence.

Culturally sensitive assessment involves a dynamic framework whereby the practitioner engages in a continual process of questioning. By incorporating cultural sensitivity into the assessment of individuals with a history of being victims or perpetrators of domestic violence, it may be possible to intervene and offer treatment more effectively.

8. INTERVENTIONS FOR DOMESTIC VIOLENCE AND ABUSE

After the assessment is complete, the patient may or may not want immediate assistance or referral. It is important for healthcare providers to assure patients in a nonjudgmental manner that the decision of what they would like in terms of assistance is their choice and that the provider will help regardless of the decisions they are currently ready to make [39].

If the patient would like to immediately implement a plan of action, information for referral to a local domestic violence shelter to assist the victim and the victim's family should be readily available. The acute situation should be referred immediately to local law enforcement officials. Other resources in an acute situation include crisis hotlines and rape relief centers. After a victim is introduced into the system, counseling and follow-up are generally available by individual counselors who specialize in the care of battered women and their spouses and children. These may include social workers, psychologists, psychiatrists, other mental health workers, and community mental health services. The goals are to make the resources accessible and safe and to enhance support for those who are unsure of their options [39].

In Florida, a 24-hour domestic violence hotline is available for toll-free counseling and information. The number is 800-500-1119. The counselors answering the toll-free line may refer the victim to her or his local domestic violence center. A list of Florida certified domestic violence centers organized by county may also be found on the Florida Department of Children and Families website at https://www.myflfamilies.com/services/abuse/domestic-violence/find-your-local-domestic-violence-center. Florida's domestic violence centers provide information and referral services, counseling and case management services, a 24-hour hotline, temporary emergency shelter for more than 24 hours, educational services for community awareness relative to domestic violence, assessment and appropriate referral of resident children, and training for law enforcement personnel.

9. DOCUMENTATION AND FOLLOW-UP

It is imperative that healthcare professionals document all findings and recommendations regarding domestic violence in the victim's medical record, including a patient's denial of abuse, if applicable. If domestic violence is disclosed, documentation should include relevant history, results of the physical examination, findings of laboratory and other diagnostic procedures, and results of the assessment, intervention, and referral. The medical record can be an invaluable document in establishing the credibility of the victim's story when seeking legal aid [39].

Healthcare professionals should offer a follow-up appointment if disclosure of past or current abuse is present. Reassurance that assistance is available to the patient at any time is critical in helping to break the cycle of abuse [39].

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58. Panos PT, Panos AJ. A model for a culture-sensitive assessment of patients in health care settings. Soc Work Health Care. 2000;31(1): 49-62.

59. Pachter LM. Culture and clinical care: folk illness beliefs and behaviors and their implications for health care delivery. JAMA. 1994;271(9):690-695.

Evidence-Based Practice Recommendations Citations

1. U.S. Preventive Services Task Force, Silverstein M, Wong JB, et al. Screening for intimate partner violence and caregiver abuse of older or vulnerable adults: U.S. Preventive Services Task Force Recommendation Statement. JAMA. 2025;334(4):329-338. Available at https://jamanetwork.com/journals/jama/fullarticle/2835641. Last accessed July 24, 2026.

91153 • Strategies for Appropriate Opioid Prescribing: The Florida APRN/PA Requirement

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

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

Table of Contents

91153 • Strategies for Appropriate Opioid Prescribing: The Florida APRN/PA Requirement

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. DEFINITIONS

3. EPIDEMIOLOGY OF CHRONIC PAIN AND OPIOID MISUSE

OPIOID MISUSE IN FLORIDA

4. INITIATION AND MANAGEMENT OF THE PATIENT WITH PAIN

ACUTE PAIN

PATIENT EVALUATION AND ASSESSMENT OF ADDICTION RISK

CREATING A TREATMENT PLAN

PERIODIC REVIEW AND MONITORING

CONSULTATION AND REFERRAL

MEDICAL RECORDS

PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

DISCONTINUING OPIOID THERAPY

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

5. CRISIS INTERVENTION: MANAGEMENT OF OVERDOSE

OPIOID ANTAGONISTS

6. COMPLIANCE WITH STATE AND FEDERAL LAWS

CONTROLLED SUBSTANCES LAWS/RULES

THE ELECTRONIC FLORIDA ONLINE REPORTING OF CONTROLLED SUBSTANCES EVALUATION PROGRAM

7. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

8. INTERVENTIONS FOR SUSPECTED OR KNOWN DRUG DIVERSION

9. CASE STUDY

ASSESSMENT

FOLLOW-UP

10. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

91153 • Strategies for Appropriate Opioid Prescribing: The Florida APRN/PA Requirement

Education Category. Management

Release Date. 08/01/2026

Expiration Date. 07/31/2029

Course Overview

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

Audience

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

Accreditations & Approvals

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

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 3 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 3 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 3 ANCC contact hour(s). NetCE designates this continuing education activity for 3 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 3.6 hours for Alabama nurses. AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 0.3 CEU(s) for this program.

Individual State Nursing Approvals

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

Special Approvals

This course, offered by the NetCE Physicians Professional Association, is approved to fulfill the Florida physician assistant requirement for 3 hours of education on the safe and effective prescribing of controlled substance medications. This course fulfills the Florida requirement for 3 hours of education on prescribing of controlled substance medications.

Course Objective

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

Learning Objectives

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

1. Define opioid prescribing and opioid misuse.

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

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

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

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

Faculty

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

Faculty Disclosure

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

Division Planners

John M. Leonard, MD

Mary Franks, MSN, APRN, FNP-C

Division Planners Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

Implicit Bias in Health Care

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

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

1. INTRODUCTION

Pain is the leading reason for seeking medical care, and pain management is a large part of many healthcare professionals' practice. Opioid analgesics are approved by the U.S. Food and Drug Administration (FDA) for moderate and severe pain and are broadly accepted in acute pain, cancer pain, and end-of-life care, but are controversial in chronic noncancer pain. In response to the long-standing neglect of severe pain, indications for opioid analgesic prescribing were expanded in the 1990s, followed by inappropriate prescribing and increasing abuse, addiction, diversion, and overdose through the 2000s. In tandem with the continued under-treatment of pain, these practice patterns led to needless suffering from uncontrolled pain, opioid analgesic addiction, and overdose. Opioid analgesic prescribing and prescription opioid overdose peaked in 2010, with both now in multi-year decline, but information on these important trends is largely absent in the medical literature and media reporting.

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

2. DEFINITIONS

Definitions and use of terms describing opioid analgesic misuse, abuse, and addiction have changed over time, and their current correct use is inconsistent not only among healthcare providers, but also by federal agencies reporting epidemiologic data such as prevalence of opioid analgesic misuse, abuse, or addiction. Misuse and misunderstanding of these concepts and their correct definitions have resulted in misinformation and represent an impediment to proper patient care.

Inappropriate opioid analgesic prescribing for pain is defined as the non-prescribing, inadequate prescribing, excessive prescribing, or continued prescribing despite evidence of ineffectiveness of opioids [1; 40]. Appropriate opioid prescribing is essential to achieve pain control; to minimize patient risk of abuse, addiction, and fatal toxicity; and to minimize societal harms from diversion. The foundation of appropriate opioid prescribing is thorough patient assessment, treatment planning, and follow-up and monitoring. Essential for proper patient assessment and treatment planning is comprehension of the clinical concepts of opioid abuse and addiction, their behavioral manifestations in patients with pain, and how these potentially problematic behavioral responses to opioids both resemble and differ from physical dependence and pseudo-addiction. Prescriber knowledge deficit has been identified as a key obstacle to appropriate opioid prescribing and, along with gaps in policy, treatment, attitudes, and research, contributes to widespread inadequate treatment of pain [2]. For example, a survey measuring 200 primary care physicians' understanding of opioids and addiction found that [3]:

- 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.

This last point is very important because confusion and conflation of the clinical concepts of dependence and addiction has led to accusations of many non-addicted patients with chronic pain of misusing or abusing their prescribed opioid and in the failure to detect treatment-emergent opioid problems [4]. Knowledge gaps concerning opioid analgesics, addiction, and pain are related to attitude gaps, and negative attitudes may interfere with appropriate prescribing of opioid analgesics. For example, when 248 primary care physicians were asked of their prescribing approach in patients with headache pain with either a past or current history of substance abuse, 16% and 42%, respectively, would not prescribe opioids under any circumstance [5]. Possibly contributing to healthcare professionals' knowledge deficit in pain treatment is the lack of educational exposure in school. A 2011 study found that U.S. medical school students received a median seven hours of pain education and Canadian medical students a median 14 hours, in contrast to the median 75 hours received by veterinarian school students in the United States [6]. Additionally, less than 3% of medical schools incorporated pain management into their curriculum in the 2010s, despite chronic pain being the most common reason patients see a provider, accounting for 40% of all visits in primary care [7]. Therefore, it is very likely that many currently practicing physicians received suboptimal proper pain management, addiction medicine, and substance use education. In a 2022–2023 Association of American Medical Colleges survey of 166 medical college deans, 98% indicated that pain management was covered in the curriculum, but it is unclear how many hours are devoted to teaching about pain management [45]. It was noted that, "while the recognition of undermanaged and mismanaged pain and substance use disorders were covered in the curriculum, these topics were covered by fewer medical schools."

The terms related to addiction are often inconsistent, inaccurate, and confusing, partially reflecting the diverse perspectives of those working in the related fields of health care, law enforcement, regulatory agencies, and reimbursement/payer organizations. Changes over time in the fundamental understanding of addiction have also contributed to the persistent misuse of obsolete terminology [8]. The Diagnostic and Statistical Manual of Mental Disorders (DSM), published by the American Psychiatric Association, is the standard reference for the diagnosis of addiction and all other psychiatric disorders. Prior to the 2013 release of the DSM-5, versions of the DSM eschewed the term "addiction" in favor of "substance dependence," with a separate diagnostic entity of "substance abuse" representing a less severe version of dependence [9]. Also, in earlier DSM versions, physiologic dependence, manifesting as substance tolerance and withdrawal, was considered a diagnostic criterion of substance dependence. The result was the perpetuation of patient and healthcare professional confusion between physical and substance dependence and the belief that tolerance and withdrawal meant addiction. This confusion also enhanced provider and patient fears over addiction developing from opioid analgesics and contributed to the undertreatment of pain. The DSM-5 has eliminated substance dependence and substance abuse by combining them into the single diagnostic entity of substance use disorder. The disorder is measured on a continuum from mild to severe [9].

In 2011, the American Society of Addiction Medicine (ASAM) published their latest revision in defining the disease of addiction. Owing to the increased public understanding and acceptance of addiction as a chronic brain disease, ASAM published an updated definition of addiction in 2019, with the goal of making it more accessible to patients, the media, and policy makers. The updated definition states that [10]:

Addiction is a treatable, chronic medical disease involving complex interactions among brain circuits, genetics, the environment, and an individual's life experiences. People with addiction use substances or engage in behaviors that become compulsive and often continue despite harmful consequences.

Prevention efforts and treatment approaches for addiction are generally as successful as those for other chronic diseases.

The ASAM Task Force also recommended that definitions for medication-assisted recovery (MAR) and medication-assisted treatment (MAT), which had been previously identified as transitional terms, be retired from use in ASAM documents. With the evolution of addiction treatment and its increasing integration with general medical care, the Task Force recommended that ASAM adopt general medical terminology to describe addiction treatment [10].

3. EPIDEMIOLOGY OF CHRONIC PAIN AND OPIOID MISUSE

Chronic pain affects about one-quarter of American adults in any given year and is the leading cause of long-term disability [2,46]. It also costs the nation up to $635 billion each year in medical treatment and lost productivity and is the leading reason for receiving disability insurance [3,11]. The lifetime prevalence of chronic pain ranges from 54% to 80%, and among adults 21 years of age and older, 14% report pain lasting 3 to 12 months and 42% report pain that persists longer than one year [2]. While 5 to 8 million Americans receive long-term opioids for the management of chronic pain, an estimated 41% of patients with chronic pain report their pain is uncontrolled, and 10% of all adults with pain suffer from severe, disabling chronic pain [11].

The increasing prevalence of chronic pain is the result of multiple factors, including the aging population; rising rates of obesity and obesity-related pain conditions, such as joint deterioration; advances in life-saving trauma interventions; poorly managed post-surgical pain; and greater public awareness of pain as a condition warranting medical attention [2]. In addition, many armed forces veterans returned from military deployments in Afghanistan and Iraq with traumatic injuries and chronic pain, and veterans' care clinicians have reported the perception that long-term pain management is lacking support in the veteran healthcare infrastructure [12].

There is a widespread misperception that opioid analgesic prescribing and overdose continues to grow, fueling an opioid epidemic [13,14,15,16,17]. Data from a 2019 Centers for Disease Control and Prevention (CDC) surveillance report show that between 2006 and 2018, the annual prescribing rate per 100 persons decreased from 72.4 to 51.4 for all opioids, an overall reduction of 29.0% [18]. Between 2019 and 2024, the annual prescribing rate per 100 persons decreased from 46.8 to 35.4 [47]. (Opioid prescriptions, including codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, propoxyphene, tapentadol, tramadol, and buprenorphine, were identified using the National Drug Code. Cough and cold formulations containing opioids were not included.) The rate for all opioid prescriptions initially increased annually by 1.9% from 2006 to 2012, but then decreased annually by 5.2% from 2012 to 2016, and continued to decrease annually by 12.4% from 2016 to 2018 [18].

Although the epidemic of drug overdoses that began in the 1990s primarily involved prescription opioids prescribed for analgesia, the rapid increase in overdose deaths in 2010 was primarily attributed to heroin, and beginning in 2013, to synthetic opioids, particularly illicitly manufactured fentanyl [18]. A total of 75,118 drug overdose deaths occurred in 41 states and the District of Columbia in 2023, a rate of 33.4 per 100,000 persons. Although deaths might have involved more than one drug, illicit fentanyl was involved in 75.1% (56,413) of these drug overdose fatalities [113]. Prescription opioids, which include natural and semisynthetic opioids (e.g., oxycodone, hydrocodone) and methadone, were solely involved in 1.4% (1,085) of overdose deaths. An additional 10.9% (8,182) of deaths involved a prescription opioid and other drug(s), typically other illicit opioids (60.0%), fentanyl (57.7%), non-opioid sedatives (45.3%), or stimulants (40.3%).

There is nearly universal agreement that opioid analgesics were injudiciously overprescribed during the 2000s. Interpretation of the broader trend of increased prescribing from 1990 might be viewed by public health professionals as entirely problematic and by pain medicine professionals as necessary in part, given the past neglect of patients in pain. This reflects the polarized nature of pain care and opioid analgesic prescribing in particular. Efforts to reduce opioid analgesic overprescribing and associated overdose have come at a cost to patients who have faced increasing barriers to access, including stigma and abuse in the healthcare system, tapering of opioids without consideration for pain or functional improvements, and difficulty finding a physician [14,19,20]. It has been found that reducing prescriptions of opioids does not lead to fewer overdoses and disproportionately harms low-income patients, and the overwhelming majority of overdoses are not among those with opioid prescriptions [20].

Worldwide consumption of opioid analgesics increased dramatically over the past few decades, driven primarily by U.S. consumption. For example, the global consumption of oxycodone was 3 tons (2,722 kg) in 1990 and 77 tons (69,853 kg) in 2009, with 62 tons (81%) consumed in the United States [21]. Global manufacture of oxycodone increased from 69.5 tons in 2022 to 103.6 tons in 2024 [22]. Consumption remained concentrated in the United States, which consumed 42.1 tons (62.3%) of the world total [22]. Global stocks of oxycodone rose to 84.6 tons in 2024, with the United States holding 30 tons, or 35.4% of the world's total [22]. The United States also accounted for almost all of the global consumption (98.4%) and manufacture (99.6%) of hydrocodone [22]. This is partially because access to opioid analgesics is virtually or entirely non-existent for much of the world's population. An estimated 3.6 billion people (50% of the global population who reside in the poorest countries) receive less than 1% of the distributed opioids [23]. Other countries with adequate opioid access prefer dihydrocodeine or low-dose morphine over hydrocodone for use in moderate or moderately severe pain [24].

Many prescribed opioid analgesic fatalities result from the co-ingestion of central nervous system (CNS)/respiratory depressants (especially benzodiazepines) or prescribed methadone. The National Institute on Drug Abuse reported that benzodiazepines contributed to 13.4% of opioid analgesic fatalities in 2020 (compared with 24% in 2017), but this may underestimate the true contribution [25]. A Canadian study evaluated 607,156 adults prescribed opioids for noncancer pain, and of those whose deaths were related to opioids, co-prescribed benzodiazepines were detected in 84.5% [26]. In another study of 2,182,374 North Carolina residents receiving one or more opioid analgesics in 2010, benzodiazepines were present in 61.4% who fatally overdosed [27]. A cross-sectional study of 386,457 ambulatory care visits in the United States from 2003 through 2015 found that the use of benzodiazepines increased substantially from 3.8% to 7.4% of visits, including co-prescribing with other sedating medications [28]. Use for back and chronic pain increased more significantly than use for anxiety and insomnia, which remained relatively unchanged. This increase likely reflected not only a growing number of individuals receiving benzodiazepines, but also an increase in those receiving them on a long-term basis, despite the lack of evidence supporting their use past 8 or 10 weeks [28].

OPIOID MISUSE IN FLORIDA

In Florida, misuse of prescription opioids became a serious problem in the 1990s and 2000s, but efforts to stem the problem appear to be working. The rate of drug overdose deaths increased 58.9% during 2003–2010, and in 2009, one in eight deaths in Florida was attributable to drug overdose [29,30]. In 2023, there were 7,235 opioid-related deaths (5,476 opioid-caused deaths) reported in Florida out of 231,925 recorded deaths; of these, fentanyl was responsible for 4,962 deaths [31,114]. Opioid-related deaths decreased by 10%, and opioid-caused deaths decreased by 11% compared with the previous year [31]. Of the 5,476 opioid-caused deaths reported in Florida in 2023, 1,015 were attributed to oxycodone, a 4% increase in oxycodone-caused deaths over the previous year [31]. The trends that occurred in the first two decades of the 2000s resulted in the enactment of several measures to address prescribing that was inconsistent with best practices, and partnership with the U.S. Drug Enforcement Administration (DEA) to close and prevent "pill mills" from introducing millions of opioid dose units into illicit markets [32,33]. In May 2017, former Florida Governor Rick Scott signed an executive order declaring the opioid epidemic a public health emergency, providing additional funding and empowering state health professions to take steps to address this pressing issue [33]. As part of this order, the State Health Officer has issued a standing order for opioid antagonists to ensure emergency responders have access [33]. The order has been extended several times (last in 2019) [34].

Drug overdose fatalities in Florida have continued rising from increased use of heroin, synthetic cannabinoids, and novel psychoactive substances such as alpha-PVP ("flakka"). An influx of clandestine fentanyl into Florida in early 2014, and several fentanyl analogs and other novel non-pharmaceutical opioids more recently, has largely driven the increases in opioid overdose fatalities [31]. Several overdose fatalities in Florida were linked to counterfeit alprazolam, oxycodone, and hydrocodone tablets that contained fentanyl [35]. The decrease in prescription opioid fatalities, offset by increasing overdose fatalities from other opioid and non-opioid agents, reflects the intervention focus on the supply side ("pill mill laws") and neglect of treatment funding that would address the demand side of problematic drug use [36].

In Florida, fatalities with benzodiazepines present peaked in 2010 with 6,188, falling to 3,419 in 2023 (32.3% were alprazolam) [31]. Of the 34,274 deaths investigated by Florida authorities, toxicology results determined that drugs were present at the time of death in 14,798 individuals, with the vast majority revealing more than one drug occurrence [31]. Other primary contributors to opioid analgesic-related fatalities include alcohol and prescribed methadone [31,37,38].

In addition to the executive order issued in 2017 (and subsequently extended), several new state laws were passed in 2018 to impose additional legal requirements on controlled substance prescribers [39]. These laws will be discussed in detail later in this course.

4. INITIATION AND MANAGEMENT OF THE PATIENT WITH PAIN

In 2016, the CDC issued opioid prescribing guidelines for chronic pain that addressed when to initiate or continue opioids for chronic pain; opioid selection, dosage, duration, follow-up, and discontinuation; and assessing risk and addressing harms of opioid use [40]. Some of the recommendations were standard risk mitigation approaches, but others were criticized by pain medicine physicians and patient advocates. A common criticism was the sole focus on curtailing prescribing and patient access to needed medications or needed dosages, which left many chronic pain patients with few other avenues for care [41,42,43,44]. The 2016 guidelines communicated the intent to evaluate and reassess evidence and recommendations as new evidence became available. In 2022, the CDC updated the guidelines, based on systematic reviews of new evidence [40]. In the update, the CDC acknowledged that policies stemming from their 2016 guidance could be harmful to patients [40].

Evidence Based Practice Recommendation

The Centers for Disease Control and Prevention recommends that clinicians should maximize use of nonpharmacologic and nonopioid pharmacologic therapies as appropriate for the specific condition and patient and only consider initiating opioid therapy if expected benefits for pain and function are anticipated to outweigh risks to the patient.

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

Last Accessed: July 24, 2026

Level of Evidence: Expert Opinion/Consensus Statement

It can be difficult to balance the benefits and harms of prescription opioids. This is exacerbated by inadequate education and by opioid prescribing guidelines based on expert opinion instead of scientific evidence. This has resulted in wide variation in clinical practice, inconsistent prescriber guidance, and clinician confusion [48]. For instance, the 2016 CDC and other opioid guidelines stated that opioids should be considered only after non-opioid therapy fails. However, when pain is severe and patients require powerful analgesic control, there is little choice because no other pain medications are as effective as opioids with lower addiction risk [49]. The first recommendation in the 2022 CDC guidelines states that physicians should "only consider opioid therapy for acute pain if benefits are anticipated to outweigh risks to the patient. Before prescribing opioid therapy for acute pain, clinicians should discuss with patients the realistic benefits and known risks of opioid therapy" [40]. They no longer suggest switching only after failure of non-opioid therapy [40].

However, many guidelines do share common recommendations. These represent the current "conventional wisdom" in opioid analgesic prescribing and can inform healthcare professionals of the best clinical practices in opioid prescribing that include approaches to the assessment of pain and function and pain management modalities. Pharmacologic and nonpharmacologic approaches should be used on the basis of current evidence or best clinical practice. Patients with moderate-to-severe chronic pain without adequate pain relief from non-opioid or nonpharmacologic therapy should be considered for a trial of opioid therapy [40,50]. Initial treatment should always be considered individually determined and as a trial of therapy, not a definitive course of treatment [40,51].

ACUTE PAIN

Long-term opioid use often begins with treatment of acute pain. In many instances, such as low back pain, neck pain, and other pain related to other musculoskeletal injuries (e.g., sprains, strains, tendonitis, and bursitis), opioids do not provide a greater benefit than NSAIDs and are associated with the most harms [40]. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids in a quantity no greater than that needed for the expected duration of severe pain. In most cases, a few days or less will be sufficient; more than seven days will rarely be needed [40]. Florida law dictates that, for the treatment of acute pain, a prescription for an opioid drug may not exceed a three-day supply; an exception may be made for a seven-day supply if [52]:

- The prescriber, in his or her professional judgment, believes that more than a three-day supply of such an opioid is medically necessary to treat the patient's pain as an acute medical condition.

- The prescriber indicates "ACUTE PAIN EXCEPTION" on the prescription. (For the treatment of pain other than acute pain, a practitioner must indicate "NONACUTE PAIN" on a prescription.)

- The prescriber adequately documents in the patient's medical records the acute medical condition and lack of alternative treatment options that justify deviation from the three-day supply limit.

With postoperative, acute, or intermittent pain, analgesia often requires frequent titration, and the two- to four-hour analgesic duration with short-acting hydrocodone, morphine, and oxycodone is more effective than extended-release formulations. Short-acting opioids are also recommended in patients who are medically unstable or with highly variable pain intensity [53,54,55].

As part of House Bill 21, passed in 2018, the Florida Board of Medicine and the Board of Osteopathic Medicine are required to establish guidelines for prescribing controlled substances for acute pain [52]. In 2019, the Florida Board of Medicine approved and published Rule No. 64B8-9.013, Standards for the Prescribing of Controlled Substances for the Treatment of Acute Pain to satisfy this requirement [56].

PATIENT EVALUATION AND ASSESSMENT OF ADDICTION RISK

Information obtained by patient history, physical examination, and interview, from family members, a spouse, or state prescription drug monitoring program (PDMP), and from the use of screening and assessment tools have been used to help the clinician stratify the patient according to level of risk for developing problematic opioid behavioral responses (Table 1). Low-risk patients receive the standard level of monitoring, vigilance, and care. Moderate-risk patients are considered for an additional level of monitoring and provider contact, and high-risk patients are likely to require intensive and structured monitoring and follow-up contact, additional consultation with psychiatric and addiction medicine specialists, and limited supplies of short-acting opioid formulations [57]. The 2022 CDC guidelines state that screening or risk assessment tools demonstrate limited and variable accuracy for classification of patients as at low or high risk for opioid use disorder or misuse. If these tools are used, they should be supplemented with other assessments, such as discussions with patients, family, and caregivers; clinical records; PDMP data; and toxicology screening data. Clinicians should always use caution when considering or prescribing opioids and should not overestimate the ability of available risk stratification tools to rule out risks of long-term opioid therapy [40].

Table 1: RISK STRATIFICATION FOR PATIENTS PRESCRIBED OPIOIDS

Low Risk

No past or current personal history of alcohol/substance use disorder (AUD/SUD)

No or minimal co-occurring psychiatric disorders

No family history of alcoholism or substance abuse

Medium Risk

Past history of AUD or SUD

Moderate concomitant psychiatric disorders

Family history of alcoholism or substance abuse/addiction

Patient history of physical, emotional or sexual abuse, especially in childhood

High Risk

Patient actively addicted to or abusing opioids, illicit drugs or alcohol

Untreated or poorly controlled major psychiatric disorder

History of diversion, prescription forgery, selling their prescription drugs

Source: [58,59,60]

Anxiety disorders, major depressive disorder, and intense emotional distress alter pain perception and response. Intensity and perception of reported pain is also influenced by factors such as mood, cultural background, social supports, and financial resources. A biopsychosocial model is required to inform pain assessment in order to address the biologic basis of pain and presence of social and psychologic contributors [49].

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

- Medical history and physical examination targeted to the condition causing pain

- Co-existing disease(s) or condition(s), particularly those which could complicate treatment (e.g., obesity, renal disease, sleep apnea, COPD)

- Description of the nature and intensity of the pain and the effect of pain on physical and psychological functioning

- Medical indication(s) for use of opioids

- Current and past treatments, including interventional treatments, with response to each treatment

- Current medications (prescription, over-the-counter drugs, and natural remedies)

- Tests of urine, blood, or other types of biological samples, and diagnostic markers

- Review of state PDMP results

- Personal and family history of substance use disorder

- History of behavioral health disorders

Depression is perhaps the single most important comorbidity in patients with chronic pain and is vastly underdiagnosed and untreated. Patients with unrecognized and untreated depression are less likely to respond to opioids and other pain therapies, but successful treatment of depression can promote analgesia [61].

If substance abuse is active, in remission, or in the patient's history, consult an addiction specialist before starting opioids [1]. In active substance abuse, do not prescribe opioids until the patient is engaged in treatment/recovery program or other arrangement made, such as addiction professional co-management and additional monitoring. When considering an opioid analgesic (particularly those that are extended-release or long-acting), one must always weigh the benefits against the risks of overdose, abuse, addiction, physical dependence and tolerance, adverse drug interactions, and accidental exposure by children [40,62].

Screening and assessment tools can help guide patient stratification according to risk level and inform the appropriate degree of structure and monitoring in the treatment plan. It should be noted that despite widespread endorsement of screening tool use to help determine patient risk level, most tools have not been extensively evaluated, validated, or compared to each other, and evidence of their reliability is poor [63].

Opioid Risk Tool (ORT)

The Opioid Risk Tool (ORT) is a five-item assessment to help predict aberrant drug-related behavior. The ORT is also used to establish patient risk level through categorization into low, medium, or high levels of risk for aberrant drug-related behaviors based on responses to questions of previous alcohol/drug abuse, psychologic disorders, and other risk factors [64,65].

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

The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) is a patient-administered, 24-item screen with questions addressing history of alcohol/substance use, psychologic status, mood, cravings, and stress. Like the ORT, the SOAPP-R helps assess risk level of aberrant drug-related behaviors and the appropriate extent of monitoring [66,67].

CAGE and CAGE-AID

The original CAGE (Cut down, Annoyed, Guilty, and Eye-opener) Questionnaire consisted of four questions designed to help clinicians determine the likelihood that a patient was misusing or abusing alcohol. These same four questions were modified to create the CAGE-AID (adapted to include drugs), revised to assess the likelihood of current substance abuse [68,69].

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

The Diagnosis, Intractability, Risk, and Efficacy (DIRE) risk assessment tool is a clinician-rated questionnaire that is used to predict patient compliance with long-term opioid therapy [70,71]. Patients scoring lower on the DIRE tool are poor candidates for long-term opioid analgesia.

CREATING A TREATMENT PLAN

Opioid therapy should be presented as a trial for a pre-defined period (e.g., ≤30 days). The goals of treatment should be established with all patients prior to the initiation of opioid therapy, including reasonable improvements in pain, function, depression, anxiety, and avoidance of unnecessary or excessive medication use [1,40]. The treatment plan should describe therapy selection, measures of progress, and other diagnostic evaluations, consultations, referrals, and therapies. All patients prescribed an opioid for pain related to a traumatic injury (severity score ≥9) should be concurrently prescribed an antagonist (e.g., naloxone) [40,52]. Florida law requires concurrent prescription of an emergency opioid antagonist if an opioid is prescribed for the treatment of pain related to a traumatic injury with an Injury Severity Score of 9 or greater [116].

In opioid-naïve patients, start at the lowest possible dose and titrate to effect. Dosages for opioid-tolerant patients should always be individualized and titrated by efficacy and tolerability [1]. The need for frequent progress and benefit/risk assessments during the trial should be included in patient education. Patients should also have full knowledge of the warning signs and symptoms of respiratory depression.

Prescribers should be knowledgeable of federal and state opioid prescribing regulations. Issues of equianalgesic dosing, close patient monitoring during all dose changes, and incomplete cross-tolerance with opioid conversion should be considered. If necessary, treatment may be augmented, with preference for non-opioid and immediate-release opioids over long-acting/extended-release opioids. Taper opioid dose when no longer needed [62].

Non-Opioid Pain Management Options

Nonpharmacologic Approaches

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

Methods to provide distraction from pain come in a wide variety, including reciting poetry, meditating with a calm phrase, watching television or movies, playing cards, visiting with friends, or participating in crafts. Music therapy and art therapy are also becoming more widely used as nonpharmacologic options for pain management.

Non-Opioid Analgesics

Non-opioid analgesics, such as aspirin, acetaminophen (Tylenol), and nonsteroidal anti-inflammatory drugs (NSAIDs), are primarily used for mild pain and may also be helpful as coanalgesics for moderate and severe pain. Acetaminophen is among the safest of analgesic agents, but it has essentially no anti-inflammatory effect. Toxicity is a concern at high doses, and the maximum recommended dose is 3–4 g per day [73]. Acetaminophen should be avoided or given at lower doses in people with a history of alcohol abuse or renal or hepatic insufficiency [73].

NSAIDs are most effective for pain associated with inflammation. Among the commonly used NSAIDs are ibuprofen (Motrin, Advil), naproxen (Aleve, Naprosyn), and indomethacin (Indocin). There are several classes of NSAIDs, and the response differs among patients; trials of drugs for an individual patient may be necessary to determine which drug is most effective [74]. NSAIDs inhibit platelet aggregation, increasing the risk of bleeding, and also can damage the mucosal lining of the stomach, leading to gastrointestinal bleeding. There is a ceiling effect to the non-opioid analgesics; that is, there is a dose beyond which there is no further analgesic effect. In addition, many side effects of non-opioids can be severe and may limit their use or dosing.

Informed Consent and Treatment Agreements

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

The treatment agreement also outlines joint physician and patient responsibilities. The patient agrees to using medications safely, to obtain opioids from only one clinician or practice (when possible), having prescriptions filled at only one pharmacy (when possible), and consenting to routine urine drug testing (when clinically appropriate). The prescriber's responsibility is to address unforeseen problems and prescribe scheduled refills. Reasons for opioid therapy change or discontinuation should be listed. Agreements can also include sections related to follow-up visits, monitoring, and safe storage and disposal of unused drugs.

PERIODIC REVIEW AND MONITORING

When implementing a chronic pain treatment plan that involves the use of opioids, the patient should be frequently reassessed for changes in pain origin, health, and function [1]. This can include input from family members or other close contacts and/or the state PDMP. During the initiation phase and during any changes to the dosage or agent used, patient contact should be increased. At every visit, chronic opioid response may be monitored according to the "5 A's" [75]:

- Analgesia

- Activities of daily living

- Adverse or side effects

- Aberrant drug-related behaviors

- Affect (i.e., patient mood)

Signs and symptoms that, if present, may suggest a problematic response to the opioid and interference with the goal of functional improvement include [76]:

- Excessive sleeping or days and nights turned around

- Diminished appetite

- Short attention span or inability to concentrate

- Mood volatility, especially irritability

- Lack of involvement with others

- Impaired functioning due to drug effects

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

- Lack of attention to hygiene and appearance

The decision to continue, change, or terminate opioid therapy is based on progress toward treatment objectives and absence of concerning adverse effects and risks of overdose or diversion [1]. Satisfactory therapy is indicated by improvements in pain, function, and quality of life. It is important to remember that for some patients with severe chronic pain, improved function may take longer than pain control. Either pain or function (not both) will improve. In some cases, preventing worsening pain/functional impairment is the best achievable outcome. Brief assessment tools to assess pain and function may be useful, as may urine drug tests (UDTs). Treatment plans may include periodic pill counts to confirm adherence and minimize diversion.

Involvement of Family

Family members or the partner of the patient can provide the clinician with valuable information that better informs decision making regarding continuing opioid therapy [1]. Family members can observe whether a patient is losing control of his or her life or becoming less functional or more depressed during the course of opioid therapy. They can also provide input regarding positive or negative changes in patient function, attitude, and level of comfort [1]. The following questions can be asked of family members or a spouse to help clarify whether the patient's response to opioid therapy is favorable or unfavorable [76]:

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

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

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

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

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

Assessment Tools

VIGIL

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

- Verification: Is this a responsible opioid user?

- Identification: Is the identity of this patient verifiable?

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

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

- Legalization: Am I acting legally and responsibly?

The foundation of VIGIL is a collaborative physician/pharmacist relationship [77,78].

Current Opioid Misuse Measure (COMM)

The Current Opioid Misuse Measure (COMM) is a 17-item patient self-report assessment designed to help clinicians identify misuse or abuse in patients with chronic pain. Unlike the ORT and the SOAPP-R, the COMM identifies aberrant behaviors associated with opioid misuse in patients already receiving long-term opioid therapy [57]. Sample questions include: In the past 30 days, how often have you had to take more of your medication than prescribed? In the past 30 days, how much of your time was spent thinking about opioid medications (e.g., having enough, taking them, dosing schedule)?

Pain Assessment and Documentation Tool (PADT)

Guidelines by the Federation of State Medical Boards (FSMB) and the Joint Commission stress the importance of documentation from both a healthcare quality and medicolegal perspective. Research has found widespread deficits in chart notes and progress documentation for patients with chronic pain who are receiving opioid therapy, and the Pain Assessment and Documentation Tool (PADT) was designed to address these shortcomings [79]. The PADT is a clinician-directed interview, with most sections (e.g., analgesia, activities of daily living, adverse events) consisting of questions asked of the patient [80]. However, the potential aberrant drug-related behavior section must be completed by the physician based on his or her observations of the patient.

Urine Drug Tests

UDTs may be used to monitor adherence to the prescribed treatment plan and to detect unsanctioned drug use. They should be used more often in patients receiving addiction therapy, but clinical judgment is the ultimate guide to testing frequency (Table 2) [81]. The CDC recommends clinicians should use UDT before starting opioid therapy and consider UDT at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs [40]. UDT is not used in a punitive manner (i.e., to dismiss patients), and patients should be informed that this will not occur. UDT is only used to inform and improve patient care.

Table 2: PATIENT RISK LEVEL AND FREQUENCY OF MONITORING

Monitoring Tool

Patient Risk Level

Low

Medium

High

Urine drug test

Every 1 to 2 years

Every 6 to 12 months

Every 3 to 6 months

State prescription drug monitoring program

Twice per year

3 times per year

4 times per year

Source: [81]

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

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

CONSULTATION AND REFERRAL

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

Ideally, providers should be able to refer patients with active substance abuse who require pain treatment to an addiction professional or specialized program. In reality, these specialized resources are scarce or non-existent in many areas [1]. Therefore, each provider will need to decide whether the risks of continuing opioid treatment while a patient is using illicit drugs outweigh the benefits to the patient in terms of pain control and improved function [82].

MEDICAL RECORDS

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

PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

Patients and caregivers should be counseled regarding the safe use and disposal of opioids. As part of its mandatory Risk Evaluation and Mitigation Strategy (REMS) for extended-release/long-acting opioids, the FDA has developed a patient counseling document with information on the patient's specific medications, instructions for emergency situations and incomplete pain control, and warnings not to share medications or take them unprescribed [62]. A copy of this form may be accessed online at https://www.fda.gov/media/79776/download.

When prescribing opioids, clinicians should provide patients with the following information [62]:

- Product-specific information

- Taking the opioid as prescribed

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

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

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

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

- The potential of serious side effects or death

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

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

- Warning and rationale to never share an opioid analgesic

- Rationale for secure opioid storage

- Warning to protect opioids from theft

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

There are no universal recommendations for the proper disposal of unused opioids, and patients are rarely advised of what to do with unused or expired medications [83]. According to the Office of National Drug Control Policy, most medications that are no longer necessary or have expired should be removed from their containers, mixed with undesirable substances (e.g., cat litter, used coffee grounds), and put into an impermeable, nondescript container (e.g., disposable container with a lid or a sealed bag) before throwing in the trash [84]. Any personal information should be obscured or destroyed. The FDA recommends that certain medications, including oxycodone/acetaminophen (Percocet), oxycodone (OxyContin tablets), and transdermal fentanyl (Duragesic Transdermal System), be flushed down the toilet instead of thrown in the trash [85]. Patients should be advised to flush prescription drugs down the toilet only if the label or accompanying patient information specifically instructs doing so and no other disposal method is appropriate [85].

The American Society of Health-System Pharmacists has established best practices to avoid diversion of unused drugs and educate patients regarding drug disposal [83,115]:

- Consider writing prescriptions in smaller amounts.

- Educate patients about safe storing and disposal practices.

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

- Refer patients to pharmacies or community "take back" services overseen by law enforcement that collect controlled substances, seal them in plastic bags, and store them in a secure location until they can be incinerated.

- The FDA recommends that patients type "drug disposal" or "medication disposal" into Google maps to check their local area for take back options, which typically returns results for all pharmacies in the area. Returning unused portions to a pharmacy is typically the easiest way for individuals to dispose of unused medications. To find a nearby pharmacy, they can also visit https://apps.deadiversion.usdoj.gov/pubdispsearch/spring/main?execution=e1s1.

DISCONTINUING OPIOID THERAPY

The decision to continue or end opioid prescribing should be based on a physician-patient discussion of the anticipated benefits and risks. An opioid should be considered for discontinuation with resolution of the pain condition, intolerable side effects, inadequate analgesia, lack of improvement in quality of life despite dose titration, deteriorating function, or significant aberrant medication use [1,40].

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

As a side note, cannabis use by patients with chronic pain receiving opioid therapy has traditionally been viewed as a treatment agreement violation that is grounds for termination of opioid therapy. However, some now argue against cannabis use as a rationale for termination or substantial treatment and monitoring changes, especially considering the increasing legalization of medical use at the state level [82]. Cannabis use for chronic pain in patients receiving opioid therapy continues to receive increased interest and support; however, experts caution that more evidence of improved patient outcomes is needed [86,87,88].

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

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

5. CRISIS INTERVENTION: MANAGEMENT OF OVERDOSE

Individuals who have first contact with persons suspected of experiencing an opioid-related overdose are in the position to intervene to prevent the potentially devastating consequences. In these cases, care begins with crisis intervention directed at immediate survival by reversing the potentially lethal effects of overdose with an opioid antagonist.

Opioid antagonists have obvious therapeutic value in the treatment of opioid overdose. A 2012 study found that wider distribution of naloxone and training in its administration might have prevented numerous deaths from opioid overdoses in the United States [89]. The first community-based opioid overdose prevention program began distributing naloxone in 1996, and between 1996 and 2010, more than 10,000 overdoses were reversed [89].

In Florida, licensed healthcare providers may prescribe and pharmacists may dispense opioid antagonists (even as a standing order) for at-risk individuals, these individuals' relatives or other caregivers, and emergency responders to be used in their course of duties [90]. Emergency responders include (but are not limited to) law enforcement officers, paramedics, and emergency medical technicians [90]. As noted, there is a statewide standing order for naloxone for all emergency responders in Florida [33].

OPIOID ANTAGONISTS

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. Interestingly, naloxone also appears to block the analgesic effects of placebo medications and acupuncture. These agents have no abuse potential [91].

In response to acute overdose, the short-acting opioid antagonist naloxone is considered the gold standard, and it remains the most widely used opioid antagonist for the reversal of overdose and opioid-related respiratory depression. It acts by competing with opioids at receptor sites in the brain stem, reversing desensitization to carbon dioxide, and reversing or preventing respiratory failure and coma. There is no evidence that subcutaneous or intramuscular use is inferior to intravenous naloxone. This has prompted some states to pass laws allowing opioid antagonists to be available to the general public for administration outside the healthcare setting to treat acute opioid overdose [92].

When used for opioid overdose, a dose of 0.4–2 mg of naloxone is administered intravenously, intramuscularly, or subcutaneously [93]. If necessary, the dose may be repeated every two to three minutes for full reversal. For ease of use, naloxone is also available in a 10-mg pre-filled auto-injection device. An intranasal formulation is also available in doses of 2 mg, 4 mg, or 8 mg [93]. It is important that standard Advanced Cardiac Life Support (ACLS) protocols be continued while naloxone is being administered and that medical treatment (at a healthcare facility) be given immediately.

6. COMPLIANCE WITH STATE AND FEDERAL LAWS

In response to the rising incidence in prescription opioid abuse, addiction, diversion, and overdose in the late 1990s and 2000s, the FDA has mandated opioid-specific REMS to reduce the potential negative patient and societal effects of prescribed opioids. Other elements of opioid risk mitigation include FDA partnering with other governmental agencies, state professional licensing boards, and societies of healthcare professionals to help improve prescriber knowledge of appropriate and safe opioid prescribing and safe home storage and disposal of unused medication [76].

Several regulations and programs at the state level have been enacted in an effort to reduce prescription opioid abuse, diversion, and overdose, including [94]:

- Physical examination required prior to prescribing

- Tamper-resistant prescription forms

- Pain clinic regulatory oversight

- Prescription limits

- Prohibition from obtaining controlled substance prescriptions from multiple providers

- Patient identification required before dispensing

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

CONTROLLED SUBSTANCES LAWS/RULES

The DEA is responsible for formulating federal standards for the handling of controlled substances. In 2011, the DEA began requiring every state to implement electronic databases that track prescribing habits, referred to as PDMPs. Specific policies regarding controlled substances are administered at the state level.

According to the DEA, drugs, substances, and certain chemicals used to make drugs are classified into five distinct categories or schedules depending upon the drug's acceptable medical use and the drug's abuse or dependency potential [95]. The abuse rate is a determinate factor in the scheduling of the drug; for example, Schedule I drugs are considered the most dangerous class of drugs with a high potential for abuse and potentially severe psychologic and/or physical dependence.

In Florida, the prescribing, dispensing, and consumption of certain controlled substances are governed by Chapter 893 of the Florida Statutes [96]. This law establishes the standards for controlled substance prescribing, including reporting system requirements, for prescribers and pharmacists in Florida. As of 2022, the Florida schedule of controlled substances aligns with the DEA schedule [97].

THE ELECTRONIC FLORIDA ONLINE REPORTING OF CONTROLLED SUBSTANCES EVALUATION PROGRAM

Emerging trends and patterns of prescription opioid abuse, addiction, and overdose are monitored by several industry and government agencies through data collection from a variety of sources. These include health insurance claims; the Automation of Reports and Consolidated Orders System, a DEA-run program that monitors the flow of controlled substances from manufacturing through distribution to retail sale or dispensing; the Treatment Episode Data Set, which monitors treatment admissions; the National Center for Health Statistics state mortality data; and the Researched Abuse, Diversion, and Addiction-Related Surveillance System, which monitors prescription drug abuse, misuse, and diversion [98,99,100,101].

Almost all states, including Florida, have enacted PDMPs to facilitate the collection, analysis, and reporting of information on controlled substances prescribing and dispensing [1]. All prescribers must consult the Electronic Florida Online Reporting of Controlled Substances Evaluation (E-FORCSE) to review a patient's controlled substance dispensing history before prescribing or dispensing a controlled substance to a patient 16 years of age or older [39,102]. This is mandated even for existing patients and should be done each time a controlled substance is prescribed or dispensed [39]. If the system is nonoperational or cannot be accessed due to a temporary technologic or electrical failure, the prescription may be issued (with documentation of the exception) for up to a maximum three-day supply.

All clinicians who prescribe or dispense controlled substances are required to report the action to E-FORCSE as soon as possible, but no later than the close of the next business day [39]. This should be repeated each time the substance is dispensed. This reporting requirement is waived in certain circumstances, including for [103]:

- The dispensing of a controlled substance in the healthcare system of the Department of Corrections

- The dispensing of a controlled substance to a person younger than 16 years of age

- All acts of administration of a controlled substance

7. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

Research has more closely defined the location of prescribed opioid diversion into illicit use in the supply chain from the manufacturer to the distributor, retailer, and the end user (the patient with pain). This information carries with it substantial public policy and regulatory implications. The 2020 National Survey on Drug Use and Health asked 9.3 million non-medical users of prescription opioids how they obtained their most recently used drugs [104]. Among persons 12 years of age or older, 47.2% obtained their prescription opioids from a friend or relative. Of this, 34.4% got the prescription opioids from a friend or relative for free, 9.2% bought them from a friend or relative, and 3.7% took them from a friend or relative without asking. Another 42.0% got their opioids through a prescription from one doctor (vs. 35.4% in 2016) [104]. Less frequent sources included a drug dealer or other stranger (6.2%); multiple doctors (1.0%); theft from a doctor's office, clinic, hospital, or pharmacy (0.6%) (vs. 0.7% in 2016); and some other way (3.1%) [104].

As discussed, UDTs can give insight into patients who are misusing opioids. A random sample of UDT results from 800 patients with pain treated at a Veterans Affairs facility found that 25.2% were negative for the prescribed opioid while 19.5% were positive for an illicit drug/unreported opioid [105]. Negative UDT results for the prescribed opioid do not necessarily indicate diversion but may indicate the patient halted his/her use due to side effects, lack of efficacy, or pain remission. The concern arises over the increasingly stringent climate surrounding clinical decision-making regarding aberrant UDT results and that a negative result for the prescribed opioid or a positive UDT may serve as the pretense to terminate a patient rather than guide him/her into addiction treatment or an alternative pain management program [106].

In addition to aberrant urine screens, there are certain behaviors that are suggestive of an emerging opioid use disorder. The most suggestive behaviors are [82,107,108]:

- Selling medications

- Prescription forgery or alteration

- Injecting medications meant for oral use

- Obtaining medications from nonmedical sources

- Resisting medication change despite worsening function or significant negative effects

- Loss of control over alcohol use

- Using illegal drugs or non-prescribed controlled substances

- Recurrent episodes of:

- Prescription loss or theft

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

- Unsanctioned dose escalation

- Running out of medication and requesting early refills

Behaviors with less association with opioid misuse include [82,107,108]:

- Aggressive demands for more drug

- Asking for specific medications

- Stockpiling medications during times when pain is less severe

- Using pain medications to treat other symptoms

- Reluctance to decrease opioid dosing once stable

- In the earlier stages of treatment:

- Increasing medication dosing without provider permission

- Obtaining prescriptions from sources other than the pain provider

- Sharing or borrowing similar medications from friends/family

8. INTERVENTIONS FOR SUSPECTED OR KNOWN DRUG DIVERSION

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

Prevention is the best approach to addressing drug diversion. As noted, the most common source of nonmedical use of prescribed opioids is from a family member or friend, through sharing, buying, or stealing. To avoid drug sharing among patients, healthcare professionals should educate patients on the dangers of sharing opioids and stress that "doing prescription drugs" is the same as "using street drugs" [83]. In addition, patients should be aware of the many options available to treat chronic pain aside from opioids. As stated, to prevent theft, patients should be advised to keep medications in a private place and to refrain from telling others about the medications being used.

Communication among providers and pharmacies can help to avoid inappropriate attainment of prescription drugs through "doctor shopping." Prescribers should keep complete and up-to-date records for all controlled substance prescribing. When possible, electronic medical records should be integrated between pharmacies, hospitals, and managed care organizations [83]. It is also best practice to periodically request a report from the E-FORCSE to evaluate the prescribing of opioids to your patients by other providers [39,83].

When dealing with patients suspected of drug seeking/diversion, first inquire about prescription, over-the-counter, and illicit drug use and perform a thorough examination [83,109]. Pill counting and/or UDT may be necessary to investigate possible drug misuse. Photo identification or other form of identification and social security number may be required prior to dispensing the drug, with proof of identity documented fully. If a patient is displaying suspicious behaviors, consider prescribing for limited quantities [109].

If a patient is found to be abusing prescribed opioids, this is considered a violation of the treatment agreement and the clinician must make the decision whether or not to continue the therapeutic relationship. If the relationship is terminated, it must be done ethically and legally. The most significant issue is the risk of patient abandonment, which is defined as ending a relationship with a patient without consideration of continuity of care and without providing notice to the patient. The American Medical Association Code of Ethics states that "physicians' fiduciary responsibility to patients entails an obligation to support continuity of care for their patients" [110]. While physicians have the option of withdrawing from a case, they cannot do so without giving notice to the patient, the relatives, or responsible friends sufficiently long in advance of withdrawal to permit another medical attendant to be secured or to facilitate the transfer of care, when appropriate [110]. The notice of termination should be sent in writing, should specifically note the cause(s) for the termination, and should give a period of time prior to termination, usually 30 days [111]. Patients may also be given resources and/or recommendations to help them locate a new clinician.

Patients with chronic pain found to have an ongoing substance abuse problem or addiction should be referred to a pain specialist for continued treatment. Theft or loss of controlled substances is reported to the DEA. If drug diversion has occurred, the activity should be documented and a report to law enforcement should be made [112].

9. CASE STUDY

An unemployed man, 64 years of age, is brought to an emergency department by ambulance, after his wife returned from work to find him lying on the couch, difficult to arouse and incoherent. He has a past history of hypertension, diabetes (non-insulin dependent), mild chronic obstructive pulmonary disease, and chronic back and shoulder pain, for which he has been prescribed hydrocodone/acetaminophen for many years. His wife reports that while he seemed his usual self when she left for work that morning, he had, in recent weeks, been more withdrawn socially, less active, and complained of greater discomfort from the back and shoulder pain. She knows little about his actual medication usage and expresses concern that he may have been taking more than the prescribed amount of "pain medicine."

On evaluation, the patient is somnolent and arouses to stimulation but is non-communicative and unable to follow commands. His blood pressure is normal, he is afebrile, and there are no focal neurologic deficits. Oxygen saturation, serum glucose, and routine laboratory studies (blood counts and metabolic profile) are normal except for mild elevation in blood urea nitrogen (BUN) and creatinine; the urine drug screen is negative except for opioids. Additional history from the family indicates that the patient has been admitted to other hospitals twice in the past three years with a similar presentation and recovered rapidly each time "without anything being found."

Following admission, the patient remains stable-to-improved over the next 12 to 18 hours. By the following day, he is awake and conversant and looks comfortable. On direct questioning, he reports recent symptoms of depression but no suicidal ideation. The patient describes an increased preoccupation with his pain syndrome, difficulty sleeping at night, and little physical activity during the day, in part because of physical discomfort. He is vague about his medication regimen and admits to taking "occasional" extra doses of hydrocodone for pain relief.

The family is instructed to bring in all his pill bottles from home, which they do. In addition to the hydrocodone prescribed by his primary care physician, there is a recent refill of a prescription for the medication given to the patient at the time of his last hospital discharge six months earlier.

ASSESSMENT

A full evaluation, including radiographic studies and consultation with psychiatry and physical therapy, is completed. The working diagnosis for the patient's acute illness is toxic encephalopathy caused by the sedative side effects of opioid medication on the CNS. It is explained that the combination of his advancing age and diabetes likely reduced the efficiency of his kidneys in clearing the medication and its metabolites, making him more susceptible to CNS sedation. It is noted that the patient and his wife have little understanding of the rationale, proper use and safeguards, potential side effects, and limited effectiveness of opioid use for chronic pain.

In addition, the patient is diagnosed with poorly controlled chronic pain syndrome secondary to osteoarthritis and degenerative disc disease; exacerbating factors include deconditioning and reactive depression. The use of an opioid analgesic, at least for the near term, is considered appropriate, if dosed properly, monitored closely, and integrated into a comprehensive, multidisciplinary plan that includes treatment of depression and the use of adjunctive, nonpharmacologic modalities of care. In the setting of possible early diabetic nephropathy, the option of utilizing an NSAID, except for very brief periods of break-through pain, is not considered to be a safe option.

At discharge, and in consultation with his primary care physician, a written treatment and management plan addressing all aspects of the patient's care is presented to the patient and his wife for discussion and consent. Among the key issues addressed are:

- Goals: Improvement in subjective pain experience; improved function of daily living manifested by regular walking exercise and improved social interaction with family and friends; relief of depression; and in the long-term, anticipated withdrawal of opioid medication and resumption of part-time work and/or volunteer community activity

- Outpatient physical therapy and back exercise program to increase core muscular strength, improve flexibility, reduce pain, and increase exercise tolerance

- Patient and family counseling regarding the safe use, dosage regulation, side effects, and proper disposal of opioid medication

- Joint patient-physician responsibilities as regards to regular follow-up, monitoring of goals and treatment effectiveness, avoidance of "doctor-shopping," and assent to single provider for prescription medication

FOLLOW-UP

On follow-up six weeks after discharge, the patient is noticeably improved. He reports that he feels stronger and is sleeping better. His affect is brighter, and he is getting out more. He has maintained his physical therapy and exercise routine and is compliant with his medication. Though he still has pain, it is noticeably less and he is coping better. He and his wife are encouraged by his progress, particularly in regard to his improved functional status.

10. CONCLUSION

For patients suffering from pain, prescribed opioid analgesics may substantially lessen pain, distress, and impairment. Inappropriate overprescribing and overdose related to opioid analgesics increased dramatically in the 2000s. These trends are in multi-year reversal, but patient safety and risk mitigation remains no less important, and clinical tools, guidelines, and recommendations are available for use when prescribing opioids to patients with pain. By implementing these tools, the clinician can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

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Evidence-Based Practice Recommendations Citations

1. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC clinical practice guideline for prescribing opioids for pain—United States, 2022. MMWR. 2022;71(RR3):1-95. Available at https://www.cdc.gov/mmwr/volumes/71/rr/rr7103a1.htm. Last accessed July 24, 2026.