Author: Marjorie Conner Allen, BSN, JD; Alice Yick Flanagan, PhD, MSW; Mark Rose, BS, MA, LP; Justin Delic, PharmD, BCCCP; www.netce.com
Date: 2026-09-01
Keywords: Ethics - Human Rights; Pharmacology; Psychiatric / Mental Health; Management
Publisher: NetCE
Rights: Copyright © 2026 NetCE, All rights reserved.

FLMD27 • Florida Physicians 2026-2027

Table of Contents

FLMD27 • Florida Physicians 2026-2027

How to Receive Credit

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 2 Hour Course #45122 • Strategies for Appropriate Opioid Prescribing: The Florida Requirement

45122 • Strategies for Appropriate Opioid Prescribing: The Florida 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

NetCE 15 Hour Course #96183 • Anxiety Disorders

96183 • Anxiety Disorders
1. INTRODUCTION
2. BACKGROUND

3. OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

4. ETIOLOGY AND PATHOPHYSIOLOGY
5. CLINICAL AND DIAGNOSTIC FEATURES
6. ASSESSMENT
7. GENERAL TREATMENT CONSIDERATIONS
8. TREATMENT OF GENERALIZED ANXIETY DISORDER
9. TREATMENT OF PANIC DISORDER
10. TREATMENT OF AGORAPHOBIA
11. TREATMENT OF SOCIAL ANXIETY DISORDER
12. TREATMENT OF SPECIFIC PHOBIA
13. TREATMENT OF SEPARATION ANXIETY DISORDER

14. EMERGING THERAPIES AND NOVEL TREATMENT APPROACHES

15. COMPLEMENTARY/ALTERNATIVE THERAPIES
16. CONCLUSION
Works Cited

Evidence-Based Practice Recommendations Citations

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

95310 • Anticoagulation and Antiplatelet Therapy: Clinical Use Guidelines

1. INTRODUCTION
2. BACKGROUND AND INTRODUCTION
3. PATHOPHYSIOLOGY OF DISEASE
4. ANTIPLATELETS
5. ANTICOAGULANTS

6. INDICATIONS FOR ANTIPLATELETS AND ANTICOAGULANTS

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 2 Hour Course #91335 • Medical Error Prevention and Root Cause Analysis

91335 • 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

FLMD27 • Florida Physicians 2026-2027

Marjorie Conner Allen, BSN, JD

Alice Yick Flanagan, PhD, MSW

Mark Rose, BS, MA, LP

Justin Delic, PharmD, BCCCP

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

FLMD27 • Florida Physicians 2026-2027

Expiration Date: 06/30/2027

How to Receive Credit

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

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

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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49. Centers for Disease Control and Prevention. Intimate Partner Violence, Sexual Violence, and Stalking Among Men. Available at https://www.cdc.gov/intimate-partner-violence/about/intimate-partner-violence-sexual-violence-and-stalking-among-men.html. Last accessed July 15, 2026.

50. Bureau of Justice Statistics. Female Murder Victims and Victim–Offender Relationship, 2021. Available at https://bjs.ojp.gov/female-murder-victims-and-victim-offender-relationship-2021. Last accessed July 15, 2026.

51. Ard KL, Makadon HJ. Addressing intimate partner violence in lesbian, gay, bisexual, and transgender patients. J Gen Intern Med. 2011;26(8):930-933.

52. National Coalition of Anti-Violence Programs. Lesbian, Gay, Bisexual, Transgender, Queer, and HIV-Affected Intimate Partner Violence in 2015. Available at http://avp.org/wp-content/uploads/2019/01/NCAVP-HV-IPV-2017-report.pdf. Last accessed July 15, 2026.

53. Calton JM, Cattaneo LB, Gebhard KT. Barriers to help seeking for lesbian, gay, bisexual, transgender, and queer survivors of intimate partner violence. Trauma Violence Abuse. 2016;17(5):585-600.

54. Bhandari M, Dosanjh S, Tornetta P 3rd, Matthews D, Violence Against Women Health Research Collaborative. Musculoskeletal manifestations of physical abuse after intimate partner violence. J Trauma. 2006;61(6):1473-1479.

55. Capaldi DM, Knoble NB, Shortt JW, Kim HK. A systematic review of risk factors for intimate partner violence. Partner Abuse. 2012;3(2):231-280.

56. Center for Justice Innovation. Intimate Partner Violence Risk Assessments and Models. Available at https://dvrisc.org/domestic-violence-homicide-prevention-tools-strategies-assessments. Last accessed July 15, 2026.

57. Sprague S, Madden K, Simunovic N, et al. Barriers to screening for intimate partner violence. Women Health. 2012;52(6):587-605.

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.

45122 • Strategies for Appropriate Opioid Prescribing: The Florida Requirement

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

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

Table of Contents

45122 • Strategies for Appropriate Opioid Prescribing: The Florida Requirement

Course Overview
Audience
Accreditations & Approvals
Designations of Credit
Special Approvals
Course Objective
Learning Objectives
Faculty
Faculty Disclosure
Division Planner
Division Planner 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
CONCURRENT USE OF BENZODIAZEPINES
CONSULTATION AND REFERRAL
MEDICAL RECORDS

PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

DISCONTINUING OPIOID THERAPY

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

5. 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

45122 • Strategies for Appropriate Opioid Prescribing: The Florida Requirement

Education Category. Pharmacology

Release Date. 09/01/2024

Expiration Date. 08/31/2027

Course Overview

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

Audience

This course is designed for all physicians and osteopath physicians 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

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. 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. 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. NetCE is authorized by IACET to offer 0.2 CEU(s) for this program.

Special Approvals

This course, offered by the NetCE Physicians Professional Association, is approved by the Florida Board of Medicine to fulfill the Florida requirement for 2 hours on the safe and effective prescribing of controlled substance medications. This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

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

Learning Objectives

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

1. 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 Planner

John M. Leonard, MD

Division Planner Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

Implicit Bias in Health Care

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

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

1. INTRODUCTION

Pain is the leading reason for seeking medical care, and pain management is a large part of many healthcare professionals' practice. Opioid analgesics are approved by the U.S. Food and Drug Administration (FDA) for moderate and severe pain and are broadly accepted in acute pain, cancer pain, and end-of-life care, but are controversial in chronic noncancer pain. In response to the long-standing neglect of severe pain, indications for opioid analgesic prescribing were expanded in the 1990s, followed by inappropriate prescribing and increasing abuse, addiction, diversion, and overdose through the 2000s. In tandem with the continued under-treatment of pain, these practice patterns led to needless suffering from uncontrolled pain, opioid analgesic addiction, and overdose. Opioid analgesic prescribing and associated overdose peaked in 2011 with both now in multi-year decline, 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]. 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 non-addicted patients with chronic pain of misusing or abusing their prescribed opioid and in the failure to detect treatment-emergent opioid problems. 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 extent of educational exposure in school. A 2011 study found that U.S. medical school students received a median 7 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].

In 2011, the American Society of Addiction Medicine (ASAM) published their latest revision in defining the disease of addiction. In 2018, ASAM's board recognized the need for an updated definition of addiction that would be more accessible to its stakeholder groups, including patients, the media, and policymakers. Accordingly, the Board appointed a Task Force that revised the definition of addiction for use in ASAM's policy statements. The revised 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.

3. EPIDEMIOLOGY OF CHRONIC PAIN AND OPIOID MISUSE

Chronic pain affects about 100 million American adults—more than the total affected by heart disease, cancer, and diabetes combined [2]. 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 have been returning from military action in Afghanistan and Iraq with traumatic injuries and chronic pain, and veterans' care clinicians have been reporting 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]. This is refuted by the following data showing that national opioid analgesic prescribing and overdose peaked in 2011 and are in multiyear decline.

According to a report from the National Forensic Laboratory Information System (NFLIS), prescription reports for hydrocodone increased dramatically from 2001 to 2010, but then steadily decreased through 2019. Oxycodone reports increased steadily from 2001 to 2004, and again from 2006 to 2010, and then steadily declined through 2019 [18]. Methadone prescribing data were not captured in the report.

Opioid analgesic-associated overdose fatalities have also decreased since 2011, despite published Centers for Disease Control and Prevention (CDC) data reporting a sharp rise in opioid analgesic fatalities in 2014 [19]. This increase was the result of the CDC adding clandestine fentanyl fatalities to figures for prescription opioids in 2014, a difference of more than 4,000 fatalities [20]. The CDC acknowledged this and presented revised 2014 figures with clandestine fentanyl overdoses removed, which supports the belief that opioid analgesic-associated overdose fatalities peaked in 2011 [21,22,23].

Opioid analgesic prescribing in the United States has declined from the 2011 peak but remains substantially higher than 1990. Before 1990, physicians seldom prescribed opioids for chronic noncancer pain. By the mid-2000s, 1 of 25 adults was prescribed an opioid for chronic pain, and annual opioid analgesic sales totaled more than $9 billion [25]. 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 been successful but have come at a cost to patients who have faced increasing barriers to access, including stigma and abuse in a healthcare system, tapering of opioids without consideration for pain or functional improvements, and difficulty finding a physician [14,26].

Many prescribed opioid analgesic fatalities result from the co-ingestion central nervous system (CNS)/respiratory depressants (especially benzodiazepines) or prescribed methadone. According to the National Institute on Drug Abuse (NIDA), deaths involving benzodiazepines rose from 1,135 in 1999 to 11,537 in 2017. In 2021, nearly 14% of persons who died of an opioid overdose also tested positive for benzodiazepines [30,31]. 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% [32]. This is significant considering that dispensed benzodiazepine prescriptions increased more than 36% between 1996 and 2013 [34]. Additionally, many users obtain benzodiazepines by getting prescriptions from more than one doctor, forging prescriptions, or buying the drugs illicitly. Alprazolam and clonazepam are the two most frequently encountered benzodiazepines on the illicit market [18].

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 [35,36]. In 2022, opioids accounted for 79% of fatal drug overdoses in the state [35]. In 2015, Florida experienced an increase in oxycodone-caused deaths, the first in six years [27]. These trends 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 [37,38]. In May 2017, 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 [38]. As part of this order, the State Health Officer has issued a standing order for opioid antagonists to ensure emergency responders have access [38]. In 2022, the Florida Department of Health issued a statewide Standing Order for Naloxone, which authorizes pharmacists to dispense certain naloxone formulations to emergency responders for administration to persons exhibiting signs of opioid overdose [24].

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. Analyses of data from 2013–2015 indicate sharp increases in overdose fatalities in Florida linked to counterfeit alprazolam, oxycodone, and hydrocodone tablets that contained fentanyl [39]. 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 [40].

In Florida, fatalities with benzodiazepines present peaked in 2010 with 6,188, falling to 1,761 in 2023 (32% were alprazolam) [41]. Other primary contributors to opioid analgesic-related fatalities include alcohol and prescribed methadone [30,42].

In addition to the executive order issued in 2017, several new state laws were passed in 2018 to impose additional legal requirements on controlled substance prescribers [43]. 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 updated opioid prescribing guidelines for chronic pain that address 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 [44]. In addition, the CDC further updated guidance against the misapplication of this guideline in 2019, noting that some policies and practices attributed to the guideline were inconsistent with the recommendations [45]. In response to this and to the availability of new evidence, the CDC published an updated guideline in 2022 [4]. The updated clinical practice guideline is intended to achieve improved communication between clinicians and patients about the risks and benefits of pain treatment, including opioid therapy for pain; improved safety and effectiveness for pain treatment, resulting in improved function and quality of life for patients experiencing pain; and a reduction in the risks associated with long-term opioid therapy, including opioid use disorder, overdose, and death [4]. It is important to remember that inappropriately limiting necessary opioid medications to address patients' pain can be damaging and should be avoided. A central tenet of the updated 2022 guideline is that acute, subacute, and chronic pain needs to be appropriately and effectively treated regardless of whether opioids are part of a treatment regimen [4].

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 can be considered for a trial of opioid therapy [44,52]. Initial treatment should always be considered individually determined and as a trial of therapy, not a definitive course of treatment [53].

ACUTE PAIN

Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids in a quantity no greater than that needed for the expected duration of severe pain. In most cases, three days or less will be sufficient; more than seven days will rarely be needed [44]. However, payers and health systems should not use the 2022 guideline to set rigid standards related to dosage or duration of opioid therapy. The guideline is not a replacement for clinical judgment or individualized, patient-centered care [5].

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 [54]:

- 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 [55,56,57].

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; these guidelines are forthcoming [54].

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 can help the clinician to 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 should be considered for an additional level of monitoring and provider contact, and high-risk patients are likely to require intensive and structured monitoring and follow-up contact, additional consultation with psychiatric and addiction medicine specialists, and limited supplies of short-acting opioid formulations [44,58].

Table 1: RISK STRATIFICATION FOR PATIENTS PRESCRIBED OPIOIDS

Low Risk

No or well-defined and controlled personal or family history of alcohol/substance use disorder

No or minimal co-occurring psychiatric disorders or medical comorbidities

Age 45 years or older

High levels of pain acceptance and active coping strategies

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

Medium Risk

Moderate concomitant psychiatric disorders, well controlled by therapy

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

History of personal or family alcoholism/substance abuse/addiction

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

Pain involving more than three regions of the body

High Risk

Widespread pain without objective signs and symptoms

Pain involving more than three regions of the body

Aberrant drug-related behavior

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

Major psychologic disorders

Age younger than 45 years

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

Source: [1,59,60,61]

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 [51].

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

- Pain indications for opioid therapy

- Nature and intensity of pain

- Past and current pain treatments and patient response

- Comorbid conditions

- Pain impact on physical and psychologic function

- Social support, housing, and employment

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

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

- Patient history of physical, emotional, or sexual abuse

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 unlikely to respond to opioids and other pain therapies, but successful treatment of depression can promote analgesia [62].

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 a treatment/recovery program or other arrangements 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 [44,63].

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 [64].

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 [65,66].

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 [67,68].

Screening Instrument or Substance Abuse Potential (SISAP)

The Screening Instrument or Substance Abuse Potential (SISAP) tool is a self-administered, five-item questionnaire addressing history developed to predict the risk of opioid misuse. The SISAP is used to identify patients with a history of alcohol/substance abuse and improve pain management by facilitating focus on the appropriate use of opioid analgesics and therapeutic outcomes in the majority of patients who are not at risk of opioid abuse, while carefully monitoring those who may be at greater risk [69].

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 [70].

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 [71]. Patients scoring lower on the DIRE tool are poor candidates for long-term opioid analgesia.

Mental Health Screening Tool

The Mental Health Screening Tool is a five-item screen that asks about a patient's feelings of happiness, calmness, peacefulness, nervousness, and depression in the past month [72]. A lower score on this tool is an indicator that the patient should be referred to a specialist for pain management.

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 [1,44]. 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) [54].

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 nonopioid and immediate-release opioids over long-acting/extended-release opioids. Taper opioid dose when no longer needed [63].

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 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.

Non-Opioid Analgesics

Nonopioid 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 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.

Informed Consent and Treatment Agreements

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

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

PERIODIC REVIEW AND MONITORING

Evidence Based Practice Recommendation

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

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

Last Accessed: August 23, 2024

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

When implementing a chronic pain treatment plan that involves the use of opioids, the patient should be frequently reassessed for changes in pain origin, health, and function [1]. This can include input from family members and/or the state PDMP. During the initiation phase and during any changes to the dosage or agent used, patient contact should be increased. At every visit, chronic opioid response may be monitored according to the "5 A's" [1,75]:

- 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 or 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 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. Family members can observe whether a patient is losing control of his or her life or becoming less functional or more depressed during the course of opioid therapy. They can also provide input regarding positive or negative changes in patient function, attitude, and level of comfort. The following questions can be asked of family members or a spouse to help clarify whether the patient's response to opioid therapy is favorable or unfavorable [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 [77]:

- 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 [58]. Sample questions include: In the past 30 days, how often have you had to take more of your medication than prescribed? In the past 30 days, how much of your time was spent thinking about opioid medications (e.g., having enough, taking them, dosing schedule)?

Pain Assessment and Documentation Tool (PADT)

Guidelines by the CDC, the Federation of State Medical Boards (FSMB), and the Joint Commission stress the importance of documentation from both a healthcare quality and medicolegal perspective. Research has found widespread deficits in chart notes and progress documentation 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. However, the potential aberrant drug-related behavior section must be completed by the physician based on his or her observations of the patient [80].

The Brief Intervention Tool

The Brief Intervention Tool is a 26-item, "yes-no," patient-administered questionnaire used to identify early signs of opioid abuse or addiction. The items assess the extent of problems related to drug use in several areas, including drug use-related functional impairment [72].

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 2016 guideline recommends clinicians should use UDT before starting opioid therapy and consider UDT at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs [44]. However, this recommendation was based on low-quality evidence that indicates little confidence in the effect estimate, and it is not included in the 2022 updated guideline [4].

Table 2: PATIENT RISK LEVEL AND FREQUENCY OF MONITORING

Monitoring Tool | Patient Risk Level
Low | Medium | High
Urine drug test | Every one to two years | Every 6 to 12 months | Every three to six months
State prescription drug monitoring program | Twice per year | Three times per year | Four times per year

Source: [81]

CONCURRENT USE OF BENZODIAZEPINES

In 2021, nearly 14% of persons who died of an opioid overdose also tested positive for benzodiazepines, a class of sedative medication commonly prescribed for anxiety, insomnia, panic attack, and muscle spasm [8]. Benzodiazepines work by raising the level of the neurotransmitter gamma-aminobutyric acid (GABA) in the brain. Common formulations include diazepam, alprazolam, and clonazepam. Combining benzodiazepines with opioids is unsafe because both classes of drug cause central nervous system depression and sedation and can decrease respiratory drive—the usual cause of overdose fatality. Both classes have the potential for drug dependence and addiction.

The CDC recommends that healthcare providers use caution when prescribing benzodiazepines concurrently with opioids whenever possible [4]. If a benzodiazepine is to be discontinued, the clinician should taper the medication gradually, because abrupt withdrawal can lead to rebound anxiety and complications such as hallucinations, seizures, delirium tremens, and, in rare instances, death. The rate of tapering should be individualized [4].

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 guide with information on the patient's specific medications, instructions for emergency situations and incomplete pain control, and warnings not to share medications or take them unprescribed [63]. A copy of this form may be accessed online at https://www.accessdata.fda.gov/drugsatfda_docs/rems/ERLA_opioids_2016-04-26_Patient_Counseling_Document.pdf[83].

When prescribing opioids, clinicians should provide patients with the following information [63]:

- 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 [84]. 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 [85]. 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]. The FDA provides a free toolkit of materials (e.g., social media images, fact sheets, posters) to raise awareness of the serious dangers of keeping unused opioid pain medicines in the home and with information about safe disposal of these medicines. The Remove the Risk Outreach toolkit is updated regularly and can be found at https://www.fda.gov/drugs/ensuring-safe-use-medicine/safe-opioid-disposal-remove-risk-outreach-toolkit[86]. 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. In 2023, the FDA issued a letter requiring all manufacturers of opioid analgesics dispensed in outpatient settings to submit a proposed modification to the Opioid Analgesic REMS. The modification requires manufacturers to make available prepaid mail-back envelopes to outpatient pharmacies and other opioid dispensers as an opioid analgesic disposal option for patients [9].

The American College of Preventive Medicine has established best practices to avoid diversion of unused drugs and educate patients regarding drug disposal [84]:

- Consider writing prescriptions in smaller amounts.

- Educate patients about safe storing and disposal practices.

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

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

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

DISCONTINUING OPIOID THERAPY

The decision to continue or end opioid prescribing should be based on a physician-patient discussion of the anticipated benefits and risks. An opioid should be discontinued with resolution of the pain condition, intolerable side effects, inadequate analgesia, lack of improvement in quality of life despite dose titration, deteriorating function, or significant aberrant medication use [1,44].

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].

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 [87]. Since the first community-based opioid overdose prevention program began distributing naloxone in 1996, more than 10,000 overdoses have been reversed [87].

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 [88]. Emergency responders include (but are not limited to) law enforcement officers, paramedics, and emergency medical technicians [88]. As noted, there is a statewide standing order for naloxone for all emergency responders in Florida [38].

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 [89].

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 [90]. In 2014, the FDA approved naloxone as an autoinjector dosage form for home use by family members or caregivers, and in 2015, the agency approved intranasal naloxone after a fast-track designation and priority review. Intranasal naloxone is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression [91,92].

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 pre-filled auto-injection device. The intranasal formulation is available in doses of 2 mg, 4 mg, or 8 mg [93]. In 2023, the FDA approved Narcan, the first over-the-counter naloxone nasal spray [69]. Narcan is available as a 3-, 4-, or 8 -mg single dose, administered in one nostril [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 [95].

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 [96]. 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 [97]. This law establishes the standards for controlled substance prescribing, including reporting system requirements, for prescribers and pharmacists in Florida. At the time of publication of this course, the Florida schedule of controlled substances aligns with the DEA schedule [43].

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].

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 [99]. This is mandated even for existing patients and should be done each time a controlled substance is prescribed or dispensed [43]. 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 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 [99]. This should be repeated each time the substance is dispensed. This reporting requirement is waived in certain circumstances, including for [99]:

- All acts of administration of a controlled substance

- 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

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 2021 National Survey on Drug Use and Health asked non-medical users of prescription opioids how they obtained their most recently used drugs [100]. Among persons 12 years of age or older, 33.9% obtained their prescription opioids from a friend or relative for free, 39.3% got them through a prescription from one doctor (vs. 17.3% in 2009–2010), 7.3% bought them from a friend or relative, and 3.7% took them from a friend or relative without asking [100]. Other sources included a drug dealer or other stranger (7.9%); multiple doctors (3.2%); and theft from a doctor's office, clinic, hospital, or pharmacy (0.7%) [100].

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 [50]. 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 [49].

In addition to aberrant urine screens, there are certain behaviors that are suggestive of an emerging opioid use disorder. The most suggestive behaviors are [47,48,82]:

- 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 [47,48,82]:

- 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" [84]. In addition, patients should be aware of the many options available to treat chronic pain aside from opioids. To prevent theft, patients should be advised to keep medications in a private place and to refrain from telling others about the medications being used.

Communication among providers and pharmacies can help to avoid inappropriate attainment of prescription drugs through "doctor shopping." Prescribers should keep complete and up-to-date records for all controlled substance prescribing. When possible, electronic medical records should be integrated between pharmacies, hospitals, and managed care organizations [84]. 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 [84].

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 [46,84]. 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 [46].

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, "Physicians have an obligation to support continuity of care for their patients. 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" [33]. The notice of termination should be sent in writing, should specifically note the causes for the termination, and should give a period of time prior to termination, usually 30 days [29]. 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 [28].

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(3):1-95. Available at https://www.cdc.gov/mmwr/volumes/71/rr/rr7103a1.htm. Last accessed August 23, 2024.

96183 • Anxiety Disorders

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2025 NetCE, All rights reserved.

Anxiety disorders are characterized by states of chronic, excessive dread or fear of everyday situations. The fear and avoidance can be life-impairing and disabling. Anxiety disorders result from the interaction of biopsychosocial factors, whereby genetic vulnerability interacts with situations, stress, or trauma to produce clinically significant syndromes. The influence from hereditary factors and adverse psychosocial experiences on anxiety disorder pathogenesis and pathophysiology is complex, but neuroscience advances have greatly improved the understanding of the underlying factors in the development and maintenance of anxiety disorders.

Table of Contents

96183 • Anxiety 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. BACKGROUND

SAFETY BEHAVIORS AND SIGNALS

PRIMARY FEATURES OF ANXIETY AND RELATED DISORDERS

3. OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

PAST YEAR AND LIFETIME PREVALENCE
OVERALL RISK FACTORS
CLINICAL COURSE
COMORBID DEPRESSION
SPECIFIC DISORDERS

4. ETIOLOGY AND PATHOPHYSIOLOGY

ANXIETY DISORDERS IN GENERAL
GENERALIZED ANXIETY DISORDER
PANIC DISORDER
AGORAPHOBIA
SOCIAL ANXIETY DISORDER
SPECIFIC PHOBIA
ADULT SEPARATION ANXIETY DISORDER

5. CLINICAL AND DIAGNOSTIC FEATURES

GENERALIZED ANXIETY DISORDER
PANIC ATTACKS
PANIC DISORDER
AGORAPHOBIA
SOCIAL ANXIETY DISORDER
SPECIFIC PHOBIA
SEPARATION ANXIETY DISORDER
SELECTIVE MUTISM

6. ASSESSMENT

SCREENING FOR ANXIETY DISORDERS IN THE PRIMARY CARE SETTING

SCREENING TOOLS
IDENTIFYING PATIENTS WHO REQUIRE TREATMENT
PATIENT HISTORY
PHYSICAL EXAMINATION
DIFFERENTIAL DIAGNOSIS

7. GENERAL TREATMENT CONSIDERATIONS

PREDICTORS OF WORSE TREATMENT RESPONSE AND OUTCOMES

OVERLAPPING PSYCHOLOGIC AND DRUG THERAPY MECHANISMS

PSYCHOTHERAPIES: OVERVIEW
PHARMACOTHERAPY: OVERVIEW
CLINICAL ISSUES

8. TREATMENT OF GENERALIZED ANXIETY DISORDER

PSYCHOTHERAPY

PHARMACOTHERAPY

9. TREATMENT OF PANIC DISORDER

PSYCHOTHERAPY
PHARMACOTHERAPY
SSRI/SNRI

10. TREATMENT OF AGORAPHOBIA

PSYCHOTHERAPY

PHARMACOTHERAPY

CONTRIBUTING FACTORS TO PANIC DISORDER WITH AGORAPHOBIA TREATMENT RESPONSE

11. TREATMENT OF SOCIAL ANXIETY DISORDER

PSYCHOTHERAPY

PHARMACOTHERAPY

12. TREATMENT OF SPECIFIC PHOBIA

PSYCHOTHERAPY

PHARMACOTHERAPY

A NOVEL APPROACH COMBINING MEDICATION AND EXPOSURE THERAPY

13. TREATMENT OF SEPARATION ANXIETY DISORDER

PSYCHOTHERAPY

PHARMACOTHERAPY

14. EMERGING THERAPIES AND NOVEL TREATMENT APPROACHES

NEUROENHANCING AGENTS TO AUGMENT EXPOSURE THERAPY

CAPNOMETRY-ASSISTED RESPIRATORY TRAINING
NEUROMODULATION THERAPIES
NEW OR NOVEL ANXIOLYTIC AGENTS

15. COMPLEMENTARY/ALTERNATIVE THERAPIES

HERBAL PRODUCTS AND SUPPLEMENTS
EXERCISE THERAPY
YOGA

16. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

96183 • Anxiety Disorders

Education Category. Psychiatric / Mental Health

Release Date. 05/01/2025

Expiration Date. 04/30/2028

Course Overview

Anxiety disorders are characterized by states of chronic, excessive dread or fear of everyday situations. The fear and avoidance can be life-impairing and disabling. Anxiety disorders result from the interaction of biopsychosocial factors, whereby genetic vulnerability interacts with situations, stress, or trauma to produce clinically significant syndromes. The influence from hereditary factors and adverse psychosocial experiences on anxiety disorder pathogenesis and pathophysiology is complex, but neuroscience advances have greatly improved the understanding of the underlying factors in the development and maintenance of anxiety disorders.

Audience

This course is designed for health and mental health providers involved in the identification, treatment, and care of patients with anxiety disorder.

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 15 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 15 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 15 ANCC contact hour(s). NetCE designates this continuing education activity for 10 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 18 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 15 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. NetCE designates this activity for 15 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-25-030-H01-P. 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 15 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 15 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 15 credit hour(s). AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 1.5 CEU(s) for this program.

Individual State Nursing Approvals

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

Special Approvals

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

Course Objective

The purpose of this course is to provide healthcare professionals with the knowledge and skills necessary to appropriately identify and treat patients with anxiety disorders, addressing knowledge gaps, enhancing clinical skills, and improving patient outcomes.

Learning Objectives

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

1. Review basic concepts related to anxiety disorders, including safety behaviors/signals and primary features.

2. Outline the epidemiology of anxiety disorders in the United States.

3. Describe general risk factors for and comorbidities of anxiety disorders.

4. Describe risk factors for and the clinical course of specific anxiety disorders.

5. Discuss the pathogenesis of anxiety disorders in relation to contributing genetic, physiologic, and psychologic factors.

6. Review the pathophysiology of specific anxiety disorders, including social anxiety disorder, agoraphobia, and specific phobia.

7. Apply the clinical and diagnostic criteria for anxiety disorders presented in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).

8. Analyze key components of screening and select appropriate screening tools for identification of anxiety disorders.

9. Conduct an informed clinical evaluation and select laboratory testing, in consideration of the differential diagnosis of anxiety disorders.

10. Describe general treatment considerations for anxiety disorders, including predictors of response or nonresponse to therapy.

11. Discuss the role and efficacy of psychotherapy approaches in the treatment of anxiety disorders.

12. Select a pharmacotherapy option appropriate to a given patient's specific diagnosis, age, and comorbidities.

13. Devise a strategy for management and follow-up designed to improve outcomes.

14. Provide patient education more effectively, in relation to specific anxiety disorders.

15. Address the efficacy, safety and limitations of novel, emerging, and alternative/complementary approaches to the treatment of anxiety disorders.

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

John V. Jurica, MD, MPH

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

Randall L. Allen, PharmD

Division Planners Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

Implicit Bias in Health Care

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

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

1. INTRODUCTION

Anxiety is an extreme form of worry, life's adaptative response to perceived impending physical and emotional threats both large and small; as such, anxiety focuses attention and, if necessary, prompts one to prepare for "fight or flight." Small moments of anxiety are useful and expected in the course everyday life; such experiences are transient, having no significant impact on social and occupational activities. Anxiety disorders are maladaptive forms of excessive apprehension and fearfulness—taxing, counter-productive, robbing life of its productivity and joy.

Anxiety disorders are characterized by several distinct clinical patterns that share a common refrain: acute exacerbation and chronic states of excessive worry and apprehension around otherwise normal circumstance and everyday situations. Anxiety syndromes include fearfulness in response to social and performance expectations, situational and triggered panic attacks, general (anticipatory) anxiety states, and avoidance (safety) behaviors. The diagnosis of anxiety disorder requires that the patient has experienced a certain number of symptoms or symptomatic episodes for more than a minimum specified period, causing significant personal distress and impairing everyday function [3,350].

Anxiety disorders are thought to develop from the interaction of genetic predisposition in the face of perceived overwhelming challenges to self—biopsychosocial stress or trauma that leads to clinically significant syndromes. The influence of hereditary factors and adverse psychosocial experiences on pathogenesis and pathophysiology is complex, but neuroscience advances have greatly improved the understanding of the underlying factors in the development and maintenance of anxiety disorders.

2. BACKGROUND

SAFETY BEHAVIORS AND SIGNALS

Safety behaviors are coping tactics used by persons with anxiety disorders to prevent, escape from, or diminish the severity of a perceived threat. Safety behaviors are particularly common in persons with panic disorder, agoraphobia, and social anxiety disorder. These behaviors emerge in response to external (e.g., situations, persons, activities) and/or internal (e.g., thoughts, emotions, memories) foci of perceived threat and are either anticipatory (avoidant) or consequential (escape) [1]. While safety behaviors may provide some measure of immediate relief, they have no impact on the individual's propensity for anxiety, nor do they diminish the frequency and severity of future symptomatic events. However, assessment of safety behavior provides guidance for implementing targeted interventions, and accurate assessment and elimination of safety behaviors is often necessary to maximize treatment of clinical anxiety [351].

Another coping mechanism observed in persons with anxiety disorder is safety signals, defined as the people or objects used to diminish distress in situations that elicit anxiety. Safety signals are also potentially counterproductive; they offer immediate relief but facilitate persistence of the anxiety disorder over time by preventing direct confrontation of feared stimuli in the absence of "safe" objects/people and by maintaining perceptions of risk/harm and coping inability. A patient's continued use of safety signals impedes therapeutic progress, in particular the response to exposure therapy. However, safety behaviors may be helpful early in treatment by making exposure therapy more tolerable and less threatening [1].

PRIMARY FEATURES OF ANXIETY AND RELATED DISORDERS

The distinguishing features of specific anxiety disorders are summarized in the following section. Related conditions of post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD) are included because, although no longer classed as anxiety disorders by the 2013 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), they are often included in research that pre-dates 2013 and can co-occur with anxiety disorders [2]. Situations or objects that evoke intense anxiety in patients with agoraphobia, social anxiety disorder, or specific phobia are either avoided or endured with significant personal distress.

Generalized Anxiety Disorder

Generalized anxiety disorder (GAD) is characterized by repetitive thinking and intrusive worrying about potentially harmful future events that is persistent (lasting more than a few months) and not restricted to circumstances [3]. While recognizing that some degree of worry may be helpful, patients with GAD report experiencing excessive, uncontrollable worry causing distress or impairment. These patients have physical anxiety symptoms and key psychologic symptoms (i.e., restlessness, fatigue, difficulty concentrating, irritability, muscle tension, and disturbed sleep). GAD is often comorbid with major depression, panic disorder, phobic anxiety disorders, health anxiety, and OCD [3].

Panic Disorder

Panic disorder is characterized by recurrent unexpected surges of severe anxiety ("panic attacks"), with varying degrees of anticipatory anxiety between attacks [3]. Panic attacks are characterized by sudden onset of intense fear (terror) accompanied by such symptoms as uncontrollable trembling, sweating, palpitations, dizziness, shortness of breath, numbness and tingling, and chest pain. These attacks are often incapacitating, typically peak within 10 minutes and last around 30 to 45 minutes. Most patients also develop a fear of having future panic attacks, which is considered a key element in classifying such episodes as panic disorder [3].

Agoraphobia

Around two-thirds of patients with panic disorder develop agoraphobia, defined as fear or avoidance of places or situations from which escape might be difficult or where help might not be available in the event of a panic attack [3]. These places or situations can include crowds, public transportation, or being alone outside of the home [2].

Social Anxiety Disorder

Social anxiety disorder (SAD) is characterized by excessive worry and apprehension in anticipation of social interactions and situations, specifically a fear of being negatively evaluated/judged by others (resulting in embarrassment or humiliation) in social group settings [3]. It is associated with physical and psychologic anxiety symptoms.

Specific Phobia

Specific, simple, or isolated phobia is excessive and unreasonable fear/avoidance of specific objects or situations such as animals (e.g., snakes, insects); the natural environment (e.g., heights, storms); closed spaces (e.g., elevators, caves); or procedures (e.g., venipuncture, dental examination) [3]. Individuals with specific phobia disorder recognize that their specific fear/avoidance reaction is unreasonable but find it intensely distressing or interfering with everyday life. The most common phobias reported by adults involve animals, heights, and flying.

Separation Anxiety Disorder

Adult separation anxiety disorder (SEPAD) is characterized by fear or anxiety concerning separation from those to whom an individual is attached. Common features include excessive distress when experiencing or anticipating separation from home and persistent and excessive worries about potential harms to attachment figures or untoward events that might result in separation [3].

Post-Traumatic Stress Disorder

PTSD is the persistent fear or episodic severe emotional distress that follows actual or threatened death, serious injury, or psychological shock to the physical integrity of self or others (the trauma), with ongoing intrusive symptoms related to the traumatic event. Exacerbations are often triggered by recollections, flashbacks, or dreams; manifestations include avoidance symptoms (e.g., efforts to avoid activities or thoughts associated with the trauma), negative alterations in cognition and mood, and hyper-arousal symptoms (e.g., disturbed sleep, hypervigilance, exaggerated startle response) [2].

Obsessive-Compulsive Disorder

OCD is characterized by recurrent uncontrollable thoughts and ruminations (obsessions) that lead to restlessness and anxiety, followed by impulsive/repetitive physical or mental rituals (compulsions) to alleviate distress. The obsessive-compulsive behaviors are destressing and time-consuming, which impedes normal social and occupational function. Common obsessions relate to fear of personal contamination, accidents, and religious or sexual matters; common rituals include washing, checking, cleaning, counting, and touching [3].

Illness Anxiety Disorder

Illness anxiety disorder is a somatic-symptom related disorder characterized by excessive or disproportionate preoccupations with having or acquiring a serious illness. This includes excessive health-related behaviors and high levels of alarm about personal health status [3].

3. OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

Taken together, anxiety disorders (DSM-5 plus PTSD and OCD) have a 12-month prevalence of approximately 19% in the United States, and a lifetime prevalence of approximately 29% [4,5]. The pattern of sex distribution is consistent among anxiety disorders, and the prevalence of any anxiety disorder is higher for girls/women (23%) than for boys/men (14%) [5,6]. Anxiety disorder is more prevalent among adolescents 13 to18 years of age (32%) but less severe, with only 8% having experienced severe impairment. The prevalence of anxiety disorder gradually declines with age, from a high of 23% among all persons 30 to 44 years of age to 9% among those older than 60 years of age. Among surveyed adults having any anxiety disorder, the proportional severity of impairment associated with symptomatic episodes occurring in the previous year was 43% mild, 34% moderate, and 23% serious [5].

PAST YEAR AND LIFETIME PREVALENCE

The reported data on anxiety disorders in the United States include 12-month prevalence, lifetime prevalence, and lifetime morbid risk (Table 1). The two lifetime measures differ. Lifetime prevalence measures the proportion of the population currently or previously diagnosed with the disorder, while lifetime morbid risk measures the proportion who may develop the disorder at some point, independent of their lifetime history at the time of assessment. By including future cases, lifetime morbid risk is believed to be more accurate. Lifetime prevalence and lifetime morbid risk are usually equivalent for disorders with early-life onset, but diverge for disorders with increasingly later onset. The ratio of lifetime prevalence to lifetime morbidity risk falls below 1.0 in disorders with increasingly later onset; the further the ratio values fall below 1.0, the later the median age of onset [7].

Table 1: COMPARISON OF PREVALENCE, MORBID RISK, AND RATIO OF LIFETIME PREVALENCE TO MORBID RISK FOR ANXIETY DISORDERS

Anxiety Disorder | 12-month | Lifetime | Lifetime Morbid Risk | Lifetime/Lifetime Morbid Risk
Generalized anxiety disorder | 2.0% | 4.3% | 9.0% | 0.5
Panic disorder | 2.4% | 3.8% | 6.8% | 0.5
Agoraphobia | 1.7% | 2.5% | 3.7% | 0.7
Social anxiety disorder | 7.4% | 10.7% | 13.0% | 0.8
Specific phobia | 12.1% | 15.6% | 18.4% | 0.8
Separation anxiety disorder | 1.2% | 6.7% | 8.7% | 0.8

Source: [7]

Anxiety disorders with earlier median age of onset are phobias and separation anxiety disorder (15 to 17 years of age), and those with latest age of onset are panic disorder and generalized anxiety disorder (23 to 30 years of age). Lifetime morbid risk is considerably higher than lifetime prevalence for most anxiety disorders, with magnitude of difference much higher for disorders with later than earlier age of onset. Also, the ratio of 12-month to lifetime prevalence roughly reflects persistence but varies meaningfully in ways consistent with differential persistence of these disorders [7].

OVERALL RISK FACTORS

Demographic

The odds for a lifetime diagnosis of any anxiety disorder were calculated, and the same pattern was found for past 12 month diagnosis [8]. These odds are organized according to sex, socioeconomic status, education level, and age. Overall, the risk of developing an anxiety disorder is greater for women/girls than men/boys.

Persons in lower income brackets also incur an increased odds of developing an anxiety disorder compared with those in higher income brackets (48% increased risk with $35,000 to $69,000; 52% with $20,000 to $34,000; 100% with $19,000 or less). Lower educational attainment is also a risk factor. Compared with college graduates, the odds of developing an anxiety disorder are increased 44% with 13 to 15 years of education, 76% with 12 years of education, and 86% with 0 to 11 years of education. These disorders are also 40% more likely in persons 15 to 24 years of age compared with older adults (45 to 54 years of age) [8].

Behavioral Inhibition and Temperament

Behavioral inhibition has been defined as a childhood temperament characterized by high levels of caution, avoidance, and fearful response to unfamiliar people, objects, and situations [352]. Children who display behavioral inhibition may exhibit limited ability to handle stress as they mature and are at increased risk of developing anxiety disorders later in life. A study of heightened anxiety in young adults during the COVID-19 pandemic found that behavioral inhibition in childhood was linked to worry dysregulation in adolescence, which in turn predicted elevated anxiety during the pandemic when participants had reached young adulthood [352,353]. Behavioral inhibition and introversion are also strongly linked to later development and severity of situational avoidance, which is a core feature and risk factor in agoraphobia and SAD [9].

CLINICAL COURSE

Anxiety disorders in the aggregate show a U-shaped age of onset—higher in childhood and young adulthood and lower in adolescence. The greatest concentration occurs during transition to early adulthood. Unlike biologically driven pubertal transitions, adulthood transitions involve distinct psychosocial events (e.g., independent living, full-time employment), and this represents a key period for understanding the development of adult anxiety disorders such as panic disorder and agoraphobia [10].

Community studies of persons with sub-diagnostic anxiety symptoms over time often show episodic symptoms and prolonged periods of remission, with symptoms reappearing or worsening during adverse life events and psychosocial stressors. In contrast, studies of clinical anxiety disorder populations typically show a chronic course with fluctuating symptom severity between periods of remission and relapse, with long-term course varying by disorder [3].

Healthcare Utilization

Distressing anxiety symptoms oftentimes consist of somatic complaints, prompting patients to visit an emergency facility or seek out a primary care provider. If anxiety disorder goes unrecognized or is considered a secondary issue, costly medical testing and delay in effective care may result. Societal costs resulting from misdiagnosis, ineffective treatment and work absenteeism attributable to anxiety disorders are substantial. The direct medical expenditure associated with anxiety in adults, including inpatient visits, prescription costs, and office-based visits is estimated at $33.7 billion annually [354]. Recognition of the patient with a pattern of subjective worrying and anxiety, coupled with validated screening, targeted examination and selective testing enhances diagnosis. Effective treatment with pharmacotherapy or cognitive-behavioral therapy (CBT) can be expected to relieve symptoms and minimize costs [2,3].

COMORBID DEPRESSION

Anxiety symptoms often co-occur with other psychologic symptoms. Depressive symptoms are highly prevalent with more severe anxiety symptoms, with anxiety and depressive symptom severity strongly correlated. Patients with anxiety disorder have high comorbidity rates of major depressive disorder (almost 50%), schizophrenia, substance use disorders, and physical illness [3,11]. Overlapping symptoms of anxiety and depression, such as sleep disturbance, fatigue, and difficulty concentrating, make differentiation challenging. Depressive disorders are sometimes termed "anxious-misery" when high levels of sadness and anhedonia are present [2]. Suicidal ideation and rates of suicide attempts are elevated in persons with anxiety disorders, and the suicide risk among patients has been reported as increased by a factor of 10 compared with the general population [54].

SPECIFIC DISORDERS

Generalized Anxiety Disorder

Epidemiology

Studies show that GAD has a 6.2% lifetime prevalence and a 2.0% to 3.1% past-year prevalence in the U.S. population [350]. The lifetime and past-year prevalences are 3.6% and 2.0% in men/boys and 6.6% and 4.3% in women/girls. Most persons with GAD diagnoses are female. The reported prevalence for GAD in primary care patient panels range 3.7% to 14.8% [54]. Childhood or adolescent onset was found in more than 50% of those seeking help for anxiety, reflecting the chronicity of the disease [2].

Risk Factors

No single etiology has been identified for GAD, but it likely involves the interaction of multiple familial/genetic and environmental risk factors. A review of twin and family studies found significant associations between GAD, other anxiety disorders, and depression, suggesting a common underlying genetic basis. A significant number of patients and their first-degree relatives develop GAD (odds ratio 6:1) [12]. Civilian trauma (e.g., motor vehicle accidents, physical or sexual assault, sudden unexpected loss of a loved one, bullying or peer victimization in childhood or adolescence) is a risk factor for GAD [13]. The presence of another anxiety disorder (e.g., panic disorder, SAD, specific phobia) is another possible factor. Panic disorder is comorbid in 25% of patients with GAD [13].

Older adults are the fastest-growing age demographic in the United States. Although late-onset GAD (on or after 65 years of age) is uncommon, clinicians should bear in mind that age-related propensity for anxiety, including the emergence of anxiety disorder, may change over the course of a lifetime. The concerns of aging that may lead to excessive worrying include personal health, the welfare of loved ones, dwindling income, loss of independence, and ability to manage one's affairs at home. The primary predictors of anxiety in the elderly include female sex, recent adverse life events, and chronic physical (e.g., respiratory and cardiac disorders, dyslipidemia, cognitive impairment) or mental health (e.g., depression, phobia, past GAD) disorders. Other risk factors include poverty, parental loss/separation or low emotional support during childhood, and history of parental mental health problems. Late-onset GAD is described as a multifactorial, stress-related affective disorder resulting from proximal and distal risk factors of which some are potentially modifiable by healthcare intervention [14].

Clinical Course

The course of GAD tends to be chronic with fluctuating symptom severity, and GAD may "switch" to other diagnoses, particularly depression and somatoform disorders [15,16]. GAD is associated with impairments in psychosocial functioning, role functioning, work productivity, and health-related quality of life comparable to major depressive disorder or panic disorder. Patients with GAD and comorbid major depression show significantly greater impairment in health-related quality of life than in either disorder alone. Primary care patients with GAD showed significantly higher annual medical costs than patients without GAD (median $2,375 versus $1,448) and higher mean annual medical costs ($2,138) than patients with other anxiety disorders. GAD is frequently under-recognized in primary care, and only 20% to 32% of patients receive adequate treatment. Suboptimal treatment adds to the health-related quality of life burden of this disorder [17].

Panic Disorder

Epidemiology

In the United States, 4% to 28% of the population experience panic attacks at some time during life. The 2.4% 12-month prevalence of panic disorder in the United States is among the highest worldwide [7,18].

Panic disorder prevalence in primary care is approximately 7%, and substantially higher in patients presenting with cardiac or gastrointestinal symptoms. Relative to white patients, the odds of developing panic attacks and panic disorder are higher in Native Americans, and lower in Asian, Hispanic, and black patients [18,19].

Panic attacks are most likely to develop in patients who are in their mid-20s and slightly earlier in men than women. Panic disorder age of onset is usually between late adolescence and 35 years of age, while the age of onset for panic disorder with agoraphobia spans the early 20s to early 30s. Panic disorder is more common among women, with a 2:1 ratio and increasing to 3:1 with panic disorder with agoraphobia. Panic symptoms during adolescence elevate risks for other anxiety and mood disorders in adulthood. Depressive disorders are highly comorbid (33% to 85%), especially among those with agoraphobia [2,20]. Panic disorder is highly comorbid with other anxiety, mood, and substance use disorders, including nicotine dependence, and cigarette smoking may increase the risk for later-onset panic disorder [21].

Risk Factors

As with GAD, the etiology of panic disorder probably results from a combination of risk factors. There is a five-fold greater risk of developing panic disorder when the disorder is present in first-degree relatives. Shared genetic factors account for 30% to 40% of panic disorder heritability [12]. In addition, major adverse life events, especially those involving physical threat (e.g., physical abuse, sexual assault, military service in a combat zone), precede the onset of panic attacks in roughly 80% of patients. Trauma history is prevalent in patients with panic disorder, especially women [22].

Behavioral inhibition may contribute to panic risk in adulthood. Learned escape and avoidance behaviors can maintain the condition and worsen functional impairment over time. Anxiety sensitivity, or the tendency to catastrophically misinterpret physical symptoms as dangerous, is a risk factor for panic disorder. Personality pathology, particularly avoidant and dependent personality traits, are predictors of panic disorder or agoraphobia development [23,24].

Asthma severity is associated with an incremental risk for panic disorder, and respiratory variability may also increase risk for later onset panic disorder [25]. Baseline respiratory abnormalities are specific to panic disorder pathophysiology [6]. As noted, cigarette smoking and nicotine dependence is disproportionately high among patients with panic disorder and may be temporally related to elevated risk for developing panic disorder [26]. Additionally, panic attacks may be related to poorer cessation outcome during smoking treatment among patients with cancer [27]. Caffeine use is also positively correlated with increased anxiety symptoms and risk of inducing panic attacks in patients with panic disorder [28].

Clinical Course

Prospective studies of panic disorder show high rates of symptom chronicity, relapse after remission, and "switching" to other diagnoses [29,30]. Panic disorder symptoms remain persistent for 50% to 80% of cases even after treatment, increasing disability and impaired quality of life [31].

Agoraphobia

Epidemiology

Agoraphobia usually, but not always, occurs with panic disorder. In community populations, about 25% of those with panic disorder also have agoraphobia, but the proportion is substantially higher in clinical populations [20].

Agoraphobia was made an independent diagnostic entity in the DSM-5, and accordingly, epidemiologic and clinical data that consider agoraphobia in the absence of panic disorder are pending. In the DSM-IV-TR, panic disorder could be specified with or without agoraphobia. Lifetime and 12-month prevalence of panic disorder with agoraphobia were 1.0% and 0.5%, respectively [32].

Risk Factors

Much of the published agoraphobia research assumes panic disorder causation or comorbidity. As such, many of the known risk factors are the same. Comorbid panic disorder and agoraphobia aggregate in families, while agoraphobia without panic disorder is non-familial but may enhance familial transmission of panic disorder [33]. The risk of agoraphobia development in patients with panic disorder is elevated with female sex, more severe dizziness during panic attacks, cognitive factors, dependent personality traits, and SAD. Panic disorder with agoraphobia is associated with greater severity and worse prognosis [34].

Longitudinal studies show low remission rates (0% to 23%) over time in panic disorder or agoraphobia, and subjects with panic disorder with agoraphobia or agoraphobia with panic attacks at baseline were more likely to develop agoraphobia, panic attacks, and other anxiety disorders and experience greater severity (e.g., impairment, disability, treatment-seeking, comorbidity) than subjects with panic disorder without agoraphobia or agoraphobia without panic attacks at baseline [35].

A late-life subtype of agoraphobia (onset at or after 65 years of age) was identified through assessing elderly patients at baseline and four years later. Baseline agoraphobia prevalence was 10.4%, and 11.2% developed agoraphobia during the four-year follow-up. Agoraphobia in the elderly, unlike younger populations, was not more common in women and not associated with panic attacks. Risk factors for late-onset agoraphobia include severe depression, trait anxiety, and poor visuo-spatial memory [36]. Incident anxiety also appears to develop in response to subjective memory complaints independent of depressive symptoms [37].

Patients with panic disorder who experience their first panic attack while driving or using public transportation had higher rates of comorbid agoraphobia. Those with first panic attack at home had higher fear-of-dying rates than with first panic attack outside of the home and felt more severe distress from their first panic attack independent of whether agoraphobia developed. Treatment of patients with panic disorder whose first panic attack was at home should address secondary aspects of fear and distress elicited by the attack [38].

Clinical Course

In persons with panic disorder with or without agoraphobia, the strongest predictors of incidence and relapse were history of panic attacks, GAD/major depression, nicotine dependence, female sex, younger age, and major financial crises. Most predictor variables were similar between panic disorder and panic disorder with agoraphobia. Clinicians should bear in mind the characteristic relapsing-remitting nature of panic disorder/panic disorder with agoraphobia in order to avoid prematurely reducing or eliminating effective treatments. Close attention should be paid to concurrent factors linked to relapse that can be clinically addressed, such as comorbid major depression, GAD, and nicotine dependence [39].

One study followed 711 participants with anxiety disorder diagnoses over 15 years. At baseline, those with early-onset (≤20 years of age) panic disorder were more likely to have comorbid major depressive disorder, GAD, and SAD. Those with early-onset panic disorder with agoraphobia were less likely to be married and more likely to have comorbid GAD and SAD. During follow-up, persons with panic disorder with agoraphobia were significantly more likely to have illness recurrence after periods of recovery, while findings for the other disorders failed to reach significance. This was thought to reflect differences in typical age of onset among anxiety disorders. The onset of panic disorder with or without agoraphobia is usually early adulthood; earlier onsets are relatively uncommon and may signal a particularly pernicious form of illness. The results further support the particularly adverse effects of early-onset psychiatric illness [40].

Social Anxiety Disorder

Epidemiology

SAD can develop at any time during a lifespan, but the average age of onset is during late childhood and adolescence. The prevalence of SAD in pre-adolescence is 3.5%, with rates increasing to about 14% during adolescence [41]. The lifetime prevalence of SAD is 13%, and the prevalence in primary care settings (7%) is high compared with that of other anxiety disorders encountered in general practice [19,350]. Gender distribution is generally equal during pre-adolescence and becomes increasingly more common in girls/women through adolescence and adulthood. An estimated 70% to 80% of individuals with SAD have comorbid anxiety, mood, or substance use disorders. There are cultural variants in Asian and Eastern cultures that involve fears of offending others or making others uncomfortable [2].

Risk Factors

A combination of biologic, familial, environmental, and cultural risk factors drive the development of SAD. Life transitions, personal loss, poverty, and experiences of humiliation or embarrassment contribute to SAD risk [42]. Compared with data from the general population, first-degree relatives are as much as six times more likely to be at risk of SAD. Concordance rates are 24% in monozygotic twins and 15% in dizygotic twins [43].

Behavioral inhibition, shyness, introversion, and anxiety sensitivity are all common among patients with SAD. Emerging early in life, behavioral inhibition is a heritable trait, and 15% to 20% of young children with behavior inhibition exhibit extreme signs. Relative to children without behavioral inhibition, these patients are typically shy, fearful, and cautious and show elevated physiologic arousal signs at rest, such as higher heart rate, increased pupil dilation, and higher cortisol levels. Brain profiles of children with behavioral inhibition show distinct patterns, including electroencephalography asymmetry, functional differences in amygdala response to facial expression challenge, and structural differences in the ventral prefrontal cortex. Roughly 40% of children with behavioral inhibition eventually develop SAD, and childhood behavioral inhibition is a primary predictor of SAD. Other components of SAD probably appear later in development, including social-evaluative concerns and coping skills deficits that contribute to functional impairment [44,45].

A bi-directional relationship exists between parenting style and childhood anxiety. Parenting styles of criticism, over-protection, over-control, and lack of warmth can create insecure attachment and risk for SAD. Likewise, temperamentally introverted and anxious children may shape and change parenting styles, with parents becoming over-protective or over-controlling [42]. Studies suggest that challenging parenting behavior (especially in fathers) may play a protective role in anxiety development in the most vulnerable children [46,47].

Early childhood anxiety disorders, especially separation anxiety and other phobias, are associated with elevated SAD risk in adulthood. SAD is highly comorbid with other anxiety disorders, mood disorders, and substance use disorders; substance abuse is often used to regulate anxiety symptoms and social skills [48].

Multiple social cues can develop the capacity to elicit anxiety-related symptoms. Learned escape and avoidance behaviors maintain anxiety, interfere with skill development, and can lead to functional impairment and disability over time. Similarly, safety behaviors, such as only entering social situations with a trusted companion, averting eye contact, and staying on the periphery of social gatherings, may maintain anxiety-related impairments. Selective attention to social cues of negative evaluation and internal cues supporting danger perception may develop [49,50].

Primary Prevention

Childhood presence of fearfulness and behavioral inhibition can lead to chronic, disabling SAD. Early recognition of childhood impairments and evidence-based treatment intervention may offset the SAD trajectory of persisting into and through adulthood. Educational-behavioral interventions involving older children/adolescents, parents, school staff, and healthcare providers have been found to reduce the development of social anxiety [51,52,53].

Clinical Course

SAD tends to run a chronic course of long duration, associated with substantial impairment of work productivity, and has a reported recovery rate of only 38% [54].

Specific Phobia

Epidemiology

Women are two to three times more likely than men to develop phobias, with the exception of blood-injection-injury phobia, which is evenly distributed by sex. Roughly 70% of individuals with specific phobia report more than one clinically relevant fear. Animals and heights are the most common stimuli, followed by flying, enclosed spaces, and blood-injection-injury. The average period of onset is 7 to 10 years of age, with declining probabilities of onset into later adulthood. Most animal phobias develop before 8 years of age [2,41,56]. The average age of treatment engagement is 31 years, although only 8% of persons with specific phobia are reported to seek treatment [56].

The odds of developing phobias are significantly less in Hispanic and Asian individuals and greater in white individuals. Animal fears are prevalent in Japan and Hong Kong [56,57].

Risk Factors

For specific phobias, familial concordance rates among first-degree relatives are moderate. The greatest heritability indices are found in animal and blood-injection-injury phobias [58,59,60].

Intense anxiety or unexpected panic responses in the presence of specific objects or situations can mark phobia onset but are not the sole causal route. Disgust, either alone or combined with fear, may trigger the onset and maintenance of animal (particularly spiders, snakes, and worms) or blood-injection-injury phobias. Onset can occur indirectly by observing others reacting fearfully. Some stimuli are more likely to induce phobias than others (e.g., animals vs. electrical outlets) through evolutionary threat relevance.

Phobia onset can be precipitated by relationship problems, relocation, employment loss, or economic difficulties. In addition, anxiety, mood, or substance use disorders can co-occur with or predate phobia onset. Substance use disorder can maintain phobic symptoms. Phobia symptoms in adolescence predict adult symptoms but are not a risk factor for developing other anxiety, mood, or substance use disorders.

Adult Separation Anxiety Disorder

Epidemiology

The lifetime prevalence of adult SEPAD is 6.6% in the general population, 12% to 40% in psychiatric clinic settings, and more than 75% among those seeking treatment at anxiety disorder clinics [61]. In adults with lifetime SEPAD, 22.5% have childhood age of onset that persisted into adulthood, while 77.5% had adult onset. Girls/women show higher overall prevalence than boys/men and substantially higher rates of childhood-onset SEPAD persisting into adulthood [62]. SEPAD and panic disorder are highly comorbid in clinical settings. Among adult patients with panic disorder, 53.2% were diagnosed with SEPAD. Patients with panic disorder and SEPAD (versus no SEPAD) were more commonly female and younger and showed higher rates of childhood SEPAD and greater lifetime prevalence of mood disorder spectrum symptoms [63].

Risk Factors

Children of adults with anxiety disorders have higher rates of anxiety disorders. Early, traumatic separation from attachment figures and a positive family history of anxiety or depressive disorders may also elevate risk of SEPAD, school phobia, and depressive-spectrum disorders during adolescence or adulthood. Early, traumatic separation can include prolonged severance of contact with the primary caregiver during the neonatal period; later sudden hospitalization; early loss of attachments from death or divorce; or an interactive pattern with an over-protective, needy, or depressed parent [64].

Clinical Course

In one study, children with SEPAD were 3.5 times more likely to later develop panic disorder and more than twice as likely to develop any anxiety disorder but did not significantly differ in later development of depression or substance use disorder. These findings were considered supportive of a developmental psychopathology model of anxiety disorders [65].

4. ETIOLOGY AND PATHOPHYSIOLOGY

ANXIETY DISORDERS IN GENERAL

Anxiety disorders are characterized by diverse neuroendocrine, neurotransmitter, and neuroanatomical disruptions, the result of interactions between multiple genetic, environmental, and social factors. Although each disorder may have unique features, this group shares some underlying pathophysiology.

Pathologic Alterations in Brain Structure and Function

Fear and anxiety are thought to involve two major brain circuits: the limbic system and the prefrontal cortex. In the limbic system, which consists of the amygdala, hippocampus, central nucleus of the amygdala, insular cortex, and cingulate cortex, emotion-processing brain structures generate primitive innate responses to simple, overtly threatening stimuli. Functions of limbic structures include processing emotionally important external stimuli and initiating behavioral responses; mediating expressions of fear, aggression, and defensive behavior; and forming and retrieving emotional and fear-related memories [66,67]. The prefrontal cortex, comprised of the orbitofrontal cortex and the prefrontal, ventromedial, and dorsomedial prefrontal cortex, dampens emotional responses to anxiety-inducing stimuli. The prefrontal cortex functions to regulate impulses, emotions, and behavior via inhibitory "top-down" control of emotional-processing structures; this works to control impulses and regulate mood [66,67].

Altered limbic and prefrontal cortex functioning characterize anxiety disorders, with amygdala hyper-responsivity to threatening stimuli and impaired ventromedial prefrontal contex inhibitory control over limbic-generated, anxiety-inducing signals, associated with aberrant communication and functional connectivity between the amygdala and the prefrontal cortex [67].

Narrowing brain region contribution, amygdala and insula hyperactivation contribute to anxiety disorders triggered by specific stimuli (e.g., panic disorder, specific phobia). The insula integrates sensory, emotional, and cognitive information through extensive connections between the lateral prefrontal cortex, ventromedial prefrontal cortex, orbitofrontal cortex, cingulate, amygdala, bed nucleus of the stria terminalis, and ventral striatum. Changes in the level of insula activation influence anxiety level [66].

Amygdala-medial prefrontal cortex functional connectivity shows a developmental trajectory, and early temperamental risk for anxiety is associated with disruption of these circuits. Aberrant amygdala-prefrontal cortex connectivity is found in patients with adult-onset anxiety disorders who showed childhood temperament risk factors but did not develop early-onset anxiety. This suggests aberrant connectivity is a lingering biomarker of risk [68].

Familial and Environmental Contribution

Persons with anxiety and mood disorders show a shared genetic predisposition, with specific manifestation the product of genetic and environmental interactions. A developmental dynamic pattern of genetic influence on individual differences in anxiety and depression symptoms is apparent. Genetic influence on psychopathology changes over the lifespan, with different developmental stages associated with a unique pattern of risk factors [67].

Significant early-life stress (e.g., maternal deprivation) may degrade prefrontal cortex functional connectivity with subcortical panic-generating circuits, elevating risks of anxiety disorders and other psychopathology. Many significant early-life stress events (e.g., child abuse, neglect, parental loss from death or abandonment) are receiving heightened attention as contributing factors to anxiety disorders and trauma pathology, as in PTSD. Previous childhood or adult trauma is considered a predisposing/contributing factor to panic disorder and SEPAD as well as major depressive disorder and PTSD that may be primary or comorbid with other anxiety disorders [69]. Aversive experiences can lead to complex behavioral adaptations, including increased levels of anxiety and fear generalization.

Alterations in Brain Transmitter Chemicals

Neurotransmitters allow communication between brain regions. Alterations in neurotransmitter systems implicated in anxiety disorder pathogenesis include the monoamines serotonin (5-hydroxytryptamine or 5-HT), norepinephrine, and dopamine. Aberrant limbic signaling is associated with decreased inhibitory signaling by gamma-amino-butyric acid (GABA) or increased excitatory neurotransmission by glutamate. Many other neurotransmitter systems participate in the modulation of fear and anxiety, including the neuropeptide substances P, N, and Y; corticotropin-releasing factor (CRF); and endocannabinoids. Abnormalities in these systems are associated with structural and functional alterations in specific brain areas, such as the amygdala, prefrontal cortex, locus coeruleus, and hippocampus, and represent the therapeutic targets of drug therapy [70].

Gene products that regulate monoamine signaling may be critical in facilitating antidepressant effect. Monoaminergic regulators include transmitter receptors; vesicular monoamine transporter, which packages monoamines into vesicles; oxytocin and vasopressin; transmitter-specific reuptake transporters, such as the serotonin transporter, norepinephrine transporter, and dopamine transporter; monoamine oxidase, which degrades monoamines; and catecholamine-O-methyltransferase, which degrades norepinephrine and dopamine [67]. However, the cause of anxiety disorders is not simply a deficiency of one neurotransmitter or excess of another. The networks governed by these transmitters are extensively inter-related, with multiple feedback mechanisms and complex receptor structures. This complexity contributes to unpredictable and sometimes paradoxical medication responses [70].

GENERALIZED ANXIETY DISORDER

Neuronal circuits implicated in GAD are distinct from panic disorder, likely involving much greater frontal and prefrontal lobe than amygdala involvement. GAD is characterized by abnormalities in frontal and limbic structures and in the connectivity between these regions. The most frequently implicated frontal regions are the prefrontal cortex and the anterior cingulate cortex; in the limbic region, the amygdala and possibly the hippocampus are involved. Structural abnormalities and decreased structural and functional connectivity between frontal and limbic regions have repeatedly been documented in GAD [71,72]. Functional neuroimaging suggests that GAD is characterized by inefficient biologic mechanisms associated with emotion regulation. Worry induction increases prefrontal cortex activation and decreases amygdala activity in patients with GAD and non-anxious controls, but unlike non-anxious subjects, patients with GAD are unable to normalize this neural activity afterward. The results from studies using tasks that require conflict monitoring and emotion regulation support a model of GAD characterized by hypoactivation in the prefrontal cortex and anterior cingulate cortex indicative of deficient "top-down" emotional control [73].

PANIC DISORDER

Core Pathophysiology

Genetic, developmental, hormonal, and environmental factors interact to impair the ventromedial prefrontal cortex's ability to inhibit panic impulses generated by limbic regions. This underlies the pathogenesis of the initial onset of unexpected panic attacks. This pathology is further compounded by recurrent panic attacks with repeated activation of panic-generating subcortical sites, leading to recruitment and plasticity within extended amygdala fear-hippocampus-cortical circuits. This in turn facilitates the development of situational and anticipated panic attacks and agoraphobia. Imaging studies have demonstrated ventromedial prefrontal cortex structural abnormalities in patients with panic disorder, reflecting the loss of inhibitory control over panic-generating sites. CBT enhances medial prefrontal cortex activity in subjects with anxiety disorders, which may explain its efficacy in treating panic disorder [69].

Other Pathophysiologic Models

In addition to ventromedial prefrontal cortex inhibition, other alterations in brain function have been suggested in panic disorder. Involvement of the central nuclei of the amygdala and activation of other fear centers in the thalamus, hypothalamus, and hippocampus may dysregulate respiratory control in the brainstem [74,75]. Additionally, it has been proposed that genetic risk variants partly drive fear network activity [76]. Exaggerated hypothalamic-pituitary-adrenal axis reactivity to environmental stimuli may be involved in panic disorder etiology [77,78].

In patients with panic disorder, CBT significantly reduces left interior frontal gyrus region activation, and reduced activity is correlated with reduced agoraphobic symptoms [79]. This reduced activation appears to be a specific substrate of CBT effects in patients with panic disorder/agoraphobia without comorbid depressive disorders [80]. Functional magnetic resonance imaging (MRI) shows that pre-treatment activation of the bilateral insula and left dorsolateral prefrontal cortex during threat processing is associated with rapid response to CBT [81].

AGORAPHOBIA

Patients with panic disorder and agoraphobia who are anticipating agoraphobia-specific stimuli have shown stronger region-specific activations in the bilateral ventral striatum and left insula versus controls. Patients processed these stimuli more intensively based on individual salience, and this activation is stronger than found in patients with panic disorder alone. Ventral striatum and insula hyperactivation when anticipating agoraphobia-specific situations may be a key neurofunction modulator in agoraphobia [82].

In patients with panic disorder/agoraphobia, fear conditioning has shown enhanced activation of the bilateral dorsal inferior frontal gyrus. Simple conditioning, safety signal processing, and anxiety sensitivity correlate with the extent of midbrain activation. These findings suggest alterations in "top-down" and "bottom-up" processes during fear conditioning, interpreted within a neural framework of defensive reactions that mediate threat through distal (forebrain) versus proximal (midbrain) brain structures. This network may play a key role in panic disorder pathogenesis [83].

Genetic polymorphism (variation) may influence panic disorder with agoraphobia treatment response. Serotonin transporter gene promoter polymorphism (5-HTTLPR) is conclusively linked to emotion regulation and related patterns of brain connectivity. During functional MRI imaging, the patient subgroup that showed inhibitory anterior cingulate cortex-amygdala coupling during fear conditioning predominantly possessed the L/L genotype of 5-HTTLPR polymorphism. This activation of inhibitory function, the normal function in non-anxious persons, suggests an intermediate connectivity phenotype that modulates response to exposure-based CBT [84].

Expanding on these results, patients with panic disorder/agoraphobia and the low-expression allele of 5-HTTLPR showed more favorable exposure therapy response than patients with other 5-HTTLPR genotypes. This genetic contribution to exposure therapy outcome implicates the serotonergic system as a response mediator to exposure treatments [85].

Balance System Abnormalities

Patients with panic disorder/agoraphobia have shown subclinical abnormalities in balance system function that seemed to influence agoraphobia severity and contribute to dizziness and disorientation symptoms in complex sensory environments (e.g., shopping malls, traffic, crowds). These patients also display greater balance control reliance on non-vestibular, proprioceptive, visually dependent cues and greater balance system reactivity to peripheral visual stimulation. These possibly link to a more active visual alarm system involving visual, vestibular, and limbic areas. Patients with panic disorder/agoraphobia also show high sensitivity to light or brightness stimuli with photophobic behavior and abnormal retinal and pupillary reflex responses possibly linked to serotonergic and/or dopaminergic dysfunction. This overall amplified sensitivity to environmental stimuli suggests that agoraphobia involves activation of complex systems beyond panic attack fear and behavioral avoidance, including emotional responses to destabilizing/distressing environmental stimuli and operant-learning avoidance of experiences that provoke this distress [86].

SOCIAL ANXIETY DISORDER

Patients with SAD have shown hyper(re)active limbic, frontal, and parietal brain regions involved in emotional and attentional processes. Compared to healthy subjects, patients with SAD display increased cortical thickness in frontal, parietal, and other brain areas. CBT treatment success and symptom improvement have been associated with changes in prefrontal regions involved in emotion regulation [87].

Persons with SAD and GAD share core features of persistent, debilitating focus on negative or potentially threatening experience. This negative affective bias is characterized by increased threat processing at the neural, psychologic, and behavioral levels, with engagement of the dorsal medial prefrontal cortex-amygdala circuit during aversive processing. Anxiety disorder subtypes frequently co-occur, and while abnormal activation of this neural circuitry that mediates bias toward threats is diagnosis-independent, it also represents a cardinal feature of SAD and GAD [88].

SAD pathophysiology includes heightened autonomic arousal to social cues and novelty. Fear processing appears mediated by the amygdala, in which neuroimaging studies show exaggerated activations with exposure to novel facial stimuli. Amygdala activation to novelty is also found in persons with a behavioral inhibition temperament. Other pathophysiologic models suggest that exaggerated hypothalamic-pituitary-adrenal axis reactivity to environmental stimuli may be involved in SAD [89,90,91,92].

SPECIFIC PHOBIA

Amygdala, anterior cingulate cortex, and insula hyperactivity is believed to be the underlying pathophysiology of specific phobia. Neuroimaging studies have shown increased amygdala activation with exposure to phobic-relevant cues, and heightened activity in thalamic, insula, and dorsal anterior cingulate cortex regions [93,94,95]. Meta-analyses suggest the left amygdala/globus pallidus, left insula, right thalamus, and cerebellum regions are all more active among patients with a phobia compared with controls when exposed to phobic-relevant stimuli. Acute, exaggerated parasympathetic nervous system activity with exposure to stimuli is thought to underlie the vasovagal syncope experienced by up to 80% of people with blood-injection-injury phobia [96]. Exposure-based therapy leads to deactivation in the right frontal cortex, limbic cortex, basal ganglia, and cerebellum, and increased activity in the thalamus [97].

ADULT SEPARATION ANXIETY DISORDER

SEPAD etiology is thought to arise during childhood by disrupted caregiving environments that promote greater hypothalamic/pituitary stress responsivity. Neuroimaging research has focused on brain circuitry that shows abnormal activity at single time points during anxiety from close attachments. The underlying neural circuitry that mediates separation-hypersensitive attachment includes subcortical areas (amygdala, hippocampus, striatum) and cortical limbic areas (insula, cingulate). Predisposing endophenotypes may interact with circuitry involved in attention, learning, and executive control (medial prefrontal cortex, superior temporal sulcus, and temporoparietal junction). With social interaction central to separation anxiety, neural circuitry involved in separation-sensitive social representations that predict danger when separation occurs may include the anterior temporal cortex [98]. SEPAD is associated with hypersensitivity to inhaled carbon dioxide, with a similar pattern to patients with panic disorder, suggesting SEPAD and panic disorder may share a common pathophysiologic basis [99,100].

5. CLINICAL AND DIAGNOSTIC FEATURES

As with other psychiatric disorders, the treatment of anxiety disorders is guided by conceptualization of the disorder and theoretical basis for disorder/treatment relationships. The understanding of anxiety disorders has changed over time with input of new evidence. In the United States, the DSM, published by the American Psychiatric Association, is the authoritative reference in defining and diagnosing psychiatric disorders. In the modern era, revised DSM editions have been published in 1980, 1994, 2000, and most recently in 2013 with the DSM-5.

To better reflect current thinking on anxiety disorders, the DSM-5 made several important changes from the 1994 DSM-IV and its 2000 text revision [32,101]. As noted, the chapter on anxiety disorders no longer includes OCD, PTSD, and acute stress disorder. New sections were added for these conditions: obsessive-compulsive and related disorders and trauma- and stressor-related disorders. Duration criteria for several anxiety disorders were extended to six months or longer to minimize overdiagnosis of transient symptoms, applied to all ages.

With agoraphobia, specific phobia, and SAD, the requirement that patients recognize their anxiety as excessive or unreasonable has been eliminated. This change was based on evidence that individuals with such disorders often overestimated the danger in "phobic" situations and that older individuals often misattributed "phobic" fears to aging. Instead, the anxiety must be out of proportion to the actual situational danger or threat, with consideration of cultural contextual factors [102].

The DSM-5 (and previous DSM editions) has been criticized for emphasis on reliability at the expense of diagnostic validity and for use of symptom-based diagnosis when symptoms alone may not best inform treatment selection. In response, the National Institute of Mental Health is developing the Research Domain Criteria, a new taxonomy for mental disorders that draws from genetics, neuroscience, and behavioral science [103]. Additionally, the DSM-5-TR, which was released in March 2022, includes the addition of prolonged grief disorder; the inclusion of symptom codes for suicidal behavior and nonsuicidal self-injury; refinement of criteria; and comprehensive literature-based updates to the text [104].

GENERALIZED ANXIETY DISORDER

GAD is characterized by excessive and inappropriate worrying that is persistent and not restricted to circumstance or situation. Patients have physical anxiety symptoms and key psychologic symptoms. GAD is often comorbid with major depressive disorder, panic disorder, phobia, health anxiety, and OCD [3]. The DSM-5 diagnostic criteria for GAD remain unchanged from previous editions [2,102]:

- Excessive anxiety and worry (apprehensive expectation) over a number of everyday concerns (e.g., school/work performance)

- Individual finds it difficult to control the worry

- Excessive anxiety and worry are associated with three or more of the following six symptoms, with at least some occurring more days than not for at least six months:

- Restlessness, feeling "on edge"
- Easily fatigued
- Difficulty concentrating
- Irritability
- Muscle tension

- Sleep disturbance (difficulty falling or staying asleep, restless sleep)

- The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning

- Symptoms not better explained by another mental disorder

- The disturbance is not attributable to the physiologic effects of a substance or another medical condition

Patients with GAD in the absence of current or lifetime comorbidity are uncommon, and patients with GAD typically present to primary care with comorbid depression, anxiety disorders, or substance use disorders. The presence of comorbidity complicates diagnosis and treatment [2].

PANIC ATTACKS

Panic attacks are abrupt, unexpected periods of intense fear or discomfort with multiple physical or psychologic anxiety symptoms, often peaking by 10 minutes and lasting around 30 to 45 minutes. Panic disorder is characterized by recurrent unexpected surges of severe anxiety (panic attacks). As noted, most patients develop a fear of having further panic attacks. The extent of anticipatory anxiety between attacks varies, and patients may alter their behavior to reduce the recurrence risk [2,3].

The essential features of panic attacks are unchanged in the DSM-5, but the complicated DSM-IV terminology for describing different types of panic attacks (i.e., situational-bound/cued, situational-predisposed, and unexpected/uncued) is replaced with unexpected and expected panic attacks. Panic attacks function as a marker and prognostic factor for severity of diagnosis, course, and comorbidity across an array of disorders, including but not limited to anxiety disorders. Hence, panic attack can be listed as a specifier, applicable to almost all DSM-5 disorders [102]. The DSM-5 criteria for panic attacks specify an abrupt surge of intense fear or intense discomfort that reaches a peak within minutes and includes four or more of the following symptoms [2]:

- Palpitations, pounding heart, or accelerated heart rate

- Sweating

- Trembling or shaking

- Sensations of shortness of breath or smothering

- Feelings of choking
- Chest pain or discomfort
- Nausea or abdominal distress

- Feeling dizzy, unsteady, light-headed, or faint

- Chills or heat sensations

- Paresthesias (numbness or tingling sensations)

- Derealization (feelings of unreality) or depersonalization (being detached from oneself)

- Fear of losing control or going crazy

- Fear of dying

Physical symptoms predominate.

Panic attack is not classified as a mental disorder and does not have a diagnostic code. Instead, an attack can occur with other mental disorders, such as depressive and anxiety disorders, and also be extant with physical disorders. While panic attack is a specifier for both mental and physical disorders, the elements of panic attack are contained within the criteria for panic disorder, making the specifier unnecessary for that diagnosis.

PANIC DISORDER

Panic disorder in the DSM-5 has an added criterion for unexpected panic attacks. This implies that expected panic attacks exist and that anticipated, situationally triggered panic attacks are somehow less pathologic than spontaneous panic attacks. This assumption is challenged on the basis that panic attacks are inherently pathologic, regardless of context or lack thereof, and individuals with panic disorder can have unexpected and expected panic attacks [18,105]. Regardless, the DSM-5 diagnostic criteria for panic disorder require [2]:

- Recurrent unexpected panic attacks

- One or more of the attacks followed by at least one month of one or both of the following:

- Persistent concern or worry about additional panic attacks or their consequences

- Significant maladaptive change in behavior related to the attacks

The symptoms must not be attributable to substance-related effects, other medical conditions, or other psychiatric disorders. Up to 70% of patients report a history of at least one nocturnal panic attack [106]. Patients may present with symptoms suggestive of heightened sympathetic nervous system activity such as palpitations, increased systolic blood pressure, hyperventilation, sweating, or flushing. Other common symptoms include chest pain and discomfort, dizziness, and paraesthesias, while gastrointestinal symptoms such as nausea and vomiting are more common among men [2,107].

The severity of distress during panic attacks by patients with panic disorder with or without agoraphobia is increasingly seen as traumatic. Panic attacks are frequently experienced as life threatening, and patients with panic disorder can experience PTSD symptoms in relation to their panic attacks. Patients with panic disorder/agoraphobia or PTSD were found to relive their trauma or panic attacks with equal frequency, report comparable bodily reactions and distress associated with trauma or panic attack memories, and avoid trauma or panic attack reminders (i.e., places and things associated with trauma or panic attacks). Trauma-like symptoms surrounding panic attacks are common, and panic attacks may be processed similarly to trauma in PTSD [108].

Intense, disorganized recollections, a core symptom of PTSD, are thought to result from inadequate processing of trauma information. A first panic attack resembles trauma; both are unexpected, frightening, and subjectively life-threatening events. Like PTSD, panic disorder with agoraphobia also involves fear conditioning after the first event. Therefore, panic attack and trauma processing may be similar, with panic attack and PTSD trauma memories sharing the characteristics of reliving and disorganization. A comparison of panic memories and PTSD trauma memories did not find differences between groups in reliving intensity and disorganization levels, suggesting that panic attacks may affect information processing similarly to a traumatic event [109,110].

Patients with panic disorder exhibit considerably worse overall mental well-being than individuals with cancer, diabetes, heart disease, arthritis, hypertension, and other chronic physical conditions [111]. Current panic disorder is also related to worse quality of life and physical function and an elevated risk of attempting suicide [112]. These effects are similar to or greater than those associated with major depression. A study found that nearly 33% of these patients in primary care had seen three or more healthcare professionals and almost 20% had visited emergency departments [113]. Another study found that although the majority of individuals with panic disorder first present to the primary care setting, only 38% of those with panic disorder with agoraphobia and 24% of those with panic disorder without agoraphobia were receiving appropriate treatment, and the use of empirically supported interventions was rare [114].

AGORAPHOBIA

Agoraphobia is defined as the fear of panic attacks occurring in places or situations from which escape might be difficult or embarrassing or where help may not be available. These situations can include crowds, going outside the home, or using public transportation and are either avoided or endured with significant personal distress [3]. Agoraphobia can become severely disabling, and more than 33% of patients diagnosed with agoraphobia cannot endure leaving their home environment. Roughly 66% of patients with panic disorder develop agoraphobia [2].

In the DSM-5, agoraphobia was de-aggregated from panic disorder and is now classed as a separate diagnostic entity. The former DSM-IV diagnoses of panic disorder with agoraphobia, panic disorder without agoraphobia, and agoraphobia without history of panic disorder are now replaced by two diagnoses with separate criteria: panic disorder and agoraphobia. Co-occurring panic disorder and agoraphobia are also coded as two diagnoses. This change recognizes that a substantial number of individuals with agoraphobia do not experience panic symptoms, although clinical prevalence is much lower than community prevalence. The diagnostic criteria for agoraphobia are derived from the DSM-IV descriptors, with endorsement of fears from two or more agoraphobia situations now required to more effectively distinguish agoraphobia from specific phobias. The criteria for agoraphobia are also extended to concord with criteria sets for other anxiety disorders [102]. Diagnosis is based on marked fear or anxiety about two or more of the following [2]:

- Public transportation (e.g., traveling in planes, automobiles, buses, trains, ships)

- Open spaces (e.g., parking lots, market places, bridges)

- Being in shops, theatres, or stadiums

- Standing in line or being in a crowd

- Being outside of the home alone in other situations

The individual with agoraphobia fears or avoids these situations due to thoughts that escape might be difficult or help might not be available in the event of panic-like symptoms. These situations almost always provoke fear or anxiety and are actively avoided, require presence of a companion, or are endured with marked fear or anxiety. The fear or anxiety is out of proportion to the actual threat posed by an agoraphobic situation. The fear, anxiety, or avoidance is persistent, typically lasting at least six months, and causes clinically significant distress or impaired functioning. Avoidance symptoms in PTSD differ in that the situations avoided are trauma-associated, such as a park or street where an assault occurred or riding in a car after a motor vehicle accident [2].

Major personality dimensions, such as introversion and neuroticism, have been studied for contribution to the risk of developing agoraphobia and other anxiety disorders. Genetic factors that influence individual variation in extraversion and neuroticism have been found to account entirely for genetic liability in SAD and agoraphobia but not animal phobia, emphasizing the importance of both introversion (low extraversion) and neuroticism as risk factors [115]. Situational avoidance is the most disabling aspect of agoraphobia. Temperament is shown to influence agoraphobia severity, with introverted temperament significantly associated with the presence and severity of agoraphobic situational avoidance [9].

The longitudinal relationship between personality disorder traits and panic disorder (with or without agoraphobia) is important for understanding agoraphobia etiology. A large-scale study that assessed community-dwelling adults at baseline and again 12 to 15 years later found that after excluding participants with baseline panic attacks, baseline timidity with avoidant, dependent, and related traits predicted the onset of panic disorder or panic disorder with agoraphobia during the follow-up period. These results suggest that avoidant and dependent personality traits are predisposing factors, or markers of risk, for panic disorder or panic disorder with agoraphobia, and not simply epiphenomena [24]. Additionally, personality and temperament traits may be potentially related to poor treatment response [116].

SOCIAL ANXIETY DISORDER

SAD is often misconstrued as mere shyness but can be considerably disabling and produce much greater distress and more severe symptoms. SAD is characterized by a marked, persistent, and unreasonable fear of being observed or evaluated negatively by other people in social or performance situations, which is associated with physical and psychologic anxiety symptoms. Feared situations, such as speaking to unfamiliar people or eating in public, are either avoided or are endured with significant distress [3]. Social phobia has been renamed SAD to reflect a new, broader understanding of the condition in a variety of social situations.

Previously, social phobia was primarily diagnosed in patients reporting extreme discomfort or fear when performing in front of others. Research indicates this definition is too narrow, and SAD in the DSM-5 can be diagnosed based on patient response to a variety of social situations. For example, the patient may be so uncomfortable engaging in conversation he or she is unable to talk to others, especially strangers. A patient with anxiety regarding being observed may be unable to go out to dinner over fears of being watched while eating and drinking [102].

The defining features of SAD diagnosis remain unchanged. However, some modifications in require features have been made, including deletion of the requirement that individuals older than 18 years of age must recognize their fear or anxiety is excessive or unreasonable, and addition of a duration criterion. A more significant change is that the "generalized" specifier has been deleted and replaced with a "performance only" specifier. The DSM-IV-TR generalized specifier was problematic in that "fears include most social situations" was difficult to operationalize. Individuals who fear only performance situations (i.e., speaking or performing in front of an audience) appear to represent a distinct subset of SAD in terms of etiology, age at onset, physiologic response, and treatment response. The DSM-5 establishes the following diagnostic criteria for SAD [2]:

- Marked fear or anxiety about social situations in which the person may be exposed to scrutiny by others

- Fear that actions or showing anxiety symptoms will cause negative evaluation (e.g., embarrassment, humiliation) or offend others

- The social situation:

- Almost always provokes fear or anxiety

- Is actively avoided or endured with marked fear or anxiety

- The fear, anxiety, or avoidance:

- Is disproportionate to actual threat posed by the social situation

- Is persistent, typically at least six months

- Causes significant distress or functional impairment

- If another medical condition is present (e.g., stuttering, obesity), the disturbance is unrelated or out of proportion to it

If the fear is restricted to speaking or performing in public, diagnosis should specify "performance only." Other diagnostic features of SAD include [2]:

- Post-event processing: Tendency to replay social encounters in a negative, self-critical manner

- Attentional bias: Heightened attention to negative evaluative threat cues and lack of attention to positive or benign cues

- Social skills deficits: Poor eye contact, closed stance, quiet tone of speech, and difficulties initiating conversations

Patients with SAD highly inflate perceived social costs from committing hypothetical blunders. Accounting for much of this social cost inflation are concerns about revealing self-flaws and, in particular, concerns over appearing socially incompetent [117].

SPECIFIC PHOBIA

Specific, simple, or isolated phobia describes excessive or unreasonable fear in the presence of phobic stimuli, typically involving specific animals, objects, or situations (e.g., dentists, spiders, elevators, flying, seeing blood). Phobic stimuli are either avoided or are endured with significant personal distress [3]. This fear or anxiety must be markedly stronger than the actual threat of the object or situation (e.g., likelihood of being stuck on a well-maintained elevator) [2]. The core features and different types of specific phobia remain unchanged from the DSM-IV, but the requirement was removed that individuals older than 18 years of age must recognize their fear and anxiety as excessive or unreasonable. The duration requirement of longer than six months now applies to all ages [102].

Specific phobias can develop after a traumatic event or from witnessing traumatic events. The fear or anxiety happens every time the person is exposed to the stimulus and may include panic attack symptoms.

The median age of onset with specific phobia is 13 years [2]. According to the DSM-5, specific phobia is diagnosed when the following criteria are met [2]:

- Marked fear or anxiety about a specific object or situation (e.g., flying, seeing blood)

- Phobic object or situation almost always provokes immediate fear or anxiety and is actively avoided or endured with marked fear or anxiety

- Fear or anxiety out of proportion to the actual danger posed by the specific object or situation

- The fear, anxiety, or avoidance is persistent, typically at least six months

- Marked distress or functional impairment

Specific phobia subtypes are organized by phobia categories:

- Animal: Dogs, snakes, insects

- Natural environment: Storms, heights, dark

- Blood-injection-injury: Injections, blood draws, medical procedures

- Situational: Driving, flying, enclosed spaces

- Other: Choking, vomiting, clowns

Specific Phobia Coding

Approximately 75% of individuals diagnosed with specific phobia fear more than one object. In the past, when this occurred, more than one ICD-10 code was given [2]. However, the ICD-11 eliminated this component. When individuals experience panic attacks in response to their phobia, clinicians should add "with panic attacks" to the diagnosis.

SEPARATION ANXIETY DISORDER

Separation anxiety is a basic human fear and readily observable in children. Close attachment to nurturing parental figures during infancy is necessary for survival, and close relationships throughout life are an important source of support in times of stress. Separation anxiety does not vanish with development and maturation, but persistant separation anxiety in adulthood should not become an issue of clinical importance. Manifestations of pathologic separation anxiety include uncontrollable apprehension over losing important attachment figures, intense fears of leaving home or going out unaccompanied, and nightmares around themes of separation. Persons with SEPAD have substantial impairments in many aspects of community life, although not all individuals show problems in attachment [118,119].

Pathologic early childhood attachments can have far-reaching consequences in adulthood. These patients often have a grossly impaired ability to experience and internalize positive relationships or to develop mental capacities for self-soothing, anxiety tolerance, affect modulation, and individuation. Adults with SEPAD feel unable to function in the absence of a mother surrogate. Separation anxiety has long been considered the distal antecedent to panic disorder. In adults, separation anxiety may reflect excessive activation of fear circuits in response to separation and over-activation of reward circuits with reunion, likely the result of abnormalities or deficits in underlying social representation and cognition systems [98].

SEPAD is characterized by fear or anxiety concerning separation from those to whom an individual is attached. Common features include excessive distress when experiencing or anticipating separation from home, and persistent and excessive worries about potential harms to attachment figures or untoward events that might result in separation [3].

The core features of SEPAD are mostly unchanged from DSM-IV, but the wording is modified to more adequately represent SEPAD expression in adulthood. For example, attachment figures may include the children of adults, and avoidance behaviors may occur in the workplace as well as at school. Diagnostic criteria no longer require childhood history of SEPAD or onset before 18 years of age, because a substantial number of adults report onset later in life. Adults with the condition include those with adult-onset and those with childhood onset and symptom persistence into adulthood. A duration criterion of six months or longer was added [64,102]. For a diagnosis of SEPAD, the persistent and excessive anxiety related to separation or impending separation from a major attachment figure (e.g., spouse, close family member) must be evidenced by at least three of the following criteria [2]:

- Recurrent excessive distress when anticipating or experiencing separation

- Persistent and excessive worry about losing a major attachment figure or about possible harm to him or her

- Persistent and excessive worry about experiencing an untoward event (e.g., getting lost, kidnapped, into an accident) that causes separation from a major attachment figure

- Persistent reluctance or refusal to go out, away from home, to school, to work, or elsewhere because of fear of separation

- Persistent and excessive fear of or reluctance about being alone or without a major attachment figure

- Persistent reluctance or refusal to sleep away from home or to go to sleep without major attachment figure near

- Repeated nightmares involving the theme of separation

- Repeated complaints of physical symptoms (e.g., headaches, stomachaches, nausea, vomiting) when separation occurs or is anticipated

To meet the criteria for this disorder, the symptoms must cause clinically significant distress or impairment in social, academic, occupational, or other important areas of functioning. Symptoms must not be better explained by another mental disorder (e.g., delusions or hallucinations concerning separation in psychotic disorders); refusal to go outside without a trusted companion (as in agoraphobia); worries about ill health or other harm befalling significant others (as with generalized anxiety disorder); or concerns about having an illness (as in illness anxiety disorder) [2]. Panic attacks commonly occur with youth and adult SEPAD.

Differential Diagnosis

In the past, adult SEPAD was often diagnosed as panic disorder, and it shares features with other psychiatric conditions. Excessive attachment toward others is a feature of a dependent personality, and avoidance behavior is a predominant feature of agoraphobia. With SEPAD, the focus involves key attachment figures, unlike dependent personality disorder, which is more indiscriminate. Panic and phobic-like behavior in SEPAD is specific to fears of separation from, or harm to, attachment figures and not spontaneous or triggered by other factors. Social and occupational function is frequently impaired, but individuals with SEPAD do not show impaired function in family life compared to controls and often function well in family environments. Borderline personality disorder differs by pervasive mood and relationship instability uncharacteristic of SEPAD [61].

A study exploring whether SEPAD in patients with panic disorder/agoraphobia was a manifestation of anxious attachment, a form of agoraphobia, or a specific condition with clinically significant consequences found that patients with SEPAD had greater panic symptom severity and quality of life impairment than those without separation anxiety. A greater rate of symptoms suggestive of anxious attachment was found among patients with panic disorder and SEPAD versus those without SEPAD. However, the relationship between SEPAD and attachment style was weak, and SEPAD occurred in some patients who reported secure attachment style. There was also little evidence SEPAD was a form of agoraphobia. SEPAD was found to be a distinct condition associated with impairment in quality of life and should be better recognized and treated in patients with comorbid panic disorder [119].

SELECTIVE MUTISM

Separation anxiety disorder and selective mutism were included in the DSM-IV section Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence, but were classed as anxiety disorders and moved to the anxiety disorder section in the DSM-5 [102]. The majority of children with selective mutism are anxious, and while selective mutism is now considered an anxiety disorder, it remains a disorder primarily of childhood and is beyond the scope of this course [102].

6. ASSESSMENT

Effective anxiety disorder treatment relies on accurate diagnosis. Diagnosis is made when diagnostic criteria for a specific disorder are established and symptoms cannot be better explained by the effects of the patient's other medical conditions, medications, substances, or pre-existing mental disorders [2].

Evidence Based Practice Recommendation

The American Psychiatric Association recommends that the initial psychiatric evaluation of a patient include assessment of anxiety and panic attacks.

https://psychiatryonline.org/doi/10.1176/appi.books.9780890426760.pe02

Last Accessed: April 27, 2025

Strength of Recommendation/Level of Evidence: 1C (Recommendation with low confidence that the evidence reflects the true effect)

The management of patients presenting with anxiety symptoms should initially follow the flow of these five components [120]:

1. Screen for anxiety and related symptoms.

2. Consider differential diagnosis and severity, impairment, and comorbidity.

3. Identify specific or multiple anxiety disorder(s), often in consultation with trained specialists using structured interview techniques.

4. Initiate psychologic and/or pharmacologic treatment.

5. Perform follow-up.

Evidence suggests that in primary care, patient tendency to ascribe pathologic anxiety symptoms to physical causes contributes to high rates of missed diagnoses and the misdiagnosis of GAD and panic disorder. To offset this requires a broad differential and caution to identify confounding variables and comorbid conditions [121].

SCREENING FOR ANXIETY DISORDERS IN THE PRIMARY CARE SETTING

Lifetime prevalence of anxiety in the general population is estimated 30%, and anxiety disorders are among the most common mental health syndromes encountered in general medical practice. In a study of 965 randomly selected patients across 15 primary care clinics, 19.5% had at least one anxiety disorder; of the four common disorders assessed in the study, 8.6% of patients had PTSD, 7.6% had GAD, 6.8% panic disorder, and 6.2% had SAD [55]. Each disorder was associated with functional impairment that became more substantial as the number of co-occurring anxiety disorders increased. The GAD-7 diagnostic scale was seen to perform well as screening tool for all four anxiety disorders studied [55]. Other studies in primary care settings have found that the prevalence of co-occurring GAD is 68% for patients with panic disorder and 38.6% for those with a diagnosis of major depression [34,122].

The American Academy of Family Physicians and other physician groups have noted that rates of failed diagnosis of anxiety disorder and misdiagnosis of GAD and panic disorder are high in primary care settings, in part because of time constraints, lack of a defining presentation, and the resemblance of symptoms to common somatic disorders [54,55,121]. Primary care clinicians have noted that patients with somatic complaints, sleep disturbance, or psychosocial distress are often unaware that anxiety disorder is the root cause of their symptoms. A study of older patients with GAD found that accurate referencing of symptoms to the onset of anxiety was low (34%), as was the rate of anxiety disorder diagnosis (9%), despite a high level of healthcare utilization [123]. In the current managed care environment, anxiety is usually treated in primary care settings, and given the increasing time constraints imposed on primary care providers, it is not surprising that anxiety disorders are under-recognized and undertreated [70].

Many patients with anxiety and depressive symptoms do not seek help, and in those who do, anxiety symptoms are often not the presenting complaint. Patients and providers often have difficulty initiating discussion of emotional problems and distress. Primary care providers with greater sensitivity to nonverbal communications have been found more likely to detect and diagnose anxiety, while those tending to "blame" patients make fewer psychologic inquiries and are less accurate in detecting distress [3,124].

SCREENING TOOLS

The American Academy of Family Physicians suggests using diagnostic screening and monitoring scales, such as the Generalized Anxiety Disorder 7-Item Scale (GAD-7) and the Severity Measure for Panic Disorder, to aide in diagnosis and monitor response to treatment [121]. The Primary Care Evaluation of Mental Disorders (PRIME-MD) was originally developed as a physician-administered screening tool for identifying mental disorders. It contained 12 different mental health disorder modules and required lengthy administration time, limiting its clinical usefulness [133]. Developers of the PRIME-MD subsequently crafted a self-administered version of the PRIME-MD, the Patient Health Questionnaire (PHQ). The PHQ includes mood, anxiety, alcohol, eating, and somatoform modules as covered in the original PRIME-MD [134]. In addition to its value in identifying anxiety and mood disorders, including depressive symptoms, panic disorder and other anxiety disorders, the PRIME-MD-PHQ is efficient for use in primary care settings; most clinicians can analyze the results in three minutes or less [134].

The GAD-7 scale is a brief, validated screening tool specifically designed to identify anxiety disorders. The patient with symptoms is asked to rate severity and frequency of occurrence over the previous two weeks. Each item is rated on a four-point scale (0 to 3), yielding a maximum score of 21. A score of 10 or greater is the cut-off point for diagnosis of anxiety disorder (sensitivity 87%; specificity 82%) [135]. The degree of distress/functional impairment varies directly with the total score. The GAD-7 scale is available online at https://adaa.org/sites/default/files/GAD-7_Anxiety-updated_0.pdf.

In theory, patients and providers should benefit from screening tools designed to detect anxiety disorders. However, regular use may require adjustments to practice structure, and it is uncertain to what extent routine screening (of all patients) and disclosure to "screened positive" patients improves clinical outcomes.

In 2022, the U.S. Preventive Services Task Force recommended screening all children older than 7 years of age for anxiety [349]. Primary care providers can improve anxiety detection skills by first acknowledging patients may be reluctant to discuss psychological and emotional distress early in the physician-patient relationship. This can be offset with greater sensitivity to nonverbal expression of distress and by allowing repeated patient encounters and deepening understanding to develop the rapport required for exploring the presence and depth of anxiety symptoms [3].

Healthcare providers can create a more comfortable environment for a patient of another culture by acknowledging the impact of culture and cultural differences on physical and mental health. The nature and expression of symptoms are influenced by cultural factors, and in some cultures anxiety is expressed through a heavy focus on somatic symptoms, such as musculoskeletal pain and fatigue. Providers may consider starting the clinical encounter by exploring such symptoms patiently and in greater depth. The concept of anxiety also varies across cultures, and patients may not seek medical treatment unless symptoms manifest as psychosis, conversion disorders, or significant physical ailments.

IDENTIFYING PATIENTS WHO REQUIRE TREATMENT

The potential chronicity and disability of anxiety disorders indicates that most patients meeting diagnostic criteria should receive psychologic and/or pharmacologic treatment. Treatment selection is guided by severity, duration, patient distress and impairment, the presence of depression and other comorbid disorders, previous treatment response or contraindication, patient preference, provider experience, and treatment availability [3,126]. However, many patients with anxiety disorder who could benefit do not receive treatment; fewer than one in five receive appropriate medication, improving to one in three for patients with comorbid depression [127].

Treatment quality is improved with accurate diagnosis and regular monitoring. Inadequate dosage and treatment duration were found common in the primary care treatment of patients with panic disorder, but improved outcomes were more likely with enhanced patient education and follow-up contact than with physician education [3,128]. Worth noting is the contrast between concerning media reports of medicalization and inappropriate psychotropic prescribing for "normal" anxiety, shyness, or situational stress, and the repeated findings in primary care studies of inadequate or no prescribing and a high level of unmet patient need [3].

General Use Screening Questions

Clinical care providers may consider incorporating a simple question format into the routine clinical encounter, asking patients if they have recently felt excessively nervous, anxious, or on edge, and if worrying is ever uncontrollable or otherwise distressing. The DSM-5-TR suggests the following questions for identifying anxiety-related symptoms [2]:

During the past two weeks, how much have you been bothered by the following problems:

- Feeling nervous, anxious, frightened, worried, or on edge

- Feeling panic or being frightened

- Avoiding situations that make you anxious

A positive history of anxiety symptoms should be explored with screening questions for specific anxiety disorders.

Screening for Specific Anxiety Disorders

In addition to the general questions suggested for all patients with complaints of anxiety, it is important to inquire regarding disorder-specific symptoms. This will allow for more specialized assessment and diagnosis.

Generalized Anxiety Disorder

- During the past four weeks, have you been bothered by feeling worried, tense, or anxious most of the time?

- Are you frequently tense or irritable, or do you have trouble sleeping?

If the patient acknowledges in the positive, then follow with the GAD-7 screening tool.

Panic Disorder

- Do you have sudden, unexpected episodes/spells/attacks of intense fear or discomfort? If yes, then continue.

- Have you had more than one of these attacks?

- Does the worst part of these attacks usually peak within several minutes?

- Have you ever had one of these attacks and spent the next month or more living in fear of having another attack or worrying about the consequences of the attack?

Agoraphobia

- Do you avoid certain situations or places where panic attacks have occurred or may occur?

Social Anxiety Disorder

- Does fear of embarrassment cause you to avoid doing things or speaking to people?

- Do you avoid activities where you are, or may be, the center of attention?

- Is being embarrassed or looking stupid among your worst fears?

Specific Phobia

- Do you feel intense anxiety or fear when confronted by certain animals, objects, or situations?

- Are you avoiding these animals, objects, or situations because of your fear?

- In what ways has this anxiety or fear interfered with your life?

- How would you react if you were exposed to the animal, object, or situation right now?

- Have you ever fainted or almost fainted around blood, injuries, or needles?

Separation Anxiety Disorder

- Do you feel anxious, fearful, or upset thinking about separation, or being away from, your (spouse, partner, primary support person)?

Evidence Based Practice Recommendation

If an adult with possible social anxiety disorder finds it difficult or distressing to attend an initial appointment in person, the National Collaborating Centre for Mental Health recommends making the first contact by phone or Internet, but aiming to see the person face to face for subsequent assessments and treatment.

https://www.nice.org.uk/guidance/cg159/resources/social-anxiety-disorder-recognition-assessment-and-treatment-pdf-35109639699397

Last Accessed: April 27, 2025

Level of Evidence: Expert Opinion/Consensus Statement

Positive responses to screening questions is followed by a formal assessment.

PATIENT HISTORY

A patient history is performed to assess patient and family history for clinically relevant information. Patients should be assessed for onset of anxiety symptoms, duration (remission or persistent), association with life events or trauma, level of distress, and effect on current functioning (academic, occupational, relationships, leisure activities, role functioning). Also inquire about a personal history of physical or emotional trauma, anxiety or mood disorders, medications or therapies, and patient response. Family history should be assessed for anxiety, mood, and substance use disorders [2]. Screening for depression is very important, given its high comorbidity rate and associated risk of suicidal behavior [129].

A thorough list of prescribed, over-the-counter, and herbal medications should be obtained [2]. Furthermore, substance use should be assessed, including:

- Current and past tobacco use

- Current and past alcohol use

- Current and past use of illicit drugs (e.g., cannabis, cocaine, heroin, methamphetamine)

- Current and past use of pharmaceutical drugs (e.g., opioids, stimulants, benzodiazepines)

- Current and past use of "legal high" or novel drugs (e.g., club drugs, "bath salts," "synthetic cannabis")

- Having been told their substance use is a problem

- Having received counseling or treatment for a substance use problem

PHYSICAL EXAMINATION

The physical examination of most patients evaluated for anxiety is usually unrevealing but necessary in order to assess the possibility of primary disorders and conditions associated with anxiety. Careful measurement and recording of resting pulse rate and blood pressure (including postural effect) are important. Patients may be uncomfortable discussing their anxiety, but physical signs of heightened sympathetic nervous system activity (e.g., tachycardia, hyperventilation, sweating, flushing) are absent in the context of a reassuring clinical encounter (excepting acute examination of a patient following panic attack). Routine examination of adolescents and young adults with recent-onset anxiety should prompt careful assessment for signs of hyperthyroidism (e.g., the stare of early proptosis; fine tremor of outstretched hands; tachycardia; brisk deep tendon reflexes). Patients with observed (or history of) vasovagal fainting, especially those suspected of specific phobia disorder, should be assessed for other medical conditions associated with fainting risk (including blood glucose levels and orthostatic hypotension) [2].

Diagnosis is made through self-report, clinical interview, and behavioral observation of impairments in personal, social, or occupational domains; no laboratory testing is necessary. Several empirically validated self-report questionnaires are available to assess baseline functioning and track treatment response. Assessment of anxiety symptoms and associated impairments optimally includes key informant interviews with family members or close friends [2].

DIFFERENTIAL DIAGNOSIS

Differential diagnosis is performed to eliminate potential underlying causes that, if present, would better account for patient anxiety complaints. As noted, screening for other anxiety, mood, and substance-related disorders should be routinely conducted due to high comorbidity rates.

Other Mental Disorders

Evidence Based Practice Recommendation

When assessing an adult with possible social anxiety disorder, the National Collaborating Centre for Mental Health recommends that clinicians be aware of comorbid disorders, including avoidant personality disorder, alcohol and substance misuse, mood disorders, other anxiety disorders, psychosis, and autism.

https://www.nice.org.uk/guidance/cg159/resources/social-anxiety-disorder-recognition-assessment-and-treatment-pdf-35109639699397

Last Accessed: April 27, 2025

Level of Evidence: Expert Opinion/Consensus Statement

To confirm or rule out the presence of comorbid anxiety or related disorders, determine the nature and focus of patient apprehension/anxiety. It may be [2]:

- Diffuse, non-specific (GAD)

- Discrete, intense anxiety episodes (panic disorder)

- Fear of one's panic attacks and avoidance of places or situations where they may occur (agoraphobia)

- Embarrassment in public (SAD)

- Fear of specific objects or situations (specific phobia)

- Attachment figure separation (separation anxiety)

- Contamination (OCD)

- Weight gain (anorexia nervosa)

- Multiple physical complaints (somatization disorder)

- Serious illness (hypochondriasis)

- Strictly trauma-related (PTSD)

A diagnosis of SAD should rule out avoidant personality disorder. Some symptoms of avoidant personality disorder resemble SAD, such as a pervasive pattern of social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation. However, avoidant personality disorder is distinguished by non-social avoidance that extends to novel situations and positive affect. Roughly 36% of patients with SAD are comorbid for avoidant personality disorder, and some believe avoidant personality disorder is a more severe variant of SAD [130,131].

Medication or Substance Use

It is important to rule out medication side effects as the underlying cause of anxiety by obtaining a complete list of currently used prescribed, over-the-counter, and herbal medications. Examples of common medications with anxiety side effects are asthma medications (e.g., albuterol, theophylline), herbal medicines (St. John's wort, ginseng, ma huang), corticosteroids, and antidepressants [2].

Patients should also be assessed for current use of alcohol, nicotine, stimulants, benzodiazepines, and opioids, because the direct, adverse, or withdrawal effects can mimic anxiety or panic symptoms [132]. Illicit or illicitly used drugs with acute effects most commonly associated with anxiety include cocaine, methamphetamine, prescription amphetamines (e.g., lisdexamfetamine), methylphenidate, and MDMA ("Ecstasy") [2]. Caffeine may also provoke anxiety in sensitive patients, including those with anxiety disorders [28]. Alcohol use disorder is highly prevalent among persons with anxiety disorders. Acute anxiety relief may powerfully reinforce alcohol use, but frequent or heavy drinking commonly exacerbates the anxiety disorder symptoms. When these two disorders co-occur, treatment can be complicated.

Medical Conditions

Careful history taking and physical examination are warranted for all patients to rule out medical causes of anxiety symptoms. Conditions that can mimic or cause anxiety complaints include hyperthyroidism and hypothyroidism, asthma, cardiac arrhythmias, pheochromocytoma, and temporal lobe epilepsy. As noted, screening for depression is very important, given its high comorbidity rate and associated risk of suicidal behavior [129].

Laboratory Tests and Imaging

Although usually negative in the absence of other suggestive evidence, laboratory testing or imaging studies may be indicated to help rule out medical cause. For example, a routine blood panel with thyroid-stimulating hormone and blood glucose levels may help to identify or rule out conditions such as hyperthyroidism or hypoglycemia that may be responsible for intense, persistent anxiety and panic. Toxicology screening may also be indicated to determine whether illicit substances are contributing to the clinical presentation. An electrocardiogram is required in all patients presenting with chest pain (to exclude cardiac causes), and pulmonary function tests are used to rule out pulmonary disease in patients with shortness of breath. It is important to note that cardiopulmonary disorders can co-occur with anxiety disorders [2].

7. GENERAL TREATMENT CONSIDERATIONS

Information in this section is derived from published research, meta-analyses, and clinical practice guidelines. The most recent anxiety disorder guideline (on panic disorder) by the American Psychiatric Association was published in 2009. The 2014 Anxiety Disorders Association of Canada (ADAC) guidelines are the most recent and comprehensive North American publication and are emphasized accordingly [120]. Successful treatment requires tailoring options to individuals and may often include a combination of modalities [121]. When selecting a treatment regimen, clinicians should consider current and prior treatments, comorbid conditions, age, cost of and access to care, and patient preference [350].

The two recommended first-line modes of therapy for anxiety disorder are psychotherapy (principally CBT) and pharmacotherapy. CBT, which includes an exposure therapy component when there are triggered episodes (e.g., SAD, specific phobia), is designed to work through maladaptive beliefs and avoidance behaviors that reinforce pathology surrounding fear-eliciting stimuli. CBT with some variant of exposure is the first-line psychotherapy approach for most adult patients and all childhood cases of anxiety disorder. Selecting CBT as treatment option has two limitations: it requires patient willingness to engage in therapy and the availability of well-trained therapists. Pharmacotherapy is also considered a first-line treatment option for anxiety disorders. While many medications have received FDA approval to treat anxiety, antidepressants have proven to be the most effective. Either a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) is recommended initial treatment of GAD, SAD, and panic disorder [350]. Benzodiazepines, which once served as a first-line option, are now best reserved for short-term use or as a supplement to the primary treatment regimen.

Advances in anxiety disorder neuroscience have increasingly pointed to the necessary role of fear extinction learning (through exposure therapy) in addressing underlying pathophysiology. While efficacy is shown with CBT and exposure, patients can have difficulty with the demanding and exhausting therapy process, and many who do manage to complete therapy respond partially and relapse with time. Efforts to improve CBT/exposure outcomes have led to the investigation of augmenting agents. In contrast to standard anti-anxiety drugs, these agents are not anxiolytic but are used to promote and accelerate long-term adaptive changes in brain function initiated by successful exposures [137].

Any review of treatment efficacy for anxiety disorders, and pharmacotherapy in particular, requires a disclaimer. Most treatment outcomes were based on studies using methodologies that excluded those with additional anxiety disorders and comorbid psychiatric or medical disorders. Patients seeking care for anxiety problems in primary care and other real-world settings often differ from carefully screened study participants. The extent that efficacy, response, and remission rates reported in the published research generalize to typically more complex clinic patients has been questioned [138].

Treatment refusal and attrition are significant problems. Patients with anxiety disorders show treatment refusal rates of 25% to 30% and treatment dropout rates of 10% to 82% [139]. Treatment dropout is very high in exposure therapy, as patients repeatedly confront (with graded intensity) the situations or objects that trigger their greatest fear or panic response. The intensity of distress during exposure can overwhelm patients, and with avoidance the hallmark feature of most anxiety disorders, attrition is significant [2,139]. Attrition can interfere with evaluating treatment efficacy (or the lack thereof), and unless explicit in study reporting, can be misleading. Attrition is also a clear concern in the clinical care of patients with anxiety.

PREDICTORS OF WORSE TREATMENT RESPONSE AND OUTCOMES

SEPAD

Severe forms of SEPAD are associated with a pervasive negative influence on treatment response. Comorbid SEPAD is highly correlated with poor treatment response and patient outcomes across a range of anxiety and mood disorders. SEPAD negatively impacts response to major depression treatment and is linked to worse symptom chronicity and quality of life. SEPAD decreases CBT response and predicts worse outcomes in patients treated for panic disorder, GAD, or SAD. SEPAD also predicts nonresponse to selective serotonin re-uptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) in patients with panic disorder with agoraphobia [98,140].

Chronic Pain

Uncontrolled pain is also increasingly recognized to negatively impact anxiety disorder treatment outcomes. In primary care patients with a GAD or panic disorder diagnosis treated for severe anxiety and followed for one year, patients with moderate or greater pain levels were found to show significantly lower rates of clinical improvement [141]. A cohort of 1,122 individuals with remitted anxiety or depressive disorders were followed up to four years, and pain (but not chronic disease) was associated with recurrence during follow-up [142].

Social Drinking

Problematic, excessive drinking clearly disrupts treatment response, but social drinking can also aggravate panic disorder and probably other anxiety syndromes. The short-acting effects of alcohol wear off rapidly, followed by rebound to a state of hyper-excitability that may be more problematic for patients with anxiety. This can occur with one to two drinks in some patients, who often do not even consider this a contributing factor to their anxiety complaint. Explaining the simple physiology of rebound excitation after profound neuronal inhibition will often convince patients that alcohol may be sensitizing the neural circuits subserving their anxiety and that a trial period of abstinence is indicated [28].

Other Anxiety Disorders

Highly symptomatic panic inhibits benefit from interpersonal psychotherapy, either alone or combined with SSRIs. The presence of any anxiety disorder impairs response to treatment of comorbid major depression [98]. Patients with major depressive disorder and a comorbid anxiety disorder demonstrate longer time to recovery and greater risk of early treatment termination. Patients with comorbid anxiety and depressive disorders generally have worse outcomes than patients with either disorder alone. Patients with comorbid GAD and major depression are significantly more likely to remain symptomatic than those with depression or GAD alone [143]. When anxiety symptoms are present within a dominant depressive disorder, antidepressant drugs are often effective in reducing anxiety [144]. However, depression that follows or is comorbid with an anxiety disorder usually indicates greater severity and worse prognosis [145].

Among treatment-seeking patients with panic disorder, SAD, or GAD followed over two years, symptom changes in GAD were most specifically related to changes in impairment, suggesting that treatment of patients with multiple anxiety disorders should initially focus on GAD symptoms or employ trans-diagnostic modalities [146].

Patients with panic disorder/agoraphobia who display the low-expression allele of the serotonin transporter gene promoter show more favorable exposure therapy response than patients with other 5-HTTLPR genotypes. This genetic contribution to exposure therapy outcome implicates the serotonergic system as a response mediator to exposure treatments [85].

OVERLAPPING PSYCHOLOGIC AND DRUG THERAPY MECHANISMS

Emerging evidence is challenging conventional wisdom by showing that antidepressant therapeutic action may begin with the first dose and that psychologic and drug therapy approaches share common mechanisms. In one study, a single dose of norepinephrine reuptake inhibitor reboxetine reduced negative affective bias in depression by increasing recognition of positive facial expressions and enhancing memory for positive vs. negative information [147]. These early changes in emotional processing reflect changes in frontolimbic circuitry involved in detection and response to biologically salient information. These findings were replicated following seven days of escitalopram treatment [148]. Changes in neurocognitive processing that precede clinical improvement predict later antidepressant response [149]. A 2013 study found that the initial session of CBT administered for panic disorder/agoraphobia led to reduced threat processing the following day, with the magnitude of early effect predictive of the therapeutic response after four weeks [150]. These findings challenge assumptions that psychologic therapies address conscious thought processes before automatic information processing and suggest a greater similarity between early effects of pharmacologic and psychologic treatments for anxiety than previously thought [149].

PSYCHOTHERAPIES: OVERVIEW

Psychologic treatments play an integral role in the management of anxiety disorders, and efficacy is established for several modalities. Most broadly effective are exposure-based and other CBT approaches. When choosing psychologic treatments for individual patients, the forms of therapy developed for the specific anxiety disorder should be used first.

Cognitive and Behavioral Approaches

Psychotherapy can be as effective as medication for GAD and panic disorder, and CBT has the best level of evidence [121]. CBT is the most extensively evaluated psychologic therapy in anxiety disorders and contains elements of cognitive and behavioral therapy approaches.

Behavior therapy consists of using exposure to modify dysfunctional behaviors that may contribute to the development and persistence of psychologic symptoms [151]. Cognitive therapy involves cognitive restructuring, a psychotherapeutic process of learning to identify and modify irrational or maladaptive thoughts using strategies such as Socratic questioning, thought recording, and guided imagery [34].

CBT is not a single treatment approach but a process that addresses factors that caused and maintain patient anxiety symptoms. The classic CBT approach involves disorder-specific treatment protocols that target the symptoms and the cognitive, behavioral, and emotional vulnerabilities that underlie development and maintenance of each disorder. This approach reflects the assumption that each form of psychopathology has a distinct cognitive profile, to which CBT is tailored accordingly. Disorder-specific CBT is the standard of care for anxiety and depressive disorders [152]. However, there are common components of CBT used in anxiety disorders (Table 2) [120].

Table 2: COMMON COMPONENTS OF CBT USED IN THE TREATMENT OF ANXIETY DISORDERS

Cognitive Strategies

Cognitive restructuring, behavioral experiments, and related strategies target exaggerated perception of danger (e.g., fear of negative evaluation in SAD).

Therapy provides corrective information regarding the level of threat and can also target self-efficacy beliefs.

Arousal Management
Relaxation and breathing control skills help control increased anxiety levels.
Exposure

Encourage patients to face fears.

Patients learn corrective information through experience.

Extinction of fear occurs through repeated exposure.

Successful coping enhances self-efficacy.

Safety Response Inhibition and Surrender of Safety Signals

Patients wean from and relinquish use of their usual anxiety-reducing safety signals and behaviors (e.g., presence of a companion, need for reassurance, knowing the location of nearest exit or toilet), which decreases negative reinforcement.

Coping with anxiety without using anxiety-reducing behavior enhances self-efficacy, allowing patients to learn adaptive self-efficacy beliefs.

Source: [120]

There is some debate regarding whether the efficacy of CBT that targets common underlying factors would be comparable to standard diagnosis-tailored CBT. Support for CBT that addresses common underlying factors includes frequent comorbidities in anxious patients, such as major depressive disorder, which some studies found present in close to 50% of patients with anxiety [153]. The frequent co-presence of mood and anxiety disorders, substantial overlap in dimensional symptom ratings, and extensive evidence of shared vulnerability factors enabled identification of common underlying factors that represent targets for CBT. These include [152]:

- Motivational enhancement
- Psychoeducation and understanding emotions
- Emotional awareness training
- Cognitive reappraisal

- Attenuation of emotional and behavioral avoidance

- Awareness and tolerance of physical sensations

- Interoceptive and situational exposure

- Relapse prevention

Psychotherapy and drug therapy show similar efficacy in most anxiety disorders. There is variability and conflicting data on outcome measures from studies of psychotherapy in combination with drug therapy; current evidence does not support routine combination therapy as initial treatment. However, patients lacking response to either CBT or drug therapy may benefit from adding the other modality [120].

Delivery of effective CBT is versatile. Individual or group delivery is effective in most anxiety disorders. A variety of self-directed or minimal intervention formats (e.g., bibliotherapy/self-help books, Internet/computer-based CBT with or without minimal therapist contact) have shown significant improvements in anxiety symptoms, and exposure therapy can be effective using a virtual reality format. These strategies can be very useful when real-life exposure is made difficult by inconvenience or patient reluctance [120].

Third-Wave Therapies

Mindfulness-based cognitive therapy, acceptance and commitment therapy, compassionate mind training, extended behavioral activation, metacognitive therapy, and schema therapy are diverse approaches originating from CBT. These modalities place greater importance on the form rather than content of patient cognitions. These third-wave therapies help patients develop more adaptive emotional responses to situations by focusing on the function of cognition. Mindfulness and acceptance are used in anxiety disorders to help patients observe symptomatic processes without overly identifying with or reacting to them in ways that perpetuate distress [154].

Mindfulness

Mindfulness involves attending to relevant aspects of experience in a non-judgmental manner. The goal of mindfulness is to maintain moment-by-moment awareness; disengage oneself from strong attachment to beliefs, thoughts, or emotions; and develop a greater sense of emotional balance and well-being. An aim of mindfulness practice is to take greater responsibility for one's life choices. Some evidence supports the efficacy of this approach in GAD and panic disorder [155,156,157].

Mindfulness versus active control was compared in ability to reduce negative thought intrusions activated by a worry-induction procedure. Negative thought intrusions significantly increased with progressive muscle relaxation and focused attention but not with brief mindfulness meditation, suggesting mindfulness might target anxiety by reducing negative elaborative processes that maintain worry [158].

Acceptance and Commitment Therapy

Acceptance and commitment therapy views psychologic events as a set of ongoing interactions between whole organisms and contexts defined historically and situationally. Acceptance and commitment therapy states that analyzing problematic behaviors but excluding the contexts that participate in the event misses the nature of the problem and pathways for its solution. This approach promotes a conscious posture of openness and acceptance of all psychologic events, including those deemed "negative" or "irrational." In acceptance and commitment therapy, when patients feel frustrated, afraid, angry, or anxious, this represents an opportunity to examine how powerful events in the present can become barriers to growth [159]. Some evidence suggests acceptance and commitment therapy may be as effective as CBT in anxiety disorder treatment, including panic disorder [151,160,161].

Acceptance-based skill training differs from traditional coping skills training by de-emphasizing control (over physiology or thoughts) to focus on acceptance of panic-related sensations and cognitions as they occur from moment to moment. Patients learn to pay nonjudgmental attention to thoughts, feelings, images, and bodily sensations. Thoughts are viewed as an ongoing process distinct from self, rather than events with literal meaning (cognitive defusion). Efficacy of acceptance approaches has been shown in patients with panic disorder/agoraphobia [162].

Education and Support

Psychoeducation states that providing information to patients with anxiety about their anxiety symptoms and theories of psychologic therapy may help reduce these symptoms. By increasing the patient's sense of control, psychoeducation may reduce catastrophic thoughts and emotions. This is especially relevant to patients with panic disorder, whose cognitive coping mechanisms are disrupted and whose anticipatory anxiety may cause additional attacks [151].

Supportive psychotherapy uses encouragement, rationalizing/reframing, and anticipatory guidance to reduce symptoms and maintain, restore, or improve self-esteem, ego function, and adaptive skills. This approach views the therapeutic alliance as the most important element. The archetype of supportive psychotherapy is the Rogerian client-centered approach; a warm, empathic, and non-directive therapeutic relationship helps clients become aware of their true feelings and achieve full self-acceptance. This approach may benefit patients with agoraphobia, but efficacy in panic disorder is unclear [151].

Physiologic Therapy

Physiologic therapies involve physical training (e.g., breathing retraining, relaxation techniques, biofeedback) to help patients control physiologic anxiety symptoms. Hyperventilation and hypocapnia are identified factors in panic disorder development and maintenance; panic attacks can be caused by acute hypocapnia states in a positive feedback loop between hyperventilation and anxiety. Breathing training is used to ameliorate panic symptoms, but it shows mixed efficacy in panic disorder [162]. Progressive muscle relaxation teaches patients with panic to reduce general tension and achieve a body state that lowers the risk for panic-inducing stressors. Applied relaxation teaches patients to observe the first signs of a panic attack and apply a rapid and effective relaxation technique to cope with and abort panic symptoms before escalation into a panic attack. Applied relaxation is comparable to progressive muscle relaxation in reducing panic attacks [151].

Psychodynamic Approaches

Psychodynamic therapies differ in length and depth, influenced by Freudian psychoanalysis and later refinements. Psychodynamic psychotherapy views mental symptoms as manifestations of intrapsychic and unconscious conflicts; treatment involves uncovering, interpreting, and resolving such conflicts using analysis of unconscious contents, dreams, past experiences, parental relationships, transference, and/or resistances [151]. A brief panic-focused psychodynamic psychotherapy, derived from psychodynamic theories, utilizes emotion-focused therapy, whereby the therapist is viewed as an "emotion coach" who works to enhance emotion-focused coping by helping patients become aware of, accept, and make sense of their emotional experience [163].

One psychodynamic psychotherapy approach is derived from the proposition that fearful parental dependency in childhood may lead to anger toward the parent. A vicious cycle is created; anger threatens the needed tie to the parent and increases fearful dependency, which promotes further frustration and rage at the parent. This cycle may recur in adulthood when threats to attachment trigger intense feelings of abandonment, anger, and anxiety, promoting the development of pathologic anxiety. The goal is to address such underlying psychologic factors to decrease panic symptoms. Some evidence suggests this approach is a valid therapeutic option, especially when SEPAD is present [98,151].

Exposure Therapies

Exposure therapy is defined as any treatment that encourages patients to systematically confront feared stimuli, which can be external (e.g., feared objects, activities, situations) or internal (e.g., feared thoughts, physical sensations) [136]. Exposure therapy is an effective, empirically supported treatment modality for anxiety disorders and a core component of CBT. Variants of exposure therapy include:

- In vivo exposure: Exposure that involves real-world confrontation of feared stimuli

- Imaginal exposure: Vividly imagining and describing the feared stimulus, including details about external (sights, sounds) and internal (thoughts, emotions) cues

- Virtual reality exposure: Patient immersion into a software-generated virtual world that allows them to confront their fears

The success of exposure therapy occurs by targeting maladaptive learning and fear conditioning, core mechanisms implicated in anxiety disorder etiology and maintenance. Standard exposure therapy involves exposure to feared objects or situations and gradual elimination of safety behaviors—the subtle avoidance behaviors that temporarily diminish distress in feared situations but interfere with long-term anxiety reduction. Patients are encouraged to continue confronting the feared situations through exposure until substantive reductions in fear occur. Exposure therapies facilitate extinction learning by diminishing the association between the avoided situation and fear and promoting new learning of the true nonthreatening nature of the situation [164,165].

Exposures are graded in intensity, with the same process used for weaning safety signals. For instance, a patient with panic disorder and agoraphobia can initially practice walking through a congested shopping mall with a family member; on the next exposure, he or she may practice walking separately through the shopping mall and eventually walk through the congested mall alone. Patients are taught that treatment setbacks are common and to distinguish between expected treatment lapses and relapses. Symptom flare-ups do not mean treatment failure, but instead are opportunities to revisit psychoeducation, cognitive restructuring, or exposure, and work toward regaining progress [166].

A substantial number of patients fail to achieve substantive symptom relief from exposure-based therapies or experience fear relapse following exposure therapy. This results from deficits in the mechanisms considered central to extinction learning (e.g., poor medial prefrontal cortex inhibition of amygdala-generated fear impulses) that contributed to the development of pathologic anxiety and avoidance in the first place. Because of this, effort is underway to optimize exposure therapies to improve significant and durable patient response [167]. This effort includes the therapeutic alliance as a potential prognostic indicator [168].

PHARMACOTHERAPY: OVERVIEW

The first-generation antidepressants monoamine oxidase inhibitors (MAOIs) and TCAs were introduced in the late 1950s and early 1960s, and the first report of antidepressant use in anxiety treatment was published in 1962. In this account, patients with agoraphobia who were given the TCA imipramine showed reductions in panic attacks and improved exposure to feared situations [169]. The benzodiazepine chlordiazepoxide (Librium) was introduced to the U.S. market in 1960. This was followed by diazepam (Valium) in 1963, which became the most prescribed drug in the United States from 1969 to 1982; in 1978, more than 2.3 billion diazepam doses were sold in the United States [170]. Panic disorder was first formalized as a psychiatric disorder in the 1980 DSM-III, and alprazolam (Xanax) became the first U.S. Food and Drug Administration (FDA)-approved drug for panic disorder treatment in 1981, remaining the most-prescribed benzodiazepine to date [171].

In the past two decades, antidepressant drugs, specifically SSRIs, have displaced benzodiazepines as the most widely prescribed and recommended anxiety disorder pharmacotherapy. Efforts to improve safety, efficacy, and tolerability led to introduction of the second-generation antidepressants, with trazodone (Oleptro) in 1982, bupropion (Wellbutrin) in 1985, and fluoxetine (Prozac)—the first domestically marketed SSRI—in 1987.

Antidepressants are generally recommended as first-line therapy for panic disorder because, unlike benzodiazepines, antidepressants treat comorbid depression and lack abuse risk and potential side effects of excessive sedation, cognitive impairment, and ataxia. All major antidepressant classes are comparably effective, but SSRIs and, increasingly, SNRIs are recommended over TCAs and MAOIs due to better safety and tolerability [172].

Tricyclic Antidepressants

Norepinephrine, serotonin (5-HT), and dopamine are termed monoamines. Monoamine reuptake transporters retrieve monoamines released into the synaptic cleft to terminate their activation of post-synaptic monoamine receptors. TCAs act by inhibiting norepinephrine and 5-HT reuptake transporters. This increases synaptic levels of norepinephrine and 5-HT by preventing their clearance, which increases post-synaptic receptor activation and signaling. TCAs generally have greater norepinephrine than 5-HT reuptake transporter potency. TCAs also act as histamine H1/H2, muscarinic acetylcholine, and alpha-adrenergic receptor antagonists, resulting in a range of undesirable side effects associated with patient intolerance and discontinuation, including [173]:

- Anticholinergic: Dry mouth, blurred vision, constipation, urinary hesitancy and retention, confusion, precipitation of glaucoma, delayed ejaculation, sweating

- Alpha-1-adrenoceptor antagonism: Postural hypotension, increased heart rate, dizziness

- Antihistaminergic: Sedation, psychomotor slowness, weight gain

- Cardiac sodium channel blockade: QTc prolongation, decreased cardiac conduction, fatal cardiac arrest in overdose

TCAs have comparable efficacy to SSRIs in panic disorder and GAD [174,175]. TCAs are lethal in overdose and, compared to SSRIs, have a markedly broader, more problematic, and less tolerable side effect profile [172]. Nonetheless, TCAs may work when first-line agents do not [136]. Also, some patients with panic disorder are sensitive to both beneficial and adverse effects of TCAs, so they cannot tolerate imipramine doses >10 mg/day but may still experience panic blockade [172].

Monoamine Oxidase Inhibitors

MAOIs inhibit MAO, an enzyme that degrades and inactivates 5-HT, norepinephrine, and dopamine, thereby increasing monoamine levels and activity. The earlier MAOIs—phenelzine (Nardil) and tranylcypromine (Parnate)—are characterized by irreversibility and nonselectivity. Irreversibility refers to tenacious drug binding to the MAO enzyme for the 14- to 28-day lifespan of the drug molecule. Nonselectivity refers to phenelzine and tranylcypromine binding to both A and B isoenzymes of MAO. While tyramine and dopamine are metabolized by both MAO-A and MAO-B, MAO-A inhibition is established as the precursor to hypertensive crises [176].

During phenelzine or tranylcypromine therapy, dangerous and potentially fatal hypertensive reactions can result from co-ingestion of drugs with monoamine activity or foods high in tyramine content (e.g., cheese, beer, wine). Concurrent use of serotonergic agents or supplements such as St. John's wort can cause potentially lethal serotonin syndrome. Common side effects include orthostatic hypotension, weight gain, sexual dysfunction, sedation, headache, and insomnia. To avoid drug interactions, washout periods are required before an MAOI is started (≥5 days) or stopped before switch to another medication (≥14 days) [136].

Moclobemide is a reversible inhibitor of monoamine oxidase type A (RIMA). With reversibility, MAO enzyme detachment and/or displacement readily occur, greatly improving safety. Compared to tranylcypromine, it takes eight times the tyramine level (8 mg vs. 63 mg) with moclobemide to induce a 30 mm Hg rise in diastolic blood pressure; dietary and co-medication concerns are greatly reduced. No washout period is required for switching anti-depressants. Moclobemide is safe in overdose, and 20,000 mg has been ingested without fatality. Common side effects include nausea, insomnia, tremor, and lightheadedness. Orthostatic hypotension is uncommon, even in the elderly [176]. Moclobemide lacks the cholinergic and histaminergic side effects of TCAs and the sexual side effects of SSRI/SNRIs. Depressive patients more commonly reported improved libido, erection/ejaculation, and orgasm with moclobemide. Weight gain or lowered seizure threshold are not side effects [177]. Moclobemide was slated for introduction in the United States in 1992. It was withdrawn from the application process because SSRI popularity cast doubts on its profit potential. This drug is available in Canada and throughout Europe and Asia [176,178].

MAOIs and RIMAs are effective for panic disorder and SAD and are thought by some to be superior options for severe, treatment-resistant anxiety disorders. As noted, MAOIs have a substantial side effect profile and impose the greatest safety burden of all antidepressants. Therefore, they are usually reserved as the last treatment option after other drug therapies have failed to achieve remission [179]. Clinicians do not routinely prescribe MAOIs for anxiety disorders, although they are probably not considered often enough in treatment-resistant patients [136].

SSRIs

SSRIs are considered first-line therapy for GAD and panic disorder [121,172]. SSRI mechanism is thought to involve serotonin transporter (SERT) inhibition at the presynaptic axon terminal of 5-HT neurons. SERT inhibition also occurs at the somatodendritic end of the neuron, where the increase in 5-HT causes 5-HT1A autoreceptors to downregulate, desensitize, and over time lose the ability to inhibit 5-HT release. The resultant increase in synaptic 5-HT level mediates the therapeutic action. SSRIs were termed "selective" because, unlike TCAs, they were believed to have little-to-no interaction with non-serotonin receptors and transporters [136,180].

It is now recognized that SSRIs differ in pharmacologic effect, including activity beyond SERT inhibition [179,180]:

- Fluoxetine: Antagonist at 5-HT2C receptors, which enhances norepinephrine and dopamine release. Therapeutic effects may emerge more slowly than other SSRIs.

- Sertraline (Zoloft): A weak dopamine transporter inhibitor, sigma-1 receptor activity. Along with fluoxetine, increases cortex monoamine levels to possibly explain patient reports of improved energy, motivation, and concentration.

- Paroxetine (Paxil): A weak norepinephrine transporter inhibitor, which contributes to antidepressant effects. Muscarinic cholinergic receptor activity may underlie some sedative and anxiolytic effects.

- Fluvoxamine (Luvox): Along with sertraline, has sigma-1 receptor activity that possibly contributes to the anxiolytic effects of both agents.

- Citalopram (Celexa): Mild antihistamine properties not observed with escitalopram.

- Escitalopram (Lexapro): Is considered the only SSRI without pharmacologic activity beyond SERT inhibition.

The atypical SSRIs vilazodone (Viibryd) and vortioxetine (Brintellix) display expanded serotonergic and other monoaminergic activity beyond those of standard SSRIs. Vilazodone and vortioxetine are likely to be treatment options for patients who do not respond to or cannot tolerate typical SSRIs/SNRIs.

Side effects associated with SSRI treatment include gastrointestinal upset (nausea, vomiting, diarrhea), activation/insomnia (restlessness, agitation, anxiety, akathisia, sleep disturbances), sexual dysfunction (loss of erectile or ejaculatory function in men, loss of libido and anorgasmia in both sexes), headache, fatigue, and weight gain. Many side effects dissipate over time. Sertraline is particularly associated with diarrhea, and paroxetine with weight gain. Discontinuation syndrome from paroxetine is more severe and protracted than other SSRIs [181]. To avoid relapse, medication should be continued for at least 12 months after symptom improvement before tapering [121].

Vilazodone

Approved by the FDA in 2011, vilazodone primarily acts as a serotonin reuptake inhibitor and 5-HT1A receptor partial agonist, with modest action as a dopamine and norepinephrine reuptake inhibitor, with 5-HT4 receptor activity [173]. This profile resembles the combination of SSRI and buspirone, and GAD efficacy of both agents suggests a potential role for vilazodone in anxiety disorder treatment. Two eight-week randomized controlled trials of vilazodone treatment of GAD have been published. One using a flexible-dose design found nominal clinical improvement with vilazodone compared with placebo, while the other study using a fixed-dose design found statistically significant reduction in anxiety scores (vs. placebo) with vilazodone 40 mg but not 20 mg [182,183]. Vilazodone does not appear to improve efficacy over drugs already in use, but it does have advantages of earlier onset of clinical response (beginning by two weeks) and little evidence of sexual dysfunction or weight gain. Vilazodone should be taken with food, which increases its absorption and bioavailability by 72% [184].

Vortioxetine

Approved by the FDA in 2013, vortioxetine is a multimodal antidepressant and potential anxiolytic with activity as an antagonist in 5-HT1D/3A/7 receptors, a 5-HT1A receptor agonist, 5-HT1B partial agonist, serotonin transporter inhibitor, and weak norepinephrine transporter inhibitor. This multiple receptor activity modulates serotonergic, noradrenergic, dopaminergic, and histaminic systems to produce clinical effect [185]. Results from four randomized controlled trials suggest vortioxetine may have potential efficacy in the treatment of severe GAD, but effects in patients with more moderate GAD were minimally improved compared with placebo. Nausea, the most common side effect, was dose dependent [186]. Sexual dysfunction rates were similar to placebo across the 5–20 mg/day dose range, and vortioxetine can be taken without regard for meals [187].

SNRIs

Venlafaxine, the first SNRI approved in the United States, was introduced as immediate release (IR) in 1993 and extended release (XR) in 1997. This was followed by the introduction of duloxetine in 2004, desvenlafaxine in 2008, milnacipran in 2009, and levomilnacipran in 2013. SNRIs increase synaptic concentrations of 5-HT and norepinephrine by blocking reuptake of these neurotransmitters by their respective transporters. SNRIs lack significant affinity for adrenergic, cholinergic, histaminergic, opioid, glutamate, or GABA receptors and transporters [136,188].

SNRIs differ in proportion of 5-HT/norepinephrine reuptake inhibition. Venlafaxine is the most serotonergic SNRI, followed by duloxetine and desvenlafaxine. Milnacipran shows relatively equal influence on 5-HT and norepinephrine reuptake inhibition, and levomilnacipran is a greater norepinephrine than 5-HT reuptake inhibitor. Such differences suggest that SNRIs are dissimilar from one another. Venlafaxine and duloxetine exhibit dose-related sequential effects on reuptake inhibition, while desvenlafaxine, milnacipran, and levomilnacipran act simultaneously on 5-HT and norepinephrine reuptake inhibition with proportionality intact with dose escalation [189].

Side effects from SNRIs overlap with SSRIs but can also include adrenergic effects of increased pulse rate and blood pressure, dilated pupils, dry mouth, and excessive sweating. Venlafaxine has a greater incidence of nausea and vomiting than SSRIs and may be associated with an increased risk for cardiovascular events [181]. Sexual side effects associated with SNRIs include decreased response to sexual stimuli, loss of interest in sex, anorgasmia, and much less frequently, genital anesthesia. Discontinuation syndrome from venlafaxine is markedly worse than other SNRIs and SSRIs [188].

Relative to SSRIs and TCAs, the SNRIs have relatively short half-lives, and few or no active metabolites for simpler overall pharmacology. In contrast to venlafaxine and duloxetine, desvenlafaxine, milnacipran, and levomilnacipran largely bypass the hepatic cytochrome P450 isoenzyme system, making drug interactions less likely. Of the five available SNRIs, only venlafaxine has an active metabolite (desvenlafaxine). Dosing with venlafaxine IR and milnacipran is twice daily; the remaining SNRIs are dosed once daily [184].

The impairing effects from synaptic plasticity induced by conditioned psychologic stress were found reversed by SNRI treatment. Long-term venlafaxine and milnacipran use suppressed long-term potentiation in hippocampal CA1 via 5-HT1A receptor and a1-adrenoceptor activity, contributing to reversal in synaptic plasticity-related impairment induced by conditioned fear stress. Increased responsiveness of a1-adrenergic and dopaminergic D3 systems, decreased responsiveness of 5-HT2 systems, and development of adaptive changes occurred despite lack of SNRI affinity for these neurotransmitter receptors [188,190,191].

Venlafaxine

Venlafaxine IR was introduced in 1993 but from the outset was plagued with side effects, leading to the 1997 introduction of venlafaxine XR. The XR formulation has become a widely prescribed agent with established efficacy in several anxiety disorders. In addition to the dose-related reuptake inhibition of 5-HT and norepinephrine mentioned, weak dopamine reuptake inhibition may appear at dosages greater than 300 mg/day. This sequential activity is mirrored by the initial predominant serotonergic side effects (headache, nausea, fatigue, sexual dysfunction), with noradrenergic effects at higher doses (activation effects, dry mouth, night sweats) [184].

Desvenlafaxine

Desvenlafaxine (Pristiq) shows a 10-fold higher selectivity for serotonin over norepinephrine reuptake inhibition at 50 mg/day, with selectivity unchanged by dose increase to 100 mg/day [184]. A primary advantage of desvenlafaxine over venlafaxine involves metabolic pathways and drug interactions. Venlafaxine is extensively metabolized by the hepatic CYP2D6 isoenzyme to desvenlafaxine, while desvenlafaxine is metabolized primarily via glucuronidation and minimally through CYP3A4 [178]. Venlafaxine, but not desvenlafaxine, clearance in patients with polymorphic 2D6 can be accelerated or delayed, resulting in non-efficacy or greater side effects/toxicity. This makes desvenlafaxine preferable to venlafaxine for these patients. The desvenlafaxine metabolic pathway also eliminates adverse drug interactions with 2D6 substrates that require consideration with venlafaxine prescribing [188,192]. However, few trials have evaluated desvenlafaxine in anxiety disorder treatment [184]. A comparison of the efficacy and safety of desvenlafaxine and escitalopram for treatment of depression with anxiety found that both drugs reported similar efficacy, but escitalopram was better tolerated with fewer adverse effects [193].

Duloxetine

Duloxetine (Cymbalta) has greater potency in 5-HT reuptake inhibition than fluoxetine. It has an elimination half-life of roughly 12.5 hours, steady-state is usually achieved after three days, and metabolism occurs mainly through hepatic CYP 2D6 and 1A2 [178,194]. Common adverse effects of duloxetine include nausea, headache, and weight loss. Certain adverse effects, including xerostomia, drowsiness, and fatigue, are dose related [178].

Milnacipran

Milnacipran (Savella) has been marketed in France since 1997 for the treatment of major depression, but it is indicated for use by the FDA solely for fibromyalgia [178]. Milnacipran is not available in a generic formulation, and the expiration of the patent is not imminent. Anxiolytic effects of milnacipran are at least partially mediated by 5-HT2A receptor agonism [188,195]. Results of a systematic review were inconclusive regarding the comparative efficacy, acceptability, and tolerability of milnacipran versus other antidepressive agents; however, milnacipran reportedly was more favorable than TCAs in terms of acceptability and tolerability [196].

Levomilnacipran

Levomilnacipran (Fetzima) differs from other SNRIs in that it is a more potent and selective inhibitor of norepinephrine than serotonin, especially at low doses. Alcohol may disrupt the extended-release mechanism to release large amounts of drug over a brief period, and co-ingestion should be avoided. With reports of milnacipran increasing hepatic transaminases to cause fulminant hepatitis, levomilnacipran should be avoided in patients with a history of alcoholism or chronic liver disease. Levomilnacipran is not associated with weight gain [173,178]. Levomilnacipran ER 40–120 mg daily was found to be effective in preventing relapse in patients with major depressive disorder [197].

Other Antidepressants

Bupropion

Bupropion (Wellbutrin) lacks effect on serotonin neurotransmission either presynaptically (through serotonin release or reuptake inhibition) or postsynaptically (acting on serotonin receptors). Instead, bupropion inhibits the reuptake of norepinephrine and dopamine without affecting release or transport of other neurotransmitters and without binding to other neurotransmitter receptors. This unique pharmacologic profile makes bupropion the only approved antidepressant that increases dopamine neurotransmission in the nucleus accumbens and prefrontal cortex. The side effect profile, distinct from other antidepressants, lacks sexual dysfunction, weight gain, and sedation. The activating effects of bupropion can increase insomnia and anxiety, leading to its infrequent use in anxiety disorders [179,198].

Trazodone and Nefazodone

The anxiolytic effects of trazodone are mediated by activity as a highly potent 5-HT2A receptor antagonist and moderately potent 5-HT1A partial agonist, with additional activity in SERT and 5-HT2C receptor inhibition. The combined actions of 5HT2A/5HT2C antagonism and SERT inhibition only occur at moderate-to-high doses, with doses lower than effective for antidepressant action frequently used for the effective treatment of insomnia [178,179,199]. Nefazodone (Serzone) is highly similar in pharmacologic activity to trazodone, but it is rarely prescribed due to liver toxicity concerns [179].

Mirtazapine

Mirtazapine (Remeron) is a tetracyclic compound with a unique mechanism of action, leading to description as a noradrenergic antagonist-specific serotonin antagonist antidepressant. Pharmacologically, mirtazapine is a 5-HT1 receptor agonist, and antagonism of 5-HT2A/C receptors increases cortical serotonin, dopamine, and norepinephrine modulation. Inhibition of norepinephrine alpha-2 autoreceptors allows greater norepinephrine release from neuron terminals. Also antagonized are receptors of 5-HT3, 5-HT5, and H1 histamine. This unique profile helps account for earlier onset of action than SSRI/SNRIs. Mirtazapine tends to promote sleep or drowsiness, and the most frequent side effect of daytime sedation can be a beneficial effect in highly anxious patients [178,179,188].

Mirtazapine is found beneficial in patients with GAD, SAD, OCD, panic disorder, and PTSD [200]. It is relatively safe in overdose. Mirtazapine is particularly useful in patients with sexual dysfunction from other antidepressants and is a good choice in patients with significant insomnia. Weight gain is a side effect, and if the risks for elevated lipid levels and rare agranulocytosis are a concern, mirtazapine may be reserved as a third-line choice [200,201].

Agomelatine

Agomelatine is approved for clinical use in Europe, Australia, and a total of 40 countries overall, but not by the FDA. It is discussed in light of its novel mechanism and particular benefit in GAD [202].

Agomelatine is a synthetic melatonin analog with activity as a melatonin MT1/MT2 receptor agonist and 5-HT2C receptor antagonist. Unique to agomelatine, and one of its most important properties, is a sleep-promoting and pro-chronobiologic effect. Its 5-HT2C antagonism promotes dopaminergic firing in the ventral tegmental area, frontal cortex, hypothalamus, hippocampus, medulla, pons, and retina by enhancing norepinephrinergic activity in the locus coeruleus [185,203].

With a unique non-monoaminergic mechanism of action, clinical trials have shown a low risk of sexual dysfunction, lack of weight gain or withdrawal symptoms, and overall side effect profile similar to placebo. However, reports of liver injury require patients to receive liver enzyme monitoring [204].

Anti-Epileptic Drugs

Gabapentinoids

Pregabalin (Lyrica) and gabapentin (Neurontin) are structurally analogous GABA analogs, with pregabalin more extensively evaluated in anxiety disorders. The anxiolytic, antinociceptive, and antiseizure properties of pregabalin are mediated through binding to presynaptic α2δ subunits of central nervous system (CNS) voltage-gated calcium channels, which decreases calcium influx at presynaptic channels and inhibits neurotransmission of excitatory glutamate, norepinephrine, and substance P [185,205].

The relative efficacy and early onset of effect of pregabalin versus benzodiazepines may represent a new therapeutic intervention for GAD as mono- and augmentation therapy. Pregabalin has a low risk of drug interactions, lacks withdrawal or physical dependence risk, is associated with minimal adverse effects (e.g., dizziness, weight gain, insomnia), and is safe and well tolerated. A potential role for pregabalin in patients with GAD tapering off long-term benzodiazepine therapy has been suggested [185].

Benzodiazepines have been the only anxiolytic agents that rapidly reduce anxiety, but trials conducted in the last decade have also found this effect with pregabalin. In 89 patients with moderate-to-severe dental anxiety (without anxiety disorder diagnosis) given single-dose pregabalin 150 mg, alprazolam 0.5 mg, or placebo four hours before a dental procedure, the onset of anxiolytic effects began within three to four hours after pregabalin and within two hours after alprazolam. The magnitude of anxiety reduction and tolerability were equivalent between pregabalin and alprazolam [206].

Common GAD comorbidities of insomnia, gastrointestinal symptoms, and depression do not impair efficacy and are specifically improved by pregabalin. Pregabalin is generally well tolerated; the adverse event profile includes dizziness, somnolence, incoordination, dry mouth, headache, and weight gain. Risk of withdrawal symptoms is low when tapered over one week [205].

Levetiracetam (Keppra) is an analog of the nootropic drug piracetam and structurally unrelated to other anti-epileptic drugs. It has a novel mechanism of action that involves binding to synaptic vesicle protein SV2A, a protein that modulates neurotransmitter release including GABA. Metabolism has no effect on the cytochrome P450 enzyme system. The most common side effects include somnolence, dizziness, and weakness [207]. In one study, adjunctive levetiracetam (mean: 1,969 mg/day for 9.3 weeks) in highly symptomatic patients with treatment-refractory anxiety disorders led to clinically and statistically significant improvement in illness severity [208]. Further research involving patients with panic disorder with or without agoraphobia given levetiracetam for 12 weeks showed significant improvement in panic attack frequency, anxiety, and global severity ratings. Clinical benefits were apparent by one to two weeks for most patients, and side effects were minimal [209]. Patients with SAD initially administered levetiracetam 250 mg/day and flexibly titrated up to 3,000 mg/day over eight weeks showed significant improvements on measures of social anxiety, overall anxiety, and illness severity [210]. In contrast to the anti-epileptic agents zonisamide and topiramate, levetiracetam has not shown decrements in neuropsychologic performance on tests of cognitive impairment in patients with seizure disorder [211].

Atypical Antipsychotics

Olanzapine, risperidone, aripiprazole, and quetiapine are dopamine D2 receptor antagonists, as with all antipsychotic drugs, but differ from typical (first-generation) antipsychotics by also acting as 5-HT2A receptor antagonists (minimizing development of extrapyramidal effects), 5-HT1A receptor partial agonists (producing anxiolytic effects), and histamine receptor antagonists (further augmenting sedative and anxiolytic effects) [185].

Quetiapine

Quetiapine (Seroquel) is the most-studied atypical in anxiety disorder treatment and has greatest efficacy in GAD. A review of quetiapine in GAD found efficacy and tolerability in all acute and long-term monotherapy trials and statistically significant changes in anxiety and symptom severity in three of five adjunct therapy studies. Quetiapine is a treatment option for patients unresponsive to first-line therapy, and potential benefits may outweigh risks with appropriate monitoring and side effect management [212]. While the unique efficacy of quetiapine monotherapy in GAD is supported by a Cochrane review, quetiapine was denied FDA approval for GAD, likely due to its tendency for inducing lipid abnormalities, weight gain, and glucose intolerance, and concerns over widespread use in primary care without careful consideration of alternatives or monitoring adverse metabolic effects during follow-up [136,213].

Buspirone

Introduced in 1986, buspirone (BuSpar) was the first anxiety-specific medication unrelated to benzodiazepines or barbiturates in pharmacology, effect, and abuse potential. The 5-HT1A receptor partial agonism mediates the anxiolytic effects. Buspirone acts as a weak presynaptic dopamine D2, D3, and D4 receptor antagonist and alpha-1 agonist [214]. Buspirone is primarily used in the treatment of GAD and to augment antidepressants for improved response.

Hydroxyzine

Hydroxyzine (Vistaril) acts mechanistically as a potent H1 receptor inverse agonist, and as a 5-HT2A, D2, and alpha-1-adrenergic receptor antagonist. The serotonergic activity of hydroxyzine is more potent than its dopaminergic and adrenergic activity and likely accounts for its anxiolytic efficacy, as other antihistamines lacking this property have not been effective in the treatment of anxiety [178,216]. Hydroxyzine efficacy in anxiety disorders is limited to GAD, for which anxiety-reducing efficacy is demonstrated [217,218,219].

Benzodiazepines

Since their introduction in the early 1960s, benzodiazepines have been the most prescribed drugs for anxiety over the majority of the past half-century. Although SSRI/SNRI agents have replaced benzodiazepines as the top-prescribed anxiolytics, benzodiazepine prescribing remains common. In 2020, alprazolam, clonazepam, and lorazepam were among the top 25 most frequently prescribed psychotropic medications in the United States; alprazolam ranked ninth, clonazepam ranked 12th, and lorazepam ranked 16th [220,221].

Pharmacology and Short-Term Effects

Numerous benzodiazepines are available and have similar pharmacodynamic properties and clinical actions; they mainly differ in pharmacokinetic properties (absorption, distribution, metabolism, elimination). Benzodiazepines bind to a specific receptor site in the GABA-A receptor complex. GABA is the primary inhibitory neurotransmitter in the CNS, and benzodiazepines cause non-selective GABA-A inhibitory effects throughout the brain that include drowsiness, cognitive impairment, dampening of fear and anxiety, memory impairment, anticonvulsant actions, and impairment of balance, motor control, muscle tone, and coordination. Adverse reactions to alprazolam also include amnesia, aggression, mood changes, and hostility. The newer Z drugs (e.g., zolpidem, zopiclone) have similar actions to benzodiazepines but are marketed for insomnia due to their pharmacokinetic profile, with high doses required for anxiolytic effects. There is evidence the Z drugs share similar risks to benzodiazepines [222,223].

Meta-analyses suggest alprazolam, lorazepam, and diazepam are effective but comparable in GAD efficacy, while clonazepam shows much greater efficacy in the treatment of panic disorder than alprazolam, lorazepam, and diazepam, which all have modest efficacy [224].

Appropriate Prescribing

Benzodiazepine treatment of anxiety disorders is controversial. While effective in rapid anxiety reduction, the potential drawbacks with long-term use are substantial. These agents are indicated when potent, short-term anxiolytic effects are necessary to permit infrequent exposure to feared stimuli and potentially severe anxiety, such as airplane travel [121,129,136]. Clonazepam, lorazepam, and alprazolam are effective for short-term use in panic disorder, GAD, and SAD, but ineffective for, and potentially worsening, comorbid depression [28]. The rapid anxiolytic effects make benzodiazepines highly appealing to patients with anxiety, but aside from this specific context, benzodiazepine prescribing for as-needed use is discouraged [136,225,226]. Benzodiazepines can reinforce pill taking, serve as a safety signal that undermines self-efficacy, and become incorporated into conditioned fear responses; these concerns are heightened with as-needed use. On-demand dosing links pill taking to rapid anxiety reduction, powerfully reinforcing avoidance in anxiety-provoking situations and encouraging longer-term reliance on the drug. This iatrogenic effect also contributes to poor CBT response.

The current recommended prescribing is for time-dependent use, instead of panic response-dependent use, to minimize the risks [121]. This would also seem to maximize risk of withdrawal syndrome from uninterrupted versus intermittent drug exposure.

Benzodiazepines are also useful in the initial weeks of SSRI/SNRI initiation, to rapidly reduce anxiety and possible early anxiogenic medication side effects before the onset of SSRI/SNRI anxiolytic effects [121,129,136]. However, patients may discontinue the antidepressant when co-prescribed a rapidly effective benzodiazepine, believing the benzodiazepine's symptom relief makes the SSRI/SNRI unneeded. Supportive therapy with regular visits or phone contacts may also help patients remain adherent until the delayed onset of antidepressant benefits appears or early antidepressant side effects lessen [227].

Another indication for benzodiazepine use is for the short-term relief (two to four weeks only) of anxiety that is severe, disabling, or subjecting the individual to unacceptable distress. Perhaps the greatest prescribing challenge with benzodiazepines is preventing short-term use from insidiously developing into long-term use. Patients with the most severe anxiety may obtain the greatest relief and become most hesitant to discontinue use [228]. In many cases, clinicians ignore the recommended two- to four-week prescribing limit, mainly because alternative options with superior anxiolytic effects are not available [229]. Clinicians intending to prescribe alprazolam should carefully consider the likelihood that its use will remain restricted to the very short term—a few days to a couple weeks—to see the patient through a crisis [228].

Benzodiazepines may be prescribed to augment SSRI/SNRI therapy for improved response in select patients with significant residual anxiety or non-response. In one study, patients with SAD and sertraline nonresponse after 10 weeks were given sertraline plus clonazepam (≤3 mg/day), venlafaxine (≤225 mg/day), or sertraline plus placebo for 12 weeks. Those with sertraline augmented by clonazepam showed greatest reduction in SAD symptoms and a better overall response rate than comparator groups, although remission rates did not differ significantly [230]. These agents are third- or fourth-line treatment in patients unresponsive or intolerant to other anxiolytic drugs who remain highly symptomatic [121,129,136]. Generally, patients with a history of substance abuse, personality disorder, or chronic pain should not be treated with benzodiazepines because of the high risk for overuse of these medications [129]. While benzodiazepines should usually be reserved for patients lacking response to at least two treatments (i.e., non-response to an SSRI/SNRI and a psychologic treatment), concerns about potential problems in long-term use should not prevent their use in patients with persistent, severe, distressing, and impairing anxiety symptoms [231].

It seems the most appropriate guidance for benzodiazepine prescribing involves occasional, context-specific use or cautious use during SSRI/SNRI initiation [3,231]. Otherwise, benzodiazepines should be reserved for patients lacking response to three or more treatments, such as an SSRI, an SNRI, and a psychologic intervention, who remain highly symptomatic.

Risks/Drawbacks

While alprazolam remains the most-prescribed benzodiazepine for anxiety disorders, evidence suggests that relative to other benzodiazepines, alprazolam is no more effective and may have specific drawbacks [171]. Alprazolam may have greater potential for dependence than other benzodiazepines due to its rapid onset of anxiolysis and short half-life. With the short half-life, persons prescribed fixed-interval alprazolam (e.g., every six to eight hours) can experience morning withdrawal symptoms following the last nighttime dose. This is frequently mistaken as relapse in anxiety for which the drug was originally prescribed, confirming the continuing need for the drug [228]. The alprazolam product monograph states that such emergence of interdose symptoms reflect insufficient plasma levels, best managed by adding the same dose for four times daily administration (but breakthrough anxiety and alprazolam withdrawal are not differentiated). The document also states that alprazolam treatment of panic disorder differs from sub-syndromal anxiety, in that recommended dosing is as close to around-the-clock as possible, or three or four times per day [232].

Long-term benzodiazepine use can result in added symptoms during stable-dose maintenance, including increasing anxiety and withdrawal-associated symptoms such as perceptual disturbances and paresthesia. This emerging withdrawal syndrome despite ongoing benzodiazepine use is much more likely with highly potent and rapidly eliminated alprazolam or lorazepam and is temporarily alleviated by dose escalation. As craving, dysphoria, and other withdrawal symptoms develop over time between doses, the motivation to continue benzodiazepine use for anxiolysis gradually merges with the need to avoid withdrawal symptoms [233].

Benzodiazepine prescriptions are associated with nonmedical use and the development of benzodiazepine use disorder unrelated to co-occurring drug use or anxiety disorder diagnosis/severity [221]. Acute cognitive-impairing side effects are drowsiness, increased reaction time, ataxia, motor incoordination, and anterograde amnesia. In one study, long-term use of an average 17 mg/day diazepam equivalent led to substantial cognitive decline that did not resolve three months after cessation [234]. Motor vehicle accident risks during benzodiazepine therapy are comparable to driving with a blood alcohol concentration of 0.050% to 0.079% [235]. Hip fracture risk is increased by ≥50% in older persons who take benzodiazepines; with zolpidem, the risk is increased 200% in persons older than 65 years of age [236]. The risk of overdose is particularly great when benzodiazepines are combined with sedative drugs such as opioids or alcohol.

Personality traits associated with long-term use, emotional dependence, and more severe/protracted benzodiazepine withdrawal have been described. Long-term benzodiazepine users often have poor stress coping abilities. Benzodiazepines compensate for these deficits, but their use interferes with learning stress coping strategies, including behavioral therapy for agoraphobia. Passive-dependent personality traits and lack of internal and external stress coping resources increases vulnerability to withdrawal symptoms and motivation for continued use. In these patients, benzodiazepine deprivation renders them unprotected from stress and re-exposes their coping deficits. Chronically anxious people have been found innately hypersensitive to punishing stimuli and punishment; benzodiazepines can be described as "depunishing" drugs [233].

Withdrawal

Withdrawal symptoms following benzodiazepine cessation are appropriately concerning and a liability of this drug class that all prescribers should understand. In patients with panic disorder discontinuing alprazolam following 1.5 to 22 months of treatment, 33% to 100% were unable to completely taper [181]. These data did not include the 50% of long-term benzodiazepine users who do not consent to withdrawal studies or who later quit the study. The experience of benzodiazepine withdrawal is known to deter patients from future attempts [237]. An estimated 25% to 76% of patients prescribed benzodiazepines are long-term users. Defining high-dose benzodiazepine varies, but users of high-dose benzodiazepines commonly have comorbid disorders and are unlikely to benefit from current discontinuation and withdrawal strategies that expose them to greater risk of impairment and injury [237].

Despite comparable dosing, patients with panic disorder often show greater difficulty tapering than patients with GAD. Problems during alprazolam tapering are most severe during the last half of the taper. Patients with panic disorder receiving diazepam or alprazolam had fewer problems during taper of the top 50% of daily dose. However, with abrupt discontinuation of the remaining dose, alprazolam caused significantly more anxiety, relapse, and rebound. This may reflect greater problems withdrawing from short half-life, high-potency benzodiazepines like alprazolam [181].

The patient experience of benzodiazepine withdrawal was studied in 41 high-dose benzodiazepine-using inpatients deciding to withdraw (median dosage: 70 mg/day diazepam equivalent; median duration: six years) [237]. Driving this decision were health concerns of cognitive and physical impairments; feeling addicted; belief benzodiazepine use was a moral burden that limited autonomy; and pressure or coercion by relatives or institutional or governmental bodies to change benzodiazepine consumption patterns. The patients had long histories of repeated unsuccessful attempts to stop taking benzodiazepines and disappointment and frustration by the outcomes. However, many wanted to withdraw completely, with abstinence the goal. Most subjects described benzodiazepine withdrawal symptoms as severe, unpredictable, diverse in manifestation, and of duration difficult to anticipate. Common symptoms included chills, weakness, headache, muscle pains, abdominal pain, nausea, vomiting, diarrhea, tachycardia, dizziness, vision disorders, irritability, nervousness, restlessness, difficulties sleeping, depression, anxiety, tickling sensations, dissociation, complete loss of appetite, and epileptic seizures. Most experienced prolonged post-withdrawal symptoms. Many initially tried withdrawing by abruptly stopping benzodiazepine usage at home; most stated this resulted in perceived epileptic seizures. All favored gradual, long-term tapering over abrupt withdrawal [237].

Normally used to reverse benzodiazepine overdose and post-surgery sedation, flumazenil has shown effects that diminish benzodiazepine withdrawal severity and duration and improve abstinence rates. Dosage and infusion rates vastly differ between these two indications [238]. Flumazenil requires IV or subcutaneous infusion, because its brief half-life and extensive gastric metabolism prohibit oral use [239].

In a study of flumazenil IV infusion, 29 patients stopped benzodiazepines and began flumazenil 1.6 mg/day and oral clonazepam 2–6 mg/day. Antidepressants were started three weeks before the trial or were maintained. Clonazepam was tapered during outpatient follow-up. No patient dropped out, withdrawal severity showed significant linear reduction through the seven-day infusion, and 53% remained free of clonazepam and other benzodiazepines at six-month follow-up [240]. In patients with protracted withdrawal at 47 weeks, IV flumazenil significantly reduced aggression and hostility compared with placebo [241].

In research focused on subcutaneous infusion of flumazenil, patients were switched to oxazepam, began a 48-hour taper, and started flumazenil 16 mg over 96 hours. Subcutaneous infusion significantly reduced psychologic distress and benzodiazepine withdrawal symptoms during treatment. Patients with the highest initial withdrawal severity showed greatest improvement. Patients reported high treatment comfort, willingness to receive the treatment again, and likelihood to recommend it to a friend [239].

Flumazenil attenuates chronic benzodiazepine withdrawal symptoms by up-regulating benzodiazepine receptor binding sites to reverse uncoupling between benzodiazepine and GABA binding sites on the GABA-A complex. This reversal of GABA-A functional alteration helps explain its effect on benzodiazepine withdrawal and reports of positive effects on mood, memory, cognition, and motor performance [229].

CLINICAL ISSUES

Poor Treatment Response or Nonresponse

An estimated 30% to 60% of patients with anxiety disorders do not achieve meaningful symptom reduction or remission with initial therapy [242]. Decades of psychopharmacologic research have yielded safer, more tolerable side-effect profiles, but without improved efficacy in anxiety disorders. With poor or non-response, clinicians and patients then must decide how treatment should proceed, but research that best informs this clinical dilemma is only beginning to emerge. Given the limitations of SSRIs and benzodiazepines, investigators are pursuing novel treatment approaches and molecular targets [136].

With apparent patient nonresponse to treatment, clinicians should explore other factors before deciding the next therapy approach. The two broad causes of treatment resistance are pseudo-resistance and true treatment resistance [28].

Treatment Pseudo-Resistance

Pseudo-resistant patients have not actually received sufficient treatment, because of ineffective treatment matching for the anxiety diagnosis, insufficient medication dose or psychotherapy delivery, or patient non-adherence. Treatment pseudo-resistance may be the result of ineffective drug therapies, such a bupropion, beta-blockers (except in performance anxiety), buspirone and trazodone (except in GAD), and TCAs in SAD. Insufficient dosages and waiting an inadequate period for onset are also factors. The time for treatment onset is often longer for anxiety than depression. Patients may not fully respond until 8 to 12 weeks, and response may further increase in the second 6 months. Waiting an adequate time for response may be difficult for patients and healthcare providers, who may feel a need to change prescriptions or the regimen if a patient is distressed over his or her continued anxiety symptoms [28].

Poor patient adherence may also present as apparent treatment resistance. Only half of patients refill their first prescription, and many patients discontinue their drug in the first six months of treatment [136,185]. Nonadherence may result from medication intolerance or side effects. Even if patients with troubling side effects do not stop the drug, the inherent distress avoidance and anticipatory anxiety with anxiety disorders can delay achieving adequate dose or taking medication long enough for response. Therapeutic skills can help to gain patient trust and overcome their anxiety of medication; adherence improves with medication counseling [136,185]. Medication beliefs or attitudes that contribute to poor adherence include [28]:

- Unrealistic expectations

- Negative beliefs of perceived harmful effects

- Stigma

- Not "buying in" to treatment rationale or difficulty believing that treatment will work

- Psychologic conflicts over dependence and fear of becoming "addicted" to the medication

- Preference for psychotherapy over medication (as patients are less likely to adhere to a treatment modality they prefer less)

Following adherence and remission or large improvement, some patients will become non-adherent, and relapse follows. This may be addressed by explaining that the disorder requires ongoing treatment, like diabetes or any other chronic disease.

Overlooked Diagnosis, Comorbid Conditions, or Psychosocial Contributors

When established that adequate treatment was delivered and received, factors contributing to treatment resistance can include misdiagnosis or overlooked comorbidities or psychosocial factors. The following should be revisited [28]:

- Primary diagnosis accuracy

- Presence and contribution of unrecognized substance use disorder, psychiatric comorbidity, and/or complicating medical condition

- Psychosocial or lifestyle factors (e.g., caffeine overuse, sleep deprivation, interpersonal or family conflict)

Necessary Treatment Duration for Evidence of Response or Dose Escalation

Compared with treatment of simple depression, SSRI/SNRI treatment of anxiety disorder typically requires somewhat higher dosage and longer initial treatment duration before realizing a therapeutic effect. With duloxetine and escitalopram, a satisfactory response is unlikely without some degree of clinical benefit within four weeks of initiating therapy. With pregabalin, onset of clinical effect within two weeks is associated with a 5.3-fold increased likelihood of treatment response; 25% of patients not showing clinical effect at two weeks will ultimately respond to treatment. A pregabalin dosage of 150 mg/day is suboptimal; a dose-response effect usually requires 300–600 mg/day [243].

In clinical trials of venlafaxine XR, therapeutic benefits usually diverged from placebo at four to six weeks. However, the percentage remitted from panic disorder in one trial increased from 18% at 6 weeks to 50% at 12 weeks [244].

SSRIs/SNRIs usually take two to six weeks to show an initial "partial" response, often defined as ≥25% improvement (i.e., beyond random noise or natural symptom fluctuations). Full benefit may not appear for another four to six weeks or longer. Data from patients with depression, and some uncontrolled data with anxiety, suggest that about 20% of patients may need 10 to 12 weeks or longer before responding. Thus, dose escalation to highest level tolerated is recommended for patients with incomplete response before adequate time has passed [245]. In contrast to depression, antidepressant efficacy in anxiety disorders appears to be lost soon after stopping, with anxiety recurrence being the rule rather than the exception [228].

Patient Education

Successful medication treatment often involves dosage adjustments and/or trials of a different medication at some point in order to maximize response and minimize side effects. Because patient adherence is the essential pre-condition for maximum clinical benefit, the following messages should be communicated to the patient to encourage and support ongoing medication adherence [246]:

- Side effects often precede therapeutic benefit and typically recede over time.

- It is important to expect some discomfort prior to the benefit.

- Successful treatment may involve dose adjustments and/or trials of different medications to maximize response and minimize side effects.

- Most people must be on medication at least 6 to 12 months after adequate response, and patients may show improvement at two weeks but need a longer length of time to really see response and remission.

- It is important to take the medication as prescribed, even after feeling better, because early discontinuation is associated with high rates of relapse/recurrence.

- Do not stop taking the medication without calling the provider.

- Side effects can often be managed by changing the dose or dosage schedule.

A novel approach to improve patient understanding of their anxiety disorder and treatment rationale incorporates anxiety neuroscience. A core concept is that anxiety disorders/symptoms with amygdala origin (e.g., panic disorder, phobias) require different approaches than anxiety of cortical origin (e.g., SAD, GAD). Educating patients of the brain-based source of their anxiety can improve treatment adherence and empower patients to modify these areas of brain function. For example, patients with cortex-related symptoms such as obsessions, perfectionism, and chronic worry benefit from an approach termed "Question Your Cortex." They can be encouraged to identify anxiety-generating thoughts in the cortex and use cognitive restructuring methods to exploit cortical neuroplasticity by modifying their thoughts. However, cortex-based interventions are not effective at reducing or managing anxiety with amygdala-mediated symptoms; for these patients, exposure to feared situations is stressed. Most patients benefit from a combination of cortex- and amygdala-focused interventions, with the rationale and order of interventions differing by disorder and individual patient [247].

Antidepressant Withdrawal

Evidence Based Practice Recommendation

The National Collaborating Centre for Mental Health asserts that all patients prescribed antidepressants should be informed that, although the drugs are not associated with tolerance and craving, discontinuation/withdrawal symptoms may occur on stopping or missing doses or, occasionally, on reducing the dose of the drug.

https://www.nice.org.uk/guidance/cg113

Last Accessed: April 27, 2025

Level of Evidence: Expert Opinion/Consensus Statement

In reference to withdrawal of SSRI therapy, "withdrawal syndrome" has been largely replaced by the term "discontinuation syndrome" with industry support to convey the message that SSRIs do not cause addiction, dependence, or withdrawal syndrome as one might experience following cessation of benzodiazepines. This has been challenged, given the potential seriousness of SSRI post-cessation symptoms, as a false dichotomy that minimizes the vulnerabilities induced by SSRIs. For the purposes of this course, the term "withdrawal syndrome" will be used [248]. Clinicians should be aware of these withdrawal syndromes, as misdiagnosis may result in inappropriate diagnostic tests and treatment and unnecessary patient distress and morbidity [248].

A 2015 meta-analysis found SSRI withdrawal symptoms can occur with any SSRI but are exceedingly more frequent with paroxetine [248]. Common symptoms include dizziness, nausea, headache, confusion, low energy, weakness, sleep disturbance, flu-like symptoms, restlessness, agitation, anxiety, panic, anger, and irritability. Less common and more severe symptoms include electric-shock sensations, vertigo, paresthesias, intensified suicidal ideation, aggression, derealization, depersonalization, and visual/auditory hallucinations. Symptoms do not greatly differ between patients with anxiety versus mood disorders. The authors concluded that the typical SSRI withdrawal syndrome begins within a few days of cessation and lasts two to three weeks [248]. Variations include late onset and protracted duration up to one-year follow-up. Several cases of persistent postwithdrawal disorders induced by paroxetine have been described.

Gradual tapering is a reasonable strategy but does not prevent the onset of SSRI withdrawal [248]. Patient characteristics that predict increased vulnerability are not known. Recognition of withdrawal symptoms requires careful exploration, as they can be misidentified as signs of impending relapse. Even when withdrawal symptoms are recognized, clinical management is hindered by the lack of research.

SSRI cessation may trigger complex phenomena related or unrelated to the onset of withdrawal, such as hypomania, mania, and persistent postwithdrawal disorders. Iatrogenic comorbidity describes the lasting effects from treatment well beyond their time of administration, such as mood instability and high reactivity to environmental stimuli in persistent postwithdrawal disorders [248].

Among 20 patients with remitted panic disorder with agoraphobia followed over one year after SSRI cessation, nine experienced SSRI withdrawal syndrome that subsided within one month [249]. Exceptions were three patients taking paroxetine, who experienced worsened mood, fatigue, and emotional lability with trouble sleeping, irritability, and hyperactivity. One patient prescribed clonazepam after three months of symptom persistence improved considerably but was later unable to discontinue clonazepam. A second patient did not improve with clonazepam or fluvoxamine, and symptoms subsided only with paroxetine reinstatement. In a third patient, clonazepam had little benefit, paroxetine reinstatement was refused, and symptoms persisted unchanged over one year [249].

Following SSRI/SNRI cessation, the rates of withdrawal syndrome range from 17.2% to as high as 78% (with venlafaxine). Among SSRI/SNRIs, venlafaxine XR may have the worst withdrawal syndrome. In addition to serotonergic withdrawal symptoms, palinopsia (persistent visual images) and sensory disturbances are frequently reported. These symptoms are described as sensations affecting the brain and head that feel like electrical shocks or the sensation of the brain shivering. This sensory disturbance, often accompanied by dizziness, headache, and disorientation, is distressing to patients and has been reported to persist for months after venlafaxine XR cessation [244,250]. Other unexpected withdrawal symptoms that may emerge include gait difficulties, delirium, suicidal ideation, and hypomania or mania. The onset of withdrawal is usually one to four days post-venlafaxine XR cessation; dose reduction can also trigger withdrawal [251].

The etiology and treatment of these highly distressing sensory symptoms are unknown. However, contribution from noradrenergic dysregulation is suggested theoretically and by reports of positive treatment response to noradrenergic agents. Abrupt cessation of venlafaxine XR 37.5 mg led to a sensation that "felt like the brain was shaking inside the skull," with anhedonia, anxiety, tinnitus, headache, nausea, and increased noise sensitivity. A trial of the norepinephrine transporter inhibitor atomoxetine 40 mg/day led to immediate improvement in "brain shivers" two to three hours from the first dose [250]. Post-venlafaxine XR electric shock-like sensations and dizziness were greatly reduced by low-dose clonidine (0.05 mg twice/day), a central α-2 adrenergic agonist. The positive response suggests an underlying noradrenergic rebound mechanism [244].

Interdose withdrawal symptoms have been reported with venlafaxine XR, probably resulting from the "ultrarapid metabolizer" genetic variant of 2D6, the hepatic cytochrome P450 isoenzyme that metabolizes venlafaxine. Occurring in 3% to 5% of white individuals, this polymorphism accelerates venlafaxine elimination, causing interdose withdrawal [251].

Antidepressant Lethality in Overdose

In some patients with anxiety disorder, and especially those with depressive comorbidity, consideration of overdose fatality is necessary when deciding on therapy options. Lethality rates from intentional overdose involving single medication ingestions of agents commonly prescribed for depression and anxiety were calculated from data obtained during the period 2000–2014 [252]. TCAs remain the most lethal antidepressants, with fatality rates from 31–142 per 10,000 ingestions. Amitriptyline is associated with the greatest lethality in overdose and alone accounted for 37% of all deaths from antidepressants [252]. Lithium, bupropion, venlafaxine, quetiapine, and valproic acid had rates of 6.9–12.0 per 10,000 ingestions, while citalopram and fluvoxamine had rates of 3.9–4.1 per 10,000. Fluoxetine, sertraline, paroxetine, and escitalopram had the lowest overdose lethality rates at 0.79–1.34 per 10,000 ingestions [252].

Substance Use Disorder

Anxious patients often use alcohol or anxiolytics to regulate general anxiety, distressing panic symptoms, or social anxiety and social skills deficits. Substance use disorder is highly prevalent in patients with anxiety disorders and interferes with treatment response and leads to poor outcomes [28]. More than 33% of patients with GAD have an alcohol use disorder, and patients with SAD have a lifetime substance use disorder prevalence of roughly 40%. Nicotine dependence is also disproportionately high among patients with panic disorder [253,254,255].

Self-medication of anxiety disorder symptoms has been conclusively identified as a significant predictor for later development of alcohol or drug dependence. This is consistent with the self-medication hypothesis, which posits that the specific substance used for anxiety relief/control tends to be the substance to which the person develops a substance use disorder [256]. Ongoing substance use problems are abundantly linked to worse outcomes in comorbid anxiety disorders. Long-term effects of substance use negatively interact with anxiety symptoms, and quitting substances may improve anxiety in some patients. A trial of abstinence will usually answer this question. The duration must be several months to evaluate the link between anxiety and substance use, and there should be ongoing treatment, preferably in a 12-step program. Twelve-step programs have been shown to have anxiolytic effects themselves due to the support and empowerment they offer. Residual anxiety then should be treated with either medication or CBT [28].

If substance use is suspected, patients should be screened during diagnosis. A motivational interviewing approach is recommended to frame the rationale for substance abuse in a non-judgmental manner and explore patient desire and readiness for change. For patients initiating efforts to decrease substance use, concurrent treatment with an SSRI or venlafaxine is reasonable; benzodiazepines should be avoided due to the abuse liability [257]. Detoxification from alcohol or benzodiazepines is indicated if signs of substance withdrawal appear, and referral to a formal substance abuse treatment is recommended. Recognition and treatment of underlying substance abuse is an essential component in the overall treatment plan [13,28].

Anxiety Disorder Treatment Effect Sizes

A 2015 meta-analysis of panic disorder, GAD, and SAD assessed treatment efficacy [224]. Studies published through 2012 were used to calculate medication, psychologic, or combination treatment efficacy. Effect sizes were calculated from pre- versus post-treatment and treatment versus control comparisons (Table 3) [224]. A significantly higher average pre-post effect size was found for medication outcomes than psychotherapy outcomes. Side effects, contraindications, drug interactions, and efficacy should all guide drug selection. Benzodiazepine abuse, dependence, and withdrawal potential; TCA side effects; and quetiapine metabolic risks make these agents second- to fourth-line options and not first-line options, as suggested by effect sizes alone [224].

Table 3: EFFECT SIZES OF TREATMENTS FOR PANIC DISORDER, GENERALIZED ANXIETY DISORDER, AND SOCIAL ANXIETY DISORDER

Treatment Modality | Effect Sizea
Medications
SNRIs | 2.25
Benzodiazepines | 2.15
SSRIs | 2.09
Tricyclic antidepressants | 1.83
Psychotherapy
Mindfulness therapies | 1.56
Relaxation | 1.36
Individual CBT/exposure therapy | 1.30
Group CBT | 1.22
Psychodynamic therapy | 1.17
Internet and self-directed therapies | 1.11
Eye movement desensitization and reprocessing | 1.03
Interpersonal therapy | 0.78
Other approaches
CBT/drug combination therapy | 2.12
Exercise | 1.23

aAn effect size greater than 0.80 is considered large, indicating that the treatment is effective.

CBT = cognitive-behavioral therapy, SNRI = serotonin-norepinephrine reuptake inhibitor, SSRI = selective serotonin re-uptake inhibitor.

Source: [224]

8. TREATMENT OF GENERALIZED ANXIETY DISORDER

The goals of GAD treatment are reduction in severity of ambient symptoms followed by prevention of symptoms and relief of disability. Pharmacotherapy (SSRIs and SNRIs) is considered the mainstay of therapy; psychotherapy (CBT or cognitive therapy) is also highly effective and may be preferred during pregnancy and by patients who cannot tolerate or wish to avoid medication [54,258]. GAD is associated with specific biases for mood-congruent information. Patients with GAD are vigilant for threatening stimuli and tend to misinterpret ambiguous information as threat. These cognitive biases diminish with successful psychologic or drug treatment [243].

PSYCHOTHERAPY

First-Line Options

CBT

Evidence Based Practice Recommendation

According to the National Collaborating Centre for Mental Health, the recommended high-intensity psychological intervention for persons with generalized anxiety disorder is cognitive-behavioral therapy (CBT) or applied relaxation.

https://www.nice.org.uk/guidance/cg113

Last Accessed: April 27, 2025

Level of Evidence: Expert Opinion/Consensus Statement

CBT for GAD uses some combination of psychoeducation (understanding safety behaviors), worry exposure, applied relaxation, and re-structuring common automatic thoughts (e.g., catastrophizing). Meta-analyses clearly demonstrate that CBT significantly reduces GAD symptoms and is markedly more effective than placebo or wait-list control conditions [120]. Sessions should occur at least weekly over 6 to 12 weeks and involve 12 to 20 sessions. While fewer than eight sessions is as effective as eight or more sessions for anxiety symptoms, more intense regimens are more effective in improving worry and depression symptoms [258,259,260]. Individual and group CBT seem equally effective in anxiety symptom reduction, but individual therapy may lead to earlier improvement in worry and depression symptoms [120].

Cognitive Therapy

Cognitive therapy teaches patients to evaluate their anxious thoughts objectively. Variants include pure cognitive therapy, cognitive restructuring, meta-cognitive therapy, and uncertainty intolerance therapy. Cognitive therapy typically involves 15 to 20 individual sessions [261].

As discussed, effective cognitive therapy/CBT treatment helps patients develop new, alternative strategies to manage worries and habits and cope with life stressors, which reduces the symptoms of anxiety. Cognitive therapy/CBT helps patients to understand [261]:

- They cannot control their fears but can control their worrying behavior as a fear response.

- Worrying has no protective value, reinforces negative thinking, and increases the risk of escalating anxiety levels in the future.

- Worrying does not assist in managing negative future scenarios, and patients are equipped to handle whatever future challenges appear.

Cognitive therapy/CBT techniques may be especially helpful for generalized anxiety in later life [120].

Internet-Based CBT

Internet-based CBT is delivered by patient-administered media interventions. Components include cognitive restructuring, exposure, problem solving, and applied relaxation, usually over six to eight sessions [261,262]. Efficacy is demonstrated, with benefits maintained at long-term follow-up. A peer-to-peer cognitive self-therapy program has been found as effective as treatment-as-usual, with a decreased need for therapist contact [120].

Applied Relaxation

Applied relaxation teaches the patient a coping skill that will enable him or her to relax rapidly in order to counteract and eventually abort the anxiety reactions. This therapy is different from simple relaxation alone, which is not helpful. Applied relaxation entails having patients relax in actual anxiety-provoking situations. Achieving effective applied relaxation technique requires around 15 individual sessions [261].

Second-Line Options

Acceptance and commitment therapy and mindfulness are CBT variants with promising initial results. They teach patients to focus on the present moment and follow actions guided by their values rather than by emotions and anxiety. Effective acceptance and commitment therapy usually involves 10 to 15 individual sessions [261].

Short- and long-term psychodynamic psychotherapy has a degree of efficacy and may be useful when CBT/cognitive therapy is unavailable. Specific psychotherapy targets in GAD include intolerance of uncertainty, poor problem-solving confidence, and positive and negative metacognitive beliefs concerning the value or utility of worry [263].

Adjunctive Approaches

Additional modalities can be added to psychotherapy and/or drug therapy. Exercise is not widely studied in GAD, but available data have shown reduction in anxiety symptoms [264]. Meditation training is an option for patients unable or unwilling to receive psychotherapy [265]. Applied relaxation is effective as adjunctive therapy and uses relaxation techniques that are self-monitoring without the use of in-depth psychotherapy [266]. In addition, physical activity has been noted as a cost-effective treatment for GAD [121].

Sleep disturbances are highly prevalent in patients with GAD. Sleep hygiene education can be a useful tool in primary care, used with CBT in GAD to ensure the best possible sleep efficiency and quality. Patients can be counseled to improve sleep hygiene by going to bed and waking up at the same time each day, eliminating alcohol after 6 p.m., avoiding caffeine after 3 p.m., and getting out of bed if unable to fall asleep to avoid development of negative associations with the bed environment [267,268]. Long-term follow-up data from a meta-analysis and randomized controlled trials suggest that benefits of psychologic treatments are maintained one to three years following treatment [120].

PHARMACOTHERAPY

In addition to demonstrated efficacy, the selection of initial drug therapy for GAD is based on illness severity (degree of distress and disability), medical and psychiatric comorbidities, substance abuse profile, patient preference, and side effect profile. In general, an SSRI or SNRI is preferred for initial pharmacological treatment. These agents have been shown to be moderately effective in multiple controlled clinical trials, and no single agent has proved more effective than others. The choice of an SNRI or SNRI over an older antidepressant (e.g., TCA) is due more to increased tolerability (side effects and toxicity) than to difference in efficacy [54].

First-Line Options

The ADAC and the Anxiety and Depression Association of America (ADAA) have created guidelines for the selection of appropriate pharmacotherapy in the treatment of GAD with differing recommendations regarding first- and second-line medications [120,261]. The ADAC recommends agomelatine, pregabalin, venlafaxine XR, duloxetine, escitalopram, paroxetine, or sertraline as first-line options, while the ADAA suggests venlafaxine XR, duloxetine, paroxetine, escitalopram, sertraline, or fluoxetine [120,261].

Pregabalin

Two randomized, placebo- and active comparator-controlled, double-blind studies evaluated the efficacy of pregabalin versus lorazepam for the treatment of GAD. The pregabalin and lorazepam groups experienced greater reductions in Hamilton Anxiety Rating Scale (HAM-A) score by week 4 compared with placebo, with no observed statistically significant differences among the active-treatment groups. Relative to placebo, pregabalin 600 mg significantly reduced psychic and somatic anxiety, while lorazepam significantly reduced somatic anxiety symptoms only. Anxiety reduction with pregabalin and lorazepam was evident within one week [185].

A four-week trial randomized 451 patients with GAD to alprazolam 1.5 mg/day; pregabalin 300, 450, or 600 mg/day; or placebo. As measured by HAM-A scores, psychic anxiety symptoms were significantly reduced (vs. placebo) with all pregabalin doses and alprazolam by weeks 1 and 4. Somatic anxiety symptoms were significantly reduced by 300 and 600 mg pregabalin, but not by 450 mg pregabalin or 1.5 mg alprazolam (vs. placebo). Pregabalin produced an early onset (≤1 week) of clinically relevant anxiety reduction comparable to alprazolam and anxiety reduction over a broader range of GAD symptoms than alprazolam by four weeks [269].

Data was combined from six placebo-controlled trials of patients with GAD randomized to pregabalin 150 mg, 300–450 mg, or 600 mg; lorazepam 6 mg/day; alprazolam 1.5 mg/day; or placebo. Pregabalin 300–600 mg significantly improved HAM-A psychic and somatic anxiety factor scores, but pregabalin 150 mg showed significance in psychic anxiety only. Of the 14 HAM-A items, significant improvement was shown on 13 with pregabalin 300–450 mg, 10 with pregabalin 600 mg, and 5 with benzodiazepines. A dose-response effect was evident for pregabalin [270].

Along with SSRIs/SNRIs, pregabalin is considered a first-line agent for long-term GAD treatment by the World Federation of Societies of Biological Psychiatry. Head-to-head studies with SSRIs/SNRIs are lacking, but pregabalin augmentation of SSRI/SNRI therapy has been found more effective than SSRI/SNRI alone [205].

Sleep dynamics were evaluated in healthy volunteers randomized to pregabalin (150 mg three times per day), alprazolam (1 mg three times per day), or placebo for three days. Pregabalin and alprazolam modestly but significantly reduced sleep-onset latency (compared with placebo). Pregabalin significantly increased the proportion of slow-wave sleep to total sleep period, and the slow-wave sleep duration of stage 4 sleep. Alprazolam significantly reduced slow-wave sleep. Rapid eye movement (REM) sleep latency with pregabalin did not differ from placebo and was significantly shorter than with alprazolam. Pregabalin and alprazolam similarly reduced the REM sleep proportion to total sleep (vs. placebo), while pregabalin significantly reduced the number of awakenings longer than one minute. Ease in getting to sleep and sleep quality were subjectively rated as improved with both active treatments. Pregabalin effects on sleep and sleep architecture were distinct from benzodiazepines. Enhancement of slow-wave sleep was relevant to frequent reports of reductions in slow-wave sleep in patients with fibromyalgia or GAD [271].

Clinical trials have reported euphoria, which emphasizes the need for careful and continuing evaluation of any potential for abuse. Reports of pregabalin abuse have appeared, usually involving individuals with a history of psychotropic medication abuse [243]. Discontinuation symptoms were reported after abruptly stopping pregabalin and were more prominent with higher daily doses. However, significantly fewer withdrawal symptoms were found after stopping pregabalin compared with lorazepam, and when tapered over one week, pregabalin withdrawal symptoms are minimal. Tentative evidence suggests pregabalin may be beneficial in withdrawal from benzodiazepines and related compounds [243].

Agomelatine

Agomelatine studies have mostly investigated its efficacy in GAD. Three randomized controlled trials have been performed. One trial with an escitalopram arm found that agomelatine led to comparable efficacy in GAD and significantly improved sleep restoration with fewer side effects and no discontinuation symptoms compared with escitalopram [202]. The low discontinuation rate reflected good tolerability, and laboratory results showed a low incidence of transient elevations in liver enzymes. Another trial that measured therapeutic response as 50% or greater reduction in HAM-A score found response rates of 66.7% with agomelatine, compared with 46.6% with placebo. Agomelatine was noted to improve sleep quality, with a lack of sexual side effects or discontinuation syndrome. Dizziness (8%) and nausea (5%) were more frequent than placebo [202,272]. Agomelatine was superior to placebo in symptom reduction beginning at six weeks and in relapse prevention at six-month follow-up [203].

Second-Line Options

When treatment with SSRIs/SNRIs proves to be ineffective or intolerable, alternative choices with demonstrable efficacy include TCAs (e.g., imipramine) or a second-generation antipsychotic agent (quetiapine or pregabalin). Pregabalin is also effective for augmenting other first- and second-line agents in patients showing partial response. Internationally, pregabalin is regarded as a first-line option for GAD, but U.S. guidelines have not yet integrated this agent into the first-line tier [185].

Several options as second-line agents have efficacy in GAD comparable to first-line agents but possess potential side effects or other risks that preclude first-line use [120]. Benzodiazepines would be considered first in most cases, except where there is a risk of substance abuse, while bupropion XL would likely be reserved for later. Quetiapine XR remains a good choice in terms of efficacy, but given the metabolic concerns associated with this atypical antipsychotic, it should be reserved for patients who lack response or cannot tolerate antidepressants or benzodiazepines [120]. It is important to note that drugs such as beta-blockers (e.g., propranolol) prescribed to address the physical symptoms of anxiety are ineffective in the treatment of GAD [243].

Quetiapine

In three 10-week randomized controlled trials of patients with GAD, quetiapine monotherapy showed clinically and statistically significant improvements in anxiety reduction and remission rates versus placebo [185]. Meaningful separation from placebo in anxiety reduction began as early as four to seven days after initiation of treatment. Somnolence, dizziness, and fatigue were more frequent with quetiapine, and sexual function improved slightly in quetiapine groups. Quetiapine has shown decreased symptom recurrence and improved sleep quality during maintenance treatment. However, quetiapine is not recommended for patients with nonresponding GAD because efficacy is inconsistent [185]. One literature review included three studies that evaluated the use of quetiapine extended-release (XR) as monotherapy for acute GAD treatment, one study that evaluated quetiapine XR monotherapy for maintenance treatment of GAD, and five studies that evaluated quetiapine (2 XR, 3 immediate release) as adjunct therapy for acute GAD treatment [273]. Quetiapine displayed both efficacy and tolerability in all monotherapy trials evaluating its use for acute and long-term treatment of GAD. Despite limitations to and heterogeneity among the five adjunct therapy studies, three studies showed that quetiapine resulted in statistically significant changes in the HAM-A scores [273].

Imipramine

While TCA use has become disfavored because of tolerability and safety issues, compelling support of imipramine efficacy for GAD came from a landmark study comparing the anxiolytic effects of imipramine, trazodone, diazepam, and placebo in non-depressed patients with GAD. Imipramine resulted in moderate-to-marked improvement between weeks 2 and 8 of therapy in 73% of patients, compared with 69% for trazodone, 66% for diazepam, and 44% for placebo [274].

Vortioxetine

Multiple randomized controlled trials involving patients with GAD found clinical improvement and symptom reduction with vortioxetine marginally greater or similar to placebo. With vortioxetine, discontinuation from side effects was modestly greater than placebo, with incidence of sexual dysfunction comparable. Patients with severe baseline GAD did show significantly greater benefit from vortioxetine [186,275,276].

Comorbid Major Depression

With a few caveats, treatment of GAD is generally the same whether comorbid major depression is present or absent. Use of buspirone and pregabalin is not recommended, while duloxetine has shown efficacy in comorbid anxiety disorder and major depressive disorder [277]. Patients with comorbid major depression and GAD prescribed benzodiazepines, sedating medications, or TCAs should be monitored for suicide risk; those with severe depression and suicidal ideation may require hospitalization while therapy is initiated [278].

Relapse Prevention

Relapse-prevention studies randomized patients showing response to acute treatment to placebo or the same medication/dose. Results in GAD showed significant advantages with continuing the active medications agomelatine, duloxetine, escitalopram, paroxetine, quetiapine, venlafaxine, or vortioxetine versus switching to placebo for periods of 6 to 18 months [243].

9. TREATMENT OF PANIC DISORDER

Evidence Based Practice Recommendation

The National Collaborating Centre for Mental Health asserts that people who have panic disorder and their families and carers need comprehensive information, presented in clear and understandable language, about the nature of their condition and the treatment options available.

https://www.nice.org.uk/guidance/cg113

Last Accessed: April 27, 2025

Level of Evidence: Expert Opinion/Consensus Statement

Treatment of panic disorder is directed at prevention of panic attacks and reducing preoccupation and anxiety around possibility of impending attacks. SSRIs and SNRIs are effective in preventing panic attacks and relieving anxiety but have no impact on acute symptoms associated with an attack. A treatment duration of four to eight weeks is generally required to see a significant reduction in symptoms. A meta-analysis of 54 psychotherapy studies found that eight standard interventions, including supportive psychotherapy, behavioral therapy, cognitive therapy, and CBT, were equally efficacious for managing panic disorder, independent of accompanying agoraphobia [125]. Another meta-analysis found that combined psycho- and pharmacotherapy was superior to single-mode therapy, with efficacy verses placebo twice as large as pharmacotherapy alone [279]. The results also suggest that the effects of pharmacotherapy and psychotherapy are largely independent from each other and roughly equal in contribution to the effects of combined treatment. The effects remain strong and significant up to two years post-treatment.

PSYCHOTHERAPY

Behavior Therapy

Behavior therapy for panic disorder consists of graded exposure to body sensations that accompany panic (interoceptive exposure), to situations perceived as threatening (in vivo exposure, imagery exposure, virtual reality exposure), or both, in order to progressively reduce apprehensive reaction toward them by the patient. Although exposure strategies alone can be effective in the treatment of panic disorder, they do not appear to be a valid alternative to CBT as a first-line treatment [151].

Cognitive Therapy

In cognitive therapy for panic disorder, panic attacks are thought to result from the catastrophic misinterpretation of certain bodily sensations. The patient perceives the sensations of normal anxiety response as much more dangerous than they are, such as palpitations viewed as evidence of impending heart attack. Cognitive therapy identifies these negative interpretations of the bodily sensations experienced in panic attacks, suggests alternative non-catastrophic interpretations, and helps the patient test the validity of these alternative interpretations. While cognitive therapy is often combined with behavioral techniques, there is some evidence that training in cognitive procedures in isolation from exposure and behavioral procedures is efficacious in reducing some aspects of panic [151,280,281,282,283].

CBT

CBT assumes that cognitions, behaviors, and emotions are interrelated and combines behavior therapy and cognitive therapy to reduce emotional distress and psychologic symptoms. CBT for panic disorder consists of psychoeducation, breathing retraining, progressive muscle relaxation, cognitive restructuring, behavioral experiments, interoceptive exposure, and in vivo exposure. A consistent body of evidence supports the efficacy of CBT for panic disorder in individual or group sessions. There is also growing evidence that supports CBT efficacy when therapist-supported and self-administered via the Internet [151,284,285]. A network meta-analysis found that the most effective combination of CBT components for treatment of panic disorder was face-to-face administration and graded interoceptive exposure to physiological aspects of the panic response, while muscle relaxation and virtual-reality exposure were the least effective components [286].

Patient Education

An essential step after diagnosis of panic disorder is to review with patients their fears of medical illness and expectations of medical testing and treatment. More than 80% of patients with panic disorder present with a medical symptom, and most are fearful of having a serious condition, such as a stroke. Clinical experience suggests that patients benefit from education about panic disorder as the cause of their symptoms and the mechanism by which a mental disorder may provoke physical symptoms. Educational materials for patients may be obtained from the ADAA (https://adaa.org) and the National Institute of Mental Health (https://www.nimh.nih.gov) [129].

PHARMACOTHERAPY

The first-line drugs recommended for the treatment of panic disorder are SSRIs or venlafaxine XR [120]. Research suggests that the largest effect size is found with clonazepam, followed by venlafaxine and fluoxetine [224]. Despite a sizeable number of pharmacologic options, less than 50% of patients with panic disorder experience full and sustained remission to first-line medication therapy [287].

SSRI/SNRI

The SSRI safety/side effect profile relative to TCAs, MAOIs, and benzodiazepines led to their recommendation as first-line drug options for patients with panic disorder. SSRI side effects occur early in treatment before the therapeutic effects. Many patients with panic disorder are highly sensitive to side effects, and SSRIs should be started at low doses, with dose titration every five to seven days, as tolerated [129].

Following 10 weeks of venlafaxine treatment for panic disorder, patients with few dissociative symptoms during panic attacks showed significantly greater treatment response than patients with greater presence of panic attack-associated dissociative symptoms. These findings suggest that dissociative symptoms accompanying panic disorder negatively impact pharmacologic treatment response. Re-evaluation of dissociative symptoms at the beginning and end of treatment would help in personalizing therapy [288].

Benzodiazepines

A meta-analysis was performed of randomized controlled trials comparing alprazolam to other benzodiazepines in the treatment of panic disorder with or without agoraphobia [289]. In the pooled results, there were no significant differences in efficacy between alprazolam and comparator benzodiazepines on improvements in panic attack frequency, anxiety rating scores, or proportion of patients panic attack-free at final evaluation. To date, the evidence fails to demonstrate alprazolam superiority to other benzodiazepines for panic disorder treatment [289]. Additionally, while alprazolam is one of the most widely prescribed benzodiazepines for the treatment of panic disorder, its clinical use is contentious due to its potential for misuse [290].

10. TREATMENT OF AGORAPHOBIA

Almost all agoraphobia studies reported treatment outcomes of patients with co-occurring panic disorder, as they were not separated into distinct diagnostic entities until the DSM-5 was published in 2013.

PSYCHOTHERAPY

CBT is the most empirically supported psychosocial treatment for panic disorder with agoraphobia, with a central focus of repeated exposure to feared situations and sensations and application of skills learned in therapy. These include cognitive skills to control negative thoughts and somatic skills to control dysregulated physiology during exposure. While CBT has clearly been established as an effective treatment for panic disorder with agoraphobia, the effect sizes are smallest among the anxiety disorders and a large percentage of treatment completers are not panic free or do not reach responder status after treatment. The largest randomized controlled trial to date for panic disorder with agoraphobia found only 32% of those assigned to CBT alone demonstrated strong treatment response at 12 months post-treatment [162]. A small 20-year follow-up of patients with panic disorder with agoraphobia found that completion of medication-free, integrated exposure and psychodynamic treatment resulted in excellent very long-term outcomes for these patients [291].

The relevance of process variables in patient response and outcomes with CBT have been studied. Among 301 patients with panic disorder/agoraphobia, changes in panic symptoms were preceded by changes in catastrophic appraisal and agoraphobic avoidance in all treatment phases, anxiety sensitivity during generalization and follow-up, and psychologic flexibility during exposure therapy. Changes in functioning were preceded by changes in agoraphobic avoidance and psychologic flexibility in all treatment phases, fear of bodily symptoms during generalization/follow-up, and anxiety sensitivity during exposure. The effects of process variables on outcomes differed across treatment phases and outcomes. Agoraphobic avoidance and psychologic flexibility should be therapeutically targeted in addition to cognitive variables [292].

Low remission rates in patients with panic disorder/agoraphobia following CBT-based therapies has led to the development and evaluation of novel psychotherapies, adjunctive drug therapies, and cognitive enhancer drugs to improve exposure therapy response and remission rates.

Novel Psychotherapies

The intervention for patients with panic disorder/agoraphobia who are nonresponsive to CBT has generally been pharmacotherapy, with few studies evaluating a switch to psychotherapy. In one study, patients with previous unsuccessful state-of-the-art treatment were randomized to immediate acceptance and commitment therapy or four-week waiting list with delayed acceptance and commitment therapy; they were then followed for up to six months. Significantly greater changes in functioning and symptomatology were found in patients who received immediate acceptance and commitment therapy versus those on the waiting list, and medium-to-large effect sizes were maintained for six or more months. Acceptance and commitment therapy may be a viable treatment option for treatment-resistant panic disorder with agoraphobia [293].

A long-term study of patients with panic disorder and agoraphobia found catastrophic beliefs to be an important mediator of change. Of 46 patients with panic disorder/agoraphobia randomized to cognitive or guided mastery therapy, 31 (67.4%) medication-free patients who completed treatment were followed up to 18 years post-treatment. Both groups showed a large effect size for avoidance of situations when alone, and 56.5% no longer met diagnostic criteria for panic disorder or panic disorder with agoraphobia. Patient outcomes between the two treatments were comparable, although guided mastery was associated with greater beneficial changes in catastrophic beliefs and self-efficacy. Greater reduction in panic-related beliefs about physical and mental catastrophes predicted lower anxiety level at follow-up [294].

Combination Therapy

Following paroxetine plus CBT (once weekly for 12 weeks), paroxetine plus CBT and virtual reality exposure (four sessions), or paroxetine only, the six-month follow-up of 99 patients with panic disorder/agoraphobia showed reduced anxiety levels in all three groups and greatest reduction in both CBT groups. The virtual reality exposure group showed greater improvement in confronting agoraphobic stimuli, although medication cessation and dropout were high [295].

The one-year follow-up of patients with panic disorder with and without agoraphobia treated with CBT, SSRI, or CBT and SSRI found that panic attack frequency significantly declined in all groups and both SSRI groups improved significantly faster than CBT [296]. The SSRI gains were maintained after tapering. Panic frequency in patients with moderate-to-severe agoraphobia decreased more rapidly with CBT plus SSRI than either sole treatment. With CBT alone, improvement was slower than with SSRI or CBT plus SSRI. SSRI monotherapy was concluded sufficient for patients with panic disorder with no or mild agoraphobia, while patients with panic disorder and moderate-to-severe agoraphobia should receive CBT plus SSRI [296].

PHARMACOTHERAPY

An efficacy analysis of drug therapy trials in the treatment of panic disorder with agoraphobia was published in 2011 [86]. It concluded that panic attack recurrence worsens agoraphobic behaviors in panic disorder with agoraphobia and disrupts agoraphobia remission. This suggests that using panic attack-blocking medication in patients with panic disorder/agoraphobia at risk of panic attack recurrence is more appropriate than CBT alone.

The meta-analysis also found that paroxetine displayed high efficacy in panic and phobic symptoms and agoraphobia severity reduction. This efficacy was similar to CBT in reducing agoraphobic behaviors and superior to CBT in reducing panic attacks during acute treatment phase [86]. Adding paroxetine to CBT in patients with poor CBT response is significantly more effective in improving agoraphobic behaviors than adding placebo, so it is strongly suggested to add paroxetine for patients lacking adequate response or panic attack reduction with CBT [86]. Sertraline, citalopram, and escitalopram are also effective in the treatment of panic disorder/agoraphobia.

A randomized controlled trial compared treatment with an SSRI (paroxetine or citalopram) to continued treatment with CBT in a sample of 68 individuals with panic disorder (with or without agoraphobia) who had not responded to an initial course of CBT [297]. Participants were randomized to three months of treatment and then followed for an additional nine months. Those who responded to treatment after 3 months were maintained on the treatment until 12-month follow-up. Participants receiving an SSRI showed significantly lower panic disorder symptoms compared with continued CBT at three months, suggesting a greater improvement in panic disorder symptoms when patients are switched to an SSRI after failure to respond to an initial course of CBT [297].

The TCA clomipramine has similar panic/phobic efficacy to paroxetine and sertraline. Imipramine is more effective than placebo in long-term maintenance, but less effective than sertraline in short-term outcomes. Venlafaxine is effective in reducing panic and phobic symptoms [86]. Reboxetine is more effective in the treatment of panic/phobia than placebo. It has similar efficacy to paroxetine in phobic avoidance and anticipatory anxiety, but lower efficacy in reducing panic attacks.

Fluvoxamine has only inconsistent efficacy in the treatment of panic disorder/agoraphobia, and while fluoxetine may be used to address panic attacks, it has limited efficacy for panic disorder/agoraphobia [86].

These results suggest noradrenergic system involvement in modulating panic disorder with agoraphobia avoidance behaviors, but serotonergic system targeting is important to decrease panic attacks. Re-analysis of prior pharmacologic randomized controlled trial data found higher efficacy with sertraline and clomipramine in reducing agoraphobic symptoms than paroxetine, fluvoxamine, or citalopram. This may reflect the added dopaminergic modulation of these agents beyond their primary serotonergic activity [86].

A novel treatment approach is based on multiple findings of balance system dysfunction in patients with panic disorder/agoraphobia. An open study found citalopram influenced the balance system in these patients by improving postural stability, as measured by static posturography. Compared with baseline scores, most patients whose balance system function improved were no longer agoraphobic, while those whose posturography scores remained abnormal continued to be agoraphobic. These findings suggest the involvement of balance system dysfunction in panic disorder with agoraphobia and serotonergic system relevance in mediating the connection between balance and agoraphobia [298]. The authors suggest that real abnormal body functioning (primarily involving cardiorespiratory and balance systems), which leads to reduced overall physical fitness, may be a primary cause of panic disorder and that the anxiety and fear it induces is sustained by repeated signals of impaired body functioning [299].

In one study, patients with panic disorder/agoraphobia received alprazolam plus exposure, alprazolam plus progressive muscle relaxation, placebo plus exposure, or placebo plus progressive muscle relaxation. The highest rate of improvement at follow-up was observed in the placebo/exposure (71%) and alprazolam/exposure (71%) groups; alprazolam/progressive muscle relaxation (51%) and progressive muscle relaxation/placebo (25%) groups were less improved [300]. Alprazolam showed no benefit over placebo when added to exposure therapy as treatment for panic disorder/agoraphobia [300].

CONTRIBUTING FACTORS TO PANIC DISORDER WITH AGORAPHOBIA TREATMENT RESPONSE

Pronounced safety behaviors during exposure therapy, but not at baseline, have been associated with poor treatment response in patients with panic disorder/agoraphobia. This underscores the importance of rigorous safety behavior assessment during therapy [301].

During 13 to 21 years post-treatment follow-up, major depression at baseline predicted worse improvement in agoraphobic avoidance in the first year. Employment and marriage/cohabitation at baseline predicted greater improvement at 1-year, 2-year, and 13- to 21-year follow-up [302].

A substantial number of patients with panic disorder/agoraphobia fail to improve following CBT. Agoraphobic avoidance is the most consistent predictor of decreased improvement, followed by low expectancy for change, high levels of functional impairment, and Cluster C personality pathology [303].

11. TREATMENT OF SOCIAL ANXIETY DISORDER

PSYCHOTHERAPY

CBT is the criterion-standard psychologic treatment for SAD. Cognitive restructuring techniques are used to challenge assumptions and maladaptive thoughts (i.e., "I will embarrass myself"), while the behavioral component centers on patient exposure to anxiety-provoking situations. Over time and with repeated exposure sessions, the goal is to reduce anxiety symptoms and to demonstrate that the situational anxiety is tolerable and without substantial risk. The efficacy of CBT is supported by many randomized controlled trials, with outcomes that vary but are typically similar to pharmacotherapy. Some reports suggest that, after treatment discontinuation, gains achieved with CBT may persist longer than those achieved with pharmacotherapy. CBT for SAD can be administered in group or individual formats. Although some studies have reported that individual CBT is superior to group CBT, meta-analyses have failed to find significant differences in efficacy between the two modalities. There is evidence to support the effectiveness of exposure therapy alone, but efficacy compared with CBT is equivocal [120].

Several CBT variants have been examined. Videotaped feedback was not shown to enhance the effects of exposure-based treatment. However, CBT with virtual reality exposure was found more effective than wait-list control and as effective as CBT with imaginal or in vivo exposure according to two meta-analyses [120].

A form of CBT focused on interpersonal behavior found similar improvements in social anxiety compared to standard CBT and also increased relationship satisfaction and social approach behaviors. Evidence to support interpersonal therapy in SAD is conflicting; while some results are negative, interpersonal therapy is probably more effective than wait-list control, but less effective than traditional CBT [120].

With Internet CBT for SAD, patients with an avoidance and depression profile showed lower remission after treatment, higher levels of social anxiety at follow-up assessments, and typically remained highly symptomatic. In patients with SAD, high levels of social avoidance and depressive symptoms constitute a risk profile for poor treatment response [304].

PHARMACOTHERAPY

Pharmacotherapy of SAD is effective but varies considerably, with room for further improvement [305]. Placebo-controlled clinical trials have shown that SSRIs and SNRIs are the most effective class of pharmacologic treatment. The ADAC recommends escitalopram, fluvoxamine (immediate- or controlled-release), paroxetine (immediate- or controlled-release), pregabalin, sertraline, or venlafaxine XR for first-line treatment of SAD [120]. Citalopram has less evidence but is likely as effective as other SSRIs. Phenelzine efficacy is established in multiple randomized controlled trials but is recommended as a second-line option due to concerns over dietary and medication restrictions that, if not strictly adhered to, can lead to hypertensive crisis [120].

Abnormalities in brain GABA and glutamate systems have been studied in patients with SAD, including whether these changed following eight weeks of levetiracetam. Compared to healthy controls, patients with SAD at baseline showed significantly higher whole brain levels of glutamate and glutamine (but not GABA) and significantly higher thalamic glutamine and lower GABA levels. Following treatment, these patients showed significant reduction in thalamic glutamine. These findings support the role of impaired GABAergic and overactive glutamatergic function in SAD and may explain the anxiolytic effects of levetiracetam [306].

12. TREATMENT OF SPECIFIC PHOBIA

Patients with specific phobias generally do not consult medical professionals when able to avoid the specific feared situations or objects. Exposure therapy is effective in treating specific phobia and is the favored approach.

PSYCHOTHERAPY

Exposure-based therapies are the treatments of choice and show a high degree of successful remission for all phobias. In vivo exposure and virtual reality exposure to phobic stimuli or situations are both effective, with in vivo exposure superior to imaginal and virtual reality exposure at post-treatment but not at follow-up [307]. The effectiveness of exposure-based therapy is enhanced when exposure sessions are grouped closely together; when exposure is prolonged, real (not imagined), and provided in different settings; and when there is some degree of therapist involvement instead of being entirely self-directed. A greater number of sessions have been shown to predict more favorable outcomes. There is no evidence that flooding is more effective, and patients usually find graded, progressive exposures more tolerable [307].

A variety of psychotherapeutic options have been found effective for the treatment of specific phobias, with some approaches recommended for particular phobias (Table 4) [120]. For blood-injection-injury phobias, an effective approach is combining exposure therapy with muscle tension exercises (applied tension) designed to prevent fainting. Using stress-reducing medical devices, such as decorated butterfly needles and syringes, has significantly reduced needle phobia and stress in pediatric and adult patients. With dental phobias, use of CBT can reduce avoidance of oral injections and decrease patient anxiety [120,307].

Table 4: PSYCHOLOGIC TREATMENTS EFFECTIVE IN SPECIFIC PHOBIA

Treatment Approach | Phobia(s)
Exposure-based treatments | All specific phobias
Virtual reality exposure | Heights, flying, spiders, claustrophobia
Computer-based self-help programs | Spiders, flying, small animals
Applied muscle tension (i.e., exposure with muscle tension exercises) | Blood-injection-injury type
Cognitive therapy and exposure | Dental, flying

Source: [120]

Evidence Based Practice Recommendation

The National Collaborating Centre for Mental Health recommends against routinely offering computerized CBT to treat specific phobias in adults.

https://www.nice.org.uk/guidance/cg159/resources/social-anxietydisorder-recognition-assessment-and-treatmentpdf-35109639699397

Last Accessed: April 27, 2025

Level of Evidence: Expert Opinion/Consensus Statement

Long-term treatment of specific phobia is rare. CBT and exposure therapies show sustained benefits at long-term follow-up assessments following a time-limited course of treatment [120].

PHARMACOTHERAPY

Pharmacotherapy has a minimal role in specific phobia treatment, largely from the lack of drug therapy research and the success of exposure therapies. Alprazolam benefit was studied in 28 women with flying phobia during two air travel exposures, one week apart. Compared with subjects given pre-flight placebo for both flights, those receiving alprazolam before the first flight had less anxiety and symptoms but greater heart and respiratory rates. Those given alprazolam had a substantial increase in panic attacks during the second flight compared with the first flight (71% vs. 7%), greater overall anxiety, and further elevation in heart rate. Alprazolam increased physiologic activation under acute stress conditions and hindered the therapeutic effects of exposure therapy for flying phobia [120,308]. These findings require replication to determine clinical utility.

Some benefit is suggested by small trials of paroxetine or escitalopram. However, there is too little evidence to recommend any drug treatment of specific phobias [224].

A NOVEL APPROACH COMBINING MEDICATION AND EXPOSURE THERAPY

In 2015, a potential landmark study of 45 subjects with spider phobia was published. A pre-treatment two-minute tarantula exposure was followed four days later by randomization to propranolol without exposure or to exposure and then propranolol 40 mg or placebo (within 10 minutes). All three groups went through tarantula exposure 9 days, 16 days, 90 days, and one year later [309].

After nine days, all exposure/propranolol subjects touched the tarantula, while the other two groups barely touched its container. By 16 days, all exposure/propranolol subjects further progressed in approach, while the two other groups did not progress. Approach behavior remained stable for all three groups throughout one year. Most interestingly, significant reduction in self-reported spider fear lagged several months behind the instant behavioral transformation in the exposure/propranolol group [309].

This study is the first to identify optimal drug and timing for durable remission of phobic anxiety and avoidance. The results challenge the fundamental tenet of CBT that changes in cognition are necessary for behavioral change. Such a novel approach is clearly needed, and similar trials enrolling subjects with agoraphobia and social phobia are expected in the future [309].

13. TREATMENT OF SEPARATION ANXIETY DISORDER

PSYCHOTHERAPY

As mentioned, the presence of pathologic separation anxiety has a pervasive negative influence on treatment response in patients with diverse anxiety and mood disorders receiving standard therapies. Patients with SEPAD show poor response to standard CBT and exposure-based therapies. This poorer treatment response may reflect the difficulties these patients experience forming and maintaining attachments, including therapeutic relationships. Growing evidence points to the incompatibility in applying the prevailing fear extinction model of anxiety to patients with SEPAD. This pathophysiologic model emphasizes desensitization to threatening stimuli. While theoretically and empirically supported in other anxiety disorders, this model does not consider the role of earlier childhood SEPAD in adult panic disorder and other anxiety disorders [98].

The unmet need for SEPAD-specific treatment has led to psychotherapies that focus on relationships and separation anxiety. These approaches use the therapist-patient relationship to recapture and better understand important elements of earlier pathologic parent-child relationships. Panic-focused psychodynamic psychotherapy is an affect-focused therapy that specifically targets separation anxiety as a core component of panic disorder. Preliminary efficacy is shown in patients with prominent separation anxiety symptoms across different anxiety and mood disorders. High separation anxiety levels constitute a central organizing element in patient self-perception as incompetent and unable to manage developmentally normative tasks without the presence of their central attachment figures. Panic-focused psychodynamic psychotherapy emphasizes free association, centrality of transference, unconscious thoughts that underlie physical sensations of panic, and difficulty with separation and autonomy. The therapist focuses on these processes as they relate to panic symptoms. Common themes of difficulty with separations and unconscious rage inform interpretive interventions. The pre-determined 24-session, 12-week time limit enhances the opportunity to work with separation anxiety and permits the re-experiencing and better understanding [98].

PHARMACOTHERAPY

With adult SEPAD becoming formalized in 2013 as a distinct diagnostic entity and anxiety disorder, little pharmacotherapy research has been performed specifically addressing this condition.

14. EMERGING THERAPIES AND NOVEL TREATMENT APPROACHES

NEUROENHANCING AGENTS TO AUGMENT EXPOSURE THERAPY

Some neuroenhancers, especially D-cycloserine (DCS), are promising for treating anxiety disorders because these agents improve extinction learning efficacy, integral in exposure therapy. They facilitate learning new memories through habituation and extinction, and these safe memories will over-ride the previous fear memories. Use of neuroenhancers to augment CBT represents a promising translational effort—taking neuroscience discovery into clinical practice. In contrast, use of anxiolytics and CBT in anxiety disorders did not originate from a theoretical basis for the mechanism of action, and overall effectiveness leaves substantial room for improvement [164].

D-Cycloserine

The most extensively studied exposure augmentation agent is DCS, an N-methyl-D-aspartate (NMDA) receptor partial agonist. Findings that extinction learning is modulated, in part, by the glutamatergic NMDA receptor complex prompted interest in the role of glutamatergic transmission in anxiety disorders. Clinical trials began to study the potential efficacy of low-dose DCS for enhancing memory consolidation and thereby improving the effectiveness of exposure therapies for anxiety disorders [165]. DCS studies of patients with specific phobia (e.g., heights, snakes), OCD, panic disorder with agoraphobia, PTSD, or SAD have been published, showing a marginal benefit when combined with exposure therapy. Following promising early findings, more recent studies have reported inconsistent results, including findings that DCS resulted in faster rates of improvement but not higher response or remission rates in SAD and even more symptoms at post-treatment in PTSD. These inconsistent trials have informed the understanding of limitations and indications of DCS augmentation of exposure therapy [310,311,312,313].

Dosing and dose timing of DCS is essential. Most trials reporting positive results used low-dose DCS (50–250 mg) one to two hours before three to five exposure sessions. Studies with negative results often used higher doses (≥250 mg), chronically (before 12 exposures), and more than one to two hours before an exposure. Higher-dose DCS shows weaker NMDA partial agonist or antagonist effects. Key extinction learning processes occur hours following exposure, and DCS blood concentration peaking at four to six hours makes it more effective taken within one to two hours before exposure for peak activity to coincide with key extinction processes. Repeated DCS use can desensitize the NMDA receptor complex, leading DCS to effectively work as an NMDA antagonist. Long-term antidepressants can induce neurochemical changes at the glycine binding site of the NMDA receptor complex, which alters the action of DCS. Therefore, use of DCS should consider the narrow therapeutic window and the need to be administered without concomitant medication, acutely, and at low doses one to two hours pre-exposure [310].

DCS is associated with serious risks. DCS not only enhances cognitive processes during fear extinction learning but also during fear memory reconsolidation, thus improving good exposures and worsening bad exposures. If fear-inducing stimulus re-exposure during fear memory reactivation is too brief relative to the strength of fear conditioning or if fear decrease during exposure is inadequate, little extinction is induced and DCS can augment the process of fear memory reconsolidation to worsen symptoms [310].

These findings led to DCS administered post-exposure, contingent on the level of fear reduced (i.e., extinction learning achieved) by the end of the exposure session. Preliminary evidence shows that this approach may be effective in capitalizing on the benefits while minimizing the risks of DCS use to augment exposure therapy [310].

Yohimbine Hydrochloride

Yohimbine hydrochloride (YOH) is a selective competitive alpha2-adrenergic receptor antagonist currently only approved for veterinary use. This compound increases extracellular norepinephrine in humans by blocking autoreceptor inhibition of norepinephrine release. This mechanism potentially facilitates extinction learning in exposure therapies. Placebo-controlled trials have been performed in specific phobia and SAD. Subjects with claustrophobia given YOH 10.8 mg before two 60-minute exposures of sitting in a closed, dark chamber showed more robust reductions in claustrophobia symptoms. Patients with SAD given YOH 10.8 mg before four exposure sessions showed accelerated treatment improvement and lower levels of social anxiety symptoms. More research is needed, but these results suggest YOH may have a role in augmenting exposure therapy [164].

Glucocorticoids

Glucocorticoids have shown enhancement of virtual reality-based exposure therapy for fear of heights and were investigated for possible outcome enhancement in exposure-based group therapy for spider phobia. In one randomized controlled trial, cortisol 20 mg or placebo was orally administered one hour before each therapy session and patients were assessed at one-month post-therapy follow-up. Compared to placebo, cortisol led to significantly greater reduction in fear of spiders at follow-up but not immediately post-treatment, as measured psychometrically and by exposure to live spiders. Groups did not differ in phobia-unrelated state-anxiety before and after exposure sessions and at follow-up [314].

Another randomized controlled trial investigated the role of hydrocortisone as an adjunct to brief CBT for specific (spider) fear [315]. Spider-fearful participants were randomized to receive either 20 mg hydrocortisone or placebo one hour prior to single-session, predominantly computerized, exposure-based CBT. Participants' fear of spiders was assessed using self-report and approach behaviors measured at baseline and at one-day and one-month follow-up. Threat processing was assessed at baseline and at one-day follow-up. Cortisol and cortisone levels from hair and saliva samples were analyzed at baseline. All measures improved following CBT. Augmentation with hydrocortisone resulted in greater improvement in self-reported fear and approach behavior but not threat bias. Neither threat bias nor endogenous glucocorticoids predicted symptom change. Evidence indicates that higher hair cortisone predicts a stronger threat bias reduction [315].

Methylene Blue

Methylene blue is a nitric oxide synthase inhibitor, central MAO inhibitor, and cerebral metabolic enhancer. A placebo-controlled trial of subjects with severe claustrophobic fear found that participants displaying low fear at the end of extinction training showed significantly less fear at follow-up if they received methylene blue post-training relative to placebo. In contrast, participants displaying moderate-to-high levels of post-training fear tended to fare worse at follow-up with methylene blue compared with placebo. Similar to the profile of DCS, methylene blue enhanced memory and retention of fear extinction when administered after a successful exposure session, but it may have deleterious effects on extinction when administered after an unsuccessful session [316].

CAPNOMETRY-ASSISTED RESPIRATORY TRAINING

Panic disorder and sensitivity to increased carbon dioxide (CO_2) levels common in patients with panic disorder may represent pathologically amplified survival mechanisms. Panic disorder reflects a "fight-or-flight" response, and CO_2 hypersensitivity is an evolutionary carry-over from when alarm response to dwindling oxygen helped ensure survival. Panic attacks that awaken people at night only occur during non-REM sleep, when deep relaxation and slowed breathing lead to rising CO_2 levels that trigger a false suffocation alarm [317].

Capnometry-assisted respiratory training (CART) is an intervention that addresses CO_2 fluctuation and its role in panic attacks for some people. CART targets respiratory dysregulation and hypocapnia through a four-week training using immediate feedback of end-tidal CO_2 pressure (PCO_2). Patients are taught how to raise subnormal PCO_2 levels (caused by hyperventilation) to control dysfunctional respiratory patterns and related panic symptoms of shortness of breath and dizziness. CART uses novel technologies that allow precise assessment and monitoring of core respiratory variables. A portable capnometer offers breath-by-breath feedback of expired CO2 and breathing rate, as measured via nasal cannula.

In one study, four weeks of CART led to reductions in panic symptom severity and frequency comparable to standard CBT, maintained at 12-month follow-up. Patients with panic disorder/agoraphobia randomized to four weeks of CART or cognitive therapy showed significant and comparable reductions in panic symptom severity and panic-related cognitions [281]. Across studies in patients with panic disorder with agoraphobia and asthma, compliance with the 17-minute, twice-daily exercises was high, and compliance correlated with the extent of panic symptom reduction [281,318]. Changes in PCO2 mediated and preceded changes in fear of panic sensations, cognitive reappraisal of symptoms, and perceived control. Reductions in respiration rate were unrelated to outcome [281,319]. These findings strengthen the idea that panic symptom reduction can be achieved through different mechanisms [162].

NEUROMODULATION THERAPIES

Brain stimulation (also referred to as neuromodulation, neurostimulation, or somatic therapy) for the treatment of neuropsychiatric disorders was developed as an option for patients with severe disorders refractory to multiple treatments. Electroconvulsive therapy, introduced more than 75 years ago, has been historically the only widely used somatic treatment of psychiatric disorders. This was changed by the development and FDA approval of several minimally or non-invasive brain stimulation modalities with much greater specificity than electroconvulsive therapy. Other modalities are undergoing evaluation and possible market entry [320]. This approach shifts the treatment focus from altering synaptic neurotransmission to altering or modulating the function of entire neural circuits, the dysfunction of which underlies anxiety disorders [120].

Repetitive Transcranial Magnetic Stimulation

The most studied neurostimulation approach in the United States is repetitive transcranial magnetic stimulation (rTMS). As discussed, patients with panic disorder often lack response or only partially respond to drug or psychologic treatments, which increases the risk of the disorder becoming chronic and disabling. Transcranial magnetic stimulation delivers non-invasive stimulation to the cerebral cortex, with currents induced by powerful, extremely brief magnetic fields. Administration in a rhythmic, repetitive form is rTMS. Modulation of cortical excitability uses high-frequency rTMS to increase cortical excitability or low-frequency rTMS to inhibit cortical excitability of targeted areas. rTMS can also affect remote brain areas connected to the stimulated site [321].

Early studies of rTMS in anxiety disorders often found no difference between active vs. sham rTMS, reflecting the inability to stimulate brain regions deeper than superficial cortical layers and inadequate treatment duration or post-treatment follow-up [322]. Subsequent technical refinements show treatment efficacy.

A randomized controlled trial treated 28 patients with panic disorder and major depression with active or sham rTMS to the right dorsolateral prefrontal cortex. Response was defined as reduction by ≥40% in panic disorder severity and ≥50% in depression ratings. After four weeks, panic disorder response rate was 50% with active and 8% with sham rTMS, with no difference in depression. After eight weeks of active rTMS, response rates were 67% for panic and 50% for depressive symptoms. Significant improvements occurred in panic disorder, major depression, clinical global impression, and social adjustment. Clinical improvements were maintained at six months post-treatment. While four weeks of rTMS was sufficient to significantly reduce panic symptoms, a longer course led to better outcomes for both panic disorder and major depression. These data suggest that inhibitory rTMS to the right dorsolateral prefrontal cortex affects symptom expression in comorbid anxiety and depressive disorder [323]. Another study found that inhibitory rTMS to the left dorsolateral prefrontal cortex showed therapeutic effects in patients with major depressive disorder [324].

NEW OR NOVEL ANXIOLYTIC AGENTS

Cannabidiol

Cannabidiol is the second most abundant cannabinoid in Cannabis plants and lacks the consciousness-altering effects of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in Cannabis. Cannabidiol is a pharmacologically broad-spectrum drug that has drawn increasing interest as a treatment for a range of neuropsychiatric conditions, including anxiety disorders. Preclinical evidence supports cannabidiol as a treatment for GAD, panic disorder, SAD, OCD, and PTSD when administered acutely, but few studies have investigated chronic cannabidiol dosing. Randomized controlled trials showed that, relative to placebo, cannabidiol significantly reduced anxiety in patients with SAD and GAD [136,325].

In a series of randomized controlled trials using fear-conditioning paradigms, subjects who received cannabidiol (vs. placebo) all showed successful conditioning, extinction, and recall. When given after resolution of symptoms, cannabidiol enhanced consolidation of extinction learning. Cannabidiol administered pre- or post-extinction reduced the reinstatement of autonomic contextual responding. No acute effects of cannabidiol were found on extinction. These results are the first evidence that cannabidiol may enhance consolidation of extinction learning in humans, suggesting cannabidiol may have potential as an adjunct to extinction therapies for anxiety disorders [326].

Brain imaging cannabidiol trials in patients with GAD or SAD consistently showed changes in functional activity in limbic and paralimbic cortical areas implicated in anxiety pathophysiology, with effects in the left para-hippocampal gyrus, the hippocampus, and the right posterior cingulate gyrus. Cannabidiol was found safe and tolerable, with few side effects and without major side effects during acute treatment. Cannabidiol administered chronically in oral doses of 10–1,280 mg/day to healthy volunteers and patients with schizophrenia, bipolar affective disorder, Parkinson disease, or Huntington disease did not find significant side effects or induction of any new neurologic, psychiatric, or general clinical conditions [136,327]. Overall, evidence indicates cannabidiol has considerable potential as a treatment for several anxiety disorders, with further study of chronic and therapeutic effects in relevant clinical populations needed [325,328].

Etifoxine

Etifoxine (also known as etafenoxine) is a non-benzodiazepine anxiolytic and anticonvulsant not yet approved in the United States. Clinical effects are mediated by GABA-Aα2 receptors, similar to benzodiazepines, and etifoxine appears to produce anxiolytic effects directly by binding to β2 or β3 subunits of the GABA-A receptor complex. The effects of etifoxine are not completely reversed by the benzodiazepine antagonist flumazenil. Etifoxine also stimulates neurosteroid production, which contributes to anxiolytic and neuroprotective effects. Several randomized controlled trials comparing etifoxine to lorazepam found vigilance, psychomotor performance, and free recall significantly impaired by lorazepam but not etifoxine. Superior anxiolytic effect and memory recall were noted with etifoxine, with fewer withdrawal symptoms than with lorazepam. Etifoxine appears promising as a non-benzodiazepine anxiolytic agent that lacks many shortcomings with benzodiazepines and SSRIs, although acute liver toxicity has been reported [329,330].

Asenapine

Asenapine is a newer atypical antipsychotic drug. Its dominant mechanism of action is mediated through 5HT2A and D2 receptor antagonism and also by antagonism of 5HT2B, 5HT2C, 5HT6, and 5HT7 serotoninergic; α1A, α2A, α2B and α2C adrenergic; and D3/D4 dopaminergic receptors [178]. Clinical efficacy in anxiety and mood disorders is predicted by its serotoninergic profile. This agent lacks affinity for muscarinic receptors and induces fewer anticholinergic side effects than other second-generation antipsychotics [331]. Asenapine is FDA-approved for schizophrenia and bipolar disorder; its use for anxiety disorders is off-label [178].

Tandospirone

Closely related to buspirone, tandospirone (also known as metanopirone) is a 5-HT1A receptor partial agonist used in China and Japan. Its efficacy was compared to sertraline in an eight-week randomized controlled trial in adolescents with SAD. Both drugs significantly improved anxiety scores from baseline, showed similar overall response and anxiety symptom-specific response rates (≥50% reduction), and resulted in significant and comparable improvements in social phobia symptoms. Tandospirone appeared non-inferior to sertraline treatment of SAD in adolescents. The drug is not FDA-approved [332].

15. COMPLEMENTARY/ALTERNATIVE THERAPIES

HERBAL PRODUCTS AND SUPPLEMENTS

Myo-Inositol

Myo-inositol is a glucose isomer and essential component of the phosphatidylinositol second messenger system critically linked to several CNS receptor-signaling systems [333]. Myo-inositol anxiolytic and antidepressant activity is mediated by a serotoninergic 5-HT2A/5-HT2C receptor-signaling pathway [334].

Several randomized controlled trials have been conducted using placebo or active controls. In 21 patients with panic disorder with or without agoraphobia given inositol 12 g/day or placebo for four weeks, significant decreases were found in the frequency and severity of panic attacks and agoraphobia severity with inositol relative to placebo [335]. Another randomized controlled trial compared myo-inositol 18 g/day with fluvoxamine 150 mg/day in patients with panic disorder with or without agoraphobia. Both drugs led to significant but comparable improvements in anxiety symptoms/severity, agoraphobia symptoms/severity, and global impression. In the first month, reduction in the number of panic attacks per week was significantly greater with inositol than fluvoxamine (4.0 vs. 2.4). Nausea and fatigue were significantly more common with fluvoxamine [336].

Other randomized controlled trials found that myo-inositol 12 g/day in 28 patients with major depression significantly reduced Hamilton Depression Rating Scale scores (vs. placebo) after four weeks; and 18 g/day given to patients with OCD for six weeks led to significant reductions in OCD symptom scores (vs. placebo) [335]. A review of supplements and herbal therapies with purported anxiolytic efficacy concluded myo-inositol was one of very few with demonstrated effectiveness [337]. The published research needs larger trials but is intriguing in light of a study in which patients with severe depression receiving treatment with rTMS showed significantly elevated prefrontal cortex myo-inositol levels, and this elevation correlated with extent of clinical improvement [338]. A meta-analysis of inositol for depression and anxiety disorders found that the agent may be particularly beneficial for treatment of depression [339].

The effective dose is 12–18 g per day, and inositol is free of side effects other than loose stools and drowsiness [335]. A drawback is the large amount required for therapeutic benefit, necessary to compensate for poor blood-brain barrier penetration. An Italian pharmaceutical company has developed a more concentrated myo-inositol formulation, with dose comparability to standard myo-inositol at 25% the dose level [338].

Overall, inositol is a natural compound with few side effects and may be an attractive option for patients with panic disorder who are ambivalent about taking psychiatric medication [336]. Myo-inositol is one of nine inositol isomers, but unless another inositol isomer is specified, inositol sold at retail is almost always myo-inositol.

Kava

Kava (Piper methysticum) extract has been used for anxiolytic effects, mediated through GABA channel modulation and weak GABA binding, β-adrenergic downregulation, and MAO-B inhibition. Efficacy studies in GAD showed superiority to placebo and comparability to buspirone. However, distribution and use of kava dropped off when reports of liver toxicity surfaced in the early 2000s [340,341,342].

Lavender Oil

A six-week randomized controlled trial compared silexan, a lavender oil capsule preparation, with lorazepam in GAD treatment efficacy. Both treatment groups showed similar reductions on the primary anxiety measure (HAM-A) and similar and comparable reductions on measures of somatic anxiety, psychic anxiety, anxiety self-rating, impression of illness severity, sleep quality, and other scales. Silexan appears to be an effective and well-tolerated alternative to benzodiazepines for GAD treatment [343]. A 10-week randomized controlled trial compared silexan with paroxetine and placebo in GAD treatment efficacy. Participants received 80 mg or 160 mg silexan, 20 mg paroxetine, or placebo once daily for 10 weeks [344]. The primary outcome measured was HAM-A total score reduction between baseline and treatment end. A total of 60.3% of participants in the silexan 160 mg group showed a HAM-A total score reduction greater than 50% of the baseline value compared with 51.9% in the silexan 80 mg group, 34.1% in the paroxetine group and 37.8% in the placebo group. Silexan additionally showed a pronounced antidepressant effect and improved general mental health and health-related quality of life. Rates of adverse effects were comparable among the silexan and placebo groups and lower for the paroxetine group [344].

EXERCISE THERAPY

Resistance exercise (i.e., strength training) includes a broad group of activities that evoke repeated muscle action against resistances above those encountered in daily life. A growing body of literature has identified anxiolytic effects of resistance exercise after both single sessions and long-term training. This research has shown that resistance training at a low-to-moderate intensity produces the most reliable and robust decreases in anxiety. Higher intensity has shown either no change or increased anxiety from baseline. One caveat is most of this research involved participants with state (not trait) anxiety [345].

YOGA

Yoga is an ancient mind/body practice that involves different techniques in physical postures, controlled breathing, deep relaxation, and meditation that have positive and specific influences. Research on yoga has demonstrated significant improvements in emotional self-regulation with consequent reductions in depression, stress, and anxiety levels and improvements in mood, quality of life, and well-being [346]. Several studies have found significant anxiolytic effects with yoga in patients with GAD or panic disorder, and it is considered the complementary therapy with strongest evidence of safety and efficacy in anxiety disorders.

One randomized controlled trial compared patients with panic disorder who received yoga or CBT plus yoga weekly over two months. Both treatment groups showed significant decreases from baseline in anxiety levels associated with panic disorder, panic-related beliefs, and panic-related body sensations, although the CBT/yoga combination group led to greater reductions over yoga alone [346].

A group of patients with GAD lacking response to pharmacotherapy received a five-day, 22-hour yoga course. Compared with baseline, follow-up at four weeks found a 73% response rate and 41% remission rate and significant reductions in HAM-A total score and psychic subscale score. Attrition was 25% [347].

Combining yoga with CBT integrates yoga and meditation with traditional and alternative CBT methods to enhance restructuring of the destructive cognitive and emotional patterns associated with physical and psychologic anxiety symptoms. Given in 90-minute sessions once per week for six weeks, CBT/yoga consisted of yoga/meditation, instruction and experiential cognitive restructuring using traditional and alternative CBT interventions, and group discussion with processing. In a group of patients with GAD receiving CBT/yoga, post-treatment scores were compared to baseline. The patients showed significant improvements on measures of state and trait anxiety, depression, panic, suicidality, sleep disturbance, sexual function, and quality of life [348].

16. CONCLUSION

Anxiety disorders are among the most prevalent mental health disorders encountered in primary care settings, yet these disorders often go under-recognized and undertreated for a variety of reasons, including reluctance to discuss emotional and psychological distress; clinic and practitioner time constraints; and attribution of symptoms to somatic conditions. Chronicity and episodic exacerbations often lead to ongoing personal distress and functional disability, resulting in excessive healthcare utilization and societal costs. Screening tools are available for diagnostic purposes, and effective pharmacotherapy and psychotherapy regimens specific to each anxiety disorder have been developed. The prevalence, distress/disability, potential for comorbidity, and management complexities associated with anxiety disorders emphasize the need for understanding (and paying attention to) the clinical presentation, differential diagnosis, and appropriate treatment selection in these patients.

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318. Meuret AE, Wilhelm FH, Ritz T, Roth WT. Feedback of end-tidal pCO2 as a therapeutic approach for panic disorder. J Psychiatr Res. 2008;42(7):560-568.

319. Meuret AE, Rosenfield D, Hofmann SG, Suvak MK, Roth WT. Changes in respiration mediate changes in fear of bodily sensations in panic disorder. J Psychiatric Res. 2009;4(6)3:634-641.

320. Schlaepfer TE, George MS, Mayberg H. WFSBP guidelines on brain stimulation treatments in psychiatry. World J Biol Psychiatry. 2010;11(1):2-18.

321. Li H, Wang J, Li C, Xiao Z. Repetitive transcranial magnetic stimulation (rTMS) for panic disorder in adults. Cochrane Database Syst Rev. 2014;9:CD009083.

322. Paes F, Machado S, Arias-Carrión O, et al. The value of repetitive transcranial magnetic stimulation (rTMS) for the treatment of anxiety disorders: an integrative review. CNS Neurol Disord Drug Targets. 2011;10(5):610-620.

323. Mantovani A, Aly M, Dagan Y, Allart A, Lisanby SH. Randomized sham controlled trial of repetitive transcranial magnetic stimulation to the dorsolateral prefrontal cortex for the treatment of panic disorder with comorbid major depression. J Affect Disord. 2013;144(1-2):153-159.

324. Kang JI Lee H, Jhung K, et al. Frontostriatal connectivity changes in major depressive disorder after repetitive transcranial magnetic stimulation: a randomized sham-controlled study. J Clin Psychiatry. 2016;77(9):e1137-e1143.

325. Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics. 2015;12(4):825-836.

326. Das RK, Kamboj SK, Ramadas M, et al. Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology (Berl). 2013;226(4):781-792.

327. Crippa JA, Derenusson GN, Ferrari TB, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011;25(1):121-130.

328. Mandolini GM, Lazzaretti M, Pigoni A, Oldani L, Delvecchio G, Brambilla P. Pharmacological properties of cannbidiol in the treatment of psychiatric disorders: a critical overview. Epidemiol Psychiatr Sci. 2018;27(4):327-335.

329. Choi YM, Kim KH. Etifoxine for pain patients with anxiety. Korean J Pain. 2015;28(1):4-10.

330. do Rego JL, Vaudry D, Vaudry H. The non-benzodiazepine anxiolytic drug etifoxine causes a rapid, receptor-independent stimulation of neurosteroid biosynthesis. PLoS One. 2015;10(3):e0120473.

331. Samalin L, Charpeaud T, Llorca PM. Asenapine in bipolar I disorder: evidence and place in patient management. Ther Adv Chronic Dis. 2013;4(1):5-14.

332. Huang X, Li C, Li WH, et al. Clinical evaluation of the efficacy and safety of tandospirone versus sertraline monotherapy for social anxiety disorder: a randomized open-label trial. Hum Psychopharmacol. 2013;28(6):594-599.

333. Vadnal R, Parthasarathy L, Parthasarathy R. Role of inositol in the treatment of psychiatric disorders. CNS Drugs. 1997;7(1):6-16.

334. Einat H, Clenet F, Shaldubina A, Belmaker RH, Bourin M. The antidepressant activity of inositol in the forced swim test involves 5-HT(2) receptors. Behav Brain Res. 2001;118(1):77-83.

335. Levine J. Controlled trials of inositol in psychiatry. Eur Neuropsychopharmacol. 1997;7(2):147-155.

336. Palatnik A, Frolov K, Fux M, Benjamin J. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol. 2001;21(3):335-339.

337. Saeed SA, Bloch RM, Antonacci DJ. Herbal and dietary supplements for treatment of anxiety disorders. Am Fam Physician. 2007;76(4):549-556.

338. Zheng H, Zhang L, Li L, et al. High-frequency rTMS treatment increases left prefrontal myo-inositol in young patients with treatment-resistant depression. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(7):1189-1195.

339. Mukai T, Kishi T, Matsuda Y, Iwata N. A meta-analysis of inositol for depression and anxiety disorders. Hum Psychopharmacol. 2014;29(1):55-63.

340. De Sousa A. Herbal medicines and anxiety disorders: an overview. J Med Plants Stud. 2013;1(6):18-23.

341. Sarris J, Byre GJ, Bousman CA, et al. Kava for generalized anxiety disorder: a 16-week double-blind, randomised, placebo-controlled study. Aust N Z J Psychiatry. 2020;54(3):288-297.

342. Ooi SL, Henderson P, Pak SC. Kava for generalized anxiety disorder: a review of current evidence. J Altern Complement Med. 2018;24(8):770-780.

343. Woelk H, Schläfke S. A multi-center, double-blind, randomised study of the lavender oil preparation silexan in comparison to lorazepam for generalized anxiety disorder. Phytomedicine. 2010;17(2):94-99.

344. Kasper S, Gastpar M, Muller WE, et al. Lavender oil preparation silexan is effective in generalized anxiety disorder: a randomized, double-blind comparison to placebo and paroxetine. Int J Neuropsychopharmacol. 2014;17(6):859-869.

345. Strickland JC, Smith MA. The anxiolytic effects of resistance exercise. Front Psychol. 2014;5:753.

346. Vorkapic CF, Rangé B. Reducing the symptomatology of panic disorder: the effects of a yoga program alone and in combination with cognitive-behavioral therapy. Front Psychiatry. 2014;5:177.

347. Katzman MA, Vermani M, Gerbarg PL, et al. A multicomponent yoga-based, breath intervention program as an adjunctive treatment in patients suffering from generalized anxiety disorder with or without comorbidities. Int J Yoga. 2012;5(1):57-65.

348. Khalsa MK, Greiner-Ferris JM, Hofmann SG, Khalsa SB. Yoga-enhanced cognitive behavioral therapy (Y-CBT) for anxiety management: a pilot study. Clin Psychol Psychother. 2015;22(4):364-371.

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Evidence-Based Practice Recommendations Citations

1. American Psychiatric Association. Practice Guidelines for the Psychiatric Evaluation of Adults. 3rd ed. Arlington, VA: American Psychiatric Association; 2015. Available at https://psychiatryonline.org/doi/10.1176/appi.books.9780890426760.pe02. Last accessed April 27, 2025.

2. National Collaborating Centre for Mental Health. Social Anxiety Disorder: Recognition, Assessment and Treatment. London: National Institute for Health and Care Excellence; 2013. Available at https://www.nice.org.uk/guidance/cg159/resources/social-anxiety-disorder-recognition-assessment-and-treatment-pdf-35109639699397. Last accessed April 27, 2025.

3. National Collaborating Centre for Mental Health, National Collaborating Centre for Primary Care. Generalised Anxiety Disorder and Panic Disorder (with or without Agoraphobia) in Adults: Management in Primary, Secondary and Community Care. London: National Institute for Health and Clinical Excellence; 2020. Available at https://www.nice.org.uk/guidance/cg113. Last accessed April 27, 2025.

95310 • Anticoagulation and Antiplatelet Therapy: Clinical Use Guidelines

Justin Delic, PharmD, BCCCP

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

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

Table of Contents

95310 • Anticoagulation and Antiplatelet Therapy: Clinical Use Guidelines

Course Overview
Audience
Accreditations & Approvals
Designations of Credit
Individual State Nursing Approvals
Special Approvals
Course Objective
Learning Objectives
Faculty
Faculty Disclosure
Division Planners
Division Planners Disclosure
Director of Development and Academic Affairs
Director Disclosure Statement
About the Sponsor
Disclosure Statement
Implicit Bias in Health Care

1. INTRODUCTION
2. BACKGROUND AND INTRODUCTION
3. PATHOPHYSIOLOGY OF DISEASE
4. ANTIPLATELETS

ASPIRIN

P2Y12 INHIBITORS

5. ANTICOAGULANTS

UNFRACTIONATED HEPARIN
LOW-MOLECULAR-WEIGHT HEPARINS
WARFARIN
DIRECT THROMBIN INHIBITORS
FACTOR XA INHIBITORS

6. INDICATIONS FOR ANTIPLATELETS AND ANTICOAGULANTS

PRIMARY PREVENTION OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

CHRONIC CORONARY DISEASE
ACUTE CORONARY SYNDROME
ATRIAL FIBRILLATION

ACUTE ISCHEMIC STROKE/TRANSIENT ISCHEMIC ATTACK

VALVULAR HEART DISEASE
VENOUS THROMBOEMBOLISM
PERIPHERAL ARTERIAL DISEASE

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

95310 • Anticoagulation and Antiplatelet Therapy: Clinical Use Guidelines

Education Category. Pharmacology

Release Date. 07/01/2024

Expiration Date. 06/30/2027

Course Overview

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

Audience

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

Accreditations & Approvals

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

Designations of Credit

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

Individual State Nursing Approvals

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

Special Approvals

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

Course Objective

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

Learning Objectives

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

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

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

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

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

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

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

Faculty

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

Faculty Disclosure

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

Division Planners

John M. Leonard, MD

Candace Pierce, DNP, RN, CNE, COI

Randall L. Allen, PharmD

Division Planners Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

Implicit Bias in Health Care

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

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

1. INTRODUCTION

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

2. BACKGROUND AND INTRODUCTION

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

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

3. PATHOPHYSIOLOGY OF DISEASE

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

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

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

Figure 1: COAGULATION CASCADE

Source: Author

4. ANTIPLATELETS

ASPIRIN

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

P2Y12 INHIBITORS

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

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

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

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

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

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

Healthcare Consideration

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

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

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

Clopidogrel Transitioned to:
Prasugrel | Begin prasugrel 60-mg loading dose, regardless of timing and dosing of clopidogrel
Ticagrelor | Begin ticagrelor 180-mg loading dose, regardless of timing and dosing of clopidogrel
Prasugrel Transitioned to:
Clopidogrel | Begin clopidogrel 600-mg loading dose, administered 24 hours after last prasugrel dosea
Ticagrelor | Begin ticagrelor 180-mg loading dose, administered 24 hours after last prasugrel dose
Ticagrelor Transitioned to:
Clopidogrel | Begin clopidogrel 600-mg loading dose, administered 24 hours after last ticagrelor dosea
Prasugrel | Begin prasugrel 60-mg loading dose, administered 24 hours after last ticagrelor dose

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

Source: Author

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

Clopidogrel Transitioned to:
Prasugrel | Begin prasugrel 10-mg maintenance dose, beginning 24 hours after last clopidogrel dose
Ticagrelor | Begin ticagrelor 90-mg BID maintenance dose, beginning 24 hours after last clopidogrel dose
Prasugrel Transitioned to:
Clopidogrel | Begin clopidogrel 75-mg maintenance dose, beginning 24 hours after last prasugrel dose
Ticagrelor | Begin ticagrelor 90-mg BID maintenance dose, beginning 24 hours after last prasugrel dose
Ticagrelor Transitioned to:
Clopidogrel | Begin clopidogrel 600-mg loading dose, administered 24 hours after last ticagrelor dosea
Prasugrel | Begin prasugrel 60-mg loading dose, administered 24 hours after last ticagrelor dose

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

Source: Author

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

Healthcare Consideration

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

5. ANTICOAGULANTS

UNFRACTIONATED HEPARIN

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

Table 3: COMMON HEPARIN DOSING REGIMENS

Indication | Heparin Dosing Regimena
VTE prophylaxis | 5,000 units subcutaneously every 8 or 12 hoursb
VTE treatment | Initial: 80 units/kg IV bolus followed by 18 units/kg/hour IV infusion

AF

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

ACS, NSTEMI (off-label) | Initial: 60 units/kg (maximum 5,000 units) IV bolus followed by 12 units/kg/hour (maximum 1,000 units/hour) IV infusion

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

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

Source: [34]

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

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

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

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

Transitioned to | Transition Strategy
Enoxaparin (SUBQ) | Begin enoxaparin within one hour of stopping heparin infusion.

Warfarin (oral)

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

DOAC (oral)a | Begin DOAC when the heparin infusion is stopped.
aIncluding apixaban, dabigatran, rivaroxaban, and edoxaban

Source: [40]

LOW-MOLECULAR-WEIGHT HEPARINS

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

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

Table 5: COMMON ENOXAPARIN DOSING REGIMENS

Indication | Enoxaparin Dosing Regimen
VTE prophylaxis | 40 mg subcutaneously every 24 hours (Select patient populations may require alternate dosing or frequencya)
VTE treatment | 1 mg/kg subcutaneously every 12 hours or 1.5 mg/kg every 24 hours
ACS (NSTEMI) or AF (periprocedural management) | 1 mg/kg subcutaneously every 12 hours
aTrauma, morbid obesity, low body weight, or reduced renal function

Source: Author

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

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

Table 6: ENOXAPARIN (SUBCUTANEOUS) TRANSITION TO OTHER AGENTS

Transitioned to | Transition Strategy

Heparin (intravenous)

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

Warfarin (oral)

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

DOAC (oral)a | Begin DOAC within 2 hours prior to when the next scheduled dose of enoxaparin would be due.
aIncluding apixaban, dabigatran, rivaroxaban, and edoxaban

Source: [40]

Healthcare Consideration

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

WARFARIN

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

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

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

Table 7: WARFARIN (ORAL) TRANSITION TO OTHER AGENTS

Transitioned to | Transition Strategy
Heparin (intravenous) | Discontinue warfarin and begin heparin once INR is ≤2 or lower INR limit of therapeutic range
Enoxaparin (subcutaneous) | Discontinue warfarin and begin enoxaparin once INR is ≤2 or lower INR limit of therapeutic range
DOAC (oral)a | Discontinue warfarin and begin DOAC once INR is <2 or lower INR limit of therapeutic range
aIncluding apixaban, dabigatran, rivaroxaban, or edoxaban

Source: [40]

DIRECT THROMBIN INHIBITORS

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

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

Table 8: COMMON DABIGATRAN DOSING REGIMENS

Indication | Dabigatran Dosing Regimen
AF (nonvalvular) | 150 mg orally every 12 hours
VTE treatment | 150 mg orally every 12 hours, after at least 5 days of initial therapy with a parenteral anticoagulant
VTE prophylaxis in total hip arthroplasty | 220 mg orally daily, after an initial dose of 110 mg or 220 mg based on timing from surgery and hemostasis

Source: [40]

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

Table 9: DABIGATRAN (ORAL) TRANSITION TO OTHER AGENTS

Transitioned to | Transition Strategy

Heparin (intravenous)

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

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

Enoxaparin (subcutaneous)

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

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

Warfarin (oral)

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

Another DOAC (oral)a | Begin the new DOAC when the next dose of dabigatran would be due.
aIncluding apixaban, rivaroxaban, or edoxaban

Source: [40]

FACTOR XA INHIBITORS

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

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

Table 10: COMMON RIVAROXABAN DOSING REGIMENS

Indication | Rivaroxaban Dosing Regimen
AF (nonvalvular) | 20 mg orally once daily with evening meal
VTE treatment | 15 mg orally twice daily with food for 21 days, followed by 20 mg once daily with food
CAD or stable PAD | 2.5 mg orally twice daily, in combination with low dose aspirin

Source: [47,48]

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

Table 11: RIVAROXABAN (ORAL) TRANSITION TO OTHER AGENTS

Transitioned to | Transition Strategy
Heparin (intravenous) | Begin heparin when the next dose of rivaroxaban would be due.
Enoxaparin (subcutaneous) | Begin enoxaparin when the next dose of rivaroxaban would be due.

Warfarin (oral)

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

Another DOAC (oral)a | Begin new DOAC when the next dose of rivaroxaban would be due.
aIncluding apixaban, dabigatran, or edoxaban

Source: [40]

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

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

Table 12: APIXABAN (ORAL) TRANSITION TO OTHER AGENTS

Transitioned to | Transition Strategy
Heparin (intravenous) | Begin heparin when the next dose of apixaban would be due.
Enoxaparin (subcutaneous) | Begin enoxaparin when the next dose of apixaban would be due.

Warfarin (oral)

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

Another DOAC (oral)a | Begin new DOAC when the next dose of apixaban would be due.
aIncluding rivaroxaban, dabigatran, or edoxaban

Source: [40]

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

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

Table 13: EDOXABAN (ORAL) TRANSITION TO OTHER AGENTS

Transitioned to | Transition Strategy
Heparin (intravenous) | Begin heparin when the next dose of edoxaban would be due.
Enoxaparin (subcutaneous) | Begin enoxaparin when the next dose of edoxaban would be due.

Warfarin (oral)

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

Another DOAC (oral)a | Begin new DOAC when the next dose of edoxaban would be due.
aIncluding apixaban, dabigatran, or rivaroxaban

Source: [40]

Healthcare Consideration

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

6. INDICATIONS FOR ANTIPLATELETS AND ANTICOAGULANTS

PRIMARY PREVENTION OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

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

CHRONIC CORONARY DISEASE

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

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

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

ACUTE CORONARY SYNDROME

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

Evidence Based Practice Recommendation

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

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

Last Accessed: June 24, 2024

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

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

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

Healthcare Consideration

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

Evidence Based Practice Recommendation

After PCI for STEMI, aspirin should be continued indefinitely.

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

Last Accessed: June 24, 2024

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

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

ATRIAL FIBRILLATION

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

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

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

Case Study: JP

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

Study Questions

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

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

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

Discussion

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

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

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

ACUTE ISCHEMIC STROKE/TRANSIENT ISCHEMIC ATTACK

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

Healthcare Consideration

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

Healthcare Consideration

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

VALVULAR HEART DISEASE

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

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

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

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

VENOUS THROMBOEMBOLISM

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

Evidence Based Practice Recommendation

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

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

Last Accessed: February 17, 2026

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

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

PERIPHERAL ARTERIAL DISEASE

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

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

7. CONCLUSION

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

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Evidence-Based Practice Recommendations Citations

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

91335 • Medical Error Prevention and Root Cause Analysis

Marjorie Conner Allen, BSN, JD

www.netce.com

Copyright © 2026 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

91335 • 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

91335 • Medical Error Prevention and Root Cause Analysis

Education Category. Management

Release Date. 09/01/2026

Expiration Date. 08/31/2029

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. 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). 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 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

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

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. Another review estimated the number closer to 200,000 deaths per year [67]. 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 [1,3].

It does appear that some progress has been made in the past decade. The Agency for Healthcare Research and Quality found a 13% decline in hospital-acquired conditions between 2014 and 2017, or 910,000 fewer conditions and 20,700 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 [68]. 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].

Beginning January 1, 2027, the Joint Commission aligned its Sentinel Event List with the National Quality Forum (NQF) Serious Reportable Events (SRE) framework. The Joint Commission's Sentinel Event List includes the NQF Serious Reportable Events together with three workforce safety events retained by the Joint Commission. These events are organized into the following broad categories:

- Procedural events: Events associated with surgical or other invasive procedures, such as surgery or an invasive procedure performed on the wrong patient or wrong body site, the wrong procedure performed, or the unintended retention of a foreign object following an invasive procedure.

- Product or device events: Events involving the use or function of medical devices, biologics, or blood products that result in serious patient harm, including preventable transfusion-related events caused by major blood group incompatibilities.

- Patient protection events: Events that compromise patient safety through failures in protection or security, including patient suicide associated with healthcare settings, infant discharge to the wrong family, patient abduction, or other serious failures to protect vulnerable patients.

- Care provision events: Preventable events related to the delivery of healthcare, including certain medication errors, diagnostic or treatment delays, maternal or neonatal events, patient falls resulting in serious harm, and other preventable adverse events that meet the criteria for serious reportable events.

In addition, the Joint Commission continues to designate the following workforce safety events as sentinel events:

- Homicide of a staff member while on the organization's premises

- Sexual assault of a staff member while on the organization's premises

- Physical assault of a staff member while on the organization's premises resulting in death or severe harm

Healthcare organizations should refer to the current Joint Commission Sentinel Event Policy and the National Quality Forum Serious Reportable Events framework for detailed inclusion and exclusion criteria, as the determination of whether an event qualifies as a reportable sentinel event may depend on specific clinical circumstances and established reporting definitions.

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/en-us/knowledge-library/support-center/standards-interpretation/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 2025, the Florida AHCA reported that a total of 127 deaths occurred as a result of hospital error, 17.8% of 715 adverse incidents reported for the year. Aside from death. the 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 (22.8%), fracture or dislocation of bones or joints (22.4%), surgical procedure to remove foreign object from a previous surgical procedure (10.3%), surgical procedures unrelated to the patient's diagnosis or medical needs (7.7%), brain damage (5.6%), and surgical procedure performed on wrong site (3.4%) [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

In 2024, the Joint Commission reviewed 1,575 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 longer, 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 2024 resulted in patient death [11]. It is important to keep in mind that delays in treatment can occur in any healthcare setting. The most common reasons for a delay in treatment include policies not being followed (e.g., monitoring, reassessment), staff lacking competency to recognize abnormal clinical signs or changes in condition, and insufficient shared understanding and awareness of patient condition, care plan, or risk factors across team members. [11]. 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 [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 [11].

UNINTENDED RETENTION OF A FOREIGN BODY

In 2024, 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 fragments of instruments or devices, instruments, 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

In 2024, the Joint Commission revised its definition of suicide in the Sentinel Event Policy [7]. The revised definition is death caused by self-inflicted injurious behavior if any of the following apply:

- While in a healthcare setting

- Within seven days of discharge from inpatient services

- Within seven days of discharge from emergency department

- While receiving or within seven days of discharge from the following behavioral healthcare services:

- Day treatment/partial hospitalization program (PHP)/intensive outpatient program (IOP)

- Residential
- Group home
- Transitional supportive living

The best available national estimate suggests that approximately 49 to 65 hospital inpatient suicides occur annually in the United States. Approximately three-quarters of these deaths occur during psychiatric hospitalization, and hanging is the most common method, accounting for about 70% of inpatient suicides [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]. Joint Commission data indicate that approximately 21% of accredited behavioral healthcare organizations and 5% of accredited hospitals were found to be noncompliant with suicide risk assessment requirements during accreditation surveys.

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 occur during prescribing/ordering, 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, MSO4, MgSO4).

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 0.01% and 2% of prescriptions are dispensed incorrectly [23,56]. 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 2026, 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, some studies of specific cancers and diagnostic pathways have reported error or missed-opportunity rates exceeding 10%, 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 [55]. 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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