ABIM201 • Internal Medicine Offer #1

Table of Contents

ABIM201 • Internal Medicine Offer #1

How to Receive Credit

NetCE 10 Hour Course #91783 • Smoking and Secondhand Smoke

91783 • Smoking and Secondhand Smoke

1. INTRODUCTION

2. DEFINITIONS

3. HISTORY OF TOBACCO USE AND RESTRICTION

4. PREVALENCE AND ECONOMIC IMPACT OF SMOKING

5. TOBACCO AND NICOTINE PRODUCTS

6. TOBACCO-RELATED CONCEPTS

7. CIGARETTE SMOKE

8. ANATOMY AND PHYSIOLOGY OF SMOKE INHALATION

9. LEARNING OF BEHAVIOR

10. SMOKING DEPENDENCE

11. HEALTH COMPLICATIONS RELATED TO SMOKING

12. COMORBID CONDITIONS

13. FETAL EXPOSURE

14. PASSIVE SMOKING EFFECTS ON CHILDREN

15. PASSIVE SMOKING EFFECTS ON ADULTS

16. MEASURING SECONDHAND SMOKE EXPOSURE

17. THIRDHAND SMOKE

18. INTERVENTIONS FOR SMOKING CESSATION

19. REDUCING TOBACCO SMOKE EXPOSURE

20. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 5 Hour Course #91573 • Diagnosing and Treating Overweight and Obese Patients

91573 • Diagnosing and Treating Overweight and Obese Patients

1. INTRODUCTION

2. CLINICAL BACKGROUND

3. PATHOPHYSIOLOGY

4. RISK FACTORS AND COMORBIDITIES

5. TREATMENT

6. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

7. INSURANCE COVERAGE

8. SUMMARY

9. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #96411 • Behavioral Addictions

96411 • Behavioral Addictions

1. INTRODUCTION

2. BEHAVIORAL ADDICTION: EVOLUTION AND CONCEPTS

3. EXPLANATORY MODELS OF ADDICTION

4. CHILD AND ADOLESCENT VULNERABILITY TO BEHAVIORAL ADDICTION

5. OVERVIEW OF GENERAL BEHAVIORAL ADDICTION TREATMENT

6. GAMBLING DISORDER

7. ADDICTIVE SEXUAL BEHAVIOR

8. INTERNET GAMING DISORDER

9. BINGE EATING DISORDER

10. COMPULSIVE BUYING DISORDER

11. TRICHOTILLOMANIA (HAIR PULLING DISORDER)

12. KLEPTOMANIA (COMPULSIVE STEALING)

13. INDUCED BEHAVIORAL ADDICTIONS

14. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

ABIM201 • Internal Medicine Offer #1

Mark S. Gold, MD, DFASAM, DLFAPA

John J. Whyte, MD, MPH

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

ABIM201 • Internal Medicine Offer #1

Expiration Date: 02/28/2022

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.

91783 • Smoking and Secondhand Smoke

Mark S. Gold, MD, DFASAM, DLFAPA

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

This course provides comprehensive clinical education on tobacco smoke in primary care and public health. It addresses core competencies as well as knowledge, assessment, and treatment-based competencies of healthcare providers. It covers the history of tobacco, epidemiology of tobacco use, tobacco smoke metabolism, dependence, treatment and relapse. It also addresses complications associated with direct and indirect exposure to tobacco smoke, effects of prenatal exposure, methods of screening for exposure, and brief intervention training. This course includes a review of available screening tools, predisposing genetic factors, associated risk and protective factors, withdrawal symptoms and treatment, lab testing procedures, diagnostic tools, and age and gender issues.

Table of Contents

91783 • Smoking and Secondhand Smoke

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. DEFINITIONS

3. HISTORY OF TOBACCO USE AND RESTRICTION

4. PREVALENCE AND ECONOMIC IMPACT OF SMOKING

5. TOBACCO AND NICOTINE PRODUCTS

6. TOBACCO-RELATED CONCEPTS

7. CIGARETTE SMOKE

POTENTIALLY THERAPEUTIC COMPONENTS OF TOBACCO

8. ANATOMY AND PHYSIOLOGY OF SMOKE INHALATION

9. LEARNING OF BEHAVIOR

RITUALISM

MEDIA INFLUENCE

GENETICS

10. SMOKING DEPENDENCE

PSYCHOLOGIC DEPENDENCE

11. HEALTH COMPLICATIONS RELATED TO SMOKING

PULMONARY COMPLICATIONS

CARDIOVASCULAR COMPLICATIONS

NEUROLOGIC COMPLICATIONS

CANCER

OSTEOPOROSIS

PROBLEMS WITH CONCEPTION AND EMBRYONIC HEALTH

12. COMORBID CONDITIONS

ALCOHOL ABUSE

DRUG ABUSE

PSYCHIATRIC DISORDERS

13. FETAL EXPOSURE

PHARMACOKINETICS AND DYNAMICS

NEUROLOGIC COMPLICATIONS

PULMONARY COMPLICATIONS

CARDIOVASCULAR COMPLICATIONS

LOW BIRTH WEIGHT AND SMALL FOR GESTATIONAL AGE

MIDDLE EAR DISEASE

CANCER

OSTEOPOROSIS

PSYCHIATRIC DISORDERS

14. PASSIVE SMOKING EFFECTS ON CHILDREN

NEUROLOGIC EFFECTS

CARDIAC COMPLICATIONS

SIDS

PULMONARY COMPLICATIONS

DENTAL CARIES

VITAMIN DEFICIENCY

RESULTANT SYMPTOMS IN ADULTHOOD

15. PASSIVE SMOKING EFFECTS ON ADULTS

OCCUPATIONAL EXPOSURE

HEART DISEASE

STROKE

LUNG DISEASE

CANCER

GLUCOSE INTOLERANCE/DIABETES

SKIN DISORDERS

WOUND REPAIR

AGE-RELATED MACULAR DEGENERATION

CERVICAL INTRAEPITHELIAL NEOPLASM (CIN)

NONALCOHOLIC FATTY LIVER DISEASE

16. MEASURING SECONDHAND SMOKE EXPOSURE

17. THIRDHAND SMOKE

18. INTERVENTIONS FOR SMOKING CESSATION

PRIMARY CARE INTERVENTION

BRIEF INTERVENTION

MOTIVATIONAL INTERVIEWING

INTERVENTIONS FOR NON-ENGLISH-PROFICIENT INDIVIDUALS

TREATING NICOTINE DEPENDENCE

19. REDUCING TOBACCO SMOKE EXPOSURE

20. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

91783 • Smoking and Secondhand Smoke

Education Category. Community Health

Release Date. 06/01/2019

Expiration Date. 05/31/2022

Course Overview

This course provides comprehensive clinical education on tobacco smoke in primary care and public health. It addresses core competencies as well as knowledge, assessment, and treatment-based competencies of healthcare providers. It covers the history of tobacco, epidemiology of tobacco use, tobacco smoke metabolism, dependence, treatment and relapse. It also addresses complications associated with direct and indirect exposure to tobacco smoke, effects of prenatal exposure, methods of screening for exposure, and brief intervention training. This course includes a review of available screening tools, predisposing genetic factors, associated risk and protective factors, withdrawal symptoms and treatment, lab testing procedures, diagnostic tools, and age and gender issues.

Audience

This course is designed for physicians, nurses, and other healthcare professionals who may intervene to stop patients from smoking.

Course Objective

The purpose of this course is to provide physicians, nurses, behavioral health professionals, and other members of the interdisciplinary team with a formal educational opportunity that will address the impact of tobacco smoking and secondhand exposure in public health and disease as well as interventions to promote smoking cessation among their patients.

Learning Objectives

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

1. Describe the history of tobacco and its impact on society.

2. Define the prevalence and economic impact of tobacco smoke exposure on public health.

3. Differentiate between available tobacco products.

4. Describe the neurophysiologic effects and addictive components of tobacco smoke.

5. Describe the anatomy and physiology of smoke inhalation, and outline key points in learning of behavior.

6. Define the psychologic and physiologic aspects of smoking dependence.

7. List the common health complications related to smoke exposure.

8. Identify the common comorbid conditions of tobacco users.

9. Describe the developmental complications related to prenatal exposure to smoke.

10. Define the effects of exposure to secondhand smoke for children and adults.

11. Identify the methods of detecting and measuring tobacco smoke exposure.

12. Define thirdhand smoke.

13. Outline the methods of tobacco cessation interventions, including necessary considerations for non-English-proficient patients.

14. Define the treatment modalities for tobacco addiction, including pharmacologic options.

15. Identify strategies to reduce exposure to tobacco smoke.

Faculty

Mark S. Gold, MD, DFASAM, DLFAPA, is a teacher of the year, translational researcher, author, mentor, and inventor best known for his work on the brain systems underlying the effects of opiate drugs, cocaine, and food. Dr. Gold was a Professor, Eminent Scholar, Distinguished Professor, Distinguished Alumni Professor, Chairman, and Emeritus Eminent Scholar during his 25 years at the University of Florida. He was a Founding Director of the McKnight Brain Institute and a pioneering neuroscience-addiction researcher funded by the NIH-NIDA-Pharma, whose work helped to de-stigmatize addictions and mainstream addiction education and treatment. He also developed and taught courses and training programs at the University of Florida for undergraduates and medical students.

He is an author and inventor who has published more than 1,000 peer-reviewed scientific articles, 20 text books, popular-general audience books, and physician practice guidelines. Dr. Gold was co-inventor of the use of clonidine in opioid withdrawal and the dopamine hypothesis for cocaine addiction and anhedonia. Both revolutionized how neuroscientists and physicians thought about drugs of abuse, addiction, and the brain. He pioneered the use of clonidine and lofexidine, which became the first non-opioid medication-assisted therapies. His first academic appointment was at Yale University School of Medicine in 1978. Working with Dr. Herb Kleber, he advanced his noradrenergic hyperactivity theory of opioid withdrawal and the use of clonidine and lofexidine to ameliorate these signs and symptoms. During this time, Dr. Gold and Dr. Kleber also worked on rapid detoxification with naloxone and induction on to naltrexone.

Dr. Gold has been awarded many state and national awards for research and service over his long career. He has been awarded major national awards for his neuroscience research including the annual Foundations Fund Prize for the most important research in Psychiatry, the DEA 30 Years of Service Pin (2014), the American Foundation for Addiction Research’s Lifetime Achievement Award (2014), the McGovern Award for Lifetime Achievement (2015) for the most important contributions to the understanding and treatment of addiction, the National Leadership Award (NAATP) from addiction treatment providers for helping understand that addiction is a disease of the brain, the DARE Lifetime Achievement Award for volunteer and prevention efforts, the Silver Anvil from the PR Society of America for anti-drug prevention ads, the PRIDE and DARE awards for his career in research and prevention (2015), and the PATH Foundation’s Lifetime Achievement Award (2016) as one of the “fathers” of addiction medicine and MAT presented to him by President Obama’s White House Drug Czar Michael Botticelli. He was awarded Distinguished Alumni Awards at Yale University, the University of Florida, and Washington University and the Wall of Fame at the University of Florida College of Medicine. Gold was appointed by the University President to two terms as the University’s overall Distinguished Professor, allowing him to mentor students and faculty from every college and institute. The University of Florida College of Medicine’s White Coat Ceremony for new medical students is named in his honor.

Since his retirement as a full-time academic in 2014, Dr. Gold has continued his teaching, mentoring, research, and writing as an Adjunct Professor in the Department of Psychiatry at Washington University and an active member of the Clinical Council at the Washington University School of Medicine’s Public Health Institute. He regularly lectures at medical schools and grand rounds around the country and at international and national scientific meetings on his career and on bench-to-bedside science in eating disorders, psychiatry, obesity, and addictions. He continues on the Faculty at the University of Florida College of Medicine, Department of Psychiatry as an Emeritus Distinguished Professor. He has traveled extensively to help many states develop prevention, education, and treatment approaches to the opioid crisis.

Faculty Disclosure

Contributing faculty, Mark S. Gold, MD, DFASAM, DLFAPA, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

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

Alice Yick Flanagan, PhD, MSW

Abimbola Farinde, PharmD, PhD

James Trent, PhD

Division Planners Disclosure

The division planners have 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.

1. INTRODUCTION

Tobacco smoke exposure is a major cause of the nation's most serious and preventable health problems. This course provides comprehensive clinical education on tobacco smoke in primary care and public health. It addresses core competencies as well as knowledge, assessment, and treatment-based competencies of healthcare providers. It covers the history of tobacco, epidemiology of tobacco use, tobacco smoke metabolism, dependence, treatment, and relapse. It also addresses complications associated with direct and indirect exposure to tobacco smoke, effects of prenatal exposure, methods of screening for exposure, and brief intervention training. This course includes a review of available screening tools, predisposing genetic factors, associated risk and protective factors, withdrawal symptoms and treatment, lab testing procedures, diagnostic tools, and age and gender issues.

2. DEFINITIONS

A clear understanding of tobacco use and smoking is dependent on a knowledge of the basic underlying concepts associated with addiction [1].

Tolerance: The need for greatly increased amounts of the substance to achieve intoxication (or the desired effect) or a markedly diminished effect with continued use of the same amount of the substance.

Withdrawal: Maladaptive behavioral change, with physiologic and cognitive concomitants, that occurs when blood or tissue concentrations of a substance decline in an individual who had maintained prolonged heavy use of the substance. After developing unpleasant withdrawal symptoms, the person is likely to take the substance to relieve or to avoid those symptoms, typically using the substance throughout the day, beginning soon after awakening.

Substance use disorder: A cluster of cognitive, behavioral, and physiologic symptoms indicating that the individual continues using the substance despite significant substance-related problems. There is also an underlying change in brain circuits that may persist beyond detoxification.

3. HISTORY OF TOBACCO USE AND RESTRICTION

Tobacco was the first export of the New World and was marketed in Europe as a remedy for stress, ulcers, headaches, asthma, and even rheumatism. Tobacco's botanical name, Nicotiana tabacum, is derived from Jean Nicot, a French ambassador to Portugal who, convinced of tobacco's medicinal value, sent the plant's seeds to the royal family in France [2].

Tobacco product use has been discouraged in the United States and abroad for centuries. In 1586 the first recorded tobacco prohibition was issued by Pope Sixtus V, who declared it a sin "for any priest to use tobacco before celebrating or administering communion." In 1604, King James I published A Counterblaste to Tobacco, describing smoking tobacco as, "a custome lothsome to the eye, hatefull to the Nose, harmefull to the braine, [and] dangerous to the Lungs" [3]. Tobacco use and distribution saw further restrictions across the globe in the early 1600s. King James I levied heavy taxes on tobacco, the czar of Russia exiled tobacco users, and the Chinese executed persons caught selling tobacco [4].

However, in contrast to strict regulations found elsewhere in the world, tobacco was brought to the United States as a cash crop. The 1880s saw the invention of an automated cigarette-making machine, which paved the way for cigarettes to become the predominant form of tobacco with the start of World War I. The twentieth century also experienced the first major outcry against tobacco in the United States. Though medical concerns were suggested, the first tobacco prohibition movements in the United States were primarily driven by religious and moral motivations. Groups including religious leaders, the Women's Christian Temperance Union, and the Non-smokers Protective supported efforts for prohibition of tobacco. However, strong public resistance against alcohol prohibition also led to the repeal of tobacco restrictions, and by the 1930s these restrictions had all but vanished [5].

One of the lesser known consequences of World War II was that German smoking research and corresponding social change were not acknowledged by the rest of the world. In the 1930s and early 1940s, Germany conducted an aggressive anti-smoking campaign based on medical research from the 1920s and 1930s, which elucidated the carcinogenic effects of smoking. As part of the German movement aimed to preserve a racial "utopia" of pure, healthy Germans, they banned smoking in the workplace, imposed cigarette taxes, restricted advertising and farming, and implemented programs to eliminate smoking [6,7].

Associations between smoking and cancer were not published in the United States until the 1950s and 1960s. The 1964 publication Smoking and Health: Report of the Advisory Committee to the Surgeon General led to immediate political notice of the tobacco issue and the advent of programs and policies to reduce smoking [8]. Anti-tobacco policies have included taxation on tobacco products, increased insurance premiums, warning labels, public health campaigns, and restrictions on tobacco sales to minors, smoking in public areas, and tobacco marketing. Prior to 1964 there were few if any laws regulating involuntary secondhand smoke (SHS) exposure. Studies revealing the detrimental effects of SHS to nonsmokers led to new anti-smoking legislation. As of June 2009, the General Services Administration (GSA) has established smoke-free environments for federal facilities. Interior areas previously designated for smoking have been closed and smoking is prohibited in courtyards and within 25 feet of doorways and air intake ducts in outdoor spaces [9]. Further, nearly all 50 states have laws restricting smoking in places such as schools, public transportation, government buildings, elevators, and restaurants. In accordance with federal law, smoking is prohibited on buses, trains, and domestic airline flights. Such laws have decreased cigarette consumption by making smoking less socially acceptable and more inconvenient [5].

On June 22, 2009, President Barack Obama signed HR1256: The Family Smoking Prevention and Tobacco Control Act. This was enacted as a result of several findings made by Congress, specifically that almost all new users of tobacco products are younger than the minimum legal age to purchase such products. Under this law, the U.S. Food and Drug Administration (FDA) now has the authority to regulate tobacco products [10]. The FDA had previously attempted to assert jurisdiction under the Food, Drug, and Cosmetic Act in 1996 to regulate tobacco advertising, labeling, and purchasing restrictions (e.g., federal minimum age of 18 years and requiring retailers to check identification). However, the tobacco industry retaliated by suing the federal government, as there was no set legislation to give the FDA this authority. As a result, all FDA regulations were dropped [11]. Due to the 2009 law, the FDA can now establish a minimum age of sale of tobacco products, test and report on tobacco product ingredients/additives, prohibit cigarettes from containing any flavors other than tobacco or menthol, and apply the same restrictions on labeling and advertising of cigarettes to smokeless tobacco products. Of note, this law states that the FDA cannot ban existing products or require nicotine be eliminated from any product.

In 2017, the FDA unveiled a comprehensive plan on tobacco and nicotine regulation to reduce the number of preventable deaths caused by smoking and tobacco use. The two key areas of focus of this plan are reducing the nicotine levels in combustible cigarettes to render them minimally or nonaddictive and harnessing new forms of nicotine delivery that could allow currently addicted adult smokers to get access to nicotine without many of the risks associated with using combustible tobacco products. Similar to the 2009 policy, this plan will also explore the extent of tobacco flavoring in attracting youth and new smokers; menthol flavoring will be included in this plan. Of note, this policy only affects newly regulated tobacco products and will not affect any current requirements for cigarettes and smokeless tobacco. As of 2019, the plan was still in development and the FDA was continuing to seek public comment and expert opinion [472,474].

4. PREVALENCE AND ECONOMIC IMPACT OF SMOKING

Approximately 480,000 Americans die each year as a result of active and/or passive smoking-related health consequences [12]. Despite the seemingly well-known and highly publicized health consequences of smoking, 13.9% of the U.S. population 18 years of age or older are current cigarette smokers [460]. Former U.S. Assistant Secretary for Health Howard Koh asserted that although evidence-based tools were successful in substantially reducing smoking prevalence between 1997 and 2004, efforts were not applied to their full potential nationwide, limiting the efficacy of anti-smoking campaigns [14]. Other experts have attributed declines in cigarette smoking to anti-smoking advertisements, stigma, smoking bans, and increased taxation [460]. Evidence-based tools remain valuable, indicated by slow, steady downward prevalence trends since 1997. However, they are only useful if they reach an audience. These tools seem not to be preventing the initiation of new smokers, despite the overall reductions in use [14,15].

Nearly 1.8 million Americans initiated cigarette smoking in 2016, continuing a downward trend noted between 2002 and 2013 (ranging from 1.9 to 2.2 million); 40.6% of these were younger than 18 years of age [13]. About one-third of new smokers will ultimately die from a smoking-related illness [16]. Higher levels of education are correlated with a lower likelihood of having smoked cigarettes in the past month [13]. The number of first-time cigar users is slowly declining, from 2.8 million in 2011 to 2.4 million in 2016 [13]. In 2016, current use of any tobacco product was highest among American Indians/Alaska Natives (42.6%) followed by persons of two or more races (40.2%), whites (31.3%), blacks (27.8%), Hispanics (22%), and Asians (11.9%) [13].

Approximately 41,000 adult nonsmokers die each year from exposure to SHS, and this continues to be a significant environmental risk in the United States [19]. According to a 2009 study by Ellis and colleagues, the prevalence of smoking in New York City was lower than the national average (23.3% vs. 29.7%), but the proportion of nonsmoking adults with elevated cotinine levels was higher (56.7% vs. 44.9%), especially among Asians, even after close to two years after implementation of smoke-free workplace legislation [20]. They attribute this finding to the large amounts of people in such small proximity (26,000 people and 10,000 housing units per square mile vs. the national average of 80 people and 33 housing units per square mile) [20]. In a 2017 study, Perlman and colleagues reviewed cotinine levels in New York City nonsmokers, and found that 37.1% had elevated levels [17]. It is thought that this reduction is a result of smoke-free air policies enforced within the previous 10 to 15 years. The researchers also agreed that greater population density and pedestrian exposure continued to contribute to the high number of nonsmokers with elevated cotinine levels [17].

Tobacco use is one of the most expensive addictive behaviors in the United States. In 2015, an estimated 299.9 billion cigarette stick equivalents (based on the weight of 0.0325 ounces of tobacco per cigarette) were consumed in the United States, of which 262.7 billion were cigarettes; the rest were other combustible tobacco products [21]. This accounted for $93.9 billion in national expenditures on cigarettes alone in the 2017 fiscal year [23].

Smoking-related costs in the United States are staggering. The total annual public and private healthcare expenditures caused by smoking are estimated to be greater than $300 billion, including nearly $170 billion in direct medical costs and more than $156 billion in lost productivity related to premature death and exposure to SHS [12].

5. TOBACCO AND NICOTINE PRODUCTS

Cigarette smoking is on the decline in the United States, but use of other tobacco products is not [21]. In addition to a rise in use of smokeless tobacco, people across the United States (especially youth) are using e-cigarettes, cigars, cigarillos (small cigars), hookahs, kreteks, pipes, and bidis (or beedis) [18,25]. Unfortunately, each of these products is just as dangerous (if not more so) as use of cigarettes. Cigarettes are defined by the U.S. Department of the Treasury as "any roll of tobacco wrapped in paper or in any substance not containing tobacco," while cigars are defined as "any roll of tobacco wrapped in leaf tobacco or in any substance containing tobacco" [26]. Cigars also differ from cigarettes in processing; they consist of filler, a binder, and a wrapper, all made of air-cured and fermented tobaccos [27]. Cigars show significant variability in physical and chemical characteristics, with total nicotine content ranging from 10.1 mg to 444 mg per cigar, length ranging from 68.0 mm to 213.5 mm, and diameter ranging from 8.0 mm to 20.5 mm [28]. Due to their size and makeup, smokers can spend up to an hour smoking a single cigar; therefore, its ensuing effects (e.g., rates of cancer, chronic obstructive pulmonary disease [COPD]) are more pronounced. Cigarillos, or "little cigars," are generally about half the size of a normal cigar, weighing 1.5 to 3 g on average [29]. Many types are made to look like cigarettes and are sold in packs of 20 with filter tips. Cigarillos are perceived as a less addictive, less harmful, and less expensive alternative to cigarette use [30; 31].

Due to increased federal taxation on cigarettes, cigarette tobacco, and small cigars, many consumers apparently switched to smoking products virtually identical to cigarettes or small cigars, but classified as large cigars, or from smoking roll-your-own tobacco to smoking pipe tobacco [22]. Subsequent to the 2009 tax increase and intensified FDA regulation, many companies simply relabeled cigarette rolling tobaccos as pipe tobaccos (not subject to increased taxation) [21]. Sales of "pipe tobacco" increased from 5.2 million pounds in 2009 to 43.7 million pounds in 2013 (a 740% change) while roll-your-own tobacco sales dropped from 21.3 million pounds to 3.8 million pounds [22]. Following a similar relabeling and marketing effort for small cigars, sales of large cigars jumped from 5.8 billion sticks in 2009 to more than 12.4 billion sticks in 2013, while small cigars decreased from 5.7 billion sticks to 0.7 billion sticks in the same years. In 2016, the FDA extended its limitations for tobacco products to include e-cigarettes, vaporizers, and other electronic nicotine delivery systems [458]. As a result, these products must include warnings and manufacturers must submit documentation to the FDA for review and limit sales to persons 18 years of age or older. The goals of these regulations are to increase public health awareness and, especially, reduce marketing and sales to adolescents, who are commonly targeted by providing tobacco flavors including apple, cherry, cream, grape, "jazz," strawberry, and wine. Before this ruling, there were no federal laws restricting sales of these types of products, but an alarming increase in unregulated tobacco products, especially among high school students, prompted the FDA to enforce regulations.

The rise of e-cigarettes in the past decade has introduced new variables in the prevention and treatment of nicotine addiction. Originally marketed as a smoking cessation tool, e-cigarettes are electronic products that typically deliver nicotine in the form of an aerosol [456]. Most e-cigarettes consist of a cartridge (which holds a liquid solution containing varying amounts of nicotine, flavorings, and other chemicals), a heating device (vaporizer), and a power source (usually a battery) [457]. In many e-cigarettes, puffing activates the battery-powered heating device, which vaporizes the liquid in the cartridge. The resulting aerosol or vapor is then inhaled (called "vaping") [457]. It is unclear if this delivery method decreases the risks seen with conventional tobacco smoking; however, it does introduce the risks of toxicity associated with consumption of the potent e-liquid.

In 2017, 2.8% of adults were current e-cigarette users. Adults 25 to 44 years of age have the highest rate of e-cigarette use (22.5%), followed by those 45 to 64 years of age (21.3%), 18 to 24 years of age (18.3%), and older than 65 (11%) [456]. Use is much higher among men (24.8%) than women (14.2%).

Adolescent use of e-cigarettes has skyrocketed from 1.5% in 2011 to 20.8% in 2018, making it the number one form of tobacco used among youth [459,465]. In 2018, the FDA issued more than 1,300 warnings and fines to retailers who illegally sold e-cigarette products to minors [464].

According to the Centers for Disease Control and Prevention (CDC), large cigar consumption increased 116% from 2000 to 2017, with cigar smoking being the third most common form of tobacco use among youth [32,33]. However, it has been shown that adolescent (and likely adult) cigar use is significantly underestimated due to systematic misreporting on statewide surveys, which is mainly attributed to the language and definitions used in questions that assume knowledge of all types of cigars [34]. For example, it was found that more than half of Black & Mild (brand of cigars and cigarillos) users did not report any cigar/cigarillo use on a 2009 Virginia survey, largely because the usage of the terms "cigar" or "cigarillo" for this (and other similar products) is not common in the youth- or culture-specific lexicon.

Bidis consist of sun-dried tobacco, finely ground and rolled into a leaf of the Diospyros melanoxylon plant native to India. They contain concentrated tobacco, with an average 21.2 mg/g of nicotine compared with 16.3 mg/g of nicotine in filtered and 13.5 mg/g in unfiltered cigarettes, but have less total nicotine because they are shorter [35]. Nonetheless, an unfiltered bidi can release three to five times more tar and nicotine and contain more ammonia and carbon monoxide (CO) than a regular cigarette. Bidis look similar to small cigars or marijuana cigarettes and are available filtered or unfiltered in many flavors, including vanilla, chocolate, strawberry, cherry, and menthol [36]. Bidis are not commonly used in the United States, and sale and distribution is banned in some states (e.g., Illinois, Vermont, West Virginia). However, these products are available on the Internet [37].

Kreteks, or clove cigarettes, are composed of a mixture of tobacco (60% to 80%) and ground clove buds (20% to 40%), available with or without filters [38]. A popular, representative kretek brand contains less nicotine than popular cigarettes (7.39 mg), but smokers extract equal amounts of nicotine by altering smoking behavior [39]. For example, clove cigarettes can be smoked slower, using more puffs. Overall, smokers will do whatever is necessary to achieve plasma levels of nicotine comparable to their usual brand of cigarette.

A hookah is a type of waterpipe comprised of a head or bowl, plate, body, jar, hose, and mouthpiece (Figure 1). The body of the hookah fits down into the jar, which is partially filled with water, although any liquid (e.g., alcohol, juice) can be used. Tobacco is placed in the bowl at the head of the body and covered with a filter, such as perforated tin foil, and then burning embers or charcoal is placed above it (and sometimes covered by a cap). The hot air from the charcoal roasts the tobacco and the ensuing smoke is passed down into the liquid in the jar where it is partially filtered, diluted, and cooled. The smoke then bubbles up and passes through the hose and mouthpiece for inhalation. Repeated inhalation is required to keep the tobacco burning. The plate stores dead coals/embers. The types of tobacco used for hookah are ajami or tumbak, which is a pure, dark tobacco paste; "honeyed" or tobamel or maassel, containing 70% honey or molasses and featuring flavors (e.g., apple, mango, banana); or jurak, which may be sweetened or contain fruits or oils. It is commonplace to use 10–20 g at a time, and these tobaccos may be mixed with other drugs [40]. Smoking sessions last up to an hour or longer, and it has been reported that the nicotine content of the tobacco used for hookah is higher than that in cigarettes [41]. Thus, the smoker is exposed to a higher volume of smoke for longer periods (not to mention those in the vicinity). A report from the World Health Organization states that a hookah user may inhale as much smoke in one session as a cigarette smoker would after consuming at least 100 cigarettes [42]. Contrary to popular belief, waterpipe smoking is not safer or less addictive than cigarette smoking [43]. The FDA began regulating the manufacture, import, packaging, labeling, advertising, promotion, sale, and distribution of tobacco mixtures used for hookah in 2016 [24]. Hookah smoke contains higher concentrations of CO, nicotine, tar, heavy metals, and carcinogens, likely because of its method of use (i.e., tobacco mixtures heated by quick-burning charcoal or wood embers and inhalation through use of a plastic hose for an hour or longer) [44,45]. It is also common to share a hookah, so users are also at risk of exposure to infections (e.g., herpes due to sharing of the mouthpiece) [46]. Hookah pipe smoking may be a gateway to cigarette smoking and other drug use. Although policies are in place to ban smoking in many public places, many times, hookah use is exempt because it is done in places which identify themselves as "tobacco bars," waterpipe smoking areas are set up outside, or the smoking is done in places where tobacco is sold.

Figure 1: SCHEMATIC OF A WATERPIPE

Source: [46]

6. TOBACCO-RELATED CONCEPTS

For many years, efforts to make cigarettes "safer" have been pursued as a compromise solution [48]. Filtering devices have been used to selectively reduce cigarette smoke constituents for almost 60 years [49]. Studies from the 1970s concluded that charcoal filters can remove up to 66% of ciliotoxic agents from mainstream smoke, and cellulose acetate filter tips can eliminate up to 75% of N-nitrosamines, which are known volatile carcinogenic compounds [50,51]. However more recent studies have shown that neither type of filter is effective for reducing the free radical and reactive oxygen species content in the particulate or gas phase of cigarette smoke [52]. Additionally, remnant (i.e., post-filter) aqueous tar can cause the formation of DNA adducts, particularly the mutagenic 8-Oxo-2'-deoxyguanosine (8-oxo-dG).

The FTC performs tar, nicotine, and CO content measurements in all domestic cigarette varieties sold in the United States, which numbered almost 1,300 in 1998, the last year the report was conducted. The FTC defines tar as the particulates of cigarette smoke minus water and alkaloids, such as nicotine, detected using a method developed in 1966 [53]. In 2016, 99.7% of cigarettes sold in the United States had filters, and the FTC reported that 87.9% of the market share of cigarettes had less than 15 mg of tar, compared with only 2% in 1967 [53,54]. Nevertheless, epidemiologic evidence does not indicate that modern cigarettes are any safer. Smokers participating in the Cancer Prevention Study II (CPS-II) from 1982 to 1988 manifested an almost sixfold increase in lung cancer death compared to Cancer Prevention Study I (CPS-I) participants during 1959 to 1965, even though filter tips were introduced in the 1950s and only the latter group benefited from their implementation [55]. Smoking pattern compensation and use of stronger tobacco strains may be at least partially responsible for this paradoxical trend.

Filter vents, usually shaped in rings of small perforations along the filter, allow air to mix with smoke, diluting the amount of tar, nicotine, and CO detected by the FTC method [53]. Interestingly, as many as 58% of smokers of cigarettes with tar less than approximately 7% (formerly labeled "ultralight") and 53% of smokers of cigarettes with tar levels of 8–14 mg of tar (formerly labeled "light") cover these vents to some extent [56,57]. Blocking half of the vents of a 4.4 mg tar cigarette, as is done when smokers pinch the cigarette with their fingers or hold the cigarette in their lips, increases yields of tar by 60%, nicotine by 62%, and CO by 73% [58]. Poor reliability of the FTC method is further made evident in the work of Byrd and Robinson, who concluded that the "FTC yield cannot precisely predict nicotine uptake for an individual smoker" and "nicotine uptake by smokers is influenced by…many possible smoker-controlled parameters" [59]. Interestingly, this publication originates from the R.J. Reynolds Tobacco Company. Another contributing factor to the increase in mortality related to smoking may be the concentration of nitrate in tobacco leaves, one of the most important precursors for the endogenous formation of N-nitrosamines during smoke inhalation [60]. Cigarette nitrate content has increased from 0.5% in the 1950s to 1.2% to 1.5% in the late 1980s, possibly due to the increased use of chemical fertilizers and the introduction of plant ribs and stems into U.S. tobacco blends [61]. The carcinogenic potential of nitrosamines has been well documented.

All in all, efforts to reduce the health hazards of smoking leave much to desire, and in spite of filter tip implementation and reportedly lower tar values, cigarettes remain a serious health hazard, affecting smokers and those around them.

7. CIGARETTE SMOKE

Cigarette smoke is a complex mixture of more than 7,000 components, including nicotine, aromatic hydrocarbons, sterols and oxygenated isoprenoid compounds, aldehydes, nitriles, cyclic ethers, and sulfur compounds [62,63,134]. At least 70 of these components are known to cause cancer [134]. Firsthand smoke is defined as the smoke that the smoker inhales. Smoking tobacco products also generates environmental tobacco smoke, also known as SHS and passive smoke, which consists of both exhaled mainstream and sidestream smoke. These two forms of smoke differ in chemical composition and have different temperatures and oxygen levels during generation. The burning end of a cigarette produces sidestream smoke, which in turn is the main component of SHS. Some known toxins of the thousands of chemical constituents in tobacco smoke are also present in SHS, including benzene, cadmium, ethylbenzene, formaldehyde, hydrazine, lead, limonene, methylamine, methylene chloride, nicotine, pyridine, toluene, and radioactive polonium-210 [64,65,66]. One study identified indoor air pollution from SHS as 10 times greater than diesel car exhaust [67].

Many of the diseases once thought only to be caused by active smoking have now been authoritatively linked to environmental tobacco smoke [62,68]. This finding is not surprising considering that many of the harmful components found in both firsthand smoke and SHS are more concentrated in SHS. Nicotine, tar, nitric oxide, and CO levels have been shown to be nearly twice as concentrated in SHS. Other harmful chemicals preferentially formed in SHS include carcinogenic aromatic amines (e.g., o-toluidine, 2-naphthylamine, and 4-aminobiphenyl) [62,65,69].

POTENTIALLY THERAPEUTIC COMPONENTS OF TOBACCO

According to Lans et al., the crushed leaves of Nicotiana tabacum are applied to wounds in Guatemala, and tobacco steam vapor is considered a cure-all in Latin America and the Caribbean. In addition to its most addictive component, nicotine, the tobacco plant contains many enzymes, flavonoids, and coumarins and malic, citric, and phenolic acids [70]. In a case-control study by Sandler et al., tobacco use and secondhand exposure (e.g., parents had smoked) reduced the risk of developing ulcerative colitis [71]. Plants of the genus Nicotiana have been manipulated in various experiments to express proteins that may be used medicinally. Indeed, transgenic tobacco plants have been used in the development of vaccines for measles, lymphoma, and diabetes [72,73,74].

8. ANATOMY AND PHYSIOLOGY OF SMOKE INHALATION

Administration of any drug via smoking is a highly efficient route, allowing rapid delivery to the brain. This act involves inhalation of a small volume of smoke (an average of about 35 ml for cigarettes) into the mouth from which it is drawn into the lungs [75]. The breathing pattern employed is different from normal tidal breathing in that a smoker's inhalation is deeper and more rapid, drawing the smoke in as a bolus at the beginning of inhalation [76]. However, this pattern varies greatly between smokers and during the course of consuming a single cigarette [77]. Uptake of smoke ingredients is determined by many factors, including chemical composition, smoker's inhalation behavior, lung morphology, and physiologic parameters such as tidal volume, vital capacity, rate of breathing, and rate of lung clearance [78]. Individual differences in size, metabolism, and genetics may also play a role. One hypothesis suggests that stimulation of nicotine-sensitive receptors in the upper airway by various elements of smoke governs the amount inhaled. Indeed, application of a topical anesthetic to the upper airway reduces the quantity of smoke inhaled [79].

Tobacco smoke consists of gaseous and particulate phases, with the particulate phase comprising about 8% of the total volume [76]. Particulate deposition depends on the size, shape, and hygroscopicity (ability to absorb water vapor) of the particles as well as the duration and depth of inhalation [77]. Smoke particles range from 0.1–1.0 mm in diameter as they exit a cigarette, doubling in size within half a second due to aggregation, cooling, and condensation [80]. Larger particles (1–5 mm) are likely to deposit in the trachea and bronchi, whereas smaller particles (0.01–1 mm) reach bronchioles, alveolar ducts, and alveoli. Irregularly shaped or fibrous particles tend to get trapped at branching points, although some of these particles can travel on to the alveoli [81]. Interestingly, smoking seems to result in a greater apical and central distribution of particles than normal tidal breathing. This finding may help to explain the pathogenesis of centrilobular emphysema [76].

Cigarettes deliver nicotine in a pulsatile manner, with plasma concentrations reaching their peak within 1.5 to 3 minutes of the commencement of smoking and gradually returning toward baseline within two to three hours [82]. Thus, nicotine levels rise and fall throughout the day with each cigarette smoked, declining to minimum amounts found in nonsmokers in the morning after the extended abstinence period of sleep. Such continuous flux in blood nicotine levels locks the user into an endless cycle of ups and downs and is thought to lead to the commonly held notion that smoking has a positive effect on mood. Considering smokers begin to experience withdrawal symptoms within hours of their last cigarette, and because these unpleasant effects are almost completely alleviated by smoking, this perception is hardly surprising. Daily repetition of this process links these perceived positive health benefits to the act of smoking in the smoker's mind and often results in the false identification of cigarettes as an effective form of self-medication [83].

9. LEARNING OF BEHAVIOR

What is it about smoking that makes it so addictive? On one hand, this form of drug delivery is very efficient; inhaled nicotine is absorbed through pulmonary rather than systemic circulation and can reach the brain within 10 to 20 seconds [84]. Once inside the central nervous system (CNS), nicotine stimulates release of dopamine from the nucleus accumbens, much like the use of cocaine and amphetamines, leading to the feeling of satisfaction and well-being. Given such rapid central reinforcement, it is not surprising that tobacco can become highly addictive. On the other hand, familial and social influences often play a crucial role in determining who might start smoking, quit, or become dependent [83]. For example, one study managed to train a small percentage of rhesus monkeys to smoke, but with such difficulty that it concluded that "environmental factors play the primary role in developing smoking behavior" [85].

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends that primary care clinicians provide interventions, including education or brief counseling, to prevent initiation of tobacco use in school-aged children and adolescents.

http://annals.org/aim/fullarticle/1748857

Last Accessed: May 13, 2019

Level of Evidence: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

Experimenting with smoking usually occurs in the early teen years and is predominantly driven by psychosocial motives [83]. For a first-time user, lighting a cigarette is a symbolic expression of autonomy and independence; acquisition of the desired image is often a sufficient incentive for a novice smoker to tolerate the body's rejection of the first few cigarettes. Despite an admitted awareness of at least some of the deleterious effects of smoking, in 2018, 1 in 4 high school students and 1 in 14 middle school students admitted to using a tobacco product in the past 30 days [135]. Almost all people (90%) who will smoke as adults have started doing so by 18 years of age, and the earlier a person begins, the more likely they are to continue [135]. Within a year, adolescents inhale the same amount of nicotine per cigarette as adults, and they too experience the craving and withdrawal symptoms associated with nicotine addiction [83]. By 20 years of age, 80% of smokers regret ever having started.

Much research has been dedicated to uncovering reasons for the development of a smoking habit. Risk factors include [86]:

- Presence of a smoker in the household

- Single parent home and/or strained relationship with parent

- Comorbid psychiatric disorders

- Low level of expressed self-esteem and self-worth

- Poor academic performance

- In boys, high levels of aggression and rebelliousness

- In girls, preoccupation with weight and body image

- Increased adolescent perception of parental approval of smoking

- Affiliation with smoking peers

- Availability of cigarettes

In addition, twin studies revealed a significant genetic contribution to both smoking initiation and dependence [87,88].

RITUALISM

In practice, many find the very act of smoking a cigarette ritualistic and calming. The process of "packing" cigarettes by tapping the box on the palm of a hand, removing a cigarette, lighting it, inhaling, and watching the smoke as it is exhaled all contribute to the perceived need to smoke. Some go so far as to claim that they "would not know what to do with their hands" if they were to stop smoking [83]. An investigation using denicotinized cigarettes illustrated that the sensorimotor experience of smoking makes a significant contribution to the perceived satisfaction [89].

MEDIA INFLUENCE

Mass media is another factor that contributes to the learning of smoking behavior. Historically, the tobacco industry recruited new smokers by associating its products with fun, excitement, sex, wealth, power, and a means of expressing rebellion and independence [90]. Such promotional efforts have proven to be especially effective on teenagers, a particularly lucrative market with a lifetime of cigarette consumption ahead of them [91]. Although at present tobacco companies can no longer directly advertise to teenagers, they retain the most potent form of marketing: movies. Smoking in film is a "more powerful force than overt advertising," perhaps because the audience is generally unaware of any sponsor involvement [92]. Philip Morris, one of the world's leading tobacco companies, stated in their 1989 marketing plan, "We believe that most of the strong, positive images for cigarettes and smoking are created by cinema and television" [90]. Although television is taking a more socially responsible stance on the subject of on-air tobacco use, movies continue to model smoking as a socially acceptable behavior, portraying it as a social behavior or a way to relieve tension [93,94]. A study exploring the connection between a child's professed favorite movie star and that actor's on-screen smoking history revealed "a clear relation between on-screen use and the initiation of smoking in the adolescents who admire them" [95]. Tobacco use in movies, albeit falling through the 1970s and 1980s, increased significantly after 1990 [90]. Furthermore, despite declining tobacco use and increasing public understanding of the dangers of nicotine, smoking in movies returned to the levels observed in the 1950s, when it was nearly twice as prevalent in society as in 2002 [96]. A study analyzing the content of the top 25 grossing films each year from 1988 to 1997 found that 87% of movies depicted tobacco use, with an average of 5 occurrences per film. The vast majority of tobacco use was portrayed as experienced use (91.5%) and rarely did it represent a character's first use (0.3%) or a relapse from a previous quit attempt (0.5%). Despite the fact that R-rated movies contained most tobacco exposure and were more likely to feature a major character using tobacco, about 60% of the total coverage of smoking occurred in youth-rated films (G, PG, and PG-13). Negative reactions to tobacco use, including comments about health effects or gestures such as coughing, were depicted in only 5.9% of the occurrences. Unrealistic portrayal of cigarette smoking on the big screen may help to explain the somewhat surprising finding that children of nonsmoking parents are especially susceptible to the effects of movie smoking exposure [93]. Between 2002 and 2017, 6 out of every 10 movies rated PG-13 contained smoking or tobacco use, with historically high average of occurrences per film in 2016 (34 per film) and 2017 (29 per film), prompting many health groups to advocate for the requirement of an R rating (i.e., younger than 17 years of age require accompanying adult) for any films containing tobacco use. Researchers estimate that requiring a R rating would reduce the number of teen smokers by 18%, preventing up to 1 million deaths from smoking in the future [184]. Since May 2007, the Motion Picture Association of America (MPAA) has made smoking a factor in assigning ratings to films. The pervasiveness of tobacco use, context in which smoking appears, and whether or not the act is glamorized are all taken into account by film raters [97].

GENETICS

It has been suggested that high genetic vulnerability to cigarette smoking may explain why some people begin and continue to smoke despite associated risks [98]. Twin studies found significant heritability for persistence of smoking versus quitting. Heritability estimates for smoking persistence ranged from 27% to 70% and were greater for older than younger cohorts [99,100,101]. Madden et al. examined cross-cultural differences in the genetic risk of becoming a regular smoker and of persistence in smoking in men and women. They found strong genetic influences on smoking behavior, 46% for women and 57% for men, consistent across country and age group [102]. In a U.S. study, estimates of the genetic contribution to risk of becoming a smoker were 60% in men and 51% in women [103].

10. SMOKING DEPENDENCE

Of the numerous ingredients in tobacco smoke, nicotine is believed to be the primary cause of cigarette addiction [104]. Commercially available forms of nicotine-replacement therapy (NRT) increase cessation rates approximately 1.5- to 2-fold [105,106,107]. Yet, the fact that only a fraction of those who use such products succeed suggests that cigarette addiction depends on specific characteristics of cigarette smoking. It appears that the rapid delivery of nicotine via inhalation is a primary contributor to cigarette dependence [108]. Indeed, a district court judge found that major U.S. cigarette companies have designed their cigarettes to precisely control nicotine delivery levels and provide doses of nicotine sufficient to create and sustain addiction [109].

Active components of cigarette smoke affect many organ systems, but the effects on the CNS may be of most clinical importance due to its mediating role in dependence. Central effects of nicotine include electroencephalogram (EEG) desynchronization, with a shift toward higher frequency [110]. Studies have demonstrated that nicotine from cigarette smoke reduces global cerebral blood flow (gCBF), most markedly in the right hemisphere, and increases regional cerebral blood flow (rCBF) by more than 10% in the cerebellum, occipital cortex, and insula. Decreases in rCBF have been observed in such subcortical structures as the hippocampus, anterior cingulate, amygdala, and nucleus accumbens [111]. Positron emission tomography (PET) studies show that nasal nicotine administration increases cerebral glucose metabolism in the left inferior frontal gyrus, left posterior cingulate gyrus, left lateral occipitotemporal gyrus, left and right cuneus, and right thalamus, while it decreases glucose metabolism in the left insula and the right inferior occipital gyrus [112].

Further, the physiology of nicotine dependence has been characterized as biphasic; it stimulates the pleasure response in the brain and creates a relaxed state. As with cocaine, amphetamines, and morphine, addiction to nicotine is believed to result from increased release of dopamine in the nucleus accumbens. Nicotinic acetylcholine receptors are located throughout the CNS. Neurons located in the ventral tegmental area become more active with nicotine administration, leading to an increase in dopamine release into the nucleus accumbens [113]. Indeed, lesions to these pathways reduce rates of self-administered nicotine [114].

PSYCHOLOGIC DEPENDENCE

Many smokers believe that smoking increases concentration, treats stress, and gives pleasure. These beliefs are false. The light-headed feeling that may accompany the act of smoking gives the smoker a false sense of pleasure or release. However, smoking actually causes a decline in physical and cognitive functioning. Additionally, a study by Ota et al. showed that nurses in Japan indulged in smoking as a result of the psychologic demands of their jobs, and this psychologic job demand was positively correlated with their Tobacco Dependence Screener score. The nurses associated stressful tasks with dysphoria, insomnia, anxiety, and other symptoms similar to that of nicotine withdrawal. To alleviate these symptoms, the nurses would smoke and become increasingly psychologically dependent on nicotine with each demanding occupational event [115].

11. HEALTH COMPLICATIONS RELATED TO SMOKING

PULMONARY COMPLICATIONS

Smoking severely compromises pulmonary function in a variety of ways, including causing infiltration of the airways with leukocytes. An imbalance among proteases, their endogenous inhibitors, and local cytokine secretion in the lung leads to airway inflammation and alveolar destruction. Smokers also experience more acute lower respiratory illnesses. Smoking has been implicated in the development of malignant and nonmalignant lung disease, including COPD, bronchitis, influenza, emphysema, pneumonia, and lung cancer. Smokers are also shown to be at increased risk of intraoperative pulmonary complications and a wide range of postoperative complications. For example, a study of postoperative care revealed smoking, being older than 65 years of age, and a history of chronic lung disease increased the risk of unplanned intensive care admittance [116].

Chronic Obstructive Pulmonary Disease

Smoking is the main cause of COPD, which encompasses both chronic bronchitis and emphysema. Between 20% and 30% of smokers (or about 1 in 4) will develop COPD, and risk is determined largely based on genetic susceptibility coupled with age at smoking initiation [117,118]. It is very rare in nonsmokers; at least 80% of deaths from this disease can be attributed to cigarette smoking. The risk of death from COPD rises concurrently with the number of cigarettes smoked. If smokers with COPD quit smoking while they are still young, an improvement in lung function can be expected. However, such improvement is not possible in older people, although after cessation further deterioration will run parallel to that of nonsmokers.

The age at which one begins smoking is important. Wiencke and colleagues discovered that smoking as an adolescent causes permanent genetic changes in the lungs and forever increases the risk of lung cancer, even if the smoker subsequently stops [119]. A Canadian community health survey conducted between 2000 and 2001 found that the risks for heart disease, COPD, and rheumatoid arthritis were far higher among people who began smoking as teenagers than among their nonsmoking peers. For COPD alone, teen smokers were three times more likely to develop the condition later in life than nonsmokers. Similarly, a retrospective cohort study of adult smokers suggests that women are particularly at risk of COPD if they start to smoke before 16 years of age [120].

Influenza

Upper respiratory tract infections are common, and tobacco smoke is a proven risk factor for bacterial infection. The link between influenza and smoking has been demonstrated both for adult smokers and children exposed to smoke-filled environments. According to Arcavi and Benowitz, influenza risk is higher and infections are more severe (e.g., more cough, phlegm production, breathlessness, and wheezing) in smokers versus nonsmokers. Apparently, the antibody response is depressed in cigarette smokers. Nonsmokers should also avoid SHS exposure to decrease the risk of contracting influenza [121]. In a study of Israeli military men, presence and severity of influenza was stronger in smokers than in nonsmokers. Of all smokers, 68.5% contracted influenza compared with 47.2% of nonsmokers, and 50.6% of smokers required bed rest or lost workdays compared with 30.1% of nonsmokers [122]. A 2018 study of patients older than 65 years of age showed that smokers had a higher rate of hospitalization due to influenza (47.4%) compared with nonsmokers (42.1%). In addition, the effectiveness of the influenza vaccine in preventing hospitalization was 21% among current and ex-smokers and 39% in nonsmokers [376].

Pneumonia

Smoking is associated with a significant increase in the relative risk of pneumonia and pneumonia-related hospitalization [123,124]. Pneumonia is not only more common among smokers, it is much more likely to be fatal. Longitudinal studies have identified an increase in the mortality rate from pneumonia in smokers associated with dose-response [125]. In general, cessation of smoking is not associated with a decrease in hospitalization for pneumonia; however, patients without COPD and a greater than 10-year history of not smoking are at a decreased risk [124]. A 2013 study found that children exposed to SHS were four times more likely to develop lower respiratory illnesses, including pneumonia [126]. Proposed explanations of the increased risk for infection in active, passive, and former smokers include increased bacterial adherence, decrease of lung and nasal clearance, and changes in the immune response.

CARDIOVASCULAR COMPLICATIONS

Cardiovascular disease, defined as acute myocardial infarction (MI) and stroke, is strongly related to smoking and comprises 34% of smoking-related mortality; conversely, smoking yields 16% of cardiovascular-related mortality [62]. The relative risk of MI for smokers has been estimated at 2.88 for men and 3.85 for women, and the relative risk of stroke for smokers is estimated at 2.80. These estimates do not include the effects of passive smoking. Low-tar cigarettes and smokeless tobacco have similarly been shown to increase the risk of cardiovascular events among users in comparison to nonsmokers [127]. Cigarette smoking impacts all phases of atherosclerosis, from endothelial dysfunction to acute clinical events. Both active and passive cigarette smoke exposure predispose to cardiovascular events. The exact toxic components of cigarette smoke and the mechanisms involved in smoking that are related to cardiovascular dysfunction are largely unknown, but smoking increases inflammation, thrombosis, and oxidation of low-density lipoprotein cholesterol (LDL-C). Experimental and clinical data support the hypothesis that increased oxidative exposure may be a potential mechanism for initiating cardiovascular dysfunction. Research also suggests that small doses of toxic materials from tobacco smoke cause a nonlinear dose-response effect on cardiovascular function [128]. The risk for cardiovascular disease declines rapidly after smoking is ceased [129].

NEUROLOGIC COMPLICATIONS

Tobacco smoking is strongly related to atherosclerosis and chronic vascular disease. Atherothrombotic ischemic stroke, transient ischemic attack, and atherothrombotic origin symptomatic or asymptomatic peripheral arterial disease are all associated with a high risk of vascular death, MI, and stroke. Exposure to tobacco smoke is a noted risk factor of all these events. A positive association was found between cigarette smoking and subarachnoid hemorrhage (SAH), especially for aneurysmal SAH in women [130].

Evidence is emerging that suggests an association between the development of other neurologic diseases and smoking. A study by Riise et al. identified the risk of multiple sclerosis as higher among smokers than among those who never smoked [131].

Studies have shown that the amount of monoamine oxidase (MAO) is reduced by 30% to 40% in the brains of smokers, compared to nonsmokers or former smokers [132]. This reduction in brain MAO levels may result in an increase in levels of dopamine. It has been suggested that nicotine may have short-term protective actions against mechanisms that cause Alzheimer disease; however, the numerous toxins in cigarette smoke negate any benefit [133]. Though the risk for dementia is slightly higher in smokers, the relative risk for Alzheimer disease is unclear. A 2013 Alzheimer study using a mouse model found that smoking hastens disease onset, exacerbates amyloid pathology, and increases neuroinflammation and tau phosphorylation [133]. Further research is needed in order to better elucidate the risk.

CANCER

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends annual screening for lung cancer with low-dose computed tomography in adults 55 to 80 years of age who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.

http://annals.org/aim/fullarticle/1809422

Last Accessed: May 13, 2019

Level of Evidence: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

In the United States beginning in the early 1950s, a series of epidemiologic, biochemical, pathologic, and animal studies demonstrated a link between cigarette smoking and lung cancer. Tobacco smoking increases the risk of all histologic types of lung cancer. More than 80% to 90% of people who develop lung cancer are current or past smokers. However, not all smokers will develop lung cancer [134]. Cited reasons include the modification of lung cancer risk by previous respiratory disease. In comparison to nonsmokers, smokers are 23 times more likely to develop lung cancer if male and 13 times more likely if female. The risk of lung cancer increases directly with the number of cigarettes smoked and decreases when smoking is ceased. The most important parameter of smoking that affects lung cancer risk is the duration of smoking. Smoking low-tar cigarettes does not substantially reduce the risk of lung cancer [14].

Tobacco smoking is also causally linked to other types of cancer, including oral, oropharyngeal and nasal cavity, urinary tract, larynx, pancreas, esophageal, stomach, liver, cervix, colon, breast, endometrial, prostate, and leukemia. In most cases, the risk increases substantially with duration of smoking and amount of cigarettes/tobacco consumed. Similarly, alcohol in combination with tobacco greatly elevates the risk of many forms of cancer [14].

OSTEOPOROSIS

Smoking can lead to adverse long-term effects on bone health, rendering smokers prone to falls and fractures. Many smokers begin smoking during adolescence—a point in which bone mass is still being constructed; thus, smoking may hinder a person from reaching their maximum bone mass, leaving them fragile and prone to fractures with longer recuperation time [136]. Further, cigarette smoking has been shown to be a key risk factor for osteoporosis and unfortunately, menopausal women are at increased risk due to a loss of estrogen during this period of life. Giampietro and colleagues suggest that a genetic variation in interleukin 6 (IL6) and lipoprotein receptor-related protein 5 (LRP5) observed in smoking white women may confer risk for osteoporosis among smokers [137]. In a study of human-derived osteoblast-like cells and trabecular bone organ culture, Walker et al. demonstrated the presence of the α4 neuronal nicotinic acetylcholine receptor (nAChR) and found that nicotine modulates proliferation in a dose-dependent manner, upregulates c-fos transcription factor, and affects synthesis of osteopontin, a bone matrix protein [138].

PROBLEMS WITH CONCEPTION AND EMBRYONIC HEALTH

Women who smoke prior to pregnancy are more likely to experience a delay in conception and have about 30% higher odds of infertility [139]. Further, men who smoke are at increased risk of erectile dysfunction due to decreased bioavailability of nitric oxide and damage to peripheral nerves, the vascular epithelium, and structure of corporal tissue. Smoking may also affect the quality and mobility of spermatozoa [140,141]. Ramlau-Hansen et al. report a dose-dependent relationship between smoking and sperm concentration, testosterone, luteinizing hormone (LH), and the LH/free testosterone ratio [142].

Success of assisted reproduction therapy (ART) is reduced among smoking couples. In a meta-analysis, Waylen and colleagues found that smokers undergoing ART (e.g., in-vitro fertilization, intracytoplasmic sperm injection, gamete intrafallopian transfer, zygote intrafallopian transfer) had lower odds of live birth per cycle (i.e., birth of one or more infants that show signs of life). They also observed lower odds of clinical pregnancy per cycle (i.e., a sonographically visible gestational sac in the uterus) and higher odds of spontaneous miscarriage and ectopic pregnancy when compared to nonsmokers undergoing the same treatments [143]. A retrospective study published in 2018 found that smoking has a negative effect on endometrial thickness on the day of the embryo transfer, resulting in lower rates of implantation and pregnancy [466].

If conception is achieved (with or without ART), maternal smoking during pregnancy increases the risk for adverse conditions including low birth weight, spontaneous abortion, placenta previa, abruptio placentae, preterm premature rupture of the membrane (PPROM), and overall poor outcomes [144,145].

The miscarriage rate among mothers who smoke may be as high as 33% [146,147]. This may be due to an increased syncytial necrosis and increased thickness of syncytio/cytotrophoblast membrane, as smoking appears to induce dysfunction of villous and invasive trophoblasts early in pregnancy. Additionally, maternal levels of estriol, estradiol, human chorionic gonadotropin, and human placental lactogen are lower in smokers than in nonsmokers [148]. All of these are markers of prenatal health and well-being.

12. COMORBID CONDITIONS

ALCOHOL ABUSE

There is a strong comorbidity between alcohol consumption and tobacco use. Drinkers are more likely to smoke than nondrinkers, and smokers are more likely to drink than nonsmokers [149]. In fact, smokers are 30% more likely to consume alcohol and 10 times more likely to develop alcoholism than nonsmokers. Between 80% and 95% of all alcoholics also smoke cigarettes, and 70% are heavy smokers who consume more than one pack per day [150]. A study examining an association between alcohol and tobacco, using a combination of short-term (1-year) and long-term (15-year) follow-up intervals, found that past-year alcohol and tobacco use disorders were associated not only cross-sectionally, but also prospectively. These associations were present even after controlling for age, gender, and race. Year 1 tobacco dependence prospectively predicted diagnosis with an alcohol use disorder (AUD) at year 2, and a baseline diagnosis of AUD increased the likelihood of diagnosis with tobacco dependence 15 years later. Having been diagnosed with tobacco dependence at year 1 predicted AUD persistence, and vice versa. These findings demonstrate the complex association between tobacco dependence and AUDs [151]. Similarly, a study examining the natural course of AUDs from adolescence to early adulthood found that daily smoking predicted future AUD when adolescent AUD and other disorders were controlled. It is possible that chronic smoking may contribute to alcohol tolerance, increasing alcohol consumption and metabolism [152].

In the instance of nonsmokers, data from a study by Romberger and Grant suggests that patterns of alcohol abuse would be similar in workers exposed to SHS; however, the severity of the alcohol abuse may be less pronounced [153].

DRUG ABUSE

Smoking usually precedes illicit drug use. Among those who used both cigarettes and marijuana by the 12th grade, 65% smoked cigarettes before marijuana, and 98% of those who used both cigarettes and cocaine smoked cigarettes first. Apparently, the earlier a person uses tobacco, the more likely he or she will be to experiment with cocaine, heroin, and other drugs. More than half of those who start smoking before 15 years of age use an illegal drug in their lifetime, compared to only a quarter of those who do not start smoking until 17 years of age or later. Moreover, those who start smoking before 15 years of age are seven times more likely to use cocaine than those who never smoke. Also, heavy smokers are more likely to use marijuana or harder drugs. For example, young people who smoke more than 15 cigarettes a day are twice as likely to use an illicit drug and 16 times more likely to use cocaine than those who smoke less frequently. They are also 10 times more likely to use an illicit drug and 100 times more likely to use cocaine than those who never smoked. Even heavy users of smokeless tobacco are more likely to experiment with drugs. High school students who used smokeless tobacco 20 to 30 days per month were four times more likely to concomitantly use marijuana than nonusers, and almost three times more likely to ever use cocaine [150].

PSYCHIATRIC DISORDERS

Many smokers report a link between smoking and anxiety. Researchers at the National Institute on Drug Abuse hypothesized that impaired respiration and the detrimental effects of nicotine on blood vessels to the brain elucidate why those exposed to smoking are at an increased risk of developing anxiety disorders [154,467].

Smoking is shown to be highly comorbid with such psychiatric disorders as major depression, panic disorder, and schizophrenia. Cigarette smoke has other psychoactive properties apart from nicotinic receptor stimulation. For example, it inhibits MAO, which is the enzyme responsible for breaking down the biogenic amine neurotransmitters norepinephrine, serotonin, and dopamine in the brain [155,156]. Not surprisingly, the association between smoking and major depression is well established [157,158,159]. Reports of severe major depressive episodes after smoking cessation are also common, with the onset of depressive symptoms ranging from two days to six weeks after the initial abstinence from smoking [160,161]. In some cases, depression was alleviated with the use of NRT or antidepressants; in others, depressive symptoms went away after a relapse to smoking [160,162]. In a trial of smoking cessation using fluoxetine (30 mg), 7% of participants with a previous history of major depressive disorder (MDD) were diagnosed with major depressive episodes after a 10-week treatment, suggesting that a subset of smokers may be particularly at risk for developing MDD after smoking cessation [163].

In addition to relieving depressive symptoms or major depressive episodes associated with nicotine withdrawal, antidepressants may aid in long-term smoking cessation by substituting for the antidepressant effects of nicotine that help maintain smoking. They may also have a specific effect on neural pathways (e.g., MAO inhibition) or receptors (e.g., nicotinic-cholinergic receptor blockade) that underlie nicotine addiction. A 2013 Cochrane review assessed the efficacy of antidepressant medications to aid long-term smoking cessation. The majority (75) of the 90 randomized trials included in the review were of bupropion and nortriptyline. The reviewers found high-quality evidence that bupropion significantly increased long-term smoking cessation when used as the sole pharmacotherapy, and moderate-quality evidence (limited by the small number of trials and participants) that nortriptyline also significantly increased long-term cessation. The drugs' effectiveness for long-term smoking cessation was independent of their antidepressant effects, with efficacy similar to NRT [156].

Smoking could also be a risk factor for panic disorder [164,467]. A disproportionate number of persons with panic disorder smoke cigarettes compared to the general population [165]. Mild-to-moderate nicotine dependence was associated with an 11% lifetime prevalence of panic disorder, a rate approximately 2.5 times greater than in persons with no nicotine dependence. Pohl et al. found that female patients with panic disorder had significantly higher smoking prevalence at the onset of their illness than did control subjects (54% versus 35%) and that smoking prevalence for the female patients was also significantly higher than for the control subjects (40% versus 25%) [166]. Male smoking rates did not differ between patients and control subjects.

Although the cause of this comorbidity remains controversial, several explanations have been offered: smoking promotes panic by inducing respiratory abnormalities/lung disease; nicotine produces the physiologic effects characteristic of panic by releasing norepinephrine; cigarette smoking is a form of self-medication for panic disorder; and/or a shared vulnerability promotes both conditions [167]. One study examined the effect of smoking cessation on the reduction of panic symptoms by monitoring the post-cessation abstinence status of 185 smokers. Abstinence was biochemically verified at weeks 1 and 2 and month 1. The severity of panic-relevant symptoms was self-reported by the participants at month 1 and month 3, post-cessation. The 80 participants (43.2%) who remained abstinent for one month, relative to the 105 (56.8%) who did not, demonstrated significant reductions in self-reported panic symptoms [168].

Smoking is also more prevalent in persons with schizophrenia, although reasons for its pervasiveness remain debatable [169,170,171]. Investigators have suggested that nicotine might temper positive or negative symptoms, and cigarette smoking is used as self-medication (e.g., to treat cognitive impairment and anhedonia) [171,172,173,174]. Nicotine may also attenuate the adverse effects of neuroleptics, perhaps by reducing elevated blood levels after use of antipsychotic medications [128,175,176]. Weiser et al. examined the prevalence of cigarette smoking in apparently healthy adolescents later hospitalized for schizophrenia. The number of cigarettes smoked was significantly associated with the risk for schizophrenia. Compared to nonsmokers, adolescents who smoked 1 to 9 cigarettes per day were 1.38 times as likely to be hospitalized later for schizophrenia, and adolescents who smoked 10 cigarettes per day or more were 2.28 times as likely; the latter difference was statistically significant. The authors concluded that the higher prevalence of smoking in future schizophrenia patients might indicate that impaired nicotinic neurotransmission is involved in the pathophysiology of schizophrenia [177]. Bupropion has been found to increase smoking abstinence rates in smokers with schizophrenia [178]. Additionally, a number of medications that target nicotinic acetylcholine receptors have been tested or are in development, but further research is necessary to determine their clinical utility in the treatment of schizophrenia [174].

13. FETAL EXPOSURE

Maternal cigarette smoking before and during pregnancy adversely affects the health of both mother and fetus. However, analysis of data from the 2016 National Vital Statistics Systems (NVSS) indicated that 7.2% of pregnant women in the United States reported smoking during pregnancy [179]. In addition to the effects on fertility and embryonic health discussed, maternal smoking before conception increases the risk of sudden infant death syndrome (SIDS), and smoking at the time of conception increases the risk of infants being born with cleft lip, with or without cleft palate [14,179,180]. A 2010 study showed that as many as 8% of preterm deliveries, 7% of preterm-related deaths, 19% of term low-birth-weight deliveries, and 34% of SIDS cases in the United States were attributable to prenatal smoking [181]. Further, several studies indicate that the offspring of mothers who smoked during pregnancy are at elevated risk of developing nicotine dependence as adults [182,183].

According to 2016 NVSS data, the prevalence of smoking during pregnancy was highest among women who were between 20 and 24 years of age (10.7%), followed by women 15 to 19 years of age (8.5%) and 25 to 29 years of age (8.2%). Among racial groups, the highest rates were found in non-Hispanic American Indian/Alaska Native women (16.7%%), followed by white (10.5%), black (6.0%), Native Hawaiian/Pacific Islander (4.5%), Hispanic (1.8%), and Asian (0.6%) women. Smoking rates were highest among those with a high school diploma or equivalent (12.2%), followed by those with less than 12 years of school completed (11.7%), and women with some college or an associate's degree (7.9%). Less than 1% of women with a bachelor's degree or higher reported smoking during pregnancy [179]. Rates of maternal smoking during pregnancy differ greatly between individual states, with West Virginia (25.1%) and Kentucky (18.4%) reporting the highest percentages, and the District of Columbia (2.6%) and California (1.6%) reporting the lowest. SHS exposure in infancy greatly increases the odds of respiratory tract infections, ear infections, and death from SIDS [14].

Ohida and colleagues performed cross-sectional surveys in Japanese obstetric clinics to investigate the effects of passive smoking on sleep disturbance during pregnancy [185]. Pregnant women exposed to passive smoking were likely to have insufficient sleep, difficulty initiating sleep, short sleep duration, loud snoring, or uncomfortable breathing. These experiences also occurred in pregnant women who were smokers.

Nicotine has a low molecular weight and high lipid solubility, allowing it to cross the placenta freely and accumulate in amniotic fluid. In animal models, nicotine could be identified in fetal tissues as early as five minutes following maternal injection [186,187]. Because less than 5% of nicotine binds to human plasma proteins, the majority of the administered dose is available to equilibrate with fetal circulation [188]. Studies in humans showed that nicotine is readily transferred to the fetal compartment throughout pregnancy, with accumulation in placental tissue and amniotic fluid [189]. Apparently, a significant amount of nicotine is retained by the placenta and may later transfer to fetal and maternal circulation, thus prolonging the effect of nicotine on the fetus [188].

Acetylcholine causes dilation of blood vessels and maintains placental blood flow by the activation of endothelial muscarinic receptors. Nicotine blocks acetylcholine-facilitated amino-acid transport, depressing diffusion of amino acids and other nutrients from the trophoblast into placental circulation. Maternal smoking actually leads to trophoblast apoptosis and thickening of the trophoblast basement membrane [190,191]. Further, CO from tobacco smoke crosses the placenta by passive diffusion, leading to increased carboxyhemoglobin in umbilical cord blood and placental hypoxia. The resultant hypoxia causes fetal growth retardation and alteration in the physiologic development of organs and tissues [192].

PHARMACOKINETICS AND DYNAMICS

Among pregnant smokers, maternal levels of cotinine correlate better with outcome measures such as birth weight than the number of cigarettes smoked per day [193]. Cotinine can accumulate in fetal compartments as early as 7 weeks' gestation in both active and passive smokers [194]. Of note, the half-life of nicotine is three to four times longer in newborns than in adults, whereas the half-life of cotinine is similar in newborns and adults. The prolonged elimination of nicotine, but not of cotinine, in the newborn compared with that in the adult may be a result of different newborn cytochrome P450 2A6 (CYP2A6) enzymatic substrate specificity, low CYP2A6 activity with another enzyme that is primarily responsible for cotinine metabolism, or differences in tissue distribution [195]. Also, pregnancy is well known for affecting metabolism of some drugs and may contribute to higher or lower clearances compared with the nonpregnant state [196]. Indeed, metabolic clearance of both nicotine and cotinine are substantially increased during pregnancy, resulting in a marked decrease in the half-life of cotinine. The mechanism for such increase in metabolic clearance is not known. It is possible that nicotine and cotinine clearances are accelerated by faster oxidation via CYP2A6 and faster glucuronide formation. Although nicotine and cotinine share the same metabolizing enzymes, their increased clearances may occur by different physiologic mechanisms. Nicotine is a rapidly cleared drug with a high affinity for CYP2A6, and the rate of clearance is primarily controlled by liver blood flow. Cotinine is a slowly metabolized chemical, with a low affinity for CYP2A6 relative to nicotine. The level of CYP2A6 in the liver, which is markedly elevated during pregnancy, primarily determines the rate of cotinine metabolism. A substantial increase in the percentage of nicotine and cotinine excreted as their glucuronide conjugates is also observed in pregnancy, but there is no increase in the percentage of 3'-hydroxycotinine excreted as a glucuronide. This suggests an acceleration of nicotine and cotinine metabolism via the N-glucuronidation pathway, but no effect on hydroxycotinine metabolism by the O-glucuronidation pathway. Also, the profile of nicotine and its metabolites in urine is altered during pregnancy. The excretion of nicotine is substantially decreased, and despite large differences in plasma cotinine concentration during smoking, there is no difference between the daily dose of nicotine absorbed from cigarette smoking during and after pregnancy [197].

NEUROLOGIC COMPLICATIONS

Fetal nicotine exposure can result in permanent abnormalities of the dopaminergic regulation of the brain [198]. These effects can occur even at low nicotine doses and lead to a greater nicotine dependence [182]. Unlike in mature organisms, where stimulation of a target cell elicits only a short-term response, receptor stimulation in the developing systems interacts with the genes controlling cell differentiation, permanently altering the cells' responsiveness. Nicotine exposure to the prenatal brain may also prematurely stimulate the shift from proliferation to differentiation; thus, nicotine may act as a cholinergic signal, mimicking trophic effects of acetylcholine. Because of the close regulatory association of cholinergic and catecholaminergic systems, adverse effects of nicotine involve multiple transmitter pathways and influence not only the immediate developmental events in the fetal brain but also the eventual programming of synaptic competence. Therefore, defects may appear after a prolonged period of apparent normality, leading to cognitive and learning defects that appear in childhood or adolescence. Similar modifications occur in peripheral autonomic pathways, leading to increased susceptibility to hypoxia-induced brain damage and perinatal mortality [199]. These changes are especially prominent in tissues rich in nicotinic cholinergic receptors, such as the brainstem [200].

Prenatal exposure to nicotine produces alterations in tegmental nuclei related to the following [201]:

- Cardiopulmonary integration (nucleus tractus solitarii, parabrachial complex)

- Regulation of arousal, attention, and rapid eye movement (REM) sleep (mesencephalic and pontine reticular formation)

- Somatic motor control (paramedian pontine and medullary reticular formation)

- Tongue and upper airway regulation (hypoglossal nucleus)

Autonomic deregulation could explain the inhibition of some homeostatic reflexes seen in infants exposed to tobacco smoke, including a deficiency in arousal responsiveness to hypoxia or hypercapnia [202]. Roy et al. evaluated cellular morphology and regional architecture in the juvenile and adolescent hippocampus and the somatosensory cortex in rats prenatally exposed to nicotine. They found a substantial decrease in cell size in the hippocampal CA3 region and dentate gyrus, with corresponding decrements in cell layer thickness and increments in cell packing density. Smaller, transient changes were seen in CA1. There was a reduction in the proportion of medium-sized pyramidal neurons in layer five of the somatosensory cortex and an increase in the proportion of smaller, nonpyramidal cells. All regions showed elevated numbers of glia. These data demonstrate that prenatal nicotine exposure compromises neuronal maturation, leading to long-lasting alterations in the structure of key brain regions involved in cognition, learning, and memory [203].

PULMONARY COMPLICATIONS

Fetal growth and duration of gestation are the major factors affecting lung development [204]. Intrauterine influences that retard fetal weight gain may irrecoverably restrict the growth of the airways, with consequences persisting throughout the individual's life span. Fetal exposure to nicotine is associated with several abnormalities in lung growth. In animal studies, nicotine has been shown to directly interact with nicotinic acetylcholine receptors in pulmonary vessels, altering connective tissue expression and producing vascular structural alterations [205]. Furthermore, maternal nicotine exposure results in larger alveolar volumes and suppresses alveolarization in the lungs of the offspring of rats, reducing the surface potentially available for gas exchange [206,207]. Human smokers have a high rate of poor perfusion patterns, suggesting that smoking during pregnancy may compromise uteroplacental blood flow and contribute to poor fetal development [208,209].

CARDIOVASCULAR COMPLICATIONS

Maternal smoking during pregnancy poses severe risks to the developing fetal heart. Nicotine alters cardiac cell differentiation to increase the cellular injury caused by hypoxia [210]. Prenatal nicotine exposure interferes with the ability of neonatal adrenal glands to secrete catecholamines in response to hypoxia [200]. Given that the neonatal heart lacks functional sympathetic innervation, there is virtually a complete dependence on circulating catecholamines secreted by the adrenal medulla to maintain heart rate response to hypoxia. Nicotine exposure reduces the number of cardiac ß-adrenergic receptors, magnifying functional consequences of impaired catecholamine release [211]. The resultant impaired cardiac function can lead to cardiovascular collapse, subsequent brain damage, and/or death during delivery [212,213].

Adenosine diphosphate (ADP) is a major factor in determining electrical stability of myocytes, because the longer the action potential, the higher the likelihood of abnormal cardiac activity [214]. It is possible that a component in smoke temporarily disables electrical properties of ventricular myocytes, rendering the ventricular muscle more susceptible to developing arrhythmias [215].

Fetuses exposed to smoke also manifest an increase in cardiac volume growth between 23 and 27 weeks' gestation [216,217]. This could be attributed to either an exaggeration of normal cardiac growth patterns or a compensatory response to an increase in upper body growth at the time.

LOW BIRTH WEIGHT AND SMALL FOR GESTATIONAL AGE

Infants born to mothers who smoke weigh less than other infants (independent of maternal body mass index), and low birth weight (<2,500 grams) is a key predictor for infant mortality. Effects of maternal smoking during pregnancy on infant birth weight have been recognized since 1957; nevertheless, smoking remains the most hazardous factor affecting a newborn's weight, even at present [218,219,220]. Similar to earlier studies, Bernstein and colleagues report that maternal third-trimester cigarette smoking is one of the strongest predictors of low birth weight. This study is thought to be the first to accurately assess maternal smoking levels, and startlingly, they purport that there is an estimated 27 g reduction in birth weight per cigarette consumed each day during the third trimester, or roughly twice the amount previously shown [220]. Another study found that 11.5% of infants born to women smoking less than six cigarettes daily had low birth weight [221]. Taken together, these studies demonstrate that there is not a safe level of smoking during pregnancy [221,222]. Additionally, Aagaard-Tillery et al. reported that tobacco-exposed infants were small for gestational age regardless of maternal body mass index or pregnancies complicated by diabetes or hypertension [223].

A study examining the effect of prenatal smoke on a fetus in midgestation identified greater early gestational upper-body growth with preferential growth of head dimensions, upper limb length, and abdominal circumference with smoke exposure. This was followed by decreases in biparietal dimensions of the head, abdominal diameter, and distal limb length. Data from the late gestation period revealed cranial dolichocephaly, proportionally longer upper limbs, and legs with relatively reduced tibias, indicating that smoke exposure altered the growth rate of individual body segments [216]. It is possible that during hypoxia, blood supply to the lower limbs and internal organs is reduced in order to preserve brain metabolism [224]. Retardation of limb growth by 32 weeks could be due to diminished oxygen availability for distribution to distal tissues. The tibia, being one of the last consumers in the fetal nutrient distribution food chain, is therefore regarded as a good marker of available oxygen resources [216].

MIDDLE EAR DISEASE

Passive smoke exposure is independently associated with an increased risk of otitis media [222,225,226]. Though the immediate complications of otitis media are significant, one must also consider the lasting complications including an increased prevalence of speech and language difficulties, attention disorders, and learning difficulty [226]. The mechanism by which cigarette smoke causes otitis media is currently unknown. Histologic changes in fetal alveolar and bronchial epithelium lend support to a contemporary theory that purports that fetal cigarette smoke exposure may interfere with the development of the middle ear and eustachian tube epithelium. An alternative theory proposes that passive smoke-related immune system depression allows for opportunistic middle ear infections [226].

CANCER

One of the potentially negative effects of smoking during pregnancy is exposure of the fetus to carcinogens [227,228]. The potent tobacco-related carcinogen 4-aminobiphenyl has been shown to cross the human placenta and bind to fetal hemoglobin [229]. Two metabolites of the tobacco-specific transplacental carcinogen NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronide (NNAL-Gluc), were detected in the urine from newborns of mothers who smoked cigarettes during pregnancy [144]. Studies relating childhood and in utero cigarette exposure to brain tumors and leukemia have been inconsistent in their findings [230]. A meta-analysis of the association between exposure to maternal tobacco smoke during pregnancy and cancer in childhood found a small increase in risk of all neoplasms (based on 12 studies) but not of specific neoplasms such as leukemia (based on 8 studies) and CNS tumors (based on 12 studies) [231].

OSTEOPOROSIS

Maternal smoking has been shown to modulate bone mineral acquisition for the fetus, which may lead to increased risk of osteoporosis later in life [232].

PSYCHIATRIC DISORDERS

Previous studies have reported an association between maternal smoking during pregnancy and behavioral problems such as hyperactivity and decreased attention span. The association with behavioral problems has been shown in investigations of hyperactive children and controls, sibling studies in which the mother smoked in one pregnancy but not in the other, and in neuropsychologic evaluations of children of smokers and nonsmokers using tests of sustained vigilance and attention [233,234,235,236]. Naeye and Peters found that hemoglobin levels in neonates increased with the number of cigarettes smoked by the mother during pregnancy and that children who were more active or had shorter attention spans had significantly higher hemoglobin levels [235]. Further, early secondhand exposure to nicotine as a child via maternal smoking during pregnancy shows an association with offspring attention deficit hyperactivity disorder (ADHD) symptoms [237,238]. Evidence also supports a statistical association between prenatal smoking and increased risk for antisocial outcomes in offspring. Maternal smoking during pregnancy has been shown to be associated with a significant increase in externalizing behavior (tendency to seek controversy, aggressive, hyperactive) but not internalizing behavior (withdrawn, depressed, anxious) problems [239]. Similarly, maternal smoking during pregnancy has been shown to have an adverse effect on the child's negativity [240]. In a sample of 99 children 2 years of age, maternal smoking was identified as a significant predictor of childhood negativity, independent of demographic factors, perinatal factors, maternal personality attributes, and the mother-child relationship. Behavior problems associated with in utero exposure to SHS seem to continue into childhood and young adolescence, demonstrated by increased risk for ADHD, conduct disorders, criminality, and substance abuse [241]. An 18-year epidemiologic study of 1,265 New Zealand children identified that maternal smoking during pregnancy contributed to risk of higher psychiatric symptom rates for conduct disorder(s), alcohol abuse, substance abuse, and depression [242,243].

14. PASSIVE SMOKING EFFECTS ON CHILDREN

It is possible that SHS exposure during childhood may be potentially more hazardous to neurodevelopment than in utero exposure to maternal smoking. Young children have higher ventilation rates, meaning they receive higher levels of SHS for the same duration and level of external exposure [244]. Passive smoking is believed to increase the prevalence of sudden infant death syndrome (SIDS); exacerbate asthma symptoms; interfere with cognition and behavior; increase cancer risk; and cause respiratory tract illness [226,245,246]. Breastfed infants with a smoking or snuff-taking mother are exposed to nicotine in breast milk, with a mean intake of nicotine of 7 mcg/kg per day [247]. Older children experience decreased physical fitness and are susceptible to tobacco-related illnesses just as adult smokers are.

Evidence Based Practice Recommendation

The National Heart, Lung, and Blood Institute recommends promoting a smoke-free home environment for all children and reinforcing this message at every encounter, including urgent visits for respiratory problems.

https://www.nhlbi.nih.gov/node/80308

Last Accessed: May 13, 2019

Level of Evidence: A (Well-designed randomized controlled trials or diagnostic studies performed on a population similar to the Guidelines' target population)

Aside from adverse health effects due to SHS exposure, parental smoking is also positively correlated to their offspring's smoking as adolescents and adults. Counseling parents on the adverse health effects of SHS on children has been shown to dramatically reduce their children's subsequent cigarette smoke exposure [6,246]. Smokers should be encouraged to smoke outside their homes and minimize SHS exposure to their children [248]. However, studies have shown that, though smoking outdoors decreases SHS exposure, children of parents who smoke outdoors still have higher prevalence of ear infections and respiratory symptoms than children of nonsmokers [249].

NEUROLOGIC EFFECTS

Prenatal and perinatal exposure to SHS adversely affects neurobehavioral development. Evidence now supports the notion that tobacco-exposed infants are more excitable and hypertonic, require more handling, and show more stress and abstinence signs than infants not exposed to tobacco. Symptoms are particularly noteworthy in the CNS, gastrointestinal system, and visual areas [250]. The presumed neurobiologic effect of SHS is altered brain development resulting from fetal hypoxia, due to either nicotine acting to reduce blood flow to the fetus, or possibly CO, which produces higher levels of carboxyhemoglobin. Nicotine may also target specific neurotransmitter receptors in the fetal brain to discoordinate the events of cell replication, differentiation, and synaptic development in the brain. Nicotine is thought to disrupt brain development via cholinergic mechanisms. In rats, exposure to nicotine alone has been shown to result in a significant increase in acetylcholinesterase (AChE) activity in the brainstem and midbrain. A significant increase in ligand binding to nAChR has been observed in the brainstem and cortex following exposure to nicotine. This suggests that exposure to nicotine may impair neurobehavioral performance and affect the cholinergic pathways [251].

In another study, postnatal SHS reduced hindbrain (comprising the pons and medulla oblongata) DNA concentration, increased the protein-to-DNA ratio, and reduced the body weight of exposed rats. These data suggest that postnatal exposure to SHS affects the hindbrain, a region that undergoes significant postnatal growth, by reducing the total number of cells and by increasing cell size. The authors concluded that, despite preserved hindbrain weight, the effects of postnatal exposure to SHS might result in neurologic dysfunction [252]. This study provided clear biologic evidence for an alteration of brain development due to postnatal, but not prenatal, SHS exposure. Interestingly, although gross dysmorphology is demonstrable in the animal brain by SHS exposure to nicotine, brain structures are not grossly abnormal when examined later in adolescence or adulthood [203]. However, longer-lasting changes in morphology are noted in the hippocampus and somatosensory cortex in the form of decreased cell size and elevated numbers of glia. In considering synaptic function, several neurochemical studies have identified multiple biochemical markers of cell injury that indicate prenatal nicotine exposure damages the developing brain [253,254].

CARDIAC COMPLICATIONS

Nicotine exposure causes myocyte cell damage in newborns, reduced platelet activation, increased resting sympathetic nerve activity, and hypertension. In rats, exposure to SHS during the neonatal period resulted in abnormal vasoconstrictor and vasodilator responses and smooth muscle dysfunction [255]. Abnormalities of endothelial cell function were found in rabbits exposed to SHS for 3 to 10 weeks [256]. Exposure to SHS also appears to directly affect endothelial function in children by means of a dose-dependent decrease in the bioavailability of nitric oxide [257]. Exposure to SHS also caused left ventricular hypertrophy in rabbits [258]. SHS exposure in childhood reduces high-density lipoprotein levels [259]. In addition, adolescents exposed to their parents' smoke show depressed levels of high-density lipoprotein cholesterol (HDL-C), suggesting that SHS exposure may accelerate atherosclerotic change and place children at increased risk for the premature development of coronary artery disease [260,261].

SIDS

SIDS occurs within the first year of life and is a significant cause of infant mortality, with an estimated 1,400 deaths in the United States annually [262]. SIDS is a diagnosis of exclusion, and etiology is presently unclear. Various risk factors have been suggested including prone sleeping position, sex, age, birth weight, parental cigarette smoking, maternal substance abuse, bed sharing, soft bedding, and overheating [262,263]. Matturi et al. found evidence supporting an association between maternal smoking and SIDS. Specifically, CO from cigarette smoke forms carboxyhemoglobin, leading to brain hypoxia. This lack of oxygen inhibits normal brain development of the arcuate nucleus and normal brain function in the locus coeruleus and arcuate nucleus. These abnormalities could potentially affect control of the respiratory and cardiovascular systems, resulting in sudden unexplained infant death. Matturi et al. concluded that the most preventable risk factor for SIDS is maternal smoking during pregnancy [264]. Zhang et al. concluded that the association between maternal smoking and elevated SIDS risk is dose-dependent and significantly increased in infants who co-sleep with smoking mothers [265]. Another study that sampled pericardial fluid in SIDS cases found that 70% had elevated levels of cotinine [266].

PULMONARY COMPLICATIONS

Children with smoking parents demonstrate higher frequencies of common respiratory symptoms including cough, phlegm, asthma, breathlessness, and wheeze. Parental smoking inhibits lung growth and function during childhood [267,268,269,270]. One study assessed the pulmonary function of 80 healthy infants soon after birth and found significantly reduced pulmonary function in infants whose mothers had higher urine cotinine concentrations [271]. Another study demonstrated an association between in utero nicotine exposure and variable DNA methylation in fetal lung and placental tissues, suggesting that this variation may have a role in the fetal origins of chronic diseases [272].

Cough/Wheeze

Both past and current SHS exposure has been shown by multiple studies to cause cough and wheeze in children. Joad et al. worked with guinea pigs to establish the mechanism by which air pollutants, particularly SHS, causes cough. Secondhand smoke modifies afferent sensory fibers (specifically C-fibers and rapidly activating receptors) in the lungs and airways, thereby activating a neurally controlled cough mechanism. The vagus nerve receives input from the afferent sensory fibers, which is modified by interneurons in the nucleus tractus solitarius (NTS). A few additional modifications of the efferent activity occur in the brain stem. Cough occurs when the efferent signal modifies input to the respiratory muscles involved in inspiration and expiration. Wheeze occurs with bronchoconstriction and mucus secretion, which can be caused by locally released neurokinins or parasympathetic fibers synapsing on airway ganglia [64].

Asthma

Asthma is a chronic inflammatory disease, often with an initial onset in childhood. An association has been established between exposure to passive tobacco smoke and pediatric asthma development, while a causal relationship has been shown between exacerbated pediatric asthma and environmental tobacco exposure [273,274]. Cigarette smoke causes an "exaggerated bronchoconstrictor response" in asthmatics, leading to an increase in severity and frequency of acute asthma attacks as well as asthma-related hospitalizations [275]. Studies have shown a decreased respiratory drive and hypoxic ventilatory response in infants of smoking mothers [247]. Exposure to nicotine for the full gestation produced an increased risk of depressed hypoxic ventilatory response in rats [18]. Parents of asthmatic children should be strongly cautioned that smoke exposure is likely to dramatically worsen their child's asthma [276,277].

DENTAL CARIES

Each year, several billion dollars are spent treating pediatric dental caries in the United States. Dental caries are an oral infectious disease caused by Streptococcus mutans colonization and subsequent lactic acid production leading to dental decay. In addition to poverty, passive smoking is a substantial risk factor for developing dental caries. The reason for an increased prevalence of dental caries in children of low socioeconomic status is unclear. However, as poor children are more likely to be exposed to SHS, it has been suggested that environmental tobacco smoke exposure may help explain the increased dental decay in this particular population. Environmental tobacco smoke is considered a causal factor for dental caries in primary but not in permanent teeth. Mechanisms for the role of cigarette smoke in the development of pediatric dental decay include nicotine promotion of bacterial growth; immunosuppression from environmental tobacco smoke; decreased levels of vitamin C leading to increased bacterial growth; passive smoking-related saliva reduction, which impairs the natural defense against bacteria-related acid production; and a general increase in inflammation [278].

VITAMIN DEFICIENCY

Vitamin C (ascorbic acid) deficiency is common among active smokers due to both increased metabolism and decreased dietary consumption [68]. Cigarette smoking-induced oxidant damage is caused by both the immune system's inflammatory response and free radicals in cigarette smoke. Vitamin C and other antioxidants play an important role in preventing oxidant-induced damage.

Studies have supported a dose-dependent inverse relationship between environmental tobacco smoke exposure and ascorbic acid and beta carotene concentrations [68,279]. A 2011 study found that children with no SHS exposure had higher levels of vitamin A, C, and E, beta carotene, and folate (controlling for dietary and supplement intake) than children with either moderate or high SHS exposure [279]. A lower concentration of these key nutrients was associated with higher cotinine levels. Vitamin B6, B12, and D levels were not found to be significantly affected.

RESULTANT SYMPTOMS IN ADULTHOOD

The relationship between childhood passive smoke exposure and resultant health consequences in childhood has been firmly established. There is less known about the long-term respiratory effects of childhood passive smoke exposure. David et al. studied Chinese adults from the Singapore Chinese Health study who were exposed to cigarette smoke as children but never actively smoked, thereby eliminating active smoking as confounding bias often found in similar studies. They found an association, independent of adult SHS exposure, between childhood environmental tobacco smoke exposure and chronic dry cough and phlegm production. Other findings included a lack of an association between childhood SHS exposure and asthma or chronic bronchitis. Also, they found low-fiber predisposed patients to respiratory maladies [280]. One study found a 50% increase in adult-onset cancer for children whose fathers smoked, and the risk of hematopoietic cancer increased when both parents smoked [281].

Peppone et al. reported that never-smoking women who grew up with a smoking parent may have more difficulty becoming pregnant. Those exposed to SHS regularly in childhood and adulthood were 39% more likely to have suffered a miscarriage or stillbirth and 68% more likely to have trouble conceiving when trying for more than one year [282]. Further, among women exposed to environmental tobacco smoke in youth undergoing ART between 1994 and 1998, there was decrease in implantation rate and increased odds of spontaneous abortion [65].

In a study by Strohsnitter et al., early menopause was more likely to occur in never-smoking women exposed to maternal cigarette smoke. They attribute this association to smoke's effects on follicle production in utero [283].

15. PASSIVE SMOKING EFFECTS ON ADULTS

The International Agency for Research on Cancer (IARC) Working Group concluded that secondhand tobacco smoke is carcinogenic to humans [284]. Complications of exposure to SHS include adverse effects on the pulmonary, cardiovascular, and neurologic systems as well as increased risk for cancer and fibroblast changes.

OCCUPATIONAL EXPOSURE

Occupational exposure to SHS affects the health of countless employees worldwide. Workplace exposure is highly influenced by the type of smoking policy in the workplace. Airborne nicotine is present, often in excessive concentrations, in various job settings due to variable public smoking laws [285,286]. Local and state regulation of smoking in public places was instituted in response to data published by the American Society of Heating, Refrigerating and Air Conditioning Engineers (ASHRAE). These standards assert that satisfactory indoor air quality cannot be maintained if smoking is allowed indoors, even with additional ventilation and air-cleaning devices [287]. Several studies have shown that smoke-free workplace policies decrease exposure of nonsmoking employees to SHS at work, while increasing rates of smoking cessation and decreasing the number of employees who smoke [14,288,289,290,291]. Policies that are less restrictive are associated with higher levels of sustained tobacco use among employees [290]. Policies that make indoor workplaces smoke-free result in improved worker health [290,292]. For example, smoke-free polices in the hospitality industry have been shown to improve health among bar workers, who are often heavily exposed to SHS in the absence of such policies [184,290,293].

Studies have shown that segregating smokers and nonsmokers within the same airspace reduces SHS exposure to nonsmokers but does not eradicate it. One such study, in smoking-segregated restaurants in Albuquerque, New Mexico, showed levels of nicotine in nonsmoking sections approximately equal to those found in smoking sections [294].

SHS remains an issue for those employed in some casinos, bowling alleys, restaurants, lounges, and bars [295]. These work environments can contain high concentrations of airborne nicotine in the air if there is a lenient smoking policy. One study found that male blue-collar workers are exposed to significantly more SHS than their counterparts in management/professional occupations [296]. Also, on average, blue-collar smokers smoke more heavily than white-collar smokers [296]. Interestingly, female blue-collar workers are far less likely to smoke than women in management/professional occupations [296]. However, women's SHS exposure is approximately equal regardless of occupation, and SHS exposure is lowest for female service industry workers.

In 1986, the National Academy of Sciences warned, "SHS (also called environmental tobacco smoke) is a hazardous substance and is the most frequent source of complaint about aircraft air quality. Because of the high concentration of SHS generated in the smoking zone, it cannot be compensated for by increased ventilation in that zone" [297]. The area, volume, and ventilation rate per smoker on an aircraft is the smallest of any workplace setting. However, essentially all airlines now prohibit smoking on their planes.

Overall, exposure to SHS in different microenvironments is based on the strength of the active source, the ventilation system, and the presence and effectiveness of air-cleaning devices. Personal SHS exposure is also affected by age, gender, and race. Constant exposure to SHS at workplaces leads to various complications to the exposed workers.

HEART DISEASE

SHS is estimated to cause 5% to 30% of premature deaths from heart disease each year in the United States among nonsmokers [14,298]. A key difference between the effects of smoking on the risk of cancer compared with the risk of heart disease is that the effects on cancer develop slowly, whereas the effects of smoking on the cardiovascular system occur rapidly. Passive smoking has been shown to cause atherosclerosis in both animal and human models, increase platelet aggregation, and increase myocardial oxygen demand. Multiple epidemiologic studies have consistently found an increased relative risk of cardiac events in nonsmokers with regular SHS exposure [299,300]. Investigators demonstrated through experimentation that 30 minutes of exposure to SHS compromised the endothelial function in coronary arteries of nonsmokers so that the endothelial response of nonsmokers was identical to that of routine smokers [301].

The CDC asserts that people at risk for heart disease should avoid SHS because it can increase one's risk of acute MI. A study was conducted to verify this assertion and concluded that smoking bans at public working places correlate with a reduced morbidity from heart disease [302]. Researchers have suggested that platelet activation, endothelial dysfunction, and broad inflammation may have some relevance [303]. Another theory states that even light exposure to smoke concomitantly restricts blood vessels and allows for blood clotting. This combination raises the risk for MI.

Atherosclerosis

Atherosclerosis, a chronic inflammatory atheromatous disease characterized by focal, noncircumferential, and (most often) proximal plaques, is a major underlying cause of cardiovascular disease, which continues to be the leading cause of death, accounting for 840,678 deaths in the United States in 2016 [304]. Monocytes play a key role in the pathogenesis of atherosclerosis. Monocytes migrate from the blood to the subendothelial space beneath injured endothelial cells, where they differentiate into macrophages. These subendothelial macrophages readily take up oxidized LDL, becoming "foam cells." Collections of "foam cells" are dubbed "fatty streaks" and may first appear in the aorta at 10 years of age. Fatty streaks are precursors to atherosclerotic plaques. Such plaques are advanced lesions characterized by the accumulation of lipid-rich necrotic debris and smooth muscle cells [63,305]. Triggers of endothelial cell injury include hyperlipidemia; bacterial or viral infection; oxidative stress through abnormal regulation of reactive oxygen species, hypoxia, turbulent blood flow, and shear stress; and environmental irritants, such as tobacco smoke [306].

Yuan et al. exposed transgenic human apoB-100 mice to sidestream whole smoke (SSW) (a major component of SHS) in order to study the effects of SHS on atherosclerosis. The transgenic mice received SHS exposure comparable to SHS exposure a nonsmoker would receive from a typical smoking housemate. They found a decrease in plasma HDL-C levels; a decrease in the ratio between HDL-C and triglyceride; and a decrease in ratio between HDL-C and total cholesterol. Yuan et al. noted increased lipid accretion in the aorta, heart vessels, and hepatocytes corresponding to the noted blood lipid profile alterations. Furthermore, they found increased levels of monocyte chemoattractant protein-1 (MCP-1) in blood, heart tissue, and aortic tissue. Increased numbers of macrophages were noted in arterial walls. This finding was significant as MCP-1 is a chemokine that attracts monocytes to the damaged subendothelial cells in the process of plaque formation. Decreased adiponectin monomer levels were noted in the smoke-exposed mice [63]. Adiponectin is an adipocyte-specific plasma protein with potential anti-atherogenic properties. In vitro, adiponectin suppresses the endothelial inflammatory response, the proliferation of vascular smooth muscle cells, and the transition of macrophages to foam cells [307]. Finally, based on examination of the cytokine profile, Yuan et al. determined that cigarette exposure caused a permanent pro-inflammatory state; the normal adaptive response (i.e., initial pro-inflammatory Th1 type cell-mediated response to a Th2 mediated immune response) did not occur [63].

Coronary Heart Disease

A strong association between active smoking and coronary heart disease has been well established, and one study found a 50% to 60% increase in risk for coronary heart disease development in passive smokers [308,309]. Active and passive smoking are known to [310]:

- Increase the incidence and frequency to cardiac arrhythmias

- Decrease the oxygen-carrying capacity of blood

- Increase the incidence of coronary artery spasm

- Promote atherosclerosis, thereby increasing the risk of cardiovascular disease

- Increase the incidence and tendency for thrombosis

The relationship between SHS and coronary heart disease is supported by a study that shows exposure to SHS is associated with increased inflammatory markers, including higher white blood cell counts and levels of C-reactive protein, homocysteine, fibrinogen, and oxidized LDL-C [311]. The intensity of inflammation markers was proportional to the number of years of reported exposure to SHS. Furthermore, subjects with only occasional SHS exposure also experienced increased levels of inflammatory markers, showing that even low SHS exposure is a significant concern. Increased coronary risk is mechanistically mediated by increased platelet aggregation, reduced oxygen uptake and exercise capacity, accelerated lipid peroxidation, and endothelial damage by SHS [312,313,314]. Passive smoke causes arteriosclerosis by altering cholesterol concentrations or by accelerating lipid peroxidation via reductions in serum antioxidant defense [315].

Many elements of tobacco smoke, including CO, nicotine, and polycyclic aromatic hydrocarbons, contribute to the damaging effects on the cardiovascular system. Studies of the effects of tobacco smoke on platelet sensitivity suggest that nicotine is not the sole cause of increased aggregation. Burghuber et al. compared the sensitivity of platelets to the antiaggregatory action of exogenous prostacyclin (PGI2) in nonsmokers and smokers exposed to SHS for 20 minutes. No change was observed in the smoking subjects' platelet sensitivity to PGI2 after SHS exposure, but the smokers' platelets were significantly lower than that of the nonsmoking subjects' before SHS exposure. The nonsmoking subjects experienced significant changes in sensitivity to PGI2 with reported platelet sensitivities matching those of smokers after SHS exposure [316]. However, another study by Benowitz et al. showed that smokers and abstinent smokers with nicotine patches differed significantly in platelet activity despite similar nicotine levels [317]. Thus, nicotine is not the only component of tobacco smoke that mediates increased platelet aggregation.

A British regional heart study examined 4,729 men 40 to 59 years of age and found a 50% to 60% increase in coronary heart disease caused by exposure to SHS [309]. This study is significant because most studies on the relationship between SHS and coronary heart disease either show significant risk increases or only show modest risk increases. Whincup et al. used cotinine measurements to determine passive exposure to smoking. This study noted that although high cotinine levels were associated with an excessive risk of coronary heart disease, they showed little association with the risk of stroke. Whincup et al. offered an explanation for the underestimated association between serum cotinine and coronary heart disease, in that the association tends to decrease over long follow-up periods since assessment of exposure. Finally, this study suggested that risks associated with passive smoking are widespread among nonsmokers.

The American Heart Association's Council on Cardiopulmonary and Critical Care, the Scientific Committee on Tobacco and Health in the United Kingdom, and the California Environmental Protection Agency have all concluded that SHS increases the risk of heart disease [318,319,320].

STROKE

According to findings of the Health and Retirement Study, a national longitudinal study of U.S. adults 50 years of age and older and their spouses, never-smokers with spouses who were current smokers had a 42% increased risk of first stroke. Former smokers married to current smokers had a stroke risk similar to respondents who were current smokers [321].

LUNG DISEASE

Environmental tobacco smoke exposure is associated with respiratory symptoms, asthma, a slight impairment of lung function, and increased bronchial responsiveness [322]. A Swiss study on air pollution and lung diseases with a sample of 4,197 nonsmoking adults, showed that SHS was associated with increased risk of asthma, wheezing, bronchitis, and dyspnea [323]. Greater levels of cumulative exposure to tobacco smoke in the home and workplace are also associated with an increased risk of COPD [324]. It is estimated that a (hypothetical) elimination of SHS in home and work environments would decrease COPD diagnoses in the United States by 18% (or 11% and 7%, respectively).

In a report by Schick and Glantz of unpublished in vivo research done by Philip Morris during the 1980s, inhaled sidestream smoke was found to be four times more toxic per gram of total particulate matter than mainstream smoke. They report that the gas/vapor phase of sidestream smoke is responsible for most of the sensory irritation and respiratory tract epithelium damage that occurs [325].

Asthma

SHS is an established trigger for the onset of asthma in children, and there is growing evidence that it is also a causal factor for asthma in adult nonsmokers [326]. Finland researchers found that subjects exposed to tobacco smoke in the workplace were twice as likely to develop asthma as those who were not exposed. Health effects for adult asthmatics include asthma attacks; increased sensitivity and reduced lung function; and irritation of the eyes, nose, and throat. Exposure to cigarette smoke for just one hour can cause 20% deterioration in short-term lung function of adults with asthma [327].

CANCER

Lung cancer holds the distinction as "the first disease linked definitively" to both active and passive smoking [299,328,329]. Zhong et al., based on epidemiologic studies, estimate a 30% risk of lung cancer in nonsmokers exposed to environmental tobacco smoke. Chinese women have one of the highest incidences of lung cancer in the world, yet active smoking does not appear to be a major risk factor for lung cancer in this population [328]. Smoking among Chinese women is relatively rare, and among those who do smoke, cigarette consumption is limited. However, smoking among Chinese men is especially common, so their spouses are exposed to considerable quantities of environmental tobacco smoke. Thus, nonsmoking Chinese women were an ideal population for a case-control study considering the effects of environmental tobacco smoke on lung cancer. Certain histologic types of lung cancer are more commonly associated with active smoking. The risk of developing squamous cell and small cell cancer is much higher than the risk of developing adenocarcinoma and large cell carcinoma [330,331]. The study by Zhong et al. showed that passive smoking also favors the development of squamous cell and small cell lung cancers over adenocarcinoma and large cell carcinoma [328].

Zhong et al. conducted a meta-analysis study on the relationship between lung cancer and environmental tobacco smoke. They found a 48% increased risk of lung cancer in nonsmoking males exposed to environmental tobacco smoke in their homes, while nonsmoking males had a 29% increased risk of lung cancer if exposed to smoke at work. A 20% increased risk of lung cancer was noted in nonsmoking females exposed to smoke in their homes, while nonsmoking females had a 15% increased risk of lung cancer if exposed to smoke at work. Furthermore, environmental tobacco smoke-exposed nonsmoking women "showed statistically significant monotonic exposure-response relationships." Finally, Zhong et al. found that childhood environmental tobacco smoke exposure did not correspond to an increased risk of lung cancer in adulthood [66].

Genetics may play an influential role in the risk of developing lung cancer from SHS exposure. Polymorphisms in the gene glutathione S-transferase (GST) M1 show a greatly increased risk of developing lung cancer with SHS exposure. GSTM1 is believed to prevent tumorigenesis by detoxifying carcinogens in tobacco smoke. Lung cancer susceptibility has been associated with anomalies in several cytochrome P450 pathways and several GST enzymes that detoxify chemical carcinogens [332,333,334,335,336]. GST enzymes are considered phase II detoxification enzymes, which conjugate glutathione to carcinogens and reactive oxygen species to detoxify them. Two of the four polymorphic gene classes of GSTs, mu (µ) and theta (θ), have been linked to tobacco-associated cancers. The GSTM1 is a variant of the mu class, which contains a null allele that may be inactivated by a deletion of DNA coding sequences [336,337]. Approximately 50% of the white populations of Europe and North America have homozygous null genotypes for the GSTM1 enzymatic activity [338]. Loss of GSTM1 enzymatic activity has been associated with increased risks of various cancers, including tobacco-associated lung cancer, head and neck cancer, larynx cancer, and bladder cancers. Bennett et al. found that SHS-exposed nonsmoking women with the null polymorphism represented 42% to 49% of the lung cancer cases [337]. Women with the homozygous null genotype have a greater risk of tobacco-associated cancer relative to men [339].

GSTTI is an isoenzyme of the theta class of GSTs, which is deactivated by a homozygous deletion in 11% to 18% of whites [338]. United deficiency of GSTT1 and GSTM1 produces a dramatically increased risk for lung cancer in U.S. populations [340]. Kawajri et al. found that a mutant variation in exon 7 of the cytochrome P450 1A1 (CYP1A1) enzyme was associated with higher rates of lung cancer in the Japanese subjects studied [341]. CYP1A1 is known to activate carcinogenic polycyclic aromatic hydrocarbons including the benzo(a)pyrene component of tobacco smoking [342]. Rebbeck et al. found a synergistic increase in lung cancer risk with both homozygous deletions of GSTM1 and the valine allele variant of exon 7 in CYP1A1 [338].

Large-scale genome-wide association studies have identified several novel lung cancer susceptibility genes, including those on chromosomes 5p15.33, 15q24-25.1, and 6p21 [343]. The 5p15.33 region is associated with risks specific to adenocarcinoma of the lung. The 15q25 region contains three nicotine acetylcholine receptor subunit genes. Their polymorphisms have been associated with nicotine dependence [343]. Associations of the 6p21 region have not been consistently replicated among studies [343,344]. Other regions (e.g., 6q23-25, 13q31.3) have also been identified by genome-wide studies as being associated with risk of lung cancer, including some studies specific to African Americans and to those who have never smoked. Further studies are necessary to assess individual susceptibility based on the combination of polymorphisms in multiple genes [343,344,345].

GLUCOSE INTOLERANCE/DIABETES

Houston and colleagues questioned whether active and passive smokers are more likely than nonsmokers to develop clinically-relevant glucose intolerance or diabetes. Of 4657 participants in the Coronary Artery Risk Development In Young Adults (CARDIA) study, 16.7% developed glucose intolerance at 15-year follow-up. Incidence of glucose intolerance was highest among smokers (21.8%), followed by never-smokers with passive smoke exposure (17.2%), then previous smokers (14.4%), and was lowest for never smokers with no passive smoke exposure (11.5%). The risk among current and never smokers remained after adjustment for sociodemographic, biologic, and behavioral factors, but risk in previous smokers was similar to that in never smokers without passive smoke exposure [346]. A meta-analysis conducted by Pan et al. found that both active and passive smoking are associated with significantly increased risks of type 2 diabetes. The risk was increased in individuals who had recently quit smoking, but decreased substantially as time from quitting increased. They also identified a dose-response relation for current smoking and risk of diabetes [347].

SKIN DISORDERS

Setty, Curhan, and Choi prospectively examined over a 14-year period (1991–2005) the relation between smoking status, duration, intensity, cessation, and exposure to SHS and incident psoriasis in 78,532 women from the Nurses' Health Study II. Prenatal and childhood exposure to passive smoke as well as current and past smoking and cumulative measures of smoking were associated with an increased risk of psoriasis. The risk of incident psoriasis among former smokers decreases nearly to that of never smokers 20 years after cessation [348].

WOUND REPAIR

Passive smoking is known to interfere with normal tissue repair and remodeling, though the underlying pathology is not well understood. Passive smoking has been shown to obstruct wound healing by decreasing blood flow to the damaged tissue and hindering granulation tissue formation and function. Tissue repair and remodeling is heavily reliant upon fibroblasts, which migrate to the site of damage, proliferate, and secrete cytokines, growth factors, and extracellular matrix molecules. Wong et al. found that SSW smoke causes cytoskeletal changes in fibroblasts, which may account for decreased fibroblast migration. Furthermore, excess scarring in SHS-exposed individuals is likely due to a combination of prolonged cell survival (due to a cellular stress response invoked by SHS) and the aforementioned decreased cell migration [62].

AGE-RELATED MACULAR DEGENERATION

Khan and colleagues designed a case-control study to investigate a possible relation between smoking and risk of development of age-related macular degeneration (AMD) among whites. Although many risk factors are related to AMD (e.g., aging, hypertension, family history, obesity), they found a strong association between AMD and pack years of cigarette smoking, and the odds ratio increased with the amount smoked. Smoking impairs the functioning of the retinal pigment epithelium, causing buildup on the retina and subsequent damage to Bruch's membrane. Stopping smoking was associated with reduced odds of AMD and the risk in those who had not smoked for over 20 years was comparable to nonsmokers [349].

CERVICAL INTRAEPITHELIAL NEOPLASM (CIN)

Cervical intraepithelial neoplasm (CIN) is a precursor to cervical cancer, which is the fourth most common cause of cancer-related death in women worldwide [350]. Firmly established major risk factors for CIN include active smoking and human papillomavirus (HPV) infection. A 2006 case-control study of Taiwanese women established SHS as a major risk factor for CIN in addition to active smoking and HPV. The authors presented an indirect and a direct potential mechanism for the development of CIN following SHS exposure. CIN could be caused indirectly by immune suppression or directly by a polycyclic aromatic hydrocarbon-DNA adduct [69]. More recent studies continue to suggest an association between SHS and CIN, and while these studies continue to be conducted, few have provided conclusive results [468,469].

NONALCOHOLIC FATTY LIVER DISEASE

Nonalcoholic fatty liver disease is one of the most common liver diseases in the United States. Nonalcoholic fatty liver disease covers a broad range of diseases from steatosis to nonalcoholic steatohepatitis (NASH) and can have dramatically varied underlying pathology. NASH is a significant clinical concern due to potential disease progression resulting in cirrhosis and end-stage liver disease [351]. Yuan et al. employed a mouse model transgenic for human apoB100 to consider the effect of passive smoke on cholesterol and triglyceride levels. They found no significant change in cholesterol levels with passive smoke exposure but a marked increase in triglycerides in the liver. The increased lipid accretion in hepatocytes is consistent with lipid changes seen in nonalcoholic fatty liver disease [63].

16. MEASURING SECONDHAND SMOKE EXPOSURE

Seventy percent to 80% of nicotine is initially metabolized to cotinine, primarily by CYP2A6 [195]. Cotinine is, for the most part, metabolized to 3'-trans-hydroxycotinine, mainly by the same CYP2A6 enzyme [352]. Both nicotine and cotinine undergo N-glucuronidation; however, 3'-hydroxycotinine undergoes O-glucuronidation [353]. Cotinine is also partly metabolized to 3'-trans-hydroxycotinine by CYP2A6 [352]. Cotinine has a half-life of 15 to 20 hours, and its serum concentrations are tenfold higher than nicotine; thus, cotinine is generally used as an index of nicotine exposure [354].

Cotinine can be measured in hair, nails, blood, saliva, or urine samples. Although other biomarkers for environmental tobacco smoke exposure exist, cotinine is currently the most sensitive and specific. Such objective quantification is especially important in studies concerning passive smoke exposure in children, as parental assessment of smoke exposure is frequently unreliable [65,69,277,355,356]. SHS exposure can also be assessed through CO breath analysis, measurement of certain carcinogens (e.g., NNAL can be found in urine, blood, and nails) or benzene, or measurement of respirable suspended particulates in the air [355].

Breath analysis has improved as an assessment tool. It utilizes the monitoring of volatile organic compounds, which are predominantly bloodborne and therefore enable monitoring of different processes in the body. One study utilizing a real-time breath analyzer identified the presence of volatile organic compounds (1,3-butadiene) after SHS exposure in the breath of nonsmokers [357]. While this method of smoking analysis is improving, studies using this tool still suffer issues of sampling and lack of normalization data. Results could be skewed by participants' varying degrees of exposure to other common sources of volatile organic compounds, for example, wood smoke and automobile exhaust [358].

Studies of genetic polymorphisms of genes that modulate cell growth and proliferation provide potentially helpful biomarkers associated with long-term exposure to carcinogens and eventual tumor formation. One such biomarker used to study lung cancer in SHS-exposed patients is the tumor suppressor gene p53. The p53 gene encodes a multifactorial transcription factor that controls cellular response to DNA damage [359]. Husgafvel-Pursiainen et al. found a three- to fourfold increase in the risk of p53 mutation in SHS-exposed patients who develop lung cancer, while in long-term heavy smokers, p53 mutations are found in 50% of patients with lung tumors [360]. Furthermore, Husgafvel-Pursiainen et al. demonstrated that the majority of the p53 mutations were G:C to A:T transitions. The CpG dinucleotide sites were mutational hotspots, accounting for 50% of the reported G:C to A:T substitutions within the p53 gene. Endogenous deaminations of methylated cysteine residues or preferential carcinogen binding are proposed explanations for G:C to A:T substitutions within CpG islands. This evidence supports the role of p53 as a biomarker for both passive and active tobacco-related carcinogenesis [360].

A combination of the measurement of body fluids for cotinine and hair for nicotine, with the questionnaire and interview-derived information, seems to be the optimal method for assessing SHS exposure. Empirical studies show general concordance of reported environmental or biologic measures of SHS exposure [361]. In addition, urinary cotinine is often used for evaluation of smoking-cessation program efficacy, monitoring of pregnancy/other at-risk groups, and assessment of occupational exposure [362].

17. THIRDHAND SMOKE

The term "thirdhand smoke," or "environmental tobacco smoke," has been and is often used synonymously with SHS, but it can be more accurately described as any airborne particulate matter originating from burning tobacco. It is comprised of both active mainstream smoke (tobacco smoke exhaled by active smokers) and sidestream smoke (smoke from the burning end of a cigarette) that is inhaled by nonsmokers, and evidence shows the possibility of harm for a significant period of time after the cigarette/tobacco product has been extinguished.

In a 2009 study by Winickoff et al., more than 80% of national survey respondents (regardless of smoking status) agreed that SHS was harmful to children, but only 43% of smokers and 65% of nonsmokers thought the same of thirdhand smoke (defined as "breathing air in a room today where people smoked yesterday") [363]. Thirdhand smoke, or any exposure to residual tobacco smoke contamination on surfaces or breathing air in a room where smoking previously occurred, can be dangerous. Unfortunately, not all smokers are cognizant of these harms. Many believe that confining smoking to one room in the home or smoking in the absence of children or even smoking outside with all household windows and doors closed is enough to protect their children. Tobacco smoke does not simply disappear after cigarettes are extinguished, and it (and other toxins) may linger even with what is perceived as adequate ventilation.

Hein and colleagues were likely the first to measure nicotine content of household dust. Nicotine has a high affinity for dust particles, and the amount of tobacco smoking that occurs in the home is highly correlated with concentration of nicotine in household dust [364]. According to a 2004 study by Matt et al., vapor components of tobacco smoke "are absorbed onto walls, furniture, clothes, toys, and other objects within 10 minutes to hours after tobacco smoke has been emitted. From there, they are re-emitted into the air over the course of hours to months" [365]. Similar to findings of a 2001 study of hair nicotine levels among children in New Zealand, whether household smokers smoked indoors in the presence of their child or attempted to limit their children's smoke exposure by smoking outside or in the children's absence, the children were not protected from exposure to nicotine in the indoor air [366]. Further, skin-to-skin contact poses additional risk as nicotine was found on the index fingers of 92% of mothers in the sample [365].

Part of the reason behind the danger of thirdhand smoke may be the lead content of tobacco smoke. According to the Environmental Protection Agency, the tobacco leaves used to make cigarettes contain radioactive lead-210. Indeed, increased blood lead levels among youth is directly associated with household smoking and house dust [367]. Mainstream smoke contains at least 58 percutaneous penetration enhancers, which are used to enhance transdermal delivery of drugs. Of these, 69% are hydrophobic or strongly hydrophobic and can therefore readily permeate the skin and likely settle in percutaneous fat for continued exposure long after the cigarette has been extinguished [368]. Further, unpublished research from Philip Morris Co. shows that 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (NNK) forms in sidestream smoke and increases up to 200% per hour during the first six hours after cigarettes are extinguished [369]. NNK has been shown to cause an exaggerated response in microglia (causing them to attack healthy brain cells) and overall neuroinflammation, which can lead to disorders such as multiple sclerosis [370].

Oie and colleagues report that low ventilation in homes can strengthen the effects of indoor pollutants. They found that odds of bronchial obstruction among children was higher in homes where they were exposed to environmental tobacco smoke as well as dampness, textile wallpaper, and plasticizer-containing surfaces [371].

The problem is not confined to homes. In a 2008 study by Matt and colleagues, it was found that cars of people who smoked in their vehicles contained elevated levels of nicotine in dust on surfaces and in the air when compared with cars of nonsmokers [372].

Haussmann et al. performed a study of fresh versus room-aged sidestream smoke to ascertain how the different types of smoke would affect rats. Their study revealed that the room-aged smoke had decreased concentrations of smoke components such as nicotine and total particulate matter. However, levels of CO remained equal to that of the fresh smoke. The rats manifested reserve cell hyperplasia in the nose and hyperplastic and metaplastic epithelial changes in the larynx; these effects were not as profound in those exposed to the room-aged smoke [373]. Rao and colleagues found that lung tissue from mice exposed to aged and diluted sidestream smoke exhibits increased angiogenesis associated with leukocyte rolling and adhesion. This phenomenon may lead to recruitment of inflammatory cells as observed in bronchitis or asthma [374]. These research studies confirm the unpublished research of Philip Morris Co. in the early 1990s, which revealed that aged sidestream smoke is more toxic to lab animals than fresh sidestream smoke [375].

18. INTERVENTIONS FOR SMOKING CESSATION

PRIMARY CARE INTERVENTION

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends that clinicians ask all adults about tobacco use, advise them to stop using tobacco, and provide behavioral interventions and U.S. Food and Drug Administration (FDA)-approved pharmacotherapy for cessation to adults who use tobacco.

http://annals.org/aim/fullarticle/2443060

Last Accessed: May 13, 2019

Level of Evidence: A (There is high certainty that the net benefit is substantial.)

Smoking cessation may be helpful in reducing firsthand and secondhand tobacco smoke exposure by eliminating the source: the smoker(s). Parents and caregivers of young children should receive cessation counseling and/or pharmacotherapy to quit smoking and eliminate the exposure of children to SHS. Parents should also be informed of the importance of a smoke-free environment for children and that it should be instituted before pregnancy. Pregnant women must learn that smoking will likely produce lasting adverse effects on their offspring. Furthermore, smoking parents should be aware that smoking is known to cause and exacerbate asthma, chronic serous otitis, otitis media, respiratory illness, and possibly childhood cancers. A healthcare provider is required to intervene if a child is suffering from one of these disorders. Healthcare providers are responsible for advising smoking parents about the harms of passive smoke as well as how to provide a smoke-free environment for their children [249]. There are many smoking cessation resources that may be provided to patients, including several "quitlines." These hotlines provide free telephone access to a smoking cessation counselor. The National Cancer Institute's quitline is 1-877-44U-QUIT (1-877-448-7848), and both English- and Spanish-speaking assistance is available. The website https://smokefree.gov also offers support, tools, and expert advice through their app, text messaging, and social media networks. Assistance for issues unique to different subgroups, such as veterans, women, adolescents, adults older than 60 years of age, and those who speak Spanish, are also available.

Although nearly 70% of patients who smoke say they would like to quit, only 7.4% are able to do so without help [376,377]. The advice of a physician alone can increase the smoking cessation rate to 10.2% [378]. It is important for physicians to add an inquiry about smoking to the questions routinely asked while a patient's vital signs are being taken (Figure 2). Further assessment using an abbreviated form of the Fagerström Test for Nicotine Dependence can provide information about whether a patient is addicted to or physically dependent on nicotine. The Fagerström test is a question and answer test that rates an individual's nicotine dependence on a scale of 0 to 10 [379].

Figure 2: PATHWAY FOR TOBACCO CESSATION TREATMENT

Source: Modified with permission from Barua RS, Rigotti NA, Benowitz NL, et al. ACC expert consensus decision pathway on tobacco cessation treatment: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2018;72(25):3332-3365.

After the diagnosis of nicotine dependence is made, the next step is to assess the patient's readiness to change. The five-stage model for readiness to change can be applied to addictive behaviors such as smoking. The stages are precontemplation, contemplation, preparation, action, and maintenance. In the precontemplation stage, a patient does not believe that smoking is a problem or refuses to consider smoking cessation. In the contemplation stage, the patient recognizes that smoking is a problem and is thinking about quitting. During the preparation stage, the patient makes specific plans to stop smoking, such as setting a quit date and determining how smoking cessation will be accomplished. In the action stage, the patient stops smoking. Finally, the maintenance stage is marked by the patient's continued abstinence from smoking. Relapse to smoking behavior is common. Patients often cycle through the stages of change several times before reaching stable abstinence [380].

Interventions can be classified into behavioral, pharmacologic, and alternative methods. Behavioral interventions include physician advice and individual, group, and telephone- or Internet-based counseling. Pharmacologic interventions include NRT and sustained-release bupropion. Alternative interventions include hypnosis, acupuncture, exercise, lobeline, anxiolytics, mecamylamine, and opioid agonists [381].

BRIEF INTERVENTION

Evidence Based Practice Recommendation

According to the University of Michigan Health System, healthcare professionals should advise all tobacco users to seriously consider making a quit attempt using a clear and personalized message. Advice as brief as three minutes is effective.

https://www.med.umich.edu/1info/FHP/practiceguides/smoking/smoking.pdf

Last Accessed: May 13, 2019

Strength of Recommendation/Level of Evidence: IA (Generally should be performed based on randomized controlled trials)

Brief intervention training allows healthcare professionals to offer basic support, ensuring that all smokers who come into contact with these health professionals are able to receive help as appropriate. Brief intervention offers short-term professional input, self-help leaflets and videos, and complementary therapies. This type of information can be applicable for smokers at any level. Milch et al. compared the effects of two brief interventions against treatment as usual. The minimal intervention consisted of a smoking status vital sign stamp, which documents the patient's smoking status. The enhanced intervention consisted of a five-question form that assessed the patient's level of cessation readiness and provided cessation counseling prompts for clinicians. Medical record documentation of screening for smoking and cessation advice and self-reported patient smoking cessation rates were collected 8 to 10 months after implementation. Self-reported patient smoking cessation was higher in the enhanced intervention group (12%) compared with the minimal intervention (2%) and control (4%) groups. This demonstrated that even a short questionnaire that assessed readiness to quit and provided documentation of cessation advice improved rates of clinician cessation advice and patient smoking cessation compared with no intervention [382]. In a study by Smith and Burgess of patients admitted to the hospital with diagnoses of coronary artery disease, a minimal intervention (i.e., advice from physicians and nurses and two pamphlets) resulted in 35% of the group confirmed abstinent at 12 months [383].

5 A's

The U.S. Public Health Service Clinical Practice Guideline was updated in 2018, but continues to recommend the 5 A's approach for intervening with the patient who smokes [384,470]:

- Ask about smoking status

- Advise to quit

- Assess willingness to quit

- Assist by suggesting and encouraging the use of problem-solving methods for cessation

- Arrange for follow-up contacts and relapse prevention

Mullen et al. found that simple changes in question format, such as moving away from requiring "yes" or "no" answers and allowing responses such as "I used to smoke" or "I have cut down," increased smoking disclosure by 40% [385]. Every clinician should ask patients about tobacco use and advise them to quit. Abrupt smoking cessation with medical and psychologic assistance is more successful than tapering or "smoking less" [461].

Given the magnitude of tobacco use as a health risk, tobacco use status should be considered a vital sign requiring regular assessment [384,386]. Nevertheless, studies continue to find that clinicians inconsistently practice assessment of tobacco use and advice to quit smoking [387]. The third step of the Five A's approach, after asking and advising, is to assess the patient's willingness to quit. For the patient who is unwilling to quit at this time, the clinician should help increase motivation by discussing the immediate and long-term risks of continued smoking, benefits of quitting, and the patient's perceived barriers to quitting. The clinician should try to make the discussion personally relevant to the patient and include risks and benefits in addition to those related to health [384]. For the patient willing to quit, the clinician should provide assistance, such as helping the patient choose a target quit date in the near future, suggesting appropriate pharmacotherapy, providing social support, advising the patient about the nature and time course of nicotine withdrawal, recommending behavioral and cognitive coping responses to use when the patient experiences urges to smoke, and perhaps making a referral to an intensive behavioral counseling program [384]. The last of the Five A's involves arranging follow-up contact. This strategy is also based on evidence that total contact time predicts treatment outcome [384]. Follow-up contact can take the form of additional office visits, telephone calls, text messages, or even written materials sent through the mail [462]. Such contact communicates the importance of the cessation attempt, provides social support, and offers the opportunity to intercede if problems have developed. Because the risk of relapse is greatest immediately after quitting, follow-up contact ideally should begin close to the target quit date [388].

MOTIVATIONAL INTERVIEWING

Introduced by Miller in 1983, motivational interviewing is a method of counseling designed to enhance patients' motivation to change by helping them explore and resolve their ambivalence about making the change [389]. It is a collaborative, non-confrontational, "guiding" approach. Motivational interviewing for tobacco cessation utilizes active listening to understand how the patient feels about his or her tobacco use in an effort to uncover any ambivalence [384]. The healthcare provider elicits the patient's own views regarding consequences of continuing to use tobacco and benefits of quitting and asks permission to share additional information on risks when necessary. Goals are developed collaboratively, based on the patient's current readiness to change. Originally developed as an intervention for alcohol abuse, it has shown promise as a successful strategy for smoking cessation. Lai et al. reviewed 28 studies and found that motivational interviewing yields a significant increase in quit rate, especially when conducted by primary care physicians or counselors for sessions lasting more than 20 minutes [390,391]. Further, in a randomized, controlled trial, Ruger and colleagues reported that motivational interviewing for smoking cessation actually saves money, and prevents relapse, among low-income pregnant women with $628/quality-adjusted life-year saved versus usual care [392].

INTERVENTIONS FOR NON-ENGLISH-PROFICIENT INDIVIDUALS

Because communication with patients regarding cessation of smoking is a vital aspect of patient care, it is important that discussions and printed materials are provided in the language with which the individual is most comfortable. 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. In this multicultural landscape, interpreters are 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 [393]. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. When providing care for patients for whom English is a second language, the consideration of the use of an interpreter and/or patient education materials in their native language may improve patient understanding and outcomes. The American Heart Association, the American Medical Association, and the American Academy of Family Physicians produce patient education references in several languages. Primary care providers may utilize these in their interactions with patients for whom English is a second language.

TREATING NICOTINE DEPENDENCE

Behavioral Modifications

Behavioral interventions are nonpharmacologic treatments delivered directly to individual smokers [388]. The main disadvantage of this approach is that relatively few smokers (about 5%) are interested in attending specific classes at any given time [394,395]. Therefore, group sessions appear to be the most cost-effective approach to delivering smoking cessation interventions [396]. Although relatively few patients want to go to classes, physicians should still have a list of referral smoking cessation clinics in their area for those smokers who express an interest in attending them and for those who have failed to respond to other approaches. Simple text, app, and web-tailored cessation messages may also be an effective alternative for behavioral support, doubling the cessation rates. This concept has been incorporated into patient support programs provided by several manufacturers of smoking cessation products [394].

There are several behavioral interventions that have empirical support, such as multicomponent coping skills training (e.g., coping response therapy, problem-focused treatment, relapse prevention training, and cognitive-behavioral therapy). This training includes social support and didactic information about nicotine dependence, withdrawal symptoms, and situations that are risks for relapse (e.g., alcohol use, negative moods, or presence of other smokers) as well as training in the use of cognitive and behavioral responses to cope with urges to smoke that reduce the risk of relapse [397,398]. Aversive therapy for smoking cessation, known as rapid smoking, involves smokers in a controlled clinical setting who deeply inhale on cigarettes at six-second intervals. Up to nine cigarettes would be smoked per treatment session to produce strong aversive reactions to cigarettes [399]. Aversive cigarette use greatly declined after the introduction of NRTs, and reviews have concluded that there is insufficient evidence to determine the efficacy of this method for smoking cessation [400,401]. Another behavioral treatment, scheduled reduced smoking, involves three weeks of gradually reduced nicotine intake. In contrast with other smoking cessation strategies involving reduction of smoking, the patient does not control when and where smoking will occur. Rather, an algorithm is used to determine when each cigarette is to be smoked based on the passage of time [402].

Pharmacotherapy

The first-line pharmacologic interventions for smoking cessation are NRT and bupropion [381,403]. However, no pharmacotherapy has been approved for use among pregnant or nursing women. The five forms of NRT available are the patch, gum, lozenge, nasal spray, and inhaler. A Cochrane review found that all commercially available forms of NRT increased the quit rate by 50% to 70%, independent of the intensity of additional support provided to the individual. Although support is beneficial, it does not appear to be essential to the success of NRT [404].

All available pharmacotherapies are safe for non-pregnant or nursing adults. In a 2016 analysis, varenicline outcomes are found to be equal to NRT plus counseling, and varenicline is also associated with a reduced risk of relapse [463]. Bupropion has the added advantage of reducing smoking cessation-related hyperphagia and weight gain. It is also an antidepressant and can ameliorate withdrawal-associated anhedonia and depression.

The nicotine transdermal system, otherwise known as the patch, releases nicotine steadily during an extended period, with blood levels rising within the first 2 to 4 hours and then remaining relatively constant between 8 and 24 hours after application, depending on the product used [405]. A number of transdermal nicotine-replacement systems are available over the counter. Prescribing information inserts for all transdermal nicotine products indicate that they should be used as part of a cessation program; yet, many patients receive the patch without any physician advice or behavioral support [406]. Adverse reactions to transdermal nicotine-replacement systems seldom cause discontinuation of therapy. Thirty percent to 50% of patients experience mild skin irritation with the patch. In most patients, rotating patch application sites can alleviate this problem. Sleep disruption is usually resolved by removing the patch at bedtime [407]. Unfortunately, use of the patch without any behavioral support is not likely to be successful.

The U.S. Food and Drug Administration adopted labeling for the patch, allowing use beyond the standard duration of eight weeks. This decision was based in part on data showing that extended-duration (24-week) transdermal nicotine therapy reduced the risk for smoking lapses and increased the likelihood of recovery to abstinence compared to the standard 8-week duration of therapy [408,409].

Nicotine chewing gum is a type of NRT that may aid in smoking cessation and/or quitting smokeless tobacco. Chewing allows nicotine to be delivered quickly into the bloodstream. Typically available in either 2- or 4-mg doses, nicotine chewing gum is expected to last one to two hours. Release of nicotine from the gum is proportional to the rate of chewing, a feature that allows for self-titration [410]. However, like the patch, nicotine gum is most successful as an adjunct to behavioral interventions. Indeed, Schneider et al. showed that merely dispensing nicotine gum resulted in a lower quit rate with active gum than with placebo treatment (8% nicotine gum, 13% placebo gum) [411].

The nicotine lozenge is similar to a hard candy. It slowly dissolves in the mouth (for 20 minutes or so) to release nicotine to the brain more quickly than the patch. Shiffman, Di Marino, and Pilliteri analyzed two trials of a 21-mg nicotine patch and 4-mg lozenge to assess the efficacy of each in heavy and dependent smokers. Both therapies were found to significantly increase six-month, continuous abstinence in heavy smokers (≥40 cigarettes per day) and the highly dependent (Fagerström score >7) [412].

A 2-mg sublingual nicotine tablet has shown efficacy in several studies and has been approved in Europe to manage nicotine withdrawal [413,414,415]. Interestingly, one study found that being married was strongly associated with smoking cessation while on this medication [416]. Sublingual tablets (2 mg) have similar pharmacokinetics to that of the 2-mg nicotine chewing gum [417]. One study of high-dependence smokers (those who smoked their first cigarette of the day within 30 minutes of waking) found that a 4-mg nicotine lozenge significantly reduced withdrawal symptoms and cravings over six weeks of treatment [418].

Nasal nicotine spray (NNS) was approved by the FDA in 1997. Available by prescription, each spray contains 0.5 mg of nicotine, and a dose is defined as one spray in each nostril. In clinical trials, subjects were allowed to take up to 5 doses/hour, with a maximum of 40 doses/day (40 mg of nicotine). The cessation rates in trials with NNS at 1 year ranged from 15% to 25% [419,420,421]. A meta-analysis of nicotine replacement suggested that NNS and the inhaler might have higher quit rates than the patch or gum [422]. Indeed, nicotine administered via nasal spray is considered to be the next fastest acting delivery method after smoking and requires 11 to 13 minutes for nicotine levels to reach peak plasma concentration [423].

The FDA also approved a nicotine inhalation system consisting of a mouthpiece and a nicotine-containing cartridge. Available with a prescription, each inhaler contains 10 mg of nicotine and 1 mg of menthol, of which 4 mg of nicotine can be extracted and 2 mg are systemically available. Shallow or deep puffing results in similar nicotine absorption. Nicotine is delivered mainly to the oral cavity, throat, and upper respiratory tract, with a minor fraction reaching the lungs. A single inhaler can be used for one 20-minute period of continuous puffing or periodic use of as many as 400 puffs per inhaler. With controlled puffing in laboratory testing, venous plasma nicotine concentrations from a single inhaler puffed 80 times for 20 minutes, averaged 8.1 mcg/L at 30 minutes. Lower concentrations of 6.4 to 6.9 mcg/L have been reported for self-administration under clinical conditions. The time to reach peak plasma concentrations varies but is always significantly longer than with cigarette delivery [424].

Quitting smoking can be a difficult process, even with use of NRT. When subjects were given denicotinized cigarettes along with IV saline or nicotine, the variable most responsible for craving satisfaction, psychologic reward, and craving reduction was the denicotinized cigarette [425]. When ad libitum smoking of preferred brands was also allowed, the combination of nicotine-less cigarette and bolus IV nicotine were the most effective in lowering craving, negative affect, and total amount smoked [89]. Sensations in the tongue, nose, back of mouth, throat, windpipe, and chest showed strong correlation between nicotine-less cigarettes and the usual brand smoked by the subjects, perhaps explaining the strong effects on smoking suppression observed [425]. Therefore, it is important to recognize that while NRT is a key part of cessation therapy, it does not address all aspects of smoking behavior. In addition, certain smoking cessation strategies, such as NRT, have been found to be less effective among women than men. Given that researchers have found that women are 31% less likely to quit smoking successfully, further studies on gender-specific smoking cessation strategies are warranted [471].

Bupropion is an atypical antidepressant that has both dopaminergic and adrenergic actions [426]. In 1998, the slow-release preparation of bupropion became available as a prescription item specifically for smoking cessation, with the trade name Zyban. This treatment could be appropriate for smokers who do not wish to use an NRT or for those whose treatment with NRT has failed. Unlike NRT, smokers begin bupropion treatment one week prior to cessation. The suggested dosage is 300 mg/day, and the duration of treatment is 7 to 12 weeks [427]. A double-blind, placebo-controlled trial randomized patients to placebo or sustained-released bupropion (50 mg twice a day, 150 mg once a day, or 150 mg twice a day) and treated them for six weeks. Smokers with active depression were excluded, though smokers with a history of depression were not. The cessation rates at the end of therapy were 10.5%, 13.7%, 18.3%, and 24.4%, respectively. Follow-up at one year suggested a continued benefit of bupropion therapy [428]. Data from a study of bupropion combined with transdermal nicotine showed high long-term quit rates with the combination therapy [429]. Discontinuation of treatment may be appropriate for individuals unable to achieve significant progress after seven weeks, as success after this point is unlikely [430].

Another effective non-nicotine therapy for smoking cessation is varenicline tartrate (Chantix), a partial agonist selective for nicotine acetylcholine receptor subtypes. Released in 2006, varenicline is available in monthly dose packs (0.5 mg and 1 mg tablets) and is approved for a 12-week course of treatment [403]. Patients able to quit smoking may continue the therapy for an additional 12 weeks for increased likelihood of long-term cessation; however, medication should be stopped and patients should be reassessed if the intervention has not led to smoking cessation [430,431]. Clinical trials reveal that varenicline may be favorable to bupropion for abstinence (44% versus 30%); the medication has also been shown to help at least 20% of patients remain smoke-free for up to one year [432,433]. Recognizing that cessation success rates increase when pharmacologic and behavioral therapies are combined, the manufacturer urges patients to combine use of varenicline with a behavioral support plan. Co-administration of varenicline and transdermal nicotine may exacerbate incidence of nausea, headache, vomiting, dizziness, dyspepsia, and fatigue. One study found varenicline alone to be more effective than other treatment options, while a meta-analysis study found that combination therapy (varenicline and NRT) was more effective than varenicline alone [434,435]. In 2021, the manufacturer halted production of varenicline due to unacceptable levels of nitrosamines [475]. In addition, all lots of 0.5-mg and 1-mg tablets of varenicline have been subject to a voluntary recall.

The two second-line drugs for smoking cessation are clonidine and nortriptyline [381]. Clonidine is an antihypertensive medication that is administered orally or transdermally. It appears to increase the smoking cessation rate by approximately 11%; however, clonidine is known to produce such side effects as dry mouth, dizziness, sedation, and orthostatic hypotension [430,436]. Clonidine has not been approved by the FDA for smoking cessation but has been used with individuals who have failed NRT or bupropion [430]. Nortriptyline is a tricyclic antidepressant that has been used to assist smoking cessation, although this is an unlabeled use [430]. A 12% improvement in cessation over controls has been reported, but the limited number of trials, combined with the adverse side effects (e.g., dry mouth, weight gain, constipation, drowsiness, sexual problems), makes nortriptyline a second-line intervention [381].

Other drugs have also been used in smoking cessation. Silver acetate, which causes cigarettes to have a bad taste, has been used as a smoking cessation aid for many years. But, there appears to be little evidence for a specific effect of silver acetate in promoting quitting [437,438]. The addition of mecamylamine, a ganglionic blocker classified as an antihypertensive agent, to transdermal nicotine replacement has been shown to improve the abstinence rate in smokers compared with use of the patch alone [439,440].

Additional pharmacotherapy options are in the development phase. A nicotine vaccine and other partial agonists for the nicotine receptors are being evaluated [441]. Interference with the liver enzymes that metabolize nicotine is another approach being tested [442].

In addition, it was found that methoxsalen, a compound used to treat skin disorders, reduces the activity of CYP2A6, the enzyme that metabolizes nicotine. This allows for more nicotine, whether from a cigarette or nicotine replacement, to be present in the blood and to remain there longer, which should minimize smokers' craving to smoke. However, methoxsalen has not been proven safe for use in humans and must undergo more trials before it can be used in a smoking cessation program [443]. Tranylcypromine (a monoamine oxidase inhibitor used to treat depression) and tryptamine (substrate of MAO) are also being investigated for this purpose [444].

Withdrawal

Similar to all addictions, nicotine withdrawal elicits a number of clinical consequences. Desire to avoid withdrawal symptoms promotes smoking. Nicotine withdrawal may last for several weeks and include such symptoms as irritability, anxiety, depression, difficulty concentrating, weight gain, restlessness, and impatience [445]. Withdrawal effects can be elicited and observed in those exposed to secondhand smoke as well as in smokers. Intensity of these withdrawal symptoms may be related to the level of nicotine dependence. In 2017, there were an estimated 34 million adults that smoked cigarettes. Although the prevalence of cigarette smoking continues to decline, there is some evidence that this decline is a reflection of a migration to non-cigarette products, especially e-cigarettes [446,456]

19. REDUCING TOBACCO SMOKE EXPOSURE

A dramatic increase in public awareness concerning the dangers of SHS has corresponded to social demand for smoking restrictions. Beginning in the 1990s, McMillen et al. found broad public support in the United States for smoking restrictions in many public places, including child care centers, hospitals, shopping malls, convenience stores, fast-food restaurants, and indoor sporting events [6]. An Irish study by Mulcahy et al. demonstrated dramatic reductions in SHS exposure following a national workplace smoking ban in Ireland. Thus, this study justified such bans given the known adverse effects of SHS, which include lung disease, heart disease, and asthma [356].

Workers suffering the detrimental effects of secondhand tobacco smoke have taken legal actions. For example, a group of 60,000 flight attendants filed a suit alleging that they had endured smoking-related illnesses from being exposed to high concentrations of environmental smoke in airplane cabins when smoking was still allowed on board [447]. Although the tobacco industry (Philip Morris, R.J. Reynolds, Brown and Williamson, the Ligett Group, and the Lorillard Group) made no admission of guilt, it established the Flight Attendant Medical Research Institute (FAMRI), a $300 million not-for-profit research institute, as a part of the settlement for flight attendants who suffered and died due to SHS exposure in air cabins. FAMRI's mission is "to sponsor scientific and medical research for the early detection and cure of diseases and medical conditions caused from exposure to tobacco smoke" [448].

Efforts to regulate tobacco products include the World Health Organization's Framework Convention on Tobacco Control (FCTC). Additionally, legislation has been passed to give the FDA regulatory authority over tobacco. The main reason for these proposals is to minimize death and disease caused by tobacco smoke by reducing the prevalence of its use and the toxicity of its products. Based on scientific studies and tobacco industry documents, it is believed that tobacco products could be made less toxic if their design, content, emissions, and manufacturing were better controlled [449].

Nationwide polls reveal broad public support for increased taxing of tobacco [450]. Since 2002, the average state cigarette tax has increased from 43.4 cents to $1.79 per pack [451,453,473]. In February 2009, President Obama signed a 61.66-cent federal cigarette tax increase into law, bringing the federal cigarette tax to $1.01. This increase resulted in an 8.3% decline in cigarette sales, one of the largest declines in years, and a continuing downward trend of cigarette sales [452,453]. As of 2016, the CDC reported an average national retail price of $6.43 per pack of cigarettes [453]. Increasing the cost of tobacco not only decreases tobacco use by creating a larger economic barrier to smoking, it also motivates people to try to quit.

Effective behavioral and pharmacologic treatments exist and can work if they are affordable, widely available, and used properly in clinics and communities. Smoking cessation group programs have been found to be more effective than minimal treatment programs, although less intensive treatment approaches, when combined with high participation rates, can still influence larger groups. Tobacco policies have reduced cigarette consumption at work and worksite tobacco smoke exposure [454]. Innovative partnerships with public- and population-based organizations to reach smokers and reduce exposure to tobacco have been initiated. There is a high level of support for smoking restrictions in public places to protect nonsmokers from tobacco smoke [455,473]. Due to the 2009 federal tax increase, several health benefits and cost savings are projected, including an increase in the number of children alive today who will not become smokers (1.2 million) and $51.9 billion in long-term healthcare savings from fewer adult and youth smokers over the lifetimes of the adults who quit and kids who never start [452,473].

Though the state and local governments and employers provide protection from tobacco smoke at work, private homes are not subject to such regulation. Educational strategies are needed to increase awareness of personal and childhood tobacco exposure both in and out of the home. As with the business microenvironment, air quality cannot be maintained if smoking is allowed indoors, even with additional ventilation and air-cleaning devices.

20. CONCLUSION

The purpose of this course was to increase awareness of the various implications of tobacco use and exposure and to provide examples of healthcare assessment and treatment. It should be noted that the health complications incorporated here are only part of an exhaustive list of issues linked to tobacco smoke—more findings are uncovered each day. Changes in policy (e.g., taxation, bans in federal and other public establishments, regulation by the FDA) may spur the public to take a second look before using tobacco products or exposing themselves and friends/family to its smoke. However, it is important to continue to combat tobacco use and exposure at the primary care level at every possible opportunity. Brief intervention methods are more helpful than many realize. Further, although cigarettes have historically been implicated for the majority of health problems, it is important to be cognizant of other tobacco products' health effects and the evolving trends of tobacco use.

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91573 • Diagnosing and Treating Overweight and Obese Patients

John J. Whyte, MD, MPH

www.netce.com

Copyright © 2021 NetCE, All rights reserved.

Although obesity has been shown to be a risk factor for numerous diseases such as diabetes, coronary artery disease, and sleep apnea, most overweight and obese people do not consider themselves at higher risk for medical problems or premature death. News stories on various diets have caused confusion among many patients and health providers, leading to frustration and subsequent inaction. This course will help educate physicians and other healthcare professionals about the epidemiology and treatment of overweight and obese patients. Using current national guidelines, the clinical management of patients will be discussed. Clinical presentation, diagnosis, behavioral, and pharmacological management will be reviewed. Surgical options for morbidly obese patients will also be examined. Steps to address and treat recidivism will be explored. Finally, current reimbursement issues will be discussed.

Table of Contents

91573 • Diagnosing and Treating Overweight and Obese Patients

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. CLINICAL BACKGROUND

DEFINITION OF OVERWEIGHT AND OBESITY

EPIDEMIOLOGY OF OBESITY

COST OF OBESITY AND RELATED ILLNESSES

3. PATHOPHYSIOLOGY

4. RISK FACTORS AND COMORBIDITIES

5. TREATMENT

BEHAVIORAL

DIET

PHYSICAL ACTIVITY

PHARMACOLOGIC AGENTS

SURGICAL OPTIONS

6. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

7. INSURANCE COVERAGE

STATE AND FEDERAL PROGRAMS

PRIVATE INSURANCE

TAX DEDUCTIONS

8. SUMMARY

9. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

91573 • Diagnosing and Treating Overweight and Obese Patients

Education Category. Community Health

Release Date. 02/01/2021

Expiration Date. 01/31/2024

Course Overview

Although obesity has been shown to be a risk factor for numerous diseases such as diabetes, coronary artery disease, and sleep apnea, most overweight and obese people do not consider themselves at higher risk for medical problems or premature death. News stories on various diets have caused confusion among many patients and health providers, leading to frustration and subsequent inaction. This course will help educate physicians and other healthcare professionals about the epidemiology and treatment of overweight and obese patients. Using current national guidelines, the clinical management of patients will be discussed. Clinical presentation, diagnosis, behavioral, and pharmacological management will be reviewed. Surgical options for morbidly obese patients will also be examined. Steps to address and treat recidivism will be explored. Finally, current reimbursement issues will be discussed.

Audience

This course is designed for all physicians, nurses, and social work/counseling groups involved in the care of patients who are overweight or obese.

Course Objective

Obesity is epidemic in the United States. As statistics indicate that the problem is growing, the purpose of this course is to educate healthcare professionals about the epidemiology and treatment of overweight and obese patients. Clinical management, presentation, diagnosis, and behavioral and medical management will be reviewed to assist healthcare professionals in encouraging their patients to lose weight and prevent obesity-related comorbidities.

Learning Objectives

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

1. Discuss the clinical background of obesity, noting the various definitions.

2. Discuss the epidemiology of overweight and obese individuals in the United States, based on age, race, and socioeconomic status.

3. Describe the pathophysiology of obesity, including genetic and environmental factors.

4. Identify the risk factors for and comorbidities of obesity.

5. Explain the various treatment modalities for overweight/obese patients.

6. Describe dietary and physical activity recommendations.

7. Discuss available pharmacologic agents, including indications and adverse reactions, used to treat obese/overweight patients.

8. Discuss surgical options, including restriction and bypass operations.

9. Explain the reimbursement climate for overweight/obesity treatments.

10. Outline considerations necessary when caring for patients for whom English is a second language.

Faculty

John J. Whyte, MD, MPH, is currently the Chief Medical Officer at WebMD. In this role, he leads efforts to develop and expand strategic partnerships that create meaningful change around important and timely public health issues. Previously, Dr. Whyte was the Director of Professional Affairs and Stakeholder Engagement at the FDA’s Center for Drug Evaluation and Research and the Chief Medical Expert and Vice President, Health and Medical Education at Discovery Channel, part of the media conglomerate Discovery Communications.
Prior to this, Dr. Whyte was in the Immediate Office of the Director at the Agency for Healthcare Research Quality. He served as Medical Advisor/Director of the Council on Private Sector Initiatives to Improve the Safety, Security, and Quality of Healthcare. Prior to this assignment, Dr. Whyte was the Acting Director, Division of Medical Items and Devices in the Coverage and Analysis Group in the Centers for Medicare & Medicaid Services (CMS). CMS is the federal agency responsible for administering the Medicare and Medicaid programs. In his role at CMS, Dr.Whyte made recommendations as to whether or not the Medicare program should pay for certain procedures, equipment, or services. His division was responsible for durable medical equipment, orthotics/prosthetics, drugs/biologics/therapeutics, medical items, laboratory tests, and non-implantable devices. As Division Director as well as Medical Officer/Senior Advisor, Dr. Whyte was responsible for more national coverage decisions than any other CMS staff.
Dr. Whyte is a board-certified internist. He completed an internal medicine residency at Duke University Medical Center as well as earned a Master’s of Public Health (MPH) in Health Policy and Management at Harvard University School of Public Health. Prior to arriving in Washington, Dr. Whyte was a health services research fellow at Stanford and attending physician in the Department of Medicine. He has written extensively in the medical and lay press on health policy issues.

Faculty Disclosure

Contributing faculty, John J. Whyte, MD, MPH, 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

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

Alice Yick Flanagan, PhD, MSW

Randall L. Allen, PharmD

James Trent, PhD

Division Planners Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

Implicit Bias in Health Care

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

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

1. INTRODUCTION

Obesity is epidemic in the United States and a growing health issue worldwide. Estimates show that more than 78% of the adult U.S. population is either overweight, obese, or extremely obese [1,75]. While the proportion of the population categorized as overweight has remained essentially static since 1960, the numbers of obese and extremely obese have increased by 65% and 170%, respectively, in just the last two decades [1]. The worldwide prevalence of overweight and obesity has doubled since 1980; at present, nearly one-third of the world's population is classified as overweight or obese. The trend is evident in all ages and geographic regions irrespective of ethnicity or socioeconomic status [120].

Although genetic and hormonal factors play a role, the foremost causes of the obesity epidemic are unhealthy eating habits and lack of work-based and/or leisure-time physical activity. According to data published by the Centers for Disease Control and Prevention (CDC), approximately half of U.S. adults do not perform the minimum amount of exercise needed to help maintain a healthy weight and prevent diseases such as diabetes and high blood pressure; 26% of adults do not perform any exercise at all [2]. This is despite the fact that the benefits of exercise are well-documented, including reducing the risk of heart disease, improving glycemic control in diabetes, improving blood pressure, alleviating depression, and generally preventing morbidity and mortality. Americans are also not making ideal nutritional choices. In 2015, only about 10% of adults and 6% of high school students met nutritional guidelines for fruit and vegetable consumption [3,4].

Compounding this problem, studies have found that less than 30% of overweight patients and approximately 40% of obese patients reported ever receiving advice from their physician to increase their physical activity or reduce their weight [41,100]. Even when physicians do give advice, too often they simply admonish patients to exercise, which has been shown to have little, if any, effect. Of the 30% who did receive advice in one study, only 38% received help in formulating a specific activity plan and only 42% received follow-up support [41].

Although obesity has been shown to be a risk factor for numerous diseases, such as diabetes, coronary artery disease, and sleep apnea, most overweight and obese people do not consider themselves at higher risk for medical problems or premature death. News stories on various diets have caused confusion among many patients and health providers, leading to frustration and subsequent inaction. However, patients generally want to receive information on weight reduction strategies. In a study asking patients to respond to the statement, "If my doctor advised me to exercise, I would follow his/her advice," more than 90% of respondents agreed with the statement [73].

Numerous treatments for obesity exist. The cornerstone of any treatment regimen includes behavioral modification, focusing on diet changes and exercise regimens. Additional therapies include pharmaceuticals, which can help sustain weight loss, as well as surgical therapies for those patients whose weight is causing significant health problems. Physicians and other healthcare professionals should recognize that recidivism and failure is quite high with all of these therapies, and successful treatment will require a concerted effort on the part of physicians and other providers.

The following case study will be referenced throughout the text to illustrate the challenges of treating overweight/obese patients:

Patient B is a white woman, 52 years of age, with a history of type 2 diabetes mellitus, arthritis, hypertension, and hyperlipidemia who presents for a new patient evaluation. She is 5'2" and weighs 150 lbs. She is currently taking metformin, simvastatin, lisinopril, and celecoxib. On exam, her blood pressure is 150/92 mm Hg; heart rate 84 beats per minute; and respiration 16 breaths per minute. Laboratory analysis demonstrates blood glucose of 140 mg/dL; glycosylated hemoglobin 9.5%; cholesterol 205 mg/dL; low-density lipoprotein (LDL) 115 mg/dL; high-density lipoprotein (HDL) 52 mg/dL; and triglycerides 190 mg/dL. She asks for help in trying to lose weight. She expresses difficulty managing her weight since adolescence and has repeatedly cycled up and down with various fad diets and exercise programs. The patient states that she does not presently exercise because of arthritis in her knees and is confused about what she should or should not be eating. She wants to know if her weight really matters, because she knows plenty of people who are heavier than she and they seem to be fine. If it does matter, she wants to know what she should be doing.

2. CLINICAL BACKGROUND

DEFINITION OF OVERWEIGHT AND OBESITY

Body Mass Index

The definition of obesity has been evolving over the past few decades. Historically, obesity has been defined simply as an excess of body fat [9]. Today, however, measurement of body weight and height is most often utilized as a measure of obesity.

Initially, weight-for-height tables were used to determine the normal weight range for a given height. These tables were replaced with other indices when they were found to be of limited value due to their general estimates of frame size and bias toward the white population [10]. These tables were replaced with the body mass index (BMI), which is calculated by weight in kg/height in meters^2 or [weight (lbs)/height (inches)2] x 703. For most individuals, BMI correlates well with the proportion of body fat.

BMI is considered the general standard for defining obesity (Figure 1). An online BMI calculator is available at https://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmicalc.htm.

Figure 1: ADULT BODY MASS INDEX

Source: [6]

In 1990, the U.S. Department of Health and Human Services' Dietary Guidelines for Americans defined overweight as a BMI of at least 27 and obesity as a BMI of at least 30. Eight years later, the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) released guidelines that lowered the cutoff for overweight to a BMI of 25, but maintained the definition of obesity as a BMI of at least 30 [11]. (Note: Roughly, a BMI >25 corresponds to about 10% over one's ideal weight; a BMI >30 typically is an excess of 30 lbs for most people. These are rough estimates.) The term extreme (or morbid) obesity refers to obesity with a BMI greater than or equal to 40. These final definitions are consistent with definitions used by other national and international organizations, such as the World Health Organization (WHO). Table 1 illustrates the similarities in the classifications used by the WHO and the NHLBI.

Table 1: BODY MASS INDEX CLASSIFICATION

WHO Classification

BMI (kg/m^2)

Underweight

<18.5

Normal

18.5–24.9

Preobese

25.0–29.9

Obese Class I

30.0–34.9

Obese Class II

35.0–39.9

Obese Class III

>40.0

The additional classification of obesity (Class I–III) was used to determine if the prevalence rate for comorbidities vary with class range. In addition, the BMI classification used 5 BMI unit intervals to classify obesity rather than using a single cut-off value.

Source: [68]

These definitions are based on epidemiologic evidence that suggests health risks are greater at or above a BMI of 25, compared to those below 25. The risk of death from all causes rises with increasing BMI, with a significant increase at BMI greater than 30. In a large cohort study published in the New England Journal of Medicine in 2006, persons with a BMI greater than 30 had mortality rates two to three times that of persons with BMI between 20 and 25 [12].

BMI does have limitations as a measurement of overweight and obesity. Although BMI provides a more accurate measure of total body fat compared with body weight alone, it can be misinterpreted in some circumstances. For instance, a muscled athlete would be considered overweight if BMI were used alone, despite his or her very low fat content. BMI can also underestimate body fat in persons who have lost muscle mass, such as elderly patients. Therefore, using other estimates, such as the triceps skinfold test, in addition to BMI may provide a better estimate of a patient's weight-related health status, especially in some atypical patients. (Note: There are various anatomic sites around the body that may be used for the triceps skinfold test, other than the triceps. The tester pinches the skin, raising only a double layer of skin and the underlying adipose tissue. The calipers are then applied 1 cm below and perpendicular to the pinch. Three readings are taken and then averaged to produce a final reading that is used in an equation to provide a more accurate estimate of body fat.) As a general reference, the U.S. Department of Defense states that the maximum allowable percent body fat of military personnel is 26% for men and 36% for women [13].

Waist Circumference

In defining obesity, NIH also identified excess fat in the abdomen out of proportion to total body fat as an independent predictor of risk factors and morbidity [11]. The gender-specific cutoffs for waist circumference are as follows:

- Men: >40 inches (102 cm)

- Women: >35 inches (88 cm)

These are of value only for those with a BMI between 25.5 and 34.9. It is not useful to measure waist circumference in individuals with BMI >35, as such patients are already at increased risk.

In this example, Patient B's BMI is 27. Her waist circumference is 35.5 inches. Both of these measurements place her at increased risk for morbidity and death. Intervention should be made.

EPIDEMIOLOGY OF OBESITY

Since 1960, the prevalence of obesity has been on an upward trajectory, with rates increasing dramatically in the past few decades. In 1980, the percentage of obese and extremely obese adults was 15% and 1.4% of the total population, respectively; by 1994, the numbers had increased to 23.2% and 3.0% [1]. In the year 2000, 30.9% of the adult population was obese and 5.0% were extremely obese [1]. Data collected in 2017–2018 show that 42.4% are obese and 9.2% are extremely obese (class III); an additional 31.9% of adults are overweight [1,75]. That means that more than 83% of Americans 20 years of age or older are above a healthy weight and are at an increased risk for disease and early death.

With race/ethnic origin not factored, the prevalences of overweight and obesity are higher for men (38.2% and 43.0%) than for women (25.8% and 41.9%), but rate of extreme obesity is higher among women [75]. In the overall population, approximately 6.9% of men and 11.5% of women are extremely obese [1,75].

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force (USPSTF) recommends that clinicians offer or refer patients with a BMI of 30 or greater intensive, multicomponent behavioral interventions.

https://jamanetwork.com/journals/jama/fullarticle/2702878

Last Accessed: January 25, 2021

Strength of Recommendation: B (The USPSTF strongly recommends that clinicians routinely screen eligible patients. The USPSTF found good evidence that obesity screening improves important health outcomes and concludes that benefits substantially outweigh harms.)

When considered as a single race, the prevalences of obesity among individuals of African (49.6%) and Hispanic (44.8%) descent are greater than that reported for adults of European or Caucasian descent (42.2%) [75]. Native American/Alaska Natives and Native Hawaiian/Pacific Islanders have an obesity prevalence of 43.7% and 34.6%, respectively [42,74]. Asian Americans are an exception, with a prevalence of 17.4%, much lower than in the general population. Although the rate of obesity is higher in many American racial/ethnic groups compared to non-Hispanic whites, white individuals make up the majority of cases [75].

Obesity is most common among individuals 40 to 59 years of age, with 44.8% of American men and women in this age group fitting this description [42,75]. However, roughly 57.5% of African American women and 51.1% of Hispanic women in this age group are obese [42,75]. There is also a higher incidence of obesity (greater in women than in men) with lower socioeconomic status among all races [42,74].

Of particular concern is the increase in the number of children who have high BMIs. Presently, nearly 14% of children 2 to 5 years of age, 18.4% of children 6 to 11 years of age, and 20.6% of adolescents between 12 to 19 years of age are obese [14,110]. Hispanics (25.8%) and non-Hispanic blacks (22.0%) have a higher prevalence of obesity than non-Hispanic whites (14.1%). The prevalence of obesity in adolescents has more than tripled since 1970 [14]. This is especially troubling because overweight adolescents have a 70% chance of becoming overweight or obese adults; if their parents are overweight or obese, this chance increases to 80% [101]. Adolescent obesity is associated with increased risk for cardiovascular disease, type 2 diabetes, and certain malignancies (e.g., leukemia, Hodgkin lymphoma, colorectal cancer, breast cancer) in adulthood [121].

COST OF OBESITY AND RELATED ILLNESSES

The impact of obesity on general health is significant. A BMI of 35 or greater increases mortality 40% for women and 62% for men, and obesity in general results in an estimated 100,000 to 300,000 preventable deaths per year [7,8]. Preventable deaths attributable to poor diet and inactivity are second only to deaths due to tobacco use, but as cigarette smoking has declined, preventable deaths attributable to obesity-related conditions are set to overtake tobacco-related deaths [76].

The economic costs are significant as well, with the total annual costs of obesity estimated to be $149.4 billion [5,16,122]. Roughly 10% of the nation's healthcare expenses are obesity-related, and this is expected to increase to between 16% and 18% by 2030 [5,102]. In addition, obese patients have a 46% increase in inpatient costs, 27% increase in physician visit and outpatient costs, and spend 80% more on prescription drugs than those with normal BMIs [112].

As noted, although the impact of obesity on general health has become highly publicized, most overweight Americans do not consider themselves at higher risk for medical problems or premature death. According to the results of a survey conducted by Shape Up America, 7 out of 10 overweight respondents said that their excess pounds were not a health concern. However, the survey results indicated that approximately 33% of the respondents had already developed a weight-related medical condition [54]. Despite the evidence linking obesity and poor health, many Americans still consider excess weight to be only a cosmetic issue. This is in light of the fact that more than 80% of patients with diabetes are overweight or obese [12].

3. PATHOPHYSIOLOGY

One of the most common, but oversimplified, explanations for obesity is that it is merely the result of sustained caloric imbalance. Caloric imbalance can be caused by either excessive intake of energy or decreased energy expenditure. With the increased availability of foods with poor nutrition content and decreasing desire for an active lifestyle, the resulting obesity is unsurprising. The cultural evolutionary explanation of obesity argues that our species evolved in an environment where food was often scarce, so our bodies developed an "evolutionary predisposition to store energy in the form of fat" in preparation for those shortages [18].

Though the scientific community has been unable to identify a single etiologic agent for obesity, there have been clinical advances in the past two decades. Obesity is known to be associated with certain exogenous causes. Genetic factors gained national attention after the discovery of leptin in 1995 by positional cloning in the leptin-deficient mouse model of obesity [19]. Leptin (derived from the Greek word leptos, meaning "thin") is a 16-kilodalton adipocyte-derived hormone from the ob gene and has been the focus of many genetic investigations to elucidate the pathophysiology of obesity. Though this finding is relatively recent, its existence was suspected twenty years ago. In 1978, Coleman proposed that a circulating factor in the plasma of the db mouse strain, which is both diabetic and obese, could reduce the obesity of the ob mouse (a strain of mice with mutations in leptin) [20]. The db mice were found to have mutations in the leptin receptor and were subsequently resistant to the leptin, unlike the ob mice who possessed a mutated leptin gene but functional leptin receptors. Further investigations revealed that injections of leptin in ob mice could cure obesity and diabetes. After locating the human homologues to the leptin gene and its receptor in 1999, the chromosomal locus containing the leptin gene was determined to be genetically related to human body weight [21]. However, only a few people with mutated leptin genes have been identified, while the majority of obese patients have fully functional leptin genes and receptors.

Genetic diseases with associated obesity include Schinzel syndrome, Bardet-Biedel syndrome, Albright hereditary osteodystrophy, and Prader-Willi syndrome. Many of these genetic disorders present with dysmorphic features, developmental delay, and obesity in addition to changes seen specifically with each disorder [22]. For instance, young males with Prader-Willi syndrome present with the features described above as well as with linear growth defects and undescended testicles.

Overall, the relationship between genetics and obesity cannot be fully determined at this time. Evidence suggests a link between the two, implying that genetics is one of the complex factors involved in the development of this prevalent condition. Although many argue that "obesity genes" cannot be responsible for the epidemic, because the gene pool in the United States had not changed significantly between 1980 and 1994, the etiology of obesity is most likely multifactorial [23]. In 2010, one group of researchers confirmed 14 genetic variations and discovered an additional 18 variations associated with obesity [77]. In 2015, the group published additional research that identified a total of 97 genetic variations [111]. Although the progress with genetic variations related to BMI is promising, further research is needed to clarify the influence of genetics.

Biologic factors must also be considered. Proteins and receptors appear to have a role in weight control. For example, orexin A and B are located in the lateral hypothalamus, an area which may regulate body weight. Ongoing research may help determine the role of orexin in obesity.

Environmental factors seem to play a significant role as well. Data from a longitudinal twin-family study and co-twin control studies combined with population-based data on patterns of dietary intake and physical activity provide some evidence that environment can contribute to obesity [74]. Environmental factors include technologic advances in food processing, marketing, advertising, and behavioral lifestyle. Some theorize that obesity is self-fulfilling in that if an individual is told they are predisposed to becoming fat, he or she will decide there is no point in eating healthy or exercising [78].

Occasionally, obesity is due to endocrinologic origins from hypothyroidism or Cushing syndrome. However, both of these conditions, along with other diseases associated with obesity, present with additional signs and symptoms. Moreover, they typically have appropriate treatment regimens that address the underlying cause of the obesity.

Given the influence of genetic and environmental factors, the issue of obesity cannot be simplified to sustained caloric imbalance. There are complex metabolic, psychologic, endocrinologic, social, and cultural influences regulating energy intake and energy expenditure, which indicates that obesity is more than a lack of self-control when presented with food.

4. RISK FACTORS AND COMORBIDITIES

Obesity is associated with large number of major medical concerns, such as elevated serum triglycerides (>200 mg/dL), and is a risk factor for many diseases, including [24,80,81,112]:

- Sleep apnea

- Stroke

- Dementia

- Hypertension

- Dyslipidemia

- Coronary heart disease

- Type 2 diabetes

- Osteoarthritis

- Colon, breast, endometrial, and possibly other cancers

- Gallbladder disease

- Stress incontinence

- Amenorrhea/menorrhagia

There is evidence that excess body weight is associated with increased risk for a range of malignancies: endometrial, esophageal, renal, pancreatic, and hepatocellular carcinomas and colorectal, postmenopausal breast, ovarian, gallbladder, and thyroid cancers [123]. In the Nurses' Health Study (a large prospective cohort study involving more than 100,000 women), women older than 35 years with a BMI greater than 27 were found to have an increased risk for cancer, heart disease, and other diseases. For instance, women gaining more than 20 pounds (9 kg) between 18 and 35 years of age doubled their risk for breast cancer compared with women who maintained their weight [25]. Additionally, the age and smoking-adjusted relative risk of non-fatal myocardial infarction and fatal coronary disease for women with BMI 25 to 29 was 1.8; for women with BMI greater than 29, it was 3.3.

Left ventricular hypertrophy (LVH) is often seen in obese patients and correlates to the resulting systemic hypertension [26]. The risk for type 2 diabetes has been reported to be twofold in the mildly obese, fivefold in moderately obese, and tenfold in extremely obese persons [27].

In one study, individuals with a BMI of at least 30 had an elevated risk of pancreatic cancer compared to those with a BMI of less than 23 [28]. A study published in 2012 involving 720,000 men found that overweight adolescents had more than double the risk of developing pancreatic cancer as young or middle-age adults compared to normal weight individuals [79]. In general, obese patients showed an increased risk of 5.4 times that of non-obese patients for endometrial cancer, 3.6 times for gallbladder cancer, 2.4 times for cervical cancer, 1.6 times for ovarian cancer, 1.5 times for breast cancer, 1.7 times for colorectal cancer, and 1.3 times for prostate cancer [29]. Cancer mortality is also increased in obese patients.

The term "metabolic syndrome" has been used when three or more of the following risk factors are present:

- Abdominal obesity: waist circumference >40 inches in men or >35 inches in women

- BMI >25

- Triglycerides >150 mg/dL

- HDL <40 mg/dL in men, <50 mg/dL in women

- Blood pressure >130/>85 mm Hg

- Fasting glucose >110 mg/dL or two-hour post glucose challenge >140 mg/dL

The development of this metabolic disorder is promoted by excess body fat and physical inactivity. It is believed to predispose patients to heart disease, cerebrovascular disease, and diabetes due to the associated dyslipidemia, hypertension, glucose intolerance, and hypercoagulability. Reduction in body weight and body fat through exercise also improves glycemic control and reduces the complications of diabetes [82].

One can stratify overweight and obese patients to determine their absolute risk by incorporating the presence of comorbidities and cardiovascular disease risk factors. Patients with coronary heart disease, other atherosclerotic diseases, type 2 diabetes, and sleep apnea are at "very high risk" for death; in comparison, those with three or more cardiovascular risk factors are at the "highest absolute risk." (Note: These risk factors include hypertension, hypercholesterolemia, smoking, family history of early heart disease, and age [men older than 45 years of age, women older than 55 years of age].)

During the course of the coronavirus disease (COVID-19) pandemic in the United States, obesity emerged as an independent risk factor for severe COVID-19, especially among adult patients younger than 60 years of age. Multiple reports, ranging from single-center studies to analyses of records from large patient care networks, consistently found that severe obesity (body mass index >35) was associated with higher rates of hospitalization, respiratory failure, and mortality from COVID-19 [124,125]. The risk varies with degree of obesity and is independent of obesity-associated comorbidities. The impact is more striking among men than women. There are multiple mechanisms by which obesity may contribute to adverse outcomes in patients with COVID-19. In addition to obstructive pulmonary physiology and sleep apnea, severe obesity is associated with immune dysfunction, depression of anti-inflammatory signaling, increased pro-inflammatory signaling, and alterations in vascular endothelium that worsen lung inflammation and alveolar damage [124].

Conditions that are associated with obesity usually worsen as the degree of obesity increases. For instance, one study showed that the risk of developing dementia increases 3.6 times in individuals with high BMIs (particularly in individuals with both high BMI and abdominal obesity) [81]. Moreover, individuals' health typically improves and risk factors lessen as obesity is successfully treated. In addition, overweight and obese patients often suffer from emotional distress and face discrimination in their personal and professional lives. Many overweight patients suffer from social stigmatization and isolation, which subsequently increases morbidity and mortality. In one study, 13% of all women reported delaying or canceling a doctor's appointment because of concerns about their weight (e.g., embarrassment, fear of a lecture), while 32% of those with BMI greater than 27 and 55% with BMI greater than 35 had done the same [30].

Patient B has several comorbidities, including diabetes, dyslipidemia, hypertension, and osteoarthritis. She is at "very high risk" for premature death. Most of these conditions would improve if her weight were reduced.

5. TREATMENT

The goal of therapy is to reduce body weight as well as body fat and maintain a lower body weight for the long term. The rate of weight loss should be 1 to 2 lbs per week, with a goal of 10% weight loss over six months. Moderate weight loss, defined as 5% to 10% reduction in baseline weight, is associated with clinically meaningful improvement in obesity-related metabolic risk factors and comorbidities, including improved pancreatic beta-cell function, increased sensitivity of liver and skeletal muscle to insulin, and significant reductions in systolic and diastolic blood pressure [126]. It is important to note that weight loss as modest as 10 lbs reduces the risk factors for several diseases. Such weight loss can lower blood pressure, lower blood sugar, reduce inflammation, and improve lipid levels. Unfortunately, most patients believe a weight loss of 30 to 40 lbs is necessary to medically benefit and become discouraged when they do not see such results [31]. Patients should set realistic expectations from the start, with the idea that small losses of 10 lbs can be considered successes. Moreover, physicians must emphasize the importance of long-term weight management and weight loss rather than short-term extreme weight reduction.

For high-risk obese persons, sustained moderate weight loss aids in prevention of disease and larger relative weight reductions may lead to disease resolution, Obese patients with impaired glucose tolerance who received an intensive lifestyle intervention had a mean weight loss of 5.6 kg at 2.8 years and a 58% relative reduction in the risk of type 2 diabetes [126]. In a study comparing lifestyle intervention with bariatric surgery for management of obese patients (BMI 30 to 40) with type 2 diabetes, the mean reduction in body weight at three years was 25% for patients randomized to Roux-en-Y gastric bypass, and 40% of patients in this cohort experienced complete or partial remission of diabetes [127].

Of note, weight reduction treatment is not recommended for pregnant women or for patients with unstable mental or medical conditions. Patients with terminal illness may also be excluded from treatment.

Before any treatment plan is attempted, one must assess the patient's willingness and motivation. If a patient is not willing to attempt weight loss, despite the risks as well as existence of current medical problems, treatment will be unsuccessful. Patients cannot be forced to lose weight, nor can they be berated or shamed into doing it. A productive dialogue focusing on the patient's goals and the health risks of being overweight will be the most successful.

In 2000, the National Institutes of Health (NIH) released guidelines for identification, evaluation, and treatment of obesity [69]. In this guideline, a 10-step treatment approach was presented. Expanding on these guidelines, in 2013, the American Heart Association (AHA) and American College of Cardiology (ACC) released an evidence-based, peer-reviewed guideline for the management of overweight and obesity in adults [112]. In these guidelines, the AHA and the ACC recommended that obesity be classified as a disease and devised a treatment plan using a chronic diagnosis management model. Both will be discussed in further detail in this course.

Patient B clearly is seeking guidance. She is interested in a treatment plan and illustrates this by seeking additional information despite her failure at past attempts. She must realize that her weight really does matter and indeed is already contributing to her morbidity. Her medical conditions are stable. She is eligible and ready for treatment.

The 10-step approach, as shown in Table 2, is recommended by the NIH in developing an assessment and treatment plan.

Table 2: TEN STEPS TO ASSESSING/TREATING OVERWEIGHT AND OBESITY IN THE PRIMARY CARE SETTING

1. Measure height and weight. Calculate BMI.

2. Measure waist circumference.

3. Assess comorbidities.

4. Determine if patient should be treated.

5. Determine if patient is ready and motivated.

6. Recommend and review diet.

7. Discuss physical activity and goal.

8. Review weekly food and activity report.

9. Consider medications/surgery.

10. Re-evaluate.

Source: [69]

The goal of the 2013 guideline published by the AHA/ACC was to, using an evidence-based approach, increase the quality and rigor of the overweight and obesity treatment guidelines, and to assist primary care physicians to more aggressively diagnose and treat obesity as a disease. The guideline consists of a review of assessment methods and treatment modalities that incorporate the steps recommended by the NIH in Table 2, but also includes a comprehensive algorithm that guides primary care physicians through specific steps, and references expanded sections describing the process that should be used to proceed with treatment [112]. The complete guideline with evidence-based findings, including algorithm, is available at https://www.ahajournals.org/doi/full/10.1161/01.cir.0000437739.71477.ee.

The treatment of obesity includes three types of therapies:

- Behavioral

- Pharmacologic

- Surgical

BEHAVIORAL

Behavioral therapy includes a combination of diet and exercise and is the cornerstone of any weight reduction treatment. Diet and exercise remain a significant challenge for most adults, as evidenced by the number of overweight and obese people. Most adults do not eat nutritiously and do not exercise regularly. About 26% of adults report engaging in no physical activity at all in the past month [2]. NHIS data show nearly 47% of adults meeting neither aerobic nor muscle-strengthening activity recommendations, with only about 20% of adults meeting these guidelines [32].

DIET

Evidence Based Practice Recommendation

The Department of Veterans Affairs and the Department of Defense assert that clinicians should offer any of several diets that produce a caloric deficit and have evidence for weight-loss efficacy and safety (e.g., low-carbohydrate, Dietary Approaches to Stop Hypertension, low-fat).

https://www.healthquality.va.gov/guidelines/CD/obesity

Last Accessed: January 25, 2021

Strength of Recommendation: A (There is high certainty that the net benefit is substantial.)

Reviewing and modifying diet is one of the most important steps in helping patients lose weight. As a simple rule, caloric intake should be reduced by 500–1,000 calories per day from a patient's current level. Patients with a BMI of 27–35 should reduce total calories by 300–500 daily; patients with BMI greater than 35 should reduce total calories by 500–1,000 daily. This reduction will produce the recommended weight loss of 1 to 2 lbs per week in most patients. The recommended number of total calories will vary depending upon activity level: 1,600 calories for most sedentary women, 2,200 calories for sedentary men or active women, 2,600 calories for active men. To calculate specific caloric requirements, the following approach is useful:

- First calculate resting energy expenditure (REE)

- For men: (10 x weight (kg)) + (6.25 x height (cm)) - (5 x age + 5)

- For women: (10 x weight (kg)) + (6.25 x height (cm)) - (5 x age -161)

- Multiply REE by activity factor (AF).

For light activity, AF is 1.5 for women, 1.6 for men. For high activity, AF is 1.6 for women, 1.7 for men.

In terms of diet specifics, conflicting information exists. Many newspapers and magazines offer detailed articles addressing the successes of individual patients on the Atkins diet, the Ornish plan, the Zone diet, the Body-for-Life program, and others (Table 3). Differences among these diets leave patients confused and discouraged. The Internet compounds the confusion by providing unfiltered information and a lack of emphasis on current research and evidence-based medicine.

Table 3: VARIOUS POPULAR DIETS

Diet Plan

Breakdown

Mechanism of Action

Atkins/Ketogenic

High fat (55% to 65%) Low carbs (<100 g/day)

Reducing carbohydrates causes ketosis, which induces use of excess body fat for fuel

Ornish

High complex carbs Low fat (<10%)

Vegetarian

Reduction in total calories and total fat

Zone

40% carbs, 30% protein, 30% fat

Reduction in total calories causes weight loss

Body-for-Life

High protein, moderate carbs, low fat, all eaten at same time, with small, frequent meals

More steady release of insulin causes less fat deposition

Source: Compiled by Author

There has been some progress in assessing these various diets, but without strong evidence in favor of any particular one. In 2003, a study conducted at the University of Pennsylvania, supported by the NIH, concluded that the Atkins diet resulted in greater weight loss (approximately 4%) at the end of one year, as well as an improvement in some cardiovascular risk factors [33]. In 2005, researchers at Tufts University compared the Atkins, Ornish, Weight Watchers and Zone diets, with weight reduction and cardiovascular disease reduction as outcomes. (The Atkins diet restricts carbohydrates, the Zone diet involves balancing macronutrient intake, the Ornish diet restricts fat, and the Weight Watchers diet restricts calories.) After one year, all diets produced moderate weight loss and improvement in HDL, C-reactive protein, and insulin levels. Increased adherence to each diet was associated with increased weight loss, but overall adherence was low [34]. In 2007, researchers reported on a randomized trial of the Zone, Atkins, Ornish, and LEARN diets in 311 overweight or obese non-diabetic, premenopausal women. (The LEARN diet is based on national nutrition guidelines.) Again, all diets provided modest weight loss at one year. The Atkins diet produced the most weight loss, with improvements in cardiovascular risk factors that were comparable to or better than the other diets. However, weight loss trajectories had not stabilized at the end of the study, suggesting that longer observation might produce different outcomes [35]. In 2014, researchers compiled information from 48 randomized trials regarding the effectiveness of named diet plans, including Atkins, Ornish, Zone, and others. It was found that significant weight loss occurred with any of the diets, with minimal differences between the amount of weight lost at 6- and 12-month follow-up. The researchers concluded that, of the diets reviewed, any diet that an individual will able to adhere to should be recommended for weight loss [113]. While information on specific diets is becoming more consistent, for each diet plan, larger and longer studies are necessary to assess long-term benefits and risks.

It is important that any diet contain food from all food groups, so that it remains nutritionally adequate. "Fad diets" typically have nutritional deficiencies, and this is one reason why they are potentially dangerous. For example, high-fat, low-carbohydrate diets are low in vitamins E and A, thiamin, folate, calcium, magnesium, and zinc. Low-fat diets are typically deficient in vitamin B12.

Instead of recommending a specific type of diet, physicians should encourage patients to focus on well-balanced meals from the various food groups. Recommendations from the Institute of Medicine provide a useful framework, as do the Dietary Guidelines for Americans.

Institute of Medicine (IOM) Dietary Reference Intakes

In 2005, the Institute of Medicine (IOM) issued its first volume in a series of reports that suggest dietary reference values for intake of nutrients. This project was released by the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board from the IOM, a division of the National Academies. The report establishes the Dietary Reference Intakes (DRIs) for energy and macronutrients: carbohydrates, fiber, fat, fatty acids, cholesterol, protein, and amino acids. A synopsis of the main findings follows. The full report, with the detailed rationale used to establish each guideline/recommendation, can be accessed online at https://www.nap.edu/read/10490/chapter/1.

The following ranges are recommended for percentage of daily caloric intake [36]:

- Carbohydrates: 45% to 65%

- Sugars: 25%

- Fats: 20% to 35%

- Protein: 10% to 35% (dietary protein should be 0.8 g/kg/day)

- Fiber:

- Men younger than 50 years of age: 38 grams per day

- Women younger than 50 years of age: 25 grams per day

- Men older than 50 years of age: 30 grams per day

- Women older than 50 years of age: 21 grams per day

The report distinguishes the different types of fat. Saturated fat and trans fatty acids typically raise the amount of LDL in the bloodstream. Because this type of fat has little value, there is no recommended intake requirement, and people should be advised to keep consumption as low as possible. Sources include meat, poultry, baked goods, and dairy products, as well as some vegetable sources, such as coconut and palm oils.

In contrast to saturated fat, monounsaturated and polyunsaturated fat reduce blood cholesterol levels. As much as possible, one should replace saturated fat with unsaturated fat. Two types of polyunsaturated fat are critical elements of a healthy diet because they are not synthesized in the body. These are omega-3 and omega-6. Omega-3, or alpha-linolenic acid, consumption should be 1.6 g for men and 1.1 g for women; omega-6, or linoleic acid, consumption should be 17 g for men and 12 g for women daily. Sources of monounsaturated fat include plants, peanuts, avocado, and canola oil. Sources of polyunsaturated fat include safflower, sunflower, corn, and soybean oils. Omega-3 fatty acids are found in oily fish and flaxseed.

An interactive dietary reference intake calculator is available at https://www.nal.usda.gov/fnic/dri-calculator. Height, weight, age, and activity level are inputted into the calculator, and a complete individualized profile of caloric needs—plus vitamin, mineral, and water intake—is outputted for the patient.

Dietary Guidelines for Americans, 2020–2025

The 2020–2025 Dietary Guidelines for Americans recommends a healthy eating pattern to "help people achieve and maintain good health and reduce the risk of chronic diseases throughout all stages of the lifespan" [70]. Decreased caloric intake with increased exercise is suggested for people who need to lose weight, with the goal of slow and steady weight loss over time. The 2020–2025 Dietary Guidelines for Americans features four new overarching guidelines that provide a flexible framework for encouraging individuals and other areas of society to assist in making healthier food choices throughout life. These guidelines use a social-ecologic model for food and physical activity choices that acknowledge individual preference, cultural differences, traditional food choices, and individual budget. The four overarching guidelines are [70]:

- Follow a healthy dietary pattern at every life stage. At every life stage—infancy, toddlerhood, childhood, adolescence, adulthood, pregnancy, lactation, and older adulthood—it is never too early or too late to eat healthfully.

- Customize and enjoy nutrient-dense food and beverage choices to reflect personal preferences, cultural traditions, and budgetary considerations. A healthy dietary pattern can benefit all individuals regardless of age, race, or ethnicity, or current health status. The Dietary Guidelines provides a framework intended to be customized to individual needs and preferences, as well as the foodways of the diverse cultures in the United States.

- Focus on meeting food group needs with nutrient-dense foods and beverages, and stay within calorie limits. An underlying premise of the Dietary Guidelines is that nutritional needs should be met primarily from foods and beverages—specifically, nutrient-dense foods and beverages.

- Limit foods and beverages higher in added sugars, saturated fat, and sodium, and limit alcoholic beverages. At every life stage, meeting food group recommendations, even with nutrient-dense choices, requires most of a person's daily calorie needs and sodium limits. A healthy dietary pattern doesn't have much room for extra added sugars, saturated fat, or sodium or for alcoholic beverages.

Specific recommendations for adults, based on a "reference diet" of 2,000 calories per day, include [70]:

- Two cups of fruit and 2½ cups of vegetables per day, with an emphasis on high-fiber choices; weekly recommendations are 1½ cups/week of dark green vegetables, 5½ cups/week of red/orange vegetables, 1½ cups/week of beans/lentils/peas, 5 cups/week of starchy vegetables, and 4 cups/week of other vegetables

- Six ounce-equivalent of grains, with at least half of all grain products consumed coming from whole grains

- 3 cups per day of fat-free or low-fat milk or equivalent dairy products

- 5 ½ ounces of protein/day, including 8 ounces of seafood per week; 26 ounces of meat, poultry, and eggs per week; and 5 ounces of nuts, seeds, and soy products

- 12 g of oils per day, with a focus on healthy oil choices

- Less than 12% of calories from other uses, including alcohol, saturated fats, and added sugars

- Less than 2,300 mg (approximately 1 tsp of salt) of sodium per day for individuals 14 years of age and older

The USDA's MyPlate plan and the DASH diet both fulfill the Guidelines' recommendations. MyPlate is an individualized guide for healthy eating based on age, sex, height, weight, and physical activity level. Patients can create their own MyPlate plans at https://www.myplate.gov. The DASH diet (Dietary Approaches to Stop Hypertension) was originally developed as a method to prevent and treat hypertension, but it provides a balanced diet that is appropriate for most adults. Patient-friendly information about the DASH diet is available at https://www.nhlbi.nih.gov/health-topics/dash-eating-plan.

PHYSICAL ACTIVITY

Patients must keep in mind that as they change their diet and begin to lose body weight, body fat and lean body mass also decrease. The optimal goal of therapy is to maximize loss of body fat and minimize loss of lean body mass.

Exercise increases energy expenditure, and regular physical exercise is an important predictor of long-term weight maintenance. It is as important as diet, and patients should understand this point. Several studies have shown that patients who diet and exercise regularly are much more likely to maintain weight loss than those who simply change their diet. Multiple studies have demonstrated that a program of diet and exercise can reduce the number of persons who progress from impaired glucose tolerance to frank diabetes by 50% or more [37,38,39,40].

As noted earlier, approximately 26% of American adults rarely (or never) exercise [2]. There are numerous reasons for this, including lack of interest, competing demands for leisure time, lack of knowledge of proper technique, and fear of injury. Compounding this problem, in a 2001 survey, it was found that only 28% of subjects reported receiving advice from their physicians to increase their physical activity [41]. Of the individuals who received advice, only 38% (or 11% total group) received help formulating a specific activity plan, and 42% received follow-up support. As noted, in 2013, the AHA/ACC published new obesity guidelines that specifically detail how primary care physicians can incorporate assessment and treatment for overweight and obesity into daily practice [112]. The recommendation to consider obesity as a disease and provide an algorithm for assessment and treatment was made due to continued undertreatment noted during systematic reviews in 1998 and 2005 [69,112].

CDC Physical Activity Recommendations

According to the CDC, adults should engage in at least 150 minutes of moderate-intensity aerobic activity (e.g., brisk walking) or 75 minutes/week of vigorous-intensity exercise (e.g., jogging, running) every week, combined with muscle-strengthening activities that work all major muscle groups (legs, hips, back, abdomen, chest, shoulders, and arms) two or more days per week for moderate health benefits [83]. (Note: A weekly workout can include a mix of exercise intensity equal to the given recommendations.) For increased health benefits, moderate-intensity aerobic exercise should be doubled to 300 minutes per week [83].

U.S. Health and Human Services Physical Activity Recommendations

The 2020–2025 Dietary Guidelines for Americans include recommendations for physical activity similar to the CDC recommendations [70,83]. It should be emphasized that usual daily activities at work or around the house should not be counted towards patients' exercise goals, but that these should continue in addition to exercise. Adults require at least 150 to 300 minutes of moderate-intensity aerobic activity (e.g., brisk walking, fast dancing) each week. It is also recommended that adults engage in muscle-strengthening activity (e.g., lifting weights, push-ups) at least two days each week [70].

American Heart Association Physical Activity Recommendations

In 2007, the AHA released guidelines for physical activity, in partnership with the American College of Sports Medicine (ACSM) [43]. These guidelines are intended to clarify recommendations originally released in 1995 by the ACSM and the CDC. For healthy adults 18 to 65 years of age, the AHA and ACSM recommend:

- Moderate-intensity aerobic activity on five days per week for 30 minutes or more, or vigorous-intensity aerobic activity on three days per week for 20 minutes or more.

- Resistance or strength training, or activity that improves strength and endurance, at least twice a week.

- Vigorous- and moderate-intensity activity can be combined to meet the goals. For example, a brisk half-hour walk twice a week plus a 20-minute jog twice a week fulfills the recommendations. Moderate-intensity bouts of exercise lasting at least ten minutes can be added together over the course of a day. Activities of daily living, such as household chores, do not count toward the goals.

- Strength training should include 8 to 10 exercises using the major muscle groups on two or more non-consecutive days. Weights should allow 8 to 12 repetitions before fatigue.

The AHA and ACSM also offer specific recommendations for older adults [44]. Aerobic and strength training goals are the same, although the guidelines note that the same exercise may be "moderate" for some older adults and "vigorous" for others, depending on baseline fitness level. Additional recommendations include:

- Exercises to promote flexibility, for at least 10 minutes two days a week.

- Balance-improving exercises for adults at risk of falls.

- Integration of preventive and therapeutic recommendations, so as to accommodate illness or restrictions on movement while avoiding a sedentary lifestyle.

Encouraging Physical Activity

The key is to make physical activity a part of everyday life by encouraging patients to choose activities of interest. Exercise should not be a chore, but rather an enjoyable activity that people look forward to. This may be light jogging, dancing, vigorous walking, or perhaps swimming for patients with arthritis. Patients should be encouraged to surround themselves with people supportive of exercise, who may join them in this activity. Patients should also consider varying their routine so they do not get bored. One study demonstrated that women older than 50 years of age who spent approximately 2.5 hours per week walking briskly reduced their risk of cardiovascular disease by 30% [45]. For patients with chronic renal insufficiency, resistance training has been shown to be effective against the catabolism of a low-protein diet and uremia [46].

It is also recommended that patients self-monitor. This entails keeping a diary of caloric intake and physical activity. Such a log encourages adherence, and most patients can see some success by noting their daily progress over time. They should bring this log to each visit, which should be one to two times per month early on. Physicians should review this diary with patients to ensure that they are properly following a structured program. Some patients will need closer monitoring, depending on cardiac risk and the presence of other medical conditions.

Although behavioral strategies can be effective, weight regain is common. Patients typically regain weight after leaving a structured program. Patients must understand that these changes must become their daily lives. They should change slowly, choosing foods and activities they can enjoy. They need to understand that occasional setbacks may occur, and that instead of becoming frustrated they should try to remain focused on long-term goals. Permanent lifestyle changes remain one of the most difficult interventions to implement. Patients need support, positive feedback, continual encouragement, and reinforcement.

Patient B should be counseled to adopt a diet and exercise regimen. She needs to decrease her calories by 500 calories per day and distribute her calories to 45% to 65% carbohydrates, 25% sugar or less, 20% to 35% fat, and 10% to 35% protein. She should choose an exercise program she enjoys—perhaps swimming, which would not only cause less stress on her joints but may also improve her arthritis. She should start slowly, 10 to 20 minutes several times a week, gradually building up to one hour, five or more times per week.

PHARMACOLOGIC AGENTS

Pharmacotherapy should only be used as an adjunct to lifestyle modification, including calorie restriction and increased physical activity. It should not be used as a primary treatment option or by people who are unwilling to make behavioral changes. Rather, if lifestyle changes do not promote weight loss after six months, drugs should be considered. Most drugs are recommended for use in patients with a BMI >30 or in those with a BMI >27 and comorbidities such as type 2 diabetes, hypertension, or sleep apnea [128].

Most weight-loss agents suppress appetite or block pancreatic lipase. Presently, four drugs (orlistat, phentermine/topiramate, liraglutide, and bupropion/naltrexone) are approved by the U.S. Food and Drug Administration (FDA) for long-term weight loss. Orlistat is available by prescription (brand name Xenical) or over-the-counter (brand name Alli). Phentermine/topiramate (brand name Qsymia), liraglutide (brand name Saxenda), and bupropion/naltrexone (brand name Contrave) are available by prescription only.

Orlistat is a gastrointestinal and pancreatic lipase inhibitor that interferes with hydrolysis of dietary triglyceride and fatty acid absorption by the intestine [129]. It causes weight loss by blocking absorption of up to one-third of ingested fat. It is typically used with a reduced calorie diet with about 30% of calories from fat. Because absorption of fat-soluble vitamins can be affected, patients are advised to take a multivitamin daily. Several clinical studies have shown that when orlistat is combined with a low-calorie, low-fat diet, it increases weight loss compared with a placebo and low-calorie, low-fat diet. For example, in a randomized controlled trial conducted in Europe, patients using orlistat and eating a low-fat diet experienced a weight loss of 10.2% compared to 6.1% in the control group at one year [47]. In this study, total cholesterol, LDL, LDL/HDL ratio, and glucose showed a significant reduction. At year two, patients who continued with orlistat regained half as much weight as those patients who switched to placebo. In another randomized trial, patients using orlistat with a low-calorie diet experienced a loss of 8.5% of their initial body weight, compared with 5.4% in the placebo group [48]. Moreover, 35% of patients using orlistat lost at least 5% of body weight, compared with 21% in the placebo group; 28% lost 10% of body weight compared with 17% in control group. In a randomized controlled trial conducted in the United States, patients treated with orlistat lost an average of 15 lbs versus 8 lbs in the control group [49]. More patients in the experimental group lost 5% of initial weight than those in the control group, and 34% of patients using orlistat sustained the weight loss at two years versus 24% in the control group.

Orlistat is contraindicated in patients with chronic malabsorption syndrome or cholestasis, and it should be used with caution in patients taking cyclosporine. Side effects of orlistat include, but are not limited to, steatorrhea, incontinence, and diarrhea. Dietary supplementation with fat-soluble vitamins is recommended. Cases of acute kidney injury from oxalate crystal deposition have been reported in 2% of patients within one year of initiating orlistat [128]. Renal function should be monitored in patients receiving orlistat, particularly those at increased risk because of age or pre-existing renal dysfunction. Rarely, patients taking orlistat have developed severe liver injury, and this risk should be weighed against potential benefits [71].

In 2012, the FDA approved phentermine/topiramate, one of the first new weight-loss mediations in more than a decade [98]. Phentermine/topiramate (extended-release) combines an anorexiant and an anticonvulsant to improve short-term weight-loss outcomes in patients who have already attempted lifestyle changes (i.e., calorie-restricted diet and increased physical activity) [95]. Eligible patients will have a BMI ≥30 or a BMI ≥27 with a weight-related comorbidity [98]. In two randomized, placebo-controlled trials involving approximately 3,700 obese and overweight patients, phentermine/topiramate was found to be effective and safe if used correctly [98]. After one year, patients taking phentermine/topiramate experienced 6.7% (at the recommended dose) to 8.9% (at the highest dose) greater weight loss compared to those taking placebo. More than 60% of participants taking phentermine/topiramate recorded at least a 5% decrease in their body weight, compared to only 20% of the placebo group [98].

The recommended initial dose of phentermine/topiramate is 7.5 mg phentermine/46 mg topiramate extended-release once per day [98]. If weight reduction is <3% at 12 weeks, the dose may be titrated to a maximum of 15 mg/92 mg. The medication is contraindicated in persons with glaucoma, uncontrolled hypertension, or hyperthyroidism, and is not recommended for patients with a recent history of stroke or heart disease [98,128]. It is also teratogenic, with proven fetal defects with first trimester exposure. Therefore, all women of childbearing age should use effective contraception consistently while taking the drug and have documented proof of a negative pregnancy test prior to the initiation of treatment and every month thereafter [98].

In 2014, combination bupropion/naltrexone was approved as a treatment option for chronic weight management [99]. Studies show that these drugs are effective in improving the percentage of total body weight lost compared to placebo [84,99]. The dosage is gradually titrated up, starting with one tablet (naltrexone 8 mg/bupropion 90 mg) once daily in the morning for one week and increasing one daily tablet each week for four weeks. The maintenance dose is two tablets twice daily [71]. If 5% of initial body weight has not been lost after 12 weeks, the medication should be discontinued.

Any patient taking bupropion should be carefully monitored for suicidal ideation and behaviors [99]. This medication may also increase blood pressure and heart rate and is contraindicated in patients with hypertension. It also should be avoided in patients with opioid dependence, a history of seizures, or who are pregnant.

Also in 2014, the GLP-1 receptor agonist liraglutide was approved by the FDA for chronic weight management. Traditionally used to treat diabetes, liraglutide has been found to aid in appetite suppression and weight loss [109]. The dosage of liraglutide used for weight management (3 mg) differs from the dose used in diabetes medication regimens (1.8 mg), and the safety and efficacy of this higher dose for the treatment of diabetes is uncertain [109]. Liraglutide is administered subcutaneously, and when used for management of obesity, it should be initiated at 0.6 mg once daily and escalated weekly by 0.6 mg up to 3 mg [128]. Common side effects are nausea (25%), vomiting (12%), diarrhea (11.6%), constipation (11%), and dyspepsia (6.4%). A meta-analysis found that liraglutide has the highest probability of discontinuation from side effects (13% of patients) among all FDA-approved medications for obesity [128]. This medication is contraindicated in those with a personal or family history of thyroid cancer.

Patients with type 2 diabetes and high cardiovascular risk randomized to treatment with liraglutide had a 22% decrease in cardiovascular mortality and 15% decrease in all-cause mortality compared with placebo after 3.8 years [128]. Among adolescents with obesity, liraglutide plus lifestyle therapy was two times more effective than lifestyle therapy alone (43.3% vs. 18.7%) in reducing BMI by 5%, and three times more effective (26% vs. 8%) in reducing BMI by 10% [130].

In 2021, the FDA approved semaglutide injection for chronic weight management in adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related condition (e.g., hypertension, type 2 diabetes, hyperlipidemia) [133]. This agent is a glucagon-like peptide-1 (GLP-1) receptor agonist and is intended to be used in conjunction with lifestyle changes. When used for weight management, semaglutide is administered subdermally at a dose of 2.4 mg once weekly [133]. Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist and works to regulate appetite and food intake. In one study involving 1,961 obese or overweight adults, once-weekly semaglutide was associated with an average weight loss of 15.3 kg after 68 weeks, compared with 2.6 in the placebo group [134].

When pharmacotherapy is effective, weight loss should exceed 2 kg (4.4 lbs) during the first month and weight should decrease by about 5% of baseline within six months. Pharmacotherapy should be discontinued if weight loss is not achieved. In cases in which the therapeutic goal includes significant metabolic improvement in addition to weight loss (e.g., a patient with type 2 diabetes), failure to achieve a 5% decline in weight at three months warrants consideration of alternative pharmacotherapy or bariatric surgery [129]. When it is successful, pharmacotherapy with orlistat may be continued past one year; data is currently available to four years with orlistat [71]. Patients should keep in mind that weight loss typically stabilizes after six months of treatment, and weight gain can occur when pharmacologic therapy is discontinued.

In 2014, researchers conducted a systematic review to compare available FDA-approved drugs for short- and long-term weight loss using existing meta-analyses, systematic reviews, and randomized, placebo-controlled trials [114]. Combined with prescribed lifestyle changes, weight loss was noted at one year at approximately 3% for both orlistat and lorcaserin, and 9% for maximum-dose phentermine/topiramate compared with placebo [114]. Clinically meaningful weight loss (defined as ≥5% of initial weight in one year) was 37% to 47% for lorcaserin, 35% to 73% for orlistat, and 67% to 70% for maximum-dose phentermine/topiramate [114]. There were no short-term weight loss drugs that met the inclusion criteria for the analysis. Additional research, with the inclusion of the two more recently FDA-approved drugs (bupropion/naltrexone and liraglutide) is required to provide more information on the drug that provides the greatest efficacy [114].

Several drugs are approved for short-term use in obese patients. These include sympathomimetic agents such as benzphetamine, methamphetamine, phentermine, phendimetrazine, and diethylpropion [71,114]. Data on long-term safety have not been demonstrated. Given that weight loss therapy is focused on long-term success, use of these drugs is rarely recommended. Leptin resistance may be a contributing factor to obesity in some cases, and leptin is being explored as a possible treatment.

The cannabinoid receptor antagonist rimonabant, which acts as an appetite suppressant, has shown promise for weight loss. It is currently available in Europe. However, the FDA declined to approve this drug for use in the United States, citing concerns about the risk-benefit profile and the need for more data. In the future, rimonabant or similar drugs may become available in the United States.

In 2022, the FDA approved weekly tirzepatide injection for the treatment of type 2 diabetes [135]. In studies of the drug's efficacy in lowering blood glucose levels, patients were also found to experience significant weight loss; in one clinical trial, the average weight loss with tirzepatide was 15 pounds more than placebo when neither were used with insulin and 23 pounds more than placebo when both were used with insulin [135]. In a study of 2,539 obese adults without diabetes, after 72 weeks of treatment, the mean percentage change in weight 72 was −15.0% for those receiving 5-mg tirzepatide, −19.5% for those receiving 10-mg tirzepatide, and −20.9% for those receiving 15-mg tirzepatide; the percent change among those who received placebo was −3.1% [136]. Additional trials are underway to assess the potential role of tirzepatide in the treatment of obesity.

Until October 2010, another drug, sibutramine, was approved by the FDA for use in the long-term management of weight. Randomized controlled trials supported the efficacy of sibutramine for short-term weight loss; however, there was some concern regarding the cardiovascular risk profile associated with the medication [50,51,52]. Postmarketing data indicated that patients with existing cardiovascular disease on long-term sibutramine therapy had an increased risk of nonfatal myocardial infarction and stroke [53]. As a result, the manufacturer (Abbott Laboratories) responded to an FDA request by voluntarily removing the agent from the U.S. market in 2010 [72].

In 2012, lorcaserin was approved to be used, in conjunction with diet modification and exercise, for adults with a BMI ≥30 or adults with a BMI ≥27 with at least one weight-related comorbidity (e.g., hypertension, dyslipidemia, sleep apnea). However, lorcaserin was voluntarily withdrawn from the market by the manufacturer in 2020 due to results from safety clinical trials showing an increased occurrence of cancer [95]. Other previously available drugs included dexfenfluramine and fenfluramine. Both have been withdrawn from the market due to either increased risk of pulmonary arterial hypertension or valvular heart disease.

SURGICAL OPTIONS

Surgery offers the most effective intervention for reducing the long-term complications of obesity and related metabolic disorders such as diabetes [17,131]. High morbidity and mortality rates are associated with severe obesity (BMI >40) and with a BMI of 35 to 39 in the presence of a coexisting condition. With refinement in surgical technique and growing evidence of safety and efficacy, bariatric surgery has become increasingly common over the past decade. In 1998, there were 13,386 procedures; by 2004, nearly 136,000 bariatric surgeries were performed [55,85]. Since then, the number has continually increased, with approximately 252,000 surgeries performed in 2018 [104]. Only 1% of the extremely obese population undergoes bariatric surgeries each year [85,86,87]. In 2008, 90.2% of bariatric surgeries were performed laparoscopically, compared to 20.1% in 2003. Surgical procedures for overweight and obese patients include:

- Gastric bypass

- Gastric banding

- Vertical banded gastroplasty

- Sleeve gastrectomy

- Intestinal bypass

Evidence Based Practice Recommendation

According to the University of Michigan Health System, bariatric surgery should be considered for highly motivated obese individuals who are unsuccessful in meeting initial weight-loss goals in six months.

https://www.med.umich.edu/1info/FHP/practiceguides/obesity/obesity.pdf

Last Accessed: January 25, 2021

Strength of Recommendation/Level of Evidence: IIB (May be reasonable to perform based on evidence from controlled trials without randomization)

The American Society for Metabolic and Bariatric Surgery (ASMBS) and the Society of American Gastrointestinal Endoscopic Surgeons have reaffirmed the 1991 National Institutes of Health guideline, which states that surgery is indicated for adult patients with a BMI greater than 40 or greater than 35 with significant comorbid conditions and who can demonstrate that dietary attempts at weight loss have failed [56,57]. In 2013, cosponsored guidelines from the American Association of Clinical Endocrinologists (AACE), the Obesity Society (TOS), and ASMBS were released reaffirming BMI criteria, and adding the consideration of bariatric surgery for individuals with a BMI between 30–34.9 with diabetes or metabolic syndrome [96]. In 2019, the AACE/TOS/ASMBS/Obesity Medicine Association (OMA)/American Society of Anesthesiologists (AASA) guidelines further added a recommendation that the BMI requirement for bariatric surgery should be adjusted for ethnicity (e.g., 18.5 to 22.9 is normal range, 23 to 24.9 is overweight, and ≥25 is obesity for Asian patients) [97].

In 2016, 45 professional societies, including the American Diabetes Association, issued a joint statement that metabolic surgery should be considered for patients with type 2 diabetes and a BMI 30.0–34.9 if hyperglycemia is inadequately controlled despite optimal treatment with either oral or injectable medications [98].

Bariatric surgery for patients older than 60 years of age has typically not been recommended. Patients should be thoroughly screened for a willingness to make lifestyle changes, as well as for any psychologic disorders that would impair a successful postoperative course. Surgical treatment is not a cosmetic procedure. It does not involve the removal of adipose tissue by suction or excisions; rather, it involves reducing the size of the stomach, with or without a degree of malabsorption.

In addition to those patients identified in the 1991 guideline, the Society of American Gastrointestinal Endoscopic Surgeons indicates that other well-selected patients may benefit from laparoscopic bariatric surgery [57]:

- Individuals with BMI 30–35

- Patients older than 60 years of age

- Select adolescents

Adolescent bariatric surgery (in patients younger than 18 years of age) has been proven effective but should be performed in a specialty center. Patient selection criteria should be the same as used for adult bariatric surgery.

Research supports the effectiveness of bariatric surgery for weight loss, and although more outcome data have been made available since the 2000s, additional studies are required to prove long-term outcomes [91,115]. In the Swedish Obese Subjects (SOS) study, a large, prospective, controlled trial of bariatric surgery (fixed or variable banding, vertical banded gastroplasty, or gastric bypass), average weight loss in surgical patients was 16% at 10 years compared to a 1.6% weight gain in controls [58]. A 2005 Cochrane Review, which included earlier SOS results as well as multiple other studies, noted that evidence was limited (largely due to study design), but that surgery appeared to be more effective than conventional treatment [59]. A meta-analysis published in 2004 in JAMA concluded that mean excess weight loss was 61.2% for bariatric surgery patients, with some variation among types of surgery [60]. One long-term systematic review used MEDLINE and Cochrane databases to analyze research from 1946 to 2014 and found that there is still insufficient long-term patient follow up needed to minimize biased results. In this review, it was found that found that gastric bypass has better outcomes than gastric band procedures; however, there was insufficient evidence regarding other types of bariatric procedures, including gastric sleeve [115].

It also appears that weight loss following bariatric surgery may be more sustainable than weight loss by conventional means. While weight regain often occurs within a few months to years after behavioral or pharmacologic treatment, studies show that weight loss can be sustained for many years after surgery [55]. A large, single-center follow-up study of laparoscopic adjustable gastric banding patients showed the band was intact in 78% of patients beyond the 10-year follow-up, with a mean excess weight loss of 47% [103]. At the 16-year mark, patients had an excess weight loss of 62%. The authors of the study reviewed other literature and noted a similar substantial long-term weight loss with other bariatric surgeries as well.

Although bariatric surgery is not without risk, there is evidence that it can reduce overall morbidity and mortality in obese patients. In a cohort study comparing 1,035 bariatric surgery patients with 5,746 age- and gender-matched controls, the surgery patients had significant reductions in the risk of cardiovascular disease, cancer, endocrine disorders, infections, and psychiatric disorders. The relative risk of death was 89% lower in the surgery group [61]. Another study compared 7925 gastric bypass subjects with community-based controls. Mortality was lower by 40% among the surgery patients. Although deaths from causes other than disease were higher in the surgery patients, deaths from diabetes, cardiovascular disease, and cancer were all substantially reduced [62]. The SOS study, the only large, well-controlled prospective trial of bariatric surgery, found the unadjusted overall mortality was reduced by 31.6% in the surgery group at 10 years [63].

Multiple studies of comorbid conditions that are common in obesity have shown improvement following bariatric surgery. A meta-analysis of bariatric surgery studies showed strong improvements in diabetes, hypertension, hyperlipidemia, and sleep apnea [60]. According to results from the SOS study, some of the improvements in morbidity may decrease over time; however, longer observation and additional studies are needed to confirm long-term effects [58].

Malabsorptive and Combined Procedures

These procedures combine creation of small stomach pouches to restrict food intake and construction of bypasses of the duodenum and other segments of the small intestine to cause malabsorption. In the past, the most common gastric bypass operation was Roux-en-Y gastric bypass (RYGB), with biliopancreatic diversion performed less frequently [104]. According to one report, in 2003–2004 more than 90% of the weight-loss surgeries performed in the United States involved the Roux-en-Y technique, even though this surgery required longer time in surgery, longer hospital stays, and a higher likelihood of requiring intensive care [63]. However, the advent of newer and less invasive techniques has led to these surgeries falling out of favor. In 2018, the ASMBS estimated that only 17% of bariatric surgeries involved RYGB and 0.8% were biliopancreatic diversion [104]. Today, sleeve gastrectomy is the most commonly performed procedure (61.4%) [104].

In the SOS study, the gastric bypass group lost the most weight, compared to banding and vertical banded gastroplasty; they were also more likely to have lost more than 5% of baseline body weight [58]. A meta-analysis of multiple studies concluded that weight loss was about 61.6% with gastric bypass and 70.1% with biliopancreatic diversion, vs. 47.5% for gastric banding. However, these procedures also carry a higher risk of nutritional deficiency.

Roux-en-Y Gastric Bypass (RYGB)

With gastric sleeve procedures becoming more common, only 17% of bariatric surgeries performed in 2018 were RYGB procedures [104]. In this procedure, a small stomach pouch, approximately 25–30 mL in size, is created by either stapling or vertical banding. This causes restriction in food intake, such that patients can only eat several bites as a meal. Next, a Y-shaped section of the small intestine is attached to the pouch to allow food to bypass the duodenum as well as the first portion of the jejunum. This causes reduced calorie and nutrient absorption, resulting in weight loss. Gastric bypass is usually done laparoscopically.

With this procedure, severe nutritional deficiencies can develop. For instance, patients are at risk to develop iron deficiency due to lack of food contact with gastric acid and consequent diminished conversion of iron. In addition, vitamin B12 deficiency may occur because food is not coming into contact with gastric intrinsic factor. Vitamin D and calcium absorption may be reduced because the duodenum and proximal jejunum, which are the sites of calcium absorption, are bypassed. Lifelong supplements of multivitamins, B12, iron, and calcium are mandatory following this procedure.

Biliopancreatic Diversion (BPD) and Biliopancreatic Diversion with Duodenal Switch (BPD/DS)

In the BPD and BPD/DS operations, portions of the stomach (approximately two-thirds) are removed. The small pouch that remains is connected directly to the final segment of the small intestine, completely bypassing both the duodenum and jejunum. Thus, the time that food mixes with digestive fluids is fairly brief.

In biliopancreatic diversion with duodenal switch the pyloric valve is kept intact, a portion of the duodenum is left in the digestive loop, and the final segment of the small intestine is connected after the duodenum. Additionally, the upper end of the bypassed segment of the small intestine is attached to the pancreas and is joined at the final, common segment. The gallbladder may or may not be removed.

Restrictive Procedures

Restrictive procedures reduce the size of the stomach without interfering with absorption of food. Food intake is restricted by creating a small pouch at the top of the stomach where the food enters from the esophagus. The pouch initially holds about 1 ounce of food and can expand to 2 to 3 ounces over time. The pouch's lower outlet usually has a diameter of about ¼ inch. The small outlet delays the emptying of food from the pouch and causes a feeling of fullness. It does not otherwise alter the digestive tract. Restriction operations are intended to reduce the amount of food a patient can comfortably eat, thus reducing total caloric intake. The two most common restriction operations are gastric banding and vertical banded gastroplasty.

Laparoscopic Gastric Banding (LGB)

In this procedure, a band is placed around the stomach near its upper end, creating a small pouch and a narrow passage into the larger remainder of the stomach. An inflatable, adjustable ring controls the flow of food from the smaller pouch to the rest of the digestive tract. The patient will feel comfortably full with a small amount of food. Because of the slower emptying, the patient continues to feel full for several hours, thereby reducing the urge to eat between meals.

Although excess weight loss with this procedure is not as rapid as with other procedures (e.g., RYGB), long-term weight loss may be comparable for some patients [90,91]. One study found that weight loss percentages for RYGB and LGB were 35% and 19% after three months; 49% and 25% after six months; 64% and 36% after one year; and 60% and 57% after three years [90]. However, other studies report that about half of LGB procedures result in inadequate weight loss [92]. A 2008 systematic review noted that complication and short-term morbidity rates of LGB are lower than those of laparoscopic RYGB; however, reoperation rates with LGB are higher [91]. This review noted that the highest quality study showed an excess weight loss percentage at one year of 48% for LGB, compared with 76% for RYGB.

It appears that LGB has quickly fallen out of favor. LGB accounted for 35.4% of bariatric procedures in 2011 but only 1.1% in 2018 [104].

Vertical Banded Gastroplasty (VBG)

In this procedure, both a band and staples are used to create a small pouch in the upper stomach with a narrow outlet reinforced by a mesh band to prevent stretching. After the procedure, the person usually can eat only a half to a whole cup of food without discomfort or nausea. Food must be well chewed. VBG, formerly one of the most common bariatric surgeries, is used less often now due to unsatisfactory weight loss results [55]. Complications from the restriction can include vomiting, gastroesophageal reflux, and erosion of the band into the gastric tissue.

Neither of these procedures involves any anastomosis of the stomach or intestine, nor is there repositioning of the stomach or intestines. Intake becomes a function of a patient's ability to chew thoroughly and eat slowly. Failure to do so can result in repeated vomiting and isolated cases of nutritional deficiency.

Laparoscopic Sleeve Gastrectomy (LSG)

Similar to the first step of BPD, laparoscopic sleeve gastrectomy (LSG) involves subtotal gastric resection, leaving a small, tubular stomach [88]. Because the fundus of the stomach contains the cells that produce ghrelin (a hormone involved in regulation of food intake), removal of the fundus may contribute to weight loss beyond simple restriction. LSG is generally done in select obese and super-obese (BMI greater than 50) patients and followed, once weight is somewhat reduced, by completion of a RYGB or either of the BPD surgeries. Advantages of this approach include simplicity, low complication rates, no nutritional deficiencies, and no "dumping syndrome" [88].

A 2009 study of 135 patients who underwent the procedure (mean BMI: 48.8; range: 37–72) found that the average excess weight loss at one year was 49.4% [89]. Complication rates were low, and none of the patients required conversion to laparotomy.

A 2010 review of 100 LSG patients (BMI greater than 40 or greater than 35 with severe comorbidity) found that the average excess weight loss was 49.1% at six months [88]. There was also significant resolution of diabetes (46%), hypertension (38%), and hyperlipidemia (19%). The authors of the study recommend LSG as a single-step procedure, with no revision to RYGB or BPD, and LSG over gastric banding due to equivalent weight reduction and better tolerance.

Complications

Bariatric surgery does have complications. Approximately 10% to 20% of all patients who have weight-loss surgery require follow-up operations. Gastric bypass operations may cause "dumping syndrome," whereby stomach contents move too rapidly through the small intestine. Typically, this is caused by the high osmolarity of simple carbohydrates in the intestine. The higher concentration causes fluids to shift towards the higher osmolarity. This results in additional fluid in the bowel, which causes it to be stretched, with subsequent pain and nausea. Activation of hormonal and nerve responses causes increased heart rate. There may be vomiting and diarrhea. A short time later, there typically is a glucose spike, as the small bowel absorbs sugar. The pancreas responds by secreting insulin, which then causes hypoglycemia, causing weakness and light-headedness. Dumping syndrome should be monitored carefully.

Abdominal hernias can also occur, requiring follow-up surgery. More than one-third of obese patients who have gastric surgery develop gallstones. Post-operative complications may include deep vein thrombosis, pulmonary emboli, bleeding, band migration, and infection. Possible later complications include breakdown of the staple line or band erosion, causing internal infections.

Depending on the type of procedure, nearly 30% of patients who have weight-loss surgery can develop nutritional deficiencies such as anemia, osteoporosis, and metabolic bone disease. Therefore, it is important that patients take supplemental vitamins and minerals.

Because bariatric surgical procedures are still evolving, true surgical mortality rates are uncertain. The overall risk of death from gastric bypass appears to be less than 0.2% at 30 days and varies by the type of procedure [105]. Older data, gathered between 1987 and 2001, suggested a 30-day mortality rate as high as 1.9%, but outcomes have improved as surgeons gained experience and lower-risk patients sought treatment [55]. The increase in laparoscopic procedures has contributed to a lower risk of death. It is estimated that the 30-day mortality rate is 0.14% for laparoscopic gastric bypass, 0.08% for laparoscopic sleeve gastrectomy, and 0.03% for laparoscopic gastric banding [105].

Selection of Surgical Procedure

The appropriate surgery depends on a number of factors, including the skill of the surgeon and patient preference. Typically, restriction operations create slower and steadier weight loss than the bypass operations, which often show rapid weight loss in the first few months, stabilizing a year after surgery. With restriction operations, weight loss is typically 1 to 2 pounds per week, continuing on average for two years. However, restriction operations have higher potential for nutritional deficiency.

Bariatric surgery will not work for all patients. Between 10% and 50% of surgical subjects will not succeed with long-term weight loss [55,92]. Ongoing follow-up is an essential part of treatment, to watch for complications and encourage ongoing weight loss efforts.

Intragastric Balloon Systems

Intragastric balloon systems, brand names Orbera and the ReShape Integrated Balloon System, were approved by the FDA in 2015. These systems are intended as a minimally invasive, short-term treatment, involving placement in the stomach of an inflatable, free-floating balloon. They are intended to be used in conjunction with diet and exercise. Both Orbera and ReShape are placed into the stomach through the mouth with the patient under mild sedation, using a minimally invasive endoscopic procedure. These balloons are then filled with 400–700 cc of saline (ReShape also adds methylene blue dye) to restrict the amount of space in the stomach. These balloons may be placed for up to six months. A third balloons system, brand name Obalon, was approved by the FDA in 2016 and consists of up to three balloons in a capsule that is attached to a thin inflation catheter. The balloons are swallowed and then inflated with air to reduce amount of free space in the stomach [117].

Intragastric balloon systems may have indications for individuals with BMIs between 30 and 40 and for morbidly obese patients who need to lose weight before bariatric surgery. A 2007 Cochrane Review suggests that intragastric balloon treatment may not provide benefits over conventional therapy. However, evidence was limited and different trials used different techniques and clinical considerations [64].

Little information is available regarding the effectiveness and long-term indications of balloon systems. In clinical trials for Orbera, patients lost an average of 21.8 lbs (10.2% total body weight) after six months, compared with 7 lbs in the same period in a group that received behavior modification. In addition, three months after placement, patients maintained an average weight loss of 19.4 lbs [118].

In February 2017, the FDA issued a letter to healthcare providers warning that there have been incidences of spontaneous overinflation of the two brands of liquid-filled balloons (Orbera and ReShape), causing abdominal pain, difficulty breathing, and vomiting [117]. A risk of acute pancreatitis caused by compression of gastrointestinal structures was also noted. Additionally, in August 2017, the FDA issued a letter to healthcare providers warning of adverse events associated with the saline-inflated versions (Orbera and ReShape). It was noted that five unanticipated deaths had occurred—one patient with ReShape and four with Orbera. A follow up letter was issued in April 2020, indicating a total of 18 deaths reported worldwide; of these, 8 were in the United States (5 with Orbera and 3 with ReShape) [132]. At the time of publication of the letter, there was no known root cause, although all patients died within hours to six months of placement [116]. Further investigation of the safety and effectiveness of these balloon devices is required.

Gastric Electrical Stimulation Technique

Gastric electrical stimulation is a technique involving an implanted device similar to a cardiac pacemaker. In 2015, the FDA approved the Maestro Rechargeable System for the treatment of obesity in patients 18 years or older with a BMI of 40 to 45, or 35 to 39.9 with one or more obesity-related health condition. In addition, the patient must have tried to lose weight with diet and exercise in a supervised program within the past five years.

Controllable from outside the body, the gastric stimulator is intended to reduce caloric intake [55]. The Maestro device is implanted into the abdomen and entails an electronic pulse generator that sends impulses to the vagus nerve. The wire leads and electrodes then directly stimulate the vagus nerve to control appetite. A study of those using the Maestro device showed that the active group lost 8.5% more weight than the placebo group. In addition, 52.5% of the active electronic device group lost at least 20% of excess weight and 38.3% lost at least 25% of their starting weight [119]. Studies are ongoing, and as of 2018 there is no reliable data on the long-term efficacy of gastric electrical stimulation.

6. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

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 the prevention and treatment of overweight and obesity and related conditions, it is each practitioners' 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.

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between clients/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.

7. INSURANCE COVERAGE

There is limited insurance coverage for obesity treatments.

STATE AND FEDERAL PROGRAMS

In 2004, Medicare, the federal program for health services for the elderly and disabled, made revisions to its Medicare Coverage Issues Manual, which removed language stating that obesity was not a disease or illness. Previously, the Medicare program did recognize gastric bypass surgery in some cases for an underlying condition that caused obesity. However, because Medicare was required to cover only "medically necessary services for illness or injury," the previous wording prevented most obesity treatments from being covered [65]. While this revision did not change coverage directly, it allows individuals or organizations to request that specific treatments be evaluated to determine if potential beneficial effects are supported by current medical evidence. Additionally, medical nutrition therapy is a supported treatment. For more information regarding Medicare services, please visit https://www.cms.gov.

Starting in January 2006, Medicare began to offer prescription drug plans, whereby it would assist in the payment of enrolled individuals' medications. Weight-loss medications such as orlistat may be covered; many variables contribute to the amount of coverage available. Effective in 2006, Medicare/Medicaid covers RYGB, BPD/DS (or gastric reduction duodenal switch), and LGB for patients with BMIs of 35 or greater, who have one or more comorbid conditions, and who have unsuccessfully attempted behavioral or pharmacologic interventions [93]. All other bariatric surgeries for obesity alone are not covered. As of 2013, the procedures are not required to be performed at an approved facility [106]. Medicare/Medicaid provides more information and implementation tools on its website at https://www.cms.gov.

Additionally, in 2011 Medicare/Medicaid began to cover preventive services to reduce obesity, including screening and counseling for eligible beneficiaries [94]. Persons with a BMI of 30 or greater qualify for one month of once-weekly counseling sessions, one session every other week for months 2 through 6, and if the patient loses 3 kg in the first 6 months, one session per month during months 7 through 12.

Medicaid is a jointly funded, federal-state health insurance program for certain low-income and needy people. Some Medicaid programs do pay for obesity surgery, although the number of such claims appears small. This may be due to either low interest in the procedure or possibly due to low reimbursement rates, and thus limited surgeons who are willing to perform the procedure for Medicaid patients. The federal statute governing Medicaid coverage of pharmacologic compounds specifically excludes payment for drugs for weight loss. However, states can apply for a waiver from this provision. Many states have received such a waiver and do cover orlistat. For the most accurate information regarding your specific state's coverage policies, contact the state Medicaid office.

PRIVATE INSURANCE

The 2010 Affordable Care Act (ACA) represented a significant shift in the delivery of private healthcare insurance [107]. Before January 2014, 35 states allowed insurers to charge more for coverage and two states explicitly permitted denial of coverage solely based on obesity status [107]. In the past, approximately 9% of existing policy cancellations were based on BMI. Annual and lifetime caps on reimbursements for obesity treatments are also nullified by the ACA.

Private insurers are now required to reimburse for screenings and counseling sessions for obese patients based on level A or B recommendations of the U.S. Preventive Services Task Force (e.g., intensive behavioral therapy for obesity, usually 12 to 26 sessions per year). In this respect, private insurers are now required to offer the same services as Medicare and various state Medicaid programs. Additionally, the ACA promotes employer wellness programs, which offer incentives (i.e., decreased healthcare premiums) for individuals who demonstrate a reduction in weight or BMI (among other healthy changes, including tobacco use reduction/cessation and achievement of cholesterol targets) [108]. Grandfathered plans are also required to provide preventive services for obesity. Discrimination based on weight is no longer allowed, which is a step toward expanding preventive care. However, the ACA included rules that allowed individual states to decide which types of treatment options would be available to obese patients in individual, family, and small-group plans (as well as state plans). As of 2015, 28 states do require private insurers to cover bariatric surgery or enrollment in weight-loss programs [15,66]. Coverage of weight-loss drugs is also not required by the ACA, but individual providers may pay for these medications.

TAX DEDUCTIONS

In 2002, the IRS announced a new policy (IRS Ruling 2002-16) stating that, "Obesity is medically accepted to be a disease in its own right." For taxpayers, this means that treatment specifically for obesity can be claimed as a medical deduction under certain conditions. According to the IRS [67]:

Uncompensated amounts paid by individuals for participation in a weight-loss program as treatment for a specific disease or diseases (including obesity) diagnosed by a physician are expenses for medical care that are deductible under § 213, subject to the limitations of that section.

This policy will likely help individuals who have high expenses related to their obesity, who itemize their deductions, and who are eligible for the medical deduction. In addition, the ruling applies to individuals who can participate in a flexible savings account because those programs use the same IRS rules. This means that many persons can put aside pre-tax dollars to use for weight management during the year.

The text of the ruling is available at https://www.irs.gov/pub/irs-irbs/irb02-16.pdf. Patients should contact a tax professional when considering this deduction.

8. SUMMARY

The number of overweight and obese people has reached epidemic proportions. Estimates show that 78% of the adult population is either overweight, obese, or extremely obese. This represents a substantial increase from the last few decades. Ample scientific evidence exists that demonstrates an increasing body mass index corresponds to increasing morbidity and mortality. Numerous treatments for obesity are available. The cornerstone of any treatment regimen is behavioral modification, focusing on diet changes and exercise regimens. Additional therapies include drugs and surgery. To improve care for overweight and obese patients, physicians and other providers need to have a thorough understanding of obesity and its treatment and to understand the importance of addressing the topic with patients. In addition, they must recognize that recidivism and failure are quite high and that successful treatment requires a concerted and sustained effort.

9. RESOURCES

CDC Resources and Publications for Overweight and Obesity

https://www.cdc.gov/obesity/resources/index.html

Managing Overweight and Obesity in Adults: Systematic Evidence Review from the Obesity Expert Panel

https://www.nhlbi.nih.gov/health-topics/managing-overweight-obesity-in-adults

Dietary Guidelines for Americans

https://health.gov/dietaryguidelines

Physical Activity Guidelines for Americans, 2nd Edition

https://health.gov/sites/default/files/2019-09/Physical_Activity_Guidelines_2nd_edition.pdf

National Institute on Aging, Exercise and Physical Activity

https://www.nia.nih.gov/health/exercise-physical-activity

AHA Diet and Lifestyle Recommendations

https://www.heart.org/en/healthy-living/healthy-eating/eat-smart/nutrition-basics/aha-diet-and-lifestyle-recommendations

Institute of Medicine (IOM) Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Protein, and Amino Acids

https://www.nap.edu/read/10490/chapter/1

U.S. Preventive Services Task Force Guide to Clinical Preventive Services

https://www.ahrq.gov/professionals/clinicians-providers/guidelines-recommendations/guide/index.html

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103. O'Brien PE, MacDonald L, Anderson M, Brennan L, Brown WA. Long-term outcomes after bariatric surgery: fifteen-year follow-up of adjustable gastric banding and a systematic review of the bariatric surgical literature. Ann Surg. 2013;257(1):87-94.

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106. Centers for Medicare and Medicaid Services. Bariatric Surgery. Available at https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDid=57&ncdver=5&CoverageSelection=Both&ArticleType=All&PolicyType=Final&s=Iowa&KeyWord=bariatric+surgery&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAABAAAAAAAA%3D&%20CMS%20NCD%20on%20bariatric%20surgery. Last accessed January 21, 2021.

107. Downey M, Still CD. The Affordable Care Act's Impact on Persons with Obesity. Available at https://www.downeyobesityreport.com/wp-content/uploads/The-Affordable-Care-Act2.pdf. Last accessed January 21, 2021.

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109. U.S. Food and Drug Administration. FDA Approves Weight-Management Drug Saxenda. Available at https://wayback.archive-it.org/7993/20170111160832/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427913.htm. Last accessed January 21, 2021.

110. Ogden CL. Carroll MD, Lawman HG, et al. Trends in obesity prevalence among children and adolescents in the United States, 1988–1994 through 2013–2014. JAMA. 2016;315(21):2292-2299.

111. Locke AE, Kahali B, Berndt SI, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518(7538):197-206.

112. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC guideline for the management of overweight and obesity in adults. Circulation. 2014;129(25 Suppl 2):S102-S138.

113. Johnston BC, Kanters S, Bandayrel K, et al. Comparison of weight loss among named diet programs in overweight and obese adults: a meta-analysis. JAMA. 2014;312(9):923-933.

114. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA. 2014;311(1):74-86.

115. Puzziferri N, Roshek TB, Mayo HG, et al. Long-term follow-up after bariatric surgery: a systematic review. JAMA. 2014;312(9): 934-942.

116. U.S. Food and Drug Administration. Update: Potential Risks with Liquid-Filled Intragastric Balloons—Letter to Health Care Providers. Available at https://www.fda.gov/medical-devices/letters-health-care-providers/update-potential-risks-liquid-filled-intragastric-balloons-letter-health-care-providers. Last accessed January 21, 2021.

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120. Chooi YC, Ding C, Magkos F. The epidemiology of obesity. Metabolism. 2019;92:6-10.

121. Weihrauch-Bluher S, Schwarz P, Klusmann JH. Childhood obesity: increased risk for cardiometabolic disease and cancer in adulthood. Metabolism. 2019;92:147-152.

122. Kim DD, Basu A. Estimating the medical care costs of obesity in the United States: systematic review, meta-analysis, and empirical analysis. Value in Health. 2016;19:602-613.

123. Averginos KI, Spyrou N, Mantzoros CS, et. al. Obesity and cancer risk: emerging biological mechanisms and perspectives. Metabolism. 2019;92:121-135.

124. Tartof SY, Qian L, Hong V, et al. Obesity and mortality among patients diagnosed with COVID-19: results from an integrated health care system. Ann Int Med. 2020;173(10):773-781.

125. Kass DA. COVID-19 and obesity: a big problem? Ann Int Med. 2020; [Epub ahead of print].

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128. Pilitsi E, Farr OM, Polyzos SA, et al. Pharmacotherapy of obesity: available medications and drugs under investigation. Metabolism. 2019;92:170-192.

129. Ammon BJ, Skarulis MC, Soran H, et al. Medical and surgical management of obesity and diabetes: what's new? Diabetic Medicine. 2019;37:203-210.

130. Kelly AS, Auerbach P, Barrientos-Perez M, et al. A randomized, controlled trial of liraglutide for adolescents with obesity. N Engl J Med. 2020;382:2117-2128.

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136. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022; [Epub ahead of print].

Evidence-Based Practice Recommendations Citations

1. U.S. Preventive Services Task Force. Behavioral weight loss interventions to prevent obesity-related morbidity and mortality in adults: U.S. Preventive Services Task Force recommendation statement. JAMA. 2018;320(11):1163-1171. Available at https://jamanetwork.com/journals/jama/fullarticle/2702878. Last accessed January 25, 2021.

2. Department of Veterans Affairs Management of Overweight and Obesity Working Group. VA/DoD Clinical Practice Guideline for Screening and Management of Overweight and Obesity. Washington, DC: Department of Veterans Affairs, Department of Defense; 2014. Available at https://www.healthquality.va.gov/guidelines/CD/obesity. Last accessed January 25, 2021.

3. University of Michigan Health System. Obesity Prevention and Management. Ann Arbor, MI: University of Michigan Health System; 2019. Available at https://www.med.umich.edu/1info/FHP/practiceguides/obesity/obesity.pdf. Last accessed January 25, 2021.

96411 • Behavioral Addictions

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2021 NetCE, All rights reserved.

This course will provide clinicians with the latest clinical and empirical evidence that addresses behavioral addictions, including phenomenology, epidemiology, comorbidity, neurobiologic mechanisms, genetic contributions, treatment response, and prevention. The distinction between impulse control disorders and behavioral addictions is discussed. For each behavioral disorder proposed for inclusion as a behavioral addiction, current evidence is presented that supports or refutes this designation.

Table of Contents

96411 • Behavioral Addictions

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. BEHAVIORAL ADDICTION: EVOLUTION AND CONCEPTS

EVOLUTION IN THE CONCEPT OF BEHAVIORAL ADDICTION

INTERNET-MEDIATED BEHAVIORAL ADDICTION

COGNITIVE AND BEHAVIORAL ASPECTS OF BEHAVIORAL ADDICTION

3. EXPLANATORY MODELS OF ADDICTION

GENERAL MODELS OF ADDICTION

BEHAVIORAL ADDICTION MODELS

UNIFIED MODELS OF INTERNET-MEDIATED BEHAVIORAL ADDICTIONS

4. CHILD AND ADOLESCENT VULNERABILITY TO BEHAVIORAL ADDICTION

5. OVERVIEW OF GENERAL BEHAVIORAL ADDICTION TREATMENT

PSYCHOLOGIC THERAPIES

PHARMACOTHERAPIES

6. GAMBLING DISORDER

EPIDEMIOLOGY

COMORBIDITY

RISK FACTORS

ASSOCIATED FEATURES

PATHOPHYSIOLOGY

DIAGNOSIS

TREATMENT

7. ADDICTIVE SEXUAL BEHAVIOR

EPIDEMIOLOGY, RISK FACTORS, AND COMORBIDITY

INTERNET PORNOGRAPHY ADDICTION

PATHOPHYSIOLOGY

ASSESSMENT

DIAGNOSIS

TREATMENT

8. INTERNET GAMING DISORDER

INTERNET GAMING GENRES

PATIENT CHARACTERISTICS AND GENRE PREFERENCE

PREVALENCE

RISK FACTORS

ASSOCIATED FEATURES

PATHOPHYSIOLOGY

ASSESSMENT AND DIAGNOSIS

TREATMENT

9. BINGE EATING DISORDER

EPIDEMIOLOGY

PATHOPHYSIOLOGY

DIAGNOSIS

TREATMENT

10. COMPULSIVE BUYING DISORDER

EPIDEMIOLOGY AND RISK FACTORS

COMORBIDITY

CLINICAL CHARACTERISTICS

PATHOGENESIS AND PATHOPHYSIOLOGY

DIAGNOSIS

TREATMENT

11. TRICHOTILLOMANIA (HAIR PULLING DISORDER)

EPIDEMIOLOGY

CLINICAL FEATURES

COMORBIDITY

PATHOPHYSIOLOGY

DIAGNOSIS

TREATMENT

12. KLEPTOMANIA (COMPULSIVE STEALING)

EPIDEMIOLOGY, RISK FACTORS, AND COMORBIDITY

CLINICAL CHARACTERISTICS AND ILLNESS COURSE

PATHOPHYSIOLOGY

DIAGNOSIS

TREATMENT

13. INDUCED BEHAVIORAL ADDICTIONS

PATIENTS WITH PARKINSON DISEASE

OTHER DISORDERS

OTHER MEDICATIONS

PATHOPHYSIOLOGY

TREATMENT

14. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

96411 • Behavioral Addictions

Education Category. Psychiatric / Mental Health

Release Date. 05/01/2021

Expiration Date. 04/30/2024

Course Overview

This course will provide clinicians with the latest clinical and empirical evidence that addresses behavioral addictions, including phenomenology, epidemiology, comorbidity, neurobiologic mechanisms, genetic contributions, treatment response, and prevention. The distinction between impulse control disorders and behavioral addictions is discussed. For each behavioral disorder proposed for inclusion as a behavioral addiction, current evidence is presented that supports or refutes this designation.

Audience

This course is designed for health and mental health practitioners who may intervene in diagnosing and treating behavioral addictions in their patients.

Course Objective

The purpose of this course is to provide clinicians with the knowledge and skills to appropriately identify, diagnose, and treat behavioral addictions.

Learning Objectives

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

1. Outline the evolution of and concepts forming the basis of behavioral addictions.

2. Compare and contrast explanatory models of addiction and their applicability to behavioral addictions.

3. Describe the factors underlying child and adolescent vulnerability to behavioral addictions.

4. Discuss psychologic and pharmacologic treatments that are generally appropriate for behavioral addiction.

5. Analyze the epidemiology, comorbidity, and risk factors of gambling disorder.

6. Evaluate the diagnosis and treatment of gambling disorder.

7. Review the pathophysiology, diagnosis, and treatment of addictive sexual behavior.

8. Describe Internet gaming disorder and how it is diagnosed and treated.

9. Explain how binge eating disorder is identified and appropriately treated.

10. Outline the epidemiology, risk factors, and clinical characteristics of compulsive buying disorder.

11. Analyze factors related to the diagnosis and treatment of compulsive buying disorder.

12. Discuss the epidemiology, comorbidities, and pathophysiology of trichotillomania.

13. List approaches to the treatment of trichotillomania.

14. Identify patients with kleptomania and create an effective treatment plan for these patients.

15. Describe behavioral addictions induced by dopamine agonists and other medications and 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

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

Division Planners Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

Implicit Bias in Health Care

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

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

1. INTRODUCTION

The term "addiction" is traditionally used to describe the pathologic behavioral patterns a subset of persons exhibit from exposure to substances with central nervous system (CNS) activity (e.g., heroin, cocaine, alcohol). However, addiction is not a unitary construct; it incorporates common features that include repetitive engagement in rewarding (at least initially) behaviors, loss of control (spiraling engagement over time), persistence despite consequences, aversive states when ingestion is halted or substantially cut back, and an appetitive urge or craving state prior to engaging in the behavior. Many of these pathologic behaviors have long been classified as impulse control disorders, including pathologic gambling, intermittent explosive disorder, kleptomania, pyromania, and trichotillomania. Research suggests that several of these impulse control disorders more accurately represent behavioral addictions.

As a distinct area of study, behavioral addiction is recent, and extensive knowledge advances have been made since 2010. Growing evidence suggests that behavioral and substance addictions overlap in clinical expression (e.g., craving, tolerance, withdrawal symptoms), comorbidity, neurobiologic profile, heritability, and treatment. Behavioral and substance addictions also share similar features in natural history, phenomenology, and adverse consequences. This course will address the most common non-substance behavioral addictions, including pathologic gambling, compulsive sexual behavior, compulsive buying, and compulsive video gaming.

2. BEHAVIORAL ADDICTION: EVOLUTION AND CONCEPTS

In some behavioral addictions, the published research is vast but confusing. Prominent investigators in this field view behavioral addictions through differing paradigms, which has interfered with expert consensus and efforts to advance the field. Disagreement on diagnostic criteria has prevented standardized measurement of treatment outcomes. Debate has also focused on whether behavioral addictions qualify as addictions or are better explained as disorders of impulse control or compulsivity, and whether "Internet addiction" as a unified construct is valid.

EVOLUTION IN THE CONCEPT OF BEHAVIORAL ADDICTION

Early Characterizations

The concept of addiction involving non-substance behaviors as repeated urges to engage in counter-productive activities was introduced in 1990. At the time, behavioral addictions were proposed to encompass obsessive-compulsive disorder (OCD), "compulsive spending" (including gambling), "overeating" (binge eating), "hypersexuality," and kleptomania. It was thought these behaviors were linked to addiction by poor impulse control and self-regulation, which led to repetitive engagement of the behavior despite negative consequences [1,2]. The concept of an obsessive-compulsive spectrum of disorders was proposed in 1993; disorders that featured an inability to control or delay repetitive behaviors were thought to fall on a spectrum from impulsivity to compulsivity [3]. Numerous psychiatric and neurologic disorders were included in this spectrum [4].

Further research suggested that impulsivity and compulsivity appeared in substance and behavioral addictions at different stages, and the "impulsive-compulsive disorder" model was proposed. In this model, impulsivity was dominant in earlier-stage addiction, when behavior is motivated and reinforced by reward, and compulsivity was dominant in later stages, when behavior is motivated and reinforced by avoidance of negative emotional states [5].

Expansion of Core Features

An influential 2006 study broadened the definition and core features of addiction as 1) a state of craving or urge that immediately precedes the behavior, 2) impaired ability to control the behavior, and 3) the behavior continues despite negative consequences [6]. Criterion 3 suggested addiction was no longer tethered to substance use. This was cemented in 2011, when the American Society of Addiction Medicine released their definition of addiction. The core features of this definition are [7]:

- The inability to consistently abstain

- Impairment in behavioral control

- Craving

- Diminished recognition of significant problems with one's behaviors and interpersonal relationships

- A dysfunctional emotional response

Numerous repetitive problematic behaviors became suggested as behavioral addictions, but criticism that excessive normal behaviors were becoming overpathologized ensued [4,8,9]. Concerns were raised that such persons could become stigmatized, based in part on study results suggesting that "brain disease" explanations of drug addiction had unforeseen consequences on clinician and public attitudes—the inability of persons with addiction to control behavior being hard-wired into their brains was perceived to make them more dangerous [10].

The DSM-5 and Classification Issues

A major step forward in the recognition of behavioral addictions as addictive disorders came in 2013 with the American Psychiatric Association (APA) publication of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [11]. In the DSM-5, pathologic gambling was renamed gambling disorder, becoming the first recognized behavioral addiction. This followed decades of research and data demonstrating similarities to substance addictions [8]. Internet gaming disorder and its proposed diagnostic criteria were placed in Section III (Emerging Measures and Models); the body of evidence was extensive, but standardized diagnostic criteria remain absent [12].

Decisions in the DSM-5 concerning behavioral addiction were based on evidence published before 2013 in an emerging and quickly evolving field. While some criticism reflected the premature state of some evidence and lack of consensus, other criticism was directed at decisions to omit behavioral addictions that were viewed as subjective and biased [4].

INTERNET-MEDIATED BEHAVIORAL ADDICTION

Internet addiction is the concept of addiction to Internet use itself, as opposed to the concept that some addictions are mediated by Internet use. The description and diagnostic criteria of Internet addiction disorder first appeared in 1996. Internet addiction disorder was considered an impulse control disorder, based on an inability to control Internet use and resulting in impaired functioning. An Internet addiction disorder typology was proposed, consisting of [13]:

- Cybersex addiction

- Cyber-relationship addiction

- Internet compulsions

- Information overload

- Computer addiction

This work in a newly evolving, unexplored area could not foresee the current reality of Internet centrality in daily life. Many aspects of Internet use deemed pathologic in 1996 have become normative [14]. The Internet is now considered the medium of choice in many gambling, gaming, sex, and other addictions, but not itself the object of addiction, and the concept of Internet addiction has been abandoned [15].

The DSM-5 unnecessarily contributed to this confusion in the introductory text for Internet gaming disorder by stating that it was also commonly referred to as Internet use disorder or Internet addiction [11]. This message was unclear, but some features unique to the Internet may promote excessive or addictive behaviors, including [16,17,18,19,20,21]:

- Accessibility through high-speed broadband connections

- Affordability, as the Internet lacks previous cost restraints

- Anonymity, which can encourage behaviors inhibited offline by stigma and fear of detection and increase perceived control over the content, tone, and nature of online experience. Anonymity can increase the comfort level of users with fears of social rejection by removing the ability to look for and detect disapproval or judgment in facial expressions or body language.

- Convenience of use in familiar, comfortable environments, reducing perceptions of risk

- Escapism. Online gaming, gambling, buying, or sex is reinforced by a subjectively experienced "high," with habitual pursuit a core feature of addiction. Relief from negative emotions and distress related to real-world problems further reinforces the behavior.

- Immersion can facilitate a dissociation-like state in which the user loses track of time, feels like someone else, blacks out, or experiences a trance-like state, a reinforcing effect for some.

- Disinhibition. The core reward for some. Users tend to lower their defenses and emotionally reveal themselves faster online than offline. Socially inhibited users can find the disinhibiting environment and perceived connection to others powerfully reinforcing.

Other contributors to online impulsivity include invisibility and the absence of authorities (e.g., police, parents, teachers) that communicate power and hierarchy offline and constrain behavior [21]. Freed of inhibitions that maintain offline behavior within the boundaries of civility, social acceptability, and legality, users may act on impulses online they would otherwise attempt to resist [22].

COGNITIVE AND BEHAVIORAL ASPECTS OF BEHAVIORAL ADDICTION

As with substance addiction, behavioral addictions are defined by the presence of cognitive, affective, and behavioral abnormalities that reflect maladaptive alteration of underlying neural structures—the core pathology. Functional magnetic resonance imaging (fMRI) and other brain imaging methods can identify these core pathologic features and their similarity to those of substance addiction. Addiction research is moving toward classifying psychopathology on dimensions of behavior and neurobiology and away from DSM-type symptom checklists. This is expected to improve assessment and diagnostic validity and treatment efficacy [23].

Impulsivity

The ability to delay, withhold, or interrupt a behavioral response is a key aspect of executive function. Suppressing an inappropriate immediate response allows time for other processes (and predicting consequences of possible actions) to promote appropriate behavioral choices. Effective inhibitory control is required for adaptive functioning, such as restraining impulses for spiteful, peculiar, and/or inappropriate expression [11,24].

Impulsivity is complex. It is broadly defined as a predisposition for rapid, unplanned reactions to internal or external stimuli without forethought or regard for negative consequences to self or others [25]. In persons with early-stage substance or behavioral addiction, impulsivity is a powerful mechanism thought to drive pursuit of immediate reward, and it is a temperament vulnerability factor for substance use disorders [26,27,28].

Those with prominent impulsivity traits tend to favor immediate rewards over long-term gains, to have poor capacity to delay gratification or resist urges, to quickly react with poorly planned response to stimuli, to be unreflective in decision-making, to dismiss the negative consequences of one's actions, and to be disinhibited, novelty- and thrill-seeking, and impatient [29]. Impulsivity includes several distinct neurocognitive mechanisms and domains.

Domains of Impulsivity

The four major domains of impulsivity are motor, choice, reflection, and delay discounting. Motor impulsivity (also known as response/rapid-response impulsivity) is defined as an impaired ability to stop motor response following changes in environmental circumstances. Impaired motor response inhibition is highly prominent in attention deficit hyperactivity disorder (ADHD) (the archetypal disorder of impulsivity), pronounced in trichotillomania, and observed in gambling disorder [30,31].

Choice impulsivity is characterized by difficulty in delaying gratification and a tendency to choose immediate small rewards at the expense of larger but delayed rewards. This type of impulsivity is consistently observed in substance use disorder and when money, health, and/or freedom are rewards [32,33,34].

Reflection impulsivity is the diminished ability to collect salient information from the environment before a decision. Reflectively impulsive persons make choices rapidly, rather than waiting for more relevant information to become available. Reflection impulsivity commonly occurs in substance use disorder and gambling disorder [35].

The subjective value of a reward decreases as a function of delay in its delivery; the value of reward is discounted with longer delay. With Internet gaming disorder, the immediate reward of online gaming increasingly comes at the cost of abandoned social and professional activities that yield greater long-term rewards [31,36]. This is referred to as delay discounting.

Measuring Impulsivity

Impulsivity-related behaviors are measured by neuropsychologic testing, personality scales, and neuroimaging. These assessments can be repeated over time to evaluate treatment response [37].

Neuropsychologic tests measure performance (i.e., functioning) in specific cognitive domains (Table 1). Testing during neuroimaging can identify the functional integrity of brain regions that mediate performance on specific neuropsychologic tasks.

Table 1: COMMON IMPULSIVITY DOMAINS AND NEUROPSYCHOLOGIC TESTS

Impulsivity Domain

Neuropsychologic Test

Cognitive Function Measured

Motor inhibitory control

Stop-signal task

Ability to withhold or cancel a planned motor response

Affective inhibitory control

Emotion regulation task

Ability to suppress a default emotional response to unpleasant stimuli

Cognitive flexibility

Reversal learning task

Perseverative response to previously rewarding stimuli when stimulus association rules have changed

Delay discounting

Delay discounting task

Degree of preference for smaller immediate rewards over larger delayed rewards

Source: [25]

Personality scales measure the extent that statements involving impulsive behaviors are endorsed. These statements include: "I make decisions quickly," "I often buy things I cannot afford," or "I act without thinking" [25].

Neuroimaging uses non-invasive technologies to identify brain regions involved in inhibitory control, presence of abnormality, and possible changes with treatment [25]. Neuroimaging has helped identify frontostriatal circuitry as contributing to action inhibition, affective inhibition, cognitive flexibility, and delay discounting. It is now known that frontostriatal circuitry and dopaminergic transmission are common neural substrates that underlie inhibitory control function [38,39].

Compulsivity

Compulsivity is less well-defined and investigated than impulsivity, but it is used to describe repetitive and functionally impairing overt or covert behaviors that lack adaptive function. These habitual, stereotyped behaviors are performed inflexibly to avoid perceived negative consequences and persist despite being harmful [40,41].

Compulsive behaviors are inappropriate and have no obvious relationship to a goal. When reward-driven substance use or behavioral pursuits persist over an extended period, reward-based learning mechanisms are thought to develop into compulsive behaviors [26].

Compulsivity appears distinct from impulsivity, but research demonstrates overlapping neural networks involved in both [4]. Deficits in cognitive flexibility may also serve as markers in disorders of addiction to drug or non-drug rewards. There are two subtypes of compulsivity (reversal learning and attentional set shifting) [42]. Reversal learning is the capacity to flexibly switch choices in response to immediate changes in the environment or setting. The orbitofrontal cortex are involved in this type of compulsivity. Attentional set shifting is the ability to shift response sets to a previously irrelevant dimension and involves the lateral prefrontal cortex (PFC).

3. EXPLANATORY MODELS OF ADDICTION

Explanatory models of psychiatric disorders, including behavioral and substance addictions, are developed to provide a conceptual framework for understanding the disorder and identifying an effective treatment approach. Theoretic models can propose an explanatory basis for entire categories of disorders or specific disorders, a pathogenic process within a larger pathophysiology, or a specific symptom or feature. In behavioral addictions, diverse models have been developed to explain symptoms and clinical course and the interpersonal, cognitive, psychologic, and neurobiologic dysfunction experienced by patients. The most relevant models serve as an organizing foundation for treatment approaches.

GENERAL MODELS OF ADDICTION

Reward-seeking is a central component of addictions. Early reward-centric models focused on the nucleus accumbens, where dopamine is released in response to natural rewards like sex or food. Drugs of abuse were thought to "hijack" the nucleus accumbens by triggering dopamine release far exceeding that of natural rewards (e.g., food, exercise, sex). The reward deficit disorder model posits that addictive behaviors develop from the need to compensate for impaired reward signaling in the mesolimbic dopamine pathway [43].

Although simplistic based on current understanding, earlier biologic models provided an important foundation for later expansion. For example, nucleus accumbens and dopamine function are now known to be involved in reward-based learning, reward anticipation and valuation, salience attribution (i.e., assigning degrees of relevance to items, decisions, or behaviors), and loss processing [43]. More recent models include the reward deficit disorder model, Gray's reinforcement sensitivity theory, the attachment theory development model, and the rejection sensitivity theory.

The Reward Deficit Disorder Model

The reward deficit disorder model describes addictions as chronic relapsing disorders characterized by a compulsion to seek and take the drug or experience the behavior, loss of control over stimuli intake, and emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) when unable to access the stimulus. The negative emotional state is termed motivational withdrawal syndrome. A key component of addiction is negative reinforcement, which describes engagement in potentially harmful behaviors to alleviate a negative emotional state [44].

"Reward deficit disorder" refers to multiple motivational mechanisms and the progression from impulsivity (positive reinforcement) to compulsivity (negative reinforcement). Compulsivity is thought to result from stress within forebrain structures and dysregulation of neurocircuits involved in reward [44].

Gray's Reinforcement Sensitivity Theory

In Gray's reinforcement sensitivity theory, behavioral addictions are understood from the context of brain system sensitivity to punishment and reward. Accordingly, punishment sensitivity regulates responses to stimuli perceived as potentially dangerous, leading to their avoidance (behavioral inhibition). Reward sensitivity directs behavior toward appetitive stimuli that provide immediate compensation (behavioral activation) [45,46].

The Attachment Theory Developmental Model

Behavioral addictions have also been examined through the lens of attachment theory. While not specifically a model of addiction, attachment theory helps explain how early environment experiences may shape beliefs and cognitions that increase risks of behavioral addiction. This model posits that the nature and quality of child attachment to a primary caregiver(s) shape the personality, beliefs in responsiveness and trustworthiness of others, and level of interpersonal security in adolescence and adulthood. The primary attachment relationship is thought to form the template from which subsequent relationships are developed [47,48,49].

A child with responsive, consistent early caregiving develops an expectation that others will be available and supportive when needed. In contrast, children raised in negligent, rejecting caregiving environments form negative expectations in future relationships and social interactions. Attachment style influences personality traits, interpersonal behaviors, and competencies that directly impact satisfaction in romance and friendships, emotional functioning, interpersonal communication, and social behavior [47,48,50].

Attachment style may also influence motivation for pathologic behavior. In persons with attachment anxiety, attachment needs are activated by relational or environmental stressors. Some persons with insecure early attachments may display attachment avoidance, which is the absence of desire for closeness in important relationships. In the context of Internet-mediated addictions, the high dependency in attachment anxiety leads individuals to seek comfort and connection online [49,51,52].

In one study of college students, attachment anxiety (both maternal and paternal) significantly predicted pathologic Internet use, but attachment avoidance did not. Maternal attachment anxiety was a significant predictor of male pathologic Internet use, while paternal attachment anxiety was most relevant in female pathologic Internet use. It is important to note that this study examined college students in the United States, where parental roles and attachment patterns may differ from those in earlier international studies [49].

Rejection Sensitivity

Another interpersonal model is rejection sensitivity, a cognitive-affective worry of rejection that impairs well-being and interpersonal function. Persons who doubt acceptance by others fear and expect rejection, are more hostile and aggressive in relationships, and experience more unstable and dissatisfying relationships that end sooner. They respond to social rejection with hostility, depression, emotional regression, jealousy, and/or over-politeness [35]. Susceptible individuals may turn to Internet-mediated activities first as a way to avoid social interactions; these behaviors may then evolve into addictions.

BEHAVIORAL ADDICTION MODELS

Most theoretical models address behavioral addictions broadly; a few are specific to Internet-mediated behavioral addictions. Many borrow from substance addiction models to address the motivational, behavioral, and cognitive factors associated with other behavioral addictions. However, a few models specific to behavioral addictions have emerged. Many psychologic therapies have been incorporated in behavioral addiction models, because patients with specific behavioral addictions show cognitive, behavioral, and personality dysfunctions successfully treated in other patient populations by the same therapy [53].

The Components Model of Addiction

The components model of addiction defines addiction as any behavior with all six core addiction components [17,54]:

- Salience: The behavior dominates activity, focus, thinking (preoccupation, cognitive distortion), feelings (craving), and behavior (deterioration of socialized behavior).

- Mood modification: The subjective experience of euphoria or relief from aversive emotional states reinforces the behavior.

- Tolerance: Escalation in frequency or stimulus intensity is required to deliver the desired level of mood modification.

- Withdrawal symptoms: Unpleasant emotional effects occur when the behavior is discontinued, interrupted, or decreased, including feeling shaky, restless, moody, depressed, or irritable.

- Conflict: Interpersonal friction occurs when the behavior supersedes obligations and responsibilities to others. Conflict can be intrapsychic, from guilt or loss of control.

- Relapse: There are repeated failed attempts to quit, cut back, or control the behavior, with previous addictive behavior patterns quickly restored.

The Cognitive-Behavioral Model

The cognitive-behavioral model addresses the role of motivational drives for reward-seeking and stress-reduction; behavioral control (related to executive inhibition); and decision-making (involving weighing the pros and cons of engaging in motivated behaviors) in addictive behaviors.

Reward and Motivation

Motivational drives linked to reward-seeking importantly contribute to addictive behavior, and diminished executive function/cognitive control over these motivational drives contributes to decision-making that leads to persistent engagement in the behaviors. Enhanced reward sensitivity and decreased loss sensitivity may increase urges to gamble (in gambling disorder) or online game (in Internet gaming disorder) [53].

Executive Control and Behavioral Inhibition

Executive systems exert cognitive and behavioral control over motivational drives, allowing inhibition of desires and control or moderation of reward-seeking behaviors [55,56]. Subjects with behavioral addiction show diminished response-inhibition and cognitive-control responses to addiction-specific stimuli, reflecting cognitive bias and altered set-shifting related to compulsive aspects of addictions. This is a reflection of alterations in executive function and neural processes that underlie attention, response inhibition, and behavioral flexibility [57,58].

Decision-Making

In deciding between pursuit of immediate reward and delayed consequences, individuals with behavioral addictions show strong tendencies for deciding on immediate reward. Decision-making is the final "check point" before a behavior is enacted [53].

Interaction of Cognitive Domains

Increased sensitivity to winning or pleasure can enhance urges to gamble, online game, or engage in sexual activity. Impaired capacity for executive control leads to inadequate control over reward-seeking behaviors, permitting urges and craving to dominate decision-making and lead to addictive behavior patterns. This promotes disadvantageous decision-making for immediate gratification over long-term gains. Gambling or gaming reinforces reward-seeking behaviors, further eroding executive-control abilities and perpetuating addictive behaviors [53].

UNIFIED MODELS OF INTERNET-MEDIATED BEHAVIORAL ADDICTIONS

Two theoretical models have been developed to describe the underlying mechanisms in the development and maintenance of Internet-mediated addictive behaviors. Both models share common components, are theoretically sound, and have empirically confirmed elements.

The Theoretical Model of Internet Gaming Disorder

The theoretical model of Internet gaming disorder links decision-making favoring immediate reward despite long-term negative consequences and motivation-seeking (craving) as drives to experience pleasure and/or reduce stress. The third domain is diminished executive control (inhibition and monitoring) over motivation-seeking, consistent with research of executive functioning in individuals with substance use disorders. This model refers to reward-centered models of substance addiction, such as incentive salience theory. Treatment interventions are suggested to target specific cognitive and motivational factors [53].

The Interaction of Person-Affect-Cognition-Execution (I-PACE) Model

The I-PACE model is a theoretic framework for specific Internet-mediated behavioral addictions (e.g., gaming, gambling, pornography/cybersex, buying). According to this model, these addictions are the result of interactions between predisposing factors, moderators, and mediators with impaired executive functioning. Conditioned processes (learning and memory) strengthen these associations in the addiction process. Biopsychologic, personality, and affective factors combine and interact to influence an individual's predisposition for Internet-mediated addictions. Interactions between predisposing affective/cognitive factors and pathologic neuropsychologic functioning during Internet-mediated addictions are bidirectional [59].

Predisposing biopsychologic factors increase vulnerability to emotional disorders and behavioral addiction. Negative early childhood experiences of trauma, emotional or physical abuse, and/or social isolation are linked to insecure attachment styles, which correlate with Internet-mediated behavioral addictions [60]. Adverse early events increase individual vulnerability to intense stress reactivity, mental disorders, and addictive behaviors in adolescence and adulthood [61,62].

Predisposing personality factors include high impulsivity, shyness, neuroticism, low self-esteem, conscientiousness, self-directedness, and procrastination. Affective/cognitive responses to environmental stimuli influence the preference of specific Internet genres. For example, a perceived lack of social support, feelings of isolation, and loneliness are linked to the use (and potential misuse) of Internet genres with prominent communication features (e.g., social networking sites) [63,64]. Specific Internet-mediated addictions are associated with specific personality profiles, such as greater rates of ADHD and impulsivity.

The neural correlates of Internet-mediated addictions reflect a maladaptive interaction between cue-reactivity/craving and reduced prefrontal/executive functioning, also observed in substance addictions. Decisions to reduce craving and increase mood through specific Internet genre use are thought to be the result of increasing dominance of immediate reward and decreasing consideration of longer-term negative impacts [59].

4. CHILD AND ADOLESCENT VULNERABILITY TO BEHAVIORAL ADDICTION

For many years, experts have expressed concerns over child and adolescent susceptibility to pathologic behavior patterns involving the Internet, video games, and other digital media use. Substantial changes in brain function and structure occur during adolescence into young adulthood. Key developmental characteristics of adolescent brains increase the likelihood of thrill-seeking and risky behaviors associated with substance use and behavioral addictions. Adolescent behavior is marked by intense affective expression and impulsive reactivity. During the transition from childhood to young adulthood, the process of enhanced myelination decreases gray matter and increases white matter. The increase in white matter is mostly uniform, but diminished grey matter (through synaptic pruning) is more selective. Myelination increases the speed of neural signaling and underlies the timing and synchrony of neuronal firing patterns that convey meaning [65].

The PFC region is involved in executive processes important in risk-reward decision-making, but is among the last brain regions to mature. Compared with mature adults, this aspect of brain development renders adolescents more vulnerable to addictions, other risky behaviors, and mental health disorders [43]. The brain mechanisms that mediate cognitive control, impulsivity, and sensitivity to reward mature during adolescence and young adulthood, and this is the period when substance use initiation and other problem behaviors most commonly emerge [66].

Immature connections between the PFC, the nucleus accumbens, and the amygdala are thought to largely influence goal-directed behaviors in adolescents [67,68]. Reduced prefrontal cognitive control may allow greater influence of affective systems over decision-making and behavior, which increases adolescent vulnerability to social and peer pressure [69]. Addiction can interrupt the normal neurodevelopmental trajectory from adolescence to early adulthood, and addiction in adolescence can be both a cause and effect of cognitive, affective, and behavioral dysfunction.

5. OVERVIEW OF GENERAL BEHAVIORAL ADDICTION TREATMENT

PSYCHOLOGIC THERAPIES

Psychologic therapies are the most extensively studied treatment approaches in behavioral addiction. The core components of many psychologic therapies are applied across behavioral addictions, while other therapies are modified for specific addictions. This section gives a broad overview of psychologic therapies used in the treatment of behavioral addictions in general. Tailored variants are discussed in later sections.

As with any patients, it is important to assess for native language (or preferred language). Patients with lower English proficiency will benefit from materials in their preferred language and/or the use of an interpreter.

Cognitive-Behavioral Interventions

Cognitive-behavioral therapies (CBTs) have evolved over the past 50 years. Behavioral therapy emerged as the "first wave" in the 1950s, followed by a second wave of cognitive therapy in the 1970s. Cognitive therapy and behavioral therapy were combined in the 1980s to become CBT. Since the mid-1990s, a range of third-wave approaches have been introduced, including acceptance and commitment therapy, cognitive-behavioral analysis system of psychotherapy, and functional analytic psychotherapy [70].

Cognitive-Behavioral Therapy

CBT is empirically supported with demonstrated efficacy across a range of substance use disorders [71,72]. CBT may work by strengthening executive control over behaviors through acquisition of cognitive skills. In behavioral addictions, CBT can help individuals improve their inhibitory control ability, recognize maladaptive cognitions, and learn and employ skills for more adaptive decision-making [73,74].

CBT and CBT-related therapies can help patients identify distortions and errors in thinking and the mistaken, irrational beliefs that underpin maladaptive functioning. Patients learn to identify these distortions by monitoring their internal dialogue (e.g., "You can't do that," "Don't even try") and remembering childhood pronouncements (e.g., "You'll never amount to anything," "You're lazy and stupid") that compromise current functioning. Assessing the validity of patients' conclusions and exploring different ways to view themselves and their capabilities are both potent CBT interventions. Through role-playing or in vivo exposure, patients can experiment with alternative views and behaviors. CBT-based approaches also teach coping skills, symptom management, relapse prevention, impulse control, and anger management [75].

CBT for Internet-mediated addiction (CBT-IA) addresses coping styles, Internet-related expectancies, attentional biases, cue-reactivity/craving, executive function, and inhibitory control. The patient's Internet behavior is monitored and analyzed for situational, emotional, and cognitive contexts, and the reinforcing effects of Internet use are considered to help understand the cognitive assumptions and distortions that underlie situational triggers. CBT-IA identifies coping responses and high-risk situations for addictive Internet use, as well as the expectancies, illusions, and reinforcing effects. Cognitive restructuring and reframing target Internet-related cognitive biases [59].

Attentional biases can be decreased by attentional retraining. When combined with the computerized Go/No-Go task (a binary pass/fail test), this approach can improve inhibitory control and executive functioning. Cue-exposure therapy is found to reduce conditioned associations and craving intensity [59].

CBT has evidential support as a treatment for several behavioral addictions. However, there is a nation-wide shortage of clinicians with specialized training in CBT in the United States. Even clinicians who believe they are delivering CBT-based interventions often do not deliver the core components of empirically supported CBT [76].

Cognitive Enhancement Therapy

As discussed, patients with behavioral addictions often show cognitive dysfunction involving elevated impulsivity, impaired cognitive control, and cognitive inflexibility, and therapies that target these domains may be helpful. Cognitive enhancement therapy (CET) involves the repeated practice of cognitive tasks involving problem-solving, response inhibition, visual tracking, and discrimination skills. These skills are practiced several hours per week over several months [56]. CET has resulted in significant improvements in impulsivity and delay discounting in patients with stimulant addiction, and similar strategies should be considered in targeting cognitive dysfunction in persons with behavioral addictions [77].

Cognitive Bias Modification

Persons with gambling or Internet gaming disorder show attentional biases towards Internet cues, and therapies that target such biases may be effective as treatment [78]. Cognitive bias modification specifically targets automatic/implicit processes such as attention bias and approach bias.

Mindfulness-Based Stress Reduction

Stress intolerance and poor stress coping are strongly associated with behavioral addictions. Mindfulness-based stress reduction interventions target stress reduction, and efficacy is supported in substance addictions. This approach may be particularly helpful in patients with behaviors driven by negative-reinforcement motivations [79].

Dialectical Behavior Therapy

Dialectical behavior therapy combines elements of CBT with mindfulness and other approaches into a structured treatment approach that emphasizes skills training in mindfulness, distress tolerance, and emotion regulation. Dialectical behavior therapy provides an atmosphere of validation with psychoeducation and coping skills training—core competencies for interpersonal functioning that ordinarily would have been learned growing up in a healthy family environment. The four primary skill sets are mindfulness, emotion regulation, distress tolerance, and interpersonal effectiveness [75].

Mindfulness helps patients cultivate present-moment awareness, enabling them to observe and describe what is occurring without judgment. Mindfulness effectively counteracts viewing the present through the lens of distorted hopes, expectations, and past experiences of rejection and abandonment. Many patients believe they miss their childhood/family/lover, but they actually miss their idealized version of the past, not the reality.

Effective emotion regulation helps patients to not over-react when facing emotions that threaten to overwhelm. Patients learn to become more aware of their feelings, the precursors to losing emotional control, and how to downregulate arousal states to relieve the pressure for impulsive behavior. Up-regulation is also taught, so patients do not ignore faintly recognized but painful reactions alerting them something is not right.

Dialectical behavior therapy also helps patients learn multiple methods of tolerating distress without resorting to self-defeating or self-destructive behavior. One method involves self-soothing by engaging the five senses when experiencing acute interpersonal anxiety or distress. This can involve listening to or singing a favorite song; watching a travel video of a beautiful location; savoring the taste of a favorite food; lighting a candle with a favorite scent; and/or touching or rubbing soft material or a smooth stone.

Interpersonal effectiveness is built by establishing a repertoire of skills that improve unstable relationship patterns. Patients learn skills related to self-respect, assertiveness, inhibition of emotions, and setting and maintaining personal limits and boundaries. Interpersonal effectiveness is the result of psychoeducation about commonly held relationship myths that encourages patients to begin dismantling maladaptive beliefs by developing statements that challenge their narratives.

Clinical psychologists administering dialectical behavior therapy are available after hours for support calls; during these contacts, patients are asked a series of standardized questions that encourage the best use of problem-solving strategies that apply dialectical behavior therapy principles. Typically, therapist-led dialectical behavior therapy consists of 2 introductory psychoeducational sessions; 16 core skill-learning and skill-building sessions on mindfulness, emotion regulation, and distress tolerance; and 2 final review and relapse prevention sessions [80].

Motivational Interviewing

The concept of motivational interviewing evolved from experience in the treatment of problem drinkers and was first described in 1983. Motivational interviewing is a systematic, evidence-based approach to complex behavior change. It is unique in eliciting and exploring patients' own arguments for change, evoking intrinsic motivation, and helping patients to resolve their ambivalence about change [81]. It is a directive but nonconfrontational method to bypass unproductive struggles. The therapist engages the patient through empathic listening, open-ended questions, reflective statements, affirmations, and summary statements. By decreasing denial and enhancing motivation, motivational interviewing is a pragmatic, practical approach that focuses on actual change [75].

Motivational interviewing helps empower patients with responsibility for their behavior. By allowing patients to resolve their ambivalence using an approach that gently pushes them, they are more inclined to acknowledge the consequences of their behavior and engage in treatment. More aggressive strategies, sometimes guided by a desire to "confront denial," can fail because they push patients to make changes for which they are not willing or ready [82].

Interpersonal Psychotherapies

Interpersonal Psychotherapy

Interpersonal psychotherapy (IPT) was originally developed as a treatment for patients with depression, but it has been modified for other clinical populations. It is a brief, focused therapy that targets problem resolution and symptom improvement within four social domains: grief, interpersonal role disputes, role transitions, and interpersonal deficits. Treatment occurs in three phases [80]:

- Developing a thorough understanding of interpersonal contexts that contributed to the primary diagnosis and identifying interpersonal problem areas

- Helping the patient make interpersonal changes in the identified problem areas

- Reviewing progress and consolidating gains in treatment to prevent relapse

Group Psychodynamic Interpersonal Psychotherapy

Group psychodynamic interpersonal psychotherapy (PIPT) differs from IPT in its de-emphasis of social roles (e.g., role disputes), with greater emphasis placed on present interactions among group members and the therapist. Group PIPT uses cyclical relational patterns and circumplex models (versus social roles) to understand interpersonal patterns. It also applies specific models to elucidate patient attachment needs, negative affect, and behavioral addiction as a coping mechanism [80].

Twelve-Step Programs

Introduced in 1935, Alcoholics Anonymous (AA) is the original and best-known 12-step program. It was followed by Narcotics Anonymous (NA), introduced in the 1950s. Twelve-step programs constitute a specific form of group-mediated recovery from substance and behavioral addictions. They are member-led groups of people with similar addictions who are committed to helping each other—new members in particular—achieve and maintain sobriety. The 12 steps refer to a specific program of recovery. In a very brief description, members of a 12-step program come to understand their powerlessness in controlling the addiction; develop a relationship(s) with a power outside oneself (i.e., a sponsor [mentor], the 12-step group, a therapist, a Higher Power of their definition, or any combination) to best protect against relapse and ensure continued recovery; identify and work through character defects; amend past harms; and become useful to others struggling with addiction. Since the introduction of AA and NA, several 12-step programs have been adapted for specific behavioral addictions [75].

The exact mechanisms of 12-step group involvement that underlie their efficacy are multiple and difficult to disentangle. For example, admitting being powerless over the addiction could permit greater control over the addictive behavior through changes in decision-making processes. Social interactions likely influence efficacy through contact with similarly motivated peers with a shared goal and social norm of abstinence, and access to sponsors for guidance in developing skills for managing crises. Specific aspects may operate through different mechanisms; influences on decision-making and risk-taking behaviors may occur through 12-step meetings and discussions with sponsors [83].

Combined Approaches

Preliminary studies suggest that combining several therapeutic strategies may be more effective than a single approach. Such approaches may include CBT, cognitive bias modification, CET, and/or mindfulness-based stress reduction, delivered in group, individual, family therapy, or school-based formats, with different strategies complementing aspects of the others. Combining behavioral and pharmacologic therapies can also be considered.

PHARMACOTHERAPIES

Almost all behavioral addictions were originally understood through the obsessive-compulsive spectrum model. By extension, and based on efficacy in OCD, selective serotonin reuptake inhibitors (SSRIs) became the most widely used drug class in the treatment of behavioral addictions, but they showed minimal benefit. More recently, neuroscience research identified similarities in the core features of behavioral and substance addictions, and the obsessive-compulsive spectrum model was discarded in favor of better-fitting addiction disorder models. Naltrexone, an opioid receptor antagonist with efficacy in substance use disorders, has suggested benefit in behavioral addictions, but there is evidence of possible adverse effect [22,84].

The brain opioid system may contribute to social attachment and bonding, and brain opioid theory of social attachment posits that endogenous opioids may mediate reward effects in social connection and closeness. The possible effect of exogenous (drug) opioids on social reward is a new area of study. One trial randomized healthy volunteers to naltrexone or placebo and then to the alternate treatment 10 days under double-blind conditions. Participants noted significantly less sense of social connection on naltrexone, which was not explained by changes in emotional state. The findings support endogenous opioid contribution to social bonding and raise unexplored questions of whether diminished social bonding contributes to patient drop-out in naltrexone studies [85,86].

6. GAMBLING DISORDER

Gambling is a popular activity in many cultures, and most people have gambled at some point or do so infrequently, without harm. A subgroup of individuals unable to control their gambling can develop gambling disorder, with potentially severe financial, emotional, relationship, occupational, and possible legal consequences. The accessibility, affordability, and anonymity of Internet gambling may facilitate disordered behavior in predisposed gamblers [87]. A key determinant in the development of gambling disorder is the structural characteristics of the game [88].

EPIDEMIOLOGY

In North America, gambling disorder affects 0.42% of the general population in their lifetime (0.64% among men, 0.23% among women) and 0.16% in the past year [89]. In epidemiologic studies, women represent about 32% of people with gambling disorder and show a telescoping phenomenon of later onset and more rapid progression also observed in women with alcohol use disorder [84].

Financial and marital problems are common among people with gambling disorder. Many of these patients also engage in illegal behaviors, including stealing, embezzlement, and fraud (e.g., writing bad checks), to fund their gambling or to cover past losses. Usually resulting from financial and legal problems, suicide attempts are common and have been reported in 17% of people in treatment for gambling disorder [84].

Among treatment-seeking disordered gamblers, women initiate gambling at an older age than men (31.3 years versus 22.4 years) and have a significantly shorter time from gambling initiation to meeting DSM criteria for gambling disorder (8.33 years versus 11.97 years). As noted, this phenomenon is consistently found in women with substance use disorders as well [90].

Individuals with subclinical but problematic gambling are referred to as "problem gamblers." Studies conducted from 2000 to 2015 found past-year adult problem gambling rates of 2% to 5% in North America [91]. Problem gamblers account for almost one-third of total industry revenue [92]. Those with problem gambling are heterogeneous, and a problem-gambling typology was developed to help account for these differences and consists of three subcategories [10]:

- Behaviorally conditioned problem gamblers

- Emotionally vulnerable problem gamblers

- Antisocial, impulsive problem gamblers

COMORBIDITY

Gambling disorder is highly comorbid with other mental health disorders, particularly substance use disorders, and shows a heritability rate of 50% to 60% [93]. Data published before widespread access to online gambling indicate that, compared with non-pathologic gamblers, pathologic gamblers show a six-fold greater risk for substance use, a four-fold greater risk for illicit substance use disorder, and a three-fold greater risk for mood disorders [94]. At-risk gamblers have higher rates of psychiatric comorbidity relative to the general population [95].

RISK FACTORS

Many attributes of online gambling have led to assumptions that Internet gambling may facilitate earlier onset, more rapid progression, and greater consequences related to gambling disorder compared with off-line gambling [95]. Land-based gamblers, characterized as older, female, and more likely to be divorced, show greater use of electronic gambling machines and table games and greater problem gambling rates than online gamblers [95]. Mixed (off-line and online) gamblers, characterized by younger age, less likely to be married, and more likely to consume alcohol and illicit drugs when gambling, show a propensity to greater involvement in gambling, sustaining higher losses and consequent harms [95]. Online gamblers, consistently identified as male, younger age, higher in education and income, and employed full-time, are significantly less likely to report gambling-related problems than other gambler subgroups [95]. Unlike other behavioral addictions, online gambling is not associated with greater risk of problem or disordered behaviors, which seems more likely to develop in gamblers who prefer offline gambling in casinos or other venues [96].

In contrast to expectations of greater gambling severity and psychopathology in lower income (vs. middle/higher income) groups, a robust positive relationship is found between alcohol use disorder and gambling disorder in middle/higher income (vs. lower income) groups [97]. Gamblers preferring rapid continuous forms in land-based venues can be motivated by emotional vulnerabilities to engage in low-skill games and may be more likely to bypass responsible gambling options to persist despite losses. Setting predetermined limits is more easily achieved with Internet gambling because registration before play is required [95].

In Australia in 2010, gambling generated $19 billion in revenue; 55% came from electronic gaming machines in clubs and hotels, and 40% of electronic gaming machine revenue came from problem gamblers (only 0.6% of the population) [10]. Termed the "crack cocaine of gambling," electronic gaming machines are considered the most hazardous form of gambling, because they incorporate features that promote gambling-related cognitive distortions to perpetuate gambling, including near-win (or near-miss) outcomes and "loss disguised as a win." These features activate the sympathetic nervous system and reward-related neural circuitry, amplified further in disordered gamblers [98,99].

"Losses disguised as wins" undermine the decision-making capacity of disordered gamblers already experiencing cognitive distortions, so they are less likely to make rational choices. Gamblers often misinterpret near-wins as evidence they are mastering the game, which fosters an illusion of control [10].

ASSOCIATED FEATURES

Smoking status is associated with more severe gambling and psychiatric symptoms. Among patients seeking treatment for gambling disorder, daily smokers (compared with non-daily smokers) were more likely to have histories of substance use disorder treatment, more severe gambling, family and social problems, and more frequent psychiatric symptoms, especially anxiety-related symptoms [100,101]. In a study of the association between smoking and gambling in adolescents, those with "at-risk/problem gambling" who smoked were more likely to report poor grades, lifetime use of cannabis and other drugs, current heavy alcohol use, depression, aggressive behaviors, and less likely participation in extracurricular activities [102].

Gambling disorder is associated with elevated rates of suicidal thoughts and behavior. Among non-treatment seeking subjects with subsyndromal gambling disorder, suicidality was identified in 18.4% [103]. Suicidality is significantly associated with mood and anxiety disorders, higher nicotine consumption, and greater impairments in decision-making and cognitive flexibility [103].

PATHOPHYSIOLOGY

Disordered gambling is associated with several cognitive impairments, including diminished reward sensitivity from reduced reward circuit activity, reduced ability to delay reward or learn from negative consequences, stronger physiologic responses to near-wins, and poor error monitoring. The neuropsychologic impact of near-wins is a key feature in developing and maintaining gambling addiction [10].

Subjects with gambling disorder have been compared to healthy controls in numerous neuropsychologic and neuroimaging studies. Brain structure abnormalities, and corresponding functional deficits, have been identified in individuals with gambling disorder in the insula (altered near-miss cognitive interpretation), ventral striatum (impaired reward-based cognitive flexibility), frontotemporolimbic circuits (impaired concentration, memory, executive functions), PFC (cognitive rigidity, impulsivity, compulsivity), dorsolateral PFC (risky decision-making), ventrolateral PFC (impaired reward-based cognitive flexibility), and orbitofrontal cortex (risky decisions, impairments in assessing future consequences, and reward-based cognitive flexibility) [104,105]. Neurochemical systems implicated in gambling disorder pathophysiology include dopaminergic, glutamatergic, serotonergic, noradrenergic, and opioidergic systems [105].

In one study of gambling disorder and control subjects, reactivity to gambling cues was imaged by fMRI. In gambling disorder subjects, gambling cues reliably induced craving to gamble and increased neural reactivity in the anterior cingulate cortex and insula [106]. Craving level was strongly linked to:

- Hyper-connectivity between the nucleus accumbens and insula

- Hypo-connectivity between the nucleus accumbens and medial PFC

Gambling cues activated brain responses in reward-related circuits. The intensity of cue reactivity (as craving) was influenced by impaired PFC control over the limbic system. As gambling abstinence increased, craving elicited by the gambling cues decreased.

Gray's theory provides a framework to understand behavioral addictions in terms of the sensitivity of brain systems to punishment and reward [45]. Patients with gambling disorder with higher reward sensitivity have been found more likely to dropout from treatment than those with lower reward sensitivity. In a community sample of gamblers, high reward sensitivity was associated with greater gambling frequency and social motives for gambling. Disordered gamblers in therapy are commonly urged to sever their ties with people and places that may trigger a relapse; when confronted by this, patients with stronger social bonds to gambling may terminate treatment. This is even more likely in early-stage gambling disorder, in which the patient attains the sought-after immediate reward and has not yet experienced distress or consequences [45].

DIAGNOSIS

According to the DSM-5, gambling disorder is categorized as a substance-related or addictive disorder. Diagnosis of gambling disorder requires four or more of the following [11]:

- Often preoccupied with gambling

- Need to gamble with increasing amounts of money to achieve excitement

- Repeated unsuccessful efforts to reduce or stop gambling

- Restlessness or irritability when trying to reduce or stop gambling

- Gambles in response to negative moods

- Chases losses

- Lies to others to conceal the extent of gambling

- Jeopardizes relationships, career, or educational opportunities because of gambling

- Relies on others to escape negative financial consequences of gambling (i.e., "bailouts")

The exclusion of illegal activity from the DSM-5 criteria was not an endorsement to downplay its relevance. The presence of illegal behavior in patients with gambling disorder is directly linked to more severe pathologic outcomes and resistance to treatment; specific and more intensive treatment may be required for these patients [107].

In differential diagnosis, it is important to rule out medication side effects when new-onset disordered gambling symptoms follow initiation of dopaminergic medication in Parkinson disease [11].

Gambling disorder is included in the International Classification of Disease, Eleventh Revision (ICD-11), published in 2018 [108].

TREATMENT

Despite serious psychosocial and financial consequences, most disordered gamblers do not seek treatment or may seek treatment only after being pressured by family members. Patient motivation and treatment adherence importantly contribute to successful treatment outcome for patients with gambling disorder [109].

Prominent barriers to seeking help for gambling problems include wanting to handle the problem by oneself, shame/embarrassment/stigma, unwillingness to admit the problem, and issues with treatment itself. Unwillingness to admit to the problem may be more prevalent than reported. Other barriers include a lack of knowledge about treatment options and practical issues involving treatment attendance [110].

A main challenge in gambling disorder treatment is the high patient dropout, ranging from 43% to 80% depending on treatment modality and setting [109]. Identifying factors that improve treatment engagement is important. One study found patients receiving antidepressants plus group CBT had the longest treatment retention, regardless of gambling disorder severity or demographic factors. Given the limited benefit of antidepressants in gambling disorder, this finding was unexpected but suggests using multiple treatment modalities may reduce patient dropout [109].

Psychologic Interventions

Many disordered gamblers can trace the course of their disease to an early win, followed by increasing gambling frequency and expenditure. Even early wins of $100 to $500 can increase excitement about gambling, distort self-perceptions of skill or expected returns, and strengthen irrational beliefs about gambling (e.g., illusion of control) [111,112]. Many erroneous beliefs and inaccurate perceptions are rewarded, learned, or become habitual during disordered gambling, and several cognitive distortions are emblematic of gambling disorder, including [70,113]:

- The gambler's fallacy (i.e., belief that a string of losses must predict an imminent win)

- The availability heuristic (i.e., selective recall of wins over losses)

- Failure to recognize net losses with intermittent small wins (e.g., spending $400, a $50 win is deemed a success, despite the $350 net loss)

- The idea of intensely needing to win makes winning likely

- Beliefs about luck

Therapies targeting erroneous cognitions, gambling urges, and motivations are effective. A meta-analysis of behavioral therapy outcomes in gambling disorder found an effect size of 2.01 at the end of treatment and 1.59 at follow-up (mean: 17 months). Efficacy seems to diminish over time, but the effect sizes were robust [83,114].

Cognitive-Behavioral Therapies

In the treatment of gambling disorder, cognitive therapy is based on the idea that gambling-related cognitive distortions contribute to disordered behavior. With this approach, the therapist helps patients identify and correct gambling-related cognitive distortions, with the goal of improving gambling abstinence by greater use of logical behavioral choices. One cognitive approach provides up to 20 weekly sessions until the patient stops gambling. Short-term outcomes show superior improvement relative to control groups. A frequent component is relapse prevention, which identifies high-risk situations for relapse and maladaptive beliefs related to control over gambling [112,115].

Behavioral therapies target gambling urges primarily with exposure-based therapies. Exposure therapy is based on classical conditioning paradigms, whereby gambling urges are eliminated through cue exposure with extinction processes. Exposure therapy is thought by some to be more beneficial in gambling disorder than other behavioral therapies, such as aversive therapy [70].

CBT focuses on changing gambling-related cognitions and behaviors; it is effective and improves treatment engagement and outcomes [113]. Brief, four- to six-session CBT interventions show some promise in problem and disordered gambling, but they require further evaluation in broader samples of treatment-seeking gamblers [112,116]. An eight-session CBT intervention for gambling disorder may follow the specific therapeutic focus outlined here [94,112]:

- Recognizing gambling triggers that precipitate gambling episodes: days/times, people, cues (cash), events (celebrations, arguments), and emotions (negative affect)

- Examine gambling episodes using functional analysis

- Increase alternate pleasurable activities

- Manage anticipated and unanticipated triggers

- Relaxation techniques to manage responses to gambling urges

- Interpersonal conflicts, practice gambling refusal skills

- Cognitive biases and distortions with gambling disorder

- Relapse prevention, coping with major life events

Evidence Based Practice Recommendation

According to a Cochrane Review, cognitive-behavioral therapy (CBT) is effective in reducing gambling behavior and other symptoms of pathologic and problem gambling immediately following therapy. However, the durability of therapeutic gain is unknown.

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD008937.pub2/full

Last Accessed: April 12, 2021

Level of Evidence: Meta-Analysis

Variants of CBT have been adapted for patients with gambling disorder.

Functional analysis teaches patients with gambling disorder to identify triggers, related feelings, and resultant behaviors; examine the positive and negative consequences of their triggers; and identify cognitive biases, such as luck-related beliefs in their gambling behaviors [83]. The process of developing improved strategies to identify and manage triggers related to craving may increase PFC control over motivational drives involving subcortical brain regions [83]. Increased awareness and understanding of irrational cognitions, such as those related to luck, near-miss events, and chasing behaviors, may increase the balance in activity of brain circuits that code conflicting motivational states [83,117].

Skills training in CBT can include interpersonal skills and conflict resolution methods through role-playing and skills training. These skills are intended to help the person recognize that gambling may provide short-lived reward and enjoyment but problematic long-term consequences of debt, interpersonal conflicts, and/or legal system involvement. This type of intervention further addresses finance management and debt settlement—important concerns in gambling disorder [118].

Brief Motivational Interventions

Brief motivational intervention shows promise in reducing gambling when delivered alone or with other therapies. Brief motivational interventions are often directed at patients with subclinical diagnoses, defined as negative gambling-related consequences without meeting the criteria for gambling disorder. Brief motivational intervention is useful for engaging patients with poor problem recognition in further treatment or for spurring self-directed change. Therapy sessions focus on personalized feedback, brief advice, review of options (e.g., treatment options, change goals), and building self-efficacy, delivered in an empathic manner. In one study, telephone brief motivational intervention combined with a self-help workbook was effective in improving gambling outcomes in problem gamblers [119]. Single-session stand-alone motivational sessions are effective compared with assessment-only control groups [116]. Direct comparisons of motivational therapy and CBT suggest both interventions are equally effective compared with control groups [120].

Gambling Disorder and Comorbid Problem Drinking

Changes in alcohol use patterns during gambling treatment were examined in a study of 163 patients with gambling disorder followed 36 weeks pre-, during, and post-treatment. Overall, alcohol use was decreased during and after treatment, but 31% showed risky drinking during and after treatment. Latent risky drinking was predicted by recent at-risk drinking, male sex, younger age, lower gambling severity, treatment condition, and gambling during treatment. This greater-drinking profile suggested ambivalence about gambling changes during treatment, and those less motivated to change their gambling may be less motivated to reduce their alcohol use [121]. One study found that problem gamblers with co-occurring lifetime alcohol dependence demonstrate addictive behavior across multiple domains and resistance to externally motivated treatment approaches [122].

Treatment for patients with gambling disorder and comorbid risky alcohol use may differ from non-risky drinkers. Disordered gamblers with low-risk alcohol use tend to have positive outcomes with group CBT, while high-risk drinkers tend to respond better to motivational interviewing. Screens for alcohol problems, such as the Alcohol Use Disorders Identification Test (AUDIT), may be used to help guide treatment selection [123].

Pharmacologic Interventions

The most studied medication class in gambling disorder is SSRIs, but results have been mixed at best [84]. Based on possible efficacy in impulsivity treatment, several mood stabilizers have been evaluated in gambling disorder treatment. In one study, lithium was superior to placebo in reducing gambling symptoms during 10 weeks of treatment in patients with gambling disorder and bipolar spectrum disorders. However, olanzapine was found no more effective than placebo [84].

Opioid Receptor Antagonists

Multiple studies have demonstrated the efficacy of opioid receptor antagonists in the treatment of gambling disorder. Opioid antagonists dampen gambling-related excitement and cravings by decreasing dopamine neurotransmission in the nucleus accumbens and interconnected reward and motivational neurocircuitry [84].

In the initial study, naltrexone (mean dose: 188 mg/day) demonstrated superiority to placebo in reducing gambling-related behaviors, thoughts, and urges, and was particularly effective in gamblers with more severe gambling urges [124]. A second naltrexone study confirmed the findings of the initial study over a longer (18-week) period [125]. The efficacy of as-needed placebo or naltrexone (50 mg) and psychosocial support on reduction of gambling severity, gambling-related thoughts and urges, and gambling frequency and expenditures was assessed among 101 problem gamblers over 20 weeks [126]. Overall, the as-needed naltrexone provided no substantial benefit over psychosocial support.

Nalmefene is a long-acting analog of naltrexone administered by injection. Nalmefene efficacy was demonstrated in 207 subjects treated for 16 weeks, with significant reductions in gambling urges, thoughts, and behavior observed in 59% with nalmefene, compared with 34% with placebo [127]. A second nalmefene trial failed to show statistically significant differences from placebo [128]. Subsequent research found low-dose nalmefene significantly more effective than higher doses. Over 16 weeks, nalmefene (25 mg and 50 mg per day) led to significantly greater reductions in pathologic gambling severity than placebo. With nalmefene (25 mg/day), 59.2% of patients were rated as "much improved" or "very much improved," compared with 34.0% with placebo. Nalmefene at a dosage of 25 mg/day was effective and showed few adverse events, but 50-mg and 100-mg doses had intolerable side effects [129].

Catechol-O-Methyl-Transferase Inhibitors

Catechol-O-methyl-transferase (COMT) is an enzyme that degrades dopamine to regulate cognitive functioning in the PFC. As discussed, PFC-mediated cognitive dysfunction is implicated in the pathophysiology of gambling disorder, and a small uncontrolled study evaluated the COMT inhibitor tolcapone in 24 patients with gambling disorder who also received fMRI before and after treatment. Compared with controls, the subjects with gambling disorder showed underactivation during executive planning tasks pretreatment. Tolcapone was associated with statistically significant reductions on measures of pathologic gambling, the extent of which significantly correlated with increased activity in brain areas previously underactive during executive planning challenge [130].

Dopaminergic Modulators

Dopamine binding is positively correlated with gambling severity and impulsivity, and dopamine release in disordered gamblers is related to excitement and worsened behavioral performance. The dopamine-1 (D1) receptor antagonist ecopipam was evaluated in patients with gambling disorder when taken as needed for nine weeks. Compared with placebo, ecopipam led to statistically significant reductions in Yale-Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) total score (25.6 baseline vs. 14.0 at study end) and subscales of thought-urge and behavior. Ecopipam may reduce pathologic gambling behavior [131].

Glutamate-Modulating Agents

Another promising area of pharmacotherapy in gambling disorder is glutamate-modulating agents. N-acetylcysteine (NAC), one such agent, was studied in subjects with gambling disorder over eight weeks; responders during open-label were then randomized to NAC or placebo for six weeks. In the open-label phase, 59% experienced significant symptom reductions and were classified as responders. At the end of the double-blind phase, 83% of those assigned to NAC remained responders (vs. 28.6% assigned to placebo) [132].

Cigarette smoking is highly prevalent in gambling disorder, and nicotine dependence is associated with greater gambling severity. Imaginal desensitization plus NAC was evaluated in patients with gambling disorder and nicotine dependence. After six weeks, subjects randomized to NAC or placebo both showed significant benefit from imaginal desensitization, but at three-month follow-up, NAC led to significant additional benefit in gambling severity reduction compared with placebo [133].

Other glutamate agents, such as topiramate, have not shown benefit [84].

Gamblers Anonymous

Founded in the 1950s, Gamblers Anonymous (GA) is a mutual help fellowship based on the 12-step program of AA. With meetings in most North American communities, GA is established worldwide as a resource for people struggling with gambling problems. GA groups are peer-led and abstinence-focused and represent the most widely available option for recovery from gambling disorder [134]. Some GA meetings welcome family and friends to attend "open meetings," recognizing the impact of disordered gambling often extends far beyond the patient and that support from non-gambling family and friends can be integral to recovery. Local groups can be found online at http://www.gamblersanonymous.org/ga/content/about-us [112].

GA has a unique culture of recovery, distinct from AA and NA in specific areas. For example, GA recognizes that for many new members, addressing the crippling financial consequences is vitally important for their recovery. Senior members who confronted and resolved their own financial consequences guide and support the new members through these challenges [134].

GA members tend to have more severe gambling symptoms, are more motivated for treatment, and have greater involvement with professional gambling treatment. GA involvement is positively associated with abstinence and improvements in abstinence, and with increased readiness for change, adaptive coping skills, and higher leisure activity involvement [134].

GA can be used alone or combined with other interventions. Individuals who engage in GA and professional treatment have better gambling outcomes than those who receive professional care alone. GA is also a valuable resource if remitted gambling problems recur in the future [33].

The potentially severe consequences of gambling disorder elevate the need to identify factors that support gambling abstinence. In a study of GA members, the greatest predictors of gambling abstinence were participation and involvement in GA, support from family and friends, and connections with other GA members. Relapse was strongly predicted by high gambling urges and erroneous gambling cognitions [92]. Of note, GA meeting attendance may be helpful, but involvement with GA meetings and members carried the greatest protection from relapse. GA and CBT are the two most widely used approaches for gambling disorder. A review of published evidence concluded that combining GA and CBT may enhance therapy engagement and reduce relapse risk [118].

7. ADDICTIVE SEXUAL BEHAVIOR

Persons with sexual addictions can spend vast amounts of time pursuing sexual encounters to the detriment of their marital, occupational, financial, and physical well-being and function. When human immunodeficiency virus (HIV) or other sexually transmitted infection (STI) exposure is possible, the behavior can be life-threatening. The lack of consensus of how to conceptualize problematic sexual behavior has invited explanatory paradigms using obsessive-compulsive, impulse control, addiction, and biopsychosocial models [75,135].

Reports in the medical literature of patients seeking professional help for extremely frequent or hypersexual urges and behaviors date to the early 1800s [136]. In addition to well-characterized manifestations of sexual addiction, more recently developing contexts include methamphetamine-driven hypersexuality in the gay community and the use of location-based online dating platforms. Arguably the most important development in the field of addictive sexual behavior is Internet-mediated sex addiction, more frequently involving pornographic videos and masturbation [15].

The terms sex addiction, sexual addiction, addictive sexual behavior, compulsive sexual behavior, hypersexual disorder, sexual compulsivity, and sexual impulsivity describe roughly the same phenomenon [137]. Other related terms include [11,138,139]:

- Paraphilias: Behaviors deemed socially unacceptable that involve non-human objects, suffering of self or partner, children, or a non-consenting person (e.g., fetishism, exhibitionism, pedophilia)

- Nonparaphilic: More typical sexual behaviors that include compulsive sexual acts with multiple partners, constant fixation on a partner that may be considered unobtainable, compulsive masturbation, compulsive use of pornography, and compulsive sex and sexual acts within a consensual relationship

- Geo-locating social media: Online dating applications (apps) that use geo-positioning satellite (GPS) technologies in smart phones to provide the proximity of users from each other

EPIDEMIOLOGY, RISK FACTORS, AND COMORBIDITY

Addictive sexual behavior may be relatively common, and while no epidemiologic data are available, researchers estimated a lifetime prevalence of 2% to 6% and rates of 2.0% to 3.7% among American college students [140]. Some data suggest addictive sexual behavior may be more common with Internet mediation. A Swedish study estimated the prevalence of "Internet sexual problems" was 17.8% in men and 6.7% in women, higher than studies from the pre-Internet era [22].

Addictive sexual behavior is more common in men, with onset usually in late adolescence. It can involve a wide range of sexual behaviors, often including a mixture of paraphilic and nonparaphilic behaviors. Sexual urges and behaviors are often distressing and uncontrollable, triggered by certain mood states, and result in feelings of shame [141,142].

Comorbidity is common in addictive sexual behavior, including substance use disorder (64%), affective disorders (14% to 39%), anxiety disorders (50%), and childhood conduct disorder (44%). In the family histories of patients with addictive sexual behavior, 40% had substance use disorder in at least one parent and 36% had sexual addiction in at least one parent [143,144].

Addictive sexual behavior is consistently linked to high-risk sexual behaviors, including multiple partners, unprotected sex, and sex under the influence of drugs or alcohol. The adverse consequences and risks of addictive sexual behavior include HIV/STI infection, unwanted pregnancies, infertility, loss of relationships, social isolation, loss of self-esteem, job loss, legal issues, financial problems, significant personal distress, and impairment in daily functioning [137].

Patients diagnosed with sex addiction differ in common personality characteristics from those diagnosed with gambling disorder. Sex addiction is associated with higher education level and lower novelty-seeking, harm avoidance, persistence, and self-transcendence. Being employed and lower cooperativeness scores also predicted the presence of sex addiction. However, patients with gambling disorder or sex addiction do not differ in comorbid psychopathology [145].

Gender Differences

In one of few Internet pornography addiction studies involving women, Internet pornography users rated pornographic images as more arousing and reported greater craving for sex than non-users. Craving, sexual arousal, sensitivity to sexual excitation, problematic sexual behavior, and severity of psychologic symptoms were predictors of Internet pornography addiction. In contrast, current relationship status, number of sexual contacts, satisfaction with sexual contacts, and use of interactive cybersex were not associated with addiction. The reinforcing nature of sexual arousal, learning mechanisms, and cue reactivity and craving in the development of Internet pornography addiction in women were found consistent with those reported in heterosexual men [146].

In a large community survey, 51% of women and 90% of men reported using Internet pornography. Internet pornography use was associated with sexual dissatisfaction from perceived addiction (perceived compulsivity, effort to access, distress from pornography use) and sexual function problems (sexual dysfunction, compulsion, avoidance). This pattern held for men and women [147].

Geo-Locating Social Media

Growing in popularity and market share, geo-locating social media gives users the ability to find each other for casual sexual encounters ("hook-ups"). Unlike standard online dating apps, location-matching apps typically do not require users to create a profile about themselves; instead, users upload one or more photos. The simplicity of appearance-based selection and proximity accounts for the increasing growth in popularity of location-based dating apps. One of the first such apps, Grindr, was introduced in 2008 specifically for gay and bisexual males, followed by other apps for gay men, lesbians, and heterosexuals (Tinder, Bumble, and others) [139,148].

INTERNET PORNOGRAPHY ADDICTION

Excessive and addictive Internet pornography use by younger men has received little attention outside of behavioral and sexual addiction research, but data suggest this has become a rapidly growing problem with serious consequences that requires fuller discussion.

Epidemiology of Adverse Effects

High-speed broadband Internet access became widely available in the early 2000s. Until the early to mid-2000s, erectile dysfunction (ED) prevalence in sexually active men younger than 40 years of age was low, consistently 2% to 4%. In contrast, studies conducted since 2005 show sharply increased prevalence of ED and low sexual desire in men younger than 40 years of age [149]. For example, new ED diagnoses in active-duty servicemen doubled from 2004 to 2013 [150]. In 2014, 53.5% of men 16 to 21 years of age had symptoms of sexual dysfunction, including ED (26%), low sexual desire (24%), and problems with orgasm (11%) [151]. In 2016, a study of persons 16 to 21 years of age followed over two years found persistent problems in boys/men of low sexual satisfaction (47.9%), low desire (46.2%), and ED (45.3%). Over time, sexual problems declined in women but not men [152]. A 2015 study found ED with low desire for partnered sex was common in men (mean age: 36 years) seeking help for Internet pornography use with excessive masturbation [153].

ED in men younger than 40 years of age is typically diagnosed as psychogenic and linked to stress, depression, generalized anxiety, or performance anxiety. Organic ED, diagnosed in 15% to 20% of cases, is linked to neurologic, hormonal, or anatomic conditions or drug side effects. ED in older men is more often diagnosed as organic, associated with smoking, alcohol use, diabetes, obesity, hypertension, or cardiovascular disease [154]. None of the known correlative factors of psychogenic ED adequately account for the rapid increase in youthful sexual dysfunction. The historical correlates of organic ED in older men have not changed proportionately, or have decreased, in younger men over the past 20 years [149,155].

PATHOPHYSIOLOGY

The bulk of recent neuroscience research in sexual addiction has studied addictive Internet pornography use and, unfortunately, almost exclusively involves male research participants. Nonetheless, this research has importantly clarified pathogenic and pathophysiologic processes, the marked similarities to substance addictions, and the pathogenesis and pathophysiology of Internet pornography addiction, hypersexuality, and Internet pornography use-induced sexual dysfunction. The importance of this research is underscored by findings of a long-term study that Internet pornography may have the highest addiction potential of any online activity (with Internet gaming a close second) [156].

Cue reactivity, or the level of sexual arousal to Internet pornography, is the greatest single predictor of Internet pornography addiction, severity of the addiction, and impairment from the addiction. Hours of use alone is unrelated to addiction. Cue reactivity is an established correlate of addictive behavior across addiction disorders [149,157]. Internet pornography addiction severity is directly related to cue-induced activation of the dorsolateral PFC and thalamus [149,157].

Male sexual response is actually complex. One core mechanism is the hypothalamic nuclei, which regulates sexual behavior and erections by integrating brain and peripheral input. Pro-erectile input comes from mesolimbic dopamine pathways—the ventral tegmental area and the nucleus accumbens. The ventral tegmental area and nucleus accumbens form the core of a set of integrated circuits, termed the "reward system," that detects reward stimuli and regulates response to sex and other rewards. The mesolimbic dopamine pathway receives excitatory input from other limbic structures and inhibitory input from the PFC [149,158,159]. The reward system promotes memory and repeat of critical pro-survival behaviors such as sex, eating, and social connections.

Internet Pornography as Supranormal Stimulus

High-speed, broadband Internet pornography is substantially more sexually arousing than other forms of pornography or fantasy and may become more immersive with three-dimensional technology. Novel sexual visuals trigger greater arousal, faster ejaculation, and more semen and erection activity than familiar visuals; arousal is further increased by ability to self-select material with ease. As an amplified mimic of stimuli with evolutionary salience that human brains have evolved to pursue, Internet pornography is a supernormal stimulus and unique activator of reward, impulsivity, and for some, addiction [149,160,161].

Pathologic Learning and Hyper-Reactivity

Reward system vulnerability to pathologic learning can make Internet pornography use self-reinforcing. The neural substrates of sexual learning and addiction overlap. Development of addictive Internet pornography use promotes neuroplastic change. The mesolimbic dopamine system receives glutamate inputs from cortical and limbic regions. Glutamate synapses associated with seeking and obtaining a specific reward become altered, enhancing mesolimbic dopamine system response to the specific reward. With the mesolimbic dopamine system sensitized to sexual reward, hyper-reactivity develops to Internet pornography cues [149,161,162].

Decreased Reward Sensitivity (Hypo-Reactivity)

Reward system hyper-reactivity to Internet pornography cues develops concurrently with hypo-reactivity and down-regulation of response to natural rewards (i.e., partnered sex) [163]. Persons with addictive Internet pornography use show strong preferences for, but rapid habituation to, novel sexual images. This often fuels the search for even more novel sexual images and escalation to hardcore and extreme pornography, indicating decreased reward sensitivity, increased habituation and tolerance, and greater stimulation needed for sexual arousal [149,161,162].

Addictive Internet pornography use is correlated with lower functional connectivity between the striatum and the PFC. Dysfunction in this circuitry is linked to behavioral choices that disregard potentially negative outcomes, including reduced executive control function during exposure to pornographic images [149,164,165,166].

Sexual Conditioning and Dysfunction

Sexual arousal conditioned to Internet pornography cues promotes sexual dysfunction [157]. Users crave the high levels of novelty, intensity, and arousal of Internet pornography that are difficult to sustain in partnered sex. When high stimulation expectations and requirements are not met, partnered sexual stimulation is ineffective. In some users, a preference for novelty arises from the need to overcome declining libido and erectile function, leading to conditioned preferences for Internet pornography use [167,168].

Pornography use is inversely related to satisfaction with partners, as measured by affection, physical appearance, sexual curiosity, and sexual performance [169]. The caudate is involved in approach-attachment behaviors and motivational states associated with romantic love [170]. Putamen activation is associated with sexual arousal and penile tumescence [171]. Users of more extensive Internet pornography show smaller right caudate and lower putamen activation when viewing sexually explicit still photos. This reflects down-regulation of natural neural response to sexual stimuli from intense, prolonged exposure to pornographic stimuli [172]. Men with greater use of degrading or extreme pornography report more frequent concerns of sexual performance, penis size, and ability to maintain an erection (compared with moderate or non-users) [149,173].

Early sexual conditioning impacts sexual arousal templates. A critical developmental period of sexual behavior forms around initial experiences with sexual arousal and desire, masturbation, intercourse, and orgasm. Younger age of onset for regular Internet pornography use and greater preference for pornography over partnered sex is associated with persistence of this pattern. In 2014, nearly 50% of college-age men reported they were first exposed to Internet pornography before 13 years of age, compared with 14% in 2008 [174,175]. Young adults with addictive Internet pornography use show greater impairments in sexual arousal and erectile function in intimate relationships, but not with pornographic material.

ASSESSMENT

In contrast to the body of research in other behavioral addictions, the published literature on sexual addiction is highly qualitative in nature. There are fewer controlled studies of treatment, but far greater material that examines the nuances of clinical assessment and care of these patients. In fact, a main criticism of research in other behavioral addictions is the lack of such qualitative work [176].

Areas to inquire about in order to identify hypersexuality subtypes during patient assessment include [136]:

- Paraphilic interests

- Behaviors that are not themselves sexual but may suggest a hypersexual subtype. For example:

- Non-sexual forms of avoidance or procrastination (may suggest problematic sexual behavior as a maladaptive avoidance strategy)

- Non-sexual symptoms of personality disorders, by embedding the problematic sexual behavior as a single feature of a more general problem

- With distress attributed to sexuality, probe to determine if sexual behavior falls within peer norms and/or the individual's distress unrelated to sexuality

- With distress attributed to sexuality, probe to determine if sexual behavior falls within peer norms and/or the individual's distress unrelated to sexuality

- Partner characteristics, such as recent or long-standing inhibitors of full sexual functioning

Evidence Based Practice Recommendation

According to the British Association for Sexual Health and HIV, sexual history-taking should take place in a confidential, private environment.

https://www.bashhguidelines.org/media/1241/sh-guidelines-2019-ijsa.pdf

Last Accessed: April 12, 2021

Strength of Recommendation/Level of Evidence: 1D (Strong recommendation based on non-analytic evidence)

Clients may lack the vocabulary to describe their sexual interests, and it can be helpful to canvas and list the pornographic websites they prefer. Other general assessment questions for patients with sexual behavior concerns include [136]:

- How much of your concern is about the amount of sex, what kind of sex, or the kinds of people you want sex with?

- Some people hire sex workers for simple, physical sex, but other people want other kinds of relationships with the sex workers. What is your ideal?

- Which porn websites do you prefer?

- Masturbating several hours per day is certainly higher than average. What would you do with that time if not masturbating?

- How do you deal with stress? What has worked for you? What has not?

- Why did you get married? How has it matched up with what you expected?

- What would your partner's sex life be like if you never met?

- How does religion influence your life aside from sex?

- How much of the problem is about risking harm to yourself (or others), and how much involves what it means about you as a person?

- Finding sex is what attracts our attention, but for many people the problem is more about finding relationships. How do these go together for you?

Sexual Dysfunction from Internet Pornography Use

A simple assessment for Internet pornography-related sexual dysfunction is asking the patient whether he can achieve a satisfactory erection and climax when masturbating without Internet pornography. If he cannot, but can easily achieve these goals with Internet pornography, then his sexual dysfunction may be associated with its use. Healthcare providers should also screen for relationship problems, low self-esteem, depression, anxiety, post-traumatic stress disorder, stress, and other mental health problems, but should avoid assuming a psychologic cause of otherwise unexplained sexual dysfunction in men younger than 40 years of age. The relationship between psychosocial factors and sexual dysfunction in younger men may be bidirectional and co-occurring or Internet pornography-induced [149].

Possible Medical Causes of Hypersexuality

The first step in the treatment begins with accurate diagnosis that rules out medical causes of hypersexuality. Neurologic disorders associated with hypersexual behavior include Alzheimer disease (4.3% to 9% of these patients experience sexual disinhibition as a result of disease effects on the frontal and temporal lobes), frontotemporal degeneration (associated with impaired regulation of socially acceptable behaviors), and Kleine-Levin syndrome (causes hypersomnia that may lead to abnormal behavior, such as hypersexuality). Some medications or illicit drugs can elevate sexual drive, such as cocaine, methamphetamine, and dopamine agonists used in Parkinson disease [138,177,178].

DIAGNOSIS

Variously worded diagnostic entities describing addictive sexual behavior have appeared in the iterations of the DSM and the ICD [179]. Diagnostic criteria for hypersexual disorder were created and proposed for the DSM-5. These criteria are [138,180]:

- Over a period of at least six months, recurrent and intense sexual fantasies, urges, or behaviors (specify if masturbation, pornography, sexual behavior with consenting adults, cybersex, phone sex, or strip clubs) in the context of three or more of the following criteria:

- Excessive time consumed by sexual fantasies and urges, and planning for and engaging in sexual behaviors, repetitively interferes with other important (non-sexual) goals, activities, and obligations

- Repetitive engagement in such sexual activity as a means to regulate dysphoric mood states of anxiety, depression, boredom, or irritability

- Repetitively engaging in such sexual activity in response to stressful life events

- Repeated but unsuccessful efforts to control or significantly reduce these sexual fantasies, urges, or behaviors

- Repetitive engagement in sexual behaviors while disregarding the risk for physical or emotional harm to self or others

- Presence of clinically significant personal distress or impairment in social, occupational, or other important areas of functioning associated with the frequency and intensity of these sexual fantasies, urges, or behaviors

- Sexual activities not due to the direct physiologic effects of a recreational drug or medication, a co-occurring general medical condition, or to manic episodes

- Age of at least 18 years

Not included in the diagnostic criteria, Kafka also proposed that seven sexual outlets (i.e., orgasms) per week represented a cutoff point for excessive sexual activity, based on his review of published research [75].

The APA rejected the recommendation of its own Sexual and Gender Identity Disorders Work Group to include hypersexual disorder in the DSM-5. The APA stated an objection to the implicit normative reference to the "right amount" of sexuality (e.g., the cutoff of seven sexual outlets per week suggested in the supporting review but not in the diagnostic criteria) [181]. The DSM-5 task force also stated there were insufficient data to support inclusion of hypersexual disorder [75].

An evaluation of various proposed diagnostic criteria for sexual addiction found common core domains [75]:

- Excessive sexual behavior, generally outside the context of sustained intimate relationships

- Intense and persistent urges to perform such sexual behavior, similar to drug craving in substance addiction

- Continuation of sexual behavior despite the potential to cause significant personal, occupational, or financial consequences and/or harm to physical health

- Difficulty stopping the behavior despite repeated attempts or significant negative consequences

The ICD-10-CM was introduced to the U.S. healthcare system in 2015. It is the most widely used mental disorders classification worldwide and permits a hypersexual disorder diagnosis for coding and reimbursement. In the United States and other countries, ICD diagnostic codes are mandated by international treaty, unlike the DSM-5, which lacks such mandate. As such, a diagnosis of hypersexual disorder can be used even though it is not included in the DSM-5 [179].

Diagnostic criteria for compulsive sexual behavior disorder also appear in the ICD-11, published in 2018. These diagnostic criteria are [108]:

- A persistent pattern of failure to control intense, repetitive sexual impulses or urges resulting in repetitive sexual behavior. Symptoms may include:

- Repetitive sexual activities become a central focus to the point of neglecting health, personal care, or other interests, activities, and responsibilities

- Numerous unsuccessful efforts to control or significantly reduce repetitive sexual behaviors

- Continued engagement in sexual behaviors despite adverse consequences

- Continued engagement in sexual behaviors even when the individual derives little or no satisfaction from it

- Pattern evident for at least six months

- Pattern leads to marked distress or significant impairment in personal, family, social, educational, occupational, or other important areas of functioning

Distress that is entirely related to moral judgments and disapproval about sexual impulses, urges, or behaviors does not fulfill these criteria. Behaviors better categorized as a paraphilic disorder (e.g., exhibitionistic disorder, voyeuristic disorder, pedophilic disorder) also do not qualify.

TREATMENT

Standard approaches for the treatment of sexual addiction include a variety of psychologic and pharmacologic options (Table 2). Understanding the characteristics of persons seeking help for out-of-control sexual behavior and differences among patients can help guide clinician decision-making for better patient-treatment matching.

Table 2: STANDARD TREATMENT OPTIONS FOR SEXUAL ADDICTION

Therapies

Treatment Target

Mechanisms

Disadvantages

Cognitive-behavioral therapy

Behavioral control, management of negative affect, social skills, relapse prevention

Functional analysis of sequence and triggers of behavior, thought records, skills building

Does not address motivation, personal meaning, or underlying character structure

Psychodynamic therapy

Self-concept and interpersonal relationships, self-awareness, underlying personality organization

Exploration of personal meaning of symptoms in context of personal history

Does not provide concrete skills to change behavior

Group therapy

Shame, stigma, social isolation, denial, rationalization

Social support, group

confrontation of denial, peer sharing of experiences

Does not provide individualized, in-depth treatment

Medication treatment of comorbidity

Comorbid anxiety, depression, OCD, impulsivity, psychosis, mania

Established treatments of comorbid conditions can reduce symptoms of sexual addiction

Works best in sexual addiction secondary to or strongly exacerbated by comorbid condition

SSRIs

Anxiety, depression, obsessional ideation, sex drive

Reduces dysphoric affect, may reduce sex drive

Largely safe, but not without side effects

Anti-androgens

Destructive sex drive in male repeat sex offenders

Greatly reduces or eliminates sex drive

Severe possible side effects such as pulmonary embolism, bone mineral loss

OCD = obsessive-compulsive disorder; SSRIs = selective serotonin reuptake inhibitors.

Source: [75]

Hypersexuality Subtypes

In patients seeking help for problematic sexual behavior, clinicians are repeatedly recommended to use a patient-tailored, multimodality approach, but there is little published guidance for matching clinical presentation with treatment options. Thus, a group of prominent sexual disorder researchers and clinicians developed a hypersexuality typology that links clinical profile and symptom clusters to suggested treatments. Diverse hypersexual behavioral patterns suggest they may be unrelated phenomena; assumed commonality is erroneous [136].

Paraphilic Hypersexuality

The paraphilic hypersexuality subtype has key features of paraphilic interests and a high frequency of one or more hypersexuality behaviors. Many of these patients lack the strong, internal directedness most men have in their sexual interest(s). Instead, they tend to test out or go along with partners' sexual interests. Interactions with sex workers are based on sex, and for many, a desire to become a part of the sex worker milieu [136].

Paraphilic hypersexuality is remarkable for the sizeable number reporting gynandromorphophilia, a rarely discussed erotic interest in persons with both male and female anatomy (usually full breasts and intact penis) typified by incompletely transitioned male-to-female transgender women. For many, this specific enduring erotic interest leads to confusion over sexual orientation or gender identity and hesitant self-reference as ''mostly heterosexual'' or as bisexual [136].

This clinical characterization of gynandromorphophilia risks pathologizing attraction to transgender women and the women themselves. Care should be taken to avoid doing so in practice settings. Methods to change paraphilic interests into euphilic attraction have no evidence or support. Treatment suggestions include integration of interests that can be expressed alone or with consenting partners, and harm reduction for those interests that cannot. Medication may be highly relevant. SSRIs can reduce libido and impulsivity, but can also delay or prevent ejaculation and lead to seeking greater stimulation sufficient to trigger orgasm [136,182].

Avoidant Masturbation

The primary presenting complaint in patients with avoidant masturbation is the extreme time spent masturbating to pornography. These patients report masturbating many hours daily, job termination from online pornography or masturbation at work, academic failure, and social relationships and other important activities abandoned in favor of masturbation. Paraphilic interests are rare [136].

Many of these patients acknowledge masturbating to avoid tasks or chores. Anxiety or dysthymia are common; masturbation is the cause of, or the coping skill for, negative emotions. Avoidant masturbation does not always interfere with relationship satisfaction or sexual activity, but many have little interest in partnered sex and prefer masturbating to pornography [136].

Avoidance and procrastination motives drive the masturbation. In the gay male community, avoidance may be expressed as excessive time frequenting bathhouses, perusing online hook-up sites, or engaging in anonymous sex with large numbers of partners. With avoidance motivation, treatment is more productive when it addresses avoidance and procrastination instead of masturbation. Motivational interviewing can be very beneficial [136].

Chronic Adultery

In clinical settings, patients with chronic adultery are almost always male and outliers in the frequency of extramarital sexual activities involving one-time hook-ups, on-going relationships, or sex workers. Extreme time involvement seeking or engaging in sex is usually absent [136].

Chronic adulterers frequently state their wives or partners have a condition or history that inhibits sexual enjoyment, such as coital pain disorders (i.e., dyspareunia), low libido, sexual abuse history, or conservative/religious backgrounds. When partners present for therapy, their histories and libido levels usually match their husband's description. Patients may seek treatment motivated by secondary gains from appearing sincere about changing their behavior, without an actual desire to change. In practice, this is less common than assumed; chronic adulterers are generally motivated to change by the time they present for help [136].

Marital distress may be a consequence of most other hypersexuality subtypes, but it is antecedent to chronic adulterer behaviors. While couples therapy is strongly indicated, because many marital issues are unresolvable without partner engagement, spouses often instruct the chronic adulterer to go fix his problem and are unwilling to participate. Mismatching atypically high and low sex drives often predate the marriage; the sex drive discrepancy goes unaddressed, and the high libido is chronically expressed outside the marriage. Demanding the adulterer fix his problem in therapy also serves to distract from or excuse unaddressed issues of the spouse [136].

Sexual Guilt

Patients with sexual guilt self-label as hypersexual or sex addicted and express intense distress, but lack evidence of sexual behavior that exceeds peer group norms. Highly conservative (usually religious) family environments are typically reported; some willfully adopt moralistic standards in adulthood that exceed the dictates of their religious.

Initially presenting with hypersexuality complaints, further assessment will identify sexual guilt and broadly expressed anxiety over sexual urges or interests. Among these patients are androphilic men who reject or resist their sexual orientation and seek treatment for their perception of addiction or compulsion to have sex with men. Psychoeducation and permission-giving is beneficial, and several therapy approaches can address inaccurate beliefs about sexuality and peer norms. These beliefs may reflect explicit religious involvement or other deeply held ideologies, such as gender roles.

The Designated Patient

Romantic partners of designated patients demand they get help and instigate sex disorder clinical assessments. These demands may reflect highly restrictive sexual beliefs with zero-tolerance for masturbation, pornography, or non-procreative sex. Designated patients may self-label as sex addicts (or a similar term) but lack the sexual behavioral patterns. These patients state their partners explicitly believe the problem is theirs to solve. Designated patients are best helped by including the partner in psychoeducation on healthy masturbation and pornography use and communication and assertiveness training. Sex-positive clinicians quickly see partner demands as unnecessarily restrictive. Some patients know this, but agree to the restrictions for the benefit of the relationship.

Better Accounted for as a Symptom of Another Condition

Hypersexuality can be a symptom or sequelae of several non-sexual diagnoses, including some personality disorders, hypomania, developmental delay, disinhibiting brain injuries, neurologic disease, and medication side effects. Borderline personality disorder is the most common associated syndrome and can present as any hypersexuality subtype. In general, personality disorders are distinguished from hypersexualities by the presence of other personality disorder symptoms and not by differences in sexual behaviors.

Psychologic Interventions

Cognitive-Behavioral Therapy

CBT can help the patient identify and work through triggers of sexually addictive behavior, permission-giving thoughts that weaken inhibition of the behavior, and the negative consequences of the behavior. Specific CBT approaches have been modified to treat sexually addictive behavior [183,184].

Motivational Interviewing

Motivational interviewing serves to help the patient consider the pros and cons of maintaining the addiction in the context of their overall goals and priorities [185]. Motivational interviewing is less focused on actual behavior change than on bolstering motivation to enter the change process. Advantages of motivational interviewing include the non-confrontational and nondirective nature, which can be more effective in those with low motivation to change [75].

Psychodynamic Therapy

Psychodynamic therapy has relatively few published clinical studies in sexual addiction treatment, but it appears to offer unique advantages [184]. Specifically, psychodynamic treatment can address the factors related to the individual's unique personal history and personality organization and can clarify the specific meaning the addictive behavior holds for the patient. For instance, sexual addiction can reflect a rebellion against a puritanical and authoritarian parent; a form of self-soothing in the context of parental abandonment; a narcissistic need for constant affirmation of one's attractiveness; or a desperate attempt to stave off feelings of emptiness. In most cases, sexually addictive behavior is thought to reflect a disturbance in the core self-concept and/or the capacity for intimate relationships [75].

Psychodynamic psychotherapists recognize the inherent human need for close intimate relationships to help regulate negative and positive emotions, and how this need must be reconciled with feeling dependent on people who remain, in large part, outside of one's control [186,187]. For those with less ability or an inability to tolerate this dilemma, often resulting from maladaptive early attachment, an addictive object can provide a convenient end-run around the vulnerability and relative powerlessness inherent in intimate relationships. In this way, sexually addictive behavior can serve as a transitional object [75].

According to psychodynamic theory, sexually addictive behavior serves as a self-soothing and emotionally regulating "other" that remains under the individual's near-total control. The sexual partners in sexually addictive behavior are rarely experienced as "subjects"—three-dimensional people who can make an emotional impact on the sexually addicted individual outside of his or her control. Instead, they are fleeting "objects," used to gratify an urge and then discarded. Paradoxically, by insisting on total control over the attachment object, the sexually addicted individual loses control and ends up controlled by their addiction. Psychodynamic therapy can help the patient to understand how these dynamics play out in his or her life and to subsequently develop healthier relational patterns [75].

Group Psychotherapy

Group psychotherapy can be highly effective in the treatment of substance and behavioral addictions and, in some cases, is more effective than individual therapy alone [184]. Group therapy serves multiple purposes and probably works through a combination of mechanisms. It provides social support during the difficult change process, information about other group members' experiences and coping strategies, support for a positive new group identity, and confrontation of the denial and rationalizations associated with sexually addictive behavior [75]. Group therapy helps individuals feel less isolated and reduces feelings of shame [143].

Couples Therapy

Due to the negative impact of sex addiction on intimate relationships, couples therapy may offer both the patient and their partner guidance on dealing with this disorder [138].

Pharmacologic Interventions

Few pharmacotherapy studies in sex addiction have been published. The research that has been published focuses on male patients. Clinical experience indicates close monitoring is needed in treating compulsive sexual behavior, as some individuals may increase risky sexual behavior to compensate for the dampening effects of medication on sex drive [84].

In a study of gay and bisexual men with complaints of compulsive sexual behaviors, 12 weeks of citalopram led to greater reductions in desire for sex, frequency of masturbation, and hours of pornography use per week compared with placebo. However, the number of sexual partners during treatment did not differ [188].

Naltrexone was evaluated over eight weeks in non-addicted, methamphetamine-using, binge-drinking men who have sex with men at high risk for HIV. Naltrexone led to significantly greater reductions in overall and condom-less receptive anal intercourse than placebo. Among frequent methamphetamine users, naltrexone led to greater reductions in methamphetamine-using days. Higher naltrexone adherence also led to greater reductions in binge drinking days [189].

The importance of close patient monitoring is underscored by a case report of three heterosexual men (24 to 35 years of age) who developed new-onset problematic sex behaviors during paroxetine (an SSRI) treatment for pathologic pornography use and masturbation. After 10 weeks of paroxetine, all showed marked reductions in anxiety and pathologic pornography use and masturbation and return of normal sexual function. However, by three months, all had new-onset sexual behaviors; none had histories of risky sexual behaviors, affairs, paying for sex, or mania/hypomania symptoms during treatment [190]. Two were in long-term relationships (one married); one was single. All described pride in overcoming inhibitions to take sexual risks with success and felt strongly motivated to continue. Both patients in relationships felt guilt but also elation over new sexual frontiers as both had remained with their first and only sex partner. None wanted to phase-out paid sexual services by increasing pornography and masturbation, which they described as isolating, time-consuming, and humiliating [190].

In this study, the authors explain that an imbalance in reward reactivity and threat reactivity promoted sexual risk-taking; problematic behaviors resulted from increased impulsivity or increased anxiety [190,191]. All three patients regulated their high pretreatment anxiety levels with pathologic pornography use and masturbation. Paroxetine helped decrease amygdala reactivity, which decreased anxiety and subsequently decreased pathologic pornography use and masturbation, with new compulsive sexual behaviors potentially emerging from diminished anxiety [190].

When sexually disordered behavior presents a grave risk to the individual or society, such as persistent uncontrolled pedophilia, anti-androgen therapy has been effective for drastically reducing sexual drive. The side effects with this drug class are notable, and such medications are rarely used outside of serious circumstances in a forensic context [75].

Twelve-Step Programs

Sex Addicts Anonymous (SAA) is a support group with a purpose of helping others with sex addiction find recovery. This organization operates similarly to AA and uses the 12-step program of recovery. Another 12-step program is Sex and Love Addicts Anonymous (SLAA) [138]. Most SAA, SLAA, and Sexual Recovery Anonymous ("S" meetings) groups admit new members only after screening and approval by the group members. Meetings focus on the goal of helping the new member stop or control his/her pathologic sexual behavior and learn new coping strategies. "S" meeting groups can play an important role in the recovery of patients by helping them become honest with themselves and their families in an atmosphere of support and fellowship [135].

8. INTERNET GAMING DISORDER

The specific game genre is essential to understanding the behavioral addiction of Internet gaming disorder. The characteristics of genres attract online gamers with specific psychologic and personality features. Gamers at risk for Internet gaming disorder gravitate to genres that deliver potent reward and reinforcement. This disorder develops from the interaction of gamer and genre factors over time.

Massive, multiplayer, online role-playing games (MMORPGs) are unique in pathogenic potential among game genres. A 2015 report described a case of two brothers (22 and 19 years of age), high academic achievers from an intact, upper-middle class family who lived at home. Both began MMORPGs two years before hospital admission for Internet gaming disorder. In the initial months, time spent gaming progressed from 2 to 4 hours to 14 to 18 hours daily. Gaming interfered with their sleep and daily routine. Both deteriorated to the point that when engaged in MMORPGs, they urinated and defecated in their clothes, did not change clothes for days, did not bathe, skipped meals, and did not answer the phone. Fixated on gaming, they were indifferent to the presence of a burglar robbing their home. Both failed their classes, became abusive and violent when their gaming was disrupted, and were admitted to inpatient care by their parents [192].

INTERNET GAMING GENRES

Despite a large variety of available games online, players typically prefer a specific game genre. With Internet gaming disorder, genre greatly matters, and MMORPGs are the most frequently reported genre among people seeking help for an Internet gaming problem [193].

Massive, Multiplayer, Online Role-Playing Games

MMORPGs are played online by thousands of gamers simultaneously, spanning vast time zone differences without spatial or temporal boundaries. The design of MMORPGs borrows from operant conditioning, incorporating random, unpredictable reward structures to maximize player engagement and time involvement. The same intermittent schedule of rewards is featured in slot machines and other gambling modes [192].

In MMORPGs, players assume the role of a fictional character and take control of that character's actions while simultaneously interacting with other gamers in a shared, virtual world. This virtual world persists independently of the players; events and interactions between other players continue when one player goes offline [8]. To advance, the player's character acquires new powers, skills, special weapons, or currency as rewards for succeeding in a mission or special quest. Online social interactions occur among players in-game or by regrouping into clans (guilds), a persistent, virtual hierarchical social network of characters with shared backgrounds and objectives [8]. The aspects of a permanent world, reinforcement schedule, and online social interaction contribute to the addictive potential of MMORPGs [194].

The uniquely problematic potential of MMORPGs is under-recognized. A 2016 report stated that only 36.7% of surveyed Canadian psychiatrists believed there was an association between psychopathology and MMORPG engagement [195].

First-Person Shooter

First-person shooter (FPS) is an action game genre and differs markedly from MMORPGs. Players engage in combat with enemies, primarily using firearms. The shoot-to-kill style of FPS games is considered highly arousing and violent, but little research has studied Internet gaming disorder in excessive FPS players [193].

Real-Time Strategy

Real-time strategy games are strategic, combat-orientated games that often use forms of strategic simulation. In real-time strategy game matches, strategic decision-making ability directly influences the results and scores. For example, a gamer might hold a combat commander position that requires use of multiple strategies to take over an enemy fortress [193].

Other Genres

Other game genres include arcade games, online sports games, casual games, and other action games [193]. These games are rarely associated with Internet gaming disorder.

PATIENT CHARACTERISTICS AND GENRE PREFERENCE

To investigate Internet gaming disorder characteristics, genre preference, and their interaction, 212 Korean patients (18 to 23 years of age, 97.6% male) underwent extensive psychologic testing after meeting criteria for Internet gaming disorder [168]. The researchers found five common themes [193]:

- Involvement more than 4 hours per day or more than 30 hours per week

- Young Internet Addiction Scale (YIAS) score >50

- Irritable, anxious, and/or aggressive when forced to stop

- Behavioral problems, distress, and financial problems from excessive gaming

- Maladaptive disruption of diurnal rhythm (i.e., sleep all day, game all night), irregular meals, failure to maintain personal hygiene, school truancy or job loss

Patient preferences were for MMORPGs (39.2%), real-time strategy games (34.9%), FPSs (16.0%), and other genres (9.9%) [193].

MMORPGs

Of all genres, MMORPG players have the highest Internet gaming disorder severity, partially explained by the variable reinforcement schedule (similar to gambling). Among gamers, MMORPG players show the greatest levels of social anxiety and social avoidance, suggesting that social dysfunction drives gamer motivation to escape interpersonal anxiety and problems. Gamers with high social anxiety and avoidance are often stress intolerant and easily distressed over interpersonal and academic problems. The MMOPRG alternate reality space provides an escape [193].

Some studies show that MMORPG gamers motivated to escape reality experience greater consequence than gamers with other motives for gaming, and escapism is a strong predictor of Internet gaming disorder [194,196]. Other research shows that MMORPGs interfere with player development of social and emotional skills; this may exacerbate deficient interpersonal skills to create a vicious cycle [194,197].

Other studies comparing Internet gaming genres found MMORPG players spent significantly more hours playing, had worse health (e.g., more cigarettes smoked, less physical exercise, worse sleep quality), and greater interference in real-life socializing and academic work [197]. MMORPG players (compared with those playing other genres) more frequently displayed signs of dysfunctional use [8,194].

Escapists use MMORPGs to avoid interpersonal and life stressors, and in-person social support is adversely impacted by the high time involvement. Social support increases online but decreases offline. Offline social support has the strongest impact on favorably affecting gamer well-being, and greater online social support for offline problems did not offset the negative effect of diminished offline support in MMORPG escapists [198].

First-Person Shooter

Social anxiety is lowest in FPS gamers. FPS players control the game character from a first-person view, making self-confidence crucial for high scores and engagement in competition. Most online FPS players do not play in isolation, and social interaction motivation highly predicts FPS time involvement. FPS players are drawn to competition and challenge [199]. The highly immersive nature and potential for online competition, achievements, and social interaction can reinforce excessive FPS involvement. Social-seeking behavior is inversely related to social anxiety and avoidance [193].

Real-Time Strategy

Among the four genre groups, self-esteem was highest in the real-time strategy group, suggesting that the strategic simulation information tasks are more rewarding in gamers with stronger self-esteem. Real-time strategy involves many challenging tasks requiring rapid switching, multiple information sources, and multiple actions for which substantial cognitive flexibility is needed [200]. Successful players must cope with simultaneous and rapidly evolving game situations in real-time, while managing funds, resources, and information concerning their opponent. When managing multiple, simultaneous game strategies, self-esteem can have a decisive effect on judgment and decision-making by reducing gamer anxiety and enhancing performance. Compared to MMORPG players, the lower social anxiety and avoidance scores of real-time strategy players may be related to higher self-esteem. Thus, relatively high self-esteem and low social anxiety and avoidance are the main characteristics in the real-time strategy group [193].

Others

Compared to the other three genres, players of arcade, online sports, and casual games had higher depression scores, with Beck Depression Inventory scores showing "moderate depression," compared with "mild depression" average scores in the other three groups. Games in this category are relatively simple in design and low in complexity, and this game preference is probably motivated by wanting a less challenging game, possibly influenced by the presence of low volition or energy, impaired concentration, or depressed mood [193].

PREVALENCE

The pooled prevalence estimates from more than 30 countries showed problematic Internet game use in 8% to 12% of young persons and addictive use in 2% to 5% of children, adolescents, and college students [17]. Nationally representative American samples show an Internet gaming disorder prevalence of 8.5% among those 8 to 18 years of age [201,202].

RISK FACTORS

Internet gaming disorder is associated with increased neuroticism, aggression/hostility, avoidant and schizoid interpersonal tendencies, loneliness, introversion, social inhibition, boredom inclination, sensation-seeking, low agreeableness, diminished self-control, narcissistic personality traits, low self-esteem, state and trait anxiety, and low emotional intelligence. These personality factors are not specific to pathologic gaming and contribution to, or direction of, causality is unclear from the research designs [17]. Gamers with Internet gaming disorder show high rates of comorbidity, including ADHD, generalized anxiety disorder, panic disorder, depression, social phobia, school phobia, and various psychosomatic symptoms [17].

ASSOCIATED FEATURES

Hostility, defined as thoughts, feelings, and behaviors expressing the negative affect state of anger, including aggression, irritability, rage, and resentment, is relatively common in adolescence. It is linked to the onset of substance use disorders, and the relationship between hostility and Internet gaming disorder in adolescence is bidirectional. Hostility may lead to Internet gaming escape-avoidance and withdrawal as a coping mechanism for emotional distress, while the anonymity and absence of oversight can make the Internet an outlet for more hostile adolescents to express aggression unacceptable offline [203,204]. As an ineffective form of coping, Internet gaming disorder could lead to poor adjustment in early adulthood, precipitating hostility [203]. The emotional regulation strategies (e.g., suppressing emotions) that characterize individuals with Internet gaming disorder may be contributing factors to their hostile tendencies [205].

In one study, adults (mean age: 35.8 years) were assessed for "social media addiction" (presence of core addiction elements), Internet gaming disorder, and risk factors for both. Social media addiction was associated with being female and single, younger age, ADHD, OCD, anxiety, and lower levels of depression. Internet gaming disorder was positively associated with being male and single, younger age, ADHD, OCD, and depression, and inversely related to anxiety symptoms. ADHD, OCD, anxiety, and depression contributed to the variance in social media addiction (15%) and Internet gaming disorder (7%) after controlling for age, sex, relationship status, and education [206]. Social media addiction and Internet gaming disorder had low inter-correlation and were associated with different variables, which along with many other studies dispels the idea of a unified construct of Internet use disorder or Internet addiction [206].

Adverse Outcomes

Numerous studies indicate that, for a player subgroup, excessive online gaming can lead to diverse negative psychosocial consequences, including sacrificing work, education, hobbies, socializing, time with partner/family, and sleep, as well as increased stress, absence of real-life relationships, lower psychosocial well-being, loneliness, worse social skills, decreased academic achievement, increased inattention, aggressive/oppositional behavior and hostility, maladaptive coping, decreases in verbal memory performance, maladaptive cognitions, and suicidal ideation [17].

One study evaluated children enrolled in grades 3 to 8 over two years. Higher Internet game involvement, lower social competence, and greater impulsivity were risk factors for developing Internet gaming disorder, while depression, anxiety, social phobia, and declining academic performance were outcomes of Internet gaming disorder. The prevalence rate of Internet gaming disorder was 9%. The authors concluded that Internet gaming disorder can develop without premorbid disorders and persist for years in young Internet gamers [207].

When considering the applicability of cross-cultural epidemiology and risk factors in Internet gaming disorder, cultural differences in attitudes towards Internet use in East Asia and elsewhere should be noted. For instance, parents in East Asia tend to pathologize behaviors that interfere with family or educational pursuits, possibly inflating Internet gaming disorder prevalence rates in Taiwan and South Korea [208]. Individuals who appear addicted to using social media and social networking sites are often engaged online to psychologically compensate for the lack of offline social rewards [15].

Psychologic Factors

Significant predictors of pathologic gaming among adult MMORPG players include expressing "true self" in game, higher levels of social anxiety, larger numbers of in-game social supports, and fewer supportive offline relationships. The number of in-game supports was significantly associated with time spent playing [209].

CBT that addresses specific gaming-related cognitions in Internet gaming disorder may have greater benefit than general approaches that solely address "preoccupation with gaming" (a DSM-5 criterion for Internet gaming disorder). Maladaptive cognitions associated with Internet gaming disorder have been identified in cross-sectional studies, but the extent to which these cognitions predict future pathologic gaming behavior requires longitudinal data. In 465 Internet gamers (84% male, mean age: 26.2 years) followed over 12 months, those who developed Internet gaming disorder had significantly higher baseline scores in perfectionism, cognitive salience, and guilt compared with gamers remaining non-problematic. Pathologic gamers who successfully transitioned to being non-problematic gamers had lower baseline perfectionism scores compared with those whose use remained problematic. Cognitive changes accounted for 28% of variance in scores beyond contributions from gender, age, and gaming frequency. Maladaptive gaming-related cognitions could be assessed to better inform treatment targets for CBT [210].

Specific achievement- and immersion-related motives have been identified as strong predictors of problematic online gaming, addiction symptoms, and adverse impact on daily life. Of these motives, problematic use was consistently associated with "advancement" (e.g., the desire to gain power, progress rapidly, accumulate in-game symbols of wealth or status) and "mechanics" (i.e., interest in the rules and system to optimize performance). Immersion-related motives highlighted "escapism." Escapers are motivated by immersion in a virtual reality instead of by reaching game-specific objectives; the game is a dissociative method to escape offline thoughts and problems. Social-related motives (e.g., playing to meet people, teamwork) were unrelated to problematic use [8].

Internet gaming disorder is linked to impulsivity and poor self-regulation, supported by the multidimensional UPPS-P model of impulsivity that describes impulsivity as five related but specific dimensions [211]:

- Urgency: Acts rashly during intense positive and negative emotions

- Premeditation: Considers consequences of an act before engaging in that act

- Perseverance: Capacity to remain focused on boring and/or difficult tasks

- Sensation seeking: Tendency to enjoy and pursue new and exciting activities

- Positive urgency: Tendency to act rashly under extreme positive emotions

Many studies highlight the strong links between these impulsivity factors and psychiatric disorders such as substance use disorders, gambling disorder, compulsive buying, suicidal ideation/attempts, and aggressive behaviors.

The "urgency" subtype of impulsivity may predict pathologic MMORPG use. Urgency, poor premeditation, and poor perseverance impede the executive functioning required for self-control, inhibitory control, decision-making ability, and resistance to cognitive interference [8].

Internet gaming disorder symptom severity may be highly relevant in adolescents 16 to 18 years of age, which precedes the age of highest Internet use (18 to 24 years). In one study, individuals more hostile at 18 years of age continued MMORPG involvement with higher Internet gaming disorder symptom severity after two years. These results agree with other longitudinal studies that show stability in addictive behavior during adolescence and onset of Internet gaming disorder coinciding with increased real-life problems [207,212]. In contrast, Internet gaming disorder is more transient in adults; this disparity may reflect age-related differences in the progression of addiction [203,213].

Among 3,041 adult recent Internet gamers (60% male), 13.8% met DMS-5 criteria for Internet gaming disorder. Compared with healthy gamers, the Internet gaming disorder group used gaming significantly more often to escape reality and specific issues or as a coping mechanism. They also scored significantly higher on measures of obsession-compulsion, depression, somatization symptoms, interpersonal sensitivity, and impulsivity. Adults with Internet gaming disorder experienced more frequent difficulty in concentrating, loneliness, and insomnia, and were five times more likely to attempt suicide and exhibit aggression. Unlike youth with Internet gaming disorder, no game genre was dominant in adult Internet gaming disorder [214].

Maladaptive Cognitions in Internet Gaming Disorder

Internet gaming disorder-related cognition is more complex than "preoccupation." The primary underlying cognitive factors in Internet gaming disorder (and therapeutic targets for CBT) include [215,216]:

- Persistent overvaluation of video gaming rewards, activities, and identities

- Over-reliance on gaming to meet self-esteem needs

- Gaming as a method to gain social acceptance

- Maladaptive, inflexible adherence to internal rules dictating gaming behavior

In a study of adolescents, those with Internet gaming disorder reported significantly more maladaptive gaming beliefs than non-disordered respondents. The association between gaming cognitions and Internet gaming disorder symptoms was very large and independent of gaming activity and psychologic distress. The distinct problematic cognitions of adolescents with Internet gaming disorder should be addressed in any therapeutic intervention [217].

PATHOPHYSIOLOGY

Neuroimaging studies comparing patients with Internet gaming disorder to matched controls have repeatedly identified the following pathophysiology [8,194,216,218]:

- Resting-state imaging: Alteration in brain regions that mediate attentional control, impulse control, emotional regulation, and sensory-motor coordination

- Presentation of gaming images (cue exposure): Alteration in reward inhibition mechanisms and loss of control

- Functional studies: Abnormal dopamine release, altered dopamine levels, decreased dopamine transporter availability, and decreased dopamine receptor D2 occupancy that reflect an overall reward deficiency involving decreased dopaminergic activity

- Structural studies: Decreased white matter density in regions involved in decision-making, behavioral inhibition, and emotional regulation; altered orbitofrontal cortex gyrus with greater Internet gaming salience and loss of control; ventral striatum (centrally involved in brain reward mechanisms) volume alterations related to changes in reward sensitivity

- Treatment studies: Reduction in Internet gaming craving and reductions in associated brain activity

In aggregate, these findings show that Internet gaming disorder is associated with neuroadaptation of reward and reinforcement pathways that develop from prolonged hyper-stimulation and structural alteration in brain regions that mediate executive functioning. While Internet gaming disorder pathophysiology highly resembles that of substance addiction, this research is early-stage and such conclusions are tentative [218,219].

Addicted Internet gamers show patterns of physiologic arousal deficits that differ by game genre. In addicted MMORPG gamers, cardiovascular activity (as measured by heart rate, blood pressure, and skin conductance) significantly decreases during gaming compared with pre-game baseline but significantly rose after gaming. Addicted FPS gamers had significant increases in blood pressure during gaming, decreasing significantly post-game. Non-addicted MMORPG and FPS gamers showed increased blood pressure during and after gaming [220].

ASSESSMENT AND DIAGNOSIS

Clinical assessment of patients with suspected Internet gaming disorder is necessary to explore the clinical severity and negative biopsychosocial impact via inquiry (Table 3).

Table 3: CLINICAL INTERVIEW QUESTIONS TO ASSESS INTERNET GAMING DISORDER

Presenting problem

When did you begin to notice problems with your gaming?

How long have you been gaming?

How much time do you spend gaming each day? Week? Month?

What was going on in your life when you began gaming?

What was going on in your life when you began to have difficulties with your gaming?

Biologic factors

Are you experiencing or have you previously experienced any health concerns? If so, please describe.

How have these health concerns been impacted by your gaming?

What treatment have you received for these health concerns?

Does your gaming interfere with your sleep/meal schedule?

What exercise patterns do you engage in?

What drugs and/or medications do you take? How much? How often? In the past?

Psychologic factors

What types of gaming do you engage in?

What do you like/dislike about gaming?

How do you feel before, during, and after gaming?

What are your thoughts before, during, and after gaming?

Have you ever used gaming to help improve your mood or change your thoughts?

In what places at home or elsewhere do you usually engage in gaming?

Have you ever felt anxious, depressed, or isolated when not gaming?

Social factors

Has your gaming caused concerns with your family?

Has your gaming caused concerns with your significant other?

Has your gaming caused concerns with your social activities and friendships?

Has your gaming interfered with your performance at school or work?

What are your social/leisure/hobby activities?

Relapse prevention

Do you believe that you have a problem with your level of gaming?

What do you see as the benefits and costs of continued gaming?

What is your level of commitment to change your current gaming patterns?

What plans have you implemented in the past to deal with your level of gaming?

Have these plans worked?

Source: [202]

The DSM-5 Task Force asked the Substance-Related Disorders Work Group to consider several potential behavioral addictions for inclusion in the DSM-5. The Work Group suggested Internet gaming disorder placement in Section III (Emerging Measures and Models). While the body of published evidence was extensive, the research did not apply standard diagnostic criteria; substance use disorder criteria were borrowed by some studies, and impulse control disorder or pathologic gambling criteria were borrowed by others. The DSM-5 included proposed criteria for Internet gaming disorder with the hope of standardizing emerging work in the field [12]. In this proposed framework, a diagnosis is given when five or more of the following criteria are met [11]:

- Preoccupation with Internet games

- Withdrawal symptoms when Internet gaming is taken away (e.g., irritability, anxiety, sadness)

- Tolerance (i.e., the need to spend an increasing amount of time engaged in Internet games)

- Unsuccessful attempts to control participation in Internet games

- Loss of interest in previous hobbies and entertainment

- Continued excessive use of Internet games despite knowledge of psychosocial problems

- Deception of family members, therapists, or others regarding the amount of Internet gaming

- Use of Internet games to escape or relieve a negative mood

- Has jeopardized or lost a significant relationship, job, or educational or career opportunity because of participation in Internet games

The ICD-11 formally includes as diagnostic entities gaming disorder (predominately online) and gaming disorder (predominately offline) [108].

A comprehensive understanding of patient motivation is necessary for optimal treatment selection. The Motives for Online Gaming Questionnaire (MOGQ) was developed to assist in this assessment. The MOGQ consists of 27 statements, such as "I play online games because gaming helps me to forget about daily hassles," which are rated from 1 (almost never/never) to 5 (almost always/always). Motivational factors identified by the MOGQ include social, escape, competition, coping, skill development, fantasy, and recreation [12,221].

TREATMENT

Psychologic Interventions

In the published research to date, psychologic treatment is the dominant modality for Internet gaming disorder, with CBTs the most-studied.

Cognitive-Behavioral Therapies

As discussed, maladaptive cognitions are a core feature of Internet gaming disorder and include self-regulation deficits, preference for a virtual life, cognitive bias, impaired cognitive control abilities, cognitive deficits, poor cognitive error processing, and decision-making deficits [202]. CBT addresses these cognitions and is the most widely used psychologic treatment for Internet gaming disorder. The first stage of CBT treatment for Internet gaming disorder deals with the behavioral aspects of addicted gaming, and subsequent stages gradually shift the focus toward the development of positive cognitive assumptions. During therapy, addicted gamers identify false beliefs and learn how to modify them into more adaptive ones. CBT also trains patients to monitor their thoughts and to identify affective and situational triggers associated with their addictive gaming behavior [202].

In the treatment of Internet gaming disorder, CBT typically involves 8 to 28 sessions that address psychoeducation, problem identification, healthy communication, Internet awareness, and cessation techniques. Treatment of Internet gaming disorder may also include short-term therapy, group therapy, and systemic therapy with parents/teachers/peer support and multilevel interventions that incorporate motivational interviewing [202].

Although CBT has some efficacy in Internet gaming disorder, the results do not appear to differ from other non-specialized psychologic treatments for Internet gaming disorder [222]. One study found that combinations of CBT and medications showed an advantage over monotherapies [223]. To improve patient response and clinical outcomes with standard psychologic approaches, therapy modalities have been developed that target the cognitive pathologies and underlying neural substrates specific to Internet gaming disorder [224].

Motivational Enhancement Therapy/CBT

CBT is combined with motivational enhancement therapy (MET/CBT) to move patients from ambivalence to engagement concerning behavioral change. MET/CBT is structured by stages:

- Contemplation stage: Rapport building during the initial sessions includes a detailed interview and case formulation.

- Preparation stage: The therapist creates an empathetic environment to deliver psychoeducation, including instruction on managing physiologic and emotional arousal through relaxation techniques and a cost-benefit analysis of gaming addiction.

- Contract stage: With the patient and parents (if appropriate), the therapist addresses behavior modification of gaming, reducing time spent online and promoting healthy activities.

MET/CBT has led to decreased symptoms and improved school performance in Internet gaming disorder [202,225].

Craving Behavioral Intervention

Based on cognitive neuroscience and behavioral addiction research, craving behavioral intervention was developed for patients with Internet gaming disorder to reduce cravings and enhance coping skills, which may improve therapeutic outcomes and prevent relapse. Craving behavioral intervention is conducted weekly in a group format with eight to nine participants. Topics for each weekly session include [62]:

- Perceiving subjective craving

- Recognizing and testing irrational beliefs regarding craving

- Detecting craving and relieving craving-related negative emotions

- Coping with cravings and altering participant fulfillment of psychologic needs

- Learning time management and skills training for coping with cravings

- Reviewing, practicing, and implementing skills

- Mindfulness training

Short-Term Treatment of Internet and Computer Game Addiction

Short-term treatment of Internet and computer game addiction (STICA) is a disorder-specific, CBT-based, individual and group treatment lasting three months. The STICA treatment protocol and focus of treatment sessions is organized into three phases [226]. In the early phase, the focus is on patient education on the mechanisms and effects of Internet gaming disorder (e.g., learning theories, development and consequences of Internet gaming disorder, the vicious cycle of addiction). Interventions promote social communication and bonding in the therapy setting. In the middle phase, patients are taught to identify triggers of dysfunctional Internet use (e.g., emotional states, maladaptive cognitions, daily stress) by keeping diaries. A functional analysis of addictive behavior is done, with the goal of enabling functional computer and Internet use by appropriate problem-solving strategies. Patients establish an in-person social network and build a repertoire of alternative activities. Sessions may include exposition training (i.e., confronting and deleting access to critical genre elements, such as the self-created avatar) and skills training (e.g., coping with stress and problems, social skills, building alternative activities) [226]. The last phase is termination and relapse prevention. During this phase, treatment tools are transferred to daily life, including functional computer/Internet use. Relapse prevention tools are provided and practiced.

The efficacy and stability of outcomes following STICA are under evaluation. Early results indicate that nearly 70% of initially enrolled patients completed the three-month treatment, with six-month follow-up showing significant decreases in Internet use, online time, and psychiatric symptomatology [227,228].

Pharmacologic Interventions

Few pharmacotherapy studies have been published in Internet gaming disorder. In one study, adolescents and adults with Internet gaming disorder were randomized to bupropion sustained-release, escitalopram, or a no-treatment control group. After six weeks of therapy, bupropion and escitalopram significantly improved all clinical symptom scores compared with controls. Bupropion led to greater improvements than escitalopram in Internet addiction severity, depression, ADHD, behavioral inhibition and activation, and global functioning. Bupropion and escitalopram were effective in reducing Internet gaming disorder symptoms, but bupropion was more effective in improving attention and impulsivity, important in the management of Internet gaming disorder [229].

Eleven patients with Internet gaming disorder received bupropion treatment for six weeks. Pretreatment MRI imaging showed higher brain activation in the left occipital cuneus, left dorsolateral PFC, and left parahippocampal gyrus compared with healthy controls. After six weeks of bupropion treatment, craving for Internet gaming and cue-induced brain activity in the dorsolateral PFC decreased from pretreatment in patients with Internet gaming disorder [230].

Atomoxetine and methylphenidate were compared in 86 adolescents with Internet gaming disorder and ADHD. After 12 weeks of treatment, both atomoxetine and methylphenidate reduced symptom severity; this reduction correlated with reductions in impulsivity. These results suggest impulsivity may contribute to the development of Internet gaming disorder [168].

9. BINGE EATING DISORDER

In the terminology for addictive patterns of eating, "food addiction" is seen as a misnomer that conveys the largely disproven concept that certain foods possess inherent properties that promote addictive behavior. More appropriate terms are "eating addiction" or "addictive eating disorder," because they correctly associate addictive patterns of food consumption with behavior originating from individual predisposition [231].

There is increasing concern that consumption of food with high sugar content may be "addictive" and promote weight gain. Claims that sugar has addictive potential are based on animal studies, but direct human evidence for symptoms of sugar-related substance dependence is lacking [232]. A study evaluated 1,495 university students for potential "food addiction" (with DSM-IV substance dependence criteria applied to food) involving high-sugar foods. In this group, 12.6% met food addiction criteria; of these, 5% mainly consumed sugar-laden foods. Overweight/obesity was unrelated to sugary food preference. "Food addiction" was concluded to result from unique individual characteristics that determined reward response to food and promoted excessive eating [232].

EPIDEMIOLOGY

The lifetime prevalence of binge eating disorder in American adults is 0.8%, based on DSM-5 criteria [233; 234]. A World Health Organization survey of more than 24,000 adults in 14 mostly upper-middle and high-income countries found lifetime prevalence of binge eating disorder ranging from 0.2% to 4.7%, with the United States second in prevalence only to Brazil [235].

Binge eating disorder is more common in women (3.5%) than men (2%), and in younger and middle-aged adults than those older than 60 years of age [80]. The prevalence is higher in obese than non-obese persons. The lifetime prevalence of binge eating disorder appears slightly lower among Latino and Asian Americans (1.9% and 2.0%, respectively) compared with the general population; the prevalence is similar among Hispanic and non-Hispanic whites [234,236].

While binge eating disorder is found across all weight categories, binge eating is a strong risk factor for obesity, and roughly 25% of those seeking treatment for obesity meet binge eating disorder criteria [237].

Binge eating disorder has a higher lifetime prevalence in the United States and worldwide than bulimia nervosa and anorexia nervosa combined [234]. Unlike bulimia nervosa and anorexia nervosa, binge eating disorder is relatively common in both sexes and across ethnic/racial minority groups, and is distributed across broader age groups [234]. As noted, binge eating disorder is significantly associated with elevated rates of medical and psychiatric comorbidity and impairment. It shares some features with, but is distinct from, the other eating disorders and obesity [238,239,240].

Binge eating disorder is typically first diagnosed during the early to mid-20s, with symptoms usually persisting well beyond mid-life. The disease course may crossover to and from bulimia nervosa and anorexia nervosa. Binge eating disorder is associated with significant role impairment and relationship dissatisfaction. It is considered a significant public health problem independently as well as for its association with chronic pain, other psychiatric disorders, obesity, and diabetes [241,242,243].

PATHOPHYSIOLOGY

Evidence suggests that binge eating disorder overlaps with other behavioral and substance addictions. Persons with binge eating disorder show impairments across a range of compulsivity indices comparable to those with alcohol use disorder [42,244].

Binge-eating episodes may be triggered by a breakdown in self-regulation induced by sudden increases in negative affect and tension. Impairment in executive function is consistently found in eating disorders. With strong impulses or urges to eat, lack of inhibitory control may lead to impulsive eating and obesity in some [245]. In addition, dysregulation in dopamine, opioid, acetylcholine, and serotonin neurocircuitry in brain reward regions is implicated in the pathogenesis and maintenance of binge eating disorder [246].

There is growing interest in and debate about whether an addictive process contributes to problematic eating outcomes such as obesity. Craving is a core component of addiction but is little-studied in the context of addictive eating. In a community sample, overall food craving partially mediated the links between addictive eating and elevated body mass index (BMI) and binge-eating episodes. Cravings for sweets and carbohydrates mediated the link between addictive eating and binge episodes. Cravings for fats mediated the link between addictive eating and elevated BMI. Craving was a key contributor to the link between addictive eating and pathologic outcomes [247].

Individuals with obesity vary in their experience of food cravings and reward-driven eating; both can be modulated by the neural reward system rather than physiologic hunger. In a trial that randomized women with obesity to naltrexone or placebo, a subgroup showed that addictive eating behavior and food-craving intensity was linked to reward-driven eating, a trait-like index of three factors (loss of control over eating, lack of satiation, and preoccupation with food). In this subgroup, opioidergic blockade with naltrexone reduced the positive association between reward-driven eating and craving intensity [248].

The stimulant lisdexamfetamine was approved for binge eating disorder treatment by the U.S. Food and Drug Administration (FDA) in 2015. Lisdexamfetamine consistently leads to weight decreases of 5.2% to 6.25%. Psychostimulants are known to facilitate response inhibition by modulating PFC function. Despite successful reduction or remission of binge eating with antidepressants or psychosocial treatment, significant weight loss in these patients has not been reported. Through modulation of prefrontal function, lisdexamfetamine may lead to additional improvements in inhibitory control that account for weight loss [246].

DIAGNOSIS

The Yale Food Addiction Scale, based on DSM-IV criteria for substance dependence, was the first assessment tool for addictive eating behavior. Despite the "food addiction" naming, this scale assesses eating behavior and identifies eating patterns similar to behaviors in substance addiction [231].

Binge eating disorder was reclassified from a provisional diagnosis in the DSM-IV to a formal eating disorder diagnosis in the DSM-5 (Table 4) [11,249,250]. This disorder is characterized by recurrent episodes of binge eating, defined as eating patterns during discrete periods (i.e., two or more hours) that involve excessive, rapid food consumption. Other core features include a sense of lacking control over eating during binge episodes, significant psychologic distress (e.g., shame, guilt) about binge eating, and the absence of recurrent compensatory behaviors (e.g., purging) [11].

Table 4: DSM-5 DIAGNOSTIC CRITERIA FOR BINGE EATING DISORDER

Criteria Set

Specific Definitions for Each Criterion

Criterion 1

Recurrent episodes of binge eating. An episode of binge eating is characterized by both of the following:

- Eating, in a discrete period of time (e.g., within any two-hour period), an amount of food that is definitely larger than most people would eat in a similar period of time under similar circumstances

- The sense of lack of control over eating during the episode (e.g., a feeling that one cannot stop eating or control what or how much one is eating)

Criterion 2

Binge-eating episodes are associated with three or more of the following:

- Eating much more rapidly than normal

- Eating until feeling uncomfortably full

- Eating large amounts of food when not feeling physically hungry

- Eating alone because of being embarrassed by how much one is eating

- Feeling disgusted with oneself, depressed, or very guilty after overeating

Criterion 3

Marked distress regarding binge eating is present

Criterion 4

The binge eating occurs, on average, at least one day per week for three months

Criterion 5

The binge eating is not associated with the regular use of inappropriate compensatory behavior (e.g., purging, fasting, excessive exercise) and does not occur exclusively during the course of anorexia nervosa or bulimia nervosa

Severity grading

Mild: 1 to 3 episodes per week

Moderate: 4 to 7 episodes per week

Severe: 8 to 13 episodes per week

Extreme: 14 or more episodes per week

Source: [11]

A sense of loss of control during binge episodes is a core feature of binge eating disorder. The term "loss-of-control eating" is used to describe these episodes, but it is also used more broadly throughout the literature to describe binge-like eating behavior accompanied by a sense of loss of control that occurs across a wide spectrum of individuals. That spectrum includes, among others, individuals who exhibit some features of binge eating disorder but do not meet full diagnostic criteria for the disorder (i.e., subthreshold binge eating disorder) and individuals with other eating disorders [80].

The spectrum of loss-of-control eating also includes individuals for whom meeting the diagnosis threshold of binge eating disorder is uniquely challenging, such as children and those who have undergone bariatric surgery. Bariatric surgery significantly reduces stomach size and capacity, rendering it physically impossible to meet the binge eating disorder criterion specifying that a larger than usual amount of food is ingested. In the bariatric surgery literature, loss-of-control eating is used to describe binge-like behavior that falls short of meeting this criterion and to describe eating behavior that is contraindicated based on meal size and meal content. Children may not meet the binge eating disorder criterion for a larger-than-normal amount of food because their parents or others limit the quantity of food they consume or because they are unable to accurately quantify the amount they eat [80]. Nevertheless, loss-of-control eating is one of the most commonly reported disordered eating behaviors in children and adolescents and is particularly common in youth who have overweight or obesity [251,252].

TREATMENT

Binge eating disorder treatment addresses the core behavioral (binge eating) and psychologic (distress and eating, weight, and shape concerns) features of the condition. Other important targets include metabolic health (in patients with obesity, diabetes, or both) and mood regulation (in patients with comorbid depression or anxiety) [80,253,254].

Although binge eating disorder is found across all weight categories and overweight/obesity is not a criterion of binge eating disorder, weight loss has been considered an important treatment outcome, due to its strong association with the disorder and the heightened risk for obesity and associated medical comorbidities [255].

Psychologic Interventions

Cognitive-Behavioral Therapy

Therapy variants in binge eating disorder include CBT combined with body image exposure or cognitive restructuring components, and ecologic momentary assessment to increase self-monitoring adherence [80,253,256]. A meta-analysis of studies that randomized patients to CBT or non-treatment (control) found improved binge frequency and abstinence outcomes with therapist-led, partially therapist-led, structured self-help, and guided self-help CBT. Therapist-led CBT outcomes were compelling, with a higher rate of abstinence (59% CBT vs. 11% control), reduction of binge episodes, reduced patient hunger and eating concerns, and improved sense of control over eating. Guided self-help CBT reduced global eating-related psychopathology. When all study results were pooled, CBT and control groups were similar in weight lost and depressive symptom reductions. Therapist-led CBT was much more effective in improving key behavioral and eating-specific psychologic domains [80].

In a separate study, patients with clinical or subclinical binge eating disorder were randomized to individual or group CBT. Significant reductions in binge eating frequency and mild weight reduction were shown in both CBT formats at three-year follow-up. Predictors of full, long-term recovery were absence of treatment history with amphetamine derivatives, lower emotional eating, and lower pretreatment binge eating severity. Low emotional eating was the only predictor of weight reduction. Predictors of treatment resistance included overweight in childhood, full binge eating disorder diagnosis, and high prevalence of emotional eating [257].

Interpersonal Psychotherapy

Patients with binge eating disorder receiving therapist-led CBT and IPT showed differing abstinence trajectories at 46-month follow-up. Patients receiving CBT had high initial abstinence (81%) at the end of treatment, declining to 52% at final follow-up. Patients undergoing IPT had lower post-treatment abstinence (64%), but this increased (to 77%) by last follow-up [258].

Group Psychodynamic Interpersonal Psychotherapy

Compared with patients on a wait list, patients receiving 16 weekly group PIPT sessions showed greater binge frequency reductions (-0.5 vs. -3.0 binge days per week) and greater binge-eating abstinence (9.1% vs. 59.5%) [259]. Group PIPT also led to greater improvements in dietary restraint, depression, and interpersonal problems, but it did not differ from controls in BMI, self-esteem, or susceptibility to hunger at the end of treatment [80].

Behavioral Weight Loss

Behavioral weight loss treatment in binge eating disorder incorporates various behavioral strategies to promote weight loss, such as caloric restriction and increased physical activity. A meta-analysis compared CBT and behavioral weight loss on measures of binge frequency, abstinence, weight, and eating-related psychopathology [80]. Both CBT and behavioral weight loss were associated with substantial improvement in binge frequency, but CBT was superior to behavioral weight loss at the end of treatment and at 12-month follow-up. Behavioral weight loss led to larger BMI reductions than CBT at the end of treatment. There were no differences in binge-eating abstinence or eating-related psychopathology at any point in the study [80].

Pharmacotherapy

Overall, strong evidence shows that second-generation antidepressants, lisdexamfetamine, and therapist-led CBT increases the likelihood of achieving abstinence. CBT and second-generation antidepressants reduce binge frequency, and second-generation antidepressants reduce obsessions and compulsions related to binge eating. Lisdexamfetamine reduces binge frequency and obsessions and compulsions related to binge eating [80].

Lisdexamfetamine

The prodrug lisdexamfetamine is the sole FDA-approved drug for the treatment of moderate-to-severe binge eating disorder. The FDA has withdrawn several investigational or approved binge eating disorder pharmacotherapies from the U.S. market over safety concerns and adverse effects (e.g., sibutramine, rimonabant, d-fenfluramine) [80].

Lisdexamfetamine improved binge-eating outcomes in several rigorously designed studies. In aggregate, patients treated with lisdexamfetamine were 2.61 times more likely to achieve binge-eating abstinence than with placebo [80]. Lisdexamfetamine led to greater reduction in binge-eating days than placebo and was associated with superior eating-related psychopathology and weight-reduction outcomes. The most common side effects reported by patients receiving lisdexamfetamine were gastrointestinal upset, sympathetic nervous system arousal, insomnia, headache, and decreased appetite [80].

Lisdexamfetamine product labeling includes a "limitation of use" that the drug is not indicated for weight loss, its effects on obesity are unknown, and similar medication classes have been associated with cardiovascular adverse events in the past. Lisdexamfetamine is also considered a controlled substance, and the product labeling includes a warning that CNS stimulants have high potential for abuse and dependence. Careful assessment and on-going monitoring for signs of misuse are indicated [255].

Another FDA-approved drug for ADHD treatment, atomoxetine, was significantly superior to placebo in reducing binge eating and achieving binge-eating remission in a small randomized controlled trial [255]. However, its use in the treatment of binge eating disorder is off-label.

Selective Serotonin Reuptake Inhibitors

SSRIs are the most frequently studied binge eating disorder medications, likely due to the efficacy and FDA approval of fluoxetine for bulimia nervosa [255]. Fluoxetine was superior on some measures of binge eating to placebo in a 6-week study, but not in a 16-week trial. In the six-week study, fluoxetine rapidly reduced binge eating versus placebo, but binge eating reduction and abstinence did not differ at study conclusion. Fluoxetine did not differ significantly from sertraline or fluvoxamine, and fluoxetine and fluvoxamine were significantly inferior to CBT alone in another trial [255].

Other SSRIs mostly fail to separate from placebo. Trials of fluvoxamine and escitalopram reported statistically significant differences in weight loss favoring the SSRI. With a mean BMI of 33–40, these patients had a mean weight loss of 2.7–3.52 pounds, which shows reports of statistically significant differences can be clinically irrelevant [255].

Adding fluoxetine or fluvoxamine to CBT or other behavioral treatments did not enhance outcomes compared with either psychologic therapy alone [255]. However, the pooled results of seven second-generation antidepressant trials (five SSRIs, one duloxetine, and one bupropion) found patients receiving second-generation antidepressants were 1.67 times more likely to achieve binge-eating abstinence than those receiving placebo. Second-generation antidepressants reduced weekly binge-eating episodes by roughly two-thirds and binge-eating days per week by roughly one day (vs. placebo) [80].

Other Antidepressants

Duloxetine, a serotonin-norepinephrine reuptake inhibitor, was studied in 40 patients with binge eating disorder and comorbid depressive disorder. After 12 weeks, duloxetine (mean dose: 78.7 mg) significantly reduced weekly binge-eating days, binge-eating episodes, and severity ratings for binge eating disorder and depressive disorders compared with placebo. However, it did not differ from placebo in BMI, eating pathology, depression, or anxiety [260].

Antiepileptic Medications

In several randomized controlled trials, topiramate was significantly superior to placebo in more rapid reductions in binge eating, binge-eating remission, and weight loss. Binge-eating remissions in two topiramate studies were 64% and 58%. Adding topiramate (vs. placebo) to CBT significantly enhanced binge-eating remission rates and led to significantly and meaningfully greater weight loss [255]. Aside from lisdexamfetamine, topiramate is the only medication to consistently demonstrate substantial weight loss in patients with binge eating disorder [80].

In one randomized, placebo-controlled trial, 18 patients were randomized to 12 weeks of either phentermine/topiramate or placebo. Eating disorder behaviors, mood, and side effects were measured. Outcome measures included objective binge-eating days/week and binge abstinence. Baseline objective binge-eating days/week decreased from 16.2 to 4.2 with phentermine/topiramate versus 13.2 with placebo. Abstinence rates were 63.6% with phentermine/topiramate versus 9.1% with placebo. Other measured effects with the combination were minimal and similar to placebo [261].

The promising outcomes with topiramate are tempered by high rates of adverse events resulting in study dropout, including sympathetic nervous system arousal, headaches, sleep disturbances, and a collection of other symptoms including rash, high blood pressure, confusion, and taste aversion [80]. Dropout from topiramate is substantially reduced by adding CBT [255].

Other antiepileptics show less robust efficacy than topiramate [255]. Lamotrigine was not superior to placebo, and zonisamide was superior to placebo in more rapid binge-eating reduction and greater weight loss, but binge-eating remissions did not differ [255].

Anti-Obesity Medications

While not a binge eating disorder criterion, obesity is strongly associated with binge eating disorder in epidemiologic studies and is nearly universal in participants in binge eating disorder studies. Orlistat is a peripherally acting drug that blocks fat absorption in the gut without CNS effects. Several trials found orlistat significantly superior to placebo in enhancing weight loss, with no difference in binge eating reductions. Orlistat added to CBT significantly enhanced weight-loss outcomes but not binge eating reductions (compared with placebo). Orlistat or placebo added to behavioral weight loss therapy enhanced weight losses in obese patients without binge eating disorder, but not among obese patients with binge eating disorder [255].

Disulfiram

A small 12-week trial of disulfiram 250 mg/day significantly decreased binge-eating episodes per week (7.9 pretreatment vs. 0.9 post-treatment), and 58.3% achieved binge-eating remission. However, 25% dropped out from side effects, and the remaining subjects reported drowsiness, headache, dysgeusia, tachycardia, dizziness, and nausea [262].

Non-Invasive Brain Stimulation Therapy

A small pilot study evaluated single-session transcranial direct current stimulation of the right dorsolateral PFC compared with sham therapy. Transcranial stimulation decreased craving for sweets, savory proteins, and food overall (with the strongest reductions in men), and significantly reduced desire to binge eat in men the day of active treatment. Greater reductions in craving and food intake correlated with less eating for reward motives and greater intent to restrict calories, respectively. Stimulation of the brain may recruit mechanisms that enhanced cognitive control and/or reduced the need for reward. Transcranial direct current stimulation in binge eating disorder was safe, and the results support evaluation of multi-session therapy [263].

Surgical Interventions

Bariatric surgery is a treatment option for binge eating disorder with severe obesity (BMI ≥40 or BMI ≥35 with comorbid conditions). In the past, an eating disorder diagnosis was a contraindication to bariatric surgery, but this restriction has been relaxed. The disability and difficulty achieving stable weight loss with standard behavioral interventions has increasingly led to surgery candidates with binge eating disorder [240,264]. Bariatric surgery can be suitable for selected patients with binge eating disorder, but the extent of weight loss depends on post-surgery binge episode reduction, and 20% to 40% fail to lose sufficient weight or regain significant weight post-surgery [265]. Patients may experience emergent post-bariatric surgery psychiatric comorbidities. Considering the demonstrable and durable behavioral and neuroplastic changes associated with addictive eating behavior, obesity treatment is not realistic for some of these patients [266].

Overeaters Anonymous

Overeaters Anonymous (OA) is a 12-step program for compulsive overeaters. Binge eating is viewed as a physical, spiritual, and emotional disorder, and OA proposes recovery through change that promotes physical, spiritual, and emotional well-being. Members have stated the tools for spiritual and emotional work provided in OA were essential to recovery. Secure attachment experiences are very likely to occur within OA, in which safe ground is provided and positive attachment figures are accessible. These factors facilitate a corrective emotional experience that compensates for childhood rejection and time spent with a caregiver who lacked the emotional availability required for the creation of a secure attachment [267].

The contribution of secure attachment figures to binge-eating recovery is consistent with other research that connects emotional overeating in women to attachment-related themes of relationship history, addiction as coping mechanism for insecure attachment, emotional eating as reminiscent of ambivalent attachment, and emotional hunger [268].

10. COMPULSIVE BUYING DISORDER

Compulsive buying disorder, also termed shopping addiction, pathologic buying, or compulsive buying, is characterized by excessive or poorly controlled preoccupations and urges to spend. The excessive, impulsive, and uncontrollable purchase of products persists despite severe psychologic, social, occupational, or financial consequences [269,270].

EPIDEMIOLOGY AND RISK FACTORS

The prevalence of compulsive buying disorder in the United States is 5.8% to 8.9% [271,272]. However, estimating compulsive buying disorder prevalence is difficult because standardized diagnostic criteria are lacking. Current definitions are based on similarities between compulsive buying disorder and substance/behavioral addictions, OCD, and eating disorders [270].

The prevalence of compulsive buying has increased worldwide in the past two last decades. The pooled results of 40 compulsive buying prevalence studies from 16 countries found rates of 4.9% in adults, 8.3% in university students, and 12.3% in shopping-specific samples (e.g., shopping mall visitors). Younger age and female sex were associated with increased risk, but prevalence rates in the United States and other studied countries did not differ [273].

In one study, among 1,441 shopping mall visitors, the rate of compulsive buying disorder was 8.7% [273]. Compared with non-compulsive buyers, compulsive buyers were younger, less educated, more likely female, and more likely to have used licit and illicit substances. They also showed higher levels of impulsivity and obsessive-compulsive symptoms, lower levels of well-being and self-esteem, and greater psychologic distress. Patients identified as compulsive buyers were five times more likely to meet diagnostic criteria for borderline personality disorder. These findings suggest that, among shopping mall visitors, compulsive buyers are prevalent and have high rates of important indicators for psychopathology [273].

COMORBIDITY

Comorbidities associated with compulsive buying disorder include [271,274]:

- Mood disorders (21% to 100%)

- Personality disorders (60%)

- Anxiety disorders (40%)

- Substance use disorders (24% to 46%)

- Eating disorders (8% to 85%)

- Impulse control disorders (35%)

Patient samples show positive associations between compulsive buying disorder and bulimia nervosa, substance use disorders, gambling disorder, and impulse control disorders (e.g., intermittent explosive disorder). Compulsive buying disorder and ADHD are highly comorbid in both community and clinical samples. Patients with compulsive buying disorder also suffer high comorbidity with depressive and anxiety disorders, OCD, and hoarding disorder [275].

In a comparison of outpatients with compulsive buying disorder, inpatients without compulsive buying disorder, and healthy controls, the patients with and without compulsive buying disorder did not differ in borderline personality disorder symptoms, ADHD symptoms, or self-harming behaviors. Current impulse control disorder diagnosis was three times greater in patients with compulsive buying disorder than those without or control groups, despite patients with compulsive buying disorder perceiving themselves as being no more impulsive than either comparison groups [275].

CLINICAL CHARACTERISTICS

Compulsive buying is a chronic, repetitive behavior that becomes a primary response to negative events and feelings [276]. Four distinct phases in compulsive buying events are described: anticipation, preparation, shopping, and spending. Negative emotions, such as anger, anxiety, boredom, and self-critical thought, were the most common antecedents to shopping binges, with euphoria or relief from negative emotions the most common immediate effects [271].

Unlike ordinary consumers with primary buying motives of value and usefulness, compulsive buyers make purchases to elevate their mood, cope with stress, gain social approval/recognition, and/or improve their self-image [277,278]. Compulsive buying through the Internet is motivated by immediate gratification, ability to buy unobserved and avoid social interactions, and the vast number of products [22]. Compulsive buying disorder is driven by mood-modifying motivation—not excessive spending or materialism alone. It can lead to serious adverse outcomes, including substantial debt, relationship problems, elevated risks of criminal behavior, and suicide attempts [279]. Emotional consequences from protracted compulsive buying include shame, guilt, and regret/remorse over purchases and failed efforts to stop [213,270].

The role of impulsivity in compulsive buying disorder is demonstrated, characterized by novelty-seeking, acting rashly without considering future consequences, and approach behavior triggered by high sensitivity to reward stimuli. Other data suggest correlations between compulsive buying disorder and positive/negative urgency (i.e., the tendency to act rashly while in positive/negative mood) [275].

The purchases of compulsive buyers are seldom used, and patient interest is quickly lost. However, the urge to shop and buy recurs, along with excessive, inappropriate buying sprees the patient is unable to control. Patients with compulsive buying disorder usually spend far beyond their means, leading to distress, debt, interference with employment and social functioning, relationship difficulty, and occasionally, criminal behavior such as fraud or embezzlement [275].

Sociodemographic and personality characteristics may help determine different clinical subtypes of compulsive buying disorder to consider during assessment and treatment planning. Three clusters of compulsive buying disorder were identified among patients attending a specialized treatment program [280]:

- Male compulsive buyers: The highest prevalence of comorbid gambling disorder and the lowest levels of reward dependence

- Female, low dysfunctional: Mainly employed women, with the highest level of education, the oldest age of onset, the lowest scores in harm avoidance, and the highest levels of persistence, self-directedness, and cooperativeness

- Female, highly dysfunctional: The youngest age of onset, the highest levels of comorbid psychopathology and harm avoidance, and the lowest scores in self-directedness

Comparisons with Other Behavioral Addictions

A study compared characteristics of patients seeking treatment for compulsive buying disorder, gambling disorder, Internet gaming disorder, Internet addiction, or sexual addiction. The results show that although compulsive buying disorder could likely be related to other addictive behaviors, significant differences in its phenomenology exist. Compulsive buying disorder is characterized by a higher proportion of women, older age of onset, poorer general psychopathologic state, higher levels of novelty seeking and harm avoidance, and moderate levels of reward dependence, persistence, and cooperativeness. In this sense, patients with compulsive buying disorder could be described as curious, easily bored, impulsive, and active seekers of new stimuli and reward. At the same time, these patients show pessimism and worry in anticipation of upcoming challenges [270].

Clinical differences were lower compared with sex addiction and higher compared with gambling disorder and Internet gaming disorder. Compulsive buying disorder and sexual addiction showed similar profiles, with their psychopathologic symptoms and personality scores being clearly worse than for gambling and Internet gaming disorder. In behavioral addictions, impulsivity is a core feature, but multiple studies also show high levels of compulsivity [281,282]. This study showed the combination of impulsive/compulsive symptoms is especially prominent in compulsive buying disorder and sex addiction [270]. In hoarding, one of the most commonly reported symptoms is acquiring behavior, and other studies have identified numerous similarities between hoarding and compulsive buying disorder [283].

Gambling disorder and compulsive buying disorder share features, including the urge to achieve immediate gratification or relieve negative emotion through impulsive/compulsive behavior, early onset of problematic addictive behavior, and impaired money management skills [270]. The inability to resist an impulse, drive, or temptation to perform a harmful act is an essential feature of most behavioral addictions [45].

Online compulsive buying disorder was studied in 240 female subjects. The relationship between excitability from shopping and pathologic online buying was partially mediated by expectancies for online shopping (i.e., the expectation that online buying will satisfy urges for excitement, distress relief, or mood elevation). Craving and pathologic online buying were strongly correlated, and increased cue-reactivity (i.e., craving after presentation of online shopping images) was observed solely in individuals scoring high for online compulsive buying disorder. This mediation model explained most of the variance for tendency to develop online compulsive buying disorder [284].

PATHOGENESIS AND PATHOPHYSIOLOGY

A breakthrough in the understanding of the pathogenesis of compulsive buying disorder came from Parkinson disease studies, in which some patients prescribed dopaminergic agents developed compulsive buying behavior. This suggests dopamine plays a role in compulsive buying, similar to substance use disorders. This parallel to substance addiction is supported by the finding that the brain does not distinguish between dopamine release in the nucleus accumbens and ventral tegmental area secondary to drug use or experience (like shopping) [285]. Furthermore, functional neuroimaging studies have shown that shopping activates many of the same brain regions as drugs of abuse, specifically the mesocorticolimbic system and the amygdala [286]. Evidence suggests that behavioral addictions may lead to neuroadaptations similar to those reported with substance use disorder, including a hijacking of the neural circuits responsible for the natural reward pathways. If a drug or experience is hyperstimulating, this neuroadaptation (namely, down-regulation of dopamine receptors) occurs with repeated exposures [272].

Different emotional (e.g., pleasure seeking, escape of negative emotions) and cognitive (e.g., impulsivity, self-regulation, decision-making deficits) mechanisms contribute to the development and maintenance of compulsive buying disorder. A growing number of researchers emphasize that compulsive buying disorder shares several key characteristics with other behavioral addictions, including preoccupation with the behavior, diminished control over the behavior, repeated unsuccessful attempts to cut down or stop the behavior, tolerance, withdrawal, and adverse psychosocial consequences. Importantly, cue-reactivity and craving has been demonstrated in individuals with compulsive buying disorder [284]. As discussed, Internet characteristics seem to encourage compulsive buying, with greater and more rapid excitation, gratification and reward response, buying opportunity 24 hours per day, buying from the convenience of home, and easy payment that can lead to unplanned overspending [284].

Brain imaging studies of compulsive buying disorder and other behavioral addictions have consistently found frontoparietal region, reward processing, and limbic system abnormalities, also commonly observed in substance use disorders [270]. Neurocognitive data suggest that subjects with compulsive buying disorder have impairments in response inhibition, risk adjustment during decision-making, and spatial working memory. Problems in these distinct cognitive domains support a neurobiologic overlap between compulsive buying and other behavioral and substance addictions [84].

As discussed, Gray's reinforcement sensitivity theory states that a hyper-responsive behavioral system predisposes individuals to engage in impulsive behaviors [287]. It has also been used to explain the addictive processes underlying compulsive buying disorder; both reinforcement and punishment systems seem to participate in the onset and development of this disorder [288]. Dysfunctional emotional regulation is also implied in the phenotype of behavioral addictions, particularly in aspects such as managing cravings and withdrawal symptoms [270].

Research indicates that individuals with high reward sensitivity are motivated to engage in behaviors that provide internal reinforcement (enhancement/winning motives) and external reinforcement (social motives). Similarly, greater compulsive buying tendencies have been positively associated with reward sensitivity, which has been reported to be a powerful predictor of disorder severity [45,289].

College students meeting the criteria for compulsive buying have shown greater psychiatric comorbidity, increased stress, and worse physical health [45]. Individuals with greater punishment sensitivity are vulnerable to negative emotions (e.g., frustration, anxiety, fear, sadness), and compulsive buying may serve as a form of negative reinforcement [45].

DIAGNOSIS

Compulsive buying disorder is characterized by a maladaptive preoccupation with buying and shopping and by repetitive purchasing of consumer goods to relieve stress, to escape from negative feelings, and to enhance a poor sense of self [275]. These patients engage in persistent, excessive, impulsive, and uncontrollable purchase of products despite severe psychologic, interpersonal, social, occupational, and financial consequences [45].

Compulsive buying disorder was classified in the DSM-III-R as an impulse control disorder not elsewhere specified, but it was omitted from the DSM-5 [11,290]. Since 2013, research demonstrates that compulsive buying disorder has several features that characterize addictions, including cue reactivity and cravings [279].

Although not recognized in the DSM-5 as a diagnostic entity, the following diagnostic criteria have been proposed for compulsive buying [84,272,274]:

- Frequent, maladaptive preoccupation with, or engagement in, buying; intrusive, irresistible, "senseless" buying impulses

- Clearly buying more than needed or can be afforded

- Distress related to buying behavior

- Significant interference with work or social functioning

- The buying behavior does not occur exclusively during hypomanic or manic episodes

The YBOCS-Shopping Version provides a robust, sensitive measure of compulsive buying disorder treatment response and can be used in the clinical screening of compulsive buying disorder [291].

TREATMENT

Psychologic Interventions

Studies suggest that CBT, dialectical behavior therapy, and psychodynamic psychotherapy may have promising results in treating compulsive buying disorder [272]. CBT focuses on identifying factors that maintain and reinforce the problematic buying behavior and delineates strategies for controlling impulsive spending. Maintaining a diary to identify triggers, describe the shopping behavior itself, and record the consequences of compulsive shopping assists patients in understanding behaviors from a different perspective. Additional options include 12-step programs such as Debtors Anonymous, debt consolidation, and credit counseling [272,292].

Group Psychotherapy

Group psychotherapy that uses a CBT approach or cognitive-behavioral methods within an eclectic approach appears beneficial, with durable improvements in reducing distress associated with compulsive buying disorder and maladaptive buying behavior. Research suggests that impulse control training should be a core component of compulsive buying disorder treatment [279]. Attrition rates show that group psychotherapy is not acceptable to all patients with compulsive buying disorder; patient choice and suitability are important considerations [279].

Stepped Care Delivery Model

Evidence suggests that a low-intensity, guided self-help approach to treating compulsive buying disorder was comparable to high-intensity group therapy. If patients can be treated with effective, brief, and less intensive psychologic interventions first, this may increase service throughput and efficiency [293]. Studies of Internet-based, therapist-assisted self-help programs also usefully mimic the shift of behavior in online shopping [294]. Research indicates that excitability regarding online shopping and compulsive buying disorder are mediated by Internet use expectancies [284]. Treatments clearly need to reflect the context within which compulsive buying occurs [279].

Effect of Reward and Punishment Sensitivity on Treatment Response

Reward and punishment sensitivity was studied for impact on treatment outcome (12 weekly CBT sessions) in female patients with compulsive buying disorder or gambling disorder [45]. In compulsive buying disorder, higher reward sensitivity was related to poorer treatment adherence but reduced risk of dropout. Patients were likely to have stronger intrusive urges to buy, interfering with ability to curb buying behavior and carry out practice homework for CBT. The lower dropout risk may reflect patient motivation by social factors, with patients more likely to form a therapeutic alliance and not abandon treatment. High punishment sensitivity correlated with harm avoidance; these patients had increased risk of treatment drop-out.

Among all patients, high reward and punishment sensitivity was associated with greater psychopathology; worse psychologic adjustment and treatment outcomes; higher novelty-seeking, persistence, and self-transcendence; and low self-directedness and cooperativeness. These results suggest patient response to CBT is conditioned by sensitivity to reward and punishment; compulsive buying disorder and gambling disorder shared this phenotype. This information could be incorporated into targeted interventions to strengthen CBT efficacy in compulsive buying disorder [45].

Pharmacologic Interventions

A review of compulsive buying disorder treatment found few published pharmacotherapy studies. SSRI antidepressants are the most-studied pharmacotherapy, based on the same premise as their use in other behavioral addictions [84]. Evaluations of citalopram, escitalopram, and fluvoxamine have reported mostly negative results, and clinicians should consider psychotherapeutic options before pharmacotherapy [279].

11. TRICHOTILLOMANIA (HAIR PULLING DISORDER)

Trichotillomania is the repetitive pulling out of one's own hair, leading to hair loss and functional impairment. Although documented in the medical literature since the 19th century, trichotillomania has received little research attention [295]. In clinical settings, the preferred term for this condition is ''hair pulling disorder'' [296].

EPIDEMIOLOGY

Community prevalence studies suggest that trichotillomania occurs in 0.5% to 2.0% of the population [297,298]. In adults, trichotillomania predominately affects women (4:1 female to male), but childhood trichotillomania shows equal sex distribution [297,298]. As a behavior, hair pulling appears quite common and often presents along a continuum from mild to severe. When hair pulling meets the criteria for trichotillomania, interventions should be considered [299].

CLINICAL FEATURES

The typical age of onset for trichotillomania is consistently found to be 10 to 13 years of age. The natural history may vary, but untreated trichotillomania is usually a chronic disorder with fluctuating intensity; studies show an average illness duration of 22 years. Symptom intensity usually waxes and wanes, but persists without treatment [299,300].

With hair pulling in trichotillomania, the scalp is the most common site (72.8% of patients) followed by the eyebrows (56.4%) and the pubic region (50.7%) [299]. Triggers to pull can be sensory (e.g., physical sensations on the scalp, hair thickness, length, and location), emotional (e.g., feeling anxious, bored, tense, angry), or cognitive (e.g., thoughts about hair and appearance, rigid thinking, cognitive errors). Many patients report not being fully aware of their pulling behaviors at least some of the time—a phenomenon termed "automatic" pulling. "Focused" pulling, in contrast, generally occurs when the patient sees or feels a hair that is "not right" or if the hair feels coarse, irregular, or "out of place" [299,301].

The inability to stop hair pulling and the resultant alopecia can lead to low self-esteem, psychosocial dysfunction, and social anxiety. Individuals commonly report failing to pursue job advancements or avoiding job interviews because of the pulling and/or their appearance. A low or very low quality of life is reported by close to 33% of adults with trichotillomania [302]. In patients with trichotillomania, greater functional impairment is associated with later symptom onset, lower quality of life, and worse disease severity [303].

Unwanted medical consequences from trichotillomania include skin damage or infection that results from using sharp instruments (e.g., tweezers, needles) to pull hair. More than 20% of patients eat hair after pulling it out (trichophagia); gastrointestinal obstruction and formation of intestinal hair-balls (trichobezoars) can ensue, requiring surgical intervention in extreme cases [304].

COMORBIDITY

Patients with trichotillomania have high rates of comorbidity, including major depressive disorder (39% to 65%), anxiety disorders (27% to 32%), and substance use disorders (15% to 19%). Trichotillomania is often misdiagnosed as OCD. Rates of comorbid OCD are significantly higher in clinical (13% to 27%) than community (1% to 3%) populations [299,305].

The age of trichotillomania onset is generally earlier than its common comorbidities. In a large trichotillomania survey, patients sought to alleviate negative feelings associated with hair pulling through use of tobacco products (17.7%), alcohol (14.1%), or illicit drugs (6.0%). Also, 83% reported anxiety and 70% reported depression due to pulling, indicating that clinicians should screen for trichotillomania and the secondary manifestations of the behavior to better ensure successful treatment outcomes [305,306].

PATHOPHYSIOLOGY

The similarity between repetitive motor symptoms of hair pulling and repetitive compulsive rituals in OCD led to proposals that both disorders shared common neurobiologic pathways. However, evidence indicates that trichotillomania and OCD are distinct. In contrast to OCD, patients with trichotillomania are more commonly female, and body-focused repetitive behavior disorders (e.g., skin picking, compulsive nail biting) more frequently occur in these patients and their first-degree relatives. In OCD, compulsions are often driven by intrusive and obsessional thoughts, which are seldom found in patients with trichotillomania and are not listed in diagnostic criteria. The typical age of onset is early adolescence for trichotillomania and late adolescence for OCD. Treatment response also differs, with SSRIs effective in OCD but not trichotillomania [307,308].

Hair pulling is considered a means of escaping or avoiding aversive experiences, and the temporary relief from negative emotions can maintain the behavior through a cycle of negative reinforcement. Patients with trichotillomania have demonstrated greater difficulty regulating negative affective states than controls. In some individuals, boredom may trigger hair pulling. Some have hypothesized that in a subgroup of patients, hair pulling alleviates negative emotions resulting from perfectionism and an inability to relax, with pulling serving the function of releasing tension [309].

In the few trichotillomania neuroimaging studies conducted, patients with trichotillomania showed volume deficits and disorganization in neurocircuits that mediate affective regulation, motor habit generation, and suppression (compared with healthy controls) [310]. Another study of subjects with trichotillomania failed to identify abnormalities in implicit learning or striatal/hippocampal activation, characteristics of OCD [311].

DIAGNOSIS

Trichotillomania was not officially endorsed as a mental health disorder by the APA until 1987, when it was included in the DSM-III-R as an impulse control disorder not elsewhere classified [290]. Trichotillomania was moved to the chapter on Obsessive-Compulsive and Related Disorders in the DSM-5, alongside OCD, excoriation disorder, body dysmorphic disorder, and hoarding disorder [11]. As discussed, this designation of trichotillomania as an OCD-related disorder can be misleading.

One trichotillomania criterion in the DSM-IV was "an increasing sense of tension prior to hair pulling or when resisting the urge; pleasure, gratification, or relief when pulling out hair" [250]. The DSM-5 omitted this criterion because not all trichotillomania sufferers had this experience [296]. The DSM-5 criteria are [11]:

- Recurrent pulling out of one's hair, resulting in hair loss

- Repeated attempts to decrease or stop hair pulling

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

- The hair pulling or hair loss is not attributable to another medical condition (e.g., a dermatologic condition)

- The hair pulling is not better explained by the symptoms of another mental disorder (e.g., attempts to improve a perceived defect or flaw in appearance in body dysmorphic disorder)

TREATMENT

Persons with trichotillomania rarely seek professional mental health treatment, largely due to concerns that providers do not understand the disorder or fears over the reactions of professionals. Others avoid seeking help from social embarrassment, believing their condition is just a bad habit or that it is untreatable. With early diagnosis and appropriate treatment, up to 50% of patients may attain at least short-term symptom reduction [295].

As noted, trichotillomania often co-occurs with anxiety disorders, and persons with trichotillomania frequently report their hair-pulling worsens during increased anxiety. Adult patients with trichotillomania and comorbid anxiety disorders show significantly worse hair pulling symptoms, are likely to have co-occurring depression and first-degree relatives with OCD, and show significantly worse motor inhibition. Male patients with trichotillomania are more likely to have substance use disorder comorbidity, older age, and marriage status than female patients [300,312].

Psychologic Interventions

The evidence base for psychotherapy in trichotillomania is small, and habit reversal therapy has the greatest empirical support. Habit reversal therapy is a behavioral therapy initially introduced for the treatment of nervous habits and tics. The core components of habit reversal therapy include self-monitoring (e.g., asking the patient to track hair-pulling or skin-picking events), awareness training, competing response training, and stimulus control procedures (e.g., removing hair-pulling or skin-picking cues from the patient's environment) [309].

Habit reversal therapy is generally delivered in weekly 60-minute sessions for 4 to 22 weeks, with more frequent sessions for patients with greater symptom severity. It can be delivered individually, in a group format, or online using a self-help manual [313]. The clinical benefits of trichotillomania symptom reduction have been augmented by adding components of acceptance and commitment therapy or dialectical behavior therapy [314,315]. Patient gains from habit reversal therapy are usually maintained for three to six months. Many clinicians combine habit reversal therapy and CBT, but published data support habit reversal therapy use as a stand-alone, first-line psychotherapy approach in trichotillomania [295]. One small study reported success combining metacognitive therapy with habit-reversal techniques for treatment of trichotillomania [316].

Pharmacologic Interventions

The classification of trichotillomania as an OCD-spectrum disorder has interfered with identifying effective drug treatment. SSRIs have been repeatedly evaluated in trichotillomania, without benefit [296]. The only antidepressant with partial efficacy in trichotillomania is clomipramine, a tricyclic agent [317].

Evidence Based Practice Recommendation

A Cochrane Review found that no particular medication class definitively demonstrates efficacy in the treatment of trichotillomania. Preliminary evidence suggests treatment effects of clomipramine, NAC, and olanzapine based on three individual trials, albeit with very small sample sizes.

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007662.pub2/full

Last Accessed: April 12, 2021

Level of Evidence: Meta-Analysis

Clinical experience and results from a single clinical trial indicate that NAC (1,200 mg twice daily) can reduce hair-pulling urges and may be considered as initial pharmacotherapy. Importantly, NAC may require daily adherence for up to nine weeks for benefits to appear. NAC is well-tolerated, with generally mild side effects of abdominal bloating and flatulence [318].

The atypical antipsychotic olanzapine was evaluated over 12 weeks (mean dose: 10.8 mg/day) and showed significant reductions in trichotillomania symptoms compared with placebo [319]. The propensity to cause metabolic syndrome requires that benefits be carefully weighed against this drug's side effect profile [295].

Dronabinol is synthetic delta-9 tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis. THC binds to cannabinoid receptors (CB); CB1 receptor activation inhibits glutamate overproduction and resultant excitotoxicity implicated in trichotillomania [296]. A 12-week uncontrolled trial of dronabinol (mean dose: 11.6 mg/day) led to marked reductions in trichotillomania symptoms. Side effects of mild sedation were reported, and no significant effects were found on memory, attention, executive function, or psychomotor speed [320]. These promising results are tentative until confirmed by placebo-controlled trials.

12. KLEPTOMANIA (COMPULSIVE STEALING)

Kleptomania is characterized by repetitive stealing behavior and is associated with severe adverse outcomes, including incarceration and increased rates of suicidal behavior [321]. Persons with kleptomania differ from ordinary shoplifters because their stealing is motivated by symptom relief and not personal gain [322].

Persons with kleptomania mostly steal from stores, usually items of little value, and then discard, hoard, secretly return, or give the items away. The urge to steal may be resisted when immediate arrest is likely, but the odds of apprehension are usually not fully considered. The exhilaration, gratification, or relief experienced during the theft is short-lived, followed by feelings of guilt, remorse, or depression [322].

EPIDEMIOLOGY, RISK FACTORS, AND COMORBIDITY

The commonly quoted kleptomania prevalence of 0.6% in the general population was extrapolated from study data of patients with eating disorders [323]. A 2010 college student survey found a lower kleptomania prevalence rate of 0.38% [324]. This latter figure is likely more accurate because it was not derived from a specific subpopulation [323]. Among those arrested for shoplifting, kleptomania rates have ranged from 0% to 8%. This may be falsely low due to incomplete psychiatric evaluation, lack of strict diagnostic criteria for kleptomania, and/or selection bias [322].

In contrast to community prevalence rates, studies of patients with psychiatric disorders suggest prevalence rates of kleptomania sufficient to potentially represent a public health concern. Among 203 inpatients with diverse psychiatric disorders, 7.8% met current and 9.3% met lifetime criteria for a diagnosis for kleptomania. The similar current and lifetime prevalence suggests that untreated kleptomania is chronic. Other studies show increased rates of kleptomania in patients with depression (3.7%), alcohol use disorder (3.8%), and gambling disorder (2.1% to 5%) [322,325].

Most kleptomania studies report female predominance. However, women are more likely to seek professional help, and the legal system is more likely to send female shoplifters for psychiatric evaluation and male shoplifters to jail [322]. So, the true prevalences in men and women may be more similar than reported. Among 101 adults meeting DSM-IV kleptomania criteria (73.3% female), the mean age of shoplifting onset was 19.4 years, persisting an average 8.2 years before full diagnostic criteria were met [326].

CLINICAL CHARACTERISTICS AND ILLNESS COURSE

The average age for stealing behavior onset is adolescence, with the first professional evaluation in the mid- to late-30s. Women tend to present for evaluation at a younger age than men. The extended length of time between onset and mental health evaluation reinforces the guilt, shame, and secrecy involved in this disorder [322].

Little data are available on the natural history of kleptomania, but three patterns have been described [11]:

- Sporadic: Brief episodes of kleptomanic behavior punctuating long periods of remission

- Episodic: Relatively equal, protracted periods of kleptomanic behavior alternating with remission

- Chronic: Long-term kleptomania with some degree of fluctuation in the behavior

Up to 68.2% of individuals report the value of stolen items increases over time, suggesting tolerance. Most persons with kleptomania unsuccessfully attempt to stop stealing; these failed efforts contribute to feelings of shame and guilt [322].

A study of persons interviewed after apprehension for theft found that shoplifters and kleptomaniacs differed by mean age (27 years vs. 41 years) and male proportion (58% vs. 32.4%). Approximately 20% had not stolen for personal use and had discarded the object. Both groups reported the same level of impulsivity and "a feeling of not being oneself," but those with kleptomania reported a greater number of thefts than shoplifters, reflecting the compulsive aspect of the disorder [323,327].

Consequences

One study found 24% of persons with kleptomania had attempted suicide, of which 92% attributed the attempt to kleptomania itself [323]. Suicide attempts were associated with comorbid bipolar disorder, other impulse control disorders, and personality disorders (especially borderline and narcissistic). These syndromes share neurobiologic deficits in executive function that also typify kleptomania. Unlike earlier studies, anxiety, depression, and substance use disorders did not correlate with increased risk of suicide attempt. Data on suicides were not included, and this group may have been under-represented. Legal problems did not correlate with suicide risk, but patients who complete suicide after arrest or conviction have been reported. Other suicide risk factors in patients with kleptomania include shame, poor self-esteem, high levels of impulsivity and disinhibition, and social isolation [323,328].

Kleptomania is associated with significant legal consequences. In one study, common legal consequences included being arrested (68.3%), arrested but not convicted (36.6%), convicted and incarcerated after conviction (20.8%), and convicted but not incarcerated after conviction (10.9%) [326].

PATHOPHYSIOLOGY

Evidence increasingly supports kleptomania as a behavioral addiction, and kleptomania shares several features with substance use disorders [322,323]:

- Urges to engage in behaviors with negative consequences

- Mounting tension unless the behavior is completed

- Rapid but temporary urge reduction following the behavior

- Return of the urge

- External and unique behavioral cues

- Secondary conditioning by external and internal cues (dysphoria, boredom)

- A hedonic quality earlier in the natural history

Substance use disorders are highly comorbid in patients with kleptomania (29% to 50%), and patients with kleptomania often have first-degree relatives with substance use disorders. Kleptomania responds to the anti-craving drug naltrexone, an opioid antagonist used in opioid and alcohol use disorders. In contrast, opioid agonists (tramadol, morphine), but not antagonists, have efficacy in OCD [322,329].

Clinical subtypes of kleptomania have been identified, based on the underlying drive of the behavior [323,330]:

- Urges often triggered by external cues (around 50% of patients), closely resembles substance use disorders

- Emotional states of feeling bored, lonely, anxious, or depressed (10% of patients) that resembles affective spectrum disorder. However, patients with this subtype describe their behavior driven by a need to "escape" similar to patients with substance use disorder who experience relief from craving.

- A combination of urges and emotion states (40% of patients), with urges to steal occurring during specific emotional states only

DIAGNOSIS

Kleptomania is a secretive disorder with a hidden nature. Patients often present for treatment from legal coercion after being arrested for shoplifting. The diagnosis is often missed in routine psychiatric evaluations, and clinicians do not usually inquire about it. Patients with kleptomania often do not initiate disclosure of the behavior, even when they are already in psychiatric treatment for another disorder, because of shame about their behavior [323]. One study found only 42% of married individuals with kleptomania had told their spouses about the behavior [322].

The 2000 DSM-IV-TR diagnostic category of impulse-control disorders not elsewhere classified was renamed disruptive, impulse-control, and conduct disorders in the DSM-5 and expanded to include oppositional defiant disorder, intermittent explosive disorder, conduct disorder, antisocial personality disorder, pyromania, and kleptomania [11,250]. Instead of assigning kleptomania to a work group, the DSM-5 Study Group placed it in this ill-fitting diagnostic category. Data that show similarity between kleptomania and conduct disorder or intermittent explosive disorder are virtually non-existent [181].

The DSM-5 diagnostic criteria for kleptomania are [11]:

- Recurrent failure to resist impulses to steal objects that are not needed for personal use or for their monetary value

- Increasing sense of tension immediately before committing the theft

- Pleasure, gratification, or relief at the time of committing the theft

- Stealing not committed to express anger or vengeance and is not in response to a delusion or a hallucination

- Stealing not better explained by conduct disorder, a manic episode, or antisocial personality disorder

Differential Diagnoses

Kleptomania should be distinguished from ordinary theft, whereby stealing is motivated by the value of the object regardless of whether it was planned or impulsive. Shoplifting and ordinary theft are common, but kleptomania is rare. Some individuals feign symptoms of kleptomania to avoid criminal prosecution, and malingering should be ruled out. Stealing in the context of conduct disorder or antisocial personality disorder is a pattern of antisocial behavior; stealing in the context of acute psychiatric or cognitive symptoms should be distinguished from kleptomania [11,323].

Kleptomania is easy to mis- or overdiagnose because most diagnostic criteria are based on self-report, which is difficult to objectively confirm. Determination that stealing is not committed to express anger or vengeance may require several sessions to understand patient motives for the behavior, as patients are usually secretive and may not be consciously aware of their motive at the time of assessment [331].

TREATMENT

Successful treatment of kleptomania involves educating patients that they have an illness that is likely to become lifelong without treatment [330]. Psychotherapy should anticipate that, in some patients, kleptomania has become a part of their identity and gives them self-esteem and temporary relief. This should not be ignored when helping patients develop healthy coping skills to handle distress and should be discussed throughout the course of treatment [323,330].

Because kleptomania is a relatively rare psychiatric disorder, few studies have evaluated psychosocial and pharmacologic treatments and empirically validated treatment options remain lacking. Most published treatment suggestions for kleptomania are extrapolated from conceptual models for substance use disorders, OCD-related or affective disorders, or ADHD [323].

Preliminary data from treatment-seeking patients show gender differences in clinical features and comorbid disorders that may reflect biologic and sociocultural factors with implication for prevention and treatment. Women and men with kleptomania both show substantial symptom severity and functional impairment. Women are more likely than men to be married (47.1% vs. 25.9%), experience shoplifting onset at a later age (20.9 years vs. 14 years), steal household items, hoard stolen items, and have a comorbid eating disorder. Men are more likely to steal electronic goods and have another impulse-control disorder [332].

Psychologic Interventions

CBT is tailored for use in the treatment of kleptomania by applying the following strategies [322]:

- Overt sensitization: The patient is instructed to imagine stealing and then to imagine a negative outcome, such as being caught or feeling nauseated or short of breath.

- Aversion therapy: Patients practice aversive breath-holding until mildly painful when experiencing a stealing urge or image.

- Systematic desensitization: The patient achieves a relaxed state through progressive muscle relaxation and is asked to imagine the different steps of a stealing episode while suggesting they can better manage the urge to steal by controlling the anxiety.

CBT or variants of cognitive and behavioral therapies seem promising for kleptomania, but large-scale studies with control groups are lacking. Furthermore, there may be a shortage of clinicians skilled in these therapies for kleptomania [322]. Findings also suggest that patients with kleptomania require longer treatment beyond the standard 6- to 12-session structure of CBT [333].

Pharmacologic Interventions

Memantine is an N-methyl-d-aspartate (NMDA)-receptor antagonist with promising results in substance and behavioral addictions. A small, uncontrolled trial in patients with kleptomania reported that after eight weeks of memantine (up to 30 mg/day), 91.7% met criteria for clinical response (defined as ≥35% improvement in symptom severity and clinician rating of improved/very much improved). All kleptomania disease severity scores decreased, and mood, anxiety, disability scores, and impulsivity improved. Memantine was generally well-tolerated, reduced shoplifting urges and behavior, and improved psychosocial functioning [321].

Naltrexone efficacy was evaluated after eight weeks and led to significantly greater reductions in overall kleptomania severity, stealing urges, and stealing behavior compared with placebo. The mean effective naltrexone dose was 116.7 mg/day, and 92% of subjects completed the study [334]. Naltrexone may decrease dopamine transmission in the nucleus accumbens, thus reducing the reward and reinforcement experienced with stealing and urges to steal [334].

The SSRI escitalopram has shown high response rates in uncontrolled trials, but failed to separate from placebo under double-blinded conditions [335]. Although SSRIs have been considered first-line pharmacotherapy in kleptomania, evidence indicates naltrexone is more effective, especially in patients with greater stealing urges. Patients with urges/cravings to steal and/or a family history of substance use disorders should receive a trial of naltrexone. If kleptomanic symptoms appear within the context of general impulsivity and inattentiveness in ADHD, psychostimulants can be considered. Consider antidepressants or mood stabilizers for comorbid affective disorders [323].

Twelve-Step Programs

Shoplifters Anonymous defines itself as a 12-step group for compulsive shoplifters, stealers, thieves, and kleptomaniacs. Groups under the names Compulsive Shoplifters Anonymous (CSA) and Cleptomaniacs and Shoplifters Anonymous (CASA) can also be found. Although there is little research about these groups, recommending them in conjunction with medication and individual treatment is reasonable to consider [323].

13. INDUCED BEHAVIORAL ADDICTIONS

As noted, impulse control disorders and behavioral addiction can emerge during treatment with dopaminergic agents. Most published cases involve patients with Parkinson disease, who at some point require the dopamine precursor levodopa or dopamine agonists.

PATIENTS WITH PARKINSON DISEASE

Evidence Based Practice Recommendation

When starting dopamine agonist therapy, patients with Parkinson disease and their family members and carers (as appropriate) should be given oral and written information about the increased risk of developing impulse control disorders (e.g., compulsive gambling, hypersexuality, binge eating, obsessive shopping) when taking dopamine agonist therapy and that these may be concealed by the person affected.

https://www.nice.org.uk/guidance/ng71

Last Accessed: April 12, 2021

Level of Evidence: Expert Opinion/Consensus Statement

Patients with Parkinson disease receiving dopaminergic therapy can develop behavioral side effects that include impulse control disorders. A multi-center study in 2010 found that gambling disorder, compulsive shopping, compulsive sexual behaviors, or binge eating developed in 17% of patients receiving dopaminergic medications. Other behaviors associated with impulse control disorders included compulsive medication use (dopamine dysregulation syndrome) and punding (repetitive non-goal-directed simple or complex behaviors, including hobbyism) [336].

Another study of patients with Parkinson disease identified addictive behaviors in 14% of patients receiving any dopaminergic medication and 17% of patients receiving dopamine agonists. Behaviors included compulsive gambling (5%), compulsive sexual behavior (3.5%), compulsive shopping (6%), and binge-eating disorder (4%). Compulsive behaviors were more common with dopamine agonists than levodopa and other medications (17.1% vs. 6.9%). The prevalence was similar with the two most commonly used dopamine agonists, pramipexole (17.7%) and ropinirole (15.5%) [337].

Underlying susceptibility factors are suggested by the relatively small proportion of patients with Parkinson disease exposed to dopamine agonists who develop impulse control disorders. In these patients, risk factors for impulse control disorder during dopamine agonist therapy include levodopa treatment, age younger than 65 years, being unmarried, high caffeine use, family history of gambling problems, and current cigarette smoking. Other associated factors were functional impairment, depression, anxiety, obsessive-compulsive symptoms, impulsivity, and novelty-seeking. These risk factors show similarity to those reported in substance use disorders and gambling disorder and suggest common neurobiologic substrates [337].

OTHER DISORDERS

Restless legs syndrome is a common sensorimotor disorder treated with levodopa or a dopamine agonist. A case study of patients with restless legs syndrome and new-onset addictive behaviors linked to dopamine agonist therapy found that patients developed pathologic gambling, kleptomania, compulsive shopping, and hypersexuality; other adverse behavioral effects included criminality, suicidality, and marital discord. The behaviors developed over a wide range of levodopa/dopamine agonist exposures and latencies and, in some patients, persisted despite discontinuation. Some of these patients suffered devastating financial, social, and marital consequences, and the authors concluded dopamine agonist use in restless legs syndrome requires careful consideration [338].

OTHER MEDICATIONS

Aripiprazole, an atypical antipsychotic drug, has been linked to treatment-emergent pathologic gambling in eight adult male patients with schizophrenia or bipolar disorder [339]. All had histories of substance use disorders and non-pathologic gambling before taking aripiprazole. Patient histories showed aripiprazole initiation coincided with intensified urges to gamble or loss of control over gambling; discontinuation of aripiprazole coincided with cessation of severe gambling urges or loss of control [339].

PATHOPHYSIOLOGY

When titrated to alleviate dorsal striatal motor neuron loss, dopaminergic agonist therapy may overload intact dopamine circuits in ventral cortico-striatal cognitive and limbic pathways, explaining the development of treatment-emergent addictive behaviors with these medications [340,341].

Patients with Parkinson disease who develop impulse control disorders show impairments in decisional but not motor impulsivity. Dopaminergic medications are thought to enhance learning from reward (positive feedback) and impair learning from consequences (negative feedback); this relative imbalance presents as impulsivity [337].

A 2014 report addressed the role of dopamine-3 receptor (D3R) agonist medications in impulse control disorders. This report emphasized the significantly greater link between addictive behaviors and dopamine agonists with higher D3R selectivity (pramipexole, ropinirole) compared with dopamine agonists with lower D3R selectivity (aripiprazole) [342]. D3R is implicated in motivation, physiologic and behavioral responses to drug cues, and novelty-seeking behaviors [337].

TREATMENT

In patients with Parkinson disease, behavioral addiction symptoms improve after decreasing or discontinuing dopamine agonists; however, many patients do not tolerate replacement with levodopa for treatment of motor symptoms. Compared with patients without impulse control disorders, patients with Parkinson disease and impulse control disorders are at increased risk for dopamine agonist withdrawal syndrome, characterized by craving, autonomic, and psychiatric symptoms. Efforts to manage behavioral addiction symptoms while maintaining dopamine agonist therapy have been evaluated with amantadine and naltrexone. Research shows mixed or incomplete response. Preclinical studies identified possible efficacy with the atypical antidepressant mirtazapine [337].

Continuous levodopa delivery has improved impulse control disorder symptoms and compulsive medication use. Continuous delivery of apomorphine improved pre-existing impulse control disorders, but novel or additional addictive behaviors may develop. Case reports indicate the antipsychotic agent clozapine is potentially useful [337].

14. CONCLUSION

The concept of non-substance behavioral addiction has grown in public awareness and clinical acceptance. While published research over the past decade has dramatically increased, confusion surrounds many aspects of this emerging field in behavioral health. The best available evidence has clarified several characteristics of behavioral addictions, including clinical management and how behavioral addictions resemble and differ from impulsivity, compulsivity, and substance use disorders in phenomenology and neural and cognitive features. Neuroimaging and neuropsychologic research have shown changes in brain structure and function associated with dysfunctional cognitive, affective, and behavioral processes in behavioral addictions. These findings are now forming the basis of targeted psychologic and pharmacologic therapies in these patients.

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