NICOTINE AND ALCOHOL DEPENDENCE
From the 13th Annual Psychopharmacology Update, presented by the University of Nevada School of Medicine and
the Nevada Psychiatric Association
Stuart Gitlow, MD, MPH, MBA, Assistant Clinical Professor of Psychiatry, Mount Sinai School of Medicine, and
Executive Director, Annenberg Physician Training Program in Addictive Disease, New York, NY; Faculty Member,
Dartmouth Medical School, Hanover, NH
Educational Objectives
| The goal of this program is to improve the management of nicotine dependence and alcoholism. After hearing and assimilating
this program, the clinician will be better able to:
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 | 1. Explain the dopamine hypothesis of nicotine dependence.
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| 2. Use the “5 As” (ask, advise, assess, assist, and arrange) to help people stop smoking.
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| 3. Assess the use of pharmacotherapy as an adjunct to behavioral therapy for smoking cessation.
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| 4. Describe how conflicting definitions affect the research on treating alcoholism and alcohol dependence.
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| 5. Discuss the uncertain efficacy of pharmacotherapy for treating alcoholism and alcohol dependence.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the
planning committee to disclose relevant financial relationships within the past 12 months that might create any personal
conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes
quality in health care and not a proprietary business or commercial interest. For this program, Dr. Gitlow and the
planning committee reported nothing to disclose.
Acknowledgements
Dr. Gitlow was recorded at the 13th Annual Psychopharmacology Update, held February 21-23, 2008, in Las Vegas,
NV, and sponsored by the University of Nevada School of Medicine and the Nevada Psychiatric Association. The
Audio-Digest Foundation thanks Dr. Gitlow and the sponsors for their cooperation in the production of this program.
| Introduction: not all people with nicotine dependence smoke, and not all smokers have nicotine dependence; “dependence,
which is the name of the disease as defined by DSM-IV (Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition), comes first; the smoking comes second”; dependence is lifelong disease, regardless of smoking
status; smoking prevalence 2 to 3 times higher among psychiatric patients than among general population
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| Dopamine hypothesis: nicotine activates dopamine neurons; increasing dopamine level in nucleus accumbens induces
motivational and reinforcing properties; drive to take drugs further mediated by glutamate and γ-aminobutyric acid
(GABA) neurons in prefrontal cortex, amygdala, and hippocampus; pharmacologic treatment could target these areas
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| Monoamine oxidase inhibitors (MAOIs): tobacco smoke has MAOI qualities, which may explain increased risk
for depression in those who quit smoking; MAOI activity may also help explain increased rates of smoking (70% to 90%)
in psychiatric population
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| Nicotine withdrawal: symptoms include headache, nausea, gastrointestinal symptoms, fatigue, change in sleep, irritability,
anxiety, depression, change in appetite, and difficulty with concentration; quitting “cold turkey” produces greater
severity of symptoms; with treatment, 40% of smokers quit in 1 yr, but since nicotine dependence is chronic illness, ongoing
support must be available
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| Helping smoker to quit: not adequate simply to advise patient to quit or to inform him or her that smoking is bad for
health; however, studies show that most clinicians never do even that much; utilize “5 As”: 1) ask —do you smoke? 2)
advise —you should stop smoking; 3) assess—are you interested in quitting? do you want help in quitting? many smokers
do not want to quit, so probe further; do you enjoy smoking? what is it that you enjoy about smoking? what does
smoking do for you? does it make you feel better? in what way? how does it make you feel comfortable? how does it
make your day more enjoyable? does it make you feel better after sex? in what way? smoker develops relationship with
smoking, “something about the drug that makes it important to them”; smokers associate smoking with certain activities,
such as first cigarette in morning, smoking while driving or while talking on telephone, cigarettes after meals and before
going to bed; usually easy to get smoker down to 6 cigarettes/day, but last 6 cigarettes difficult to eliminate because of
their association with daily rituals; 4) assist—advise patient to change environment in way that will not remind him or
her of smoking; paint inside walls of home; take ashtray and cigarette lighter out of car; discard ashtrays in house; clean
or replace carpeting, draperies, and upholstery; help patient rethink rituals (eg, if patient smokes after breakfast, change
location of breakfast; instead of eating at table, eat in car or at work or in some other environment not linked to previous
smoking-after-breakfast experiences); have patient set quit date; enlist support from family and friends (if family member
smokes, ask him or her not to smoke around patient); 5) arrange—frequent follow-up
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| Substance use disorder: how is nicotine dependence similar to other substance dependence?—perhaps most important
difference is smoking often allowed in situations where other substance use unacceptable; moreover, treatment
programs for alcohol or drug dependence often allow patients to continue smoking, even when they no longer use alcohol
or drugs; how does it differ?—are similarities and differences result of science or of stigma?
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| Pharmacotherapy: not first-line treatment for nicotine dependence, but adjunct to behavioral therapy; all pharmacotherapy
studies presume that behavioral support provided simultaneously with medications
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| Nicotine replacement: treat for 8 to 12 wk; monitor for insomnia, nausea, and palpitations, all of which are signs of overdose;
change modalities or brand of transdermal system (ie, patch) if first version intolerable or ineffective; very heavy
smokers may apply 2 patches simultaneously; avoid acidic products (eg, coffee, juice) for ≥15 minutes before oral nicotine
replacement, as they reduce nicotine absorption; allow no smoking simultaneously with use of nicotine replacement
product; transdermal system (patch)—only method that provides continuous source of nicotine for 16 to 24 hr;
start with 21 to 42 mg once daily; patients often worry that patch is dangerous; advise them that patch is never as dangerous
as cigarettes; gum—nicotine level peaks in 20 minutes; 8 to 10 pieces per day, 2 to 4 mg each; inhaler—same
peak as gum; 4 to 6 puffs per day; nasal spray—nicotine level peaks in 5 to 10 min; other—lozenge (9 to 20 per
day); tablet; pregnancy—nicotine replacement likely to be harmful, but less so than smoking; adolescents—use off-
label; patch probably most acceptable approach for adolescents
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| Bupropion (eg, Wellbutrin SR, Zyban): blocks nicotine receptor function, so if patient smokes in addition to taking bupropion,
“they won’t feel as much”; use doubles chances of smoking cessation (about equal to efficacy of nicotine replacement);
give 150 mg/day for 3 days, then 150 mg bid; reverse this titration for 1 wk before quit date; may be used
in concert with nicotine replacement; may be used to prevent relapse; likelihood of seizure 0.1%; use cautiously in patients
with cardiovascular disease; warn all patients against alcohol intake and ensure that patient is not heavy and/or
binge drinker; not necessary to taper sedative drugs during use; treat for 8 wk for initial attempt to quit, and for up to 1
yr to prevent relapse
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| Varenicline (Chantix): nicotine receptor partial agonist that elicits moderate increase in mesolimbic dopamine levels; by
competitively binding to nicotine receptors, drug protects against further activation if patient smokes, thus disrupting
reinforcing effects; higher efficacy than bupropion for continued abstinence (44% for varenicline, 29% for bupropion,
17% for placebo); has not been compared with nicotine replacement; dosage 0.5 mg/day for 3 days, then bid for 4 days,
then 1 mg bid thereafter; treat for 12 to 24 wk; possible side effects include sleep disturbance, bad taste in mouth, and
gastrointestinal symptoms; use lower dosage in patients with kidney disease
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| Conclusions: studies indicate that majority of successful efforts to stop smoking take place without pharmacotherapy;
weight gain usually 5 to 7 lb (appetite increases due to absence of activation in some dopamine areas of brain); patients
must increase activity level to prevent weight gain; start exercise program concurrently with smoking cessation program
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| PHARMACOLOGIC TREATMENT OF ALCOHOLISM
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| Introduction: first thing noticed about many diseases is behavior, but disease begins much earlier, perhaps at birth, perhaps
when environmental component combines with genetic component, or perhaps some other time altogether; addictive
disease does not equal substance use; patient can have alcoholism but not drink, while not all drinkers have
alcoholism
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| Terminology: presents problems; DSM-IV and literature seem to indicate that alcoholism and alcohol dependence not
same disease, but studies often use terms interchangeably; although no definitions include criteria for quantity and frequency
of drinking, these are what studies often use as exclusion or inclusion criteria or as outcome measures
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| Definition of alcoholism formulated by Joint Committee of the National Council on Alcoholism and Drug Dependence
and American Society of Addiction Medicine to Study the Definition and Criteria for the Diagnosis of Alcoholism:
“alcoholism is a primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development
and manifestations. The disease is often progressive and fatal. It is characterized by impaired control over
drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking,
most notably denial. Each of these symptoms may be continuous or periodic”
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| Definition of alcohol dependence formulated by DSM-IV: requires ≥3 of following criteria to be met; tolerance; withdrawal;
use of more alcohol or use over longer duration than intended (speaker questions validity of this criterion; how
much does alcohol-dependent person “intend” to drink?); desire or unsuccessful effort to cut down or to control alcohol
use; spending much time obtaining, using, or recovering from effects of alcohol; reduction in social, occupational,
or recreational activities; continued use despite presence of persistent physical or psychologic problems
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| Alcoholism not synonymous with alcohol dependence: speaker suggests “alcoholism” applies to any sedative drug, of
which alcohol is but one, while “alcohol dependence” applies only to alcohol; alcoholic not in recovery unless abstinent;
person dependent on alcohol can continue to drink while being in “full sustained remission”
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| Sedatives: all sedatives, including alcohol, produce period of sedation followed by period of low agitation; initial sedation
and amplitude of agitation depend on quantity of intake, but sedation “is the part people drink for”; part they do not
drink for is being wide awake next morning with headache and general discomfort; with alcohol, period of agitation lasts
longer than period of sedation
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| Stimulus: some people are stimulus augmenters, others are stimulus reducers; stimulus augmentation may be physiologic
basis of sedative dependence, and represents phenotypic expression of genetic and neurologic underpinnings of disease
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| 13-yr study of children followed from 5 to 18 yr of age: discovered that “psychological differences between frequent
drug users, experimenters, and abstainers could be traced to the earliest years of childhood and related to the quality of
parenting received,” suggesting strong behavioral component to alcoholism; children who got along with parents and
others drank “normally” later on; those who got along with family but did not have many close interpersonal relationships
(“loners”) were teetotalers; and those who were bullies and had poor parenting became heavy drinkers later on;
author of study noted that predictors of substance dependence are present as early as 3 or 4 yr of age
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| Understanding literature: necessary to read studies carefully to see what disease being studied (ie, alcoholism or alcohol
dependence?); outcome measures must measure symptoms of illness; control and comparison groups must be selected
carefully; “the disease does not equal substance use”; increased quantity and frequency are not symptoms of either
disease; study duration must take into account that both diseases lifelong; closely monitor—inclusion criteria (which
must address disease in question); outcome measures (which must measure symptoms of illness); control and comparison
groups; duration of study (5 yr standard for morbidity and mortality of lifelong disease)
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| Combined Pharmacotherapies and Behavioral Intervention for Alcohol Dependence (COMBINE)
study: speaker concludes that study used wrong inclusion criteria, wrong outcome measures, and wrong control and
comparison groups; speaker also believes duration of treatment and follow-up insufficient, and published conclusions not
applicable to alcoholism or to alcohol dependence
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| Injectable naltrexone (study): naltrexone compared to placebo, but not to gold standard treatment; outcome not applicable
to broad scope of patients with alcoholism or alcohol dependence, and not necessarily beneficial to patients with
illness under study
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| Acamprosate study: abstinence rate, as defined by study, was not percentage of participants achieving abstinence;
rather, abstinence defined as cumulative percentage of days on which participant did not drink; principal outcome measure
(percentage of alcohol-free days) did not differ significantly across groups in study population, although trends in
hypothesized direction were noted
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| Topiramate study: inclusion group not characterized with respect to study; outcome criteria irrelevant to disease state;
conclusion did not follow logically from premises
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| Why is research going astray? definition failure (conflicting definitions used by practitioners, researchers, and DSM-
IV); researchers’ lack of clinical expertise (cessation of sedative use is only first step toward recovery from alcoholism;
treatment begins after patient has stopped using substance); public health and political drivers (important public health
goal is to reduce use of illicit substances and of licit substance in quantities that cause morbidity; this goal has been confused
with desire to reduce impact of addictive disease); bias (many studies funded by pharmaceutical companies that
produce drugs used to treat substance abuse, or include authors paid by pharmaceutical companies; read disclosures carefully,
and note that all disclosures may not appear in original publication); scope of practice (physicians growing increasingly
distressed at their “turf” being taken over by nonphysician clinicians; in addictive disease, many states certify
clinicians with bachelor-level degrees; availability of pharmacotherapy for addictive disease seen by some physicians as
opportunity to bring treatment back to physicians
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| Conclusions: pharmacotherapy for sedative dependence may work, but has not been demonstrated as effective in any
area of clinical importance; sedative dependence 30 times more prevalent than opioid dependence; every published study
of alcoholism treatment that involves long-term treatment provided primarily by physicians shows long-term recovery
rate ≥70%, so be skeptical of drug shown to have only 40% success rate in reducing alcohol intake
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Suggested Reading
Anton RF et al: COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for
alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA 295:2003, 2006; Benowitz NL:
Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clin
Pharmacol Ther 83:531, 2008; Benowitz NL: Neurobiology of nicotine addiction: implications for smoking cessation
treatment. Am J Med 121(4 Suppl 1):S3, 2008; Bouza C et al: Efficacy and safety of naltrexone and acamprosate
in the treatment of alcohol dependence: a systematic review. Addiction 99:811, 2004; David SP et al:
Bupropion efficacy for smoking cessation is influenced by the DRD2 Taq1A polymorphism: analysis of pooled data
from two clinical trials. Nicotine Tob Res 9:1251, 2007; Doggrell SA: Which treatment for alcohol dependence:
naltrexone, acamprosate and/or behavioural intervention? Expert Opin Pharmacother 7:2169, 2006; Donovan DM
et al: COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence
(The COMBINE Study): examination of posttreatment drinking outcomes. J Stud Alcohol Drugs 69:5,
2008; Garbutt JC et al: Vivitrex Study Group. Efficacy and tolerability of long-acting injectable naltrexone for alcohol
dependence: a randomized controlled trial. JAMA 293:1617, 2005; Gitlow S, Willenbring ML: Are medications
that reduce risk of drinking or heavy drinking, or that promote abstinence, of value in the treatment of alcohol
dependence? Am J Addict 17:1, 2008; Gitlow S: Recovery and research: a better paradigm. J Subst Abuse Treat
33:277, 2007; Grant KM et al: Bupropion and nicotine patch as smoking cessation aids in alcoholics. Alcohol
41:381, 2007; Hays JT et al: Efficacy and safety of varenicline for smoking cessation. Am J Med 121(4 Suppl
1):S32, 2008; Heilig M, Egli M: Pharmacological treatment of alcohol dependence: target symptoms and target
mechanisms. Pharmacol Ther 111:855, 2006; Johnson BA et al: Topiramate for Alcoholism Advisory Board;
Topiramate for Alcoholism Study Group. Topiramate for treating alcohol dependence: a randomized controlled trial.
JAMA 298:1641, 2007; Mason BJ et al: Effect of oral acamprosate on abstinence in patients with alcohol dependence
in a double-blind, placebo-controlled trial: the role of patient motivation. J Psychiatr Res 40:383, 2006;
Morse RM, Flavin DK: The definition of alcoholism. The Joint Committee of the National Council on Alcoholism
and Drug Dependence and the American Society of Addiction Medicine to Study the Definition and Criteria for
the Diagnosis of Alcoholism. JAMA 268:1012, 1992; Nides M: Update on pharmacologic options for smoking cessation
treatment. Am J Med 121(4 Suppl 1):S20, 2008; Piper ME et al: Efficacy of bupropion alone and in combination
with nicotine gum. Nicotine Tob Res 9:947, 2007; Steinberg MB et al: The case for treating tobacco
dependence as a chronic disease. Ann Intern Med 148:554, 2008.
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