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Cigarette Smoking, Nicotine Dependence, and Treatment KAREN LEA SEES, DO, San Francisco

Since the 1988 Surgeon General's report on nicotine addiction, more attention is being given to nicotine dependence as a substantial contributing factor in cigarette smokers' inability to quit. Many new medications are being investigated for treating nicotine withdrawal and for assisting in long-term smoking abstinence. Medications alone probably will not be helpful; they should be used as adjuncts in comprehensive smoking abstinence programs that address not only the physical dependence on nicotine but also the psychological dependence on cigarette smoking. (Sees KL: Cigarette smoking, nicotine dependence, and treatment, In Addiction Medicine [Special Issue]. West J Med 1990 May; 152:578-584)

Physicians have long been frustrated in attempts to help patients stop smoking, and, until recently, they have had few tools other than advice. Cigarette smoking and other forms of tobacco consumption, however, are now acknowledged as causing nicotine dependence, and with that recognition comes the acceptance of treating tobacco use not merely as a bad habit, or nasty vice, but as the disease of nicotine addiction. The recognition that using tobacco products causes nicotine addiction helps remove the longaccepted idea that it takes only will power to stop smoking and thereby brings all treatment modalities normally used in treating other chemical dependencies into the treatment arena for nicotine addiction. In 1990 physicians have many more treatment options to offer patients who continue to smoke.

Nicotine Addiction The diagnosis of tobacco dependence was first added to the Diagnostic and Statistical Manual of Mental Disorders by the American Psychiatric Association in the 1980 third edition (DSM-III)1; the diagnosis was changed to nicotine dependence in the revised third edition (DSM-III-R) published in 1987.2 In the years since this diagnosis was first introduced as a chemical dependence, not much had happened until recently to emphasize the need for treatment. This is finally starting to change.3 Since former Surgeon General C. Everett Koop's 1988 report, "The Health Consequences of Smoking-Nicotine Addiction,"'4 more attention is being focused on the addictive aspects of cigarette smoking and the use of other tobacco products. If the DSM-III-R criteria for psychoactive substance use disorders are considered, it is difficult to argue that cigarette smoking does not cause addiction. All nine of these diagnostic criteria apply almost universally to cigarette smokers. In addition, according to the DSM-III-R, only three of the nine criteria need be met to make the diagnosis of psychoactive substance dependence.

DSM-III-R Diagnostic Criteria for Psychoactive Substance Dependence * Substance often taken in larger amounts or over a longer period than the person intended. * Persistent desire or one or more unsuccessful efforts to cut down or control substance use. Most cigarette smokers have tried unsuccessfully to quit in the past, and it is estimated that more than 90% of current smokers would like to

quit smoking.5 * A great deal of time spent in activities necessary to get the substance, taking the substance, or recovering from its effects. Smokers spend considerable amounts of time and effort each day involved with cigarettes: making sure cigarettes are available, making sure they never run out, going out of the way to buy them, cleaning up after smoking, and actual time spent smoking, especially with chain smoking. In addition, each year cigarette smokers spend a substantial amount of time recovering from smoking-related or smoking-exacerbated illnesses. * Frequent intoxication or withdrawal symptoms when expected to fulfill major role obligations at work, school, or home or when substance use is physically hazardous. Smoking is the leading cause of fire deaths in the United States,6 and smoking in bed is one of the leading causes of domestic fires. Certainly this constitutes "when substance use is physically hazardous." * Important social, occupational, or recreational activities given up or reduced because ofsubstance use. Fewer and fewer persons, social gathering places, workplaces, and medical care facilities tolerate smoking. Smokers, therefore, frequently limit their social activities because of where they can and cannot smoke and may choose to not work in smokefree workplaces. * Continued substance use despite knowledge of having a persistent or recurrent social, psychological, or physical problem that is caused or exacerbated by the use of the substance. All of the US Surgeon General's reports since 1964

From the Department of Psychiatry, University of Califomia, San Francisco, School of Medicine, and the Substance Abuse Inpatient Unit, Veterans Administration Medical Center, San Francisco. Reprint requests to Karen Lea Sees, DO, Assistant Chief, Substance Abuse Inpatient Unit, 116-M, VA Medical Center, 4150 Clement St, San Francisco, CA 94121.

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have adjudged cigarette smoking the most important cause of preventable morbidity and premature mortality. Most cigarette smokers have experienced some smoking-related health problem, be it as simple as a prolongation of a viral syndrome or as critical as a life-threatening illness. * Marked tolerance: need for markedly increased amounts ofthe substance in order to achieve intoxication or desired effect, or markedly diminished effect with continued use of the same amount. Many smokers, when they first smoked, became sick and intoxicated after the first few puffs from the cigarette-with exposure to small amounts of nicotine. After only a few weeks of smoking, smokers can tolerate large doses of nicotine that would have been profoundly toxic on first exposure.7 Changes in behavior, heart rate, electroencephalograms, and psychoactive tolerance develop quickly.4 * Characteristic withdrawal symptoms. Some or all of the following symptoms are frequently encountered during nicotine withdrawal: difficulty concentrating, increased appetite or hunger, tobacco craving, gastrointestinal disturbances, sleep disturbances, stress intolerance, restlessness, nervousness, drowsiness, fatigue, depression, irritability, impatience, anxiety, headache, and tension.4 Many of the symptoms of cognitive impairment during nicotine withdrawal peak at 24 to 48 hours of abstinence. Some aspects of cognitive functioning remain substantially altered even after ten days, however, and it is unclear how long it takes for these to return to normal readings.8 The time course for many nicotine withdrawal symptoms has not been studied. * Substance often taken to relieve or avoid withdrawal symptoms. Many smokers who return to smoking after a cessation attempt attribute their relapse to some or several withdrawal symptoms. Former Surgeon General Koop's 1988 report summarized criteria for drug addiction.4 Addiction involves drug-reinforced behavior with patterns of drug use that are stereotypic, highly controlled, or compulsive, and that continue despite harmful effects from the drug. Drugs that produce addiction frequently have psychoactive effects that are pleasant or euphoriant. Drug-seeking behavior is common. Th-e use of these drugs often leads to tolerance, and, therefore, an increasing amount is needed to produce the desired effect; the use of these drugs often leads to physical dependence that produces withdrawal symptoms when the drugs are discontinued. Relapse to the use of these drugs and recurrent craving for these drugs following abstinence attempts are frequent. All of these criteria apply for nicotine. Thus, if the DSM-III-R diagnostic criteria for psychoactive substance use disorders and former Surgeon General Koop's criteria for drug addiction are accepted, it is difficult to deny that cigarette smoking produces nicotine addiction.

Importance of Nicotine Addiction Although reports of the health consequences of cigarette smoking began appearing in the medical literature in the 1950s, the social climate in the United States was such that the medical community for many years did not stress the importance of these problems and did not strongly confront the need to stop smoking. The substance abuse treatment community until recently has tried even harder to ignore this problem. Cigarette smoking is recognized as the leading cause of

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preventable death in the United States,9 the death rate in smokers being 30% to 80% higher than that in nonsmokers. 0 More than 350,000 deaths occurring annually in the United States can be directly attributed to cigarette smoking4; in contrast, the annual deaths from other drugs of abuse are as follows: alcohol, 125,000; alcohol plus another drug, 4,000; heroin, 4,000; cocaine, 2,000; and marijuana, 75. Another way of looking at these statistics is on a relative mortality base to user base. With illicit drug use, approximately 7,000 die from a user base of 5 million; with alcohol there are approximately 150,000 deaths from a user base of 100 million; cigarette smoking accounts for approximately 350,000 to 390,000 deaths from a user base of 50 million.'1 Cigarette smoking kills more than 1,000 people in the United States each day. In the United States, estimates are that 25% of deaths from fire, 30% to 40% of deaths from coronary heart disease, 80% to 85% of deaths from lung cancer, and 80% to 90% of deaths from chronic obstructive lung disease are directly related to cigarette smoking.6 In addition to lung cancer, the relationship between cigarette smoking and other forms of cancer is clearly established, including cancer ofthe mouth, larynx, pharynx, esophagus, urinary bladder, pancreas, kidney, and possibly stomach and cervix. Cigarette smoking also increases the risk of peripheral vascular disease, spontaneous pneumothorax, peptic ulcers, periodontal disease, chronic stomatitis, and chronic laryngitis. An increased incidence of respiratory tract and ear infections, especially in children of parents who smoke, and an exacerbation of symptoms of asthma and hypertension are also well

documented.6"l0'12 Studies linking medical-complications to cigarette smoke are impressive not only for the active smoker but also for the passive smoker.'3 Several additional alarming consequences exist for women smokers. Women who smoke and use oral contraceptives are at dramatically increased risk for heart attacks, strokes, and thromboembolic events. This is particularly important because oral contraception continues to be supported as a rational means of birth control. Women who smoke during pregnancy not only increase their own risk, with a higher incidence of placenta previa, abruptio placentae, and premature birth, but they also place their unborn child at risk with these complications. Cigarette smoking during pregnancy is directly related to a higher rate of spontaneous abortions, fetal death, and neonatal death. Furthermore, babies born to smoking mothers may have impaired intellectual development and tend to be small for gestational age.6"10"12 Unfortunately, all the implications of a woman smoking during pregnancy are not known. In 1985 the direct health care costs of smoking-related illnesses exceeded $16 billion annually; the indirect smoking-related cost, iflost productivity and earnings from excess morbidity, disability, and premature death are considered, totaled more than $37 billion.6 In 1988 it was estimated that a typical employer incurred at least $1,000 in excess expense per smoking employee per year compared with that for an otherwise similar nonsmoking employee. 14 Because of inflation, these costs continue to rise. These statistics should be even more alarming for the substance abuse treatment community. Approximately a third of the adult population in the United States smokes 15; the smoking rate in alcoholics is 90% or greater,'6"7 placing this population at a far higher risk of encountering one or

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more of these unfortunate consequences. Furthermore, concomitant alcohol consumption and cigarette smoking greatly increase the risk of oral, pharyngeal, laryngeal, and esophageal cancer. `8 19 Blot and colleagues have reported a 35-fold increase in the rate of oropharyngeal cancer in men who were both heavy cigarette smokers and heavy alcohol drinkers compared with nonsmoking men who rarely drank. I8 They estimate approximately 75% of all cases of oropharyngeal cancer in the United States can be attributed directly to the simultaneous use of cigarettes and alcohol.

Nicotine Addiction and the Substance Abuse Treatment Community Although many of the detrimental health consequences of cigarette smoking are clearly established, and cigarette smoking is now recognized as causing nicotine dependence, the substance abuse treatment community, to a large degree, continues to minimize the importance of cigarette smoking. Treatment specialists resist the need to treat cigarette smoking as an addiction, and smoking is frequently condoned. In the past, if smoking cessation was mentioned at all during drug abuse treatment, it was simply as a passing comment that no patient should attempt to quit smoking until sometime in the future, after the primary addiction had stabilized. Many treatment specialists even put a time line on this, telling patients to wait until they have been sober at least a year before thinking about stopping smoking. If patients expressed a specific interest in smoking cessation during drug treatment, they were usually overtly discouraged. The dogma in the substance abuse treatment community was and to a large extent continues to be that it is too difficult to give up all addictions at the same time. The contention was that an alcoholic or cocaine addict who had attempted and failed to quit smoking was subsequently at a higher risk to relapse to the primary addiction and that even after years of sobriety from the drug of choice, attempting smoking cessation might put the recovering addict or alcoholic at an increased risk of relapse. Bobo and Gilchrist reported the results of a survey of 311 alcoholism treatment professionals and found that 23 % would never encourage an alcoholic client to quit smoking, even after five years of abstaining from alcohol.20 In this study, alcoholism treatment professionals who thus responded were most likely to be recovering alcoholics who continued to smoke. Although this survey was done several years ago, to a large extent these notions continue to the present day, but treatment specialists are beginning to question this conventional wisdom. The limited research available suggests that abstinent alcoholics, even those with extensive substance abuse histories, can successfully stop smoking without relapsing to alcohol or jeopardizing their sobriety.2' In addition, alcoholics who successfully stop smoking are more likely to maintain long-term abstinence from alcohol. I7 To date no research has been reported on the relationship between abstaining from other psychoactive drugs of abuse and abstaining from smoking. Data indicate that when an alcoholic has stopped smoking and drinking and subsequently returns to drinking, he or she almost always also returns to smoking; the relapse rate to alcohol after first returning to smoking is essentially the same as the relapse rate for alcoholics in general.22 Although there is only a small amount of research done on this topic, it indicates that relapsing first to alcohol increases the relapse

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rate to cigarettes, but relapsing first to cigarettes does not increase the relapse rate to alcohol. A few chemical dependence treatment programs are pio-

neering addressing nicotine dependence concurrently with the treatment of the primary drug (M. Branch, J. Knapp, K. Berntson, "Minneapolis Veterans Hospital Goes SmokeFree," Countdown, 1988; 3:1-7).17,23,24 Just as they refuse to ignore social drinking of alcohol in cocaine users or occasional marijuana use in alcoholics, they are putting the emphasis on a psychoactive drug-free status-including nicotine. Anecdotal reports are encouraging, but rigorous outcome studies are needed. Survey results of smoking in Minnesota's substance abuse treatment units revealed that 72 % of the program directors thought nicotine dependence should be treated as an addiction; only 11 % had nicotine treatment as a part of their chemical dependence treatment program, however. Although 41 % thought tobacco treatment should be offered after the treatment of other drug abuse, 31 % thought it should be done concurrently with other drug abuse treatment, and 26% were not sure.25 Obstacles are frequently encountered in treating nicotine addiction simultaneously with other forms of chemical dependence or in making a chemical dependence treatment unit smoke-free, or both. Those most often noted include the following: * Fear of jeopardizing the progress of recovery from other forms of chemical dependence; * Financial concerns about losing patients to treatment programs that do not address nicotine dependence; * Concern about reimbursement from insurance companies or from patients; * Resistance to change because historically smoking cessation programs have developed outside of traditional medical settings; * Worry about being in competition with already established smoking cessation programs; * Speculation that it will be a problem for patients to abstain from nicotine during involvement in 12-step programs; * A lack of research regarding when to treat nicotine addiction; * A lack of research regarding how to treat nicotine dependence-Should it be voluntary or mandatory? Is there a need for pharmacologic detoxification? What medication should be used? Are special groups needed, or will generic substance abuse groups suffice? * Concerns about intruding on individual rights of the patients and staff; * Concerns about enforcing the smoking policy; and * Continued abuse of and dependence on nicotine by treatment staff. 7,24'26 All of these obstacles must be overcome. Although cigarette smoking is now readily accepted as causing nicotine dependence, the notion that nicotine addiction pales in comparison with other drug addictions like cocaine, heroin, and alcohol persists. Hand in hand with that notion is the belief that nicotine addiction should not be addressed concurrently with other addictions. The reluctance by the substance abuse treatment community to accept cigarette smoking as a serious life-threatening addiction and to aggressively treat nicotine addiction is appalling. The question should not be

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whether to treat nicotine addiction, but when and how to treat nicotine addiction.24'27 Research is needed to answer the many questions that arise.

Treating Nicotine Addiction A physician has to do more than offer patients the good advice to stop smoking, although mere advice from a physician to quit smoking does increase the number of patients who successfully stop smoking, with the one-year abstinence rate increasing from 0.3 % with no advice to 3.3 % to 5. 1 % when advice is given.28 These percentages are small, but this research is notable in that it reinforces the idea that even in a busy physician's office, a few minutes of advice can substantially affect a patient's motivation to quit smoking. When a physician can link this advice to a patient's health problem that is caused or exacerbated by smoking, the abstinence rate may increase to as high as 24% to 39 % one year later.28 There is a positive correlation between a patient's severity of illness and adherence to a physician's advice to stop smoking.29 Unfortunately, many smokers have never been advised by their physician to stop smoking,30 although an analysis of such physician's advice has shown that it is cost-effective even if it helps only 1 % of smokers to quit.31 Therefore, at a minimum, a physician should continue to advise all patients who are smokers to quit and make an attempt to link any health complaint to the cigarette smoking.

Pharmacologic Adjuncts for Nicotine Withdrawal It has been asserted that most smokers who are quitting are less dependent on nicotine.32 Consequently, those who remain smokers today and in the future increasingly will be those who are physiologically addicted to nicotine.33'34 As smokers recognize the importance of the psychoactive effects of nicotine in their continuing to smoke and the importance of the nicotine withdrawal symptoms in their relapse to smoking when attempting abstinence, their requests for medical adjuncts to assist in nicotine withdrawal will increase as they attempt once again to quit smoking. As a result, physiologic interventions should play a larger role in the effort to stop smoking. For greatest efficacy, these interventions need to be used in conjunction with a comprehensive treatment strategy. Pharmacologic adjuncts for nicotine withdrawal fall into four categories of medications: nicotine replacement therapy, which involves providing nicotine maintenance through a less hazardous means of nicotine delivery and a more manageable form of the drug; blockade therapy, which involves an antagonist medication that blocks the effects of nicotine; deterrent therapy, which produces aversive effects when triggered by cigarette smoke; and nonspecific supportive or symptomatic therapy, which attempts to alleviate the craving and symptoms of nicotine withdrawal.7 35 Nicotine replacement therapy. Nicotine replacement therapy was introduced in the United States in 1984. Its use is based on the idea that it is.too difficult to simultaneously give up both the psychological dependence on cigarette smoking and the physical dependence on nicotine. Consequently, with nicotine replacement, a patient initially concentrates on the psychological aspects of smoking cessation and at a later date addresses the physical dependence by weaning off the nicotine replacement. Nicotine gum, or nicotine polacrilex, was the first pharmacologic therapy proved to aid in smoking cessation.36

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Chewing nicotine gum attenuates or completely abolishes some nicotine withdrawal symptoms, most notably the persistent irritability, but also frequently reduces the hunger, anxiety, annoyance, hostility, restlessness, difficulty in concentrating, depression, and other somatic complaints.' Nicotine gum has been useful in smoking cessation programs, but several problems with its use exist. Chewing nicotine gum does not decrease the urge to smoke.4 The efficacy of nicotine gum diminishes considerably when simply dispensed by a physician with nothing or little else done to support smoking abstinence.4' 35'37 Nicotine gum is not well tolerated by some patients and is frequently misused, in large part because physicians do not properly instruct their patients. Patients should not be given a prescription for nicotine gum without also being given detailed instructions concerning its proper use. They should not simply be told to read the package insert on how to chew the gum. Most patients assume they know how to chew gum and do not read it. Instructions for using nicotine gum should include the

following: * It is not to be chewed like regular chewing gum; it should be chewed slowly and intermittently; * It takes approximately 15 chews to release the nicotine from the polacrilex; at that time a tingling sensation will be felt in the mouth; * When the tingling sensation starts, the gum should be parked between the cheek and teeth or gums; * When the tingling is almost gone, chewing should begin again; * One piece of nicotine gum should be chewed for no longer than 20 to 30 minutes, and after that time period it should be discarded for another piece; * Do not swallow immediately; 70% of the nicotine in swallowed saliva is inactivated by first-pass metabolism in the liver, and patients get minimal effect from the gum if most or all of the nicotine is swallowed; the nicotine must be absorbed in the mouth to be effective. Also, swallowing the nicotine increases the amount of nausea and potential vomiting; * Nicotine gum should be used in sufficient quantitiesusually 10 to 15 pieces per day for the average smoker, but as many as 30 may be used; * It should be used steadily day to day, not 2 pieces today, 20 tomorrow, and 7 the next day; * It should be used for the relief of discomfort as well as for urges to smoke; * Avoid drinking liquids when chewing or when about to chew the gum because most liquids change the pH in the mouth, which will decrease nicotine absorption; * Nicotine gum should be weaned gradually after a three- to six-month maintenance period. Table 1 lists brief instructions and several recommended exclusion criteria for the use of nicotine gum. Other nicotine replacement therapies presently under investigation include a nicotine transdermal patch,38 a nicotine vapor inhaler, a nicotine nasal spray,39 a roll-on tobacco extract applicator,40 some chewable food products, and a toothpaste-like formulation.4 At this time nicotine gum is the only nicotine replacement product with approval by the Food and Drug Administration for the treatment of nicotine withdrawal. A concern with nicotine replacement is that one form of

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TABLE 1-Nicotine Gum Proper Use

Exclusion Criteria

Chew slowly Chew intermittently About 15 chews to release Park the gum One piece lasts 20-30 minutes Do not swallow immediately Use enough Use steadily Use for relief of discomfort Use for urges to smoke Avoid drinking liquids Gradually wean

Active temporomandibular joint disease Postmyocardial infarction Serious cardiac dysrhythmias Systemic hypertension Vasospastic disease Active peptic ulcer disease Active esophagitis Oral or pharyngeal inflammation Pheochromocytoma Hyperthyroidism Pregnancy Lactation Insulin-dependent diabetes mellitus* Extensive dental work*

*Although not absolute exclusion criteria, exercise caution when prescrbing nicotine gum for these patients.

nicotine dependence is being substituted for another. Some patients have difficulty weaning off nicotine gum after the recommended period of use of three to six months. In addition, there is some evidence that the use of nicotine polacrilex is being abused by people other than those initially dependent on tobacco-delivered nicotine (H.W. Clark, MD, oral communication, 1989). More abuse of nicotine gum probably is not occurring in part owing to the amount of work, or chewing, it takes to extract the nicotine from the gum resin and the relatively unpleasant taste of the gum. As these inconveniences are eliminated, however, the potential for the abuse of nicotine delivery products increases. Alternatives to nicotine replacement. Several non-nicotine medications are presently being investigated as adjuncts in smoking cessation programs. The nicotine antagonist mecamylamine hydrochloride may prove helpful, in the same way naltrexone hydrochloride is for opioid addicts, by attenuating or completely blocking the subjective effects of nicotine.4' The major obstacle in its use for smoking cessation treatment is its anticholinergic and antihypertensive effects; it also does nothing for the conditioned and non-nicotinemediated reinforcers from cigarette smoking.7 A citric acid aerosol inhaler is being studied at the University of California, Los Angeles; when used it appears to satisfy the momentary urge to smoke (S. Blakeslee, "New Drug Therapies Are Being Tested to Help Smokers Quit." New York limes, June 9, 1988, p B6). Silver acetate has been formulated into several products as a smoking deterrent, including a chewing gum and lozenge; the exposure of silver acetate to cigarette smoke causes an unpleasant taste in the mouth. These products are complicated by the possible development of argyria, silver poisoning, with prolonged use.42 A small study has investigated the use of naloxone hydrochloride in smoking cessation. This opioid antagonist, which is sometimes used as an adjunct in maintaining opioid abstinence, reduced the desire to smoke and actual smoking.43 Naloxone's usefulness in smoking cessation will probably be limited by its numerous side effects, most notably lethargy, mild dysphoria, and gastrointestinal disturbances. Several over-the-counter smoking cessation preparations contain lobeline, a partial nicotinic receptor agonist, which has been found to be no more effective than placebo.35'44

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Glassman and co-workers found that a history of depression was unexpectedly common in cigarette smokers."4 Since their findings were reported, several investigators have looked at antidepressant and antianxiety medications as adjuncts to smoking cessation. A relatively new antidepressant, fluoxetine hydrochloride, which is a serotonin reuptake blocker, reportedly decreases the desire to smoke.33 Although not yet reported in the medical literature, some clinical trials that have been completed have studied the efficacy of fluoxetine in promoting nicotine abstinence. Doxepin hydrochloride is under investigation at the University of Tennessee, and although the initial results are promising, a side effect of weight gain may limit this product's usefulness because many patients are already concerned about the normal weight gain associated with stopping smoking.46 A small, open, uncontrolled clinical trial has looked at buspirone hydrochloride, an antianxiety agent that appears to decrease craving, anxiety, fatigue, and the weight gain that frequently accompany smoking cessation.47 Buspirone is now being investigated alone and in combination with clonidine hydrochloride for treating nicotine withdrawal. Recently clonidine has been given a great deal of attention. It is an a2-noradrenergic agonist that was first used as a medication to treat hypertension and has gained widespread recognition for its usefulness in treating many of the signs and symptoms of both opioid and alcohol withdrawal.4853 In the past five years, several studies have supported clonidine's usefulness in diminishing cigarette craving and the nicotine withdrawal symptoms of anxiety, tension, irritability, and restlessness.46,54-56

Clonidine has potentially serious side effects, and several exclusion criteria must be observed, including hypotension, hypersensitivity to tape (if the transdermal patch is used), hypersensitivity to clonidine, the concurrent use of amitriptyline medications, a history of auditory hallucinations or delirium, notable liver disease, pregnancy, lactation, current heavy alcohol consumption, Sj6gren's syndrome, cerebrovascular disease, severe coronary artery insufficiency, a recent myocardial infarction, chronic renal failure, a patient younger than 12 years, and surgical procedures planned during the period of clonidine treatment or within a week of stopping clonidine treatment.57 In addition to these exclusion criteria, there are side effects to the use of clonidine that may limit its usefulness. Those most frequently noted include postural hypotension causing lightheadedness and dizziness, dry mouth, tiredness, and lethargy. Rarely, sexual dysfunction occurs. These side effects decrease or may not occur when the transdermal patch form of the medication is used in place of oral medication. 58-61

The transdermal form of clonidine has several other advantages, including a therapeutic steady-state drug level,

with only once-a-week dosing. This improves patient compliance and is less disruptive to participation in a drug treatment program by decreasing drug-seeking behavior.49 Transdermal clonidine has a gradual onset of action that decreases the chance of precipitously lowering the blood pressure, and once removed it is an essentially self-tapering medication that may help prevent rebound hypertension.58 62 Many questions remain unanswered about the dose of clonidine needed, the length of time to continue the medication, the differences between men and women taking clonidine, and what effect depression has on treatment.

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Franks and colleagues recently reported the results of a study that disputes clonidine's effectiveness an an adjunct in stopping smoking.63 This clinical trial used clonidine in a primary care setting as essentially the sole therapy for quitting smoking. This setting consisted of dispensing the medication, giving the advice to stop smoking, encouraging patients to read a booklet on quitting smoking, briefly reviewing triggers to smoking and coping techniques, and evaluating weekly to ensure the patients continued to be medically stable. Just as nicotine gum has questionable effectiveness when used without being part of a comprehensive stop smoking program, so may clonidine. A unique physiologic intervention for nicotine dependence was developed at the Haight-Ashbury Free Medical Clinic's Drug Detoxification, Rehabilitation, and Aftercare Project in San Francisco." This approach combines both a rapidly decreasing dose of a nicotine replacement (nicotine gum) and a medication for the symptomatic treatment of nicotine withdrawal symptoms (transdermal clonidine). The

of nicotine withdrawal can be controlled by the amount of the nicotine polacrilex used in 24 hours, and the withdrawal symptoms can be controlled with the dose of the transdermal clonidine. The doses of both of these medications can be adjusted. Nicotine detoxification is thereby accomplished effectively and comfortably, not unlike using clonidine as an adjunct at the end of a methadone detoxification for opioid addiction. To be most effective, this technique for nicotine withdrawal should be used as an adjunct to a comprehensive smoking cessation program. Further research on all of these pharmaceutical adjuncts for nicotine withdrawal and abstinence is needed. Nonpharmacologic Therapy for Smoking Abstinence In the past six years much searching has been done for the "cure") or "quick fix" for smokers who want to quit. The correlation between the success rate of simply assisting nicotine withdrawal and maintaining long-term cigarette abstinence is not known. Speculation based on other types of chemical dependence can be made, however. Detoxification from alcohol is easily and comfortably accomplished with the use of either benzodiazepines or barbiturates, but these medications for treating withdrawal symptoms do nothing to assist an alcoholic in maintaining long-term sobriety. Detoxification from opioids is easily and comfortably accomplished with either clonidine, methadone, or a combination of the two. Managing withdrawal symptoms has little to do with keeping the opioid addict from using again, however. Likewise, pharmaceutical adjuncts that may assist in nicotine withdrawal can be expected to do little for assisting an exsmoker from relapsing to cigarettes. Simple detoxification is the easy part; remaining abstinent is more difficult. Glassman and co-workers noted, Smokers may continue to smoke primarily because they derive positive effects from smoking and not because they experience withdrawal symptoms when they attempt to stop.45(P2863) Just as alcoholism and other forms of chemical dependence are relapsing diseases, so is nicotine dependence. Quitting smoking is rarely a one-time proposition. It is estimated that more than 80 % of smokers fail to quit on the first attempt, and even after seven attempts, more than half return to smoking.65 It is, therefore, ideal for physicians to have additional resources to support smoking abstinence or to know what community services and programs are available rate

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for patients who are interested in stopping smoking. Some communities have Smokers Anonymous meetings that are modeled on Alcoholics Anonymous. These meetings are free and open to anyone who is interested in stopping smoking. In many areas, the American Lung Association and the American Cancer Society sponsor stop-smoking programs. More information on the availability of these programs can be obtained from local offices of these organizations. Gritz has compiled an excellent list of resources available to physicians and other health professionals on smoking cessation.29 Stress management, coping skills, relaxation, relapse prevention training, weight management, leisure planning, contingency contracting, hypnosis, acupuncture, and social support groups are all helpful to some smokers who are trying to quit.4 Smoking cessation programs traditionally have dealt with the psychological and overlearned behavioral aspects of cigarette smoking. Behavioral, cognitive, psychodynamic, and peer support treatments of nicotine addiction will continue to play a primary role in smoking abstinence successes. There are now several treatment options available for patients who smoke. Physician advice that helps to motivate patients and medications that assist with nicotine withdrawal are usually not enough, however; they are only adjuncts in a comprehensive smoking abstinence program. REFERENCES 1. Diagnostic and Statistical Manual of Mental Disorders, 3rd Ed. Washington, DC, American Psychiatric Association, 1980 2. Diagnostic and Statistical Manual of Mental Disorders, 3rd Ed Revised. Washington, DC, American Psychiatric Association, 1987 3. Sees KL: Editor's introduction: Tobacco smoking-Clinical and social issues. J Psychoactive Drugs 1989; 21:277-279 4. The Health Consequences of Smoking-Nicotine Addiction: A Report of the Surgeon General. Washington, DC, US Dept of Health and Human Services, 1988 5. Fielding JE: Smoking: Health effects and control (Part 2). N Engl J Med 1985; 313:555-561 6. Fielding JE: Smoking: Health effects and control (Part 1). N Engl J Med 1985; 313:491-498 7. Jarvik ME, Henningfield JE: Pharmacological treatment of tobacco dependence. Pharmacol Biochem Behav 1988; 30:279-294 8. Snyder FR, Davis FC, Henningfield JE: The tobacco withdrawal syndrome: Performance decrements assessed on a computerized test battery. Drug Alcohol Depend 1989; 23:259-266 9. Slade J: Learning to fight Nicotiana tabacum. NJ Med 1988; 85:102-106 10. Holbrook JB: Tobacco smoking, In Petersdorf RG, Adams RD, Braunwald E, et al (Eds): Harrison's Principles of Intemal Medicine. New York, McGraw-Hill, 1983 11. Blum A: Tobacco promotion and sports. American Medical Society on Alcoholism and Other Drug Dependencies. Presented at the Second National Conference on Nicotine Dependence, Chicago, September 1989 12. Burns DM: Tobacco and health, chap 1 1, In Wyngaarden JB, Smith LH (Eds): Cecil Textbook of Medicine, 18th Ed Philadelphia, WB Saunders, 1988, pp 36-40 13. Meinert LA: Scientific basis for workplace clean air. NJ Med 1988; 85:141142 14. Kristein MM: Economic issues related to smoking in the workplace. NY State J Med 1989; 89:44-47 15. Fiore MC, Novotny TE, Pierce JP, et al: Trends in cigarette smoking in the United States-The changing influence of gender and race. JAMA 1989; 261:49-55 16. Wallace J: Smoke gets in our eyes: Professional denial of smoking. J Subst Abuse Treat 1986; 3:67-68 17. Bobo JK: Nicotine dependence and alcoholism epidemiology and treatment. J Psychoactive Drugs 1989; 21:323-329 18. Blot WJ, McLaughlin JK, Winn DM, et al: Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 1988; 48:3282-3287 19. Tuyns AJ, Esteve J, Raymond L, et al: Cancer of the larynx/hypopharynx, tobacco and alcohol: IARC international case-control study in Turin and Varese (Italy), Zaragoza and Navarra (Spain), Geneva (Switzerland) and Calvados (France). Int J Cancer 1988; 41:483-491 20. Bobo JK, Gilchrist LD: Urging the alcoholic client to quit smoking cigarettes. Addict Behav 1983; 8:297-305 21. Bobo JK, Schilling RF. Gilchrist LD, et al: The double triumph: Sustained sobriety and successful cigarette smoking cessation. J Subst Abuse Treat 1986; 3:21-25 22. Bobo JK: Treatment of nicotine dependence and alcoholism: Is smoking cessation a threat to sobriety? American Medical Society on Alcoholism and Other Drug Dependencies, Presented at the First National Conference on Nicotine Dependence, Minneapolis, September 1988 23. Delaney GO: Tobacco dependence in treating alcoholism. NJ Med 1988; 85:131-132

584 24. Goldsmith RJ: Development of smoke-free chemical dependency units. American Medical Society on Alcoholism and Other Drug Dependencies. Presented at the Second National Conference on Nicotine Dependence, Chicago, September 1989 25. Knapp JM: Smoking in Minnesota's chemical dependency facilities: Survey results. American Medical Society on Alcoholism and Other Drug Dependencies. Presented at the Second National Conference on Nicotine Dependence, Chicago, September 1989 26. Donnelly RJ: Obstacles to the provision of nicotine dependence counseling to chemically dependent patients. American Medical Society on Alcoholism and Other Drug Dependencies. Presented at the Second National Conference on Nicotine Dependence, Chicago, September 1989 27. Battjes RJ: Smoking as an issue in alcohol and drug abuse treatment. Addict Behav 1988; 13:225-230 28. Philips BU, Longoria JM, Calhoun KH, et al: Behavioral prescription writing in smoking cessation counseling: A new use for a familiar tool. South Med J 1989; 82:946-953 29. Gritz ER: Cigarette smoking: The need for action by health professionals. CA 1988; 38:194-212 30. Anda RF, Remington PL, Sienko DG, et al: Are physicians advising smokers to quit? The patient's perspective. JAMA 1987; 257:1916-1919 31. Cummings SR, Rubin SM, Oster G: The cost-effectiveness of counseling smokers to quit. JAMA 1989; 261:75-79 32. Modification of Smoking Behavior, In Smoking and Health-A Report of the Surgeon General. Washington DC, US Dept of Health, Education, and Welfare 1979 33. Hughes JR: Clonidine, depression, and smoking cessation. JAMA 1988; 259:2901-2902 34. Hughes JR, Gust SW, Pechacek TF: Prevalence of tobacco dependence and withdrawal. Am J Psychiatry 1987; 144:205-208 35. Prignot J: Pharmacologic approach t.o smoking cessation. Eur Respir J 1989; 2:550-560 36. Hughes JR, Miller S: Nicotine gum to help stop smoking. JAMA 1984; 252:2855-2858 37. Lam W, Sze PC, Sacks HS, et al: Meta-analysis of randomised controlled trials of nicotine chewing-gum. Lancet 1987; 2:27-30 38. Rose JE, Herskovic JE, Trilling Y, et al: Transdermal nicotine reduces cigarette craving and nicotine preference. Clin Pharmacol Ther 1985; 38:450-456 39. Jarvis MJ, Hajek P, Russell MAH, et al: Nasal nicotine solution as aid to cigarette withdrawal: A pilot clinical trial. Br J Addict 1987; 82:983-988 40. Allen DW: Transdermal tobacco extract reduces reported cigarette consumption. Med J Aust 1988; 149:342 41. Stolerman IP: Could nicotine antagonists be used in smoking cessation? Br J Addict 1986; 81:47-53 42. Jensen EJ, Rungby J, Hansen JC, et al: Serum concentrations and accumulation of silver in skin during three months' treatment with an anti-smoking chewing gum containing silver acetate. Hum Toxicol 1988; 7:535-540 43. Karras A, Kane JM: Naloxone reduces cigarette smoking. Life Sci 1980; 27:1541-1545 44. Henningfield J: Neuropharmacology of nicotine. American Medical Society

CIGARETTE SMOKING Alcoholism and Other Drug Dependencies. Presented at the Second National Conference on Nicotine Dependence, Chicago, September 1989 45. Glassman AH, Stetner F, Walsh T, et al: Heavy smokers, smoking cessation, and clonidine. JAMA 1988; 259:2863-2866 46. Edwards NB, Murphy JK, Downs AD, et al: Doxepin as an adjunct to smoking cessation: A double-blind pilot study. Am J Psychiatry 1989; 146:373-376 47. Gawin F, Compton M, Byck R: Buspirone reduces smoking. Arch Gen Psychiatry 1989; 46:288-289 48. Baumgartner GR, Rowen RC: Clonidine vs. chlordiazepoxide in the management of acute alcohol withdrawal syndrome. Arch Intern Med 1987; 147:1223-1226 49. Clark HW, Longmuir N: Clonidine transdermal patches: A recovery oriented treatment of opiate withdrawal. Calif Soc Treat Alcohol Other Drug Depend News 1986; 13:1-2 50. Mahern P, Nilsson LH, Moberg A, et al: Alcohol withdrawal: Effects of clonidine treatment on sympathetic activity, the rehin-aldosterone system, and clinical symptoms. Alcohol Clin Exp Res 1985; 9:238-243 51. Walinder J, Balldin J, Bokstrom K, et al: Clonidine suppression of the alcohol withdrawal syndrome. Drug Alcohol Depend 1981; 8:345-348 52. Gold MS, Pottash AC, Sweeney DR, et al: Opiate withdrawal using clonidine. JAMA 1980; 243:343-346 53. Gold MS, Redmond DE Jr, Kleber HD: Clonidine in opiate withdrawal (Letter). Lancet 1978; 1:929-930 54. Glassman AH, Jackson WK, Walsh BT, et al: Cigarette craving, smoking withdrawal, and clonidine. Science 1984; 226:864-866 55. Appel D: Clonidine helps smokers stop smoking. Am Rev Respir Dis Suppl 1987; 135:A354 56. OOmish SA, Zisook S, McAdams LA: Effects of transdermal clonidine treatment on withdrawal symptoms associated with smoking cessation. Arch Intern Med 1988; 148:2027-2031 57. Sees KL, Clark HW: Clonidine use in nicotine withdrawal. J Psychoactive Drugs 1988; 20:263-268 58. Josse S, Danays T, Lafferre M, et al: Substitution of oral clonidine with transdermal clonidine in hypertensive patients. Curr Ther Res 1987; 42:579-584 59. Burnis JF, Mroczek WJ: Transdermal administration of clonidine: A new approach to antihypertensive therapy. Pharmacotherapy 1986; 6:30-34 60. Hollifield J: Clinical acceptability of transdermal clonidine: A large-scale evaluation by practitioners. Am Heart J 1986; 112:900-906 61. Weber MA: Clinical experience with transdermal antihypertensive therapy. Pract Cardiol 1986; 12:104-120 62. Lowenthal DT, Saris S, Paran E, et al: Efficacy of clonidine as transdermal therapeutic system: The inteemational clinical trial experience. Am Heart J 1985; 112:893-900 63. Franks R, Harp J, Bell B: Randomized, controlled trial of clonidine for smoking cessation in a primary care setting. JAMA 1989; 262:3011-3013 64. Sees KL, Stalcup SA: Combining clonidine and Nicorette for treatment of nicotine withdrawal. J Psychoactive Drugs 1989; 21:355-359 65. The Health Consequences of Smoking-Chronic Obstructive Lung Disease: A Report of the Surgeon General. Washington DC, US Dept of Health and Human Services, 1984 on