Pharmacotherapy of Smoking Cessation

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University of Montana ScholarWorks at University of Montana

Public and Community Health Sciences Faculty Publications Public and Community Health Sciences

3-2000

Kolawole S. Okuyemi

Jasjit S. Ahluwalia

Kari J. Harris University of Montana - Missoula, [email protected]

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Recommended Citation Okuyemi, Kolawole S.; Ahluwalia, Jasjit S.; and Harris, Kari J., "Pharmacotherapy of Smoking Cessation" (2000). Public and Community Health Sciences Faculty Publications. 29. https://scholarworks.umt.edu/pchs_pubs/29

This Article is brought to you for free and open access by the Public and Community Health Sciences at ScholarWorks at University of Montana. It has been accepted for inclusion in Public and Community Health Sciences Faculty Publications by an authorized administrator of ScholarWorks at University of Montana. For more information, please contact [email protected]. CLINICAL REVIEW Pharmacotherapy of Smoking Cessation

Kolawole S. Okuyemi, MD, MPH; Jasjit S. Ahluwalia, MD, MPH, MS; Kari J. Harris, PhD, MPH

obacco use is the number one cause of preventable diseases in the United States. Smok- ing accounts for more than 400 000 deaths yearly and 30% of all cancer deaths. Pri- mary care physicians have access to 70% of smokers, approximately 60% of whom are perceived to be in excellent health. Recent advances in the pharmacotherapy of nico- tineT addiction, including nicotine nasal spray, nicotine inhaler, bupropion hydrochloride, and over- the-counter transdermal nicotine patches, have increased the treatment options physicians can offer to smokers. Physicians, especially those in primary care specialties, should familiarize themselves with these products to improve efforts to help their patients stop smoking. This article reviews scientific data on the efficacy of approved medications, benefits, adverse effects, and appropriate use of these products. We also discuss nicotine addiction and treatment for special populations, including women, ethnic minorities, light smokers, and patients with cardiovascular and pulmonary diseases. Arch Fam Med. 2000;9:270-281 Tobacco use is the number one cause of of smokers who considered themselves to preventable diseases in the United States. be in “excellent health.”6,7 Smoking accounts for about 435 000 deaths yearly and 30% of all cancer deaths.1 HEALTH CONSEQUENCES Cigarette smoking is responsible for $50 OF CIGARETTE SMOKING billion annually in direct medical costs, and $47 billion in indirect, nonmedical costs.2 Cigarette smoking is associated with sig- Despite widespread efforts to educate the nificant morbidity and mortality, and re- public on the risks of smoking, the preva- mains a continued significant threat to lence of smoking in the United States re- public health. For years, studies have docu- mains high. Approximately 46 million mented that smokers are at increased risk American adults are still current smok- of developing numerous diseases includ- ers.3 Although smoking prevalence for US ing cardiovascular disease (eg, coronary adults has fallen from 42% in 1965 to artery disease, stroke, hypertension, and 25.5% in 1997,4 the proportion of heavy peripheral vascular disease), cancer (eg, smokers is higher today than 20 years ago.5 of the lung, stomach, and bladder), res- One of the goals of Healthy People piratory disease (eg, chronic bronchitis and 2000 is to increase by 75% the propor- chronic obstructive pulmonary disease), tion of primary care providers who rou- and gastric ulcers.8 In addition, cigarette tinely provide smoking cessation coun- smoking may create an antiestrogen ef- seling for their patients who smoke.1 fect, accelerating early menopause (and Primary care clinicians have access to ap- consequently osteoporosis and other con- proximately 36 million (70%) of the 50 ditions related to estrogen deprivation), million people who smoke, including 61% cataracts, and wrinkling.9 While mortality among nonsmokers has remained stable, death rates among smokers from From the Departments of Family Medicine (Dr Okuyemi), Preventive Medicine (Drs Okuyemi, Ahluwalia, and Harris), and Internal Medicine (Dr Ahluwalia), School lung cancer, coronary heart disease, and of Medicine, University of Kansas, Kansas City. Dr Ahluwalia has received honoraria other smoking-related diseases has in- and grant support from Glaxo Wellcome Inc, Research Triangle Park, NC; SmithKline creased from 26 per 100 000 to 155 per Beecham Consumer Healthcare, Pittsburgh, Pa; and McNeil Consumer Products Co, 100 000 population in women and from Fort Washington, Pa. 187 per 100 000 to 341 per 100 000 among

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©2000 American Medical Association. All rights reserved. men, from 1959 to 1986, respec- Nicotine acts on nicotinic ace- also known as the 5A’s, to be used tively.10 Some minority groups, such tylcholine receptors in both the cen- by primary care physicians: Ask— as African Americans, bear a dispro- tral nervous system and the periph- systematically identify all tobacco us- portionate share of health conse- eral nervous system. Its psychoactive ers at every visit, incorporate smok- quences of smoking, having the effects are facilitated when nicotine ing status as fifth vital sign; Advise— highest overall cancer mortality rates binds to these acetylcholine recep- strongly urge all smokers to quit; compared with other racial and eth- tors, producing an enhanced alert- Assess—determine patient’s willing- nic groups.11 ness and a mild euphoria.16 How- ness to make a quit attempt; As- ever, exogenous nicotine binds to the sist—if patient is willing to make a IMPACT OF SMOKING acetylcholine receptors for longer quit attempt, help set a quit date, and CESSATION than endogenous neurotransmit- encourage nicotine replacement ter, thereby producing a secondary therapy (NRT) except in special cir- Smoking cessation significantly re- blockade of these receptors. Over cumstances; and Arrange—sched- duces most of the increased health time, the body adapts to this chronic ule follow-up contact. The recom- risks that smokers have incurred. secondary antagonism and up- mendation by the AHCPR that NRT The degree of improvement, how- regulates its central nervous sys- (specifically nicotine gum and trans- ever, depends on the disease pro- tem acetylcholine receptors. This is dermal patches) be offered to all cess involved, the amount of dam- the physical basis for nicotine tol- smokers wishing to quit was made age produced, and the reversibility erance. The increased number of since these were the only drugs ap- of this damage at the time of cessa- nicotine receptors makes the nor- proved for smoking cessation when tion. According to the 1990 US Sur- mal amount of acetylcholine re- the guidelines were developed. How- geon General’s report, the higher all- leased into the synapse insufficient ever, a number of other treatment cause mortality risk in smokers to maintain the previous mood, and options, including other NRT and returns to that of never-smokers the biological basis for the physical nonnicotine products, have be- within 10 to 15 years of quitting.12 dependence is established. come available since the release of Former smokers reduce their the guidelines. The AHCPR guide- risk of developing coronary heart dis- TRENDS IN SMOKING lines are currently being updated and ease 50% within 1 year of quitting, CESSATION will be released in mid-2000. and after 2 years of quitting smoking, former smokers have only twice the Quitting smoking is exceedingly dif- NONPHARMACOLOGICAL risk of having a first myocardial in- ficult. Surveys show 74% of smok- TREATMENT farction as never-smokers.12 After 4 ers report a desire to quit smoking years, this risk becomes equal to that and 70% of smokers have made pre- Although the focus of this article is of never-smokers. Cancer risk varies vious attempts to quit smoking, yet pharmacotherapy, a brief review of with the type of cancer involved. The success in quitting remains low.5 The other available interventions is pro- risk of lung cancer in former smok- difficulty in quitting that most smok- vided to put pharmacotherapy in ers, for example, always remains ers encounter reflects both a habit perspective. Behavioral interven- higher than that for never-smokers; and a physiological addiction. In ad- tions are beneficial to the long- however, this risk decreases progres- dition, cessation involves discon- term success of smoking cessation. sivelyandconsiderablywiththenum- tinuing a dependency that smokers Studies have shown that brief (5 ber of years of abstinence.8 acquired at a vulnerable period in minutes or less) advice on quitting their lives. Cessation prevalence, or given by physicians to smokers dur- NICOTINE DEPENDENCE the quit ratio, defined as the pro- ing an office visit have resulted in portion of ever-smokers who are higher quit rates compared with no Cigarette smoking is an addiction, former smokers (former/ever), has advice.18 In a review of 20 studies as powerful in many respects, as co- increased since 1965 from 24% to conducted in primary care settings, caine or opiate dependence.13 Evi- 50% in 1993.3 Although a sex dif- Law and Tang19 reported that 2% of dence that tobacco use is more likely ference in smoking cessation ex- all smokers who received brief phy- to lead to dependence than any other ists, with a quit ratio of 52% for men sician advice quit smoking as a di- drug use is supported by the fact that and 47% for women, the greater ten- rect consequence of it, compared among those who have ever tried dency of men to switch from ciga- with 0.1% in smokers who re- even a single cigarette, almost one rettes to other tobacco products may ceived no advice. With additional en- third develop nicotine depen- account for this difference.3 couragement and support (fol- dence.14 Although most smokers low-up letters, telephone calls, want to quit, they experience well- GUIDELINES FOR SMOKING demonstration of spirometry, and characterized barriers and with- CESSATION additional visits), quit rates in- drawal symptoms during their at- creased to 5%. In that same review, tempts to quit, and they are largely In 1996, the Agency for Health Care supportive group sessions for smok- unsuccessful in quitting. In fact, Policy and Research (AHCPR) pub- ers produced similar quit rates as no spontaneous quit rates without any lished its Smoking Cessation Clini- advice. While these results suggest cessation intervention range from cal Practice Guideline.17 The Agency that more intensive interventions 2% to 5% in the United States.15 recommended a 5-step approach, achieve higher quit rates, time con-

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©2000 American Medical Association. All rights reserved. straints experienced by primary care and the nicotine inhaler in 1998 transdermal nicotine patches, nico- physicians during office visits20 and (Table 1). tine nasal spray, and nicotine in- reluctance of many patients to en- haler. Only the first 2 products are ter intensive programs21 make brief Nicotine Replacement Therapy available without prescription. interventions the more feasible approach. Readers interested in other Since nicotine dependence is a sig- Nicotine Polacrilex Gum. In 1984, nonpharmacological treatments nificant element of most patients’ nicotine polacrilex gum (Nico- should consult other sources for smoking behavior, one strategy for rette, SmithKline Beecham Con- more detailed reviews.22-24 The low aiding cessation is to pharmacologi- sumer Healthcare, Pittsburgh, Pa) quit rates associated with unaided cally replace nicotine. Smokers can became available in the United States and nonpharmacological quit at- then engage in behavioral therapy to as a prescription-only medication. tempts demands that pharmacologi- decondition their conditioned trig- Approval for nonprescription sale cal treatment be offered to all smok- gers without experiencing with- was given in 1995 for 2-mg and 4-mg ers planning to quit unless there is drawal symptoms during absti- doses. A box of 48 pieces costs ap- a medical contraindication. nence. In general, indications and proximately $30 (Table 2). The contraindications for use of all NRT nicotine is buffered in sodium bi- PHARMACOLOGICAL products are similar. Although the carbonate, which facilitates absorp- TREATMENT product insert labels for all NRT tion through the buccal mucosa. products advise caution in their use Patients generally absorb 50% of In 1984, the Food and Drug Admin- for patients with cardiovascular dis- the nicotine in each piece of gum, istration (FDA) approved the first eases, studies have shown that these providing a bolus of nicotine that pharmacological agent, nicotine po- products cause fewer cardiovascu- reaches peak venous plasma con- lacrilex gum, for smoking cessa- lar effects than nicotine delivered by centrations within 30 minutes. The tion. It was the only NRT product tobacco smoke, and are generally venous level of nicotine then slowly available until the introduction in safe for the vast majority of smok- tapers in a pattern resembling, but 1992 of transdermal nicotine patch, ers.26 Nicotine replacement prod- significantly slower and less potent the nicotine nasal spray in 1996, ucts that are FDA approved in- than, that from cigarette smoke. To bupropion hydrochloride in 1997, clude nicotine polacrilex gum, benefit from the gum, patients must

Table 1. Drugs Approved for Smoking Cessation*

Drug Usual Dosage Advantages Disadvantages Contraindications Nicotine polacrilex Start with 2 mg, use 4 mg if Convenient, flexible dosing; No food or drink 15 min Dental problems; TMJ syndrome; (nicotine gum) not successful with 2 mg; faster delivery of nicotine before use; frequent use in pregnancy† (category C) chew 1 gum every 1-2 h than the patch dosing; jaw pain, mouth if nonpharmacological (maximum 30 pieces/d of soreness, dyspepsia, measures fail and if benefits 2-mg gum or 15 pieces/d hiccups outweigh risks; avoid use of 40-mg gum); usual length 1 mo post-MI, serious of treatment is 1-3 mo arrhythmias, or unstable angina, unless benefits outweigh risks Transdermal Nicoderm, Habitrol: 21 mg/24 h Easy to use; daily application; Skin irritation; less flexible Pregnancy (category D) and nicotine patch for 6-8 wk, then 14 mg/24 h OTC availability; overnight dosing; slow delivery of cardiovascular warnings (Nicoderm, for 2-4 wk, then 7 mg/24 h use may reduce early nicotine; wearing at same as for gum Habitrol, for 2-4 wk; Nicotrol: 15 morning cravings; few side night may cause sleep Nicotrol) mg/16 h for 6 wk effects problems Nicotine nasal spray Use 1-2 doses/h (minimum, Flexible dosing; fastest delivery Frequent dosing; nose and Pregnancy (category D) and Nicotrol NS 8 doses/d; maximum, of nicotine among all eye irritation; cough cardiovascular warnings (nasal spray) 40 doses/d); usual length products; reduces cravings same as for gum of treatment is 3 mo; taper within a few minutes over 4-6 wk Nicotine inhaler 10-mg cartridge, but only 4 mg Flexible dosing mimics Mouth and throat irritation; Pregnancy (category D) and (Nicotrol Inhaler) absorbed; 6-16 cartridges/d; hand-to-mouth behavior; frequent dosing cardiovascular warnings treat for 3 mo, taper over few side effects necessary same as for gum 6-12 wk Bupropion 150 mg orally once daily for 3 d, Nonnicotine; tablet form; easy Insomnia, dry mouth, Pregnancy (category B); seizure (hydrochloride) then twice daily for 7-12 wk to use; may be used with NRT headache, tremors disorder; concurrent use of SR (Zyban) Wellbutrin (former trade name) or an MAO inhibitor; bulimia or anorexia nervosa

*OTC indicates over the counter; NRT, nicotine replacement therapy; TMJ, temporomandibular joint; MI, myocardial infarction; SR, sustained release; and MAO, monoamine oxidase. †Pregnancy risk definitions25 are as follows: A, controlled studies in women fail to demonstrate a risk to the fetus; B, animal studies have either not demonstrated a fetal risk or have shown an adverse effect not confirmed in controlled studies in women; C, studies in women and animals not available or animal studies have revealed adverse effects on the fetus but there are no controlled studies in women; and D, there is no positive evidence of human fetal risk, but benefits from use may be acceptable for a serious disease if safer drugs are unavailable or ineffective.

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©2000 American Medical Association. All rights reserved. chew at least 10 pieces of the gum ucts Co, Fort Washington, Pa). Only for smoking relapse is greatest. Se- per day to absorb about half of the the first product requires a prescrip- rum levels decline 1 to 2 hours after daily dose of nicotine that they tion (Table 1). Patch brands differ in removing the patch. would otherwise receive from ciga- the rate control mechanisms, start- Continuous controlled release rettes. Patients who smoke fewer ing dose, and weaning regimen. of nicotine through a transdermal than 15 cigarettes per day should use Patches are sold in 1- to 2-week boxes nicotine patch resolves some of the the 2-mg dose while the 4-mg dose at a cost of approximately $30 per problems associated with nicotine should be reserved for those who week (Table 2) and initial therapy of gum, such as difficulty with use and smoke more. The gum should be some of the products includes a cas- side effects. Also, the potential for chewed slowly until a “peppery” sette tape and a self-help booklet. The addiction to the medication is much taste appears in the mouth, and then Habitrol and Nicoderm CQ patches lower by daily self-administration of “parked” between the gum and the are available as 21-mg (6-8 weeks), nicotine replacement with the patch cheek until the taste fades. Intermit- 14-mg (2-4 weeks), and 7-mg (2-4 than hourly replacement with the tent chewing and “parking” should weeks) regimens. The overall regi- gum.30,33 The most common side ef- continue for 30 minutes. men for using these 2 patch brands fects of the transdermal nicotine The gum may be difficult to use is consistent: after approximately 1 to patches include a mild skin reac- correctly since it requires special 2 months, patients switch to progres- tion with pruritis and edema. Less chewing techniques, and a high fre- sively lower-dose patches until they commonly, sleep disturbance has quency of use. Adverse effects from are effectively weaned off of the patch. been reported with the 24-hour the gum include jaw fatigue and Patients who smoke at least 10 ciga- patches. The transdermal patches are soreness and gastrointestinal up- rettes per day can begin with the high- contraindicated for patients with sys- set, such as gaseous distention, hic- est dose patch. The Nicotrol patch is temic eczema, unstable angina, preg- cups, and nausea.27 The gum is con- a single-dose patch of 15 mg, and is nancy, and within 1 month of a myo- traindicated in patients with gastric intended for daytime use only as a 16- cardial infarction. A number of ulcers, and is difficult to use for hour patch (ie, removal before going studies have shown the success of patients with dentures.28 Abruptly to sleep). Treatment is recom- the patch under controlled and real- stopping polacrilex gum use may mended for 6 weeks. The transder- world settings,34,35 including inner- precipitate nicotine withdrawal mal nicotine patch is applied to the city minority populations.36 Effi- symptoms, especially when used be- skin daily and nicotine is gradually ab- cacy of the nicotine patch is reported yond the recommended 3 months.29 sorbed throughout the day. Each to be about 20% to 30% at 6 months, Up to 20% of smokers who success- patch delivers 0.9 mg/h of nicotine, which is approximately double the fully quit taking the gum use it for and delivery reaches its daily peak af- cessation rate for placebo.37 One im- more than 1 year.30 Perhaps second- ter approximately 6 hours.16 Cumu- portant question that remains un- ary to its demanding use require- latively, the nicotine reaches thera- answered is how much behavioral ments, nicotine gum has been shown peutic peak levels (about 13-17 ng/ therapy is needed to maximize the to be more efficacious when used in mL) after 2 to 3 days, when the risk therapeutic effect of the transder- specialized clinics than when used in general medicine practices. In a Table 2. Cost of Drugs Approved for Smoking Cessation meta-analysis of randomized controlled trials, the success rates in spe- Drug (Manufacturer) Dosage Quantity* Cost, $† cialized cessation clinics were sig- Nicorette (SmithKline Beecham 2 mg 48s 28.50 nificantly higher with nicotine gum Consumer Healthcare) than with placebo gum at 6 months 108s 49.11 (27% vs 18%) and 12 months (23% 4 mg 48s 32.08 vs 13%).31 In contrast, success rates 108s 55.26 Nicoderm CQ (SmithKline Beecham 7 mg/24 h in general medical practices were no 7s 28.50 different with the gum and placebo Consumer Healthcare) 14 mg/24 h 32 14s 49.11 (11.7%) at 6 months. Higher quit 21 mg/24 h rates in specialized smoking cessa- Habitrol (Novartis Consumer Health) 7 mg/24 h 30s 120.52 tion clinics may be a result of more 14 mg/24 h 30s 127.22 in-depth counseling, better trained 21 mg/24 h 30s 138.87 counselors, and possibly smokers Nicotrol (McNeil Consumer Products Co) 15 mg/16 h 14s starter plus 2 refills 43.06 with higher motivation to quit. 15 mg/16 h 7s refill 24.71 14s refill 43.06 Nicotrol NS (nasal spray) 0.5 mg/inhalation 10 mL 40.80 Transdermal Nicotine Patches. (McNeil Consumer Products Co) Three major brands of transdermal Nicotrol Inhaler 10 mg 42s 40.80 nicotine patches are currently avail- (McNeil Consumer Products Co) able in the United States: Habitrol Zyban (Glaxo Wellcome Inc) 150 mg 60s 83.74 (Novartis Consumer Health, Sum- 30s 49.47 mit, NJ), Nicoderm CQ (SmithKline *Given as number of pieces of gum, patches, or cartridges. Beecham Consumer Healthcare), and †Average wholesale prices from the 1999 Drug Topics Red Book (Medical Economics Co, Nicotrol (McNeil Consumer Prod- Montvale, NJ).

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©2000 American Medical Association. All rights reserved. mal nicotine patch. Two meta- quency. Although use of the spray tive inhalers had continuous absti- analyses published in 1994 have at- may be stopped abruptly by many nence rates of 29% and 24% tempted to address this issue.35,37 The patients without withdrawal ef- compared with 14% and 10% with analyses concluded that intensive fects, some patients may need taper- placebo at 6 weeks and 3 months follow-up was more efficacious but ing. Although no tapering strategy postquit date, respectively.44 Other the results were not statistically sig- has been shown to be optimal, a studies have reported similar find- nificant. number of tapering strategies can be ings.45 The average daily dose in Availability of the transdermal used. Such strategies include hav- clinical trials was more than 6 car- patches as nonprescription prod- ing patients use half a dose (1 spray) tridges for patients who were able to ucts improves access to their use, at a time, use spray less frequently, quit smoking successfully. Patients which theoretically would increase skip a dose, try to meet a steadily re- should therefore be encouraged to their public health effectiveness. ducing usage target, and setting a use at least 6 cartridges per day for Some studies have reported similar date to stop use of the spray.42 the first 3 to 6 weeks of treatment. quit rates in double-blind, placebo- In a randomized, double- Patients should be allowed to self- controlled trials in nonprescrip- blind, placebo-controlled study,40 titrate dosage based on severity of tion setting when compared with the 32% of patients using active spray withdrawal signs and symptoms. prescription setting.38,39 However, were abstinent at 6 months com- Treatment should be continued at patients enrolled in the nonprescrip- pared with 12% taking the placebo. the selected dose for 6 to 12 weeks tion arm of these studies were al- The rates at 1 year after quit dates in patients who have successfully ready motivated to quit smoking, were 26% and 10% for active and quit smoking, followed by tapering and may not be representative of placebo sprays, respectively. These over 3 months. A common taper- most smokers. findings suggest that the nicotine na- ing strategy used in some trials45 was sal spray is helpful in aiding smok- to reduce usage by 25% monthly for Nicotine Nasal Spray. Nicotine na- ing cessation. The most commonly 3 months. Each puff releases ap- sal spray (Nicotrol NS, McNeil Con- reported side effects of the nicotine proximately 16 µg at room tempera- sumer Products Co) is a relatively nasal spray include nasal irritation, ture, and each inhaler is designed to new (FDA approved in 1996) form runny nose, sneezing, throat irrita- produce approximately 300 puffs.46 of nicotine replacement delivery tion, coughing, and watery eyes. An intensive inhalation regimen system, available only by prescrip- Patients develop tolerance to these (about 80 deep inhalations over 20 tion. It is designed to deliver nico- effects within the first week. Less fre- minutes) is required to approxi- tine more rapidly than the gum or quently, heart pounding, nausea, mate the amount of nicotine deliv- patch, but less rapidly than smok- headache, dizziness, and sweating ered by smoking 1 cigarette. The ing cigarettes.40 Users tend to self- have been reported. same cartridge can be used up to 5 administer to plasma nicotine con- times before replacing with a new centrations that are approximately Nicotine Inhaler. In 1998, the nico- one. The device should be stored at 50% of those achieved by smok- tine inhaler (Nicotrol Inhaler, room temperature as it may lose sig- ing.41 The rapid delivery and rela- McNeil Consumer Products Co) be- nificant bioavailability at tempera- tively high plasma concentrations came available as a prescription drug tures below 10°C. The mouthpiece make the nasal spray more suitable for smoking cessation. It consists of is reusable and should be cleaned for treating withdrawal symptoms, a mouthpiece and a plastic car- regularly. Adverse effects are gen- and especially beneficial to highly tridge designed to deliver 4 mg of erally mild consisting of throat irri- dependent smokers. When nico- nicotine from a porous plug con- tation and cough. tine is administered by nasal spray, taining 10 mg of nicotine. The car- peak plasma concentrations are tridge also contains 1 mg of men- Nonnicotine Drugs reached at a rate comparable to that thol as an inactive ingredient to from cigarette smoking, and thus can reduce irritation by nicotine. The Several nonnicotine products have be used for treating acute nicotine cartridge is inserted into the mouth- been tested for smoking cessation, but withdrawal symptoms. The nozzle piece prior to use. Nicotine inhaler only one has been approved by the is inserted into the nostrils similar is different from other inhalers in FDA. Initially developed and mar- to the technique for antihistamine that most of the nicotine released keted as an antidepressant under the or steroid nasal sprays. Each spray from the inhaler is absorbed in the trade name Wellbutrin, the sustained- (.05 mL) delivers 0.5 mg of nico- mouth, with less than 5% reaching release form was approved in 1997 tine, and a dose is a spray in each the lower respiratory tract.43 A ma- as an aid for smoking cessation un- nostril. Patients should be started jor difference between the nicotine der a new the trade name, Zyban with 1 to 2 doses per hour, which inhaler and other NRT products is (Glaxo Wellcome Inc, Research Tri- may be titrated up to the maximum that it mimics the hand-to-mouth angle Park, NC). Bupropion is an dose of 5 mg/h or 40 mg/d for 3 routine similar to cigarette smok- aminoketone, chemically unrelated months. Recommended dosing is 1 ing. It may therefore reduce fears as- to other known antidepressants. It to 2 doses every hour for 6 to 8 sociated with abrupt cessation of the has both doperminergic and adren- weeks, followed by 4 to 6 weeks of hand-to-mouth ritual. ergic actions.47 Although the mecha- gradual reduction by halving the In a double-blind, placebo- nism by which bupropion enhances dose, and decreasing the daily fre- controlled trial, individuals using ac- ability of smokers to quit smoking is

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©2000 American Medical Association. All rights reserved. not known, it is presumed to in- some physicians began using polac- propion may be used in combina- volve both doperminergic and rilex gum in conjunction with the tion with the nicotine patch in adrenergic mechanisms.48 Bupro- transdermal nicotine patches. In a patients without contraindications pion is an alternative for smokers double-blind, placebo-controlled to either drugs when deemed nec- who either cannot tolerate NRT or trial published in 1995, Kornitzer et essary. Patients should be started on prefer nonnicotine treatment. In a al51 randomly assigned 374 smok- bupropion hydrochloride at 150 randomized, double-blind, placebo- ers (who smoked at least 10 ciga- mg/d for 3 days, then 150 mg twice controlled trial,49 27% of patients who rettes a day) to 3 groups: placebo daily for 1 to 2 weeks prior to quit received the active drug were absti- gum plus placebo patch, active patch date. Transdermal nicotine patch nent at 6 months, compared with plus placebo gum, and active patch therapy should then be added start- 16% of patients taking placebo. An plus active gum. They reported that ing on the quit date. We recom- earlier study50 also reported similar the addition of nicotine gum to the mend that treatment be continued results. The recommended dose is patch significantly increased quit for 3 to 6 months. 150 mg orally once daily for 3 days, rates from 23% to 34% at 12 weeks then 150 mg twice daily (at least 8 and from 15% to 28% at 24 weeks. SPECIAL POPULATIONS hours apart) for 7 to 12 weeks. Al- Also, a review of 4 studies that docu- though 2 brand products are available mented statistical significance52 con- Minorities for bupropion, Zyban and Wellbutrin, cluded that for heavy smokers, com- we recommend that Zyban be pre- bined use of 5 to 7 pieces per day of Tobacco use varies within and scribed as “do not substitute” because polacrilex gum with the 16- or 24- among racial and ethnic minority its package comes with the Zyban Ad- hour transdermal patch signifi- groups in the United States.55 Mem- vantage Plan, which includes self-help cantly reduces withdrawal symp- bers of racial and ethnic minorities brochures and a workbook and access toms and increases initial cessation populations bear a disproportion- to a personalized support program for rates more than use of either prod- ate share of adverse health conse- smoking cessation. Unlike NRT, pa- uct alone. Side effects were not sig- quences of tobacco use, such as can- tients should set their quit date 1 to nificantly increased by combined use cer, cardiovascular diseases, and 2 weeks after initiating therapy with of nicotine patch and gum. A re- preterm births.11,56 Paradoxically, the bupropion to allow steady state serum cent study53 also reported higher quit 1998 Surgeon General’s report noted levels to be achieved. Cigarette smok- rates when the patch is combined that ethnic and racial minorities ing does not significantly affect the with the nasal spray than with the are less likely than the general popu- pharmacokineticsofbuproprion.47 Ad- patch alone (51% vs 35% at 6 weeks lation to participate in smoking verse effects are generally mild, con- and 37% vs 25% at 3 months for cessation groups and to receive ces- sisting of insomnia and dry mouth. the combination and patch only, sation advice from health care pro- The latter effect may be minimized by respectively). Combination treat- viders.55 Compared with whites, Af- encouraging patients to drink small ments should be considered for rican Americans smoke fewer amountsofwateratfrequentintervals, smokers with significant craving or cigarettes, but are more likely to andinsomniacanbereducedbyavoid- withdrawal despite adequate doses smoke mentholated brands and ing bedtime doses. Initial concerns of single agents and should be con- brands with higher tar and nicotine about increased risk of seizures have tinued for 3 to 6 months. content.57 Although African Ameri- not been confirmed.47 Recent studies49 can adults are more likely to have a with 300 mg/d or less of sustained- Combined Use of Transdermal greater number of quit attempts than release bupropion hydrochloride for Nicotine Patch and Bupropion. In white Americans in any given year, smoking cessation have found the risk a recent double-blind, placebo- these attempts are 34% less success- of seizures to be similar to that of other controlled study54 comparing sus- ful than they are for whites.3,58 Re- antidepressants.Thedrugispregnancy tained-release bupropion, a nico- search in pharmacological interven- category B, and contraindicated in pa- tine patch, and both for smoking tion for smoking cessation has been tients with a history of seizures, an- cessation in 732 smokers, absti- conducted almost exclusively in orexia or bulimia, head trauma, or nence rates at 12 months were 35.5% white, middle-class populations. A heavy alcohol use. in the combination (bupropion plus double-blind, randomized, placebo- nicotine patch) group compared controlled trial of the transdermal Combination Drug Therapy with 30.3% for bupropion alone, nicotine patch among inner-city Af- 16.4% for nicotine patch alone, and rican Americans36 found that the Although all the drugs discussed 15.6% for the placebo patch and pill patch significantly improves quit above have only been approved as group. They concluded that absti- rates in this population. The re- single pharmacological agents, com- nence rates were significantly higher sults from a National Cancer Insti- bination treatments may be appro- with bupropion in combination with tute–funded clinical trial on the ef- priate for smokers who are unable nicotine patch than with the patch ficacy of bupropion among African to quit with monotherapy. alone. However, the difference in ab- Americans will not be available for stinence rates between the combi- another year. Another study59 in His- Combined Use of NRT Products. nation treatment and bupropion panic smokers found that the trans- Given its acute delivery and, there- alone was not statistically signifi- dermal nicotine patch resulted in fore, usefulness for acute cravings, cant. These findings suggest that bu- nearly doubling of quit rates com-

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©2000 American Medical Association. All rights reserved. pared with placebo. Due to paucity lower than that from cigarettes. Re- function seen with chronic obstruc- of data on pharmacological inter- views on use of the gum and patch tive pulmonary disease.12 Docu- ventions among minority popula- during pregnancy suggest that their mented changes in pulmonary func- tions, the AHCPR recommended use should still be considered. The tion may be used as a motivational that clinicians who see minority pa- risk-benefit ratio appears favorable factor for smoking cessation in these tients should offer treatments proven if efforts to quit without medi- patients. As with patients with car- to be effective for the general popu- cation has failed.67 Use of nicotine diovascular diseases, those who con- lation. Until more conclusive data inhaler or nicotine nasal spray dur- tinue to smoke despite having pul- become available, physicians should ing pregnancy has not been exam- monary diseases are likely to be follow the AHCPR recommenda- ined. Bupropion carries pregnancy highly nicotine dependent71; hence, tions that “whenever possible, smok- category B label, and could be used treatment with pharmacological ing cessation treatment should be if nonpharmacological efforts have agents is very important in this modified or tailored to be appropri- failed. The risks and benefits of any population of smokers. ate for ethnic or racial populations medication used for smoking cessa- with whom they are used.”17 Nev- tion during pregnancy should be ex- Light Smokers ertheless, clinicians should be aware plained to mother. of the limitations of such generali- Current data suggest that 5% to 10% zation. Smokers With of smokers consume 5 or fewer ciga- Cardiovascular Diseases rettes a day,72 although the propor- Women and Pregnancy tion is much higher among African Smokers are clearly at higher risk of Americans and Hispanic popula- Although the number of male smok- dying from smoking-related cardio- tions.73 These smokers in general are ers continues to outnumber female vascular diseases such as coronary not addicted to nicotine, and may ab- smokers (26% for men vs 21% for artery disease, stroke, congestive stain from smoking for days with- women in 1997), mortality from heart failure, and other heart dis- out significant withdrawal ef- lung cancer in women continues to eases.68 Also important is the fact that fects.74 Light smokers are invariably rise.60 In fact, lung cancer, mostly the risk of cardiovascular disease de- excluded in virtually all pharmaco- due to smoking, is the leading cause creases markedly within 1 year of logical smoking cessation trials. The of cancer deaths in women.60 Cur- stopping smoking and approxi- quit rates of the pharmacological rent data suggest that women are mates the risk in never-smokers 5 agents discussed herein were de- quitting at same rate as men.61 Fac- years after cessation. Quitting smok- rived from studies in regular smok- tors that undermine cessation in ing has a greater impact on morbid- ers who smoke 10 or more ciga- women include depression, social ity and mortality than changing diet, rettes a day. Consequently, there is support, and weight gain.62 It is not weight, or exercise.12 On the other insufficient data about effective clear whether women experience hand, studies have shown that NRT smoking cessation interventions for more withdrawal symptoms than is safe in patients with stable car- light smokers. However, light smok- men during abstinence.61 Some data diovascular diseases.69 There is no ers should equally be strongly en- have suggested that men do better evidence that bupropion use in- couraged to quit, as there is no safe with NRT, but these results have not creases the cardiovascular risk of level of smoking. It is logical that been replicated.63 Smoking during smokers. In view of the favorable drug therapy should only be con- pregnancy has well-documented risk-benefit ratio in patients with sidered after nonpharmacological consequences on maternal and fe- stable cardiovascular diseases, phar- measures have failed. tal health, including low birth macotherapy should be offered to weight, spontaneous abortion, and this population of smokers. Physi- ADJUNCTIVE MATERIALS preterm births.64 Many pregnant cians should adopt a more aggres- women find it difficult to quit on sive approach in this population, in- Primary care physicians should con- their own.65 Quitting cigarette smok- cluding the use of combination sider offering adjunctive materials to ing during early pregnancy reduces pharmacological therapy as these pa- supplement educational and sup- the risk of low birth weight.12 Even tients are likely to be more nicotine portive counseling. All pharmaco- women who quit smoking as late as dependent. logical agents discussed herein were the 30th week of gestation have in- approved to be used in conjunc- fants with higher birth weights than Smokers With tion with a behavioral smoking ces- those who continue to smoke.41 Cur- Pulmonary Diseases sation program. Virtually all these rent evidence suggests that behav- products provide some form of self- ioral therapy for pregnant smokers Cigarette smoking is an important help kits in their initial or starter is effective66 and should be encour- risk factor for pulmonary diseases, packages. Some also provide smok- aged before pharmacological ap- being responsible for 85 000 deaths ing cessation videotapes and infor- proaches are used. All the NRT prod- per year from respiratory diseases mation about where smokers may ucts are pregnancy category D except such as chronic obstructive pulmo- call in to receive counseling. The the gum, which is category C. The nary disease and pneumonia.70 Stop- American Lung Association has pro- level of nicotine to which the fetus ping smoking halts the smoking- duced a number of materials, 2 pub- is exposed with the patch or gum is induced accelerated decline in lung lications of which are specifically

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©2000 American Medical Association. All rights reserved. produced for patients wishing to quit dermal nicotine patch or bupropion) CHOICE OF on their own: a 64-page cessation plus a shorter-acting, quick-onset PHARMACOLOGICAL guide, Freedom From Smoking in 20 agent (nicotine polacrilex gum, nico- AGENTS Days, and a 28-page maintenance tine inhaler, or nicotine nasal spray). booklet, A Lifetime of Freedom From Treatment should be continued Given the many options of pharma- Smoking. The National Cancer In- for 3 to 6 months followed by 6 to cotherapy available for smoking ces- stitute has also produced many pub- 12 weeks of tapering of the short- sation today, physicians are likely to lications, including Clearing the Air, acting nicotine product if neces- be asked which of these products all of which are available free. A list- sary. Patients should be given ad- their patients should use. This situ- ing of these and other resources that equate instructions in proper use of ation is further compounded in man- may be helpful to both physicians the medication and the necessary fol- aged care settings where health plans and their patients is provided at the low-up provided. Follow-up con- may recommend certain agents over end of this article. tact is vital and should be made others. Factors that should be con- within 1 week of the quit date be- sidered in drug therapy include effi- GENERAL CONSIDERATIONS cause relapse rates are highest dur- cacy, cost, ease of use, adverse effect ing the first few days after cessa- profile, and patient characteristics. Relapse tion.78,79 Follow-up could be in the There are limited data on the com- office, by telephone, or by mail, and parative efficacy of the 5 approved Physicians should be aware that re- can be made by the physician or agents (Table 3) —nicotine polac- lapse is quite common among smok- other trained office staff. We recom- rilex gum, transdermal nicotine ers both during and after cessation mend that patients who relapse patch, nicotine nasal spray, nicotine treatment. In fact, studies have after 2 or 3 attempts despite ad- inhaler, and bupropion. In a recent shown that it takes an average of 4 equate treatment and careful con- study, Hajek et al91 conducted a com- to 5 quit attempts before eventual siderations of the factors discussed parative trial of nicotine polacrilex success at cessation.13 Patients herein should be referred to a smok- gum, transdermal nicotine patch, should therefore be encouraged to ing cessation specialist. nicotine nasal spray, and nicotine in- try to quit again as soon as possible haler. These researchers found that after a failed attempt. In assessing pa- Addictive Potential the 4 NRTs did not differ in their ef- tients who relapse, physicians should fects on withdrawal discomfort, urges address patient and treatment fac- Some studies have reported that 5% to smoke, or rates of abstinence with tors that may have contributed to the to 20% of patients prescribed the po- 12-week continuous abstinence rates failed attempt. Patient factors in- lacrilex nicotine gum for smoking of 20%, 21%, 24%, and 24% for gum, clude lack of motivation (provide cessation continue to use the gum patch, spray, and inhaler groups, re- motivational counseling such as dis- for 1 year or more.72,80 Although spectively. In the same study, com- cussing the pros and cons of smok- abrupt cessation of use of the gum pliance was high for the patch (82%), ing); environmental stressors such can produce withdrawal symptoms low for the gum (38%), and very low as death or illness within the fam- similar to but milder than that from for the spray (15%) and the inhaler ily, loss of job, being around or cigarettes,81 the use of the gum can (11%). The spray was underused be- living with other smokers (provide be safely eliminated by gradual re- cause of adverse effects, and the in- relevant counseling or refer as ap- duction. Long-term use may repre- haler was rated as more embarrass- propriate); and presence of comor- sent patient’s desire to extend du- ing to use than other products. These bidities, especially alcohol abuse and ration of therapy for fear of returning findings suggest that although the 4 depression as up to 20% of heavy to smoking.82 Abrupt cessation of the products are equally efficacious, com- smokers have current alcohol prob- transdermal nicotine patch does not pliance and adverse event profile ap- lems and 40% have a history of de- appear to be associated with with- pear to favor the patch. However, that pression.75-77 Treatment consider- drawal symptoms.83 Nicotine nasal the higher compliance and lower ad- ations include adequacy of dosage spray seems to have a higher poten- verse event rates did not lead to bet- (whether dose prescribed was ad- tial for long-term use than the gum ter quit rates in the patch group sug- equate or patient used medication as as evidenced by findings from clini- gest that various NRTs may have prescribed), cost (whether prescrip- cal trials that up to 43% of those ab- different appeal and efficacy in dif- tion was affordable or was paid for stinent at 1 year were still using the ferent populations of smokers. In an- by insurance plan), and drug ad- spray at 1 year.41 Gradual dose re- other study, Jorenby et al54 com- verse effects that affected treatment duction (over 1-3 months) should pared the efficacy of bupropion and compliance. If the patient agrees to be implemented for those using the nicotine patch as single agents and as try again, a new quit date should be spray beyond 3 months. Long-term combined therapy. The abstinence set. If dosage of the medication used use did not appear to be a problem rates were 18.8%, 21.3%, 34.8%, and in prior attempt was adequate, and for the nicotine inhaler as all pa- 38.8% at 6 months, and 15.6%, relapse was due to uncontrolled tients were able to discontinue 16.4%, 30.3%, and 35.5% at 12 withdrawal, the patient should be inhaler use within 6 months in months for placebo, nicotine patch considered for combination treat- clinical trials. No problems with only, bupropion only, and com- ment. We recommend a combina- long-term use have been reported bined bupropion and nicotine patch, tion of one long-acting agent (trans- with bupropion. respectively. Although this study sug-

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©2000 American Medical Association. All rights reserved. minorities, light smokers, and pa- Table 3. Studies Reporting 6-Month and 1-Year Quit Rates tients with cardiovascular and pul- of Approved Pharmacological Agents* monary diseases. Given the proven effective- Quit Rate at 6 mo, % Quit Rate at 1 y, % ness of smoking cessation interven- Active Active tions and their potential to reduce Study Treatment Placebo P Treatment Placebo P smoking-related morbidity and mor- Nicotine gum tality, failure to identify, advise, and Schneider et al84 48.0 20.0 Ͻ.05 30.0 20.0 Ͻ.05 offer pharmacological agents to Lam et al32 27.0 18.0 Ͻ.05 23.0 13.0 Ͻ.05 smokers may soon be judged as de- Nicotine patch viation from standard of care. Phy- Hurt et al85 29.2 15.0 Ͻ.05 27.5 14.2 Ͻ.05 Sachs et al86 33.6 12.1 Ͻ.05 24.8 9.4 Ͻ.05 sicians may consider the efficacy of Tonnesen et al87 19.3 2.8 Ͻ.05 12.4 2.8 Ͻ.05 smoking cessation intervention as Nicotine nasal spray generally low compared with that of Blondal et al88 29 18 .05 25 17 .09 treatment with antibiotics or anti- Hjalmarson et al89 44 19 Ͻ.05 34 18 Ͻ.05 hypertensives. However, smoking Schneider et al90 25 10 Ͻ.05 18 8 Ͻ.05 cessation should be put into proper Nicotine inhaler perspective. If physicians achieve a Leischow et al45 21.0 6.0 Ͻ.05 11.0 5.0 .14 Tonnesen et al46 17.2 7.8 Ͻ.05 15.2 5.0 Ͻ.05 5% quit rate in 70% of the 50 mil- Bupropion hydrochloride lion (35 million) smokers seen by Hurt et al49 27 16 Ͻ.05 23.1 12.4 Ͻ.05 primary care physicians yearly, this Jorenby et al54 34.8 18.8 Ͻ.001 30.3 15.6 Ͻ.001 will result in 1.73 million smokers quitting each year. As physicians en- *These rates are derived from noncomparative studies, so quit rates can only be compared within rows deavor to educate and empower their but not across rows. patients with regard to their health, this significant contributor to per- gests superior efficacy for bupro- ing cessation provides primary care sonal and social morbidity cannot pion over the patch, it is premature physicians with a wide range of treat- be ignored. Of all preventive care to draw conclusions or make recom- ment approaches. When used cor- efforts, smoking cessation promo- mendations based on a single study. rectly, all currently approved prod- tion has the potential to achieve The comparative efficacy and toler- ucts appear to be equally efficacious, the most dramatic reduction in ability of all 5 products have not been approximately doubling quit rates morbidity and mortality, and reported in the literature. It is good compared with placebo.92 It is there- improvement in public health. judgment to consider using prod- fore logical that patient’s prefer- The ultimate disease prevention ucts with better compliance and fewer ence, comorbidities, and adverse ef- strategy would be to prevent initia- adverse events such as the transder- fect profile of individual agents tion of smoking. In spite of wide- mal patch before other NRTs. It is im- should guide treatment choice. In- spread knowledge of health con- portant to note, however, that cer- creased access created by nonpre- sequences, 3000 Americans, mostly tain patient characteristics such as scription availability of some NRTs teenagers and children, start smok- preferences, comorbidities, experi- has been credited with substantial in- ing each day. Although we ad- ence in prior quit attempts, and de- crease in smokers quitting in the dressed the important role of phar- gree of nicotine dependence may war- United States.93 Some studies re- macotherapy of smoking cessation, rant use of the spray and inhaler as ported finding no difference in ab- it should be recognized that a sus- initial therapy. Bupropion may be stinence rates with nonprescrip- tained reduction in smoking preva- used as initial therapy either alone or tion use of nicotine patch compared lence will require a comprehensive (for more nicotine-dependent pa- with its use in prescription setting, population-based approach. Such an tients) in combination with NRTs. Al- suggesting physician advice had no approach should include efforts though there are anecdotal reports effect in the use of these products. aimed at reducing social desirabil- that some health plans are recom- However, since the major role of ity of smoking, limiting access to mending bupropion as first-line physician advice is to motivate cigarettes, and increasing availabil- therapy over the NRTs, such recom- smokers to quit,94-96 failure to dem- ity as well as utilization of effective mendations are not supported by cur- onstrate a significant effect in the cessation intervention. Finally, as ef- rent research. We recommend that studies may be because these smok- forts to promote smoking cessation physicians consider using an algo- ers were already motivated. Given interventions are sustained, we ex- rithm (Figure) to assist them in iden- the fact that primary care physi- pect to see an increase in the provi- tification and triaging of therapy for cians have contact with 70% of sion of cessation interventions, in- smokers. smokers in a given year, they are in creased quit rates, and an ultimate a unique position to influence a sig- reduction in smoking-related mor- CONCLUSIONS nificant proportion of smokers. Phy- bidity and mortality. sicians should be aware of the spe- The recent increase in approved cial needs of certain populations of Accepted for publication November 16, pharmacological options for smok- smokers, including women, ethnic 1999.

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©2000 American Medical Association. All rights reserved. capita tax-paid sales of cigarettes—United States, General Population 1997. MMWR Morb Mortal Wkly Rep. 1998;47: 922-926. 5. US Department of Health and Human Services. Contact With Physician Healthy People 2000 Review, 1994. Washing- ton, DC: US Government Printing Office; 1994. Ask About Smoking 6. Physician and other health care professional counseling of smokers to quit—United States, 1991. MMWR Morb Mortal Wkly Rep. 1993;42:854- 857. Never Smoker Current Smoker Former Smoker 7. Ockene JK. Physician-delivered interventions for smoking cessation: strategies for increasing ef- Advise Congratulate and fectiveness. Prev Med. 1987;16:723-737. Reinforce Abstinence 8. Samet JM. The health benefits of smoking cessation. Med Clin North Am. 1992;76:399-414. Assess Stage of Change 9. Frank E. Benefits of stopping smoking. West J Med. 1993;159:83-87. 10. Thun MJ, Day-Lally CA, Calle EE, Flanders WD, Precontemplation Preparation/Willing to Quit Now Contemplation Heath CW Jr. Excess mortality among cigarette smokers: changes in a 20-year interval. Am J Pub- lic Health. 1995;85:1223-1230. Motivate: Discuss Concerns 11. Harris RE, Zang EA, Anderson JI, et al. Race and and Benefits of Quitting sex differences in lung cancer risk associated with cigarette smoking. Int J Epidemiol. 1993;22:592- 599. 12. US Department of Health and Human Services. The Have Tried to Quit Before Never Tried to Quit Before or Tried Health Benefits of Smoking Cessation. Washing- With Pharmacotherapy to Quit Without Pharmacotherapy ton, DC: Public Health Service, Center for Chronic Disease Prevention and Health Promotion, Of- Assist: Set Quit Date, Recommend Different Assist: Set Quit Date, Discuss Treatment fice of Smoking and Health; 1990. DHHS publi- Therapy or Consider Combination: Patch Plus Options, Consider Patch or Gum (Over cation (CDC) 90-8416. Other Nicotine Replacement Therapies or the Counter) vs Spray, Inhaler, or 13. US Department of Health and Human Services. The Patch Plus Bupropion Hydrochloride Bupropion (Prescription) Health Consequences of Smoking: Nicotine Addic- tion: A Report of the Surgeon General. Rockville, Md: Public Health Service; 1988. 14. Anthony JC, Warner LA, Kessler RC. Compara- Succeed Fail (Recycle) Succeed tive epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the comorbidity survey. Exp No Psychiatric or Psychiatric or Arrange Follow-up Clin Psychopharmacol. 1994;2:244-268. Alcohol Problem Alcohol Problem 15. Fiscella K, Franks P. Cost-effectiveness of the transdermal nicotine patch as an adjunct to physicians’ smoking cessation counseling. JAMA. Set Quit Date, Use Combination 1996;275:1247-1251. Therapy With Other Agents 16. Benowitz NL. Pharmacology of nicotine: addiction and therapeutics. Annu Rev Pharmacol Toxi- col. 1996;36:597-613. Succeed Fail 17. The Smoking Cessation Clinical Practice Panel and Staff. The Agency for Health Care Policy and Re- search Smoking Cessation Clinical Practice Guide- Arrange Follow-up Refer line. JAMA. 1996;275:1270-1280. 18. Slama K, Redman S, Perkins J, Reid ALA, Sanson- Algorithm for smoking cessation. Fisher RW. The effectiveness of two smoking cessation programs for use in general practice: a randomized clinical trial. BMJ. 1990;300:1707- 1709. 19. Law M, Tang JL. An analysis of the effectiveness This work was supported in part REFERENCES of interventions intended to help people stop smok- by National Cancer Institute grants ing. Arch Intern Med. 1995;155:1933-1941. R01CA77856 and RO1CA77856- 20. Gilchrist V, Miller RS, Gillanders WR, et al. Does fam- 1. US Department of Health and Human Services. ily practice at residency teaching sites reflect com- 03S1 and a Robert Wood Johnson Gen- Healthy People 2000. Washington, DC: US Gov- munity practice? J Fam Pract. 1993;37:555-563. eralist Physician Faculty Scholars ernment Printing Office; 1991. DHHS publication 21. Lichtenstein E, Hollis JF. Patient referral to a smok- Award (032586) to Dr Ahluwalia. (PHS) 91-50212. ing cessation program: who follows through? We thank Anne D. Walling, MD, 2. Centers for Disease Control and Prevention. Medi- J Fam Pract. 1992;34:739-744. for her assistance in the preparation cal expenditure attributable to cigarette smoking— 22. Baillie AJ, Mattick RP, Hall W, Webster P. Meta- United States, 1993. MMWR Morb Mortal Wkly analytic review of the efficacy of smoking cessa- of the manuscript. Rep. 1994;43:469-472. tion interventions. Drug Alcohol Rev. 1994;13: Reprints: Kolawole S. Okuyemi, 3. Centers for Disease Control and Prevention. Ciga- 153-166. MD, MPH, Department of Family rette smoking among adults—United States, 1993. 23. Schwartz JL. Methods of smoking cessation. Med Medicine, School of Medicine, Uni- MMWR Morb Mortal Wkly Rep. 1994;43:925- Clin North Am. 1992;76:451-476. 930. 24. Kottke TE, Battista RN, DeFriese GH, Brekke ML. versity of Kansas, 3901 Rainbow 4. Centers for Disease Control and Prevention. State- Attributes of successful smoking cessation inter- Blvd, Kansas City, KS 66160-7370 specific prevalence among adults of current ciga- ventions in medical practice. JAMA. 1988;259: (e-mail: [email protected]). rette smoking and smokeless tobacco use and per 2882-2889.

ARCH FAM MED/ VOL 9, MAR 2000 WWW.ARCHFAMMED.COM

©2000 American Medical Association. All rights reserved. 25. Brigga GG, Freeman RK, Yaffe SJ. Drugs in Preg- Behav. 1996;20:364-371. 64. US Department of Health and Human Services. The nancy and Lactation. Baltimore, Md: Williams & 46. Tonnesen P, Norregaard J, Mikkelsen K, et al. A Health Consequences of Smoking for Women: A Wilkins; 1994. double-blind trial of nicotine inhaler for smoking Report of the Surgeon General. Washington, DC: 26. Hughes JR. Risk-benefit assessment of nicotine cessation. JAMA. 1993;269:1268-1271. US Government Printing Office; 1980. preparations in smoking cessation. Drug Safety. 47. Ascher JA, Cole JO, Colin J, et al. Bupropion: a 65. Burling TA, Bigelow GE, Robinson JC, Mead AM. 1993;8:49-56. review of its mechanism of antidepressant activ- Smoking during pregnancy: reduction via objec- 27. Henningfield JE. Nicotine medications for smok- ity. J Clin Psychiatry. 1995;56:395-401. tive assessment and directive advice. Behav Ther. ing cessation. N Engl J Med. 1995;333:1196- 48. Glaxo Wellcome Inc. Physicians’ Desk Refer- 1991;22:31-40. 1203. ence. 52nd ed. Montvale, NJ: Medical Econom- 66. Gritz ER, Kristeller JL, Burns DM. Treating nico- 28. Hjalmarson A, Franzon M, Westin A, Wiklund O. ics Co; 1998:1139-1144. tine addiction in high risk groups and patients with Effect of nicotine nasal spray on smoking cessa- 49. Hurt RD, Sachs DPL, Glover ED, et al. A compari- medical co-morbidity. In: Orleans CT, Slade JD, tion: a randomized, placebo-controlled, double- son of sustained-release bupropion and placebo eds. Nicotine Addiction: Principles and Manage- blind study. Arch Intern Med. 1994;154:2567- for smoking cessation. N Engl J Med. 1997;337: ment. New York, NY: Oxford University Press; 2572. 1195-1202. 1993:279-309. 29. Hughes JR. Dependence potential and abuse 50. Ferry LH, Burchette RJ. Efficacy of bupropion for 67. Benowitz NL. Nicotine replacement therapy dur- liability of nicotine replacement therapies. Biomed smoking cessation in non-depressed smokers. ing pregnancy. JAMA. 1991;266:3174-3177. Pharmacother. 1989;43:11-17. J Addict Dis. 1994;13:249. 68. Centers for Disease Control and Prevention. Ciga- 30. Hughes JR, Gust SW, Keenan R, Fenwick JW, 51. Kornitzer M, Boutsen M, Thijs J, et al. Combined rette smoking among adults—United States, 1991. Skoog K, Higgins ST. Long-term use of nicotine use of nicotine patch and gum in smoking ces- MMWR Morb Mortal Wkly Rep. 1993;42:230-233. vs placebo gum. Arch Intern Med. 1991;151:1993- sation: a placebo-controlled clinical. Prev Med. 69. Working Group for the Study of Transdermal Nico- 1998. 1995;24:41-47. tine in Patients With Coronary Artery Disease. Nico- 31. Capeda BA. Meta-analytical review of the effi- 52. Fagerstrom KO. Combined use of nicotine re- tine replacement therapy for patients with coronary cacy of nicotine chewing gum in smoking treat- placement products. Health Values. 1994;18:15- arterydisease. ArchInternMed. 1994;154:989-995. ment programs. J Consult Clin Psychol. 1993;61: 20. 70. Centers for Disease Control and Prevention. Ciga- 822-830. 53. Blondal T, Gudmundsson LJ, Olafsdottir I, Gus- rette smoking—attributable mortality and years 32. Lam W, Sze PC, Sacks HS, Chalmers TC. Meta- tavsson G, Westin A. Nicotine nasal spray with of potential life lost, United States, 1990. MMWR analysis of randomized controlled trials of nico- nicotine patch for smoking cessation: random- Morb Mortal Wkly Rep. 1993;42:645-649. tine chewing-gum. Lancet. 1987;2:27-30. ized trial with six year follow up. BMJ. 1999;318: 71. Kennnedy JA, Crowley TJ, Cottler LB, Mager DE. 33. Benowitz NL. Pharmacologic aspects of ciga- 285-288. Substance use diagnoses in patients with lung dis- rette smoking and nicotine addiction. N Engl J Med. 54. Jorenby DE, Leischow SJ, Nides MA, et al. A con- ease. Am J Addict. 1993;2:126-130. 1988;319:1318-1330. trolled trial of sustained-release bupropion, a nico- 72. US Department of Health and Human Services. The 34. Orleans CT, Resch N, Noll E, et al. Use of trans- tine patch, or both for smoking cessation. N Engl Health Consequences of Smoking: Nicotine Ad- dermal nicotine in a state-level prescription plan J Med. 1999;340:685-691. diction: A Report of the Surgeon General, 1988. for the elderly. JAMA. 1994;271:601-607. 55. US Department of Health and Human Services. To- Atlanta, Ga: Centers for Disease Control, Office on 35. Silagy C, Mant D, Fowler G, Lodge M. Meta- bacco Use Among US Racial/Ethnic Minority Smoking and Health; 1988. DHHS publication analysis on efficacy of nicotine replacement thera- Groups—African Americans, American Indians (CDC) 88-8406. pies in smoking cessation. Lancet. 1994;343:139- and Alaska Natives, Asian American and Pacific 73. Evans NJ, Gilpin E, Pierce JP, et al. Occasional 142. Islanders, and Hispanics: A Report of the Sur- smoking among adults: evidence from the Cali- 36. Ahluwalia JS, McNagny SE, Clark WS. Smoking geon General. Atlanta, Ga: US Dept of Health and fornia survey. Tob Control. 1992;1:169-175. cessation among inner-city African Americans us- Human Services, Centers for Disease Control and 74. Shiffman S, Fisher LB, Zettler-Segal M, Benowitz ing the nicotine transdermal patch. J Gen Intern Prevention, National Center for Chronic Disease NL.Nicotineexposureamongnondependentsmok- Med. 1998;13:1-8. Prevention and Health Promotion, Office of Smok- ers. Arch Gen Psychiatry. 1990;47:333-336. 37. Fiore MC, Smith SS, Jorenby DE, Baker TB. The ing and Health; 1998. 75. Hughes JR. Smoking and alcoholism. In: Hat- effectiveness of the nicotine patch for smoking ces- 56. Centers for Disease Control. Cigarette smoking sukami DK, Cox J, eds. Behavioral Approaches to sation. JAMA. 1994;271:1940-1947. among blacks and other minority populations. Addiction. New York, NY: Calmers; 1994:1-3. 38. Leischow SJ, Castellini S, Merikle E. The efficacy MMWR Morb Mortal Wkly Rep. 1987;36:405- 76. Glassman AH. Cigarette smoking: implications for of nicotine patch as an over-the-counter medica- 407. psychiatric illness. Am J Psychiatry. 1993;150: tion. J Addict Dis. 1997;16:140. 57. US Department of Health and Human Services. Re- 546-553. 39. Hays JT, Croghan IT, Offord KP, et al. Over-the- ducing the Health Consequences of Smoking: 25 77. Hall SM, Munoz RF, Reus VI, Sees KL. Nicotine, counter (OTC) transdermal nicotine patch therapy. Years of Progress: A Report of the Surgeon Gen- negative affect, and depression. J Consult Clin Psy- J Addict Dis. 1997;16:136. eral. Washington, DC: US Dept of Health and Hu- chol. 1993;61:761-767. 40. Schneider NG, Lunell E, Olmstead RE, Fager- man Services, Public Health Service, Centers for 78. Hughes JR, Gulliver SB, Fenwick JW, et al. Smok- strom KO. Clinical pharmacokinetics of nasal nico- Disease Control, Center for Chronic Disease Pre- ing cessation among self-quitters. Health Psy- tine delivery: a review and comparison to other vention and Health Promotion, Office on Smok- chol. 1992;11:331-334. nicotine systems. Clin Pharmacokinet. 1996;31: ing and Health; 1989. DHHS publication (CDC) 89- 79. Kottke TE, Brekke ML, Solberg LI, Hughes JR. A 65-80. 8411. randomized trial to increase smoking interven- 41. Sutherland G, Stapleton JA, Russel MAH, et al. 58. Fiore MC, Novotny TE, Pierce JP, Hatziandreu EJ, tion by physicians: doctors helping smokers, round Randomized controlled trial of nasal nicotine spray Patel KM, Davis RM. Trends in cigarette smok- 1. JAMA. 1989;261:2101-2106. in smoking cessation. Lancet. 1992;340:324- ing in the US: the changing influence of gender 80. Hughes JR, Gust SW, Keenan R, et al. Long- 329. and race. JAMA. 1989;261:49-55. term use of nicotine vs placebo gum. Arch Intern 42. McNeil Consumer Products. Physicians’ Desk Ref- 59. Leischow SJ, Hill A, Cook G. The effects of trans- Med. 1991;151:1993-1998. erence. 52nd ed. Montvale, NJ: Medical Econom- dermal nicotine for the treatment of Hispanic 81. Hughes JR. Dependence potential and abuse li- ics Co; 1998:1545-1548. smokers. Am J Health Behav. 1996;20:304-311. ability of nicotine replacement therapies. Biomed 43. Bergstorm M, Nordberg A, Lunell E, Antoni G, 60. Parker SL, Tong T, Bolden S, Wingo PA. Cancer Pharmacother. 1989;43:11-17. Landstrom B. Regional deposition of inhaled 11C- statistics, 1997. Cancer J Clin. 1997;47:5-27. 82. American Psychiatric Association. Practice guide- nicotine vapor in human airway as visualized by 61. Grunberg NE, Winders SE, Wewers ME. Gender line for the treatment of patients with nicotine de- positron emission tomography. Clin Pharmacol differences in tobacco use. Health Psychol. 1991; pendence. Am J Psychiatry. 1996;153(suppl):1-31. Ther. 1995;57:309-317. 10:143-153. 83. Fiore MC, Jorenby DE, Baker TB, Kenford SL. To- 44. Schneider NG, Olmstead R, Nilsson F, Mody FV, 62. Solomon LJ, Flynn BS. Women who smoke. In: bacco dependence and the nicotine patch: clini- Franzon M, Doan K. Efficacy of a nicotine inhaler Orleans CT, Slade JD, eds. Nicotine Addiction: Prin- cal guidelines for effective use. JAMA. 1992;268: in smoking cessation: a double-blind, placebo- ciples and Management. New York, NY: Oxford 2687-2694. controlled trial. Addiction. 1996;91:1293-1306. University Press; 1993:339-349. 84. Schneider NG, Jarvik ME, Forsythe AB, Read LL, 45. Leischow SJ, Nilsson F, Franzon M, Hill A, Otte 63. Gourlay SG, Benowitz NL. Is clonidine an effec- Elliot ML. Nicotine gum in smoking cessation: a P, Merikle EP. Efficacy of the nicotine inhaler tive smoking cessation therapy? Drugs. 1995;50: placebo controlled, double-blind trial. Addict Be- as an adjunct to smoking cessation. Am J Health 197-207. hav. 1983;8:253-261.

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©2000 American Medical Association. All rights reserved. 85. Hurt RD, Dale LC, Fredrickson PA, et al. Nicotine Great American Smokeout and availability of over- to Parents. Contact a local chapter, or write the Ameri- patch therapy for smoking cessation combined the-counter nicotine medications. MMWR Morb can Heart Association, 7272 Greenville Ave, Dallas, with physician advice and nurse follow-up. JAMA. Mortal Wkly Rep. 1997;46:867-871. TX 75231. Telephone (800) AHA-USA1 (242-8721). 1994;271:595-600. 94. Baillie A, Mattick RP, Hall W, Webster P. Meta- Internet: http://www.americanheart.org. 86. Sachs DPL, Sawe U, Leischow SJ. Effectiveness analytic review of the efficacy of smoking cessa- 3. The American Cancer Society offers a wide variety of a 16-hour transdermal nicotine patch in medi- tion interventions. Drug Alcohol Rev. 1994;13: of materials including antismoking programs cal practice setting, without intensive group coun- 157-170. aimed at young people. Consult a local chapter to seling. Arch Intern Med. 1993;153:1881-1890. 95. Kottke TE, Battista RN, DeFriese GH, Brekke ML. obtain materials, or write the American Cancer 87. Tonnesen P, Norregaard J, Simonsen K, Sawe U. Attributes of successful smoking cessation inter- Society, 1599 Clifton Rd NE, Atlanta, GA 30329. A double-blind trial of a 16-hour transdermal nico- ventions in medical practice. JAMA. 1988;259: Telephone: (800) ACS-2345. Internet: http:// tine patch in smoking cessation. N Engl J Med. 2882-2889. www.cancer.org. 1991;325:311-315. 96. Law M, Tang JL. An analysis of the effectiveness 88. Blondal T, Franzon M, Westin A. A double-blind of interventions intended to help people stop smok- 4. The National Cancer Institute offers free publica- randomized trial of nicotine nasal spray as an aid ing. Arch Intern Med. 1995;155:1933-1941. tions Quit for Good and Clearing the Air. Call (800) in smoking cessation. Eur Respir J. 1997;10: 4-CANCER (422-6237). Internet: http://www 1585-1590. SUGGESTED HELPS .nci.nih.gov. 89. Hjalmarson A, Franzon M, Westin A, Wiklund O. 5. National Heart, Lung, and Blood Institute, Building Effect of nicotine nasal spray on smoking cessa- 1. The American Lung Association (ALA) offers sev- 31, Room 4A21, Bethesda, MD 20892. Telephone tion. Arch Intern Med. 1994;154:2526-2572. eral manuals, including Freedom From Smoking in (301) 496-4236. 90. Schneider NG, Olmstead R, Mody FV, et al. Effi- 20 Days (how to quit), A Lifetime of Freedom From 6. Nicotine Anonymous, PO Box 591777, San Francisco, cacy of a nicotine nasal spray in smoking cessa- Smoking (avoiding relapse), and Freedom From CA 94159-1777. Telephone (415) 750-0328. tion: a placebo-controlled, double-blind trial. Smoking for You and Your Baby (a quit program 7. American Academy of Family Physicians (AAFP) of- Addiction. 1995;90:1671-1682. for pregnant women). A contribution of $7 is re- fers the “AAFP Stop Smoking Kit” for use in office 91. Hajek P, West R, Foulds J, Nilsson F, Burrows S, quested for the manuals, which can be obtained practice, with audiotapes for physicians and office Meadow A. Randomized comparative trial of nico- through local ALA chapters, or by writing the Ameri- staff, a charting system, and self-help materials for tine polacrilex, a transdermal patch, nasal spray, patients. The cost is $60 for AAFP members and $90 and an inhaler. Arch Intern Med. 1999;159:2033- can Lung Association, 1740 Broadway, New York, 2038. NY 10019. Telephone (800) LUNG-USA. Internet: for nonmembers. Call (800) 274-2237, ext 5500. 92. Hughes JR, Goldstein MG, Hurt RD, Shiffman S. http://www.lungsusa.org. 8. Kits that come alongside the display or with the pur- Recent advances in the pharmacotherapy of smok- 2. The American Heart Association offers free publica- chase of nicotine replacement products and bupro- ing. JAMA. 1999;281:72-76. tions including Calling It Quits, Smoking and Heart pion, including such helps as a toll-free counseling 93. Burton SL, Kemper KE, Baxter TA, Shiffman S, Disease, Smoking and Strokes: Two Things You Can telephone number, a smoking cessation guide, Gitchell J, Currence C. Impact of promotion of the Live Without, and Children and Smoking: A Message and/or smoking cessation videotapes.

Clinical Pearl

Spironolactone for Heart Failure In a large randomized trial of patients with severe heart failure (left ventricular ejection fracture of no more than 0.35), at a mean follow-up of 2 years, patients in the group that received 25 mg of spironolactone had a relative risk of death of 0.70 (95% CI, 0.60-0.82; PϽ.001) compared with the group that received placebo. The patients who received spironolactone also had fewer hospital admissions and better cardiac function status. Gynecomastia or breast pain was reported by 10% of the men who received spironolactone. (N Engl J Med. 1999;341:709-717.)

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