MICHAEL C. FIORE, MD, MPH Professor of Medicine and Director, Center for Tobacco Research and Intervention, University of Wisconsin Medical School,
Madison; and Guideline Panel Chair, US Public Health Service clinical practice guideline, Treating Tobacco Use and Dependence.
ERIC C. WESTMAN, MD, MHS Associate Professor of Medicine, Duke University Medical Center, Medical Director, Duke Center for Nicotine and Smoking Cessation
Research, Durham, NC.
Within seconds of inhaling cigarette smoke, a bolus of nicotine travels from the carotid arteries to the brain where the
molecules bind to nicotine receptors. Nicotine stimulates the norepinephrine and serotonin systems, enhancing concentration
and memory and decreasing anxiety. This results in dopamine secretion that causes pleasurable sensations and relief of symptoms
of nicotine deprivation. Nicotine also interacts with acetylcholine receptors, creating a variety of physiologic reactions.
Some reactions are beneficial, such as suppression of appetite and pain, while others are not, such as elevated BP and nicotine
addiction. Nicotine replacement therapy mimics but does not match these intense effects caused by the nicotine in cigarette
smoke. ILLUSTRATION: DNA ILLUSTRATIONS INC.
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Forty years after the first report on smoking and health, in May 2004, the US Surgeon General released a new report, revealing
for the first time that cigarette smoking causes diseases in nearly every organ of the body and is conclusively linked to
diseases such as leukemia, cataracts, pneumonia, and cancers of the cervix, kidney, pancreas, and stomach.1 According to the Surgeon General, smoking kills an estimated 440,000 Americans prematurely each year. On average, men who
smoke cut their lives short by 13.2 years, and female smokers lose 14.5 years (see "Women and smoking"). The economic toll
exceeds $157 billion each year in the United States—$75 billion in direct medical costs and $82 billion in lost productivity.
A number of smoking cessation programs have been found to be effective, particularly those that combine pharmacological treatment
and behavioral interventions, such as counseling.2 According to a review of 123 trials in the Cochrane Tobacco Addiction Group, all of the commercially available forms of nicotine
replacement therapy are effective as part of a strategy to promote smoking cessation.3 They increase the odds of quitting approximately 1.5- to 2-fold regardless of setting.
Incorporating screening and treatment for tobacco use is a sensible, cost-effective way to reduce this mortality and the morbidity
that precedes it. While repeated physician interventions may be required to help patients achieve permanent abstinence from
smoking, effective treatments are now available that can be offered as part of standard medical care.
The guideline from the US Public Health Service (PHS), Treating Tobacco Use and Dependence: A Clinical Practice Guideline, emphasizes the critical role that primary care physicians play in helping patients quit.2 It offers practical tips and evidence-based treatment recommendations that are easy to implement (http://www.surgeongeneral.gov/tobacco/).
SCREENING FOR TOBACCO USE Primary care physicians can institutionalize the identification, documentation, and treatment of every patient who uses tobacco
by using the following recommendations that the guideline calls the 5 As. They are
Ask At every visit, ask all patients about tobacco use, and document their response. Strategies for implementation include asking
about tobacco use as part of the vital signs examination, placing tobacco-use-status stickers on patient charts, or using
computerized medical-record flags. Patients who have never used tobacco or who stopped using it years ago do not need repeated
assessments.
Advise Let patients know, in a clear, strong, and personalized manner, that you urge them to quit.
Assess Find out whether patients are willing to quit now or at least within the next 30 days.
Assist Help patients plan to quit by setting a date; anticipating challenges such as nicotine withdrawal symptoms; providing practical
counseling; reviewing past attempts to quit; and urging total abstinence. Prescribe pharmacotherapy and provide educational
materials on smoking cessation.
Arrange follow-up Smokers trying to quit are at high risk of relapse, particularly during the first 2 weeks after the quit date. Follow up
in person or by telephone during this time.
How often do physicians actually incorporate these types of smoking cessation efforts into routine office visits, and what
are the effects of patient, physician, and office characteristics on the frequency of these efforts? Researchers from the
Robert Wood Johnson Foundation gathered data on these issues in 38 primary care practices using direct observation of physician-patient
encounters, a physician survey, and on-site examination of office systems for supporting smoking cessation.4
Tobacco was discussed during 633 of 2963 encounters (21%) and discussion was more common in the 58% of practices with standard
forms for recording smoking status. It was also more common during new patient visits, but this dialogue occurred less often
with older patients and with physicians in practice more than 10 years. Of 244 smokers identified, physicians implemented
smoking cessation therapy for 38%.4
Table 1: Pharmacotherapy for smoking cessation
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PRESCRIBING PHARMACOTHERAPY The PHS guideline urges that all smokers wanting to quit be offered pharmacotherapy, except those smoking fewer than 10 cigarettes
a day, women who are pregnant or breastfeeding, and adolescent smokers (see Table 1). Because tobacco dependence clearly meets
all criteria for a drug dependence disorder, the guideline panel concluded that it is inappropriate to reserve pharmacotherapy
until patients have tried to quit on their own; because 95% of these unaided quit attempts fail.1 The first-line pharmacotherapies recommended in the guideline are
- Bupropion, sustained-release (SR)
- Nicotine patch
- Nicotine polacrilex (gum)
- Nicotine inhaler
- Nicotine nasal spray.
The second-line recommended therapies are
Because of the lack of data on which of the first-line medications is most effective, choice of treatment depends on your
familiarity with the medications, previous patient experience with a therapy, and patient preferences and characteristics.
Some suggestions for specific subgroups are available, however. Patients with cardiovascular disease may safely receive any
of these therapies. Bupropion SR or nicotine gum may reduce, but not prevent, weight gain—a consideration in patients concerned
about this issue. Prescribe lower dosages of any therapy for relatively light smokers (10-15 cigarettes daily), although dosage
changes are unnecessary for bupropion SR. For depressed patients, consider bupropion SR or nortriptyline first. Finally, recent
data suggest that women smokers may be more successful with bupropion SR.5
Drugs mentioned in this article
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Bupropion SR This FDA-approved medication for smoking cessation (with the brand name Zyban, as opposed to Wellbutrin, which is primarily
for depression) is the first non-nicotine medication to be found effective for this purpose. Bupropion, with a mechanism of
action apparently involving the blocking of dopamine and/or norepinephrine reuptake, doubles long-term abstinence rates compared
with placebo. It is contraindicated in patients with a seizure disorder, bulimia, or anorexia nervosa, those taking a monoamine
oxidase inhibitor, or those taking another medication containing bupropion.
Several recent studies identified specific prescribing strategies for bupropion. Predictors of abstinence were targeted by
researchers conducting a double-blind, placebo-controlled, dose-response trial to identify which of 615 patients would benefit
most from the SR form of bupropion for smoking cessation.6 Participants smoked 15 or more cigarettes a day and wanted to quit. They were randomly assigned to take placebo or bupropion
SR, 100, 150, or 300 mg/d, for 7 weeks, and were followed for 45 weeks. Predictors of abstinence included bupropion SR dosage,
older age, few cigarettes smoked per day, time previously abstinent, absence of other smokers in the household, and many previous
cessation attempts.
The efficacy of repeated use of bupropion SR was tested in 450 smokers in a randomized, double-blind trial.7 Patients who had previously used bupropion in a failed smoking cessation attempt were given bupropion SR or placebo. In participants
receiving bupropion SR, 27% remained abstinent compared with 5% of participants receiving placebo.
Even though bupropion SR is FDA approved for only 6 months of treatment, a recent study shows that use of the drug for 12
months is not only safe but it reduces the relapse rate.8 The 784 participants all took bupropion SR for smoking cessation, but after 7 weeks, half of the participants were switched
to placebo. At the end of the year, 55% of the patients who continued on bupropion were abstinent versus 42% in the placebo
group. Researchers also found that patients taking bupropion gained less weight than those taking placebo.
Nicotine patch Most nicotine replacement therapies were introduced within the past 10 years, and data continue to support their safety and
efficacy. It has been firmly established that there are no contraindications to their use and that these products do not promote
cardiovascular disease.9 Evidence suggests that there is little chance that nicotine replacement therapies pose any risk of cancer. The safety and
abuse liability records of these products are excellent. Unlike cigarettes, they do not produce carbon monoxide and carcinogens.
The nicotine patch is available both as an OTC and prescription medication. A new patch is placed on a hairless body site
each morning, usually on the trunk between the neck and waist. Local skin reactions can be treated with hydrocortisone or
triamcinolone cream. Rotating patch sites can reduce irritation.
Nicotine gum This exclusively OTC agent improves long-term abstinence rates by 30% to 80% compared to placebo.1 The 4-mg dose gum is more effective than the 2-mg gum, especially in highly dependent smokers.1
Proper chewing technique is important—the gum should be chewed slowly until a peppery or minty taste is sensed. It should
then be tucked between the cheek and gum to facilitate absorption through the oral mucosa. Chewing and tucking should be performed
intermittently for about 30 minutes or until the taste fades. Eating or drinking anything except water for 15 minutes before
and during chewing should be avoided. Patients need to chew enough gum on a fixed schedule to obtain the intended benefit.
Nicotine inhaler and nasal spray These agents are available exclusively as prescription medications and have been shown to more than double long-term abstinence
rates compared with placebo. Frequent puffing is recommended with the inhaler, and eating or drinking before and during administration
should be avoided. A nicotine inhaler cartridge contains 10 mg of nicotine, of which approximately 4 mg is delivered.
For the nasal spray, the head should be tilted slightly back during use, and patients should not sniff, swallow, or inhale
the medication. Initial dosing should be 1 to 2 doses per hour, increasing the number of doses as needed.
Nicotine lozenge Nicotine lozenges were recently approved by the FDA and are available in 1-, 2-, and 4-mg doses. Dosage is chosen according
to how soon smokers have their first cigarette after waking. Those who wait less than 30 minutes before lighting up should
use the higher dose. One-mg dose lozenges can be used as an alternative to nicotine gum when chewing is contraindicated (denture
wearers).
Second-line therapies Although clonidine and nortriptyline can be effective for treating tobacco dependence, they are not FDA approved for this
indication and side effects may be greater than with first-line treatments. They should only be considered when first-line
therapies have failed or are contraindicated.
Clonidine A specific dosage for treating tobacco dependence has not yet been established for this medication, which is primarily used
to treat hypertension. Clonidine should not be withdrawn abruptly because side effects, such as nervousness, agitation, headache,
rapid rise in BP, and elevated catecholamine levels, may occur.
Nortriptyline This agent is FDA approved only as an antidepressant. In smoking cessation therapy, it is initiated 10 to 28 days before
the quit date. Because nortriptyline produces sedation, patients should be careful when driving and using machinery. The risk
of overdose is relatively high, and the drug may be cardiotoxic, therefore a physician should monitor its use.
Combination nicotine replacement therapy Although the FDA has not approved any specific combination therapies, the guideline recommends them as second-line therapies.
Some experts think combination therapy may be more effective than monotherapy, especially when one of the therapies involves
passive dosing that produces steady drug levels and the other permits ad libitum dosing. Most studies on combination therapy
investigated the nicotine patch in combination with either nicotine gum, nicotine lozenge, or nicotine nasal spray.10
Combination nicotine inhaler and nicotine patch therapy appears safe and tolerable when used for smoking cessation. In an
open-label trial, 30 healthy volunteers used a combination of inhaler and patch therapy (15 mg for 16 hours) for 6 weeks,
then inhalers alone for an additional 6 weeks. Abstinence at 12 weeks was 30%.11
Long-term use of pharmacotherapy Most patients who have persistent withdrawal symptoms or have difficulty quitting can safely use pharmacotherapy for 6 months
or longer.1 Some who quit may prefer to continue using nicotine replacement gum, nasal spray, or inhalers on a long-term basis for security.
Although weaning should be encouraged, continuation of smoking cessation therapy is preferable to relapse.
Unproven pharmacotherapies Although many patients who find it difficult to quit smoking have a history of depression, antidepressants other than nortriptyline
and bupropion are not recommended for this purpose. Anxiolytics such as diazepam have been studied for smoking cessation with
inconclusive results. The guideline also cautions that studies of mecamylamine were equivocal.
PATIENTS UNABLE OR UNWILLING TO QUIT Because so many people have quit smoking, the population of remaining smokers may be more difficult to treat because of greater
nicotine dependence, a higher comorbidity of psychiatric and substance abuse disorders, or less education. In a meta-analysis
of 23 clinical trials on smoking cessation, negative correlations were found between year of publication and end-of-treatment
abstinence rates.12 The researchers concluded that the efficacy of clinical trials appears to be declining, the probable cause being the increasing
recalcitrance of patients who continue to smoke despite social and medical pressures to quit.
The guideline recommends implementing these 5 Rs to motivate reluctant patients to quit:
Relevance Ask patients to identify personal reasons why they should quit.
Risks Emphasize the risks that are most relevant to the individual patient. Acute risks include difficulty breathing and increased
serum carbon monoxide levels. Long-term risks include MI, stroke, and cancer. Environmental risks include family members'
exposure to secondhand smoke that can cause lung cancer, heart disease, and respiratory tract infections.
Rewards Highlight the benefits of quitting, including better health, setting a good example for children, saving money, reducing
skin aging and wrinkling, and getting rid of smoker's cough and tobacco odor on clothes.
Roadblocks Acknowledge the barriers to quitting, and offer patients resources to overcome them. Common barriers are withdrawal symptoms,
weight gain, and fear of failure.
Repetition Repeat these interventions at every visit. Let patients know that it is very common to need many attempts to quit and that
they can be successful in the future despite past failures.
Concerns about weight gain are cited frequently by patients who are unwilling to quit. Researchers have found that a treatment
program focusing on reducing women's concerns about weight gain significantly improves smoking cessation.13 Unlike previous interventions that assumed preventing weight gain after quitting was the best approach, this study concentrated on reducing patient concerns about weight, rather than the weight
gain itself. The study emphasized to patients that the health benefits of quitting far exceed the health risks of weight gain.
In addition, bupropion SR and nicotine gum have been shown to blunt, but not eliminate, weight gain.14,15
CONSIDERING COMORBIDITIES Vulnerability to smoking and lack of treatment response may be due to psychiatric comorbidities. Although this factor is well-documented,
a recent study at Harvard Medical School, Boston, Mass, enrolled 120 smokers in a multicenter, double-blind, randomized, 10-week
smoking cessation trial with fluoxetine plus behavioral treatment.16 Self-report measures were used to assess psychiatric symptoms throughout treatment and during a 6-month follow-up.
A lifetime mood, anxiety, or substance use disorder was diagnosed in about 62% of participants despite stringent study exclusion
criteria. These conditions correlated with higher smoking rates and nicotine dependence, depressed mood, and greater self-report
of anxiety and stress. Psychiatric comorbidity did not predict treatment outcome, however. The investigators suggest that
clinicians carefully evaluate psychiatric diagnoses and symptoms in chronic smokers to optimize patient-treatment matching.
The guideline recommends referral for mental health counseling in addition to pharmacotherapy for these patients.
Smoking cessation after MI is associated with a 50% reduction in mortality, but in-hospital smoking cessation interventions
are not implemented regularly in clinical practice.17 Researchers at Connecticut's Hartford Hospital assigned 100 smokers admitted with MI to minimal care or a hospital-based smoking
cessation program.17 Intervention consisted of bedside cessation counseling followed by 7 telephone calls during the 6 months after discharge.
At follow-up, 34% of participants in minimal care and 55% of participants in intervention were abstinent at 6 and 12 months.
Wendy Theobald, PhD, University of Wisconsin Medical School, Center for Tobacco Research and Intervention, Madison, assisted
with the update of this article.
This consensus article is based on interviews with Dr Fiore and Dr Westman.
Dr Fiore discloses that he has served as a consultant, given lectures, and conducted research for GlaxoSmithKline, Pfizer,
and Sanofi-Synthelabo.
Dr Westman discloses that he has no financial involvements with any companies doing business in this field.
REFERENCES 1. Annual smoking-attributable mortality, years of potential life lost, and economic costs—United States, 1995-1999. MMWR Morb Mortal Wkly Rep. 2002; 51:300-303.
2. Fiore MC, Bailey WC, Cohen SJ, et al. Treating Tobacco Use and Dependence. A Clinical Practice Guideline. Rockville, Md: US Dept of Health and Human Services, Agency for Health Care Research and Quality; 2000. AHRQ publication
00-0032.
3. Silagy C, Lancaster T, Stead L, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev, 2004;(3):CD000146.
4. Ellerbeck EF, Ahluwalia JS, Jolicoeur DG, et al. Direct observation of smoking cessation activities in primary care practice.
J Fam Pract. 2001;50:688-693.
5. Smith SS, Jorenby DE, Leischow SJ, et al. Targeting smokers at increased risk for relapse: treating women and those with
a successful outcome. Nicotine Tob Res. 2003;5:99-109.
6. Dale LC, Glover ED, Sachs DP, et al. Bupropion for smoking cessation: predictors of successful outcome. Chest. 2001;119:1357-1364.
7. Gonzales DH, Nides MA, Ferry LH, et al. Bupropion SR as an aid to smoking cessation in smokers treated previously with
bupropion: a randomized placebo-controlled study. Clin Pharmacol Ther. 2001;69:438-444.
8. Hays JT, Hurt RD, Rigotti NA, et al. Sustained-release bupropion for pharmacologic relapse prevention after smoking cessation:
a randomized, controlled trial. Ann Intern Med. 2001;135:423-433.
9. Hughes JR. New treatments for smoking cessation. CA Cancer J Clin. 2000;50:143-151.
10. Covey LS, Sullivan MA, Johnston JA, et al. Advances in non-nicotine pharmacotherapy for smoking cessation. Drugs. 2000;59:17-31.
11. Westman EC, Tomlin KF, Rose JE. Combining the nicotine inhaler and nicotine patch for smoking cessation. Am J Health Behav. 2000;24:114-119.
12. Irvin JE, Brandon TH. The increasing recalcitrance of smokers in clinical trials. Nicotine Tob Res. 2000;2:79-84.
13. Perkins KA, Marcus MD, Levine MD, et al. Cognitive-behavioral therapy to reduce weight concerns improves smoking cessation
outcome in weight-concerned women. J Consult Clin Psychol. 2001;69:604-613.
14. Richmond R, Zwar N. Review of bupropion for smoking cessation. Drug Alcohol Rev. 2003;22:203-220.
15. Nordstrom BL, Kinnunen T, Utman CH, et al. Long-term effects of nicotine gum on weight gain after smoking. Nicotine Tob Res. 1999;1:259-258.
16. Keuthen NJ, Niaura RS, Borrelli B, et al. Comorbidity, smoking behavior and treatment outcome. Psychother Psychosom. 2000;69:244-250.
17. Dornelas EA, Sampson RA, Gray JF, et al. A randomized controlled trial of smoking cessation counseling after myocardial
infarction. Prev Med. 2000;30:261-268.
SUGGESTED READING Breslau N, Johnson EO, Hiripi E, et al. Nicotine dependence in the United States: prevalence, trends, and smoking persistence.
Arch Gen Psychiatry. 2001;58:810-816.
Glassman AH, Covey LS, Stetner F, et al. Smoking cessation and the course of major depression: a follow-up study. Lancet. 2001;357:1929-1932.
Hughes J. Distinguishing nicotine dependence from smoking. Why it matters to tobacco control and psychiatry. Arch Gen Psychiatry. 2001;58:817-818.
Klimek V, Zhu MY, Dilley G, et al. Effects of long-term cigarette smoking on the human locus coeruleus. Arch Gen Psychiatry. 2001;58:821-827.
Stevens VJ, Glasgow RE, Hollis JF, et al. Implementation and effectiveness of a brief smoking-cessation intervention for hospital
patients. Med Care. 2000;38:451-459.
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Women and smoking The evidence on women and smoking together makes reducing and preventing smoking one of the highest contemporary priorities
for women’s health.1 Women who stop smoking greatly reduce their risk of dying prematurely, and quitting smoking is beneficial at all ages. Although
some clinical intervention studies suggest that women may have more difficulty quitting smoking than men, national survey
data show that women are quitting at rates similar to or even higher than those for men. Prevention and cessation interventions
are generally of similar effectiveness for women and men. The following statistics show the scope of the problem:
- Lung cancer, once rare among women, has surpassed breast cancer as the leading cause of female cancer death in the United
States, now accounting for 25% of all cancer deaths among women. About 90% of all lung cancer deaths among women who continue
to smoke are attributable to smoking.
- Smoking prevalence today is nearly 3 times higher among women who have only 9 to 11 years of education (32.9%) than among
women with 16 or more years of education (11.2%).
- In 2000, 29.7% of high school senior girls reported having smoked within the past 30 days.
- Since 1980, approximately 3 million US women have died prematurely from smoking-related neoplastic, cardiovascular, respiratory,
and pediatric diseases, as well as cigarette-caused burns.
- Each year during the 1990s, US women lost an estimated 2.1 million years of life due to smoking-attributable premature deaths.
Additionally, women who smoke experience gender-specific health consequences, including increased risk of various adverse
reproductive outcomes.
1. Women and smoking: a report of the surgeon general. MMWR Morb Mortal Wkly Rep. 2002;51(RR12):1-20.
On the horizon
Quit smoking and lose weight with one pill?
A drug that blocks a cellular pathway involved in cravings could help patients quit smoking and lose weight. Researchers at
the European Society of Cardiology’s annual meeting in Munich, Germany, in August, presented the results of a trial that placed
1507 overweight subjects on a diet and exercise program designed to help them lose weight.1 Half of the subjects also took a single 20-mg dose of a drug called rimonabant hydrochloride; half took placebo. After a
year, those on rimonabant had lost an average of 8.6 kg, and 8.5 cm off their waistline. Those taking a placebo averaged 3.8
kg and 4.5 cm.
The drug’s manufacturer Sanofi-Synthelabo is also investigating rimonabant’s ability to help with smoking cessation. Rimonabant
is the first of a new class of drugs called selective CB1 blockers. CB1 blockers act on the endocannabinoid (EC) system, a
natural system that modulates the body’s energy balance and nicotine dependence. An overstimulated EC system is thought to
play a role in obesity and in tobacco dependence, and CB1 blockers are supposed to reduce this overstimulation.
In addition to the endocannabinoids, recent developments in understanding the neurobiology of nicotine dependence have also
identified several other neurotransmitter systems that might contribute to smoking maintenance including endogenous opioids,
gamma-aminobutyric acid (GABA), and glutamate.2 The national Institute on Drug Abuse (NIDA) is turning its attention to smoking cessation research. One new line of research
focuses on methoxsalen, a compound that inhibits cytochrome P-450 2A6. Inhibiting this cytochrome keeps nicotine circulating
in the blood longer, decreasing the desire to smoke. Selegiline, an inhibitor of monoamine oxidase, an enzyme that breaks
dopamine in the brain, is another focus of smoking cessation research.3
1. Available at: http://www.nature.com/news/2004/040830/full/040830-3.htm. Accessed October 5, 2004.
2. George TP, O’Malley SS. Current pharmacological treatments for nicotine dependence. Trends Pharmacol Sci. 2004;25:42-48.
3. Available at: http://www.drugabuse.gov/NIDA_notes. Accessed October 5, 2004.
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