Chapter 3

Table of Contents

The burden of suffering due to tobacco use is staggering, and irreconcilable with the relative social and medical complacency with which it is treated. Smoking is the leading cause of preventable premature death in our society, claiming more lives around the world each year than war: it may be the most important public health issue of our time.^, Since most smokers see a physician each year, and most smokers report a desire to quit, primary care clinicians are well positioned to assist smokers in their cessation efforts. It is essential to provide effective cessation intervention for all smokers at each visit. Based on extensive reviews of the evidence, the following stepwise strategy is recommended:^,

1. Ask… about smoking at every opportunity;

2. Advise… all smokers to quit;

3. Assess… smokers' willingness to quit;

4. Assist… smokers' cessation efforts; and

5. Arrange… follow up.

1. Ask about smoking at every opportunity. One recommendation is to make tobacco use a "vital sign," querying about smoking at every visit. If a computerized record or reminder system can prompt for tobacco-use assessments, its use is strongly encouraged.

2. Advise all smokers to quit. In a clear, unambiguous, and personalized manner, the primary care provider should urge every user of tobacco to quit smoking at every clinical opportunity. Studies have shown that physician counseling can change behavior. Up to 70 percent of current smokers say that they would be more likely to quit if they were encouraged to do so by their physicians. Components of effective counseling interventions include relevance, risks, rewards, and repetition. Motivational information will have the greatest impact if it is relevant to the smoker's concerns and disease status, family and social situation, age, sex, and other personal characteristics. The patient should be helped to identify potential negative consequences of smoking, and assisted with personalizing the most relevant of these risks. The patient should then be helped to identify the benefits of smoking cessation, and assisted with personalizing the most relevant of these rewards, such as improved health, improved sports performance, and/or provision of a healthier home environment for children. Finally, this motivational intervention should be repeated or re-explored at every clinical opportunity. In general, it is effective to stress the rewards of giving up smoking rather than relying on risks and "scare tactics" alone.

• For example, it might be relevant for a concerned parent to learn of the increased risk of lung cancer in their spouse and children; and higher rates of smoking, increased risk of SIDS, asthma, ear disease, and respiratory infections in their children.^,
• For anyone, a "cold and cough" could immediately raise relevant discussion about the increased number and severity of respiratory infections in smokers, and the expectation of fewer illnesses with smoking cessation.
• A diagnosis of hypertension or hypercholesterolemia offers an opportunity to point out that smoking magnifies the risk of other cardiovascular diseases, and that the risk of heart attack declines significantly after only a year of abstinence from smoking.
• The need for even minor surgery should raise relevant discussion of poorer wound healing and higher complication rates among smokers.
• Besides short and long term health benefits, it can be useful to review the economic and social benefits of quitting as well. Most smokers are unaware that a one pack per day habit costs about $1000 per year, plus excess health care and insurance costs. Younger patients might be less responsive to concerns about the long-term consequences of smoking, but may be motivated to quit when advised that smoking causes premature facial wrinkling, stains teeth, causes bad breath, makes clothes smell and has detrimental effects on sports performance.

3. Assess each smoker's willingness to quit. Ask every smoker if he or she would be willing to quit at this time. If the patient is willing to make an attempt, provide Assistance (Step 4). If he or she is unwilling, then a weaning protocol may be suggested. Reinforce relevant motivations for quitting (Step 2) and provide some supportive written material if possible. Indicate that you will review the facts and their concerns with them during the next visit.

Smokers go through six stages in adjusting from smoking to a non-smoking lifestyle. When in precontemplation, a smoker is not ready to think about quitting, (and forceful urging may actually increase resistance to cessation) but relevant and thought-provoking information should be supplied. In contemplation, the smoker is considering quitting and may be receptive to encouragement and advice about the benefits of cessation. In preparation, the smoker is making plans to quit, and is very susceptible to assistance. In the action stage, a quit attempt is made and cessation efforts are strenuous throughout a period of high risk for relapse, typically three to six months. In the maintenance phase, a smoker moves beyond active cessation effort and is at lower risk for relapse, but is still adjusting to a smoke-free lifestyle. If successful, the smoker moves into termination after a year or so at which time there is much less risk for relapse.

4. Assist the smoker's cessation efforts. Assist the patient by suggesting a plan to quit including key advice regarding success factors, by encouraging the use of proven pharmacotherapy (nicotine replacement therapy or bupropion), and by providing supplementary self-help materials. In addition, the patient may be referred to a smoking cessation specialist or group cessation program.

A plan to quit should include a definitive "quit" date, preferably within two weeks of the counseling visit. During this time the patient should prepare for quitting by informing family, friends, and coworkers of the impending attempt and asking for their understanding and support. The patient should also prepare by removing cigarettes and avoiding smoking in places where he or she spends a lot of time, such as in the home or car (in order to decrease tobacco odors and break associations that provide an environmental cue for the urge to smoke). Planning should also include a review of any previous quit attempts to reinforce factors previously found helpful, and to plan around past reasons for relapse to minimize their recurrence. Either way, challenges to the cessation effort should be anticipated, particularly during the first few weeks.

Advice and suggestions to patients about expected physiological, psychological, and environmental barriers to quitting can help patients anticipate and cope. The most important physiologic barriers are nicotine withdrawal symptoms with tobacco craving, which are experienced by about 80 percent of abstinent smokers, and the problem of weight gain. Withdrawal symptoms include mild CNS disturbances (anxiety, irritability, difficulty concentrating, restlessness, headache, and drowsiness) and GI disturbances including hunger for sweets, which peak at 24-48 hours after cessation. Patients should be reassured that their symptoms are real, but will not last longer than a few weeks. Tobacco craving and hunger after this period is psychological, not physical. Mild weight gain (averaging about 10 pounds) is possible due to changes in caloric intake. This should be considered a negligible health threat compared to continued smoking, but is of particular concern to some patients. Nicotine replacement has been shown to delay the weight gain associated with smoking cessation.

Psychological reasons for relapse include stressful events, negative emotional states, and inadequate motivation to quit. If negative mood or depression is a serious problem, appropriate medications or referral to a specialist may be considered. Environmental causes of relapse include peer pressure, habitual smoking cues, alcohol consumption and social celebrations. The use of alcohol and/or marijuana is highly associated with relapse, and patients who stop smoking should consider limiting or abstaining from alcohol and marijuana during the cessation effort. The presence of other smokers in the household is also associated with smoking relapse. Patients should consider quitting with their partner, or developing special plans to maintain abstinence (e.g. no smoking by the partner in the house and car or in the quitter's presence). After the "quit" date, total abstinence is essential due to risk of relapse.

Encourage the use of proven pharmacotherapy except in special circumstances. Pharmacotherapy for smoking cessation includes nicotine replacement therapy (NRT) and treatment with Zyban, a long-acting form of the antidepressant bupropion, which are described in detail under "Pharmacotherapeutic strategies," below.

Provide supplementary self-help materials. Self-help written materials may be informational and supportive, or relatively complete multi-step programs for smoking cessation. Self-help materials may be obtained free or for a nominal charge from a variety of organizations, and useful materials are now available free from reputable online sources:

Consider referral to a smoking cessation specialist or group cessation program. Group behavior modification programs generally have better results than self-help programs. Some available programs at CPMC include:

CPMC's Dental & Oral Surgery Smoking Cessation Program (305-9054). Programs are individualized for each person, typically four to eight sessions in duration. Once a patient is tobacco free, maintenance of abstinence is promoted by group sessions. The program is available to anyone, including Medicaid, Medicare, and self-pay patients.

CPMC's Clinical Psychopharmacology Smoking Cessation Program (543-5754). This smoking clinic offers individual behavior counseling and medication therapy to smokers in the setting of clinical trials. There is no fee for treatment. Typically, individuals between the ages of 18 and 70 who have smoked a pack a day for at least one year and have made previous attempts to stop smoking are eligible for the program.

CPMC Smoking Cessation Program (305-9985, Dr. Daniel Siedman). This program suits the need for referrals in the private practice setting. It is an individual and group behavior modification program including medical support for smokers with co-occurring depression or other psychological disorders. The program costs $110 for the initial evaluation. Group sessions are then $50 per session, individual one-hour sessions cost $110 per session, and individual half-hour sessions are $75 per session. Medicare is accepted.

5. Arrange follow-up. For patients who have decided to quit, schedule follow-up visits to reinforce their decision, to deal with withdrawal and to discuss relevant concerns. Follow-up contact should occur soon after the quit date, preferably during the first week of smoking cessation, either by phone or in person. A second follow-up visit is recommended within the first month. Any successes should be profusely congratulated while continuing to impart individualized messages to patients about the benefits of quitting. If smoking has occurred, review the circumstances with the view that a lapse can be a valuable learning experience and is not a sign of inability or failure. Most smokers who succeed have done so only after making several attempts. It is important for smokers who relapse to know this, gain motivation, and try again. Assess adequacy of nicotine replacement therapy and its proper use (see below), and revise as indicated. Obtain a recommitment to total abstinence while anticipating repeated and new challenges in the immediate future.

Although nicotine has acute physiologic effects and causes addiction, it is not carcinogenic and does not play a role in the adverse health consequences associated with smoking. Meta-analyses support the effectiveness of all forms of nicotine replacement therapy (NRT) independent of the treatment setting or the intensity of additional support.^,,,, NRT doubles the quit-rate above any base rate determined by the level of supportive therapy and may also delay or decrease the weight gain associated with smoking cessation. Therapy should generally last for at least two to three months, during the period of greatest risk for a smoking relapse.

Many smoking cessation failures are associated with inadequate nicotine replacement. The immediate goal of NRT is to prevent the peaks and nadirs of blood nicotine levels that are characteristic of tobacco ingestion and that lead to, respectively, stimulation and tobacco craving. Higher levels of nicotine replacement, near 100 percent of a smoker's average daily intake, are more successful. Some people may require more or less (usually more) due to individual variation in absorption or metabolism of nicotine. Since smokers smoke to extract about 1 mg of nicotine per cigarette, a 1 pack per day (20 cigarettes per day) smoker likely receives near 100 percent nicotine replacement using a 21-mg/day patch. However, this patch dose likely underdoses heavier smokers, and higher nicotine doses (44-mg/day) have been shown to provide better relief from withdrawal symptoms and to increase short-term efficacy.^,

Stated contraindications to nicotine replacement include recent myocardial infarction or unstable angina and pregnancy or breast feeding, but these risks are speculative compared to known risks of continued smoking.^, Replacement therapy delivers nicotine more slowly than smoking, resulting in lower peak levels, and typically results in ingestion of less nicotine than normally consumed by smoking. It also eliminates the risks contributed by carbon monoxide and the roughly 4000 other chemicals and toxic constituents absorbed during cigarette combustion. Transdermal nicotine use has been shown to be safe in high-risk outpatients with cardiac disease.

The labeling of nicotine products includes potentially misleading suggestions. One recommendation directs users of medications for asthma and depression to consult their physician. This is because non-nicotine compounds in tobacco smoke increase the hepatic metabolism of many medications, and smoking cessation can result in increased medication levels. Nicotine use does not influence this effect, and there is no drug interaction between nicotine and medications for asthma or depression. Another labeled recommendation states that nicotine gum and patch should not be used at the same time. However, combined use has been shown to decrease withdrawal symptoms more than either form of nicotine alone, with no increase in adverse effects, so many smoking cessation specialists routinely recommend combined use of patch and gum. Lastly, the label recommends not smoking while using the patch or gum, but several studies have used NRT with continued smoking (as a harm-reduction strategy) without adverse events, and other studies indicate that the combined use of cigarettes and NRT is relatively safe. The main risk of simultaneous NRT and cigarette use is relapse or lack of cessation, with nicotine toxicity being a more remote possibility.

Nicotine polacrilex is available in a 2-mg dose (Nicorette) and a 4-mg dose (Nicorette DS). The 4-mg dose has been shown to be better in heavily dependent smokers, or those that smoke more than 25 cigarettes per day. The cost is about $48 for a "starter kit" box of 108 pieces, and about $28 for a "refill" box of 48 pieces.

The advantages of nicotine gum over the patch are that the dose can be easily titrated to the individual and it may satisfy some oral craving. Disadvantages are that it may cause side effects (unpleasant taste, throat irritation, mouth ulcers, hiccups, nausea, vomiting, and palpitations), absorption of nicotine may be decreased by acidic foods and liquids (cola, citrus juices, coffee) which should be avoided, smokers frequently underdose or dose themselves inconsistently, nighttime nadirs can result in morning tobacco craving and it requires more time to educate patients on proper use.

Nicotine gum should be chewed slowly and intermittently to allow proper absorption. Patients should chew it a few times, then "park it" between the gum and cheek for several minutes to allow absorption of nicotine before chewing it again. The amount of nicotine actually delivered to the systemic circulation is about half of the labeled amount. The suggested dosing is 1 piece every 30-60 minutes while awake, for a total of 10-16 pieces per day for an average 1 pack per day smoker (max 30 pieces per day for the 2-mg gum, and 20 pieces for the 4-mg gum). There is evidence to suggest that a fixed, rather than ad lib, dosing schedule may have superior results, and it is felt that the ad-lib schedule may promote behavioral and physical dependence.

Assuming absorption of about 1 mg of nicotine per smoked cigarette, the initial goal can be to replace 50-80 percent of a smoker's daily nicotine requirement. Thus a 1 pack per day smoker ingests about 20 mg of nicotine, and should replace 10 -16 mg of it with 20 - 32 mg of gum, or 10 - 16 pieces of 2 mg gum, chewed slowly and spaced evenly throughout the waking day. It should be used prophylactically, and patients should be advised not to wait to feel withdrawal symptoms before chewing a piece. The recommended use is for one to three months, with a weaning period of similar length. Weaning from the gum can be done by tapering the number of pieces used by one piece per week. The officially recommended duration of use is for a maximum of six months, but longer-term use has resulted in better abstinence rates.

In summary, first make sure the patient desires to quit, has selected a quit day, and has a behavioral strategy, even if it is as simple as written information and ongoing visits for cessation advice. Make sure there are no contraindications to nicotine therapy or use of the gum. If not, then prescribe or suggest the patient purchase one box of 2 mg gum, or consider the 4 mg gum for more heavily dependent smokers (>20 cigs/d or Fagerstrom Tolerance Scale > 6). Instruct in the proper use of gum (above) and caution against simultaneous smoking and gum use. Suggest starting on the "quit" day with a fixed dose schedule of 1 piece/hr while awake (or as above), and follow up within two weeks. If total abstinence has been maintained, then weaning can start after one to three months. If abstinence from smoking has not been maintained due to withdrawal symptoms, increase the dose to the maximum or change to the 4 mg gum. If side effects or dosing problems occur, review proper use or switch to the nicotine patch, or nasal or oral inhaler. Follow up at least monthly for three to six months.

Nicotine patches are available from four different manufacturers each with their own transdermal delivery system. Each patch is meant for application once daily on an upper body skin site and is labeled for the amount of nicotine that is absorbed during one day's use. The over the counter products are NicoDerm CQ and Nicotrol, which have very different usage profiles. Nicotrol comes as a single dose meant to deliver 15 mg of nicotine over 16 hours (applied in the morning and removed before sleep). Suggested use is for 6 weeks with no tapering period. In contrast, NicoDerm CQ comes in three dosages: "Step 1" with 21 mg/d, "Step 2" with 14 mg/d, and "Step 3" with: 7 mg/d of nicotine. Nicotrol CQ patches may be worn 16 or 24 hours per day, and suggested use is for 6 weeks at Step 1, followed by 2 weeks at Step 2 and then 2 weeks at Step 3. Although the longer duration of therapy, 24-hour nicotine coverage, and tapering with NicoDerm CQ may be more effective, this has not been tested, and it is also possible that the easier and shorter-term use of Nicotrol may result in greater success. Both NicoDerm CQ and Nicotrol are available in 7 and 14-patch boxes. The cost is about $25 for a 7 day supply of Nicotrol, and about $28 for a 7 day supply of NicoDerm.

The remaining (prescription-only) products are Habitrol (21, 14, 7 mg/d; 30 patches per box) and ProStep (22, 11 mg/d; 7 patches per box). Higher-dose (e.g. 44 mg) nicotine patch therapy reduces withdrawal symptoms in heavier smokers, but with potentially increased risk for nicotine toxicity and no proven improvement in long term abstinence from smoking.

The advantages of patches over the gum are that they are easy to use, have no oral side effects, provide a steady nicotine concentration for up to 24 hours that helps to decrease morning withdrawal symptoms, and weaning off nicotine may be easier than with the gum. Disadvantages include local cutaneous reactions, allergic reactions to the adhesive, and an inability to individualize or self-titrate dosing. Rigid dosing means that patches may not deliver enough nicotine (leading to withdrawal symptoms or early relapse) or that individuals may get an overdose of nicotine (causing diarrhea, nausea, nervousness, myalgias, arthralgias, insomnia, abdominal pain, and/or sweating).

Although there is no clear advantage of one patch over the other for smoking cessation, providers only need become familiar with the use of one patch. Since there are theoretical advantages that make the NicoDerm delivery system less sensitive to skin permeability factors, its use will be explained. First make sure the patient desires to quit, has selected a "quit" day, and has a behavioral strategy, even if it is as simple as written information and ongoing visits for cessation advice. Make sure there are no contraindications to nicotine therapy or use of the patch. If not, then prescribe or have the patient purchase a box of the "Step 1" (21 mg/d) NicoDerm CQ patches to be started on the quit day. Smokers should begin with a lower dose patch if they smoke less than 1/2 pack per day, if they weigh less than 100 pounds, or if they have significant coronary artery disease. Instruct in the proper use of the patch (above) and caution against the danger of simultaneous smoking and patch use. Follow up in 2-4 weeks and at least monthly while on the patch. If signs of nicotine overdose occur, then drop to the "Step 2" (14 mg/d) patch. If total abstinence has been maintained, then weaning can start after 6 weeks by using the "Step 2" for two weeks, and then the "Step 3" (7 mg/d) patch for 2 weeks. If complete abstinence from smoking has not been maintained due to withdrawal symptoms, consider combining patches (21 mg + 7 mg) or adding nicotine gum or the oral or nasal inhaler. Nicotine plasma levels produced by evenly spaced use of 7 pieces of 2-mg nicotine gum are roughly equivalent to levels produced by the 7-mg/d patch. If slipping or relapse occurs while on a lower dose patch, go to the next higher dose where abstinence was maintained, and continue for the recommended time. If relapse occurs while off the patch, the process can begin over again at the beginning. If weaning is successful, one option can be to prescribe nicotine gum to use for relapse prevention.

A theoretical benefit of the Nicotrol Inhaler is that it can provide smokers the comfort of a cigarette ritual with hand-to-mouth nicotine delivery during cessation, although the importance of these behavioral features in smoking cessation is unknown. The Nicotrol Inhaler is a plastic rod that looks like a cigarette holder and contains a replaceable cartridge of nicotine-impregnated cotton that delivers up to 4 mg of nicotine vapor when puffed. Although called an inhaler, the device is actually a puffing apparatus meant to deliver the majority of its nicotine to the mouth and posterior pharynx for mucosal absorption, similar to nicotine gum; no significant amount of nicotine actually reaches the lungs. Thus, the pharmacokinetics of the Inhaler are similar to nicotine gum; of the 4 mg that may be delivered buccally, only about 2 mg are absorbed after about 80 puffs over 20 minutes. Peak plasma concentrations occur within 15 minutes of the end of "inhalation" and are lower than occur in smoking. As with other forms of NRT, the Inhaler consistently doubles quit-rates compared to placebo.

Recommended dosing is 6 to 16 cartridges (12 to 32 mg of absorbed nicotine) per day for 3 to 12 weeks. Gradual reduction can occur over the following 12 weeks, such as by 1 cartridge/day per week. The Inhaler cartridges are supplied 42 to a box, which contains 7 blister packs with 6 cartridges in each. The Nicotrol Inhaler is available only by prescription. Adverse effects are mild and consist of dyspepsia, mouth and throat irritation, and coughing.

Nicotrol NS, also available by prescription only, is designed to deliver nicotine more rapidly than other NRT products, and thereby provide a potentially better substitute for cigarettes than gum, patch, or inhaler. While systemic absorption of Nicotrol NS from the nasal mucosa is more rapid, it is still not as fast as absorption of nicotine in the lungs from tobacco smoke. Peak levels occur within 10 minutes of use and are lower than occur in smoking. As with other forms of NRT, Nicotrol NS consistently doubles quit-rates compared to placebo.

One dose of Nicotrol NS is 2 sprays (1 mg) of nicotine, one spray in each nostril, directed to the lower nasal mucosa where it is to be absorbed (it is not meant to be sprayed or sniffed into the upper nasal passages). Patients should be started with one or two doses per hour (16-32 mg/day), which may be increased up to 5 doses per hour and a max of 40 doses (40 mg, 80 sprays) per day. Patients who are abstinent should be treated at the successful dosage for up to 8 weeks, following which use of the spray can be discontinued or tapered over the next 4 to 6 weeks. A majority of users experience nasal and throat irritation, rhinitis, sneezing, coughing, and watering eyes during early use, but tolerance to these effects occurs in the first week.

Zyban^TM is a slow-release formulation of bupropion, which is an atypical antidepressant with both dopaminergic and adrenergic action, chemically unrelated to SSRIs or other known antidepressants. Norepinephrine and dopamine appear to play key roles in the development of nicotine dependence, since nicotine stimulates the release of these and other neurotransmitters. Release of norepinephrine in the locus ceruleus of the mid-brain activates higher cortical functions, such as alertness, concentration, and memory, and lack of this stimulation when nicotine is withdrawn may account for characteristic withdrawal symptoms. Nicotine also stimulates neurons in the mesolimbic system resulting in enhanced dopamine release in the nucleus accumbens, a well-known pleasure-reinforcing area for other addictive drugs, such as heroin, cocaine, and amphetamines. Another substance in tobacco smoke appears to act synergistically by inhibiting MAO-B to boost dopamine levels even higher. Bupropion, a synaptic reuptake inhibitor, may help maintain some degree of stimulation of the pleasure-response area in the absence of nicotine. Bupropion may also attenuate some of the weight gain associated with smoking cessation.

As with NRT, bupropion has consistently doubled smoking quit-rates compared to placebo. It appears to work equally well in smokers with and without a past history of depression. Thus Zyban seems appropriate for smokers who do not wish to use NRT or those who have failed NRT. Combined nicotine patch and Zyban therapy has produced somewhat higher quit-rates than either one alone. Unlike NRT, smokers should begin therapy one week prior to actual cessation of smoking in order to build a steady-state level of the drug. Dosing should begin at 150 mg/day given every day for the first three days, followed by an increase to 150 mg BID (there should be an interval of at least 8 hours between successive doses). The suggested dose is 150 mg BID for 7 to 12 weeks, and doses above 300 mg/day should not be used. Adverse effects with bupropion are most commonly dry mouth and insomnia. Although Zyban use at 300 mg/day has not been associated with an excess risk of seizures, higher doses of bupropion may be associated with seizures in some individuals, so Zyban is not recommended for smokers with a history of seizures, anorexia, alcoholism, or head trauma.