Promising Pharmacotherapy on the Horizon for Nicotine Dependence

Abstract

Nicotine dependence pharmacotherapy is important to psychiatrists, as epidemiological studies indicate that a majority of individuals with schizophrenia or affective disorders are daily smokers. The epidemiology of nicotine dependence and the efficacy of nicotine dependence pharmacotherapies are reviewed briefly. Then, novel pharmacotherapies for which FDA approval is expected next year are described.

Epidemiology of Nicotine Dependence

Smoking is the leading cause of preventable morbidity and premature mortality worldwide.¹ Regular smoking typically begins in adolescence.^2–4 Approximately 13 percent of American adults are nicotine dependent.⁵ The nicotine in tobacco is the primary rewarding compound that establishes and maintains tobacco use,⁶ and most persons who smoke regularly (daily for at least 1 month) develop nicotine dependence.^2,7 Nicotine dependence pharmacotherapy is important to psychiatrists, as epidemiological studies indicate that a majority of individuals with schizophrenia or affective disorders are daily smokers.^5,8

For a Diagnostic and Statistical Manual of Mental Disorders, Fouth Edition (DSM-IV) diagnosis of nicotine dependence, a smoker must meet three or more of the six major criteria, which are listed in Table 1.

Table 1.

DSM-IV criteria for nicotine dependence

Tolerance (e.g., the absence of nausea or dizziness despite substantial levels of smoking) Withdrawal Daily use for at least several weeks After abrupt cessation, reports of four or more of the following signs: dysphoric or depressed mood insomnia irritability, difficulty managing anger anxiety difficulty in concentration restlessness decreased heart rate increased appetite or weight gain Repeated unsuccessful attempts to quit or reduce nicotine use Reduction or elimination of social or occupational activities because smoking tobacco is not allowed in those settings Continued use despite medical or psychological harm Use that is often greater than intended or more frequent than intended.

Once smoking becomes established (daily smoking for 1 month), approximately 20 percent of smokers develop nicotine dependence,^2,7 based on responses to the Fagerstrom Test for Nicotine Dependence, which consists of six questions (Appendix 1).⁹ Although the maximal score is 10, a score >4 indicates probable nicotine dependence. The Fagerstrom Test for Nicotine Dependence is a highly reliable questionnaire,⁹ which is recommended for use by psychiatrists in their daily practice. It can be completed by the patient is less than five minutes.

Most nicotine-dependent persons report annual attempts to quit smoking, but less than 15 percent are successful over the long-term.¹⁰ These disappointing results with bupropion and nicotine replacement suggest that current pharmacotherapies are inadequate. Newer pharmacotherapeutic approaches to nicotine dependence treatment are needed. Some of these new approaches may be available to US physicians within the next year, depending on Food and Drug Administration (FDA) approval. These newer pharmacotherapies are described next.

Rimonabant

Mice lacking cannabinoid type 1 (CB1) receptors do not show nicotine place preference,¹¹ an animal model of the rewarding valence of nicotine. This study and other studies have led to the development of a promising compound for smoking cessation, the CB1 receptor antagonist rimonabant.^12,13 This compound blocks CB1 receptors and blunts the rewarding valence of nicotine in a conditioned place preference paradigm.¹⁴ In another animal model of nicotine reward, intravenous self-administration, rimonabant decreases the number of nicotine infusions in rats.¹⁵

Based on this promising profile in pre-clinical studies of animal models for nicotine dependence, rimonabant was studied in multi-site, double-blind, placebo-controlled trials.¹⁶ The study found that 20mg of rimonabant was efficacious for smoking cessation. The authors reported that smokers who quit in the rimonabant group gained less weight than those that quit in the placebo group. This is a key observation, as smokers who quit smoking tend to gain weight, and weight gain after smoking cessation is a major factor promoting relapse.¹⁷

Varenicline

Varenicline is a partial nicotinic receptor agonist, meaning that, even at maximal doses, it does not elicit the full response of nicotine.¹⁸ As such, it may be able to blunt symptoms of withdrawal and craving, without the dose-limiting effects of nicotine replacement therapies. In two phase two clinical trials, varenicline at 1mg was able to help approximately 50 percent of the smokers to quit.¹⁹ The phase three clinical trials have recently been completed; the results clearly indicate that varenicline is superior to placebo and possibly superior to bupropion, although more data are needed.¹⁹ But the studies also showed that many smokers relapsed after about a year, a common problem among nicotine addicts.

Two of the studies involved 2,000 patients. They were given either varenicline, the proposed Pfizer drug, or Zyban, a GlaxoSmithKline PLC drug that is used as a smoking-cessation treatment, or a placebo. The patients were treated for 12 weeks with medication and then followed for 40 weeks without treatment.

In both studies, 44 percent of the varenicline-treated patients quit by the end of 12 weeks, compared with 30 percent in the Zyban group and 18 percent in the placebo group. After an additional 40 weeks, one study showed that 22 percent of patients who had received varenicline had continued to abstain from smoking, compared with 16 percent in the Zyban group—a finding that didn' t reach statistical significance. About 8.4 percent of patients in the placebo group remained smoke-free.

The second study showed similar results, with 23 percent in the varenicline group, 15 percent for the Zyban group, and 10 percent in the placebo group who didn' t return to smoking. Patients in the study smoked, on average, one pack of cigarettes a day.

Pfizer said it submitted an application to the Food and Drug Administration and European regulators for approval of the drug as a smoking-cessation treatment. If approved, the drug would be marketed under the brand name Champix.

Conclusions

Nicotine dependence is a major public health problem, and the burden of addiction falls most heavily on those with comorbid psychiatric diseases.⁵ Thus, psychiatrists must be concerned with effective pharmacotherapies for nicotine dependence. The existing FDA-approved pharmacotherapies, bupropion and nicotine replacement, show efficacy only in a minority of individuals and relapse is common.¹⁰ Thus there is a great need for novel pharmacotherapies. Rimonabant, a CB-1 receptor antagonist, shows promise in clinical trials and can blunt smoking abstinence-associated weight gain¹⁶ at a dose of 20mg. Varenicline, a partial nicotinic receptor agonist, shows promise in clinical trials, with more than half of smokers becoming abstinent, at a 1mg dose.¹⁹ It can be expected that both these compounds will become available in 2006. Because nicotine dependence characterizes so many psychiatric patients, psychiatrists should be aware of these novel pharmacotherapies, soon to be available.

Appendix 1. Fagerstrom Test for Nicotine Dependence

Question and Answer	Points for Answer
1. How many cigarettes do you smoke daily? 10 or less 11-20 21-30 31 or more	0 1 2 3
2. If you had to give up one cigarette, which one would be the most difficult to give up? The first one in the morning Any other	1 0
3. How soon after arising in the morning do you smoke the first cigarette of the day? Within 5 minutes 6-30 minutes 31-60 minutes After 60 minutes	3 2 1 0
4. Do you find it difficult to refrain from smoking in places where it is forbidden? Yes No	1 0
5. Do you smoke even when you are so ill that you are in bed most of the day? Yes No	1 0
6. Do you smoke more frequently during the first few hours of each day, than during the rest of the day? Yes No	1 0