MANAGEMENT AND THERAPEUTICS OF NICOTINE ADDICTION

Ideally, therapeutics for nicotine addiction should be available for the 80% of the world’s smokers who live in low- and middle-income countries. Within those countries, smokers have the lowest income, are the least educated, and have the poorest access to health care.
Thus, from a world view, cost of therapeutics and access become important considerations. Prevention is obviously an important strategy, but strategies to prevent tobacco addiction must deal with a politically powerful and wealthy multinational industry promoting use of tobacco . The tobacco industry in the United States alone spent 6 billion dollars in 1998 to market cigarettes, about 18 million dollars each day. More is spent promoting tobacco use elsewhere in the world. Although successful prevention strategies exist, well-funded competition encouraging tobacco use will remain .

More intensive therapeutics typically include behavioral interventions combined with NRT delivered over a series of sessions. Individual or group behavioral treatments appear almost equally effective. Intensive treatment programs are effective in assisting even very dependent smokers to stop for a few months. However, as with other addictions, relapse is a major problem. Initial quitting rates of 50% to 60% at 1 month typically decrease to 20% to 30% at 1 year. Various relapse-prevention procedures have been tried. None has proven clearly effective. Most tobacco addicts repeat the quitting process on average every 3.5 years and try three or four times before finally stopping forever (66). In that respect, stopping smoking is similar to overcoming addictions to other psychoactive drugs. Tobacco addiction treatment programs are cost-effective. Average treatment costs per year of life saved are $1,000 to $2,000 per year for brief counseling alone and $2,000 to $4,000 per year of life saved with more intensive counseling and pharmacotherapy to aid in smoking cessation. Smoking cessation treatments are less costly per year of life saved than are enerally accepted therapies for hypertension, hypercholesterolemia, and other chronic disorders.

Therapeutics: Clinical Guidelines

Guidelines for treating tobacco dependence were published in 2000 by the United States Public Health Service. The detailed report resulted from critical review of approximately 6,000 peer-reviewed articles on tobacco addiction therapeutics and 50 metaanalyses based on that literature.

The major general conclusions were as follows:

1. Tobacco dependence is a chronic condition warranting repeated treatment until bstinence is achieved.

2. Effective treatments for tobacco dependence exist. All tobacco users should be offered treatment.

3. Clinicians and health care systems must institutionalize consistent identification, documentation, and treatment

of every tobacco user at every visit.

4. Brief tobacco dependence treatment is effective. Every tobacco user should be offered at least brief treatment.

5. There is a strong relationship between the intensity of tobacco dependence counseling and effectiveness.

6. Three types of counseling are especially effective: practical counseling, social support as a part of treatment, and social support outside of treatment.

7. Five pharmacotherapies for tobacco dependence are effective: nicotine gum, nicotine inhaler, nicotine nasal spray, nicotine patch, and bupropion. At least one of these medications should be prescribed in the absence of contraindications.

8. Tobacco dependence treatments are cost-effective when compared with other medical and disease prevention interventions. Health insurance plans should include as a

benefit the counseling and pharmacotherapies identified as effective in the guideline.

Contemporaneous reviews of tobacco addiction therapeutics and an extensive report on tobacco addiction pharmacology and therapeutics from the Royal College of Physicians offered similar conclusions. A summary review from the Cochrane Tobacco Addiction Review Group identified and summarized evidence of efficacy for tobacco addiction therapeutics. Details of the 20 systematic reviews are available on the Internet in the Cochrane Library. The reviews used a similar strategy and reviewed much the same literature on tobacco addiction therapeutics as did the Public Health Service review. The Cochrane reviews considered the results from randomized controlled trials having at least 6 months of followup. Sustained abstinence or point prevalence quit rates were used in the metaanalysis as necessary. Simple advice from physicians presented during routine care was studied in 31 trials that included 26,000 smokers in a variety of clinical settings. Brief advice increased quit rate more than no advice (odds ratio, 1.69; 95% confidence interval, 1.5 to 1.98). Individual counseling was better than brief advice or usual care. Group therapy was more effective than selfhelp materials alone but not consistently better than interventions with more personal contact. Self-help informational material and printed descriptions of behavioral strategies had a small treatment effect.

Nicotine Replacement Therapeutics

NRT decreases the discomfort of nicotine withdrawal. The relatively stable brain nicotine levels resulting from NRT should facilitate a desensitized state for some nicotinic cholinergic receptors. Because some nicotinic receptor subtypes are more desensitized than others, both nicotine agonistic and desensitization mechanisms could operate together in NRT. In a nicotine-induced desensitized state, norepinephrine release normally stimulated by endogenous acetylcholine would be diminished. Other neurotransmitter release normally stimulated by endogenous acetylcholine could be diminished as well. The resulting NRT modulation of mood states in itself could be rewarding. In addition, some blunting of the reinforcing effects of cigarettes smoked during cessation lapses is likely during NRT. However, the mechanisms of NRT still remain uncertain because the intensity of withdrawal alone is not a good predictor of success for ultimately stopping smoking. Even though withdrawal symptoms can be diminished by NRT, other mechanisms, learning coping skills, and replacing some of the positive effects of nicotine are important as well. Whatever the mechanisms, NRT is clearly effective and safe for helping smokers to quit. The ochrane review of clinical trials with nicotine gum, transdermal nicotine patches, nasal spray, and inhalers concluded that NRT enhanced early cessation and reduced early relapse when compared with placebo. All products enhanced quitting smoking about twofold. Quitting rates, depending on intensity of concurrent behavioral interventions, ranged from 10% to 30% of patients with a 1-year follow-up. Higher nicotine doses were more effective, although the dose–response function is shallow. NRT did not appear to have significant dependence potential or to cause significant harm. Characteristics of long-term NRT users resembled those of treatment failures. It appeared many would be smoking or smoking more if NRT were not available. However, 70% to 90% of addicted smokers fail to stop smoking despite NRT. Why? Most studies included only nicotine-addicted smokers, so the usefulness of NRT for less addicted smokers remains uncertain. Although recommendations have been made for use of combinations of NRT products, for example, patch plus spray, patch plus gum, or higher-dose NRT, too few trials preclude clear evidence of effectiveness. Long-term reduction in smoking by concomitant use of NRT while smoking continues is being investigated. Nicotine inhalers and skin patches have been used safely and with sustained reduction in smoking for up to 30 months.

Particularly for highly dependent smokers, nicotine replacement from patches and gum probably delivers nicotine to the brain too gradually and without the transient but rewarding brief surges in brain nicotine levels from puffing on a cigarette. Nicotine nasal sprays or inhalers more closely approximate smoking in this respect, but only partially so, and clinically they do not offer advantages to patch failures. An inhaled nicotine aerosol would, in principle, be an ideal substitute nicotine delivery system, but despite many attempts, a practical inhaled aerosol system providing the control over dose offered by a tobacco cigarette has not been brought to market.

Non–Nicotine Replacement Pharmacotherapies

The consequences of neuroadaptive changes in brain function associated with chronic nicotine exposure should, in principle, be modified by appropriate neurochemical interventions. Pharmacotherapies mimicking nicotine’s neurochemical effects by increasing or modulating brain levels of dopamine, epinephrine, serotonin, and other neurotransmitters should correct the neurochemical deficiency states associated with nicotine withdrawal. Pharmacotherapies may also mimic some of nicotine’s actions on brain reward systems. Nicotinic receptor antagonism offers an additional strategy. Although treatment with anxiolytics did not improve outcome, antidepressants, bupropion, and nortriptyline increased quit rates. The mechanisms by which antidepressant drugs benefit smoking cessation are yet to be determined. The neurochemical consequences of chronic nicotine exposure have similarities to the effects of some antidepressants.

Bupropion

As with many pharmacotherapies, recognition that bupropion could be useful for treating tobacco addiction resulted from serendipitous observations. Smokers being treated with bupropion for depression reported less desire to smoke or greater success in stopping smoking. Bupropion is structurally related to phenethylamines resembling an anorectic drug diethylproprion and is believed to assist smoking cessation by blocking neuronal uptake of dopamine and norepinephrine and possibly by decreasing firing of the locus ceruleus. Bupropion and some other antidepressants functionally antagonize some nicotinic cholinergic receptors in muscle and autonomic ganglia and reduce receptor response to nicotine. Whether antidepressant drugs similarly antagonize brain nicotine receptors is undetermined.Bupropion was effective judging from two large trials and two smaller unpublished ones. Bupropion alone or combined with a nicotine patch was more effective than the patch alone. Although the drug caused dry mouth and insomnia, serious side effects were uncommon. Bupropion was as effective in patients with a history of depression as with those without such a history. When given to a group of smokers not trying to quit permanently, bupropion decreased some withdrawal symptoms but had no effect on craving. Bupropion was a more cost-effective therapeutic agent for tobacco addiction than NRT.

Other Therapies With and Without Utility

Clonidine shares some pharmacologic effects of bupropion and tricyclic antidepressants. The Cochrane review of six clinical trials of clonidine found increased smoking quit rates, but side effects of sedation and postural hypotension posed problems for many patients. Sensory stimulants mimic mouth and airway sensory responses to smoking that become associated with the pharmacologic effects of nicotine and thus become reinforcers. Ascorbic acid aerosols and citric acid inhalers evaluated in cessation trials reduce craving and some withdrawal symptoms over the short term. The effects of opiate antagonists on cigarette smoking have been studied to examine how opioid systems modulate smoking behavior and to determine whether opioid antagonists could be useful to aid in smoking cessation. Naloxone precipitates opiate withdrawal-like symptoms and increases desire to smoke. The effects of naloxone or naltrexone on ad libitum smoking over brief periods in a laboratory were inconsistent, but some smokers smoked less.

A clinical trial compared naltrexone, 50 mg daily for 12 weeks, or placebo, with or without transdermal nicotine. Only transdermal nicotine increased abstinence rates.

Naltrexone had no effect on cessation rates. Transdermal nicotine reduced craving and cigarette smoking in smokers who did not quit. Naltrexone had no such effects. Another 4-week trial of naltrexone or placebo found no difference in smoking 6 months later. Thus, the clinical trial data indicate no useful role for opioid antagonists in smoking cessation therapy despite the suggestive laboratory results.

Nicotinic receptor antagonism offers another possible strategy. A nicotine antagonist mecamylamine has been investigated as a cessation aid both alone and in combination with NRT. Mecamylamine started before quitting smoking and continued afterwards appeared useful in two studies. Combined use of mecamylamine and nicotine patch increased quit rate more than nicotine alone, a finding leading to consideration of mecamylamine blockade of nicotine’s rewarding effects.

Circulating antibodies binding nicotine in blood and preventing its reaching the brain would be functionally equivalent to a receptor antagonist’s preventing nicotine receptor access. Antibodies have been induced by immunization of rats with nicotine linked to an immunogen.

Immunized animals had reduced brain nicotine concentrations and reduced behavioral and cardiovascular effects after intravenous nicotine. Whether immunization alters the reinforcing effects of nicotine remains to be determined. Lobeline, a nonpyridine alkaloid and partial nicotine receptor agonist from the Indian tobacco plant (Lobelia inflata),has long been used in proprietary smoking treatments. Although no longer marketed in the United States, lobeline is available elsewhere. No clinical trials had more than a 6-month follow-up. The drug was judged unproven by the Cochrane review.

ACTH has been suggested to aid smoking cessation, based on the notion that nicotine increases ACTH and cortisol release and that during nicotine withdrawal, there may be a state of hypoadrenocorticism. Uncontrolled trials with small numbers of smokers given a few ACTH injections during the first week after quitting reported high quit rates or decreased smoking, but without controlled clinical trials, ACTH must still be considered unproven.

Silver acetate has long been available as an over-the-counter smoking deterrent in the form of chewing gum, lozenges, and spray. A reaction with cigarette smoke produces an unpleasant metallic taste, the basis for this aversive therapy.

Several clinical trials reported short-term efficacy, particularly in less addicted smokers. Whenever the urge to smoke is great, it is easy to stop silver acetate use, so it does not appear an effective therapeutic for severe nicotine addiction.

The effectiveness of other aversion therapies, acupuncture, hypnotherapy, and exercise was at best considered uncertain.