Addicted to Nicotine
A National Research Forum

Section VI: Treatment of Nicotine Dependence
John Hughes, M.D., Chair

NEW MEDICATIONS FOR NICOTINE DEPENDENCE TREATMENT

Richard D. Hurt, M.D.
Nicotine Dependence Center
Mayo Clinic

Introduction

Approved nicotine replacement therapy (NRT) products that have shown a doubling of the stop rates in randomized control trials are nicotine gum, nicotine patch, and nicotine nasal spray. The former two are now available over the counter and the latter by prescription. Newer treatments recently approved for marketing in the United States include bupropion and the nicotine inhaler.

What We Know

• Newer Approved Medications. Bupropion is the first nonnicotine pharmacologic treatment approved for smoking cessation. It is a monocyclic antidepressant that has both noradrenergic and dopaminergic activity. It is hypothesized that bupropion is effective for smoking cessation because of its dopaminergic activity on the pleasure and reward pathways in the mesolimbic system and nucleus accumbens. In a multicenter dose response study, smokers received either placebo or bupropion at 100 mg/day, 150 mg/day, or 300 mg/day for a 7-week treatment trial. At the end of treatment and at 1 year, the point prevalence abstinence rates were significantly higher in those assigned to the 150 mg and 300 mg groups compared with placebo. Furthermore, a significant dose effect was detected at all timepoints. In addition, there was an attenuation of weight gain during the treatment period for those who were continuously abstinent on the 300 mg/day dose. However, the attenuation of weight gain did not persist at 1-year followup. Side effects to bupropion greater than placebo were insomnia and dry mouth. The approval of bupropion is a great addition to the treatment alternatives, but more importantly, it has spurred the investigation of other drugs with a similar pharmacology.

  The nicotine inhaler has also been shown to be effective in placebo-controlled trials. This device delivers a vaporized form of nicotine to the oral mucosa that does not reach the pulmonary alveoli. As with other NRT products, clinical trials have shown a doubling of the stop rate in those assigned to the active inhaler compared with placebo. The use of about six inhalers per day produces cotinine levels that are about 60 percent of the levels while smoking. Common side effects included throat and mouth irritation and coughing. One of the major benefits of the nicotine inhaler is that it mimics the behavior of smoking. It also lends itself to use with other NRT products or bupropion.

• Combination Treatments. Though few studies have been reported, there is excellent rationale to use combined therapies for nicotine dependence. This is especially true when a slow-delivery form of NRT (patch) or other pharmacologic therapy is combined with a more rapid delivery system (nicotine gum or nicotine nasal spray). Nicotine gum, in combination with nicotine patch therapy, has been shown to reduce withdrawal symptoms better than either medication alone. Furthermore, when used in combination, the nicotine patch and nicotine gum produce significantly higher abstinence rates compared with nicotine gum alone. In addition, a single 1 mg dose of nicotine nasal spray was shown to provide more immediate relief for craving for a cigarette compared with a single 4 mg dose of nicotine gum. These findings provide a rationale for the "as-needed" use of nicotine nasal spray to control withdrawal symptoms, in combination with other medications with longer acting effects.

  In an as yet unreported patch-bupropion trial, bupropion SR 300 mg/day was used in combination with a 21 mg nicotine patch. All three active treatment groups were more effective than placebo, and bupropion SR showed significantly higher stop rates compared with the nicotine patch. Though the combination of bupropion SR and the nicotine patch produced the highest smoking cessation rates, this was not significantly different than bupropion SR alone (p = 0.06). Nonetheless, because NRT and bupropion act on different parts of the neuron, the combination of the two makes pharmacologic sense.

  Furthermore, use of higher doses of nicotine patch therapy (i.e., more than one patch at a time) may be appropriate for some more addicted smokers. This is especially important for heavy (2 packs/day) smokers, since they will be significantly underdosed using single-dose patch therapy. High dose therapy can also be used in smokers who previously failed single-dose therapy because their nicotine withdrawal symptoms were not adequately relieved. High-dose therapy has been shown to be safe and tolerable in smokers smoking 20 or more cigarettes per day. No trials to date have reported using more than two pharmacologic agents at a single time. However, in clinical practice, as many as four pharmacotherapies (three NRTs + bupropion) have been used simultaneously in patients with severe nicotine dependence in an inpatient treatment program.

• Newer Treatments Undergoing Testing. A new NRT product, a sublingual tablet (which delivers 2 mg of nicotine), has been tested in a double-blind placebo control trial. There was a doubling of the stop rate and excellent relief of withdrawal symptoms and craving. The nicotine sublingual tablet was well accepted by the smokers. Though the method of delivery (transbuccal) is similar to nicotine gum, the sublingual tablet avoids the problem of proper use associated with the gum.

  The antihypertensive mecamylamine has been found to have efficacy in smoking cessation in a small trial of smokers that concomitantly received a 21 mg nicotine patch. At the dose of 5 to 10 mg/day, side effects were minimal, the most frequent being mild constipation. This study was restricted to smokers ages 20 to 40; thus, it is unclear whether the side effect profile will be as acceptable in older smokers where the side effect of constipation could be a problem.

• Promising Medications. Because of the known relationship between smoking and depression, other antidepressant drugs have been tested. The tricyclic antidepressant nortriptyline appears to have promise for smoking cessation. When used in combination with cognitive behavioral psychological counseling, 10 mg/day of nortriptyline was found to be effective for smoking cessation. The only other antidepressant that has been shown to have some promise is doxepin, but this study was limited by its small sample size.

• Harm Reduction. Long-term nicotine replacement therapy appears to be safe and less harmful than continued smoking. However, there is no evidence that, when an adult reduces smoking, the harm is actually reduced, nor is there evidence that adults can sustain smoking reduction indefinitely, even with concomitant use of NRT. Furthermore, there is concern that harm reduction strategies may decrease the number of smokers who try to stop smoking.

What We Need To Know More About

• What is the optimal dose and duration of treatment for NRT?

• What is the optimal duration of treatment using bupropion?

• What are the best combination treatments, and which smokers are best suited for combination treatment?

• Assuming bupropion works through its dopaminergic/noradrenergic properties, what other drugs with a similar pharmacology should be tested for nicotine dependence treatment?

Recommended Reading

Glover, E.D. "Safety and Efficacy of a Nicotine Sublingual Tablet for Smoking Cessation: 3-Month Preliminary Data." Paper presented at the SRNT Meeting in Nashville, TN, June 13-15, 1997.

Hall, S.M.; Reus, V.I.; Muñoz, F.; Sees, K.L.; Humfleet, G.; Hartz, D.T.; and Frederick, S. Nortriptyline and cognitive-behavioral treatment of cigarette smoking. Arch Gen Psychiatry, in press.

Hurt, R.D.; Sachs, D.P.; Glover, E.D.; Offord, K.P.; Johnston, J.A.; Dale, L.C.; Khayrallah, M.A.; Schroeder, D.R.; Glover, P.N.; Sullivan, C.R.; Croghan, I.T.; and Sullivan, P.M. A comparison of sustained release bupropion and placebo for smoking cessation. N Engl J Med 337:1195-1202, 1997.

Puska, P.; Korhonen, H.J.; Vartiainen, E.; Urjanheimo, E.-L.; Gustavsson, G.; and Westin, A. Combined use of nicotine patch and gum compared with gum alone in smoking cessation: A clinical trial in North Karelia. Tob Control 4:231-235, 1995.

Rose, J.E.; Westman, E.C.; and Behm, F.M. Nicotine/mecamylamine combination treatment for smoking cessation. Drug Dev Res 38:243-256, 1996.

Schneider, N.G.; Olmstead, R.; Nilsson, F.; Mody, F.V.; Franzon, M.; and Doan, K. Efficacy of a nicotine inhaler in smoking cessation: A double-blind, placebo controlled trial. Addiction 91(9):1293-1306, 1996.