Correspondence

Sustained-Release Bupropion for Smoking Cessation

N Engl J Med 1998; 338:619-620February 26, 1998

Article

To the Editor:

In their report on the results of a dose–response trial of sustained-release bupropion for smoking cessation, Hurt et al. (Oct. 23 issue)1 “recommend using the 300-mg dose (150 mg twice a day) as the target dose for most patients, given the favorable side-effect profile and the fact that there was less weight gain during the medication phase with this dose.” We believe an initial dose of 150 mg a day may be more reasonable.

Safety is a concern because of dose-related risks of seizures (1 case per 1000), anaphylactoid reactions (1 to 3 cases per 1000), and insomnia (in 34.6 percent of cases). In addition, if a million people (2 percent of U.S. smokers) used bupropion, the difference in cost between 150 mg a day and 300 mg a day would be $45 million to $60 million a year (assuming a cost of $90 to $120 for seven weeks of therapy with the 300-mg dose).

At one year, the point-prevalence cessation rates for the 150-mg and 300-mg doses were 22.9 percent and 23.1 percent, respectively. At the end of treatment, the rates were 38.6 percent and 44.2 percent — not a significant difference. The suggestion that a higher dose should be used because it is associated with less weight gain is curious; at the end of treatment, the difference in the mean weight change between the 300-mg group and the 150-mg group was less than 2 lb (0.9 kg) and no effect on weight was seen for any dose after six months.

Another rationale given for routine use of the 300-mg dose is that it “was the only one to show a difference in the rates of continuous abstinence from the target quitting date through the end of treatment.” However, there was no significant difference between the rates of continuous abstinence associated with the 300-mg and 150-mg doses at the end of treatment. The authors do not report continuous-abstinence rates at one year, although the data submitted to the Food and Drug Administration showed no significant differences between the continuous-abstinence rates associated with placebo and bupropion (10 percent for placebo, 15 percent for 150 mg, and 13 percent for 300 mg) (Karath BM, Glaxo Wellcome: personal communication). From the perspectives of public health and individual patients, what matters most is permanent cessation, for which the point prevalence at one year is a better measure than abstinence at the end of treatment.

Tim McAfee, M.D., M.P.H.
Group Health Cooperative of Puget Sound, Seattle, WA 98101

Eric France, M.D., M.S.P.H.
Kaiser Permanente, Denver, CO 80231

1 References

1. 1

   Hurt RD, Sachs DPL, Glover ED, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997;337:1195-1202
   Full Text | Web of Science | Medline

To the Editor:

Was the study by Hurt et al. truly blinded? They state, “A dose of 50 mg twice a day was sufficient to produce side effects.” Could the study participants have recognized that they were receiving the smoking-cessation medication, and could they have been influenced to quit by that perception? Since the relapse rates among the quitters were essentially equivalent for all the groups, is it possible that quitting, whether due to an actual medication effect or to suggestion, was the key?

Mark Pasternak, M.D.
2722 Stanton St., North Bend, OR 97459

Author/Editor Response

The authors reply:

To the Editor: Drs. McAfee and France seem to miss the importance of the significant linear dose responses at all time points during the study, including the one-year follow-up. These data indicate that the dose of 300 mg per day resulted in the highest abstinence rate. Furthermore, the study was designed to assess a dose response and to make pairwise comparisons of the active doses versus placebo at the end of short-term treatment. It was not designed to have adequate statistical power for a comparison of the 150-mg and 300-mg doses.

Continuous abstinence and long-term abstinence are important issues. Continuous abstinence, however, is a very conservative estimate. Subjects who miss visits or have any interval of smoking (even a puff) are considered to be smoking. Furthermore, expecting a treatment effect to persist for 46 weeks beyond the end of treatment is demanding a lot of any medication for a chronic medical condition. We have observed in this study as well as others that once the medication is stopped, the relapse rate is similar regardless of the initial medication assignment. The relapse rate might be decreased were the medication used for a longer period of time. The optimal duration of treatment with sustained-release bupropion that might result in higher long-term abstinence rates has not been determined.

The importance of the attenuation of the weight gain should not be underestimated. Fear of weight gain keeps many smokers from even attempting to stop. At the end of treatment, there was a clear difference, with less weight gain in the continuously abstinent subjects assigned to 300 mg per day. Unfortunately, the difference was not present at the end of a year. This finding also speaks to the issue of the optimal duration of treatment.

Safety is always a concern, but some of the issues are misstated. Seizures can occur with doses lower than 300 mg per day, but most seizures occur with doses of 450 mg per day or higher. Anaphylactic reactions are not dose-related. Insomnia was more frequent among the subjects receiving 300 mg per day than among those receiving placebo, but this finding could have been confounded by insomnia caused by nicotine withdrawal.

We assure Dr. Pasternak that this was a true double-blind study. In general, adverse events were similar in all the treatment groups, including the placebo group, and all the participants received two tablets daily along with brief counseling.

On the basis of the available data, we believe that the 300-mg dose of sustained-release bupropion is the best dose. Questions remain about the optimal duration of therapy, though 7 to 12 weeks seems to be a reasonable starting point for most patients.

Richard D. Hurt, M.D.
Mayo Clinic, Rochester, MN 55905

David P.L. Sachs, M.D.
Palo Alto Center for Pulmonary Disease Prevention, Palo Alto, CA 94304

Elbert D. Glover, Ph.D.
West Virginia University, Morgantown, WV 26506

Citing Articles (2)

Citing Articles

1. 1

   Maher Karam-Hage, Stephen Strobbe, Jason D. Robinson, Kirk J. Brower. (2011) Bupropion-SR for Smoking Cessation in Early Recovery from Alcohol Dependence: A Placebo-Controlled, Double-Blind Pilot Study. The American Journal of Drug and Alcohol Abuse 37:6, 487-490
   CrossRef

2. 2

   D.R. Lewis, J.F. Bolton, S. Hebard, F.C. Smith, R.N. Baird, P.M. Lamont. (2003) Risk Factor Documentation in Elective and Emergency Vascular Surgical Admissions. European Journal of Vascular and Endovascular Surgery 25:6, 568-572
   CrossRef