Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

10th Annual Society for Research on Nicotine and Tobacco (SRNT) Europe Conference

Rome, Italy / September 23-26, 2008

According to The Canadian Lung Association, smoking will lead to 37,000 Canadian deaths in 2008, including 1000 from second-hand smoke. However, approximately 90% of the estimated five million current smokers in Canada want to quit, and half want to be smoke-free within the next six months. Most family physicians and allied health professionals want to help their patients stop smoking. Tobacco dependence is now recognized as a chronic medical condition with a high rate of relapse. It requires thoughtful, individualized treatment plans that may include the use of medication. Some safety concerns surfaced recently when Health Canada received 46 reports of depressed mood, agitation and changes in behaviour among other symptoms. Yet smoking cessation with or without the use of medication has also been linked to psychiatric symptoms including depressed mood, insomnia, irritability, frustration or anger, and anxiety. In an effort to separate out the causes of these symptoms, researchers reviewed the clinical trials of smoking cessation with particular attention to psychiatric adverse events (AEs).

Depressed Mood Disorders and Disturbances

Dr. Serena Tonstad, University of Oslo and Ullevål University Hospital, Norway, and colleagues reviewed clinical trials of smoking cessation strategies to better understand the true risk of depression and other psychiatric AEs. As Dr. Tonstad declared, “Spontaneous AE reporting does have some limitations. The data are not controlled.” She explained that we know the number of cases reported but not the total number of patients who have taken varenicline within the same time frame. Continuing, Dr. Tonstad indicated, “This can be estimated but not precisely calculated. And some key information might be missing in some of these reports. All this makes meaningful medical assessment of causation difficult.” To that end, Dr. Tonstad and colleagues took a systematic approach and analyzed post hoc the incidence and relative risks of AEs classified as depressed mood disorders and disturbances (DMDDs) in all nine randomized, double-blind, placebo-controlled phase II to IV clinical trials of varenicline completed to date.

The participants were smokers of at least 10 cigarettes per day who wished to quit, ranging in age from 18 to 75 years, with no serious or unstable disease or history of psychiatric disorders (other than depression that did not require treatment). Varenicline dosages ranged from 0.3 mg q.d. to 1 mg b.i.d., and study lengths ranged from six weeks to 52 weeks. A total of 2738 participants received varenicline, 795 bupropion SR and 1655 placebo. All AEs reported during treatment and within 30 days’ post-treatment for individuals receiving at least one dose of study drug were included in this analysis. The authors concluded that both varenicline and bupropion SR might increase the risk of DMDDs compared with placebo, but no statistically significant difference was found between the two smoking cessation medications. Incidences of DMDDs were very low, <3%. The relative risk of DMDDs for varenicline vs. placebo was 1.55 (CI 1.02-2.36), while the relative risk of DMDDs for varenicline vs. bupropion was 0.89 (CI: 0.57-1.39). No dose effect of varenicline could be demonstrated, i.e. the incidence of AEs did not increase with increasing dosages (Table 1).

Dr. Tonstad noted that varenicline was given in both lower and higher doses than the now standard 1 mg b.i.d. dose in some of the earlier studies until the dose effect was established. “When you look at the depressed mood disorders in comparison to placebo, the relative risk all seems to be with the low doses, not in the usual dose. This is quite contrary to what is expected if there is a dose response between the drug and adverse events.”

Table 1. Depressed Mood Disorders and Disturbances <u><</u>3.1%

Other Psychiatric Adverse Events

In a second report, the researchers evaluated post hoc the incidence of sleep disorders and other psychiatric AEs (excluding depression, which was discussed in the first report) in the same nine clinical studies. No evidence of increased risk of psychiatric AEs was found in participants receiving varenicline vs. bupropion SR or placebo. The psychiatric AE with incidences greater than 1% are summarized in Ta
ychiatric AEs >1%

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The incidences of AEs related to suicidal ideation and self-injurious behaviours were 0.0%, 0.1% (CI 0.0-0.7) and 0.1% (CI 0.0-0.4) for participants receiving varenicline, bupropion SR and placebo, respectively. “There is no increase of psychiatric disorders with varenicline in controlled studies compared to placebo and in particular there is no suicide with varenicline,” Dr. Tonstad confirmed. “In this data set of 2738 patients who received varenicline, it was extremely safe.” She added, “There have indeed been reports outside our studies of suicide or suicidal ideation allegedly associated with varenicline. . . However, our studies are controlled studies. That’s the crucial difference.” Dr. Tonstad told the audience, “The key message in these analyses for community physicians who treat, for pharmacists who dispense and for patients given varenicline is that there is no increase of psychiatric disorders with this drug compared to placebo. There is a slight increase in depression with varenicline (and bupropion) compared to placebo but it is very slight, less than 2%. We do not know whether this increase is due to cessation and nicotine withdrawal [because there is more smoking cessation and more nicotine withdrawal with the two drugs than there is with placebo], or if it is a direct effect of the drugs on the central nervous system.”

When asked about future research, Dr. Tonstad replied, “We are planning to analyze depression in more detail because we want to understand and identify ahead of time which people will be at risk of depression.”

Dr. Charls Els, University of Alberta Hospital, Edmonton, remarked, “This analysis of the clinical trials is highly relevant and important to clinicians, policy makers, the public, and very importantly, to all smokers. It echoes what health providers are witnessing in clinical practice, namely, that quitting smoking, with or without medication, may be associated with the development of symptoms like depression.” He also noted that “the incidence of the development of depressive disorders associated with bupropion and varenicline is consistent with what is seen in tobacco cessation clinical practice. The management of tobacco addiction in a chronic disease paradigm yields the most favourable outcomes, and the neuropsychiatric effects do not pose a significant barrier to helping people safely and successfully quit smoking.”

Summary

In a review of all nine randomized, double-blind, placebo-controlled phase II to IV clinical trials of varenicline completed to date, the incidences of DMDDs were low. While varenicline and bupropion SR may increase the risk of DMDDs compared with placebo, no statistically significant difference was found between the two smoking cessation medications. A second report concluded there was no increased risk of other psychiatric AEs (excluding depression) with the use of varenicline, although abnormal dreaming was more frequent with varenicline use and insomnia was more frequent in participants receiving bupropion SR. Most psychiatric symptoms occur with low frequency during smoking cessation treatment in persons with no history of psychiatric or substance abuse.