Varenicline, Smoking Cessation, and Neuropsychiatric Adverse Events

Abstract

Objective In 2009 FDA issued a black box warning for varenicline and neuropsychiatric events. We studied efficacy (smoking cessation) of varenicline, and safety (neuropsychiatric events) in both randomized clinical trials (RCTs) and a large observational study. The observational study was included to determine the generalizability of the RCT findings to the general population. Method RCTs: Re-analysis of all 17 placebo controlled RCTs (n=8027) of varenicline conducted by Pfizer using complete intent-to-treat person-level longitudinal data. Observational Study Analysis of Department of Defense collected adverse neuropsychiatric adverse event data in inpatients and outpatients taking varenicline versus nicotine replacement therapy (NRT) (n=35,800). The primary endpoints for the RCTs were smoking abstinence and adverse event reports of suicidal thoughts and behavior, depression, aggression/agitation, and nausea. The effect of varenicline in patients with (n=1004) and without (n=7023) psychiatric disorders was examined. The primary endpoints for the observational study were anxiety, depression, drug induced mental disorder, episodic and mood disorder, other psychiatric disorder, post traumatic stress disorder, schizophrenia, suicide attempt, transient mental disorder. Results RCTs: Varenicline did not increase rates of suicidal events, depression, or aggression/agitation. Varenicline increased risk of nausea (OR=3.69, 95% CI = (3.03, 4.48), p<0.0001). Varenicline increased rate of abstinence by 124% compared to placebo (p<0.0001), and 22% compared to bupropion (p<0.0001). While having a current psychiatric disorder or history of psychiatric illness increased the risk of neuropsychiatric events, it did so equally in treated and control patients. Observational Study Following propensity score matching, overall rate of neuropsychiatric disorders was lower for varenicline versus NRT (2.28% versus 3.16%, p<0.0001). Conclusions In the RCTs, varenicline revealed no increased risk of neuropsychiatric adverse events relative to placebo. Varenicline provided greater benefit in terms of smoking cessation relative to both placebo and bupropion. The same results were observed in patients with and without a current psychiatric disorder or history of psychiatric illness. In the observational study, the overall rate of neuropsychiatric disorders was lower in patients treated with varenicline relative to NRT, revealing that the finding of no increased risk of neuropsychiatric adverse events in RCTs generalizes to the population of patients engaging in treatment with varenicline.

Relapse Rate and Factors Related to Relapse in a 1-Year Follow-Up of Subjects Participating in a Smoking Cessation Program

“…The presence of adverse effects was noteworthy, as the P value was close to significant after regression analysis, and it may be a factor affecting the success of pharmacotherapy indirectly. The reported adverse effects of varenicline, the most frequently prescribed agent used in our subjects, include the increased risk for cardiovascular accident development, 34 nausea, [35][36][37][38] abnormal dreaming, sleeplessness, 36,38 headache, 37,38 depression, and possible serious psychiatric conditions. 39,40 The most frequent adverse effect we observed with varenicline was nausea.…”

Managing smoking cessation

“…A review of the neuropsychiatric safety of varenicline, including data from 22 industry-and 17 non-industry-funded RCTs that involved 10 761 participants, found no increased risk of suicide or attempted suicide, suicidal ideation, depression, irritability, aggression or death in participants taking varenicline compared with those taking placebo, 20 which is consistent with other reviews. 21,22 An RCT mandated by the US Food and Drug Administration, which assessed the incidence of neuropsychiatric events among 8144 participants who smoke and were given treatment with varenicline, bupropion, nicotine replacement therapy patches or placebo, found no increased risk of neuropsychiatric events attributable to varenicline or bupropion relative to nicotine replacement therapy or placebo. 23 Data from surveillance studies involving patients using bupropion for smoking cessation showed an increased risk of seizures; 24,25 safety could be improved if clinicians avoid treatment with bupropion in patients at risk of seizures, including older adults.…”

Follow-Up Study Results of Patients of a Cigarette Cessation Clinic and Factors Affecting These Results

“…24 In a meta-analysis where randomized controlled studies were re-evaluated, varenicline proved to be successful in both the notreatment group and the bupropion group. 25 According to the results of this research, participants remaining longer in their treatment regardless of the modality stay free of smoking for longer periods. In their research, Schnoll et al found that participants remaining for 24 weeks in their treatment proved to be more successful in quitting smoking compared to participants remaining for 8 weeks in their treatment.…”