Nicotine &Nicotine Tobacco & Research Tobacco Research Advance Access published May 21, 2013
Original Investigation
Effect of Varenicline on Individual Nicotine Withdrawal Symptoms: A Combined Analysis of Eight Randomized, Placebo-Controlled Trials Jonathan Foulds PhD1, Cristina Russ MD2, Ching-Ray Yu PhD2, Kelly H. Zou PhD2, Aaron Galaznik MD, MBA2, Mikael Franzon PhD2, Arthur Berg PhD1, John R. Hughes MD3 1Department of Public Health Sciences, Penn State University, Hershey, PA; 2Pfizer Inc., New York, NY; 3Departments of Psychiatry, Psychology, and Family Practice, University of Vermont, Burlington, VT
Received December 13, 2012; accepted April 18, 2013
Abstract Introduction: Concerns exist that varenicline may cause neuropsychiatric side effects. Some of these symptoms (e.g., depression, irritability) have been measured in clinical trials using nicotine withdrawal scales. This study assessed the effect of varenicline on neuropsychiatric and other symptoms, as measured by the Minnesota Nicotine Withdrawal Scale (MNWS). Methods: We analyzed weekly individual MNWS symptom ratings in 8 randomized double-blind, placebo-controlled smoking cessation trials funded by Pfizer with similar methodology (n = 2,403 varenicline; n = 1,434 placebo). Ratings for the past 24 hr were obtained prior to quitting and starting treatment and at Weeks 1–6 and 11 after the quit date. Results: In repeated measures analyses controlling for baseline values, ratings for 5 neuropsychiatric symptoms (depressed mood, irritability, anxiety, difficulty concentrating, and restlessness) and urge to smoke were lower (p < .01) for varenicline than placebo at each timepoint. Worsening in scores from 0–2 (baseline) to 4 was less frequent on varenicline than placebo for all ratings except appetite- (significantly more frequent for varenicline, p < .0001) and sleep-related items. Repeated measures analysis for individuals with low levels of exhaled carbon monoxide revealed similar patterns except for a nonsignificant difference for increased appetite. Conclusions: Use of varenicline while trying to quit smoking reduces and does not increase neuropsychiatric symptoms such as depressed mood and irritability measured on the MNWS in smokers without current psychiatric disorders. It is associated with increases in sleep disturbance and appetite although the latter appears due to enabling more subjects to abstain from smoking.
Introduction Varenicline tartrate is a selective α4β2 nicotinic acetylcholine receptor partial agonist that is approved internationally as a smoking cessation aid at a dose of 1 mg twice daily (bid) for 12 weeks starting with a 1-week up-titration (Pfizer Inc., 2011a, 2011b). Postmarketing pharmacovigilance reports have raised concerns that varenicline may be associated with neuropsychiatric side effects (Federal Aviation Administration, 2008; Food and Drug Administration, 2008, 2009) and the prescribing information was updated to include a warning. However, results from a number of placebo-controlled trials of smokers without psychiatric disorders (Cahill, Stead, & Lancaster, 2012; Garza, Murphy, Tseng, Riordan, & Chatterjee, 2011; Tonstad, Davies, Flammer, Russ, & Hughes, 2010), from retrospective cohort comparative studies in approximately 10,000 smokers treated
with varenicline in general medical practices (Gunnell, Irvine, Wise, Davies, & Martin, 2009; Meyer et al., 2012), from studies of 400–700 smokers treated in specialist smoking cessation services (Stapleton et al., 2008; Steinberg et al., 2011), and from a trial in patients with schizophrenia (Williams et al., 2012) have been largely reassuring. Some studies without a control group that would allow comparisons between varenicline and smoking cessation without medication have been conducted, including a study of 78 patients with posttraumatic stress disorder (Campbell & Anderson, 2010), which reported that varenicline appeared to have a destabilizing effect on mental health, and a prescription event monitoring report in more than 3,000 smokers (HarrisonWoolrych & Ashton, 2011), reporting common psychiatric events in patients taking varenicline. Most studies have primarily relied on spontaneous reports of adverse events; however, some of the symptoms that have been
doi:10.1093/ntr/ntt066 © The Author 2013. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail:
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Corresponding Author: Jonathan Foulds, PhD, Penn State University, College of Medicine, Cancer Institute, Cancer Control Program, T3428, CH69 500 University Drive, P.O. Box 850, Hershey, PA 17033-0850, USA. Telephone: +1 (717) 531 3504; Fax: +1 (717) 531 0480; E-mail:
[email protected]
Effect of varenicline on individual nicotine withdrawal symptoms
Methods All randomized, double-blind, placebo-controlled Phase II– IV studies of varenicline for smoking cessation, in which the MNWS was completed at predrug/precessation baseline, and for at least 4 weeks after the target quit date (TQD) were included. The trials for which patient level data were available were sponsored by Pfizer Inc., and data were available before July 31, 2012. Eight studies met these criteria (Garza et al., 2011; Gonzales et al., 2006; Jorenby et al., 2006; Nakamura et al., 2007; Niaura et al., 2008; Nides et al., 2006; Oncken et al., 2006; Tsai et al., 2007) and were included in the pooled analysis. The design and methods of each study were very similar, and each has been previously published. A total of five additional clinical trials conducted by the manufacturer did measure MNWS, but did not qualify for inclusion in the pooled analyses. These were as follows: a Phase I study using a single dose of varenicline (Hitsman et al., 2013);
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a study investigating maintenance therapy with varenicline with a double-blind, randomized withdrawal design that measured MNWS at study Weeks 13 and 24 only (Tonstad et al., 2006); a small open-label study (NCT00635401; Pfizer data on file); an open-label study comparing varenicline with a transdermal nicotine patch, which had no placebo arm (Aubin et al., 2008); and a study investigating a flexible quit date paradigm using varenicline, collecting MNWS measurements in a subset of participants, which was not included as subjects could quit at any time during Weeks 2–5 (Rennard et al., 2012). Participants Adult smokers of at least 10 cigarettes/day in the 3 months prior to study enrollment who were motivated to quit smoking and had given informed consent indicating their willingness to be randomized to varenicline or placebo tablets and to attend follow-up appointments were included in these studies. Additional exclusion criteria were similar for all studies and included serious illness; major depressive disorder in the past 12 months that required treatment, history of psychosis, panic disorder, bipolar disorder, or eating disorders; drug or alcohol abuse/dependence in the last 12 months; and use of another medication that could interfere with the outcome of the trial (e.g., a medicine for smoking cessation). Baseline subject characteristics are summarized in Table 1. Characteristics in the two groups were similar. Interventions In four of the studies included in this analysis, participants were randomized at baseline to receive varenicline (0.5 mg once daily on Days 1–3, 0.5 mg bid on Days 4–7, followed by 1 mg bid for the remainder of a 12-week treatment period) or identical placebo tablets (Garza et al., 2011; Gonzales et al., 2006; Jorenby et al., 2006; Tsai et al., 2007). The other four studies used different doses of varenicline, two studies investigated multiple doses over a 12-week treatment period (Nakamura et al., 2007; Oncken et al., 2006), one study used multiple doses over a 7-week treatment period (Nides et al., 2006), and one study investigated a flexible dosing paradigm over a 12-week treatment period (Niaura et al., 2008). In Table 1. Pooled Baseline Subject Characteristics by Treatment
Age, years, mean (SD) Sex, male, n (%) Race, n (%) White Other FTND score, mean (SD) Number of cigarettes/day (last month), mean (range)
Varenicline (n = 2,403)
Placebo (n = 1,434)
41.9 (11.2) 1,378 (57.3)
41.7 (11.5) 879 (61.3)
1,530 (63.7) 873 (36.3) 5.4 (2.1) 22.5 (8–90)
934 (65.1) 500 (34.9) 5.4 (2.1) 22.3 (6–80)
Note. FTND = Fagerström Test for Nicotine Dependence; SD = standard deviation. Subjects who smoked
