SLEEP, Vol. 38, No. 5, 2015 833 Varenicline and Abnormal Sleep-Related Events—Savage et al. INTRODUCTION Varenicline is indicated as an aid for cessation of tobacco smoking. It binds as a partial agonist to the α4β2 subtype of nicotinic acetylcholine receptors on neurones. It is postulated that varenicline reduces both craving for nicotine and nicotine withdrawal symptoms through its agonist activity at the recep- tors. At the same time it prevents nicotine binding to the re- ceptors, thus blocking the ability of nicotine to stimulate the mesolimbic dopamine system, the neuronal mechanism under - lying reinforcement and reward. 1 Abnormal dreams (e.g., vivid, unusual) were reported com- monly (12.4%) and at a greater frequency than with placebo (4.5%) in a pooled analysis of clinical trials of varenicline. Sleep disorders, unspecifed and excluding insomnia and somnolence, were also reported commonly (4.8%) compared with a placebo rate of 2.8%. Nightmares and somnambulism have been re- ported since marketing and are listed in product information. Aggressive acts during wakefulness have also been reported. 1–3 A pooled analysis of 10 randomized placebo-controlled clinical trials indicated that sleep disorders and disturbances occurred signifcantly more frequently with varenicline com- pared with placebo (relative risk [RR] 1.70 [95% confdence interval (CI) 1.50–1.92]). 4 Examination of the individual pub- lished trial results indicated that this group of adverse effects Study Objectives: To assess adverse drug reaction reports of “abnormal sleep related events” associated with varenicline, a partial agonist to the α4β2 subtype of nicotinic acetylcholine receptors on neurones, indicated for smoking cessation. Design: Twenty-seven reports of “abnormal sleep related events” often associated with abnormal dreams, nightmares, or somnambulism, which are known to be associated with varenicline use, were identifed in the World Health Organisation (WHO) Global Individual Case Safety Reports Database. Original anonymous reports were obtained from the four national pharmacovigilance centers that submitted these reports and assessed for reaction description and causality. Measurements and Results: These 27 reports include 10 of aggressive activity occurring during sleep and seven of other sleep related harmful or potentially harmful activities, such as apparently deliberate self-harm, moving a child or a car, or lighting a stove or a cigarette. Assessment of these 17 reports of aggression or other actual or potential harm showed that nine patients recovered or were recovering on varenicline withdrawal and there were no consistent alternative explanations. Thirteen patients experienced single events, and two had multiple events. Frequency was not stated for the remaining two patients. Conclusions: The descriptions of the reports of aggression during sleep with violent dreaming are similar to those of rapid eye movement sleep behavior disorder and also nonrapid eye movement (NREM) sleep parasomnias in some adults. Patients who experience somnambulism or dreams of a violent nature while taking varenicline should be advised to consult their health providers. Consideration should be given to clarifying the term sleep disorders in varenicline product information and including sleep related harmful and potentially harmful events. Keywords: aggression, nightmares, somnambulism, varenicline Citation: Savage RL, Zekarias A, Caduff-Janosa P. Varenicline and abnormal sleep related events. SLEEP 2015;38(5):833–837. SHORT NOTE Varenicline and Abnormal Sleep Related Events Ruth L. Savage, MSc (Clin Pharmacol) 1,2,3 ; Alem Zekarias, MSc 1 ; Pia Caduff-Janosa, MD 1 1 Uppsala Monitoring Centre, Uppsala, Sweden; 2 Department of General Practice, University of Otago, Christchurch, New Zealand; 3 New Zealand Pharmacovigilance Centre, Department of Preventive and Social Medicine, University of Otago, Dunedin Submitted for publication July, 2014 Submitted in fnal revised form September, 2014 Accepted for publication September, 2014 Address correspondence to: Ruth L. Savage, MB BS, MSc, Department of General Practice, University of Otago, Christchurch, PO Box 4345, Christchurch, New Zealand; Tel: +64 3 3643613; Fax: +64 3 3643637; Email: ruth.savage@otago.ac.nz pii: sp-00448-14 http://dx.doi.org/10.5665/sleep.4686 included insomnia, a recognized adverse effect of nicotine withdrawal, somnolence, abnormal dreams, and also in two trials, unspecifed sleep disorder. 5,6 In a study of reports of aggression in the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database, Moore et al. 7 found that among 26 patients with well-documented reports of aggressive reactions during wakefulness occurring in a clear temporal association with varenicline use, 17 patients also experienced sleep distur - bances or nightmares. In two reports the aggressive actions oc- curred directly on waking. Another patient was “kicking and screaming” during sleep. 7 The WHO Global Individual Case Safety Reports Database (VigiBase®) holds details of suspected adverse drug reactions (ADRs) voluntarily reported by healthcare professionals and others to national pharmacovigilance agencies worldwide in- cluding those from the FDA AERS database. 8 These reports are the chief source of information about medicines after they are marketed and may in themselves suggest changes and ad- ditions to product information or lead to further studies. The suspected adverse reactions in VigiBase are coded using the WHO Adverse Reaction Terminology (WHO-ART), a hierar - chical system. Investigation of this database in 2013 revealed a range of sleep disorders related to varenicline use, including 143 reports of somnambulism and 2,642 reports of nightmares. Of concern was that some of these reports also included ADR terms indicating aggression or injury, although it was unclear whether these occurred during sleep. It was also noted that a WHO-ART low-level term “abnormal sleep related event” oc- curring under the preferred term “sleep disorder” appeared 27 times, usually together with somnambulism or nightmares. Because the preceding observations raised concern about the relationship between varenicline-related sleep disorders and Downloaded from https://academic.oup.com/sleep/article-abstract/38/5/833/2417011 by guest on 09 June 2020