Systematic Review and Meta-Analysis Evaluating the impact of gabapentinoids on sleep health in patients with chronic neuropathic pain: a systematic review and meta-analysis Daniel Kapustin a , Anuj Bhatia b,c,d , Aidan McParland a , Aditya Trivedi e , Alexandra Davidson a , Richard Brull b,c , Mandeep Singh b,c, * Abstract Chronic neuropathic pain (NP) is debilitating and impacts sleep health and quality of life. Treatment with gabapentinoids (GBs) has been shown to reduce pain, but its effects on sleep health have not been systematically evaluated. The objective of this systematic review and meta-analysis was to assess the relationship between GB therapy dose and duration on sleep quality, daytime somnolence, and intensity of pain in patients with NP. Subgroup comparisons were planned for high- vs low-dose GBs, where 300 mg per day or more of pregabalin was used to classify high-dose therapy. Trial data were segregated by duration less than 6 weeks and 6 weeks or greater. Twenty randomized controlled trials were included. Primary outcome measures included pain-related sleep interference and incidence of daytime somnolence. Secondary outcomes included daily pain scores (numerical rating scale 0-10) and patient global impression of change. Significant improvement in sleep quality was observed after 6 weeks of GB treatment when compared with placebo (standardized mean difference 0.39, 95% confidence interval 0.32-0.46 P , 0.001). Increased daytime somnolence was observed among all GB-treated groups when compared with placebo. Treated patients were also more likely to report improvement of patient global impression of change scores. Pain scores decreased significantly in patients both after 6 weeks of treatment (P , 0.001) and in trials less than 6 weeks (P 5 0.017) when compared with placebo. Our data demonstrate that GBs have a positive impact on sleep health, quality of life, and pain in patients with NP syndromes. However, these benefits come at the expense of daytime somnolence. Keywords: Gabapentinoids, Neuropathic pain, Postherpetic neuralgia, Diabetic peripheral neuropathy, Sleep health, Sleep quality, Sleepiness, Quality of life 1. Introduction Neuropathic pain (NP) is a debilitating condition resulting from lesions or diseases that affect the somatosensory system. 18 Neuropathic pain affects an estimated 10% of the population, 10 and its commonest manifestation is peripheral neuropathy. Postherpetic neuralgia (PHN) and painful diabetic neuropathy (PDN) are 2 most well-characterized peripheral neuropathic pain (PNP) conditions. These chronic pain syndromes are characterized by dermatomal pain, paresthesia, and sensory gain or deficits. Despite the high prevalence of PNP syndromes, current therapeutic options for treatment are limited. Pharmacotherapy strategies for pain man- agement include antidepressants, gabapentinoids (GBs), and other anticonvulsants, opioids, or local anesthetics. 37 In view of the recent increase in opioid-related mortality rate 27 and concerns with use of opioid-related side effects, there is increased interest in using nonopioid medications in pain management. The g-aminobutyric acid (GABA) analogues gabapentin and pregabalin, commonly referred to as GBs, are an effective alternative to opioids given their analgesic efficacy and positive effects on sleep health. 17,55 The efficacy of GBs in reducing NP, reversibility of their adverse effects, and their ability to be a component of multimodal therapy has resulted in the recommendation of these medications as a first-line therapy for NP. 20 Sleep disturbance is a common and significant comorbidity of NP. 13 As NP often worsens during the night, patients commonly report pain-associated sleep interference. 17 Recent evidence has additionally suggested a bidirectional relationship between impaired sleep and subsequent reductions in pain tolerance, resulting in cyclical exacerbation of both chronic pain and sleep health. 44,45 Although several randomized controlled trials (RCTs) have examined the effects of GBs on pain management and sleep health in PNP syndromes, there has been no attempt to evaluate the relationship between GB dose or treatment duration on these outcome measures. An systematic review and meta-analysis (SR-MA) of this topic would thus help clarify the benefits and side effects of GB therapy in PNP syndromes. The objective of this SR- MA was therefore to assess the effects of GB therapy dosage and Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. a University of Toronto, Faculty of Medicine, Toronto, ON, Canada, b Department of Anesthesia and Pain Medicine, Women’s College Hospital, Toronto, ON, Canada, c Department of Anesthesia and Pain Medicine, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada, d Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, ON, Canada, e Department of Chemistry, McMaster University, Hamilton, ON, Canada *Corresponding author. Address: Department of Anesthesia, Women’s College Hospital and Toronto Western Hospital, University Health Network, 399 Bathurst St, McL 2-405, Toronto, ON M5T 2S8, Canada. Tel.: 11-416-603-5118; fax: 11-4166036494. E-mail address: mandeep.singh@uhn.ca (M. Singh). Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.painjournalonline.com). PAIN 00 (2019) 1–15 © 2019 International Association for the Study of Pain http://dx.doi.org/10.1097/j.pain.0000000000001743 Month 2019 · Volume 00 · Number 00 www.painjournalonline.com 1 Copyright © 2019 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.