Gabapentinoids for chronic pain unexpected benefits or added risk?

In response to the opioid crisis, clinical practice guidelines recommend opioid tapering and deprescribing in patients with chronic noncancer pain (CNCP), where appropriate. The search for alternate analgesic options has resulted in the use of gabapentinoids, specifically gabapentin and pregabalin. With moderate quality evidence in several pain conditions and a hypothetically low risk of misuse, use of these agents increased dramatically over the last 15 years.1-3 Expectedly, as gabapentinoid exposure rates increase, we continue to gain interesting and clinically meaningful insight on these agents. Let’s start with the good news. Pleasant surprises It is well documented that people who suffer from chronic pain are at an increased risk of comorbid anxiety disorders.4 Given this, therapeutic options that can effectively target both CNCP and anxiety would be clinically useful. Interestingly, a growing body of evidence supports the use of gabapentinoids for the treatment of anxiety disorders. So far, the most compelling evidence supports the use of pregabalin for generalized anxiety disorder (GAD), with several trials demonstrating a significant beneficial effect of pregabalin (150–600 mg daily) in reducing Hamilton Anxiety Rating Scale (HAM-A) scores (number needed to treat [NNT]=8).5-7 Further, when evaluated against active comparators, pregabalin was found to be at least as effective as alprazolam, lorazepam and venlafaxine on HAM-A score reduction.5 Despite these promising results, most trials were less than eight weeks in duration, leaving the long-term efficacy and safety of gabapentinoids for the treatment of GAD unclear.5,6,8 Too good to be true? Despite the use of gabapentinoids for both CNCP and anxiety, there is a paucity of evidence evaluating their anxiolytic effects specifically in chronic pain populations. We identified one recent meta-analysis reviewing the use of pregabalin in the management of neuropathic pain that included anxiety scores as a secondary outcome; no significant difference in Hospital Anxiety and Depression Scale (HADS) scores was noted between pregabalin and placebo.9 One study from this meta-analysis did show improvement in HADS scores in favour of pregabalin; however, it did not provide sufficient data to be included in statistical pooling for this secondary outcome.9,10 These findings should be interpreted judiciously, as they could indicate a true absence of anxiolytic effect in CNCP populations, or they could simply be a result of studies not being powered to capture a statistically significant difference in anxiety outcomes. Additionally, the existing evidence supporting the use of pregabalin for anxiety has been demonstrated exclusively in patients who met DSM-IV criteria for GAD and minimum HAM-A score. Therefore, further studies in CNCP with those meeting GAD criteria are needed to support clinical decision-making in this area. The bad with the good Despite a possible role in patients with CNCP and comorbid anxiety, gabapentinoids may not be the innocuous alternatives to opioids that we were hoping for. With increased prescribing, we have seen a synchronous and undeniable rise in abuse, misuse and diversion.11-14 Importantly, it has also been identified that rates of misuse are substantially higher among those with opioid use disorder (OUD) and that rates of recreational use in this population are continuing to increase.11,13,14 In addition to OUD, additional risk factors for recreational gabapentinoid use include history of substance abuse, comorbid psychiatric conditions, and new users of this drug class.11,15 The highs and the lows Recreational gabapentinoid use often involves single doses above recommended daily maximums to achieve effects such as euphoria, improved sociability, dissociation and relaxation.11,16 When interviewed, those with known problematic gabapentinoid use cited additional desired effects, including a reduced “come down” from other drug highs, enhanced/prolonged effects of opioids when used in combination, and improvements in pain, anxiety and sleep.16 Further, some individuals chose gabapentinoids over other recreational drug use due to their lower cost, easier access, and perceived lack of detection in standard drug screens.16 It is interesting to note that pregabalin is often favoured by users over gabapentin, likely due to its more potent and rapid effects, and the lower doses needed to achieve the desired effects.11,17 A deadly combination Evidence suggests that the harms of gabapentinoid misuse may be greater than originally appreciated.16,17 Overuse has been associated with an increase in all-cause hospitalizations, a risk that was found to be three times higher in those concurrently taking high-dose opioids.16,18 Reasons for hospitalizations include respiratory depression, reduced consciousness, bradycardia, coma and seizures.11,18,19 Importantly, it has been suggested that the potential harms of gabapentinoid misuse may be underestimated by users, with prescription status adding a potential veil of safety for some.16 This is further compounded by the fact that the majority (63.1%) of misused gabapentinoids are obtained from healthcare providers.20 Clinical pearl As more studies are conducted and the amount of evidence increases, we can expect to see gabapentinoids used more in CNCP for both analgesic and anxiolytic effects. With that, benefits of use should be weighed against potential risks, particularly misuse, abuse and diversion.1,2,21 With recreational gabapentinoid use soaring, there are numerous ways pharmacists can get involved to support harm reduction. In the community pharmacy, essential practices include checking provincial databases and filling histories to monitor for early refills, double doctoring and inappropriate dose escalations. Most importantly, empowering patients with harm reduction knowledge through counselling on safer gabapentinoid use may interrupt the transition from prescribed to unsafe use. With these and other strategies, pharmacists are well positioned to help ensure we aren’t simply replacing one drug crisis with another. Dana Turcotte is a clinical pharmacist at a multidisciplinary primary care clinic in Winnipeg, MB, and an Assistant Professor at the College of Pharmacy, University of Manitoba. Her practice focuses on safer opioid use and pain management. The author thanks Alyssa Marino and Kelli McCarthy, pharmacy interns in Winnipeg, MB for their co-authorship of this article. References: Wiffen PJ, Derry S, Bell RF, et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2017;6(6):CD007938. doi:10.1002/14651858.CD007938.pub4. Derry S, Bell RF, Straube S, et al. Pregabalin for neuropathic pain in adults. Cochrane Database Syst Rev 2019;1(1):CD007076. doi:10.1002/14651858.CD007076.pub3. Hägg S, Jönsson AK, Ahlner J. Current evidence on abuse and misuse of gabapentinoids. Drug Saf 2020;43(12):1235-54. doi:10.1007/s40264-020-00985-6. Ramage-Morin PL, Gilmour H. Chronic pain at ages 12 to 44. Health Rep 2010;21(4):53-61. Baldwin DS, den Boer JA, Lyndon G, et al. Efficacy and safety of pregabalin in generalised anxiety disorder: a critical review of the literature. J Psychopharmacol 2015;29(10):1047-60. Wensel TM, Powe KW, Cates ME. Pregabalin for the treatment of generalized anxiety disorder. Ann Pharmacother 2012;46:424-9. doi:10.1345/aph.1Q405. Aurobindo Pharma. Pregabalin (SmPC). 2021. https://www.medicines.org.uk/emc/product/7132/smpc#gref (accessed May 25, 2023). Horowitz MA, Kelleher M, Taylor D. Should gabapentinoids be prescribed long-term for anxiety and other mental health conditions? Addict Behav 2021;119:106943. doi:10.1016/j.addbeh.2021.106943. Onakpoya IJ, Thomas ET, Lee JJ, et al. Benefits and harms of pregabalin in the management of neuropathic pain: a rapid review and meta-analysis of randomised clinical trials. BMJ Open 2019;9(1):e023600. doi:10.1136/bmjopen-2018-023600. Stacey BR, Barrett JA, Whalen E, et al. Pregabalin for postherpetic neuralgia: placebo-controlled trial of fixed and flexible dosing regimens on allodynia and time to onset of pain relief. J Pain 2008;9:1006-17. 10.1016/j.jpain.2008.05.014. Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of pregabalin and gabapentin. Drugs 2017;77:403-26. doi:10.1007/s40265-017-0700-x. Chiappini S, Schifano F. A decade of gabapentinoid misuse: an analysis of the European Medicines Agency’s ‘Suspected Adverse Drug Reactions’ database. CNS Drugs 2016;30:647-54. doi: 10.1007/s40263-016-0359-y. Meaadi J, Obara I, Eldabe S, et al. The safety and efficacy of gabapentinoids in the management of neuropathic pain: a systematic review with meta-analysis of randomised controlled trials [published online ahead of print, February 27, 2023]. Int J Clin Pharm 2023;10.1007/s11096-022-01528-y. doi:10.1007/s11096-022-01528-y. Smith RV, Lofwall MR, Havens JR. Abuse and diversion of gabapentin among nonmedical prescription opioid users in Appalachian Kentucky. Am J Psychiatry 2015;172:487-8. Driot D, Jouanjus E, Oustric S, et al. Patterns of gabapentin and pregabalin use and misuse: results of a population-based cohort study in France. Br J Clin Pharmacol 2019;85:1260-9. Evoy KE, Sadrameli S, Contreras J, et al. Abuse and misuse of pregabalin and gabapentin: a systematic review update. Drugs 2021;81(1):125-56. doi:10.1007/s40265-020-01432-7. Schifano F, D’Offizi S, Piccione M, et al. Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data. Psychother Psychosom 2011;80):118-22. Peckham AM, Fairman KA, Sclar DA. All-cause and drug-related medical events associated with overuse of gabapentin and/or opioid medications: a retrospective cohort analysis of a commercially insured US population. Drug Saf 2018;41):213-28. Antunovic M, Vucinic S, Kotur-Stevuljevic J, et al. Rise of pregabalin poisoning and abuse cases in Serbia: a ten-year retrospective study. Int J Gen Med 2023;16:1239-50. doi:10.2147/IJGM.S405616. Kapil V, Green JL, Le Lait MC, et al. Misuse of the γ-aminobutyric acid analogues baclofen, gabapentin and pregabalin in the UK. Br J Clin Pharmacol 2014;78(1):190-1. doi:10.1111/bcp.12277. Derry S, Cording M, Wiffen PJ, et al. Pregabalin for pain in fibromyalgia in adults. Cochrane Database Syst Rev 2016;9(9):CD011790. doi:10.1002/14651858.CD011790.pub2.

Managing Pain

Gabapentinoids for chronic pain unexpected benefits or added risk?

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Dana Turcotte

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