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. 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