Gabapentinoid Benefit and Risk Stratification: Mechanisms Over Myth

Recent years have seen a dramatic escalation of off-label prescribing for gabapentin and pregabalin (gabapentinoids) owing in part to generic versions of each being released over the past two decades, but also in part as a response to increasing calls for multimodal and non-opioid pain management strategies. In this context, several recent articles have been published alleging widespread misuse, with speculations on the unappreciated addictive potential of the gabapentinoid class of drugs. Reports of a 1% population-level abuse prevalence stem from a single internet survey in the UK, and the vanishingly small adverse event outcomes data do not support such frequency. In this targeted narrative review, we aim to disabuse pain physicians and other clinicians, pharmacists, and policymakers of both the positive and negative myths concerning gabapentinoid medications.

Gabapentinoids inhibit the joint action of voltage-gated calcium channel (VGCC) α2δ subunits in conjunction with the n-methyl-D-aspartate (NMDA) receptor, with subsequent downregulation of VGCC expression and excitatory neurotransmitter release, and possibly synaptogenesis as well, through actions on thrombospondins. These activities reduce the likelihood of central sensitization, which explains in part the efficacy of the gabapentinoids in the management of neuropathic pain. Gabapentinoids also facilitate slow-wave sleep, a relatively rare phenomenon among central nerve system-acting agents, which is also thought to explain some of the therapeutic benefit of the class in conditions such as fibromyalgia. The number needed to treat to see benefit overlaps that of the nonsteroidal anti-inflammatory drugs, but with a considerably improved safety profile. Along these lines, in the context of over 50 million prescriptions per year in the USA alone, the gabapentinoids display remarkably low risk, including risks of misuse, abuse, and dependence. Furthermore, the neurobiology of these agents does not lend plausibility to the allegations, as they have never been shown to elicit dopaminergic activity within the nucleus accumbens, and in addition likely confer a "negative-feedback loop" for habituation and dependence by serving as functional NMDA antagonists, possibly through their actions on thrombospondins. Clinical and epidemiological addictionology studies corroborate the lack of any significant addictive potential of the gabapentinoids, and these drugs are increasingly being used in the treatment of addiction to other substances, with excellent results and no evidence of cross-addiction. However, among individuals with other substance use disorders and, in particular opioid use disorder, there are consistent data showing misuse of gabapentinoids in up to 20% of this population. Although there are allegations of using gabapentinoids to amplify the hedonic effects of opioids, the vast majority of misuse events appear to occur in an attempt to ameliorate opioid withdrawal symptoms. Furthermore, rare but potentially serious respiratory depression may occur, again amplified in the context of opioid or other sedative use. Careful risk:benefit assessment and stratification are warranted when prescription of a gabapentinoid is under consideration, in particular among individuals using opioids.

Gabapentinoids remain a vital tool in the pain physician's multimodal armamentarium, but these drugs may not be effective in every clinical situation. Individuals with central sensitization and pain associated with slow-wave sleep deficits and potentially persons with comorbid addictions may benefit the most. The gabapentinoids appear to possess no addictive potential on their own, based on laboratory and clinical data, but they may be abused by persons with opioid use disorders; consequently, cautious risk stratification must take place.