Gabapentinoid Pharmacology in the Context of Emerging Misuse Liability

Abstract

This article will review the epidemiology and pharmacology of gabapentinoids (gabapentin and pregabalin) relevant to their emerging misuse potential and provide guidance for clinical and regulatory management. Gabapentinoids are γ‐aminobutyric acid analogues that produce their therapeutic effects by inhibiting voltage‐gated calcium channels and decreasing neurotransmitter release. Recently gabapentinoid prescribing and use have increased tremendously. Although traditionally thought to possess a favorable safety profile, gabapentinoid misuse has also risen significantly. Gabapentinoid misuse generally occurs in combination with other substances, most notably opioids, and may be for purposes of eliciting euphoric effects, enhancing the effects of other substances, or self‐treating conditions such as withdrawal, pain, anxiety, or insomnia. Given its faster onset, increased bioavailability and potency, and nonsaturable absorption, pregabalin's pharmacokinetics theoretically enhance its misuse liability versus gabapentin. However, gabapentin can produce similar euphoric effects, and epidemiologic studies have identified higher rates of gabapentin misuse in the United States, likely because of greater availability and less regulated prescribing. Although adverse events of gabapentinoid‐only ingestion are relatively benign, a growing body of evidence indicates that gabapentinoids significantly increase opioid‐related morbidity and mortality when used concomitantly. In addition, significant withdrawal effects may occur on abrupt discontinuation. As a result of these trends, several US states have begun to further regulate gabapentinoid prescribing, reclassifying it as a controlled substance or mandating reporting to local prescription drug‐monitoring programs. Although increased regulation of gabapentin prescribing may be warranted, harm reduction efforts and increased patient and provider education are necessary to mitigate this concerning gabapentinoid misuse trend.

The Mechanisms of Plasticity of Nociceptive Ion Channels in Painful Diabetic Neuropathy

“…However, the use of these drugs is not devoid of side effects, and more than half of patients treated with gabapentinoids experience various side effects such as sedation, ataxia and dizziness as well as weight gain ( 4 ). Furthermore, recent reports indicate that misuse and drug abuse of gabapentinoids is on the rise ( 5 , 6 ).…”

A rationally designed peptidomimetic modulator of CaV2.2 (N-type) voltage-gated calcium channels for chronic pain

“…Gabapentin (Neurontin®) and Pregabalin (Lyrica®) -ligands of α2δ-1 auxiliary subunit of Ca v 2.2 channels -alleviate chronic pain by disrupting Ca v 2.2 -α2δ-1 interaction to prevent Ca v 2.2 trafficking to the plasma membrane (Bauer, Rahman, Tran-van-Minh, Lujan, Dickenson & Dolphin, 2010;Hendrich et al, 2008;Sutton, Martin, Pinnock, Lee & Scott, 2002). Both gabapentinoids have low efficacy and present with serious side effects (Evoy, Peckham, Covvey & Tidgewell, 2021). Misuse of gabapentinoids has led to an increase in overdoserelated deaths between 2019 and 2020 (Kuehn, 2022).…”

Risk of Pregabalin‐Induced Hypoglycemia: Analysis of the Japanese Adverse Drug Event Report Database

“…2,3 The use of pregabalin has been increasing as a potential alternative to opioids for pain management because of the recent increase in opioid abuse. 4 In the United States, nondiscounted spending on pregabalin was the sixth highest, at $5.2 billion in 2018. 4 Although the adverse effects of pregabalin are generally mild, including somnolence, dizziness, and edema, pregabalin can sometimes cause serious adverse events such as respiratory depression.…”

“…4 In the United States, nondiscounted spending on pregabalin was the sixth highest, at $5.2 billion in 2018. 4 Although the adverse effects of pregabalin are generally mild, including somnolence, dizziness, and edema, pregabalin can sometimes cause serious adverse events such as respiratory depression. 4 Moreover, the increased use of pregabalin may increase the number of patients who develop rare but serious adverse events.…”

“…Pregabalin, a gabapentinoid derivative of the inhibitory neurotransmitter gamma‐aminobutyric acid (GABA), 1 is one of the first‐line drugs for the treatment of neuropathic pain 2,3 . The use of pregabalin has been increasing as a potential alternative to opioids for pain management because of the recent increase in opioid abuse 4 . In the United States, nondiscounted spending on pregabalin was the sixth highest, at $5.2 billion in 2018 4 .…”