[On the risk of dependence on gabapentinoids]

In the last ten years, the prescriptions of the gabapentinoids gabapentin and pregabalin increased largely also in Germany. Since several national and international pharmacovigilance-databases have warned for abuse liabilities and overdose fatalities in association with both gabapentinoids, which moreover, became to be sold on internet and black-markets, their addictive power has been subject to an ongoing clinical debate. As pre- and post-approval clinical trials did not reveal significant signs of dependence on gabapentin or pregabalin, we systematically searched in PubMed and Scopus for clinical studies and case reports being associated with abuse of and dependence on these drugs. We found 14 clinical-epidemiologic studies and 38 case reports/series. These were evaluated for i) fulfilled dependence criteria according to ICD-10, ii) non-medical self-administration and their duration, iii) relapses, iv) social sequels, and v) cases seeking treatment for misusing gabapentin or pregabalin. Mostly, the cases of abuse of and dependence on gabapentinoids appeared to be associated with other substance dependencies, primarily opiate dependence and polyvalent drug use. Drug users preferred pregabalin citing a faster and stronger euphoria ("liking") than achievable with oral gabapentin. Both gabapentinoids were anxiolytic in therapeutic doses, stimulating in lower and sedating along with increasing doses. Fatalities have been described mainly in the population of opiate dependents and polyvalent drug users, predominantly together with excessive pregabalin overdosing. It is debated whether the gabapentinoids were indeed the main cause of death in these cases or whether gabapentin and pregabalin had been only bystanders. Tolerance and withdrawal symptoms (physical dependence) of gabapentinoids appeared to be common in medical and non-medical use of gabapentinoids. There were only 4 persons who had fulfilled behavioral dependence criteria of gabapentinoids (all had used pregabalin) and had no association with other substance use disorders (apart from nicotine). Regarding the transitions from prescription to non-medical self-administration, the frequency and duration of self-administrations as well as the number of reported relapses, pregabalin appeared also to be more addictive than gabapentin. However, all these events were reported rather infrequently compared with traditional substances of abuse. We did not find a case with social sequalea due to the use of gabapentinoids or a person who sought treatment for his gabapentin or pregabalin use. Therefore, the gabapentinoids were assumed to possess a lower "wanting" in consideration of Berridge's and Robinsons's incentive-sensitization theory of addiction. Also, anti-adverse selection of gabapentinoids is discussed to be present in the population of opioid and multi-drug users. Based upon all these results and assumptions, we have estimated the relative risk of dependence on gabapentinoids by using an algorithm which was previously developed by Griffith and Johnson for evaluation of the abuse liabilities of sedatives. Overall, the risk of harm and dependence on gabapentinoids appeared to be lower than that of other sedatives (and stimulants). In addition, pregabalin appeared to be somewhat riskier than gabapentin. We think that in patients with current or past substance use disorders, the treatment with gabapentinoids should be avoided or if indispensable, these drugs should be administered exclusively over a limited time span with caution by using a therapeutic and prescription monitoring.