LAUSR

We read with great interest the informative and well-conducted systematic review update by Evoy et al. [1] about the risks of gabapentinoid (GP) use (and misuse). The authors concluded that evidence suggests that GP-misuse/abuse is growing and comprises a significant individual and public health threat [1]. However, as the authors stated in their Limitations section, the studies included offer limited generalizability [1] due to small sample sizes, mostly retrospective designs and homogenous cohorts of opioidand other substance-dependent subjects [1]. Clinical studies focusing on individuals without past and/or present substance use disorders are clearly lacking. From a standpoint of scale, not only are reported outcomes (frequently surrogate in nature as admitted by the authors [1]) relatively rare, we are aware of only a miniscule number of patients worldwide seeking treatment for GP misuse/addiction. The emergence of a substantial sample seeking detoxification and other addiction medicine services should be a conditio sine qua non for a widely used/misused, allegedly strongly addictive, and thereby potentially socially harming substance; and yet we have not yet witnessed this phenomenon despite years of opportunity for its development. From the perspective of evidence-based medicine (EBM), level I experimental studies use randomized, prospective experimental designs to confirm causal relationships [2] not unequivocally derivable from non-experimental observational studies [3]. Although regulatory approval/disapproval does not always require randomized trials at every level of decision making, whenever randomization is not possible, the effect of various predictors and confounders must be taken into account in the planning of the study and in data analysis [3–6]. We are not aware of studies that have done so sufficiently to support presumptions of a causal connection between GP-use/misuse and related harms including psychological dependence and death. For example, a PubMed® database search using the key words “mediation analysis” [5] and “gabapentin” or “pregabalin” linked to “harm” or “addiction” or “abuse” or “dependence” or “use disorder” or “death” or “respiratory depression” did not reveal any human studies. Among 46 new observational studies, there were only very few (either small or less specific or too homogeneous (opioid users)) prospective investigations involving the topic of GP addiction and deaths (c.f. Table 1 in [1]). Well-powered and controlled [3–6] prospective trials comparing the occurrence of psychological dependence and deaths in an opioid-dependent sample versus a general population-based sample are needed to identify possible key effect modifiers. We would like to provide some further information aimed at balancing the assessment of GPs’ risk:benefit profile. As mentioned above, there is a glaring paucity of clinical studies about the addictive power/harms potential of GP—apart from the studies utilizing limited cohorts of people with other substance-use disorders [1]. Into this dearth we can add a clinical cross-over study showing that GP-dependence (assessed by face-to-face DSM-IV-based SKID-I interview) was quite rare in the elderly population of a German This is letter relates to the original article available at https:// doi. org/ 10. 1007/ s4026502001432-7.