Secondly, due to the stigma attached to drug dependence, many opioid-dependent subjects may be unwilling or unable to participate in case-control studies. Thus, the case subjects may not be representative of the general opioid-dependent population. Thirdly, multiple drug dependency was not an exclusion criterion. Therefore, other drug dependencies such as alcohol and nicotine may be acting on the brain-reward pathway, making investigation of a direct association between opioid dependence and A118G difficult to observe. Finally, two of the included studies did not screen their control groups for psychiatric disorders,16,22 whilst a third relied on participants’ self-reported psychiatric history for excluding subjects.18 Consequently, in these three studies, it is possible that their respective control groups included subjects with psychiatric illness(es) which may have impacted on the phenotypes of the cases versus the controls to mask the association. It should be noted that the degree of heterogeneity observed in the present study was similarly reported by the two previous meta-analyses5,9 (χ2 = 4.35, P = 0.037 and χ2 = 41.72, P = 0.003, respectively). This heterogeneity is suggestive of potential moderating variables
