The accumulating findings linking polymorphisms and haplotypes in OPRM1, as well as epigenetic changes with opioid, alcohol and nicotine dependence and treatment responses do warrant further investigations to elucidate the contribution of genetic variations to OPRM1 expression, the risk for opioid dependence and failure to abstain (Bart et al., 2005; Hernandez-Avila et al., 2003; Levran et al., 2008; Oroszi et al., 2009; Shabalina et al., 2009; Wand et al., 2002; Yuferov et al., 2010; Zhang et al., 2007; Zhang et al., 2006a; Zhang et al., 2006b). It is possible, for example, that the action of the 118A>G polymorphism is not in increasing the risk to develop opioid dependence but rather its severity. This is suggested by a study in a Han Chinese sample, where no association was found between 118A>G and drug dependence, but where haplotypes involving the 118A>G and the IVS2 +31 G/A variant were associated with higher tolerance in heroin dependent individuals (Shi et al., 2002). However, this study, the large scale Australian study (E.C. Nelson, personal correspondence), and recent meta-analyses indicate that there is no direct association between this polymorphism alone and heroin dependence.
