Table 4.

Concluding summary

• The 118A>G single nucleotide polymorphism (SNP) in OPRM1 results in amino acidic substitution at position 40 from asparagine to aspartic acid (N40D) that probably causes the loss of a N-glycosylation site in the extracellular region of the receptor. The 118G allele has a frequency of 27%–48% in Asians, of 11%–17% among Caucasians, of 2.2% in African-Americans and of 0.8% in Sub-Saharan Africans.

• In vitro experiments show that the variant receptors are associated to higher binding affinity and potency of the endogenous ligand β-endorphin, but, conversely, to lower potency of exogenous opioid ligands (i.e. morphine). The variant receptor was also less expressed than the wild-type.

• In vivo studies confirmed the higher binding affinity of the variant receptor for endogenous ligands and a lower potency of exogenous opioids observed in vitro. Transgenic mice carrying the variant allele show a lower analgesic effect of morphine compared to the wildtype.

• Studies on humans show that the effect of 118A>G SNP on interindividual sensitivity to pain and analgesic response to opioid is slight and not always confirmed. Despite patients carrying the 118G allele may require higher opioid doses to get the analgesic response of the drug compared to carriers of the 118 A allele they are not more at risk of opioid-related side effects. To date the analysis of 118A>G SNP alone seems to have a poor clinical (predictive) utility.

• Description of 118G-related phenotypes during clinical studies reveals that the 118A>G SNP has not the same influence on all opioid effects. The characteristics of variant μ-opioid receptors controlling gastrointestinal, respiratory and other opioid-related effects should be explored in future preclinical studies.

• Pain is a complex experience: the interaction of multiple genes, each with a small individual effect, in addition to emotional and environmental factors may influence opioid efficacy in clinical settings. Evaluation of the combined effects of OPRM1 118A>G and SNPs in other pain-related genes, as well as studies of 118A>G containing haplotypes emerge as intriguing tools in pharmacogenetics of opioids.