The Relationship between methylation and genes associated with opioid response in humans.

Opioids are used to alleviate pain however ~10–30% of the Caucasian population obtain ineffective pain relief and / or intolerable side effects. Genetic polymorphisms in opioid pharmacodynamic and pharmacokinetic important genes have been investigated however there has been a lack of conclusive results. Epigenetic gene regulation is another study field of interest. DNA methylation is a gene regulatory mechanism that has been associated with gene repression or expression. Thus it was hypothesised that variable opioid response was influenced by methylation alterations. The promoter region methylation of ABCB1/MDR1, CYP2D6 and OPRM1 genes were analysed by pyrosequencing in smoking, opioid exposed and control pilot populations. Genetic variations within ABCB1/MDR1, COMT, CYP2B6, CYP2D6 and OPRM1 genes were also investigated. Tissue opioid concentrations were determined by HPLCMS/ MS and GC-MS/MS. DNA methylation was influenced by chronic opioid exposure and / or the lifestyle associated with opioid dependency, but not by cigarette smoke exposure. An increase in DNA methylation was observed in the opioid exposed baby population but this was not indicative of development of neonatal abstinence syndrome (NAS). Associations between the CYP2B6*6 genotype and NAS development were found. No relationship was observed between gene methylation and opioid response but variants in OPRM1 and ABCB1/MDR1 exhibited a relationship with opioid response in cancer pain. This investigative pilot research revealed that some genetic variants can be used as diagnostic markers to predict susceptibility of methadone exposed babies to NAS development, and others are associated with variable opioid response in a cancer patient population. Although DNA methylation was not observed to be a contributory factor to opioid response, this research has ascertained the influence of chronic opioid exposure on DNA methylation of various biological samples. This finding is significant for future studies