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Background  A long-term opioid use has been associated with hypermethylation of the opioid receptor mu 1 ( OPRM1 ) promoter. Very little is currently known about the early epigenetic response to therapeutic opioids. Here, we examine whether we can detect DNA methylation changes associated with a few days’ use of prescribed opioids. Genome-wide DNA methylation was assayed in a cohort of 33 opioid-naïve participants who underwent standard dental surgery followed by opioid self-administration. Saliva samples were collected before surgery (visit 1), and at two postsurgery visits at 2.7 ± 1.5 days (visit 2), and 39 ± 10 days (visit 3) after the discontinuation of opioid analgesics.    Results  The perioperative methylome underwent significant changes over the three visits that were primarily due to postoperative inflammatory response and cell heterogeneity. To specifically examine the effect of opioids, we started with a candidate gene approach and evaluated 10 CpGs located in the  OPRM1  promoter. There was a significant cross-sectional variability in opioid use, and for participants who self-administered the prescribed drugs, the total dosage ranged from 5–210 morphine milligram equivalent (MME). Participants were categorized by cumulative dosage into three groups: < 25 MME, 25–90 MME, and ≥ 90 MME. Using mixed-effects modeling, 4 CpGs had significant positive associations with opioid dose at two-tailed  p  value < 0.05, and overall, 9 of the 10  OPRM1  promoter CpGs showed the predicted higher methylation in the higher dose groups relative to the lowest dose group. After adjustment for age, cellular heterogeneity, and past tobacco use, the promoter mean methylation also had positive associations with cumulative MME (regression coefficient = 0.0002, one-tailed  p  value = 0.02) and duration of opioid use (regression coefficient = 0.003, one-tailed  p  value = 0.001), but this effect was significant only for visit 3. A preliminary epigenome-wide association study identified a significant CpG in the promoter of the RAS-related signaling gene,  RASL10A , that may be predictive of opioid dosage.    Conclusion  The present study provides evidence that the hypermethylation of the  OPRM1  promoter is in response to opioid use and that epigenetic differences in  OPRM1  and other sites are associated with a short-term use of therapeutic opioids.

Effect of short-term prescription opioids on DNA methylation of the OPRM1 promoter