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

Abstract

BackgroundLong-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 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.ResultsThe perioperative methylome underwent significant changes over the three visits that was 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 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, ≥90 MME. Using mixed effects modeling, 4 CpGs had significant positive associations with opioid dose at 2-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, 1-tailed p-value = 0.02), and duration of opioid use (regression coefficient = 0.003, 1-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.ConclusionThe 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 short-term use of therapeutic opioids.

Epigenome-Wide Study of Brain DNA Methylation Among Opioid Users and Controls

“…To date, epigenetic studies of opioid use have focused on candidate genes, namely OPRM1 , which encodes for the μ-opioid receptor (9–12). This receptor plays a role in the tolerance and physical dependence of opiates (13).…”

The role of the OPRM1 gene polymorphism and its methylation in people in dependence on substances and with different intensity of pain

“…There was also suggestion that by initial intake of opioids, DNA methylation level increases. It was confirmed that among 33 patients with prescribed opioid drugs, there was a significant higher DNA methylation at OPRM1 promotor, which was result of opioid exposure [67]. Methylation of OPRM1 could be used also as a status indicator, whose subject is more likely to be opium dependent [68].…”

Genome-wide association study of nociceptive musculoskeletal pain treatment response in UK Biobank

“…Some preliminary published results indicate that epigenetic restructuring can happen in response to opioid analgesics use. For instance, hypermethylation in both the promoter region of a candidate gene ( OPRM1) and global DNA methylation were observed after opioid use [68,69].…”