Abstract
BackgroundA 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.ResultsThe 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.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 a short-term use of therapeutic opioids.
Highlights
A long-term opioid use has been associated with hypermethylation of the opioid receptor mu 1 (OPRM1) promoter
For many individuals who develop opioid use disorder (OUD), the initiation phase may begin with treatment for acute pain or minor surgery, with primary care physicians and dentists accounting for a large fraction of prescribed opioids [5,6,7,8,9,10,11]
Studies in model organisms have shown that drugs of abuse trigger intracellular signaling cascades that alter gene transcription, repeated exposure to the drug results in remodeling of the epigenome that persists over time, and these epigenetic processes maintain the long-term changes in steadystate gene expression that underlie addiction [16, 18,19,20]
Summary
A long-term opioid use has been associated with hypermethylation of the opioid receptor mu 1 (OPRM1) promoter. We examine whether we can detect DNA methylation changes associated with a few days’ use of prescribed opioids. For many individuals who develop opioid use disorder (OUD), the initiation phase may begin with treatment for acute pain or minor surgery, with primary care physicians and dentists accounting for a large fraction of prescribed opioids [5,6,7,8,9,10,11]. Studies in model organisms have shown that drugs of abuse trigger intracellular signaling cascades that alter gene transcription, repeated exposure to the drug results in remodeling of the epigenome that persists over time, and these epigenetic processes maintain the long-term changes in steadystate gene expression that underlie addiction [16, 18,19,20]. Accessible peripheral tissues are clearly the practical choice when it comes to defining biomarkers of drug use and/or predictors of individual risk for addiction
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