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 RASrelated 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.

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.

Staphylococcus aureus has long been known as one of the most virulent microbes, with capabilities that make it threatening in both nosocomial and community-acquired infections. It remains the most frequent cause of skin-structure and traumatic infections in the community. S. aureus infections in the maxillofacial region are likely to be associated with a known portal of entry, but this is not always the case. Once invasion occurs, the organism may produce virulent enzymes including coagulase, hyaluronidase, proteases, DNA-ase, lipases, hemolysins, and lysozyme as well as exotoxins. Markel et al point out that cellulitis associated with coagulase-positive staphylococci will often resolve without abscess formation. Hence, there is often no site from which to obtain specimens, making this infection a diagnostic and therapeutic challenge. This report describes an infection in which the etiologic organism was identified as S. aureus. The source of the infection, however, remained unclear.

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Results from machine learning indicated that opioid self-administration could be identified with reasonable accuracy, suggesting that wearable technology can be for prevention and treatment.