DNA methylation at the mu-1 opioid receptor gene (<em>OPRM1</em>) promoter predicts preoperative, acute, and chronic postsurgical pain after spine fusion

Abstract

IntroductionThe perioperative pain experience shows great interindividual variability and is difficult to predict. The mu-1 opioid receptor gene (OPRM1) is known to play an important role in opioid-pain pathways. Since deoxyribonucleic acid (DNA) methylation is a potent repressor of gene expression, DNA methylation was evaluated at the OPRM1 promoter, as a predictor of preoperative, acute, and chronic postsurgical pain (CPSP).MethodsA prospective observational cohort study was conducted in 133 adolescents with idiopathic scoliosis undergoing spine fusion under standard protocols. Data regarding pain, opioid consumption, anxiety, and catastrophizing (using validated questionnaires) were collected before and 2–3 months postsurgery. Outcomes evaluated were preoperative pain, acute postoperative pain (area under curve [AUC] for pain scores over 48 hours), and CPSP (numerical rating scale >3/10 at 2–3 months postsurgery). Blood samples collected preoperatively were analyzed for DNA methylation by pyrosequencing of 22 CpG sites at the OPRM1 gene promoter. The association of each pain outcome with the methylation percentage of each CpG site was assessed using multivariable regression, adjusting for significant (P<0.05) nongenetic variables.ResultsMajority (83%) of the patients reported no pain preoperatively, while CPSP occurred in 36% of the subjects (44/121). Regression on dichotomized preoperative pain outcome showed association with methylation at six CpG sites (1, 3, 4, 9, 11, and 17) (P<0.05). Methylation at CpG sites 4, 17, and 18 was associated with higher AUC after adjusting for opioid consumption and preoperative pain score (P<0.05). After adjusting for postoperative opioid consumption and preoperative pain score, methylation at CpG sites 13 and 22 was associated with CPSP (P<0.05).DiscussionNovel CPSP biomarkers were identified in an active regulatory region of the OPRM1 gene that binds multiple transcription factors. Inhibition of binding by DNA methylation potentially decreases the OPRM1 gene expression, leading to a decreased response to endogenous and exogenous opioids, and an increased pain experience.

Epigenetic variation in OPRM1 gene in opioid‐exposed mother‐infant dyads

“…This may in turn lead to increased need for medication to treat the symptoms of opioid withdrawal. The associations between hypermethylation of the OPRM1 promoter after chronic opioid exposure, decreased OPRM1 gene expression, reduced pain tolerance and subsequent need for opioid medications have been showed in an adult cancer population, as well as in postoperative adult patients …”

Transgenerational influence of parental morphine exposure on pain perception, anxiety-like behavior and passive avoidance memory among male and female offspring of Wistar rats

“…The chronic opioid misuse alters opioid receptor genes that may impair germ cell development and roles epigenetic transmission in addicted phenotypes (Chorbov et al, 2011[18]; Chidambaran et al, 2017[17]). We conclude that sex difference in the perception of pain in the offspring might be influenced by hormonal excretion, which was altered in female offspring of the morphine-treated parent.…”

“…The chronic opioid misuse through epigenetic transmission may impair germ cell development in the addicted phenotypes (Chorbov et al, 2011[18]; Chidambaran et al, 2017[17]). The accumulative evidence suggests that the behavioral changes of addicted individuals is under control of epigenetics factors.…”

Association between Neuropathic Pain Characteristics and DNA Methylation of <em>TRPA1</em> in Human Peripheral Blood

“…Several previous reports have stated that the level of DNA methylation, which is one of the principal mechanisms of epigenetic changes, in the peripheral blood of humans correlates with chronic pain in patients with persistent postsurgical pain [13][14][15],…”