OPRM1 Methylation Contributes to Opioid Tolerance in Cancer Patients

Viet, Chi T.; Dang, Dongmin; Aouizerat, Bradley E.; Miaskowski, Christine; Ye, Yi; Viet, Dan T.; Ono, Kentaro; Schmidt, Brian L.

doi:10.1016/j.jpain.2017.04.001

Cited by 27 publications

(18 citation statements)

References 38 publications

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“…In that study, a methylating effect of opioid treatment had been proposed based on higher methylation levels in opioid treated than in non-opioid treated pain patients. This effect has been reproduced independently [71]. Nevertheless, the global methylation levels of in median 80% in that study [23] agreed with the presently observed levels.…”

Section: Discussionsupporting

confidence: 80%

Machine-learned analysis of global and glial/opioid intersection–related DNA methylation in patients with persistent pain after breast cancer surgery

et al. 2019

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BackgroundGlial cells in the central nervous system play a key role in neuroinflammation and subsequent central sensitization to pain. They are therefore involved in the development of persistent pain. One of the main sites of interaction of the immune system with persistent pain has been identified as neuro-immune crosstalk at the glial-opioid interface. The present study examined a potential association between the DNA methylation of two key players of glial/opioid intersection and persistent postoperative pain.MethodsIn a cohort of 140 women who had undergone breast cancer surgery, and were assigned based on a 3-year follow-up to either a persistent or non-persistent pain phenotype, the role of epigenetic regulation of key players in the glial-opioid interface was assessed. The methylation of genes coding for the Toll-like receptor 4 (TLR4) as a major mediator of glial contributions to persistent pain or for the μ-opioid receptor (OPRM1) was analyzed and its association with the pain phenotype was compared with that conferred by global genome-wide DNA methylation assessed via quantification of the methylation in the retrotransposon LINE1.ResultsTraining of machine learning algorithms indicated that the global DNA methylation provided a similar diagnostic accuracy for persistent pain as previously established non-genetic predictors. However, the diagnosis can be based on a single DNA based marker. By contrast, the methylation of TLR4 or OPRM1 genes could not contribute further to the allocation of the patients to the pain-related phenotype groups.ConclusionsWhile clearly supporting a predictive utility of epigenetic testing, the present analysis cannot provide support for specific epigenetic modulation of persistent postoperative pain via methylation of two key genes of the glial-opioid interface.

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Section: Discussionsupporting

confidence: 80%

Machine-learned analysis of global and glial/opioid intersection–related DNA methylation in patients with persistent pain after breast cancer surgery

et al. 2019

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“…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 …”

Section: Discussionmentioning

confidence: 99%

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

Wachman

Hayes

Shrestha

et al. 2018

Genes Brain and Behavior

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Neonatal abstinence syndrome (NAS) due to in-utero opioid exposure has significant variability of severity. Preliminary studies have suggested that epigenetic variation within the μ-opioid receptor (OPRM1) gene impacts NAS. We aimed to determine if DNA methylation in OPRM1 within opioid-exposed mother-infant dyads is associated with differences in NAS severity in an independent cohort. Full-term opioid-exposed newborns and their mothers (N = 68 pairs) were studied. A DNA sample was obtained and then assessed for level of DNA methylation at 20 CpG sites within the OPRM1 promoter region by next-generation sequencing. Infants were monitored for NAS and treated with replacement opioids according to institutional protocol. The association between DNA methylation level at each CpG site with NAS outcome measures was evaluated using linear and logistic regression models. Higher methylation levels within the infants at the -18 (11.4% vs 4.4%, P = .0001), -14 (46.1% vs 24.0%, P = .002) and +23 (26.3% vs 12.9%, P = .008) CpG sites were associated with higher rates of infant pharmacologic treatment. Higher levels of methylation within the mothers at the -169 (R = 0.43, P = .008), -152 (R = 0.40, P = .002) and +84 (R = 0.44, P = .006) sites were associated point-wise with longer infant length of stay. Maternal associations remained significant point-wise for -169 (β = 0.07, P = .007) and on an experiment-wise level for +84 (β = -0.10, P = .003) using regression models. These results suggest an association of higher levels of OPRM1 methylation at specific CpG sites and increased NAS severity, replicating prior findings. These findings have important implications for personalized treatment regimens for infants at high risk for severe NAS.

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“…Inadequate pain management in cancer patients has been linked to hypermethylation of OPRM1 , yielding a decreased response to the analgesic effects of opioids. Chronic or high-dose use of opioids was correlated with this hypermethylation and downregulation of receptors, confirming a mechanism of tolerance 69. Furthermore, the presence of a specific A118G polymorphism in OPRM1 leads to a less active receptor that has been linked to individuals with reduced analgesic responses to morphine postoperatively 70…”

Section: Biological Polymorphisms Involved In Painmentioning

confidence: 84%

<p>Update on the pharmacogenomics of pain management</p>

Kaye¹,

Garcia²,

Hall³

et al. 2019

PGPM

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Pharmacogenomics is the study of genetic variants that impact drug effects through changes in a drug’s pharmacokinetics and pharmacodynamics. Pharmacogenomics is being integrated into clinical pain management practice because variants in individual genes can be predictive of how a patient may respond to a drug treatment. Pain is subjective and is considered challenging to treat. Furthermore, pain patients do not respond to treatments in the same way, which makes it hard to issue a consistent treatment regimen for all pain conditions. Pharmacogenomics would bring consistency to the subjective nature of pain and could revolutionize the field of pain management by providing personalized medical care tailored to each patient based on their gene variants. Additionally, pharmacogenomics offers a solution to the opioid crisis by identifying potentially opioid-vulnerable patients who could be recommended a nonopioid treatment for their pain condition. The integration of pharmacogenomics into clinical practice creates better and safer healthcare practices for patients. In this article, we provide a comprehensive history of pharmacogenomics and pain management, and focus on up to date information on the pharmacogenomics of pain management, describing genes involved in pain, genes that may reduce or guard against pain and discuss specific pain management drugs and their genetic correlations.

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OPRM1 Methylation Contributes to Opioid Tolerance in Cancer Patients

Cited by 27 publications

References 38 publications

Machine-learned analysis of global and glial/opioid intersection–related DNA methylation in patients with persistent pain after breast cancer surgery

Machine-learned analysis of global and glial/opioid intersection–related DNA methylation in patients with persistent pain after breast cancer surgery

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

<p>Update on the pharmacogenomics of pain management</p>

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