<i>OPRM1</i>A118G Gene Variant and Postoperative Opioid Requirement

Hwang, In Cheol; Park, Ji Young; Myung, Seung‐Kwon; Ahn, Hong Yup; Fukuda, Ken‐ichi; Liao, Qin

doi:10.1097/aln.0000000000000405

Cited by 118 publications

(86 citation statements)

References 70 publications

(88 reference statements)

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“…Meta-analyses suggest that carrying the OPRM1-118G allele increases postsurgical opioid analgesic requirement (Hwang et al, 2014), although association with opioid dependence is not robust outside of Asian populations (Haerian and Haerian, 2013). It is possible that, given our findings, decreased drug reward is protective against opioid abuse in some individuals, while resistance to negative drug effects promotes intake in others.…”

Section: Discussionmentioning

confidence: 93%

Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism

Robinson

Vardy

DiBerto

et al. 2015

Neuropsychopharmacol

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The OPRM1 A118G polymorphism is the most widely studied μ-opioid receptor (MOR) variant. Although its involvement in acute alcohol effects is well characterized, less is known about the extent to which it alters responses to opioids. Prior work has shown that both electrophysiological and analgesic responses to morphine but not to fentanyl are moderated by OPRM1 A118G variation, but the mechanism behind this dissociation is not known. Here we found that humanized mice carrying the 118GG allele (h/mOPRM1-118GG) were less sensitive than h/mOPRM1-118AA littermates to the rewarding effects of morphine and hydrocodone but not those of other opioids measured with intracranial self-stimulation. Reduced morphine reward in 118GG mice was associated with decreased dopamine release in the nucleus accumbens and reduced effects on GABA release in the ventral tegmental area that were not due to changes in drug potency or efficacy in vitro or receptor-binding affinity. Fewer MOR-binding sites were observed in h/mOPRM1-118GG mice, and pharmacological reduction of MOR availability unmasked genotypic differences in fentanyl sensitivity. These findings suggest that the OPRM1 A118G polymorphism decreases sensitivity to low-potency agonists by decreasing receptor reserve without significantly altering receptor function.

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Section: Discussionmentioning

confidence: 93%

Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism

Robinson

Vardy

DiBerto

et al. 2015

Neuropsychopharmacol

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“…Genetic factors can also impact postoperative analgesic responses, which may impact CPSP since acute pain severity is among the strongest predictors of CPSP. In addition to multiple genes that impact drug metabolism [144], COMT [29,36] and OPRM1 [80,152] have been associated with postoperative opioid analgesic requirements.…”

Section: General Considerationsmentioning

confidence: 99%

Research design considerations for chronic pain prevention clinical trials

Gewandter

Dworkin

Turk

et al. 2015

Pain

130

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Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (i.e., chronic post-surgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (i.e., surgery, viral infection, injury, and toxic/noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

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“…On the other hand, higher binding affinity for endogenous opioids has been found, as discussed in (49 ). More recently, 2 independent metaanalyses on postoperative pain in adults, sample size 4607 (49 ) and 3144 (18 ) respectively, showed that carriers of the 118AϾG variant have indeed higher opioid requirements (17,50 ) and a lower risk for adverse events (17 ).…”

Section: Oprm1mentioning

confidence: 99%

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

et al. 2017

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BACKGROUND The use of opioids to alleviate pain is complicated by the risk of severe adverse events and the large variability in dose requirements. Pharmacogenetics (PGx) could possibly be used to tailor pain medication based on an individual's genetic background. Many potential genetic markers have been described, and the importance of genetic predisposition in opioid efficacy and toxicity has been demonstrated in knockout mouse models and human twin studies. Such predictors are especially of value for neonates and young children, in whom the assessment of efficacy or side effects is complicated by the inability of the patient to communicate this properly. The current problem is determining which of the many potential candidates to focus on for clinical implementation. CONTENT We systematically searched publications on PGx for opioids in 5 databases, aiming to identify PGx markers with sufficient robust data and high enough occurrence for potential clinical application. The initial search yielded 4257 unique citations, eventually resulting in 852 relevant articles covering 24 genes. From these genes, we evaluated the evidence and selected the most promising 10 markers: cytochrome P450 family 2 subfamily D member 6 (CYP2D6), cytochrome P450 family 3 subfamily A member 4 (CYP3A4), cytochrome P450 family 3 subfamily A member 5 (CYP3A5), UDP glucuronosyltransferase family 2 member B7 (UGT2B7), ATP binding cassette subfamily B member 1 (ABCB1), ATP binding cassette subfamily C member 3 (ABCC3), solute carrier family 22 member 1 (SLC22A1), opioid receptor kappa 1 (OPRM1), catechol-O-methyltransferase (COMT), and potassium voltage-gated channel subfamily J member 6 (KCNJ6). Treatment guidelines based on genotype are already available only for CYP2D6. SUMMARY The application of PGx in the management of pain with opioids has the potential to improve therapy. We provide a shortlist of 10 genes that are the most promising markers for clinical use in this context.

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OPRM1A118G Gene Variant and Postoperative Opioid Requirement

Cited by 118 publications

References 70 publications

Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism

Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism

Research design considerations for chronic pain prevention clinical trials

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

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