Expansion of the human -opioid receptor gene architecture: novel functional variants (original) (raw)
Related papers
Pharmacogenomics, 2013
The human µ-opioid receptor variant 118 A>G (rs1799971) has become one of the most analyzed genetic variants in the pain field. At the molecular level, the variant reduces opioid receptor signaling efficiency and expression, the latter probably via a genetic-epigenetic interaction. In experimental settings, the variant was reproducibly associated with decreased effects of exogenous opioids. However, this translates into very small clinical effects (meta-ana lysis of 14 studies: Cohen's d = 0.096; p = 0.008), consisting of slightly higher opioid dosing requirements in peri-and post-operative settings. An effect can neither be maintained for chronic analgesic therapy nor for opioid side effects. It seems unlikely that further studies will reveal larger effect sizes and, therefore, further analyses appear unwarranted. Thus, due to its small effect size, the SNP is without major clinical relevance as a solitary variant, but should be regarded as a part of complex genotypes underlying pain and analgesia.
A cohort, double blind, and randomized study was conducted to investigate the effect of a single nucleotide polymorphism of the μ-opioid receptor at nucleotide position 118 (OPRM1:c.118A>G) on the association with the most common side effects (nausea or vomiting) induced by intravenous patient control analgesia (IVPCA) with morphine, including incidence and severity analysis. A total of 129 Taiwanese women undergoing gynecology surgery received IVPCA with pure morphine for postoperative pain relief. Blood samples were collected and sequenced with high resolution melting analysis to detect three different genotypes of OPRM1 (AA, AG, and GG). All candidates 24 h postoperatively will be interviewed to record the clinical phenotype with subjective complaints and objective observations. The genotyping after laboratory analysis showed that 56 women (43.4%) were AA, 57 (44.2%) were AG, and 16 (12.4%) were GG. The distribution of genotype did not violate Hardy-Weinberg equilibrium test. ...
Opioids for chronic pain: molecular and genomic basis of actions and adverse effects
Current Opinion in Supportive and Palliative Care, 2007
Opioid analgesics are being increasingly used for pain control in both cancer and noncancer patients. Despite thousands of years of their use, the biological basis of their action and adverse effects are only now being understood. It is important to understand these agents better so that the potentially large sections of the population who may eventually be eligible to receive therapeutic opioids are treated rationally and safely.
Anesthesia & Analgesia, 2006
In this prospective, observational study we explored whether A118G single nucleotide polymorphism in the human -opioid receptor (MOR) gene could explain the inter-individual differences in opioid analgesic requirements in patients with acute postoperative pain and chronic pain. The frequency of the wild-type A118 MOR (major) and variant G118 MOR (minor) alleles in the subjects with chronic, noncancer pain (n ϭ 121) and opioid-naïve subjects with acute postoperative pain (n ϭ 101), serving as the control group, were examined. The relationships among the A118G MOR genotype, opioid requirements, and the numerical pain score were analyzed in both groups. The frequency of the minor allele was significantly lower in the subjects with chronic pain when compared with the group with acute postoperative pain (0.079 versus 0.158; P ϭ 0.009 by 2 test). No statistically significant association was observed between the presence of A118G MOR polymorphism and the average postoperative pain score or the doses of morphine used in the immediate postoperative period. In the high-quartile, opioid utilization, chronic pain patients, the homozygotic carriers of the major allele required significantly higher opioid dose than did the carriers of the minor allele.
Pain polymorphisms and opioids: An evidence based review
Molecular Medicine Reports, 2018
Despite the various different candidate genetic polymorphisms of potential clinical relevance, there is not enough understanding of the inter-individual variability in analgesic administration. The cytochrome P450 2D6 (CYP2D6) genotype is thought to be one of the most studied. The aim of the present evidence-based review was to determine if there is now sufficient evidence to make clinical recommendations based on a specific genomic profile. The data sources utilized were as follows: PubMed (NLM) database, Evidence Based Medicine Guidelines and Google. Research on clinical guidance standards, systematic reviews, meta-analyses and clinical trials, published prior to January 2018, were evaluated in English, using the MeSH terms 'cancer pain', 'polymorphism', 'genetic' and 'gene polymorphism'. To assess the level of evidence, the Strength of Recommendation Taxonomy of the American Family Physician was applied. From the initial search, 12 systematic reviews and/or meta-analyses, 5 clinical trials and 10 guidelines were selected. The results indicated that genetic variation of µ-opioid receptor 1 (OPRM1) may contribute to inter-individual differences in morphine consumption with recommendation grade A for OPRM A118G single nucleotide polymorphism (rs1799971). Polymorphisms associated with the metabolization process of morphine and other opioid drugs are very relevant in opioid titration and ethnic subgroup differences which have to be taken into account (particularly, for the recommendation grade A for the CYP2D6 polymorphism). In human studies, the catechol-O-methyl transferase (COMT) genotype affects the efficacy of opioids in acute and chronic pain under different settings, with recommendation grade B to the COMT single nucleotide polymorphism rs4680 (Val/Met). Finally, polymorphisms of the ATP-binding cassette family of efflux transporters were highlighted. Consistent data on pain polymorphisms is now widely available; however, these results have had very little impact on clinical guidelines and daily oncologist practice. Persisting pain, side effects of grade 3 (NCI-CTCAE v4.0) and breakthrough pain with more than 4 episodes/day should be considered the criteria for pain multidisciplinary team discussions and for polymorphism screening.
O PIOIDS are currently the most versatile analgesics, making them the drugs of choice for moderate to severe pain associated with invasive procedures, cancer, and various other chronic disease states. However, there is a large interindividual response to the analgesic effect of opioids and a relatively narrow therapeutic index. 1 Genetic factors contribute to the differential response to opioids by regulating their pharmacokinetics (metabolizing enzymes and transporters) and pharmacodynamics (receptors and signal transduction). The μ-opioid receptor (OPRM1) A118G single nucleotide polymorphism has been a major focus of research into the pharmacogenetics of opioid response. Emerging knowledge regarding the molecular mechanisms regulating pain in animal models has increased the hopes of identifying personalized pain therapies. In vitro experiments show that variant receptors are associated with higher binding affinity to and potency of the endogenous ligand, β-endorphin, but lower
Fundamental & Clinical Pharmacology, 2009
Oxycodone is a semisynthetic, l-opioid receptor agonist [1] with analgesic effect in several pain conditions [2,3]. It is widely used as first choice opioid in pain conditions although the basic pharmacokinetic studies have been a neglected area [2]. It is suggested, that oxycodone, like many other opioids, is a P-glycoprotein substrate [4]. The A118G single nucleotide polymorphism (SNP) of the opioid receptor l 1 gene (OPRM1) has been found to have a variant allele frequency of 10-15% in the Caucasian population [5]. In experimental pain, the participants carrying the variant 'G' allele exhibited less miosis than the wild-type carriers after intravenous administration of morphine's active metabolite morphine-6-glucuronide (M6G) [6]. Romberg et al. confirmed these findings in healthy
Do Opioids Induce Hyperalgesia in Humans? An Evidence-Based Structured Review
Pain Medicine, 2009
Design/Objectives. Consistent rodent evidence indicates that opioid exposure will decrease the rodent's pain threshold (ptr). This is termed opioids-induced hyperalgesia (OIH). Currently, the consistency of the evidence for the occurrence of OIH in humans is unclear. This is a structured evidence-based review for all levels of evidence (all studies and case reports) on OIH in humans in order to determine the consistency of this evidence. Methods. Computer and manual literature searches yielded 504 OIH references (human and animal). Of these, 48 remained after application of inclusion/exclusion criteria. These references addressed 10 hypotheses that the OIH literature has utilized to test for the possibility of OIH in humans. These are the following: opioid addicts maintained on opioids will have decreased ptr and/or tolerance; detoxifying opioid addicts from opioids will increase their ptr and/or tolerance; stopping, decreasing, or rotating to a different opioid or detoxifying from an opioid will improve pain and/or allodynia; chronic pain patients(CPPs) placed on opioids will develop decreased ptr and/or tolerance; CPPs on opioids will have decreased ptr and/or tolerance vs CPPs not on opioids; opioid infusion in normal volunteers or CPPs will decrease ptr and/or tolerance; former opioid addicts exposed to opioids will demonstrate a decrease in ptr and/or tolerance; opioid infusion in normal volunteers will increase secondary hyperalgesia as measured by allodynia or hyperalgesia; perioperative opioids will increase postoperative pain and/or opioid requirements; and placement on opioids postsurgery leads to progressive increased intake (acute tolerance). Each report was characterized by the type of study it represented according to the Agency for Health Care Policy and Research (AHCPR) guidelines and independently rated by two raters according to 14 quality criteria with a quality score calculated. For studies under each hypothesis, an average quality score and the percentage of studies supporting the hypothesis was calculated. Finally, for studies under each hypothesis, utilizing AHCPR criteria, a consistency rating was derived based on the percentage score of studies supporting the hypothesis.
Medicine
Nausea and vomiting are probably the most unpleasant side effects that occur when morphine used. A number of studies have investigated the effect on pain relief of single nucleotide polymorphisms (SNPs) in genes involved in morphine's metabolism, distribution, binding, and cellular action. The mechanism through which morphine causes nausea and vomiting has not been elucidated clearly. We examined all the reported SNPs which are associated with the complications of morphine, including SNPs in genes for phase I and phase II metabolic enzymes, ABC binding cassette drug transporters, k and d opioid receptors, and ion channels implicated in the postreceptor action of morphine. A prospective, observational study in 129 female patients was conducted to investigate the effect of 14 SNPs on nausea or vomiting induced by intravenous patient-controlled analgesia (IVPCA) with morphine after gynecology surgery. Clinical phenotype, subjective complaints, and objective observations were recorded. DNA from blood samples was used to record the SNPs. Eleven SNPs were then analyzed further. No significant association with the presence of phenotype (nausea or vomiting) versus genotype was observed (all P > .05). No significant association with severity of phenotype versus genotype of the 11 SNPs was observed except for unadjusted data for rs2737703. There was no significant difference between severity or incidence of IVPCA morphine-induced nausea and vomiting and genotype (11 SNPs). Further study should perhaps be focused on mRNA and proteinomics rather than SNPs. Abbreviations: BMI = body mass index, CI = confidence interval, GI = gastrointestinal, IVPCA = intravenous patient-controlled analgesia, OR = odds ratio, SNPs = single nucleotide polymorphisms, VAS = visual analogue scale.