Polymorphism of μ-Opioid Receptor Gene (OPRM1:c.118A&amp;gt;G ) Does Not Protect Against Opioid-induced Respiratory Depression despite Reduced Analgesic Response

Romberg, Raymonda; Olofsen, Erik; Bijl, Hans; Taschner, Peter E.M.; Teppema, Luc J.; Sarton, Elise; Kleef, Jack W. van; Dahan, Albert

doi:10.1097/00000542-200503000-00008

Cited by 138 publications

(89 citation statements)

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“…Our results are not consistent with findings of a handful of studies assessing the clinical efficacy and toxicity of morphine-6-glucuronide compared to morphine in subjects with 304A/G polymorphism [29,30,42], and several trials examining chronic morphine requirements in cancer patients [5,23,25] or the use of postoperative i.v. morphine via patient-controlled analgesia [10,11,14,23].…”

Section: Discussioncontrasting

confidence: 99%

Genetic variability of the μ-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women ☆

Landau

Kern

Columb

et al. 2008

Pain

137

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Labor initiates one of the most intensely painful episodes in a woman's life. Opioids are used to provide analgesia with substantial interindividual variability in efficacy. μ-Opioid receptor (μOR, OPRM1) genetic variants may explain differences in response to opioid analgesia. We hypothesized that OPRM1 304A/G polymorphism influences the median effective dose (ED 50 ) of intrathecal fentanyl via combined spinal-epidural for labor analgesia. Nulliparous women were prospectively recruited around 35 weeks gestation (n = 224), and genotyped for 304A/G polymorphism. Those requesting neuraxial labor analgesia were enrolled in one of the two double-blinded trials: up-down sequential allocation (SA, n = 50) and a separate confirmatory random-dose allocation trial (RA, n = 97). Effective analgesia from intrathecal fentanyl was defined by ⩾ 60 min analgesia with verbal rating score ≤1 (scale 0-10) and was compared between μOR 304A homozygotes (Group A) and women carrying at least one 304G allele (Group G). OPRM1 304G allele frequency f(−) was 0.18. Using SA, intrathecal fentanyl ED 50 was 26.8 μg (95% CI 22.7-30.9) in Group A and 17.7 μg (95% CI 13.4-21.9) in Group G (p < 0.001; 304A homozygosity increased the ED 50 1.5-fold). RA confirmed that 304A homozygosity significantly increases intrathecal fentanyl ED 50 (27.4 μg in Group A and 12.8 μg in Group G [p < 0.002; 2.1-fold]). We demonstrate for the first time that the μOR 304G variant significantly reduces intrathecal fentanyl ED 50 for labor analgesia, suggesting women with the G variant may be more responsive to opioids and require less analgesic drugs. These Conflict of interestNone of the authors presents any commercial association or other issues that might pose a conflict of interest. Financial disclosures

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Section: Discussioncontrasting

confidence: 99%

Genetic variability of the μ-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women ☆

Landau

Kern

Columb

et al. 2008

Pain

137

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“…In both postmortem and in vitro studies (28)(29)(30), the variant G allele is associated with reduced levels of MOR mRNA and protein relative to the A allele. Lower levels of MOR may underlie the reduced potency of opiates in G allele carriers (31)(32)(33), as carriers of the variant G allele require greater quantities of morphine to deal with postsurgical pain [(34-37), but see ref . 38] and cancer related pain (39,40).…”

mentioning

confidence: 99%

Variation in the μ-opioid receptor gene (OPRM1) is associated with dispositional and neural sensitivity to social rejection

Way

Taylor

Eisenberger

2009

Proc. Natl. Acad. Sci. U.S.A.

240

195

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Scientific understanding of social pain-the hurt feelings resulting from social rejection, separation, or loss-has been facilitated by the hypothesis that such feelings arise, in part, from some of the same neural and neurochemical systems that generate the unpleasant feelings resulting from physical pain. Accordingly, in animals, the painkiller morphine not only alleviates the distress of physical pain, but also the distress of social separation. Because morphine acts on the -opioid receptor, we examined whether variation in the -opioid receptor gene (OPRM1), as measured by the functional A118G polymorphism, was associated with individual differences in rejection sensitivity. Participants (n ‫؍‬ 122) completed a self-report inventory of dispositional sensitivity to social rejection and a subsample (n ‫؍‬ 31) completed a functional MRI session in which they were rejected from an online ball-tossing game played with two supposed others. The A118G polymorphism was associated with dispositional sensitivity to rejection in the entire sample and in the fMRI subsample. Consistent with these results, G allele carriers showed greater reactivity to social rejection in neural regions previously shown to be involved in processing social pain as well as the unpleasantness of physical pain, particularly the dorsal anterior cingulate cortex (dACC) and anterior insula. Furthermore, dACC activity mediated the relationship between the A118G polymorphism and dispositional sensitivity to rejection, suggesting that this is a critical site for -opioid-related influence on social pain. Taken together, these data suggest that the A118G polymorphism specifically, and the -opioid receptor more generally, are involved in social pain in addition to physical pain.anterior cingulate ͉ brain ͉ exclusion ͉ genetic ͉ social pain

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“…The SNP has been previously reported to decrease the clinical potency of alfentanil, 8 morphine 3,7 and M6G. [3][4][5][6] An altered responsiveness of the hypothalamic-pituitary-adrenal axis in 118G carriers 26,27 further supports a functional consequence of the 118A4G SNP and probably affects a greater range of other clinical opioid effects. Possible therapeutic consequences of the 118A4G SNP are still controversial.…”

Section: Discussionmentioning

confidence: 70%

“…Possible therapeutic consequences of the 118A4G SNP are still controversial. An increased therapeutic range of opioids, as suggested from the observation of fewer vomits in six 118G carriers as compared to six non-carriers, 3 and from the good tolerance of high plasma M6G in a patient homozygous for the 118G allele, 9 has been contradicted in a study that included only four heterozygous 118G carriers and compared them with 12 non-carriers 6 ). The 118A4G OPRM1 SNP causes an amino-acid exchange from asparagine at position 40 of the m-opioid receptor protein, which is highly preserved among species, to aspartate (i.e., N40D receptors).…”

Section: Discussionmentioning

confidence: 99%

“…Functional associations with opioid therapy have so far mainly focused on the 118A4G single nucleotide polymorphism (SNP) located in exon 1 of the gene. Morphine 3 and its active metabolite www.nature.com/tpj morphine-6-glucuronide (M6G) 3,4 constricted pupils with a decreased potency and produced smaller analgesic effects 5,6 in carriers of the mutated OPRM1 118G allele as compared to non-carriers. Patients carrying the mutated 118G allele required higher doses of morphine 7 or alfentanil for pain therapy.…”

Section: Introductionmentioning

confidence: 99%

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Relevance of frequent μ-opioid receptor polymorphisms for opioid activity in healthy volunteers

Lötsch

Geißlinger

2006

Pharmacogenomics J

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Polymorphisms in the m-opioid receptor gene (OPRM1) are primary candidate sources of clinical variability in opioid therapy. Apart from the 118A4G single nucleotide polymorphism, nothing is known about the role of OPRM1 mutations in opioid therapy. The influence of the OPRM1 mutations on opioid pharmacodynamics was assessed in pooled data from 31 healthy volunteers obtained in previous studies with available plasma concentrations and pupil diameters after intravenous administration of morphine or morphine-6-glucuronide (M6G). A total of 24 candidate ORPM1 mutations were screened for and those found at an allelic frequency of at least 5% in the 31 subjects were analyzed for functional consequences, using population pharmacokinetic-pharmacodynamic modeling of the miotic effects of the opioids as a reliable and sensitive surrogate parameter of the central nervous opioid effects. Polymorphisms at an allelic frequency of X5% (n ¼ 310) were 118A4G in exon 1 (11.5%), the IVS2-31G4A (8.9%) and IVS2-691C4G (44.5%) SNPs in intron 2. The 118A4G SNP significantly increased the values of EC 50 by a factor of more than 2 (nonmutated: EC 50,morphine ¼ 30 nmol/l, EC 50,M6G ¼ 750 nmol/l, 118G carriers: EC 50,morphine ¼ 66 nmol/l, EC 50,M6G ¼ 1650 nmol/l), whereas the IVS2-691C4G SNP had no effect. Based on morphine and M6G, the present analysis encourages focusing on the 118A4G SNP when investigating the role of OPRM1 mutations for the activity of opioid analgesics. Other OPRM1 mutations are probably less important either owing to low allelic frequency or due to poor indications for functional consequences. This applies to opioid potency in the context of opioid therapy but not to pain processing or substance addiction, in which opioid receptors are involved but other or additional OPRM1 mutations may be important.

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Polymorphism of μ-Opioid Receptor Gene (OPRM1:c.118A>G ) Does Not Protect Against Opioid-induced Respiratory Depression despite Reduced Analgesic Response

Cited by 138 publications

References 0 publications

Genetic variability of the μ-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women ☆

Genetic variability of the μ-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women ☆

Variation in the μ-opioid receptor gene (OPRM1) is associated with dispositional and neural sensitivity to social rejection

Relevance of frequent μ-opioid receptor polymorphisms for opioid activity in healthy volunteers

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