The 118 A &gt; G polymorphism in the human µ‐opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease

Klepstad, Pål; Rakvåg, Trude T.; Kaasa, Stein; Holthe, M; Dale, Ola; Borchgrevink, Petter C.; Baar, Cecilie; Vikan, T; Krokan, Hans E.; Skorpen, Frank

doi:10.1111/j.1399-6576.2004.00517.x

Cited by 357 publications

(262 citation statements)

References 25 publications

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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: 56%

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: 56%

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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“…Abnormal blood flow accounts for most of the clinical morbidity of sickle cell disease (SCD) [1,2]. Most notably, occlusion of flow in the microvasculature causes the acute pain crises [3] that are the commonest cause for patients with SCD to seek medical attention [4] and major determinants of their quality of life [5].…”

Section: Methodsmentioning

confidence: 99%

“…For pharmacodynamics, the OPRM1 A118G and the COMT G322A single nucleotide polymorphisms (SNPs) were chosen for their negative effects on the m receptors [1,2]. For pharmacokinetics [3], important SNPs for the CYP2D6 gene (codeine to morphine conversion) and for three genes involved in morphine elimination (namely CYP3A, UGT2B7, and ABCB1) were genotyped.…”

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confidence: 99%

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Genotypic screening of the main opiate‐related polymorphisms in a cohort of 139 sickle cell disease patients

Joly¹,

Gagnieu²,

Bardel³

et al. 2012

American J Hematol

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10. Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Much of sickle cell disease (SCD) morbidity is due to recurrent painful crises mainly treated by codeine and morphine. However, surprisingly, there are no genotypic data that relate to the frequency of the main opiate-related SNPs in SCD populations [4]. One may argue that the allelic frequencies for African-Americans (AA) are known and that, since SCD patients are mostly of AA origins, their allelic frequencies should be the same. Obviously, this remark is true but we thought it was important to consider the particular subgroup of SCD patients to ensure that some SNPs were not under-or over-represented because of a founder effect. We, thus, decided to perform, in a cohort of 139 SCD patients, a quite extensive genotyping of these SNPs (Table I) with a haplotypic interpretation for those located on the same locus (Table II).Codeine is a pro-drug inactive by itself until it is metabolized into morphine by the CYP2D6 pathway. After oral or parenteral administration, morphine is partially metabolized by the CYP3A pathway (CYP3A4 and CYP3A5 genes) and by the UGT2B7 enzyme. Independently, an increased ABCB1 activity (a well-known drug efflux protein) is also expected to decrease the bioavailability of both morphine (brain efflux) and codeine (gut efflux) [10]. Very logically, the most frequent polymorphisms that modify the enzymatic activity were chosen for each pathway. For the CYP3A pathway, we genotyped two SNPs associated with a lower CYP3A activity: rs2740574 (A-392G 5 *1B allele) on the CYP3A4 gene (wild-type *1A) and rs776746 (A6986G 5 *3 allele) on the CYP3A5 gene (wild-type *1) [11]. For the UGT2B7 gene, we genotyped two SNPs associated with a lower glucuronidation of morphine and codeine: rs7438135 (A-840G) and rs73823859 (G-79A) [12,13]. For the CYP2D6 gene, we searched: (i) two polymorphisms associated with a null activity: rs892097 (G1846A 5 *4 allele) and the whole gene deletion (*5 allele), (ii) a SNP associated with an intermediate activity and very prevalent in the African population: rs28371706 (C1023T 5 *17 allele), and (iii) a gene duplication associated with an enhanced activity [8,14]. For the ABCB1 gene, we genotyped three SNPs associated with a variation (decrease or increase) of the efflux activity for many drugs: rs1128503 (C1236T) on exon 12, rs2032582 (G2677T) on exon 21 and rs1045642 (C3435T) on exon 26 [15]. Interestingly, the mutant T nucleotide for rs1045642 has been associated with a better morphine pain relief in two independent studies [16,17]. By taking these three SNPs together, some authors have defined the three main ABCB1 haplotypes [6,7]: (i) the *1 allele (C/G/C) which is the wild-type allele, (ii) the *2 allele (T/T/T), and (iii) the *2Kr allele (C/G/T).Two SNPs are mainly responsible for a lower analgesic effect of opioids. The most important one is A118G (Asn40Asp-rs1799971) on the OPRM1 gene [1,18], and the second one is G322A (Val158Met-rs4680) on the C...

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“…We used data from the study of Klepstad et al(2004) and Ravkag et al(Rakvag, Klepstad, Baar, Kvam, Dale, Kaasa, Krokan, and Skorpen 2005) that includes genotyping data and clinical variables for 207 patients admitted for cancer pain treatment. All patients were Caucasians and in-patients during the period June 1999 to February 2000 at St Olav University Hospital, a 900-bed tertiary hospital in Trondheim, Norway.…”

Section: Methodsmentioning

confidence: 99%

Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene

Reyes‐Gibby

Shete²,

Rakvåg

et al. 2007

Pain

278

191

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Pain is a complex human trait. It is likely that the interaction of multiple genes, each with a small individual effect, along with the effect of environmental factors, influences the clinical efficacy of opioids rather than a single gene alone. Polymorphisms in genes coding for the mu-opioid receptor (A118G) and catechol-O-methyl transferase (Val158Met) may be important modulators of opioid efficacy. We assessed joint effects of the OPRM1 and COMT genes in predicting morphine dose for cancer pain relief. We used genotype and clinical data from a pharmacokinetic study of morphine in 207 inpatients treated with stable morphine dose for at least 3 days by Palliative Medicine Specialists. Results showed significant variation in morphine dose requirement by genotype groups: carriers of COMT Val/Val and Val/Met genotype required 63% and 23%, respectively, higher morphine dose compared to carriers of Met/Met genotype (p=0.02). Carriers of OPRM1 GG genotype required 93% higher morphine dose compared to carriers of AA genotypes (p=0.012). When we explored for joint effects, we found that carriers of the OPRM1 AA and COMT Met/Met genotype required the lowest morphine dose to achieve pain relief (87mg/24h; 95% CI=57,116) and those with neither Met/Met nor AA genotype needed the highest morphine dose (147mg/24h; 95%CI=100;180). The significant joint effects for the Met/Met and AA genotypes (p<0.012) persisted, even after controlling for demographic and clinical variables in the multivariable analyses. Future studies are needed to further characterize the joint effects of multiple genes, along with demographic and clinical variables, in predicting opioid dose.

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The 118 A > G polymorphism in the human µ‐opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease

Abstract: Patients homozygous for the 118 G allele of the mu-opioid receptor need higher morphine doses to achieve pain control. Thus, genetic variation at the gene encoding the mu-opioid receptor contributes to variability in patients' responses to morphine.

Cited by 357 publications

References 25 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 ☆

Genotypic screening of the main opiate‐related polymorphisms in a cohort of 139 sickle cell disease patients

Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene

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