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

Reyes‐Gibby, Cielito C.; Shete, Sanjay; Rakvåg, Trude T.; Bhat, Samrat; Skorpen, Frank; Bruera, Éduardo; Kaasa, Stein; Klepstad, Pål

doi:10.1016/j.pain.2006.10.023

Cited by 278 publications

(211 citation statements)

References 49 publications

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“…Regarding the COMT genotype as it relates to cancer pain, individuals with a A/A (Met/Met) genotype had a lower regional opioid signal response to pain and a higher sensitivity to pain, compared with heterozygous individuals (24). On the other hand, several clinical studies have demonstrated that the required dose of morphine was lower in subjects with an A/A genotype of COMT, compared with others (25)(26)(27). These results are consistent with our result.…”

Section: Discussionsupporting

confidence: 91%

Expression changes in arrestin β 1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients

et al. 2012

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Abstract. Genetic differences in individuals with regard to opioid-receptor signaling create clinical difficulties for opioid treatment; consequently, useful pharmacodynamic and predictive biomarkers are needed. In this prospective study, we studied gene expression changes in peripheral blood leukocytes using a microarray and real-time RT-PCR analysis to identify pharmacodynamic biomarkers for monitoring the effect of morphine in a cohort of opioid-treatment-naïve cancer patients. We also examined genetic variations in opioid receptor mu 1 (OPRM1, 118A→G) and catechol-O-methyltransferase (COMT, 472G→A) to evaluate predictive biomarkers of the treatment outcome of morphine. The plasma concentration of morphine was measured using a liquid chromatography-tandem mass spectrometry method. Microarray analysis revealed that the mRNA expression levels of arrestin β 1 (ARRB1) were significantly down-regulated by morphine treatment. Real-time RT-PCR analysis against independent samples confirmed the results (P=0.003) and changes during treatment were negatively correlated with the plasma morphine concentration (R=-0.42). No correlation was observed between the genotype of OPRM1 and morphine treatment; however, the plasma concentration of morphine and the required dose of morphine were significantly lower for the A/A genotype of COMT (vs. A/G+G/G, P=0.008 and 0.03). We found that changes in the expression of ARRB1 may be a novel pharmacodynamic biomarker and the COMT 472G→A genotype may be a predictive biomarker of the response to morphine treatment.

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Section: Discussionsupporting

confidence: 91%

Expression changes in arrestin β 1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients

et al. 2012

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“…Individuals genotyped with MET158MET (rs4680) had higher MOR protein expression and lower met-enkephalin concentrations (54 ). In line with these findings, MET158MET-genotyped patients required less opioid for cancer pain (55)(56)(57)(58) and postoperative pain (59 -62 ) or showed fewer side effects (63 ). In line with this protective effect of the rs4680 polymorphism, preterm infants with the MET158 allele sooner reached a pain-free state after remifentanil or morphine premedication for endotracheal intubation (64 ).…”

Section: Comtmentioning

confidence: 66%

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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“…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).…”

mentioning

confidence: 99%

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

Cited by 278 publications

References 49 publications

Expression changes in arrestin β 1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients

Expression changes in arrestin β 1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients

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

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

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