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      Pain management with morphine: variation in analgesic response secondary to genetic polymorphisms

      Therapeutics and Clinical Risk Management

      Dove Medical Press

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          Abstract

          To the editor The recent article by Villesen et al in a recent issue of your journal was most interesting.1 Recent studies show that the potency of morphine in efficacious pain control may be influenced greatly by polymorphisms of certain genes. For instance, Klepstad et al have recently shown that cancer patients on opioid maintenance therapy who are homozygous for the variant G allele of the 118 A > G polymorphism of the mu opioid receptor (OPRM1) gene require higher doses of morphine for efficacious pain control in comparison with patients who are heterozygous.2 In fact, the morphine requirement is almost 93% less in AA genotypes in contrast with morphine requirements in cancer patients who carry the GG genotype of the OPRM1 gene.3 Similar pain modulation variation is seen with polymorphisms of the OPRM1 gene and perioperative fentanyl administration.4 Furthermore, more profound CNS depressant side effects after morphine administration are noticed in cancer patients with certain polymorphisms of the multidrug resistance-1 gene.5 Similarly, the potency of morphine in pain management in cancer patients is influenced and varies greatly with polymorphisms of the catechol-O-methyl transferase gene.6 For instance, individuals with the Met/Met genotype of the catechol-O-methyl transferase gene require 63% less morphine in comparison with those who have the Val/Val genotype of the catechol-O-methyl transferase gene.3 More profound central nervous system side effects are seen following morphine administration in cancer patients with single nucleotide polymorphisms in intron 1 of the catechol-O-methyl transferase gene.5 The above examples clearly illustrate the variation in adequate pain control with morphine secondary to genetic mutations. Further research is needed to identify other similar gene polymorphisms that may affect opioid requirements in patients being managed with other nonmorphine narcotics.

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

           C Baar,  M Holthe,  P Klepstad (2004)
          Dispositions for genes encoding opioid receptors may explain some variability in morphine efficacy. Experimental studies show that morphine and morphine-6-glucuronide are less effective in individuals carrying variant alleles caused by the 118 A > G polymorphism in the mu-opioid receptor gene (OPRM1). The purpose of the study was to investigate whether this and other genetic polymorphisms in OPRM1 influence the efficacy of morphine in cancer pain patients. We screened 207 cancer pain patients on oral morphine treatment for four frequent OPRM1 gene polymorphisms. The polymorphisms were the -172 G > T polymorphism in the 5'untranslated region of exon 1, the 118 A > G polymorphism in exon 1, and the IVS2 + 31 G > A and IVS2 + 691 G > C polymorphisms, both in intron 2. Ninety-nine patients with adequately controlled pain were included in an analysis comparing morphine doses and serum concentrations of morphine and morphine metabolites in the different genotypes for the OPRM1 polymorphisms. No differences related to the -172 G > T, the IVS2 + 31 G > A and the IVS2 + 691 G > C polymorphisms were observed. Patients homozygous for the variant G allele of the 118 A > G polymorphism (n = 4) needed more morphine to achieve pain control, compared to heterozygous (n = 17) and homozygous wild-type (n = 78) individuals. This difference was not explained by other factors such as duration of morphine treatment, performance status, time since diagnosis, time until death, or adverse symptoms. 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.
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            Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene.

            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 (87 mg/24 h; 95%CI=57,116) and those with neither Met/Met nor AA genotype needed the highest morphine dose (147 mg/24 h; 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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              Genetic variation in the Catechol-O-Methyltransferase (COMT) gene and morphine requirements in cancer patients with pain

              Background Genetic variation contributes to differences in pain sensitivity and response to different analgesics. Catecholamines are involved in the modulation of pain and are partly metabolized by the catechol-O-methyltransferase (COMT) enzyme. Genetic variability in the COMT gene may therefore contribute to differences in pain sensitivity and response to analgesics. It is shown that a polymorphism in the COMT gene, Rs4680 (Val158Met), influence pain sensitivity in human experimental pain and the efficacy for morphine in cancer pain treatment. In this study we wanted to investigate if variability in other regions in the COMT gene also contributes to interindividual variability in morphine efficacy. Results We genotyped 11 single nucleotide polymorphisms (SNPs) throughout the COMT gene, and constructed haplotypes from these 11 SNPs, which were in Hardy-Weinberg equilibrium. We compared both genotypes and haplotypes against pharmacological, demographical and patient symptoms measurements in a Caucasian cancer patient cohort (n = 197) receiving oral morphine treatment for cancer pain. There were two frequent haplotypes (34.5% and 17.8%) in our cohort. Multivariate analyses showed that patients carrying the most frequent haplotype (34.5%) needed lower morphine doses than patients not carrying the haplotype, with a reduction factor of 0.71 (p = 0.005). On the allele level, carriers of alleles for six of the SNPs show weak associations in respect to morphine dose and the alleles associated with the lowest morphine doses constitute part of the most frequent haplotype. Conclusion This study suggests that genetic variability in the COMT gene influence the efficacy of morphine in cancer patients with pain, and that increased understanding of this variability is reached by expanding from analyses of single SNPs to haplotype construction and analyses.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2012
                2012
                21 May 2012
                : 8
                : 243-244
                Affiliations
                Mechanicsville, Richmond, VA, USA
                Author notes
                Correspondence: Shailendra Kapoor, 2300 E Cary St Richmond, VA 23223, USA, Tel +1 804 2342345, Fax +1 804 3454561, Email shailendrakapoor@ 123456yahoo.com
                Article
                tcrm-8-243
                10.2147/TCRM.S32184
                3373199
                22701325
                © 2012 Kapoor, publisher and licensee Dove Medical Press Ltd

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Categories
                Letter

                Medicine

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