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Human studies on experimentally induced pain are of value to elucidate the genetic influence on morphine analgesia under controlled conditions. The aim of this study was to investigate whether genetic variants of mu-, kappa- and delta-opioid receptor genes (OPRM1, OPRK1 and OPRD1) and catechol-O-methyltransferase gene (COMT) are associated with the morphine analgesia. The study was a randomized, double-blind, two-way, crossover, single-dose study conducted in 40 healthy participants, where morphine was compared with placebo. Pain was induced by contact heat, muscle pressure, bone pressure, rectal stimulations (mechanical, electrical and thermal) and cold pressor test (immersion of the hand into ice water). Sixteen genetic polymorphisms of four candidate genes were explored. Variability in morphine analgesia to contact heat stimulation was associated with COMT rs4680 (p = 0.04), and rectal thermal stimulation was associated with OPRM1 rs9479757 (p = 0.03). Moreover, in males, variability in morphine analgesia to rectal thermal stimulation was associated with OPRD1 polymorphisms: rs2234918 (p = 0.01) and rs533123 (p = 0.046). The study was explorative and hypothesis-generating due to the relatively small study size. However, results suggest that genetic variants in the COMT and OPRM1 irrespective of gender, and OPRD1 in males may contribute to the variability in morphine analgesia in experimental pain models., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Polymorphisms in the opioid receptor genes may affect the pharmacodynamics (PD) of oxycodone and be part of the reason behind the diversity in clinical response. The aim of the analysis was to model the exposure-response profile of oxycodone for three different pain variables and search for genetic covariates. Model simulations were used to predict how population and effect-size impact the power to detect clinical significant SNPs., Method: The population pharmacokinetic-pharmacodynamic (PKPD) model of oral single-dosed oxycodone was based on pooled data from three published studies in healthy volunteers. Pain tolerance data from muscle pressure (n=36), visceral pressure (n=54) and skin pinch (n=34) were included. Genetic associations with 18 opioid-receptor SNPs were explored using a stepwise covariate approach. Model simulations were performed using the estimated model parameters., Results: None of the selected SNPs were associated with analgesic response of oxycodone at P<0.001. Baseline response in muscle cuff pressure was associated with OPRK1 rs7016778 and rs7824175 (P<0.001). Simulations indicated that large differences in drug response between genotypes (>50% for similar population sizes) or large populations (n>200 for a 20% response difference) are necessary to identify clinical significant SNP effects due to high population variability., Conclusion: A population PKPD model has been developed for oral oxycodone using three different pain variables to explore impact of genetic covariates and study design. None of the selected polymorphisms were significantly associated with analgesic response of oxycodone, but an association of baseline response in muscle cuff pressure with two OPRK1 SNPs was identified., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Human experimental pain studies are of value to study basic pain mechanisms under controlled conditions. The aim of this study was to investigate whether genetic variation across selected mu-, kappa- and delta-opioid receptor genes (OPRM1, OPRK1and OPRD1, respectively) influenced analgesic response to oxycodone in healthy volunteers. Experimental multimodal, multitissue pain data from previously published studies carried out in Caucasian volunteers were used. Data on thermal skin pain tolerance threshold (PTT) (n = 37), muscle pressure PTT (n = 31), mechanical visceral PTT (n = 43) and thermal visceral PTT (n = 41) were included. Genetic associations with pain outcomes were explored. Nineteen opioid receptor genetic polymorphisms were included in this study. Variability in oxycodone response to skin heat was associated with OPRM1 single-nucleotide polymorphisms (SNPs) rs589046 (P < 0.0001) and rs563649 (P < 0.0001). Variability in oxycodone response to visceral pressure was associated with four OPRM1 SNPs: rs589046 (P = 0.015), rs1799971 (P = 0.045), rs9479757 (P = 0.009) and rs533586 (P = 0.046). OPRM1 SNPs were not associated with oxycodone visceral heat threshold, however, one OPRD1 rs419335 reached significance (P = 0.015). Another OPRD1 SNP rs2234918 (P = 0.041) was associated with muscle pressure. There were no associations with OPRK1 SNPs and oxycodone response for any of the pain modalities. Associations were found between analgesic effects of oxycodone and OPRM1 and OPRD1 SNPs; therefore, variation in opioid receptor genes may partly explain responder characteristics to oxycodone., (© 2015 Société Française de Pharmacologie et de Thérapeutique.)

On an individual level, there is a difference in the analgesic response to a given opioid. Various factors such as gender, age, and genetic variation can affect the analgesic response. The genetic variation can influence pharmacokinetics (eg drug transporters and drug-metabolizing enzymes) and/or pharmacodynamics (eg opioid receptor and catechol-O-methyltransferase enzymes). We present recent experimentally induced pain, postoperative pain, and cancer pain and chronic non-malignant pain conditions studies in humans, focusing on the association between genetic variation and analgesic response assessed as opioid consumption or changes in pain scores. Studies have shown promising results regarding pharmacogenetics as a diagnostic tool for predicting the individual response to a given opioid in the experimental settings; however, in the clinic, it is a more complicated task to accomplish., (© 2014 World Institute of Pain.)

Context: There is wide interindividual variation in response to morphine for cancer-related pain; 30% of patients do not have a good therapeutic outcome. Alternative opioids such as oxycodone are increasingly being used, and opioid switching has become common clinical practice., Objectives: To compare clinical response to oral morphine vs. oral oxycodone when used as first-line or second-line (after switching) treatment in patients with cancer-related pain., Methods: In this prospective, open-label, randomized, controlled trial (ISRCTN65155201) with a selected crossover phase, patients with cancer-related pain were randomized to receive either oral morphine or oxycodone as first-line treatment. Dose was individually titrated until the patient reported adequate pain control. Patients who did not respond to the first-line opioid (either because of inadequate analgesia or unacceptable adverse effects) were switched to the alternative opioid., Results: Two hundred patients were recruited. On intention-to-treat analysis (n = 198, morphine 98, oxycodone 100), there was no significant difference between the numbers of patients responding to morphine (61/98 = 62%) or oxycodone (67/100 = 67%) when used as a first-line opioid. Similarly, there was no significant difference in subsequent response when patients were switched to either morphine (8/12 = 67%) or oxycodone (11/21 = 52%). Per-protocol analysis demonstrated a 95% response rate when both opioids were available. There was no difference in adverse reaction scores between morphine and oxycodone either in first-line responders or nonresponders., Conclusion: In this population, there was no difference between analgesic response or adverse reactions to oral morphine and oxycodone when used as a first- or second-line opioid. These data provide evidence to support opioid switching to improve outcomes., (Copyright © 2015. Published by Elsevier Inc.)

Aims: To present a statistical model for defining interindividual variation in response to morphine and to use this model in a preliminary hypothesis-generating multivariate genetic association study., Methods: Two hundred and sixty-four cancer patients taking oral morphine were included in a prospective observational study. Pain and morphine side-effect scores were examined using principal components analysis. The resulting principal components were used in an exploratory genetic association study of single nucleotide polymorphisms across the genes coding for the three opioid receptors, OPRM1, OPRK1 and OPRD1. Associations in multivariate models, including potential clinical confounders, were explored., Results: Two principal components corresponding to residual pain and central side-effects were identified. These components accounted for 42 and 18% of the variability in morphine response, respectively, were independent of each other and only mildly correlated. The genetic and clinical factors associated with these components were markedly different. Multivariate regression modelling, including clinical and genetic factors, accounted for only 12% of variability in residual pain on morphine and 3% of variability in central side-effects., Conclusions: Although replication is required, this data-driven analysis suggests that pain and central side-effects on morphine may be two separate dimensions of morphine response. Larger study samples are necessary to investigate potential genetic and clinical associations comprehensively., (© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Background: Pain tolerance is subject to considerable inter-individual variation, which may be influenced by a number of genetic and non-genetic factors. The mu, delta and kappa opioid receptors play a role in pain perception and are thought to mediate different pain modalities. The aim of this study was to explore associations between pain thresholds and gender and genetic variants in the three opioid receptor genes (OPRM, OPRD and OPRK). Experimental multi-modal pain data from previously published studies carried out in healthy Caucasian volunteers were used in order to limit the number of confounders to the study outcome. Data on thermal skin pain (n=36), muscle pressure pain (n=31) and mechanical visceral pain (n=50)) tolerance thresholds were included., Results: Nineteen genetic polymorphisms were included in linear regression modeling. Males were found to tolerate higher thermal and muscle pressure pain than females (p=0.003 and 0.02). Thirty four percent of variability in thermal skin pain was accounted for by a model consisting of OPRK rs6473799 and gender. This finding was just outside significance when correction for multiple testing was applied. Variability in muscle pressure pain tolerance was associated with OPRK rs7016778 and rs7824175. These SNPs accounted for 43% of variability in muscle pressure pain sensitivity and these findings remained significant after adjustment for multiple testing. No association was found with mechanical visceral pain., Conclusion: This is a preliminary and hypothesis generating study due to the relatively small study size. However, significant association between the opioid receptor genes and experimental pain sensitivity supports the influence of genetic variability in pain perception. These findings may be used to generate hypotheses for testing in larger clinical trials of patients with painful conditions.

Context: Morphine is the opioid of choice for cancer-related pain, but for many patients the benefits of morphine are outweighed by its side effect profile. Morphine is metabolized to morphine-3-glucuronide and morphine-6-glucuronide; however, little is known about the contribution of these metabolites to analgesia and morphine-related side effects., Objectives: We investigated the association between plasma morphine and metabolite concentrations and the clinical effects of morphine in cancer patients., Methods: A prospective study was performed in cancer patients taking oral morphine for moderate-to-severe cancer pain. Subjects who responded well to morphine (responders) and subjects who failed to respond to morphine because of lack of analgesia and/or the presence of intolerable side effects (nonresponders/switchers) were recruited. Pain and toxicity scores were recorded and blood samples were analyzed for plasma morphine, morphine-3-glucuronide, and morphine-6-glucuronide concentrations., Results: Results showed that 1) morphine responders have higher plasma morphine and metabolite concentrations compared with nonresponders, 2) lower pain scores are associated with higher plasma morphine and metabolite concentrations, 3) central side effects are associated with a higher metabolite:plasma morphine ratio, and 4) myoclonus is associated with extremely high concentrations of plasma morphine and metabolites., Conclusion: This study has shown that plasma morphine and metabolite concentrations are associated with the clinical effects of morphine therapy. These results are important because they demonstrate the relevance of measuring plasma metabolite concentrations in clinical trials and the potential for metabolite data to deepen our understanding of factors that influence an individual's response to morphine., (Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

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.

Background: Pain is a common symptom for patients with cancer, and opioids are the treatment of choice for moderate or severe cancer-related pain. Central side effects, such as drowsiness, confusion, and hallucinations, can limit the use of opioids in clinical practice., Methods: The authors prospectively recruited 228 cancer patients who received morphine. Clinical data, including pain and side-effect scores, were correlated with genotype data., Results: Genetic variation in the multidrug resistance-1 gene (MDR-1) was associated with moderate or severe drowsiness and confusion or hallucinations. Patients who carried the common guanosine (G) allele at position 2677 in exon 26 were less likely to experience drowsiness and confusion or hallucinations than patients who carried the variant thymidine or adenosine alleles, which code for alternate amino-acid substitutions (chi-square statistic, 13.3; P=.0003). In addition, genetic variation in the catechol-O-methyltansferase (COMT) enzyme was associated independently with these central side effects. Single nucleotide polymorphisms (SNPs) in intron 1 were associated significantly with central side effects; the most significant was at position -4873G (chi-square statistic, 9.1; P=.003). SNPs in intron 1, defined as haplotype, were present in 10.4% of the population and were associated significantly with central side effects (chi-square statistic, 7.7; P=.005). Genotype data did not correlate with morphine dose or serum morphine or metabolite concentrations in this study., Conclusions: COMT and MDR-1 genotypes were correlated with morphine-related central side effects. The authors believe that this work adds significantly to the current understanding of genetic variants that may influence an individual's response to opioids., (Copyright (c) 2008 American Cancer Society.)