The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes

Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
Fundamental and Clinical Pharmacology (Impact Factor: 2.12). 10/2009; 24(4):517-24. DOI: 10.1111/j.1472-8206.2009.00781.x
Source: PubMed


The aim of this study was to search for a possible association between the variant allele of the single nucleotide polymorphisms A118G in the OPRM1 gene and C3435T and G2677T/A in the ABCB1 gene and altered antinociceptive effect and adverse drug reactions of oxycodone. Thirty-three healthy subjects exposed to experimental pain including electrical stimulation and the cold pressor test were included. A118G: We found that the variant G allele was associated with reduced antinociceptive effect as measured by pain tolerance thresholds to single electrical nerve stimulation (8% increase vs. 25% for the wild-type carriers, P = 0.007). C3435T: The carriers of the variant T allele generally had less adverse drug reactions on oxycodone than the carriers of the wild-type genotype. G2677T/A: The carriers of the variant T allele had a better antinociceptive effect of oxycodone than the carriers of the wild-type genotype in the cold pressor test (25% reduction vs. 15%, P = 0.015 in the discomfort rating and 25% reduction vs. 12%, P = 0.007 in the pain time AUC) and less adverse drug reactions. The combined wild-type genotype 3435CC-2677GG was associated with less antinociceptive effect of oxycodone in the discomfort rating of the cold pressor test (13% reduction vs. 23%, P = 0.019) and more severe adverse drug reactions than the carriers of the variant alleles. We found a moderate association between less antinociceptive effect of oxycodone and the variant allele of A118G. There was strong association between less adverse drug reactions of oxycodone and the variant alleles of C3435T and G2677T/A.

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    • "Another study that examined the association of the ABCB1 and µ-opioid genes and adverse opioid drug reactions focused on oxycodone. In this study, Zwisler et al. (2009) recruited 33 healthy volunteers who were exposed to experimental pain. In this small sample, there were no significant differences between the genotypes for the µ-opioid A118G; however, they observed a significant difference in adverse reactions (nausea and vomiting) based on the ABCB1 genotype. "
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    ABSTRACT: Postoperative nausea and vomiting (PONV) continues to be a most common complication of surgery and anesthesia. It has been suggested that the inherited factors may play a significant role in the background sensitivity to both PONV and also chemotherapy-induced nausea and vomiting (CINV), including resistance to antiemetic prophylaxis and/or therapy. This notion could be best exemplified by occurrence of PONV in several generations of families and concordance of PONV in monozygotic twins. The most frequently addressed issue in the research on genomic background of PONV/CINV relates to the inherited resistance to the antiemetic treatment (pharmacogenomics), and in lesser degree to their genomic background. The most common group of antiemetics consists of 5HT3 receptor antagonists, and this group was an initial target of pharmacogenomic research. Most research approaches have been based on the investigation of polymorphic variations in the target for the antiemetic 5HT3 receptor antagonists, i.e., serotonin receptor subunits A and B (HTR3A and HTR3B). The other area of pharmacogenomic investigations includes metabolic pathways of 5HT3 antagonists, in particular polymorphic variants of the CYP450 2D6 isoform (CYP2D6) because most of them are metabolized in various degrees by the CYP2D6 system. The results of targeted genomic association studies indicate that other genes are also associated with PONV and CINV, including OPRM1, and ABCB1. In addition, genes such as DRD2 and CHRM3 genes have recently been associated with PONV. The new genome-wide association studies seem also to indicate that the background genomic sensitivity to PONV and CINV might be multifactorial and include several genomic pathways.
    Experimental Brain Research 05/2014; 232(8). DOI:10.1007/s00221-014-3968-z · 2.04 Impact Factor
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    • "A study in a Han Chinese cohort of healthy female volunteers demonstrated that pressure-pain threshold is influenced by another polymorphism of OPRM1 (IVS2 + A31G) but not the A118G polymorphism.121 Other studies assessing the influence of genetic variants on experimental pain demonstrated no effect of OPRM1 A118G genotype on pain processing122 or lower pain-tolerance thresholds to single electrical nerve stimulation in individuals carrying the G118 allele.123 It has been determined that the effect size of various determinants for experimental pain perception is greatest for heat sensitization by capsaicin, followed by gender (higher pain sensitivity in women) and a more modest effect size for genetic determinants.33 "
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    ABSTRACT: Translating pharmacogenetics to clinical practice has been particularly challenging in the context of pain, due to the complexity of this multifaceted phenotype and the overall subjective nature of pain perception and response to analgesia. Overall, numerous genes involved with the pharmacokinetics and dynamics of opioids response are candidate genes in the context of opioid analgesia. The clinical relevance of CYP2D6 genotyping to predict analgesic outcomes is still relatively unknown; the two extremes in CYP2D6 genotype (ultrarapid and poor metabolism) seem to predict pain response and/or adverse effects. Overall, the level of evidence linking genetic variability (CYP2D6 and CYP3A4) to oxycodone response and phenotype (altered biotransformation of oxycodone into oxymorphone and overall clearance of oxycodone and oxymorphone) is strong; however, there has been no randomized clinical trial on the benefits of genetic testing prior to oxycodone therapy. On the other hand, predicting the analgesic response to morphine based on pharmacogenetic testing is more complex; though there was hope that simple genetic testing would allow tailoring morphine doses to provide optimal analgesia, this is unlikely to occur. A variety of polymorphisms clearly influence pain perception and behavior in response to pain. However, the response to analgesics also differs depending on the pain modality and the potential for repeated noxious stimuli, the opioid prescribed, and even its route of administration.
    Pharmacogenomics and Personalized Medicine 08/2012; 5(1):73-87. DOI:10.2147/PGPM.S23422
    • "The A118G genotype also has been associated with postoperative pain intensity, increased opioid demands, and acute pain severity in various postoperative populations [10] [11] [18] [29] [84] [85], and in experimental pain [85] [88], although the direction and magnitude of these effects varies [82]. We previously demonstrated a significant association of A118G with pressure pain thresholds (PPTh) in a sex-dependent fashion whereby males, but not females, with AG or GG genotype had increased PPTh. "
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    ABSTRACT: Robust interindividual variation in pain sensitivity has been observed, and recent evidence suggests that some of the variability may be genetically mediated. Our previous data revealed significantly higher pressure pain thresholds among individuals possessing the minor G allele of the A118G SNP of the mu-opioid receptor gene (OPRM1) compared with those with 2 consensus alleles. Moreover, ethnic differences in pain sensitivity have been widely reported. Yet, little is known about the potential interactive associations of ethnicity and genotype with pain perception. This study aimed to identify ethnic differences in OPRM1 allelic associations with experimental pain responses. A total of 247 healthy young adults from three ethnic groups (81 African Americans; 79 non-white Hispanics; and 87 non-Hispanic whites) underwent multiple experimental pain modalities (thermal, pressure, ischemic, cold pressor). Few African Americans (7.4%) expressed the rare allele of OPRM1 compared to non-Hispanic whites and Hispanics (28.7% vs. 27.8%, respectively). Across the entire sample, OPRM1 genotype did not significantly affect pain sensitivity. However, analysis in each ethnic group separately revealed significant genotype effects for most pain modalities among non-Hispanic-whites (P<.05) but not Hispanics or African Americans. The G allele was associated with decreased pain sensitivity among whites only; a trend in the opposite direction emerged in Hispanics. The reasons for this dichotomy are unclear; they may involve ethnic differences in haplotypic structure, or A118G may be a tag-SNP linked to other functional polymorphisms. These findings demonstrate an ethnicity-dependent association of OPRM1 genotype with pain sensitivity. Additional research is warranted to uncover the mechanisms influencing these relationships.
    Pain 06/2012; 153(8):1610-9. DOI:10.1016/j.pain.2012.03.022 · 5.21 Impact Factor
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