PI-44Correlation of CYP2D6 genotype with response to oxycodone in orthopedic injury related pain

Myers, Amanda B.; Sullivan, Jacqueline; Koller, Darwin M.; Godambe, Sandip A.; Kennedy, Mary Jayne

doi:10.1016/j.clpt.2005.12.065

Cited by 3 publications

(3 citation statements)

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“…Inversely, PM had a 2-20-fold reduction of the effects as compared with EM. This is in agreement with the few case reports describing reduced analgesic effect of oxycodone in PM (Maddocks et al, 1996;Myers et al, 2005;Susce et al, 2006;Foster et al, 2007). Differences according to CYP2D6 phenotype were similarly demonstrated in the other assessed pharmacodynamic parameters (pupil size, saturation, sedation and psychomotor effects).…”

Section: Cyp2d6 Genetic Polymorphism and Oxycodone Pharmacodynamicssupporting

confidence: 91%

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Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety

Samer

Daali

Wagner

et al. 2010

British J Pharmacology

167

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Background and purpose:The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored. Experimental approach: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg·kg -1 ) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed. Key results: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone Cmax was correlated with SPT assessment (rS = 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers. Conclusions and implications:The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism.

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Section: Cyp2d6 Genetic Polymorphism and Oxycodone Pharmacodynamicssupporting

confidence: 91%

“…Inversely, PM had a 2–20‐fold reduction of the effects as compared with EM. This is in agreement with the few case reports describing reduced analgesic effect of oxycodone in PM (Maddocks et al ., 1996; Myers et al ., 2005; Susce et al ., 2006; Foster et al ., 2007).…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety

Samer

Daali

Wagner

et al. 2010

British J Pharmacology

167

View full text Add to dashboard Cite

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“…However, analgesia was never assessed in those studies. A few case reports describe reduced analgesic effect in PMs [135][136][137] and a case of neuropsychiatric toxicity has been reported in an UM [138]. In our laboratory we conducted a randomized controlled PK-PD study assessing the analgesic effect of oxycodone in the experimental pain setting according to CYP2D6 genotype as well as CYP2D6 and/or 3A drug inhibitions by quinidine and ketoconazole, respectively.…”

Section: Opioidsmentioning

confidence: 98%

Pharmacogenetics of Analgesics: Toward the Individualization of Prescription

et al. 2008

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The use of analgesics is based on the empiric administration of a given drug with clinical monitoring for efficacy and toxicity. However, individual responses to drugs are influenced by a combination of pharmacokinetic and pharmacodynamic factors that can sometimes be regulated by genetic factors. Whereas polymorphic drug-metabolizing enzymes and drug transporters may affect the pharmacokinetics of drugs, polymorphic drug targets and disease-related pathways may influence the pharmacodynamic action of drugs. After a usual dose, variations in drug toxicity and inefficacy can be observed depending on the polymorphism, the analgesic considered and the presence or absence of active metabolites. For opioids, the most studied being morphine, mutations in the ABCB1 gene, coding for P-glycoprotein (P-gp), and in the micro-opioid receptor reduce morphine potency. Cytochrome P450 (CYP) 2D6 mutations influence the analgesic effect of codeine and tramadol, and polymorphism of CYP2C9 is potentially linked to an increase in nonsteroidal anti-inflammatory drug-induced adverse events. Furthermore, drug interactions can mimic genetic deficiency and contribute to the variability in response to analgesics. This review summarizes the available data on the pharmacokinetic and pharmacodynamic consequences of known polymorphisms of drug-metabolizing enzymes, drug transporters, drug targets and other nonopioid biological systems on central and peripheral analgesics.

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The role of cytochrome P450 pharmacogenomics in chronic non-cancer pain patients

Tverdohleb

Dinc

Knezevic

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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The Human Genome Project (HGP) revolutionized the future of medicine and the way health care providers approach individualized patient treatment, and chronic pain management is one of those areas. The key findings in the literature appear to be related to the CYP2D6 expression and its high polymorphism influencing the metabolism of opioid medications, and the impact of that on the patient's therapeutic outcome thus exemplifying the importance of genetic testing for CYP2D6 in the process of physician therapeutic decision making.

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PI-44Correlation of CYP2D6 genotype with response to oxycodone in orthopedic injury related pain

Cited by 3 publications

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Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety

Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety

Pharmacogenetics of Analgesics: Toward the Individualization of Prescription

The role of cytochrome P450 pharmacogenomics in chronic non-cancer pain patients

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