Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The analgesic effect and adverse events of the weak opioid codeine is assumed to be mediated by its metabolite morphine. The cytochrome P-450 enzyme CYP2D6 catalysing the formation of morphine exhibits a genetic polymorphism. Two distinct phenotypes, the extensive (EMs) and poor metabolisers (PMs), are present in the population. The prevalence of PMs in the Caucasian population is 7% to 10%. Since PMs do not express functional CYP2D6, they have a severely impaired capacity to metabolise drugs which are substrates of this enzyme. Provided the analgesic effect and the adverse events of codeine are mediated by its metabolite morphine, large phenotype-related differences are to be expected and PMs, as they form only trace amounts of morphine, can serve as a model to test the hypothesis whether the analgesia and adverse events of codeine are mediated by the parent drug or its metabolite morphine. Therefore we have studied in a randomised placebo-controlled double-blind trial the analgesic effect of 170 mg codeine (p.o.) compared to 20 mg morphine (p.o.) and placebo in 9 EMs and 9 PMs using the cold pressor test. The duration and intensity of the side effects were assessed using visual analogue scales (VAS). Codeine and morphine concentrations were measured in serum and urine. Compared to placebo, 20 mg morphine caused a significant increase in pain tolerance in both phenotypes, EMs and PMs (16.2+/-27.4 vs. -0.66+/-27.4 s x h, n=18). However, following administration of codeine, analgesia was only observed in EMs but not in PMs (EMs: 54.9+/-42.2 vs. 1.7+/-4.2 s x h, P < 0.01; PMs: 9.6+/-10.9 vs. 3.3+/-23.7 s x h, not significant). Adverse events were significantly more pronounced after morphine and codeine compared to placebo in both EMs and PMs. In contrast to the phenotype-related differences in the analgesic effect of codeine, however, no difference in adverse events between the phenotypes could be observed. In the pharmacokinetic studies, significant differences between the two phenotypes in the formation of morphine after codeine administration could be observed. Whereas morphine plasma concentrations were similar in PMs (Cmax: 44+/-13 nmol/l: AUC: 199+/-45 nmol x h/l) and EMs (Cmax: 48+/-17 nmol/l); AUC: 210+/-65 nmol x h/l) after morphine administration, following 170 mg codeine, morphine plasma concentrations comparable to those after morphine application were only observed in EMs (Cmax: 38+/-16 nmol/l; AUC: 173+/-90 nmol x h/l). In PMs only traces of morphine could be detected in plasma (Cmax: 2+/-1 nmol/l; AUC: 10+/-7 nmol x h/l). The percentage of the codeine dose converted to morphine and its metabolites was 3.9% in EMs and 0.17% in PMs. The interindividual variability in analgesia of codeine which is related to genetically determined differences in the formation of morphine clearly indicate that this metabolite is responsible for the analgesic effect of codeine. In contrast to the analgesic effect, frequency and intensity of the adverse events did not present significant differences between the two phenotypes. These findings have implications for the clinical use of codeine. Since side effects occurred in both EM and PM subjects, the use of codeine as an analgesic will expose 7% to 10% of patients who are PMs to the side effects of the drug without providing any beneficial analgesic effects.
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PMID:Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. 969 56

Bupivacaine is used to provide prolonged anesthesia and postoperative analgesia. The human cytochrome P450 (CYP) involved in bupivacaine degradation into pipecolylxylidine (PPX), its major metabolite, has, to our knowledge, never been described. Microsome samples were prepared from six human livers and incubated in the presence of bupivacaine. The concentrations of PPX in the microsomal suspensions were assessed, and K(m) and V(max) values were calculated. Bupivacaine incubations were then performed with specific CYP substrates and inhibitors. For each sample of hepatic microsomes, the correlation between the rate of PPX formation and the corresponding erythromycin N-demethylase activity was analyzed. Finally, an immunoinhibition study using an anti-rabbit CYP3A6 antibody and assays with cDNA-expressed human CYP were conducted. The apparent K(m) and V(max) values of bupivacaine were, respectively, 125 microM and 4.78 nmol/min/mg of microsomal protein. The strongest inhibition of bupivacaine metabolism was obtained for troleandomycin (-95% at 50 microM), a specific CYP3A inhibitor. The correlation between PPX formation and erythromycin N-demethylase activity showed an R value of 0.99 whereas anti-rabbit CYP3A6 antibody inhibited the degradation of bupivacaine into PPX by 99%. Finally, CYP1A2 and CYP2E1 cDNA-expressed forms of human CYP did not allow PPX formation, CYP2C19 and CYP2D6 produced only small amounts whereas CYP3A4 most efficiently metabolized bupivacaine into PPX. These results demonstrated that bupivacaine degradation into PPX was mediated in humans by CYP3A.
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PMID:Oxidative metabolism of bupivacaine into pipecolylxylidine in humans is mainly catalyzed by CYP3A. 1072 4

Respiratory depression following change of medication from tramadol to morphine is described in two patients. Tramadol is metabolized by cytochromoxidase CYP2D6 to O-desmethyl-tramadol with opioid agonist activity. Of the western population 7% have a mutation of the gene responsible for CYP2D6, resulting in low enzyme activity. These persons will have little effect of tramadol. When tailoring analgesia, the lack of response to tramadol may be interpreted as a need for opioid dose increase. In such cases, excessive opioid doses may be prescribed resulting in opioid side effects.
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PMID:[Respiratory depression following medication change from tramadol to morphine]. 1077 58

Oxycodone is an opioid analgesic that closely resembles morphine. Oxymorphone, the active metabolite of oxycodone, is formed in a reaction catalyzed by CYP2D6, which is under polymorphic genetic control. The role of oxymorphone in the analgesic effect of oxycodone is not yet clear. In this study, controlled-release (CR) oxycodone and morphine were examined in cancer pain. CR oxycodone and morphine were administered to 45 adult patients with stable pain for 3-6 days after open-label titration in a randomized, double-blind, cross-over trial. Twenty patients were evaluable. Both opioids provided adequate analgesia. The variation in plasma morphine concentrations was higher than that of oxycodone, consistent with the lower bioavailability of morphine. Liver dysfunction affected selectively either oxycodone or morphine metabolism. Three patients with markedly aberrant plasma opioid concentrations are presented. Significant individual variation in morphine and oxycodone metabolism may account for abnormal responses during treatment of chronic cancer pain.
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PMID:Morphine or oxycodone in cancer pain? 1120 1

Patient-controlled analgesia (PCA) has become standard procedure in the clinical treatment of pain. Its widespread use in patients with all kinds of diseases opens a variety of possible interactions between analgesics used for PCA and other drugs that might be administered concomitantly to the patient. Many of these drug interactions are of little clinical importance. However, some drug interactions have been reported to result in serious clinical problems. Drug interactions can either predominantly affect the pharmacokinetics or pharmacodynamics of the drug. Most important pharmacokinetic drug interactions occur at the level of drug metabolism or protein binding. Acceleration of methadone metabolism caused by cytochrome P450 (CYP) 3A4 induction by antiretroviral drugs or rifampicin (rifampin) has caused methadone withdrawal symptoms. Lack of morphine formation from codeine as a result of CYP2D6 inhibition by quinidine results in an almost complete loss of the analgesic effects of codeine. Alterations of methadone protein binding caused by an inhibition of alpha1-acid glycoprotein synthesis by alkylating substances are another possibility for predominantly pharmacokinetically based drug interactions during PCA. Furthermore, inhibition of P-glycoprotein by anticancer drugs could result in altered transmembrane transport of morphine, methadone or fentanyl, although this has not been shown to be of clinical relevance. Synergistic effects of systemically administered opioids with spinally or topically delivered opioids or anaesthetics have been reported frequently. The same is true for the opioid-sparing effects of coadministered non-opioid analgesics. Antidepressants, anticonvulsants or alpha2-adrenoreceptor agonists have also been shown to exert additive analgesic effects when administered together with an opioid. Inconsistent findings, however, are reported regarding the treatment of patients with opioid-induced nausea and sedation, since coadministration of antiemetics either increased or decreased the respective adverse effects or revealed additional unwanted drug effects.
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PMID:Drug interactions with patient-controlled analgesia. 1182 96

Genetic polymorphisms result in absent enzyme activity of CYP2D6 (poor metabolizers, PM) in about 10% of the Caucasian population. This study investigates whether the PM genotype has an impact on the response to tramadol analgesia in postoperative patients. A prospective study design was used and 300 patients recovering from abdominal surgery were enrolled. After titration of an individual loading dose, patients could self-administer 1 ml bolus doses of the drug combination tramadol 20 mg/ml, dipyrone 200 mg/ml and metoclopramide 0.4 mg/ml via patient-controlled analgesia (PCA). Patients' genotype was analyzed considering the most prevalent PM associated CYP2D6 mutations using a real-time PCR and hybridization based genotyping method. Demographic data, surgery related variables, pain scores, analgesic consumption and need for rescue medication were compared between extensive metabolizers (EM) and PM. The primary outcome criterion 'response' was defined as responder or non-responder status by the need for rescue medication and patients' satisfaction at the final interview. Demographic and surgery related data were comparable between EM (n=241) and PM (n=30). The percentage of non-responders was significantly higher in the PM group (46.7%) compared with the EM group (21.6%; p=0.005). Tramadol loading dose amounted to 108.2+/-56.9 and 144.7+/-22.6 mg (p<0.001) in EM and PM, respectively. More patients displaying the PM genotype needed rescue medication in the recovery room and during PCA period than patients with at least one wild type allele (21.6 versus 43.3%, p=0.02). PM for CYP2D6 showed a lower response rate to postoperative tramadol analgesia than EM. Therefore, CYP2D6 genotype has an impact on analgesia with tramadol. Pharmacogenetics may explain some of the varying response to pain medication in postoperative patients.
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PMID:Impact of CYP2D6 genotype on postoperative tramadol analgesia. 1449 40

Tramadol analgesia results from a monoaminergic effect by tramadol itself and an opioid effect of its metabolite (+)-M1 formed by O-demethylation of tramadol by CYP2D6. In this study we sought to determine the impact of (+)-M1 on the analgesic effect of tramadol evaluated by experimental pain models. The effect of an IV injection of 100 mg tramadol on experimental pain was studied 15-90 min after dosing in volunteers, 10 extensive metabolizers with CYP2D6 and 10 poor metabolizers without CYP2D6 in 2 placebo-controlled trials. The pain tests included detection and tolerance threshold to single electrical sural nerve stimulation, pain summation threshold to repetitive electrical sural nerve stimulation (temporal summation), and the cold pressor test. In extensive metabolizers, tramadol reduced discomfort experienced during the cold pressor test (P = 0.002). In poor metabolizers, the pain tolerance thresholds to sural nerve stimulation were increased (P = 0.04). (+)-M1 could be detected in the serum samples from all extensive metabolizers except one, but (+)-M1 was below the limit of determination in all poor metabolizers. The opioid effect of (+)-M1 appears to contribute to the analgesic effect of tramadol, but the monoaminergic effect of tramadol itself seems to create an analgesic effect.
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PMID:The analgesic effect of tramadol after intravenous injection in healthy volunteers in relation to CYP2D6. 1636 20

Genomic variations influencing nociceptive sensitivity and susceptibility to pain conditions, as well as responses to pharmacotherapy of pain are currently under investigation. Candidate genes involved in pain perception, pain processing and pain management such as (opioid) receptors, transporters and other targets of pharmacotherapy are discussed. Drug metabolizing enzymes represent a further major target of ongoing research in order to identify associations between an individual's genetic profile and drug response (pharmacogenetics). Polymorphisms of the cytochrome P 450 enzymes influence analgesic efficacy of codeine, tramadol and tricyclic antidepressants (CYP2D6). Blood levels of some non-steroidal anti-inflammatory drugs (NSAIDs) are dependent on CYP2C9 activity, whereas opioid receptor polymorphisms are discussed with respect to differences in opioid-mediated analgesia and side-effects. Pharmacogenetics is seen as a potential diagnostic tool for improving patient therapy and care and will contribute to a more individualized drug treatment in the future.
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PMID:[Genetics, pain and analgesia]. 1662 60

Tramadol (Ultram, Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ) is considered a Step 2 analgesic under the World Health Organization's guidelines for the treatment of patients with cancer pain. It is a centrally acting analgesic that has affinity for opioid receptors and influences the action of norepinephrine and serotonin at the synapse. This dual mechanism of analgesia makes it unique among Step 2 agents. It is metabolized by CYP2D6, which increases the potentialfor drug interactions. Unlike other opioids, it does not cause respiratory depression. Tramadol has been studied in cancer pain and neuropathic pain. It compares well with low-dose morphine as an analgesic. The purpose of this review is to critically examine the pharmacodynamics, pharmacology, drug interactions, and adverse effects of the drug, and, based on the data presented, discuss the drug's role in cancer care.
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PMID:Tramadol: does it have a role in cancer pain management? 1731 16

The influence of CYP2D6 genotype and CYP2D6 inhibitors on enantiomeric plasma levels of tramadol and O-desmethyltramadol as well as response to tramadol was investigated. One hundred and seventy-four patients received one hundred intravenous tramadol 3 mg/kg for postoperative analgesia. Blood samples drawn 30, 90, and 180 min after administration were analyzed for plasma concentrations of the enantiomers (+)-, (-)tramadol and (+)-, (-)O-desmethyltramadol by liquid chromatography-tandem mass spectrometry. Different CYP2D6 genotypes displaying zero (poor metabolizer (PM)), one (heterozygous individual (HZ)/intermediate metabolizer (IM)), two extensive metabolizer (EM), and three (ultra rapid metabolizer (UM)) active genes were compared. Concentrations of O-desmethyltramadol differed in the four genotype groups. Median (1/3 quartile) area under the concentration-time curves for (+)O-desmethyltramadol were 0 (0/11.4), 38.6 (15.9/75.3), 66.5 (17.1/118.4), and 149.7 (35.4/235.4) ng x h/ml for PMs, HZ/IMs, EMs, and UMs (P<0.001). Comedication with CYP2D6 inhibitors decreased (+) O-desmethyltramadol concentrations (P<0.01). In PMs, non-response rates to tramadol treatment increased fourfold compared with the other genotypes (P<0.001). In conclusion, CYP2D6 genotype determined concentrations of O-desmethyltramadol enantiomers and influenced efficacy of tramadol treatment.
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PMID:Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. 1736 Nov 24


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