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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the hypoalgesic effect of codeine (100 mg) after blocking the hepatic O-demethylation of codeine to morphine via the sparteine oxygenase (CYP2D6) by quinidine (200 mg). The study was performed in 16 extensive metabolizers of sparteine, using a double-blind, randomized, four-way, cross-over design. The treatments given at 3 h intervals during the four sessions were placebo/placebo, quinidine/placebo, placebo/codeine, and quinidine/codeine. We measured pinprick pain and pain tolerance thresholds to high energy argon laser stimuli before and 1, 2, and 3 h after codeine or placebo. After codeine and placebo, the peak plasma concentration of morphine was 6-62 (median 18) nmol.l-1. When quinidine pre-treatment was given, no morphine could be detected (less than 4 nmol.l-1) after codeine. The pin-prick pain thresholds were significantly increased after placebo/codeine, but not after quinidine/codeine compared with placebo/placebo. Both placebo/codeine and quinidine/codeine increased pain tolerance thresholds significantly. Quinidine/codeine and quinidine/placebo did not differ significantly for either pin-prick or tolerance pain thresholds. These results are compatible with local CYP2D6 mediated formation of morphine in the brain, not being blocked by quinidine. Alternatively, a hypoalgesic effect of quinidine might have confounded the results.
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PMID:The effect of quinidine on the analgesic effect of codeine. 162 98

It has recently been shown that O-demethylation of the opioid drug codeine to morphine depends on the sparteine/debrisoquine oxygenase (CYP2D6) which in man exhibits genetic polymorphism. Morphine may be an endogenously formed substance in mammalians. Therefore, it may be hypothesized that the final step in an endogenous synthesis of morphine from codeine also depends on CYP2D6. CYP2D6, which is present in the liver and presumably also in the brain, is not expressed in subjects who are poor metabolisers of the sparteine/debrisoquine type. We have determined sensitivity to painful stimuli in 94 extensive metabolisers and 82 poor metabolisers of sparteine in 2 phasic (pain thresholds to heat and pressure) and 1 tonic (cold pressor test) experimental pain model. Extensive and poor metabolisers did not differ significantly in the 2 phasic pain models neither with respect to pain detection nor pain tolerance thresholds. However, for the cold pressor test, peak pain ratings and area under the pain rating-time curve during 2 min were significantly higher in poor than in extensive metabolisers (P = 0.0024 and 0.044). Furthermore, a substantially higher fraction of poor metabolisers prematurely withdrew their hand from the ice water during the cold pressor test due to intolerable pain (32 vs. 18%, P = 0.0545). We conclude that poor metabolisers of sparteine may be less tolerant to tonic pain than extensive metabolisers, and we hypothesize that this may be related to an inherited defect in endogenous synthesis of morphine via CYP2D6 in the brain.
Pain 1993 Jun
PMID:Are poor metabolisers of sparteine/debrisoquine less pain tolerant than extensive metabolisers? 835 Nov 62

Codeine is an old drug that is still widely used to treat mild and moderate pain. It is mainly metabolised by glucuronidation, but minor pathways are N-demethylation to norcodeine and O-demethylation to morphine. The latter pathway depends on the genetically polymorphic CYP2D6 which is absent in 7% of the white population (PM) and present in the remainder (EM). Lack of influence of codeine on experimental pain in PM as well as in EM treated with the CYP2D6 blocker quinidine, who are both practically unable to convert codeine to morphine, has supported an old hypothesis that codeine acts through metabolically formed morphine. Possibly, local codeine O-demethylation in the CNS is of major importance for its hypoalgesic effect. Such a local morphine formation from codeine, which supposedly is also catalysed by CYP2D6, could explain why the hypoalgesic effect of codeine stems from morphine despite relatively low plasma levels of morphine after standard hypoalgesic doses of codeine. Dependence of codeine hypoalgesia on morphine formation via CYP2D6 makes this effect liable to interaction with drugs that are inhibitors of CYP2D6. Examples of potent inhibitors of CYP2D6 are quinidine, some selective serotonin reuptake inhibitors and some neuroleptics. Less potent inhibitors, such as tricyclic antidepressants, will probably also reduce the pain relieving effect of codeine, since codeine has a low affinity for CYP2D6. Biosynthesis of morphine in humans may also include steps catalyse by CYP2D6. Experimental studies in large groups of EM and PM indicate that this may lead to interphenotype differences in pain tolerance.
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PMID:The pharmacogenetics of codeine hypoalgesia. 884 55

Tramadol inhibits norepinephrine reuptake, stimulates serotonin release, and acts with mu-opioid receptors by way of its metabolite (+)-M1. Formation of M1 seems to depend on the genetic polymorphic CYP2D6. The analgesic effect of 2 mg/kg tramadol was evaluated in 15 extensive and 12 poor metabolizers of sparteine in two parallel, randomized, double-blind, placebo-controlled crossover studies that used experimental pain models. In extensive metabolizers, tramadol increased pressure pain detection (p = 0.03) and tolerance (p = 0.06) thresholds, as well as thresholds for eliciting nociceptive reflexes, after single (p = 0.0002) and repeated (p = 0.06) stimulation of the sural nerve. Peak pain and pain area in the cold pressor test were reduced (p = 0.0006 and 0.0009). In poor metabolizers, only thresholds to pressure pain tolerance (p = 0.02) and nociceptive reflexes after single stimulation (p = 0.04) were increased and the reflex threshold was less increased in poor metabolizers than in extensive metabolizers (p = 0.02). The serum concentration of (+)-M1 2 to 10 hours after tramadol ranged from 10 to 100 ng/L in extensive metabolizers, whereas in poor metabolizers serum concentrations of (+)-M1 were below or around the detection limit of 3 ng/ml. It is concluded that formation of (+)-M1 by way of CYP2D6 is important for the effect of tramadol on experimental pain.
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PMID:The hypoalgesic effect of tramadol in relation to CYP2D6. 898 65

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.
Pain 1998 May
PMID:Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. 969 56

Dextromethorphan (DEM)-mediated N-methyl-D-aspartate receptor blockade may result from an action of unchanged DEM or its active metabolite, dextrorphan (DOR). In humans, DEM is metabolized into DOR by the polymorphic enzyme CYP2D6. We therefore investigated the impact of quinidine (Qd), a selective inhibitor of CYP2D6, on DEM disposition and the contribution of CYP2D6 phenotype on DEM antinociceptive and neuromodulatory effects. Using a randomized, double-blind, crossover, placebo-controlled design, healthy volunteers (n = 7) received Qd (50 mg Qd sulfate orally) or a placebo and, 12 h later, either DEM (50 mg DEM hydrobromide orally) or a placebo. DEM and DOR pharmacodynamics were assessed for their antinociceptive and neuromodulatory effects. Antinociceptive effects were assessed over 4 h by subjective pain threshold and RIII nociceptive reflex (RIII) monitoring. Neuromodulatory effects were studied using the primary and secondary hyperalgesia induced by the topical application of capsaicin. Two of seven subjects were genotypic CYP2D6 PM. Pretreatment of EM by Qd suppressed DOR formation and increased the plasma level of DEM to the levels of poor metabolizers. In poor metabolizers, DEM induced a significant increase in objective (+45%) and subjective (+35%) pain thresholds. In extensive metabolizers, only a slight and short-lasting increase in the subjective threshold was observed, whereas no effect was seen on the objective threshold. DEM modulates secondary hyperalgesia compared with DOR. The CYP2D6 phenotype affects the disposition of DEM and the production of the active metabolite DOR. The impact of the CYP2D6 phenotype is of major importance for the spinal antinociceptive and neuromodulatory effects of DEM.
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PMID:Contribution of cytochrome P-4502D6 phenotype to the neuromodulatory effects of dextromethorphan. 991 65

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

The cytochrome P450 CYP2D6 is a polymorphic drug-metabolizing enzyme that is involved in the metabolism of several drugs and xenobiotics. Several independent studies indicate that the CYP2D6 metabolic status is a secondary factor in the risk of developing lung cancer, with individuals with high activity being at increased risk. The occurrence of functionally active duplications of the CYP2D6 gene is a phenomenon that affects 3-8% of Caucasians and up to 30% in some ethnic groups. These duplications cause ultrarapid metabolism of CYP2D6 substrates. In order to establish whether the highest CYP2D6 enzyme activity is associated with an increased risk of cancer, we analyzed the frequency of CYP2D6 gene duplications and enzyme-inactivating mutations in 199 Caucasian patients with lung or larynx cancer and in 335 healthy controls. A significantly increased frequency of carriers of the CYP2D6 gene duplication were found among lung and larynx cancer patients (13%), as compared with healthy controls (6.9%; p < 0.02). The frequency of the mutated active CYP2D6*9 allele was increased in lung cancer patients (p < 0.01) but not in larynx cancer patients. Global findings indicate that over 20% patients with lung or larynx cancer show CYP2D6 genotypes leading to ultrarapid metabolism or to the expression of an enzyme with altered kinetics (p < 0.01 vs. healthy controls). This may influence the metabolism of CYP2D6 substrates, including antineoplastic drugs and opioid derivatives used for pain relief in cancer patients. These patients would require higher doses than those considered as standard. We conclude that dosages for CYP2D6 substrates should be adapted to lung and larynx cancer patients.
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PMID:Functionally active duplications of the CYP2D6 gene are more prevalent among larynx and lung cancer patients. 1147 50

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

Pharmacogenomics, the study of the impact of heritable traits on pharmacology and toxicology, may serve as an adjunct for certifying opioid fatalities. Oxycodone, frequently prescribed for the relief of moderate to severe pain, is metabolized by cytochrome P450 (CYP) 2D6, encoded by a polymorphic gene with three mutations (*3, *4, and *5) with a combined 95% allelic frequency and about 10% prevalence. Individuals with variant alleles are more susceptible to oxycodone toxicity. By assessing the prevalence of CYP2D6 polymorphisms and covariables, we hypothesized that oxycodone fatality may be partially due to poor drug metabolism caused by CYP2D6 variant alleles. From the Milwaukee County Medical Examiner's Office (MCMEO), a retrospective analysis of 15 oxycodone cases was followed by genotyping blood samples for the variant alleles by conventional and real-time PCRs. Institutional Review Board approval was obtained. Oxycodone, extracted from blood and/or urine, was quantitated by GC-MS. The results show two homozygous for 2D6*4 and four heterozygous for 2D6*4. The MCMEO was not significantly different from those in the control group (n = 26) (p > 0.05, Fisher's Exact Test). However, genotyping CYP2D6 provided a more definitive interpretation of the oxycodone toxicity in four cases. Therefore, pharmacogenomics may serve as an adjunct in the determination of the cause and manner of death in forensic toxicology and a pharmacogenomic algorithm for genotyping has been proposed.
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PMID:Pharmacogenomics as molecular autopsy for postmortem forensic toxicology: genotyping cytochrome P450 2D6 for oxycodone cases. 1242 98


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