Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Pain 2003 Sep
PMID:Impact of CYP2D6 genotype on postoperative tramadol analgesia. 1449 40

Tramadol (CAS 36282-47-0) plays an important role in the management of pain. With its dual mechanism of action (opioid agonist; weak noradrenaline and serotonin reuptake inhibitor) tramadol provides a kind of combined/adjuvant pain therapy. Besides its proven clinical efficacy tramadol is a safe drug as respiratory depression, cardiovascular side effects, drug abuse and dependence are of minor clinical relevance, unlike some other opioids. Following oral administration the bioavailability of tramadol is high (70-90%) and with new slow release preparations twice daily administration enables effective pain control. Tramadol is characterised by low plasma protein binding (20%) and quite extensive tissue distribution (apparent volume of distribution about 3 l/kg). Elimination is primarily by the hepatic route (metabolism by CYP2D6 to an active metabolite and by CYP3A4 and CYP2B6) and partly by the renal route (up to 30% of dose). Elimination half-lives of the active agents range between 4.5 and 9.5 h and total plasma clearance of tramadol is moderately high (600 ml/min). The interaction potential of tramadol is neglectable, as it does not affect the disposition of other drugs. It should be taken into account that inducers (e.g. carbamazepine) or inhibitors (e.g. quinidine for CY2D6) of drug metabolism might modify the elimination of tramadol. Likewise, if kidney (creatinine clearance below 30 ml/min) or hepatic function is severely impaired, some dosage reduction (approximately by 50%) or extension of the dosage interval should be considered. In conclusion, tramadol is an effective and safe analgesic with a very low interaction potential. Therefore it represents a drug of first choice if moderate to severe pain states have to be treated in pediatric, adult and elderly patients including those with poor cardiopulmonary function.
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PMID:Tramadol--the impact of its pharmacokinetic and pharmacodynamic properties on the clinical management of pain. 1465 Mar 59

In this review, novel clinical studies on postoperative pain therapy are summarized. Based on these studies, several conclusions can be drawn: i) following tonsillectomy, postoperative therapy with NSAIDs leads to a significant increase in the number of reoperations; thus NSAIDs should be used with caution; ii) COX-2 inhibitors in combination with intravenous opioids improve recovery and functional outcome after knee replacement surgery; iii) the combination therapy of different non-opioid analgesics has no proven clinical efficacy and should not be used routinely; iv) patients' age is not a determinant in postoperative opioid titration after surgery; in contrast, it does predict opioid consumption during the first postoperative day; v) morphine and piritramide have identical analgesic efficacy and induce nausea and vomiting with the incidence; opioid selection can, thus, be based on economic considerations and vi) if tramadol is ineffective in postoperative pain therapy, this might be caused by an allelic variant of one of the cytochrome P450 enzymes (CYP2D6); these patients should be treated with a different opioid.
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PMID:[New insights in postoperative pain therapy]. 1504 6

A frameshift mutation 138delT generates an open reading frame in the pseudogene, cytochrome P4502D7 (CYP2D7), and an alternate spliced functional transcript of CYP2D7 containing partial inclusion of intron 6 was identified in human brain but not in liver or kidney from the same individual. mRNA and protein of the brain variant CYP2D7 were detected in 6 of 12 human autopsy brains. Genotyping revealed the presence of the frameshift mutation 138delT only in those human subjects who expressed the brain variant CYP2D7. Genomic DNA analysis in normal volunteers revealed the presence of functional CYP2D7 in 4 of 8 individuals. In liver, the major organ involved in drug metabolism, a minor metabolic pathway mediated by CYP2D6 metabolizes codeine (pro-drug) to morphine (active drug), whereas norcodeine is the major metabolite. In contrast, when expressed in Neuro2a cells, brain variant CYP2D7 metabolized codeine to morphine with greater efficiency compared with the corresponding activity in cells expressing CYP2D6. Morphine binds to micro-opioid receptors in certain regions of the central nervous system, such as periaqueductal gray, and produces pain relief. The brain variant CYP2D7 and micro-opioid receptor colocalize in neurons of the periaqueductal gray area in human brain, indicating that metabolism of codeine to morphine could occur at the site of opioid action. Histio-specific isoforms of P450 generated by alternate splicing, which mediate selective metabolism of pro-drugs within tissues, particularly the brain, to generate active drugs may play an important role in drug action and provide newer insights into the genetics of metabolism.
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PMID:A frameshift mutation and alternate splicing in human brain generate a functional form of the pseudogene cytochrome P4502D7 that demethylates codeine to morphine. 1505 13

High doses of dextromethorphan (DM) have been clinically investigated for the treatment of multiple neuronal disorders including neuropathic pain. Several authors have suggested the concomitant administration of DM and a CYP2D6 reversible inhibitor in order to enhance the exposure of DM and limit the exposure to total dextrorphan (DX). The present study proposes to determine whether or not a single dose of quinidine is sufficient to enhance the plasma concentrations of DM in rats and keep those of DX at a minimal level. Oral doses of DM (50 mg/kg) were administered with increasing dose levels of quinidine (0, 2, 20, and 50 mg/kg) to male Sprague-Dawley rats and blood samples were collected over 24 h. Plasma concentrations of DM and total DX were determined using ESI-LC/MS/MS. Quinidine coadministration resulted in a more than twofold increase in the area under the curve of DM with an ED(50) of approximately 2 mg/kg whereas those of total DX were only increased by 21%. These results support the working hypothesis that a single dose of quinidine may enhance the plasma concentrations of DM relative to those of total DX and may therefore improve the treatment of neuropathic pain.
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PMID:Influence of concomitant quinidine administration on dextromethorphan disposition in rats. 1509 9

Previous studies evaluating the efficacy and tolerance of tropisetron for the treatment of fibromyalgia (FM) used the drug either intravenously or orally, and at different dosage levels ranging from 2 mg to 15 mg daily. The shortest treatment was a single dose and the longest treatment period covered 28 days. A significant reduction of the pain intensity was achieved by using tropisetron 5 mg per day. Apart from the fact that treatment periods were different, the efficacy of oral and intravenous administration did not differ significantly. Tropisetron was well tolerated; but in the 15 mg group in one of the studies, the decrease in pain was less than in the placebo group, however, the frequency of constipation and other gastrointestinal symptoms increased. Furthermore, it was hypothesized that due to the impacts of CYP2D6 activities, a daily dose of tropisetron 2 mg may be efficacious in slow metabolizers only. Although tropisetron proved to be efficacious in a group of fibromyalgia patients, the dose-response curves cannot yet be explained in a fully satisfactory manner, which may encourage research focusing on possible subgroups of FM.
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PMID:Treatment of fibromyalgia with tropisetron--dose and efficacy correlations. 1551 18

This review uses a candidate gene approach to identify possible pharmacogenetic modulators of opioid therapy, and discusses these modulators together with demonstrated genetic causes for the variability in clinical effects of opioids. Genetically caused inactivity of cytochrome P450 (CYP) 2D6 renders codeine ineffective (lack of morphine formation), slightly decreases the efficacy of tramadol (lack of formation of the active O-desmethyl-tramadol) and slightly decreases the clearance of methadone. MDR1 mutations often demonstrate pharmacogenetic consequences, and since opioids are among the P-glycoprotein substrates, opioid pharmacology may be affected by MDR1 mutations. The single nucleotide polymorphism A118G of the mu opioid receptor gene has been associated with decreased potency of morphine and morphine-6-glucuronide, and with decreased analgesic effects and higher alfentanil dose demands in carriers of the mutated G118 allele. Genetic causes may also trigger or modify drug interactions, which in turn can alter the clinical response to opioid therapy. For example, by inhibiting CYP2D6, paroxetine increases the steady-state plasma concentrations of (R)-methadone in extensive but not in poor metabolisers of debrisoquine/sparteine. So far, the clinical consequences of the pharmacogenetics of opioids are limited to codeine, which should not be administered to poor metabolisers of debrisoquine/sparteine. Genetically precipitated drug interactions might render a standard opioid dose toxic and should, therefore, be taken into consideration. Mutations affecting opioid receptors and pain perception/processing are of interest for the study of opioid actions, but with modern practice of on-demand administration of opioids their utility may be limited to explaining why some patients need higher opioid doses; however, the adverse effects profile may be modified by these mutations. Nonetheless, at a limited level, pharmacogenetics can be expected to facilitate individualised opioid therapy.
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PMID:Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives. 1553 Jan 29

The human genome project has revealed data on genomic variation which may influence the pharmacological responses. In pain therapy, the genetic background influencing the efficacy of opioid therapy is of special interest. Screening for variations in expression of drug metabolizing enzymes has been suggested as a potential tool for improving patient therapy. CYP2D6 genetic variability is supposed to be a major factor of adverse drug reaction, possibly influencing hospital stay and total costs. Further candidate genes involved in pain perception, pain processing and pain management like opioid receptors, transporters and other targets of pharmacotherapy are under investigation. Aspects of genetic differences influencing efficacy, side effects and adverse outcome of pharmacotherapy will be of importance for future pain management.
Eur J Pain 2005 Apr
PMID:Genetics and variability in opioid response. 1573 94

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


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