CYP2D6 in the Metabolism of Opioids for Mild to Moderate Pain

In most cancer patients, pain is successfully treated with pharmacological measures using opioid analgesics for moderate to severe pain (strong opioids) alone or in combination with adjuvant analgesics (coanalgesics). Opioids for mild to moderate pain (weak opioids) are usually recommended in the treatment of cancer pain of mild to moderate intensity. There is a debate whether the second step of the WHO analgesic ladder comprising weak opioids such as tramadol, codeine and dihydrocodeine is still needed for the treatment of cancer and chronic pain since low doses of strong opioids show similar efficacy. However, many patients with mild, moderate and in some cases strong pain intensity are still successfully treated with weak opioids. All these drugs are metabolized through CYP2D6, an important enzyme for approximately 25% of all drugs administered in clinical practice. The aim of this review is to summarize data on the impact of CYP2D6 polymorphism on pharmacokinetics, pharmacodynamics and adverse effects of weak opioids. Copyright © 2011 S. Karger AG, Basel Received: November 29, 2010 Accepted after revision: February 14, 2011 Published online: April 15, 2011 Wojciech Leppert Chair and Department of Palliative Medicine Poznan University of Medical Sciences Osiedle Rusa 25 A, PL–61 245 Poznan (Poland) Tel. +48 61 8738 303, E-Mail wojciechleppert @ wp.pl © 2011 S. Karger AG, Basel 0031–7012/11/0876–0274$38.00/0 Accessible online at: www.karger.com/pha D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /1 9/ 20 17 2 :3 2: 07 P M CYP2D6 in the Metabolism of Weak Opioids Pharmacology 2011;87:274–285 275 More than 80 distinct allelic variants for CYP2D6 are known, which leads to a wide spectrum of metabolic capacity and phenotype diversity within populations [7, 8] . Individuals carrying two wild-type alleles display normal enzyme activity and are known as extensive metabolizers (EMs). Poor metabolizers (PMs) display two inactive alleles and are characterized by deficient hydroxylation of several classes of drugs, such as  -blockers, antiarrhythmics, antidepressants, neuroleptics and some opioid analgesics. In approximately 7–10% of the Caucasian populations, an autosomal recessive trait of nonfunctional alleles is present [9, 10] . These PMs are at an increased risk of sustaining excessive pharmacodynamic and adverse effects due to a relative drug overdose when the parent compound is responsible for the therapeutic effects [11] . When the prodrug is metabolized to its active metabolite(s) therapeutic failure may be observed in PMs [12] . In comparison to Caucasians, the incidence of PMs is much lower in Asian and African populations. Caucasians have a significantly increased frequency of three defective genes: CYP2D6 * 4, CYP2D6 * 3 and CYP2D6 * 6 whereas the frequency of CYP2D6 * 5 defective alleles is similar to that of other ethnic groups, all contributing to the PM phenotype [13] . The duplication or multiduplication of the CYPD6 gene (mostly CYP2D6 * 1 and CYP2D6 * 2 alleles in Caucasians) is associated with an ultrarapid metabolism of some compounds. Ultrarapid metabolizers (UMs) may experience either a lack of efficacy if the parent compound is responsible for the therapeutic effect of a given drug or very intense therapeutic effects associated with the production of an excessive amount of active metabolite(s) that may also be responsible for intense adverse effects. The incidence of UMs is low in northern (1–2%), middle Europe, North America (4–5%) and Asia (0.5–2.5%) but is significantly higher in Mediterranean (7–12%), Saudi-Arabian (21%) and Ethiopian (29%) populations [14] . Other polymorphisms include CYP2D6 * 10 that leads to instable enzyme activity with a high occurrence (41–51%) in Asian populations and CYP2D6 * 17 that leads to reduced affinity for substrates with a high incidence in African populations (20–35%); both are responsible for the intermediate metabolizer (IM) phenotype [15, 16] . The IM phenotype may also be relevant to the clinical effects of CYP2D6 substrates although to a lesser extent when compared with PM and UM phenotypes. Tramadol Tramadol (1 RS ,2 RS )-2-[(dimethylamino)methyl]-1-(3methoxyphenyl)-cyclo-hexanol is a synthetic opioid of the aminocyclohexanol group, an analgesic with opioid agonist properties and acting on noradrenalin and serotonin neurotransmission [17, 18] . Tramadol is a racemic mixture; (–)-tramadol is about 10 times more potent than (+)-tramadol in inhibiting noradrenalin uptake and (+)-tramadol is about 4 times stronger than (–)-tramadol in inhibiting serotonin uptake. Both enantiomers act synergistically to improve analgesia without increasing the adverse effects [19] . Tramadol is mainly metabolized by the CYP enzyme system in the liver and excreted by the kidneys. Tramadol undergoes biotransformation in the liver, firstly by the phase I reactions (mainly Oand N-demethylation), and secondly by the phase II reactions (mainly conjugation of Oand N-demethylated compounds) [20, 21] . In the phase I reactions, 11 metabolites and in the phase II reactions, 12 metabolites are produced; the main metabolite is Odesmethyltramadol (M 1 ) [22] . It shows analgesic activity and has a higher affinity for -opioid receptors than the parent compound [23, 24] ; (+)-M 1 has 300–400 times greater affinity for -opioid receptors than tramadol [25] whereas (–)-M 1 mainly inhibits noradrenalin reuptake [26] . Apart from O,N-didesmethyltramadol (M 5 , which exhibits weaker analgesic activity than M 1 ), other metabolites are pharmacologically inactive. Mono-O-demethylation leading to M 1 production is possible owing to the polymorphic CYP2D6 enzyme (sparteine oxygenase) of cytochrome P450 in the liver, which is inhibited by quinidine, a selective inhibitor of this enzyme [27] . The elimination half-life of tramadol is about 5–6 h and that of M 1 is approximately 8 h [28] . Upon oral administration of tramadol, about 90% of the drug is excreted by the kidneys and 10% with the feces [21] . Patients with renal impairment (creatinine clearance ! 79 ml/min) show a decreased excretion of tramadol and M 1 in comparison to healthy individuals with normal renal function (creatinine clearance 1 100 ml/min) [27] . In patients with advanced cirrhosis, there is a decrease in tramadol metabolism with a concomitant decrease in hepatic clearance and a rise in the blood serum levels. In these patients a 2.5-fold increase in the elimination half-life is observed [29] . The starting dose of immediate-release (IR) tramadol is about 25–50 mg every 4–6 h and, in the case of controlled-release (CR) tablets or capsules, 50–100 mg twice daily [28] . Studies conducted in patients with postoperative pain demonstrated that patients devoid of CYP2D6 activity D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /1 9/ 20 17 2 :3 2: 07 P M Leppert Pharmacology 2011;87:274–285 276 (PMs) need approximately 30% higher tramadol doses than those with normal CYP2D6 activity (EMs) [30] . Assays of tramadol and M 1 enantiomers conducted in healthy volunteers and in patients with postoperative pain [30] demonstrated that tramadol analgesia depends on CYP2D6 genotype, with less analgesic effects observed in PM, which is associated with a lack of (+)-M 1 enantiomer formation that is responsible for the opioid component of tramadol analgesia [31] . Genotyping is helpful in patients with duplication of the CYP2D6 gene (UMs) as these patients are at greater risk to develop adverse effects to tramadol [14, 32] . Tramadol is also metabolized through CYP3A4 and CYP2B6 to N-desmethyltramadol (M 2 ), and through CYP2D6 and CYP3A4 to M 5 ( fig. 1 ) [27, 33, 34] . Stamer et al. [30] investigated whether the PM genotype had an impact on the response to tramadol in 300 postoperative patients treated with a 1-ml bolus dose of a combination of tramadol 20 mg/ml, dypirone 200 mg/ml and metoclopramide 0.4 mg/ml via patient-controlled analgesia after titration to an individual loading dose. Patients classified as PMs (n = 30) needed higher loading doses of tramadol than patients classified as EMs (n = 241; 144.7 8 22.6 and 108.2 8 56.9 mg, respectively; p ! 0.001); the percentage of nonresponders was significantly higher in the PM group (46.7 vs. 21.6%; p ! 0.005); more patients from the PM group needed rescue analgesia in the recovery room (43.3 vs. 21.6%; p ! 0.02). In another study, tramadol was administered intravenously at a dose of 3 mg/kg for postoperative analgesia in 170 patients. The concentration of M 1 differed between PMs, IMs, EMs and UMs. Median (1/3 quartile) area under the concentration-time curves for (+)-M 1 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 ! h/ml for PMs, IMs, EMs and UMs, respectively (p ! 0.001). Medications inhibiting CYP2D6 administered with tramadol decreased (+)-M 1 concentrations (p ! 0.01). In PMs nonresponder rates to tramadol treatment increased fourfold compared with the other genotypes (p ! 0.001) [31] . Wang et al. [15] investigated whether the CYP2D6 * 10 allele had an impact on the postoperative analgesia effect of tramadol in 70 Chinese patients after gastrectomy. The allele frequency of CYP2D6 * 10 is 52.4%; patients were categorized into three groups according to the CYP2D6 genotype: patients without CYP2D6 * 10 (group 1; n = 17), patients heterozygous for CYP2D6 * 10 (group 2; n = 26), and patients homozygous for CYP2D6 * 10 (group 3; n = 20). The demographic data of the three groups were comparable. The total consumption of tramadol for 48 h in group 3 was significantly higher than that in groups 1 and 2, while it did not differ between groups 1 and 2. The CYP2D6 * 10 allele has a significant impact on analgesia with tramadol in a Chinese population and pharmacogenetics may explain some of the varying responses to analgesics in patients with postoperative pain. Gan et al. [16] investigated the influence of the CYP2D6 * 10 allele on the disposition of tramadol hydrochloride in Malaysian subjects. A single dose of 100 mg tramadol was given intravenously to 30 healthy orthopedic patients undergoing various elective surgeries. Patients were genotyped for CYP2D6 * 10 and the presence of CYP2D6 * 1, * 3, * 4, * 5, * 9 and * 17 mutations. The pharmacokinetics of tramadol was studied during 24 h after drug administration. The allele frequency for CYP2D6 * 10 was high (0.43). Subjects who were homozygous for CYP2D6 * 10 had significantly (p = 0.046) longer mean serum half-lives of tramadol (12.1 h) than subjects of the normal (7.2 h) or heterozygous group (10 h). When patients were screened for the presence of other alleles, the values of the pharmacokinetic parameters were more easily explained. The CYP2D6 * 10 allele, in particular, was associated with high serum levels of M5-glucoronide (M15) CYP2D6