Opioid Metabolism

Abstract

Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability. Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor-binding profiles of opioids. However, altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified. For example, the risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease). This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may compromise effective pain management. Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed. Articles selected for inclusion discussed general physiologic aspects of opioid metabolism, metabolic characteristics of specific opioids, patient-specific factors influencing drug metabolism, drug interactions, and adverse events. Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability. Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor-binding profiles of opioids. However, altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified. For example, the risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease). This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may compromise effective pain management. Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed. Articles selected for inclusion discussed general physiologic aspects of opioid metabolism, metabolic characteristics of specific opioids, patient-specific factors influencing drug metabolism, drug interactions, and adverse events. Opioids are a cornerstone of the management of cancer pain1World Health Organization Cancer Pain Relief: With a Guide to Opioid Availability. 2nd ed. WHO Office of Publication, Geneva, Switzerland1996Google Scholar and postoperative pain2Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management.Anesthesiology. 2004; 100: 1573-1581Crossref PubMed Scopus (447) Google Scholar and are used increasingly for the management of chronic noncancer pain.3AGS Panel on Persistent Pain in Older Persons The management of persistent pain in older persons.J Am Geriatr Soc. 2002; 50: S205-S224PubMed Google Scholar, 4American Pain Society Guideline for the Management of Pain in Osteoarthritis, Rheumatoid Arthritis and Juvenile Chronic Arthritis. 2nd ed. American Pain Society, Glenview, IL2002: 184Google Scholar Understanding the metabolism of opioids is of great practical importance to primary care clinicians. Opioid metabolism is a vital safety consideration in older and medically complicated patients, who may be taking multiple medications and may have inflammation, impaired renal and hepatic function, and impaired immunity. Chronic pain, such as lower back pain, also occurs in younger persons and is the leading cause of disability in Americans younger than 45 years.5Andersson GB Epidemiological features of chronic low-back pain.Lancet. 1999; 354: 581-585Abstract Full Text Full Text PDF PubMed Scopus (2210) Google Scholar In younger patients, physicians may be more concerned with opioid metabolism in reference to development of tolerance, impairment of skills and mental function, adverse events during pregnancy and lactation, and prevention of abuse by monitoring drug and metabolite levels. Experienced clinicians are aware that the efficacy and tolerability of specific opioids may vary dramatically among patients and that trials of several opioids may be needed before finding one that provides an acceptable balance of analgesia and tolerability for an individual patient.6Grilo RM Bertin P Scotto di Fazano C et al.Opioid rotation in the treatment of joint pain: a review of 67 cases.Joint Bone Spine. 2002; 69: 491-494Crossref PubMed Scopus (36) Google Scholar, 7Mercadante S Opioid rotation for cancer pain: rationale and clinical aspects.Cancer. 1999; 86: 1856-1866Crossref PubMed Scopus (316) Google Scholar, 8Mercadante S Bruera E Opioid switching: a systematic and critical review.Cancer Treat Rev. 2006 Jun; 32 (Epub 2006 Apr 19.): 304-315Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 9Quang-Cantagrel ND Wallace MS Magnuson SK Opioid substitution to improve the effectiveness of chronic noncancer pain control: a chart review.Anesth Analg. 2000; 90: 933-937Crossref PubMed Scopus (112) Google Scholar Pharmacodynamic and pharmacokinetic differences underlie this variability of response. Pharmacodynamics refers to how a drug affects the body, whereas pharmacokinetics describes how the body alters the drug. Pharmacokinetics contributes to the variability in response to opioids by affecting the bioavailability of a drug, the production of active or inactive metabolites, and their elimination from the body. Pharmacodynamic factors contributing to variability of response to opioids include between-patient differences in specific opioid receptors and between-opioid differences in binding to receptor subtypes. The receptor binding of opioids is imperfectly understood; hence, matching individual patients with specific opioids to optimize efficacy and tolerability remains a trial-and-error procedure.6Grilo RM Bertin P Scotto di Fazano C et al.Opioid rotation in the treatment of joint pain: a review of 67 cases.Joint Bone Spine. 2002; 69: 491-494Crossref PubMed Scopus (36) Google Scholar, 7Mercadante S Opioid rotation for cancer pain: rationale and clinical aspects.Cancer. 1999; 86: 1856-1866Crossref PubMed Scopus (316) Google Scholar, 8Mercadante S Bruera E Opioid switching: a systematic and critical review.Cancer Treat Rev. 2006 Jun; 32 (Epub 2006 Apr 19.): 304-315Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 9Quang-Cantagrel ND Wallace MS Magnuson SK Opioid substitution to improve the effectiveness of chronic noncancer pain control: a chart review.Anesth Analg. 2000; 90: 933-937Crossref PubMed Scopus (112) Google Scholar This review primarily considers drug metabolism in the context of pharmacokinetics. It summarizes the basics of opioid metabolism; discusses the potential influences of patient-specific factors such as age, genetics, comorbid conditions, and concomitant medications; and explores the differences in metabolism between specific opioids. It aims to equip physicians with an understanding of opioid metabolism that will guide safe and appropriate prescribing, permit anticipation and avoidance of adverse drug-drug interactions, identify and accommodate patient-specific metabolic concerns, rationalize treatment failure, inform opioid switching and rotation strategies, and facilitate therapeutic monitoring. To that end, recommendations for tailoring opioid therapy to individual patients and specific populations will be included. Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed databases for literature published between January 1980 and June 2008. The opioid medication search terms used were as follows: codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, opioid, opioid analgesic, oxycodone, oxymorphone, and tramadol. Each medication search term was combined with the following general search terms: metabolism, active metabolites, pharmacokinetics, lipophilicity, physiochemical properties, pharmacology, genetics, receptor, receptor binding, receptor genetics or variation, transporter, formulations, AND adverse effects, safety, or toxicity. The reference lists of relevant papers were examined for additional articles of interest. Metabolism refers to the process of biotransformation by which drugs are broken down so that they can be eliminated by the body. Some drugs perform their functions and then are excreted from the body intact, but many require metabolism to enable them to reach their target site in an appropriate amount of time, remain there an adequate time, and then be eliminated from the body. This review refers to opioid metabolism; however, the processes described occur with many medications. Altered metabolism in a patient or population can result in an opioid or metabolite leaving the body too rapidly, not reaching its therapeutic target, or staying in the body too long and producing toxic effects. Opioid metabolism results in the production of both inactive and active metabolites. In fact, active metabolites may be more potent than the parent compound. Thus, although metabolism is ultimately a process of detoxification, it produces intermediate products that may have clinically useful activity, be associated with toxicity, or both. Opioids differ with respect to the means by which they are metabolized, and patients differ in their ability to metabolize individual opioids. However, several general patterns of metabolism can be discerned. Most opioids undergo extensive first-pass metabolism in the liver before entering the systemic circulation. First-pass metabolism reduces the bioavailability of the opioid. Opioids are typically lipophilic, which allows them to cross cell membranes to reach target tissues. Drug metabolism is ultimately intended to make a drug hydrophilic to facilitate its excretion in the urine. Opioid metabolism takes place primarily in the liver, which produces enzymes for this purpose. These enzymes promote 2 forms of metabolism: phase 1 metabolism (modification reactions) and phase 2 metabolism (conjugation reactions). Phase 1 metabolism typically subjects the drug to oxidation or hydrolysis. It involves the cytochrome P450 (CYP) enzymes, which facilitate reactions that include N-, O-, and S-dealkylation; aromatic, aliphatic, or N-hydroxylation; N-oxidation; sulfoxidation; deamination; and dehalogenation. Phase 2 metabolism conjugates the drug to hydrophilic substances, such as glucuronic acid, sulfate, glycine, or glutathione. The most important phase 2 reaction is glucuronidation, catalyzed by the enzyme uridine diphosphate glucuronosyltransferase (UGT). Glucuronidation produces molecules that are highly hydrophilic and therefore easily excreted. Opioids undergo varying degrees of phase 1 and 2 metabolism. Phase 1 metabolism usually precedes phase 2 metabolism, but this is not always the case. Both phase 1 and 2 metabolites can be active or inactive. The process of metabolism ends when the molecules are sufficiently hydrophilic to be excreted from the body. Opioids undergo phase 1 metabolism by the CYP pathway, phase 2 metabolism by conjugation, or both. Phase 1 metabolism of opioids mainly involves the CYP3A4 and CYP2D6 enzymes. The CYP3A4 enzyme metabolizes more than 50% of all drugs; consequently, opioids metabolized by this enzyme have a high risk of drug-drug interactions. The CYP2D6 enzyme metabolizes fewer drugs and therefore is associated with an intermediate risk of drug-drug interactions. Drugs that undergo phase 2 conjugation, and therefore have little or no involvement with the CYP system, have minimal interaction potential. The CYP3A4 enzyme is the primary metabolizer of fentanyl10Duragesic (fentanyl transdermal system) [package insert]. Janssen Pharmaceuticals, Inc, Titusville, NJ2008Google Scholar and oxycodone,11OxyContin (oxycodone HCl controlled-release tablets) [package insert]. Purdue Pharma LP, Stamford, CT2007Google Scholar although normally a small portion of oxycodone undergoes CYP2D6 metabolism to oxymorphone (Table 110Duragesic (fentanyl transdermal system) [package insert]. Janssen Pharmaceuticals, Inc, Titusville, NJ2008Google Scholar, 11OxyContin (oxycodone HCl controlled-release tablets) [package insert]. Purdue Pharma LP, Stamford, CT2007Google Scholar, 12Coffman BL King CD Rios GR Tephly TR The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268).Drug Metab Dispos. 1998; 26: 73-77PubMed Google Scholar, 13Codeine Contin (codeine controlled-release tablets) [product monograph]. Purdue Pharma, Pickering, Ontario, Canada2006Google Scholar, 14Hydrocodone [package insert]. Watson Laboratories, Corona, CA2004Google Scholar, 15Methadone hydrochloride tablets [package insert]. Mallinckrodt, Inc, Hazelwood, MO2004Google Scholar, 16Ultram ER (tramadol hydrochloride) [package insert]. Ortho-McNeil, Raritan, NJ2008Google Scholar, 17Dilaudid-HP injection 10 mg (hydromorphone hydrochloride) full prescribing information. Abbott Laboratories, North Chicago, IL2008Google Scholar, 18OPANA ER (oxymorphone hydrochloride extended-release tablets) [package insert]. Endo Pharmaceuticals Inc, Chadds Ford, PA2008Google Scholar). Tramadol undergoes both CYP3A4- and CYP2D6-mediated metabolism.16Ultram ER (tramadol hydrochloride) [package insert]. Ortho-McNeil, Raritan, NJ2008Google Scholar Methadone is primarily metabolized by CYP3A4 and CYP2B6; CYP2C8, CYP2C19, CYP2D6, and CYP2C9 also contribute in varying degrees to its metabolism.19Foster DJ Somogyi AA Bochner F Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4.Br J Clin Pharmacol. 1999; 47: 403-412Crossref PubMed Scopus (173) Google Scholar, 20Totah RA Allen KE Sheffels P Whittington D Kharasch ED Enantiomeric metabolic interactions and stereoselective human methadone metabolism.J Pharmacol Exp Ther. 2007 Apr; 321 (Epub 2007 Jan 26.): 389-399Crossref PubMed Scopus (97) Google Scholar, 21Wang JS DeVane CL Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro.Drug Metab Dispos. 2003; 31: 742-747Crossref PubMed Scopus (145) Google Scholar, 22Li Y Kantelip JP Gerritsen-van Schieveen P Davani S Interindividual variability of methadone response: impact of genetic polymorphism.Mol Diagn Ther. 2008; 12: 109-124Crossref PubMed Scopus (108) Google Scholar, 23Crettol S Déglon JJ Besson J et al.ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment.Clin Pharmacol Ther. 2006; 80: 668-681Crossref PubMed Scopus (222) Google Scholar The complex interplay of methadone with the CYP system, involving as many as 6 different enzymes, is accompanied by considerable interaction potential.TABLE 1Metabolic Pathway/Enzyme InvolvementOpioidPhase 1 metabolismPhase 2 metabolismCommentMorphine12Coffman BL King CD Rios GR Tephly TR The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268).Drug Metab Dispos. 1998; 26: 73-77PubMed Google ScholarNoneGlucuronidation via UGT2B7Codeine13Codeine Contin (codeine controlled-release tablets) [product monograph]. Purdue Pharma, Pickering, Ontario, Canada2006Google ScholarCYP2D6NoneHydrocodone14Hydrocodone [package insert]. Watson Laboratories, Corona, CA2004Google ScholarCYP2D6NoneOne of the metabolites of hydrocodone is hydromorphone, which undergoes phase 2 glucuronidationOxycodone11OxyContin (oxycodone HCl controlled-release tablets) [package insert]. Purdue Pharma LP, Stamford, CT2007Google Scholar CYP3A4CYP2D6NoneOxycodone produces a small amount of oxymorphone, which must undergo subsequent metabolism via glucuronidationMethadone15Methadone hydrochloride tablets [package insert]. Mallinckrodt, Inc, Hazelwood, MO2004Google Scholar CYP3A4CYP2B6CYP2C8CYP2C19CYP2D6CYP2C9NoneCYP3A4 and CYP2B6 are the primary enzymes involved in methadone metabolism; other enzymes play a relatively minor roleTramadol16Ultram ER (tramadol hydrochloride) [package insert]. Ortho-McNeil, Raritan, NJ2008Google Scholar CYP3A4CYP2D6NoneFentanyl10Duragesic (fentanyl transdermal system) [package insert]. Janssen Pharmaceuticals, Inc, Titusville, NJ2008Google ScholarCYP3A4NoneHydromorphone17Dilaudid-HP injection 10 mg (hydromorphone hydrochloride) full prescribing information. Abbott Laboratories, North Chicago, IL2008Google ScholarNoneGlucuronidation via UGT2B7Oxymorphone18OPANA ER (oxymorphone hydrochloride extended-release tablets) [package insert]. Endo Pharmaceuticals Inc, Chadds Ford, PA2008Google ScholarNoneGlucuronidation via UGT2B7CYP = cytochrome P450; UGT2B7 = uridine diphosphate glucuronosyltransferase 2B7. Open table in a new tab CYP = cytochrome P450; UGT2B7 = uridine diphosphate glucuronosyltransferase 2B7. Each of these opioids has substantial interaction potential with other commonly used drugs that are substrates, inducers, or inhibitors of the CYP3A4 enzyme (Table 2).24Zhou SF Xue CC Yu XQ Li C Wang G Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring.Ther Drug Monit. 2007; 29: 687-710Crossref PubMed Scopus (282) Google Scholar, 25Zhou SF Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4.Curr Drug Metab. 2008; 9: 310-322Crossref PubMed Scopus (509) Google Scholar Administration of CYP3A4 substrates or inhibitors can increase opioid concentrations, thereby prolonging and intensifying analgesic effects and adverse opioid effects, such as respiratory depression. Administration of CYP3A4 inducers can reduce analgesic efficacy.10Duragesic (fentanyl transdermal system) [package insert]. Janssen Pharmaceuticals, Inc, Titusville, NJ2008Google Scholar, 11OxyContin (oxycodone HCl controlled-release tablets) [package insert]. Purdue Pharma LP, Stamford, CT2007Google Scholar, 16Ultram ER (tramadol hydrochloride) [package insert]. Ortho-McNeil, Raritan, NJ2008Google Scholar In addition to drugs that interact with CYP3A4, bergamottin (found in grapefruit juice) is a strong inhibitor of CYP3A4,26Girennavar B Jayaprakasha GK Patil BS Potent inhibition of human cytochrome P450 3A4, 2D6, and 2C9 isoenzymes by grapefruit juice and its furocoumarins.J Food Sci. 2007; 72: C417-C421Crossref PubMed Scopus (65) Google Scholar and cafestol (found in unfiltered coffee) is an inducer of the enzyme.27Huber WW Rossmanith W Grusch M et al.Effects of coffee and its chemopreventive components kahweol and cafestol on cytochrome P450 and sulfotransferase in rat liver.Food Chem Toxicol. 2008; 46: 1230-1238Crossref PubMed Scopus (62) Google ScholarTABLE 2Cytochrome P450 3A4 Substrates, Inhibitors, and InducersFrom Ther Drug Monit,24Zhou SF Xue CC Yu XQ Li C Wang G Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring.Ther Drug Monit. 2007; 29: 687-710Crossref PubMed Scopus (282) Google Scholar with permission.SubstratesInhibitorsInducers CCBs AmlodipineDiltiazemFelodipineNicardipineNifedipineVerapamilStatins AtorvastatinLovastatinSimvastatinOther cardiovascular agents AmiodaroneDigoxinIvabradineQuinidineWarfarinPhosphodiesterase inhibitors SildenafilTadalafilBenzodiazepines AlprazolamClonazepamFlunitrazepamMidazolamTriazolamSSRIs CitalopramFluoxetine Other psychiatric drugs AripiprazoleBromocriptineBuspironeCarbamazepineDonepezilHaloperidolMirtazapineNefazodonePimozideReboxetineRisperidoneValproateVenlafaxineZiprasidoneSleep aids ZolpidemZopicloneAntibiotics AzithromycinClarithromycinErythromycinOleandomycinAzole antifungal agents ItraconazoleKetoconazole Antiretroviral agents IndinavirLopinavirNelfinavirNevirapineRitonavirSaquinavirTipranavirChemotherapeutic agents CyclophosphamideDocetaxelDoxorubicinEtoposideGefitinibIfosfamidePaclitaxelTamoxifenTeniposideVinblastineVindesineHormonal therapies EstradiolEthinyl estradiolLevonorgestrelRaloxifeneTestosterone CCBs AmlodipineDiltiazemFelodipineNicardipineNifedipineVerapamilStatin SimvastatinAntiarrhythmic agents AmiodaroneQuinidinePhosphodiesterase inhibitor TadalafilPsychiatric drugs BromocriptineClonazepamDesipramineFluoxetineFluvoxamineHaloperidolNefazodoneNorclomipramineNortriptylineSertraline Antibiotics CiprofloxacinClarithromycinErythromycinJosamycinNorfloxacinOleandomycinRoxithromycinTelithromycinAzole antifungal agents ClotrimazoleFluconazoleItraconazoleKetoconazoleMiconazoleVoriconazoleAntiretroviral agents AmprenavirAtazanavirDelavirdineEfavirenzIndinavirLopinavirRitonavirNelfinavirNevirapineSaquinavirTipranavir Chemotherapeutic agents 4-IpomeanolImatinibIrinotecanTamoxifenHormonal therapies Ethinyl estradiolLevonorgestrelRaloxifeneOther drugs CimetidineDisulfiramMethyl-prednisolonePhenelzineFoods Bergamottin (grapefruit juice)Star fruit Statins AtorvastatinFluvastatinLovastatinSimvastatinAntiretroviral agents EfavirenzLopinavirNevirapineHypnotic agent PentobarbitalAnticonvulsant agents CarbamazepineOxcarbazepinePhenobarbitalPhenytoinPrimidoneValproic acidFood Cafestol (caffeine)CCB = calcium channel blocker; SSRI = selective serotonin reuptake inhibitor. Open table in a new tab CCB = calcium channel blocker; SSRI = selective serotonin reuptake inhibitor. Induction of CYP3A4 may pose an added risk in patients treated with tramadol, which has been associated with seizures when administered within its accepted dosagerange.16Ultram ER (tramadol hydrochloride) [package insert]. Ortho-McNeil, Raritan, NJ2008Google Scholar This risk is most pronounced when tramadol is administered concurrently with potent CYP3A4 inducers, such as carbamazepine, or with selective serotonin reuptake inhibitors, tricyclic antidepressants, or other medications with additive serotonergic effects.16Ultram ER (tramadol hydrochloride) [package insert]. Ortho-McNeil, Raritan, NJ2008Google Scholar The CYP2D6 enzyme is entirely responsible for the metabolism of hydrocodone,14Hydrocodone [package insert]. Watson Laboratories, Corona, CA2004Google Scholar codeine,13Codeine Contin (codeine controlled-release tablets) [product monograph]. Purdue Pharma, Pickering, Ontario, Canada2006Google Scholar and dihydrocodeine to their active metabolites (hydromorphone, morphine, and dihydromorphine, respectively), which in turn undergo phase 2 glucuronidation. These opioids (and to a lesser extent oxycodone, tramadol, and methadone) have interaction potential with selective serotonin reuptake inhibitors, tricyclic antidepressants, β-blockers, and antiarrhythmics; an array of other drugs are substrates, inducers, or inhibitors of the CYP2D6 enzyme (Table 328Flockhart DA Drug interactions: cytochrome P450 drug interaction table. Indiana University School of Medicine.http://medicine.iupui.edu/flockhart/table.htmGoogle Scholar).TABLE 3Cytochrome P450 2D6 Substrates, Inhibitors, and InducersFrom Indiana University School of Medicine,28Flockhart DA Drug interactions: cytochrome P450 drug interaction table. Indiana University School of Medicine.http://medicine.iupui.edu/flockhart/table.htmGoogle Scholar with permission.SubstratesInhibitorsInducers Antiarrhythmic agents EncainideFlecainideLidocaineMexiletinePropafenoneSparteineβ-Blockers AlprenololCarvedilolMetoprololPropranololTimololAntipsychotic agents AripiprazoleHaloperidolPerphenazineRisperidoneThioridazineZuclopenthixolSNRIs DuloxetineVenlafaxine SSRIs FluoxetineFluvoxamineParoxetineTricyclics AmitriptylineAmoxapineClomipramineDesipramineDoxepinImipramineNortriptylineOther drugs AmphetamineChlorpheniramineDebrisoquineDextromethorphanHistamine H1 receptor antagonists MetoclopramidePhenforminTamoxifen Antiarrhythmic agents AmiodaroneQuinidineAntipsychotic agents ChlorpromazineReduced haloperidolLevomepromazineSNRI DuloxetineSSRIs CitalopramEscitalopramFluoxetineParoxetineSertralineTricyclic ClomipramineOther antidepressant/antianxiolytic agents BupropionMoclobemide Antihistamine ChlorpheniramineHistamine H2 receptor antagonists CimetidineRanitidineOther drugs CelecoxibDoxorubicinRitonavirTerbinafine Antibiotic RifampinGlucocorticoid DexamethasoneSNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor. Open table in a new tab SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor. Although CYP2D6-metabolized drugs have lower interaction potential than those metabolized by CYP3A4, genetic factors influencing the activity of this enzyme can introduce substantial variability into the metabolism of hydrocodone, codeine, and to a lesser extent oxycodone. An estimated 5% to 10% of white people possess allelic variants of the CYP2D6 gene that are associated with reduced clearance of drugs metabolized by this isoenzyme,29Evans DA Mahgoub A Sloan TP Idle JR Smith RL A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population.J Med Genet. 1980; 17: 102-105Crossref PubMed Scopus (528) Google Scholar, 30Heiskanen T Olkkola KT Kalso E Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.Clin Pharmacol Ther. 1998; 64: 603-611Crossref PubMed Scopus (212) Google Scholar, 31Bertilsson L Lou YQ Du YL et al.Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin.Clin Pharmacol Ther. 1992; 51: 388-397Crossref PubMed Scopus (419) Google Scholar and between 1% and 7% of white people carry CYP2D6 allelic variants associated with rapid metabolism.32Bathum L Johansson I Ingelman-Sundberg M Hørder M Brosen K Ultrarapid metabolism of sparteine: frequency of alleles with duplicated CYP2D6 genes in a Danish population as determined by restriction fragment length polymorphism and long polymerase chain reaction.Pharmacogenetics. 1998; 8: 119-123Crossref PubMed Google Scholar, 33Løvlie R Daly AK Molven A Idle JR Steen VM Ultrarapid metabolizers of debrisoquine: characterization and PCR-based detection of alleles with duplication of the CYP2D6 gene.FEBS Lett. 1996; 392: 30-34Abstract Full Text PDF PubMed Scopus (192) Google Scholar The prevalence of poor metabolizers is lower in Asian populations (≤1%)34Sohn DR Shin SG Park CW Kusaka M Chiba K Ishizaki T Metoprolol oxidation polymorphism in a Korean population: comparison with native Japanese and Chinese populations.Br J Clin Pharmacol. 1991; 32: 504-507Crossref PubMed Scopus (95) Google Scholar and highly variable in African populations (0%-34%).35Aklillu E Persson I Bertilsson L Johansson I Rodrigues F Ingelman-Sundberg M Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles.J Pharmacol Exp Ther. 1996; 278: 441-446PubMed Google Scholar, 36Bathum L Skjelbo E Mutabingwa TK Madsen H Hørder M Brøsen K Phenotypes and genotypes for CYP2D6 and CYP2C19 in a black Tanzanian population.Br J Clin Pharmacol. 1999; 48: 395-401Crossref PubMed Scopus (53) Google Scholar, 37Relling MV Cherrie J Schell MJ Petros WP Meyer WH Evans WE Lower prevalence of the debrisoquin oxidative poor metabolizer phenotype in American black versus white subjects.Clin Pharmacol Ther. 1991; 50: 308-313Crossref PubMed Scopus (103) Google Scholar, 38Masimirembwa C Persson I Bertilsson L Hasler J Ingelman-Sundberg M A novel mutant variant of the CYP2D6 gene (CYP2D6*17) common in a black African population: association with diminished debrisoquine hydroxylase activity.Br J Clin Pharmacol. 1996; 42: 713-719Crossref PubMed Scopus (175) Google Scholar, 39Mbanefo C Bababunmi EA Mahgoub A Sloan TP Idle JR Smith RL A study of the debrisoquine hydroxylation polymorphism in a Nigerian population.Xenobiotica. 1980; 10: 811-818Crossref PubMed Scopus (58) Google Scholar The prevalence of rapid metabolizers of opioids has not been reported in Asian populations; estimates in African populations are high but variable (9%-30%).35Aklillu E Persson I Bertilsson L Johansson I Rodrigues F Ingelman-Sundberg M Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles.J Pharmacol Exp Ther. 1996; 278: 441-446PubMed Google Scholar, 36Bathum L Skjelbo E Mutabingwa TK Madsen H Hørder M Brøsen K Phenotypes and genotypes for CYP2D6 and CYP2C19 in a black Tanzanian population.Br J Clin Pharmacol. 1999; 48: 395-401Crossref PubMed Scopus (53) Google Scholar The clinical effects of CYP2D6 allelic variants can be seen with codeine administration. Patients who are poor opioid metabolizers experience reduced efficacy with codeine because they have a limited ability to metabolize codeine into the active molecule, morphine. In contrast, patients who are rapid