REVIEW Opioid Metabolism HOWARD S. SMITH, MD Clinicians undeistand that Individual patients differ In their re- Experienced clinicians are aware that the efficacy and sponse to specific opioid analgesics and that patients may require trials of several opioids tiefbre finding an agent that provides tolerability of specific opioids may vary dramatically effective analgesia with acceptahle tolerahlllty. Reasons fer this among patients and that trials of several opioids may be variability Include factors that are not clearly understood, such as needed before finding one that provides an acceptable bal- allellc variants that dictate the complement of opioid receptors and sutttle differences In the receptor-binding profiles of opioids. ance of analgesia and tolerability for an individual patient,*"' However, aitered opioid metaboiism may aiso infiuence response Pharmacodynamic and pharmacokinetic differences under- In terms of efficacy and toierabllity, and severai fectors contribut- lie this variability of response. Pharmacodynamics refers to ing to this metaboiic variability have been identified. For exampie, the risk of drug Interactions with an opioid is determined iargeiy by how a drug affects the body, whereas pharmacokinetics which enzyme systems metabolize the opioid. The rate and path- describes how the body alters the drug, ways of opioid metaboiism may also be infiuenced by genetic Pharmacokinetics contributes to the factors, race, and medicai conditions (most notabiy iiver or kidney For editorial disease). This review describes the basics of opioid metaboiism variability in response to opioids by af- comment, as weli as the factors Infiuencing it and provides recommenda- fecting the bioavailability of a drug, the see page 572 tions for addressing metaboiic issues that may compromise effec- production of active or inactive metabo- tive pain management. Articies cited in this review were identified lites, and their elimination from the body. Pharmacodynamic via a search of iVIEDUNE, EiVflBASE, and PubMed. Articies se- iected fer Inciusion discussed gênerai physioiogic aspects of factors contributing to variability of response to opioids opioid metaboiism, metaboiic characteristics of specific opioids, include between-patient differences in specific opioid recep- patient-specific factors infiuencing drug metaboiism, drug interac- tors and between-opioid differences in binding to receptor tions, and adverse events. subtypes. The receptor binding of opioids is imperfectly Mayo Clin Proc. 2009;84<7):613-624 understood; hence, matching individual patients with spe- cific opioids to optimize efficacy and tolerability remains a CYP = cytochrome P450; Ml = (Mesmethyttramadol; M3G = morphlne- 3^ucuronlde; M6G = niorphin»€-glucuronide; UGT = uridlne dlphos- trial-and-error procedure,*"' phate glucuronosyltransferase This review primarily considers drug metabolism in the context of pharmacokinetics. It summarizes the basics of opioid metabolism; discusses the potential influences of pioids are a cornerstone of the management of cancer patient-specific factors such as age, genetics, comorbid Opain' and postoperative pain^ and are used increas- conditions, and concomitant medications; and explores the ingly for the management of chronic noncancer pain,'''* differences in metabolism between specific opioids. It aims Understanding the metabolism of opioids is of great practi- to equip physicians with an understanding of opioid me- cal importance to primary care clinicians, Opioid metabo- tabolism that will guide safe and appropriate prescribing, lism is a vital safety consideration in older and medically permit anticipation and avoidance of adverse drug-drug complicated patients, who may be taking multiple medica- interactions, identify and accommodate patient-specific tions and may have inflammation, impaired renal and he- metabolic concerns, rationalize treatment failure, inform patic function, and impaired immunity. Chronic pain, such opioid switching and rotation strategies, and facilitate as lower back pain, also occurs in younger persons and is the therapeutic monitoring. To that end, recommendations for leading cause of disability in Americans younger than 45 tailoring opioid therapy to individual patients and specific years.' In younger patients, physicians may be more con- populations will be included, cerned with opioid metabolism in reference to development of tolerance, impairment of skills and mental function, ad- verse events during pregnancy and lactation, and prevention METHODS of abuse by monitoring drug and metabolite levels. 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 From the Department of Anesthesiology, Albany Medical Coiiege, Albany, NY. medication search terms used were as follows: codeine, Individual reprints of this articie are not avaiiabie. Address con-espondence to Howard S. Smith, MD, Department of Anesthesiology, Albany Medicai College, fentanyl, hydrocodone, hydromorphone, methadone, mor- 47 New Scotland Ave, MC-131, Albany, NY 12208 (smithh@maii,amc.edu). phine, opioid, opioid analgesic, oxycodone, oxymorphone, © 2009 Mayo Foundation for Medical Education and Research and tramadol. Each medication search term was combined Mayo Clin Proc. July 2W9;84(7):613-624 wwwmayoclinicproceedings.com 613 OPIOID METABOLISM with the following general search terms: metabolism, active glucuronidation, catalyzed by the enzyme uridine diphos- metabolites, pharmacokinetics, lipophilicity, physio- phate glucuronosyltransferase (UGT). Glucuronidation chemical properties, pharmacology, genetics, receptor, re- produces molecules that are highly hydrophilic and there- ceptor binding, receptor genetics or variation, transporter, fore easily excreted. Opioids undergo varying degrees of formulations, AND adverse effects, safety, or toxicity. The phase 1 and 2 metabolism. Phase 1 metabolism usually reference lists of relevant papers were examined for addi- precedes phase 2 metabolism, but this is not always the case. tional articles of interest. Both phase 1 and 2 metabolites can be active or inactive. The process of metabolism ends when the molecules are suffi- ciently hydrophilic to be excreted from the body. BASICS OF OPIOID METABOLISM Metabolism refers to the process of biotransformation by FACTORS INFLUENCING OPIOID METABOLISM which drugs are broken down so that they can be elimi- nated by the body. Some drugs perform their functions and PATHWAYS then are excreted from the body intact, but many require Opioids undergo phase 1 metabolism by the CYP pathway, metabolism to enable them to reach their target site in an phase 2 metabolism by conjugation, or both. Phase 1 me- appropriate amount of time, remain there an adequate time, tabolism of opioids mainly involves the CYP3A4 and and then be eliminated from the body. This review refers to CYP2D6 enzymes. The CYP3A4 enzyme metabolizes opioid metabolism; however, the processes described oc- more than 50% of all drugs; consequently, opioids metabo- cur with many medications. lized by this enzyme have a high risk of drug-drug interac- Altered metabolism in a patient or population can result tions. The CYP2D6 enzyme metabolizes fewer drugs and in an opioid or metabolite leaving the body too rapidly, not therefore is associated with an intermediate risk of drug- reaching its therapeutic target, or staying in the body too drug interactions. Drugs that undergo phase 2 conjugation, long and producing toxic effects. Opioid metabolism re- and therefore have little or no involvement with the CYP sults in the production of both inactive and active metabo- system, have minimal interaction potential. lites. In fact, active metabolites may be more potent than the parent compound. Thus, although metabolism is ulti- PHASE 1 METABOUSM mately a process of detoxification, it produces intermediate The CYP3A4 enzyme is the primary metabolizer of fenta- products that may have clinically useful activity, be associ- nyl'" and oxycodone," although normally a small portion of ated with toxicity, or both. oxycodone undergoes CYP2D6 metabolism to oxymor- Opioids differ with respect to the means by which they phone (Table 1'"-'*). Tramadol undergoes both CYP3A4- are metabolized, and patients differ in their ability to me- and CYP2D6-mediated metabolism.'* Methadone is prima- tabolize individual opioids. However, several general pat- rily metabolized by CYP3A4 and CYP2B6; CYP2C8, terns of metabolism can be discerned. Most opioids un- CYP2C19, CYP2D6, and CYP2C9 also contribute in vary- dergo extensive first-pass metabolism in the liver before ing degrees to its metabolism.""^ The complex interplay of entering the systemic circulation. First-pass metabolism methadone with the CYP system, involving as many as 6 reduces the bioavailability of the opioid. Opioids are typi- different enzymes, is accompanied by considerable interac- cally lipophilic, which allows them to cross cell mem- tion potential. branes to reach target tissues. Drug metabolism is ulti- Each of these opioids has substantial interaction poten- mately intended to make a drug hydrophil ic to facilitate its tial with other commonly used drugs that are substrates, excretion in the urine. Opioid metabolism takes place pri- inducers, or inhibitors of the CYP3A4 enzyme (Table marily in the liver, which produces enzymes for this pur- 2) 2425 Administration of CYP3A4 substrates or inhibitors pose. These enzymes promote 2