REVIEW
`OPIOID METABOLISM
`
`Opioid Metabolism
`
`HOWARD S. SMITH, MD
`
`Clinicians understand that individual patients differ in their re-
`sponse 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 contribut-
`ing 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 path-
`ways 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 recommenda-
`tions for addressing metabolic issues that may compromise effec-
`tive pain management. Articles cited in this review were identified
`via a search of MEDLINE, EMBASE, and PubMed. Articles se-
`lected for inclusion discussed general physiologic aspects of
`opioid metabolism, metabolic characteristics of specific opioids,
`patient-specific factors influencing drug metabolism, drug interac-
`tions, and adverse events.
`Mayo Clin Proc. 2009;84(7):613-624
`
`CYP = cytochrome P450; M1 = O-desmethyltramadol; M3G = morphine-
`3-glucuronide; M6G = morphine-6-glucuronide; UGT = uridine diphos-
`phate glucuronosyltransferase
`
`Opioids are a cornerstone of the management of cancer
`
`pain1 and postoperative pain2 and are used increas-
`ingly for the management of chronic noncancer pain.3,4
`Understanding the metabolism of opioids is of great practi-
`cal importance to primary care clinicians. Opioid metabo-
`lism is a vital safety consideration in older and medically
`complicated patients, who may be taking multiple medica-
`tions and may have inflammation, impaired renal and he-
`patic 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.5 In younger patients, physicians may be more con-
`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
`of abuse by monitoring drug and metabolite levels.
`
`From the Department of Anesthesiology, Albany Medical College, Albany, NY.
`
`This article is freely available on publication.
`
`Individual reprints of this article are not available. Address correspondence to
`Howard S. Smith, MD, Department of Anesthesiology, Albany Medical College,
`47 New Scotland Ave, MC-131, Albany, NY 12208 (smithh@mail.amc.edu).
`
`© 2009 Mayo Foundation for Medical Education and Research
`
`For editorial
`comment,
`see page 572
`
`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 bal-
`ance of analgesia and tolerability for an individual patient.6-9
`Pharmacodynamic and pharmacokinetic differences under-
`lie 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 af-
`fecting the bioavailability of a drug, the
`production of active or inactive metabo-
`lites, and their elimination from the body. Pharmacodynamic
`factors contributing to variability of response to opioids
`include between-patient differences in specific opioid recep-
`tors and between-opioid differences in binding to receptor
`subtypes. The receptor binding of opioids is imperfectly
`understood; hence, matching individual patients with spe-
`cific opioids to optimize efficacy and tolerability remains a
`trial-and-error procedure.6-9
`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 me-
`tabolism 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.
`
`METHODS
`
`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, mor-
`phine, opioid, opioid analgesic, oxycodone, oxymorphone,
`and tramadol. Each medication search term was combined
`
`Mayo Clin Proc. • July 2009;84(7):613-624 • www.mayoclinicproceedings.com
`
`For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
`
`613
`
`1
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`

`

`OPIOID METABOLISM
`
`with the following general search terms: metabolism, active
`metabolites, pharmacokinetics, lipophilicity, physio-
`chemical properties, pharmacology, genetics, receptor, re-
`ceptor binding, receptor genetics or variation, transporter,
`formulations, AND adverse effects, safety, or toxicity. The
`reference lists of relevant papers were examined for addi-
`tional articles of interest.
`
`BASICS OF OPIOID METABOLISM
`
`Metabolism refers to the process of biotransformation by
`which drugs are broken down so that they can be elimi-
`nated 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 oc-
`cur 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 re-
`sults in the production of both inactive and active metabo-
`lites. In fact, active metabolites may be more potent than
`the parent compound. Thus, although metabolism is ulti-
`mately a process of detoxification, it produces intermediate
`products that may have clinically useful activity, be associ-
`ated with toxicity, or both.
`Opioids differ with respect to the means by which they
`are metabolized, and patients differ in their ability to me-
`tabolize individual opioids. However, several general pat-
`terns of metabolism can be discerned. Most opioids un-
`dergo extensive first-pass metabolism in the liver before
`entering the systemic circulation. First-pass metabolism
`reduces the bioavailability of the opioid. Opioids are typi-
`cally lipophilic, which allows them to cross cell mem-
`branes to reach target tissues. Drug metabolism is ulti-
`mately intended to make a drug hydrophilic to facilitate its
`excretion in the urine. Opioid metabolism takes place pri-
`marily in the liver, which produces enzymes for this pur-
`pose. 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 oxida-
`tion 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 diphos-
`phate glucuronosyltransferase (UGT). Glucuronidation
`produces molecules that are highly hydrophilic and there-
`fore 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 suffi-
`ciently hydrophilic to be excreted from the body.
`
`FACTORS INFLUENCING OPIOID METABOLISM
`
`METABOLIC PATHWAYS
`Opioids undergo phase 1 metabolism by the CYP pathway,
`phase 2 metabolism by conjugation, or both. Phase 1 me-
`tabolism of opioids mainly involves the CYP3A4 and
`CYP2D6 enzymes. The CYP3A4 enzyme metabolizes
`more than 50% of all drugs; consequently, opioids metabo-
`lized by this enzyme have a high risk of drug-drug interac-
`tions. 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.
`
`PHASE 1 METABOLISM
`The CYP3A4 enzyme is the primary metabolizer of fenta-
`nyl10 and oxycodone,11 although normally a small portion of
`oxycodone undergoes CYP2D6 metabolism to oxymor-
`phone (Table 110-18). Tramadol undergoes both CYP3A4-
`and CYP2D6-mediated metabolism.16 Methadone is prima-
`rily metabolized by CYP3A4 and CYP2B6; CYP2C8,
`CYP2C19, CYP2D6, and CYP2C9 also contribute in vary-
`ing degrees to its metabolism.19-23 The complex interplay of
`methadone with the CYP system, involving as many as 6
`different enzymes, is accompanied by considerable interac-
`tion potential.
`Each of these opioids has substantial interaction poten-
`tial with other commonly used drugs that are substrates,
`inducers, or inhibitors of the CYP3A4 enzyme (Table
`2).24,25 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.10,11,16 In addition to
`drugs that interact with CYP3A4, bergamottin (found in
`grapefruit juice) is a strong inhibitor of CYP3A4,26 and
`cafestol (found in unfiltered coffee) is an inducer of the
`enzyme.27
`Induction of CYP3A4 may pose an added risk in pa-
`tients treated with tramadol, which has been associated
`with seizures when administered within its accepted dos-
`
`614
`
`Mayo Clin Proc. • July 2009;84(7):613-624 • www.mayoclinicproceedings.com
`
`For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
`
`2
`
`

`

`TABLE 1. Metabolic Pathway/Enzyme Involvement
`
`Opioid
`
`Phase 1
`metabolism
`
`Phase 2
`metabolism
`
`Comment
`
`OPIOID METABOLISM
`
`One of the metabolites of hydrocodone is hydromorphone,
`which undergoes phase 2 glucuronidation
`Oxycodone produces a small amount of oxymorphone,
`which must undergo subsequent metabolism via glucuronidation
`CYP3A4 and CYP2B6 are the primary enzymes involved in
`methadone metabolism; other enzymes play a relatively minor role
`
`Morphine12
`
`None
`
`Codeine13
`Hydrocodone14
`
`Oxycodone11
`
`Methadone15
`
`Tramadol16
`
`Fentanyl10
`Hydromorphone17
`
`CYP2D6
`CYP2D6
`
`CYP3A4
`CYP2D6
`CYP3A4
`CYP2B6
`CYP2C8
`CYP2C19
`CYP2D6
`CYP2C9
`CYP3A4
`CYP2D6
`CYP3A4
`None
`
`Oxymorphone18
`
`None
`
`Glucuronidation
`via UGT2B7
`None
`None
`
`None
`
`None
`
`None
`
`None
`Glucuronidation
`via UGT2B7
`Glucuronidation
`via UGT2B7
`
`CYP = cytochrome P450; UGT2B7 = uridine diphosphate glucuronosyltransferase 2B7.
`
`age range.16 This risk is most pronounced when tramadol is
`administered concurrently with potent CYP3A4 inducers,
`such as carbamazepine, or with selective serotonin re-
`uptake inhibitors, tricyclic antidepressants, or other medi-
`cations with additive serotonergic effects.16
`The CYP2D6 enzyme is entirely responsible for the
`metabolism of hydrocodone,14 codeine,13 and dihydro-
`codeine to their active metabolites (hydromorphone, mor-
`phine, 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 in-
`hibitors, tricyclic antidepressants, β-blockers, and anti-
`arrhythmics; an array of other drugs are substrates, induc-
`ers, or inhibitors of the CYP2D6 enzyme (Table 328).
`Although CYP2D6-metabolized drugs have lower inter-
`action potential than those metabolized by CYP3A4, ge-
`netic 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 re-
`duced clearance of drugs metabolized by this isoenzyme,29-31
`and between 1% and 7% of white people carry CYP2D6
`allelic variants associated with rapid metabolism.32,33 The
`prevalence of poor metabolizers is lower in Asian popula-
`tions (≤1%)34 and highly variable in African populations
`(0%-34%).35-39 The prevalence of rapid metabolizers of
`opioids has not been reported in Asian populations; esti-
`mates in African populations are high but variable (9%-
`30%).35,36
`
`The clinical effects of CYP2D6 allelic variants can be
`seen with codeine administration. Patients who are poor
`opioid metabolizers experience reduced efficacy with co-
`deine because they have a limited ability to metabolize
`codeine into the active molecule, morphine. In contrast,
`patients who are rapid opioid metabolizers may experience
`increased opioid effects with a usual dose of codeine be-
`cause their rapid metabolism generates a higher concen-
`tration of morphine.40 Allelic variants altering CYP2D6-
`mediated metabolism can be associated with reduced
`efficacy of hydrocodone or increased toxicity of codeine,
`each of which relies entirely on the CYP2D6 enzyme for
`phase 1 metabolism.41,42 In patients treated with oxycodone,
`which relies on CYP3A4 and to a lesser extent on CYP2D6,
`inhibition of CYP2D6 activity by quinidine increases
`noroxycodone levels and reduces oxymorphone production.
`In one study, such alterations were not accompanied by
`increased adverse events.30 However, individual cases of
`reduced oxycodone efficacy42 or increased toxicity41 in
`CYP2D6 poor metabolizers have been reported.
`
`PHASE 2 METABOLISM
`Morphine, oxymorphone, and hydromorphone are each
`metabolized by phase 2 glucuronidation17,18,43 and therefore
`have little potential for metabolically based drug interac-
`tions. Oxymorphone, for example, has no known pharma-
`cokinetic drug-drug interactions,18 and morphine has few.43
`Of course, pharmacodynamic drug-drug interactions are
`possible with all opioids, such as additive interactions with
`benzodiazepines, antihistamines, or alcohol, and antago-
`nistic interactions with naltrexone or naloxone.
`
`Mayo Clin Proc. • July 2009;84(7):613-624 • www.mayoclinicproceedings.com
`
`For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
`
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`OPIOID METABOLISM
`
`TABLE 2. Cytochrome P450 3A4 Substrates, Inhibitors, and Inducers
`
`Substrates
`
`Other psychiatric
`drugs
`Aripiprazole
`Bromocriptine
`Buspirone
`Carbamazepine
`Donepezil
`Haloperidol
`Mirtazapine
`Nefazodone
`Pimozide
`Reboxetine
`Risperidone
`Valproate
`Venlafaxine
`Ziprasidone
`Sleep aids
`Zolpidem
`Zopiclone
`Antibiotics
`Azithromycin
`Clarithromycin
`Erythromycin
`Oleandomycin
`Azole antifungal
`agents
`Itraconazole
`Ketoconazole
`
`Antiretroviral
`agents
`Indinavir
`Lopinavir
`Nelfinavir
`Nevirapine
`Ritonavir
`Saquinavir
`Tipranavir
`Chemotherapeutic
`agents
`Cyclophosphamide
`Docetaxel
`Doxorubicin
`Etoposide
`Gefitinib
`Ifosfamide
`Paclitaxel
`Tamoxifen
`Teniposide
`Vinblastine
`Vindesine
`Hormonal therapies
`Estradiol
`Ethinyl estradiol
`Levonorgestrel
`Raloxifene
`Testosterone
`
`CCBs
`Amlodipine
`Diltiazem
`Felodipine
`Nicardipine
`Nifedipine
`Verapamil
`Statin
`Simvastatin
`Antiarrhythmic
`agents
`Amiodarone
`Quinidine
`Phosphodiesterase
`inhibitor
`Tadalafil
`Psychiatric drugs
`Bromocriptine
`Clonazepam
`Desipramine
`Fluoxetine
`Fluvoxamine
`Haloperidol
`Nefazodone
`Norclomipra-
`mine
`Nortriptyline
`Sertraline
`
`Inhibitors
`
`Antibiotics
`Ciprofloxacin
`Clarithromycin
`Erythromycin
`Josamycin
`Norfloxacin
`Oleandomycin
`Roxithromycin
`Telithromycin
`Azole antifungal
`agents
`Clotrimazole
`Fluconazole
`Itraconazole
`Ketoconazole
`Miconazole
`Voriconazole
`Antiretroviral
`agents
`Amprenavir
`Atazanavir
`Delavirdine
`Efavirenz
`Indinavir
`Lopinavir
`Ritonavir
`Nelfinavir
`Nevirapine
`Saquinavir
`Tipranavir
`
`CCBs
`Amlodipine
`Diltiazem
`Felodipine
`Nicardipine
`Nifedipine
`Verapamil
`Statins
`Atorvastatin
`Lovastatin
`Simvastatin
`Other cardio-
`vascular agents
`Amiodarone
`Digoxin
`Ivabradine
`Quinidine
`Warfarin
`Phosphodiesterase
`inhibitors
`Sildenafil
`Tadalafil
`Benzodiazepines
`Alprazolam
`Clonazepam
`Flunitrazepam
`Midazolam
`Triazolam
`SSRIs
`Citalopram
`Fluoxetine
`
`CCB = calcium channel blocker; SSRI = selective serotonin reuptake inhibitor.
`From Ther Drug Monit,24 with permission.
`
`Chemotherapeutic
`agents
`4-Ipomeanol
`Imatinib
`Irinotecan
`Tamoxifen
`Hormonal therapies
`Ethinyl estradiol
`Levonorgestrel
`Raloxifene
`Other drugs
`Cimetidine
`Disulfiram
`Methyl-
`prednisolone
`Phenelzine
`Foods
`Bergamottin
`(grapefruit
`juice)
`Star fruit
`
`Inducers
`
`Statins
`Atorvastatin
`Fluvastatin
`Lovastatin
`Simvastatin
`Antiretroviral
`agents
`Efavirenz
`Lopinavir
`Nevirapine
`Hypnotic agent
`Pentobarbital
`Anticonvulsant
`agents
`Carbamazepine
`Oxcarbazepine
`Phenobarbital
`Phenytoin
`Primidone
`Valproic acid
`Food
`Cafestol
`(caffeine)
`
`However, the enzymes responsible for glucuronida-
`tion reactions may also be subject to a variety of factors
`that may alter opioid metabolism. The most important
`UGT enzyme involved in the metabolism of opioids that
`undergo glucuronidation (eg, morphine, hydromorphone,
`oxymorphone)12,44 is UGT2B7. Research suggests that
`UGT2B7-mediated opioid metabolism may be altered by
`interactions with other drugs that are either substrates or
`inhibitors of this enzyme.45 Moreover, preliminary data
`indicate that UGT2B7 metabolism of morphine may be
`potentiated by CYP3A4, although the clinical relevance of
`this finding is unknown.46-48
`The activity of UGT2B7 shows significant between-
`patient variability, and several authors have identified al-
`lelic variants of the gene encoding this enzyme.12,44 Al-
`though the functional importance of these allelic variants
`with respect to glucuronidation of opioids is unknown, at
`least 2 allelic variants (the UGT2B7-840G and -79 alleles)
`have been linked to substantial reduction of morphine
`glucuronidation, with resulting accumulation of morphine
`and reduction in metabolite formation.49,50 Moreover, re-
`search has shown that variation in the amount of messenger
`RNA for hepatic nuclear factor 1α, a transcription factor
`
`responsible for regulating expression of the UGT2B7 gene,
`is associated with interindividual variation in UGT2B7
`enzyme activity.51
`
`CLINICAL IMPLICATIONS OF METABOLIC PATHWAYS
`Most opioids are metabolized via CYP-mediated oxidation
`and have substantial drug interaction potential. The excep-
`tions are morphine, hydromorphone, and oxymorphone,
`which undergo glucuronidation. In patients prescribed
`complicated treatment regimens, physicians may consider
`initiating treatment with an opioid that is not metabolized
`by the CYP system. However, interactions between opioids
`that undergo CYP-mediated metabolism and other drugs
`involved with this pathway often can be addressed by
`careful dose adjustments, vigilant therapeutic drug moni-
`toring, and prompt medication changes in the event of
`serious toxicity.
`Response to individual opioids varies substantially, and
`factors contributing to this variability are not clearly under-
`stood. Because an individual patient’s response to a given
`opioid cannot be predicted, it may be necessary to adminis-
`ter a series of opioid trials before finding an agent that
`provides effective analgesia with acceptable tolerability.6-9
`
`616
`
`Mayo Clin Proc. • July 2009;84(7):613-624 • www.mayoclinicproceedings.com
`
`For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
`
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`

`OPIOID METABOLISM
`
`Inducers
`
`Antibiotic
`Rifampin
`Glucocorticoid
`Dexamethasone
`
`TABLE 3. Cytochrome P450 2D6 Substrates, Inhibitors, and Inducers
`
`Inhibitors
`
`Antihistamine
`Chlorpheniramine
`Histamine H2 receptor antagonists
`Cimetidine
`Ranitidine
`Other drugs
`Celecoxib
`Doxorubicin
`Ritonavir
`Terbinafine
`
`Substrates
`
`SSRIs
`Fluoxetine
`Fluvoxamine
`Paroxetine
`Tricyclics
`Amitriptyline
`Amoxapine
`Clomipramine
`Desipramine
`Doxepin
`Imipramine
`Nortriptyline
`Other drugs
`Amphetamine
`Chlorpheniramine
`Debrisoquine
`Dextromethorphan
`Histamine H1 receptor antagonists
`Metoclopramide
`Phenformin
`Tamoxifen
`
`Antiarrhythmic agents
`Encainide
`Flecainide
`Lidocaine
`Mexiletine
`Propafenone
`Sparteine
`β-Blockers
`Alprenolol
`Carvedilol
`Metoprolol
`Propranolol
`Timolol
`Antipsychotic agents
`Aripiprazole
`Haloperidol
`Perphenazine
`Risperidone
`Thioridazine
`Zuclopenthixol
`SNRIs
`Duloxetine
`Venlafaxine
`
`Antiarrhythmic agents
`Amiodarone
`Quinidine
`Antipsychotic agents
`Chlorpromazine
`Reduced haloperidol
`Levomepromazine
`SNRI
`Duloxetine
`SSRIs
`Citalopram
`Escitalopram
`Fluoxetine
`Paroxetine
`Sertraline
`Tricyclic
`Clomipramine
`Other antidepressant/
`antianxiolytic agents
`Bupropion
`Moclobemide
`
`SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor.
`From Indiana University School of Medicine,28 with permission.
`
`In some patients, the most effective and well-tolerated
`opioid will be one that undergoes CYP-mediated metabo-
`lism. For example, in a 2001 clinical trial, 50 patients with
`cancer who did not respond to morphine or were unable to
`tolerate it were switched to methadone, which undergoes
`complex metabolism involving up to 6 CYP enzymes.
`Adequate analgesia with acceptable tolerability was ob-
`tained in 40 (80%) of these patients.52
`In short, for some patients, selecting an opioid without
`considerable potential for drug interactions may not be
`possible. Under such conditions, an understanding of
`opioid metabolism can guide dose adjustments or the selec-
`tion of a different opioid when analgesia is insufficient or
`adverse events are intolerable.
`
`PRODUCTION OF ACTIVE METABOLITES
`
`Some opioids produce multiple active metabolites after
`administration (Table 410,11,16-18,28,43,53-60). Altered metabo-
`lism due to medical comorbidities, genetic factors, or drug-
`drug interactions may disrupt the balance of metabolites,
`thereby altering the efficacy and/or tolerability of the drug.
`Moreover, opioids that produce metabolites chemically
`identical to other opioid medications may complicate the
`interpretation of urine toxicology screening.
`
`CODEINE
`Codeine is a prodrug that exerts its analgesic effects after
`metabolism to morphine. Patients who are CYP2D6 poor or
`
`rapid metabolizers do not respond well to codeine. Codeine
`toxicity has been reported in CYP2D6 poor metabolizers
`who are unable to form the morphine metabolite42 and in
`rapid metabolizers who form too much morphine.61,62 In fact,
`a recent study found that adverse effects of codeine are
`present irrespective of morphine concentrations in both poor
`and rapid metabolizers,63 suggesting that a substantial pro-
`portion of patients with CYP2D6 allelic variants predispos-
`ing to poor or rapid codeine metabolism will experience the
`adverse effects of codeine without benefitting from any of its
`analgesic effects. Codeine is also metabolized by an un-
`known mechanism to produce hydrocodone in quantities
`reaching up to 11% of the codeine concentration found in
`urinalysis.58 The clinical effect of the hydrocodone metabo-
`lite of codeine is unknown.
`
`MORPHINE
`In addition to its pharmacologically active parent compound,
`morphine is glucuronidated to 2 metabolites with potentially
`important differences in efficacy, clearance, and toxicity:
`morphine-6-glucuronide (M6G) and morphine-3-glucu-
`ronide (M3G). Morphine may also undergo minor routes of
`metabolism, including N-demethylation to normorphine or
`normorphine 6-glucuronide, diglucuronidation to morphine-
`3, 6-diglucuronide, and formation of morphine ethereal sul-
`fate. A recent study found that a small proportion of
`morphine is also metabolized to hydromorphone,55 al-
`though there are no data suggesting a meaningful clinical
`effect.
`
`Mayo Clin Proc. • July 2009;84(7):613-624 • www.mayoclinicproceedings.com
`
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`OPIOID METABOLISM
`
`Opioid
`
`Inactive metabolites
`
`Active metabolites
`identical to pharmaceutical opioids
`
`Active metabolites
`that are not pharmaceutical opioids
`
`TABLE 4. Major Opioid Metabolites
`
`Morphine28,43,53-55
`
`Normorphine
`
`Hydromorphonea
`
`None
`Hydromorphone
`Hydrocodonea
`Morphine
`Oxymorphone
`None
`None
`None
`None
`
`Morphone-3-G glucuronide
`Morphone-6-G glucuronide
`Hydromorphone-3-glucuronide
`None
`None
`
`Noroxycodone
`6-Hydroxy-oxymorphone
`None
`O-desmethyltramadol
`None
`
`Hydromorphone17
`Hydrocodone56
`Codeine57,58
`
`Minor metabolites
`Norhydrocodone
`Norcodeine
`
`Oxycodone11
`Oxymorphone18
`Fentanyl10
`Tramadol16
`Methadone59
`
`None
`Oxymorphone-3-glucuronide
`Norfentanyl
`Nortramadol
`2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine
`2-Ethyl-5-methyl-3,3-diphenylpyrroline
`Heroin60
`Normorphine
`Morphine
`6-Monoacetylmorphine
`a Only very low levels are seen in the urine: less than 11% for hydrocodone after codeine administration and less than 2.5% for hydromorphone after
`morphine administration.53,54,58
`
`Like morphine, M6G is a µ-opioid receptor agonist with
`potent analgesic activity. However, morphine has greater
`affinity than M6G for the µ
`2-opioid receptor thought to be
`responsible for many of the adverse effects of µ-receptor
`agonists,64,65 most notably respiratory depression, gas-
`trointestinal effects, and sedation.65,66 Although the affini-
`ties of morphine and M6G for the µ
`1-opioid receptor are
`similar, a study of low-dose morphine, M6G, and M3G
`found that morphine had greater analgesic efficacy.67 The
`M3G metabolite of morphine lacks analgesic activity, but it
`exhibits neuroexcitatory effects in animals and has been
`proposed as a potential cause of such adverse effects as
`allodynia, myoclonus, and seizures in humans.68-70 In a
`clinical trial, however, low-dose M3G exhibited no analge-
`sic effects, did not potentiate the analgesic effects of mor-
`phine or M6G, and did not produce adverse effects.67
`Clinical data regarding morphine and its glucuronide
`metabolites are unclear. Two studies found no correlation
`between plasma concentrations of morphine, M6G, or
`M3G in either clinical efficacy or tolerability.71,72 More-
`over, in patients with impaired renal function, the pharma-
`cokinetics of morphine appear to be less affected than that
`of its M6G and M3G metabolites, which were found to
`accumulate.73-76 Although M6G appears to be better toler-
`ated than morphine, increased toxicity in patients with
`reduced clearance was primarily related to the accumula-
`tion of the M6G metabolite.
`
`HYDROMORPHONE
`The production of active metabolites is also an issue with
`hydromorphone. The primary metabolite of hydromor-
`phone, hydromorphone-3-glucuronide, has neuroexcitatory
`potential similar to68,70 or greater than69 the M3G metabolite
`of morphine. Clinical data on the neuroexcitatory potential
`of hydromorphone during long-term therapy are unavail-
`able. However, hydromorphone is available only in short-
`
`acting formulations and extended-release formulations are
`recommended in patients with chronic pain requiring long-
`term therapy.3,4
`
`TRAMADOL
`Like codeine, tramadol requires metabolism to an active
`metabolite, O-desmethyltramadol (M1), to be fully effec-
`tive. The parent compound relies on both CYP3A4 and
`CYP2D6, with metabolism of M1 relying on CYP2D6.16 In
`a group of patients receiving multiple medications and
`treated with tramadol under steady-state conditions, the
`concentration of M1 after correcting for dose and the M1/
`tramadol ratio were each approximately 14-fold higher in
`patients with a CYP2D6 allelic variant associated with
`extensive metabolism than in poor metabolizers.77 Both
`tramadol and its M1 metabolite exert analgesic effects
`through opioidergic mechanisms (µ-opioid receptor) and
`through 2 nonopioidergic mechanisms, serotonin reuptake
`inhibition and norepinephrine reuptake inhibition. Al-
`though M1 has more potent activity at the µ-opioid recep-
`tor,16,78 tramadol is the more potent inhibitor of serotonin
`and norepinephrine reuptake and the more potent promoter
`of serotonin and norepinephrine efflux.79,80 Although the
`precise function of M1 in humans remains unclear,
`tramadol-mediated analgesia appears to depend on the
`complementary contributions of an active metabolite with
`a route of metabolism that differs from that of the parent
`compound.
`
`OXYCODONE
`Oxycodone is metabolized by CYP3A4 to noroxycodone
`and by CYP2D6 to oxymorphone.11 Noroxycodone is a
`weaker opioid agonist than the parent compound, but the
`presence of this active metabolite increases the potential
`for interactions with other drugs metabolized by the
`CYP3A4 pathway. The central opioid effects of oxycodone
`
`618
`
`Mayo Clin Proc. • July 2009;84(7):613-624 • www.mayoclinicproceedings.com
`
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`
`6
`
`

`

`are governed primarily by the parent drug, with a negli-
`gible contribution from its circulating oxidative and re-
`ductive metabolites.81 Oxymorphone is present only in
`small amounts after oxycodone administration, making
`the clinical relevance of this metabolite questionable. Al-
`though the CYP2D6 pathway is thought to play a rela-
`tively minor role in oxycodone metabolism, at least 1
`study has reported oxycodone toxicity in a patient with
`impaired CYP2D6 metabolism.41 The authors of this re-
`port suggested that failure to metabolize oxycodone to
`oxymorphone may have been associated with accumula-
`tion of oxycodone and noroxycodone, resulting in an
`inability to tolerate therapy.
`
`OPIOIDS WITHOUT CLINICALLY RELEVANT
`ACTIVE METABOLITES
`
`Fentanyl, oxymorphone, and methadone do not produce
`metabolites that are likely to complicate treatment. Fen-
`tanyl is predominantly converted by CYP3A4-mediated
`N-dealkylation to norfentanyl, a nontoxic and inactive me-
`tabolite; less than 1% is metabolized to despropionyl-
`fentanyl, hydroxyfentanyl, and hydroxynorfentanyl, which
`also lack clinically relevant activity.82 An active metabolite
`of oxymorphone, 6-hydroxy-oxymorphone, makes up less
`than 1% of the administered dose excreted in urine and is
`metabolized via the same pathway as the parent compound,
`making an imbalance among metabolites unlikely.18
`Methadone does not produce active metabolites, exerting
`its activity—both analgesic and toxic—through the parent
`compound. However, methadone has affinity for the N-
`methyl-D-aspartate receptors83; this affinity is thought to
`account not only for a portion of its analgesic efficacy but
`also for neurotoxic effects that have been observed with
`this opioid.84-86
`
`ADHERENCE MONITORING:
`THE IMPORTANCE OF ACTIVE METABOLITES
`
`Opioids that produce active metabolites structurally identi-
`cal to other opioid medications can complicate efforts to
`monitor patients to prevent abuse and diversion. Current
`urine toxicology tests do not provide easily interpretable
`information about the source or dose of detected com-
`pounds. Thus, in a patient prescribed oxycodone, both
`oxycodone and oxymorphone will appear in toxicology
`results, but the urine test results will not establish whether
`the patient took the prescribed oxycodone alone or also
`self-medicated with oxymorphone.
`Patients treated with codeine will have both codeine and
`morphine in urine samples. If too much morphine is
`present, t