Advertisement
Mayo Clinic Proceedings Home

Opioid Metabolism

  • Howard S. Smith
    Correspondence
    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
    Affiliations
    Department of Anesthesiology, Albany Medical College, Albany, NY
    Search for articles by this author
      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.
      CYP (cytochrome P450), M1 (O-desmethyltramadol), M3G (morphine-3-glucuronide), M6G (morphine-6-glucuronide), UGT (uridine diphosphate glucuronosyltransferase)
      Opioids are a cornerstone of the management of cancer pain
      • World Health Organization
      and postoperative pain
      Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management.
      and are used increasingly for the management of chronic noncancer pain.
      • AGS Panel on Persistent Pain in Older Persons
      The management of persistent pain in older persons.
      • American Pain Society
      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.
      • Andersson GB
      Epidemiological features of chronic low-back pain.
      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.
      • Grilo RM
      • Bertin P
      • Scotto di Fazano C
      • et al.
      Opioid rotation in the treatment of joint pain: a review of 67 cases.
      • Mercadante S
      Opioid rotation for cancer pain: rationale and clinical aspects.
      • Mercadante S
      • Bruera E
      Opioid switching: a systematic and critical review.
      • Quang-Cantagrel ND
      • Wallace MS
      • Magnuson SK
      Opioid substitution to improve the effectiveness of chronic noncancer pain control: a chart review.
      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.
      • Grilo RM
      • Bertin P
      • Scotto di Fazano C
      • et al.
      Opioid rotation in the treatment of joint pain: a review of 67 cases.
      • Mercadante S
      Opioid rotation for cancer pain: rationale and clinical aspects.
      • Mercadante S
      • Bruera E
      Opioid switching: a systematic and critical review.
      • Quang-Cantagrel ND
      • Wallace MS
      • Magnuson SK
      Opioid substitution to improve the effectiveness of chronic noncancer pain control: a chart review.
      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.

      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, 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.

      BASICS OF OPIOID METABOLISM

      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.

      FACTORS INFLUENCING OPIOID METABOLISM

      Metabolic Pathways

      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.

      Phase 1 Metabolism

      The CYP3A4 enzyme is the primary metabolizer of fentanyl
      and oxycodone,
      although normally a small portion of oxycodone undergoes CYP2D6 metabolism to oxymorphone (Table 1
      • Coffman BL
      • King CD
      • Rios GR
      • Tephly TR
      The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268).
      ). Tramadol undergoes both CYP3A4- and CYP2D6-mediated metabolism.
      Methadone is primarily metabolized by CYP3A4 and CYP2B6; CYP2C8, CYP2C19, CYP2D6, and CYP2C9 also contribute in varying degrees to its metabolism.
      • Foster DJ
      • Somogyi AA
      • Bochner F
      Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4.
      • Totah RA
      • Allen KE
      • Sheffels P
      • Whittington D
      • Kharasch ED
      Enantiomeric metabolic interactions and stereoselective human methadone metabolism.
      • Wang JS
      • DeVane CL
      Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro.
      • Li Y
      • Kantelip JP
      • Gerritsen-van Schieveen P
      • Davani S
      Interindividual variability of methadone response: impact of genetic polymorphism.
      • Crettol S
      • Déglon JJ
      • Besson J
      • et al.
      ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment.
      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 Involvement
      OpioidPhase 1 metabolismPhase 2 metabolismComment
      Morphine
      • Coffman BL
      • King CD
      • Rios GR
      • Tephly TR
      The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268).
      NoneGlucuronidation via UGT2B7
      Codeine
      CYP2D6None
      Hydrocodone
      CYP2D6NoneOne of the metabolites of hydrocodone is hydromorphone, which undergoes phase 2 glucuronidation
      Oxycodone
      • CYP3A4
      • CYP2D6
      NoneOxycodone produces a small amount of oxymorphone, which must undergo subsequent metabolism via glucuronidation
      Methadone
      • CYP3A4
      • CYP2B6
      • CYP2C8
      • CYP2C19
      • CYP2D6
      • CYP2C9
      NoneCYP3A4 and CYP2B6 are the primary enzymes involved in methadone metabolism; other enzymes play a relatively minor role
      Tramadol
      • CYP3A4
      • CYP2D6
      None
      Fentanyl
      CYP3A4None
      Hydromorphone
      NoneGlucuronidation via UGT2B7
      Oxymorphone
      NoneGlucuronidation via UGT2B7
      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).
      • Zhou 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.
      • Zhou SF
      Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4.
      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.
      In addition to drugs that interact with CYP3A4, bergamottin (found in grapefruit juice) is a strong inhibitor of CYP3A4,
      • Girennavar B
      • Jayaprakasha GK
      • Patil BS
      Potent inhibition of human cytochrome P450 3A4, 2D6, and 2C9 isoenzymes by grapefruit juice and its furocoumarins.
      and cafestol (found in unfiltered coffee) is an inducer of the enzyme.
      • Huber 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.
      TABLE 2Cytochrome P450 3A4 Substrates, Inhibitors, and Inducers
      From Ther Drug Monit,
      • Zhou 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.
      with permission.
      SubstratesInhibitorsInducers
      • CCBs
        • Amlodipine
        • Diltiazem
        • Felodipine
        • Nicardipine
        • Nifedipine
        • Verapamil
      • Statins
        • Atorvastatin
        • Lovastatin
        • Simvastatin
      • Other cardiovascular agents
        • Amiodarone
        • Digoxin
        • Ivabradine
        • Quinidine
        • Warfarin
      • Phosphodiesterase inhibitors
        • Sildenafil
        • Tadalafil
      • Benzodiazepines
        • Alprazolam
        • Clonazepam
        • Flunitrazepam
        • Midazolam
        • Triazolam
      • SSRIs
        • Citalopram
        • Fluoxetine
      • 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
        • Norclomipramine
        • Nortriptyline
        • Sertraline
      • 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
      • 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
      • 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)
      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.
      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.
      The CYP2D6 enzyme is entirely responsible for the metabolism of hydrocodone,
      codeine,
      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 3
      • Flockhart DA
      Drug interactions: cytochrome P450 drug interaction table. Indiana University School of Medicine.
      ).
      TABLE 3Cytochrome P450 2D6 Substrates, Inhibitors, and Inducers
      From Indiana University School of Medicine,
      • Flockhart DA
      Drug interactions: cytochrome P450 drug interaction table. Indiana University School of Medicine.
      with permission.
      SubstratesInhibitorsInducers
      • 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
      • 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
        • Amiodarone
        • Quinidine
      • Antipsychotic agents
        • Chlorpromazine
        • Reduced haloperidol
        • Levomepromazine
      • SNRI
        • Duloxetine
      • SSRIs
        • Citalopram
        • Escitalopram
        • Fluoxetine
        • Paroxetine
        • Sertraline
      • Tricyclic
        • Clomipramine
      • Other antidepressant/antianxiolytic agents
        • Bupropion
        • Moclobemide
      • Antihistamine
        • Chlorpheniramine
      • Histamine H2 receptor antagonists
        • Cimetidine
        • Ranitidine
      • Other drugs
        • Celecoxib
        • Doxorubicin
        • Ritonavir
        • Terbinafine
      • Antibiotic
        • Rifampin
      • Glucocorticoid
        • Dexamethasone
      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,
      • Evans 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.
      • Heiskanen T
      • Olkkola KT
      • Kalso E
      Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.
      • Bertilsson L
      • Lou YQ
      • Du YL
      • et al.
      Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin.
      and between 1% and 7% of white people carry CYP2D6 allelic variants associated with rapid metabolism.
      • Bathum 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.
      • Løvlie 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.
      The prevalence of poor metabolizers is lower in Asian populations (≤1%)
      • Sohn 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.
      and highly variable in African populations (0%-34%).
      • Aklillu 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.
      • Bathum L
      • Skjelbo E
      • Mutabingwa TK
      • Madsen H
      • Hørder M
      • Brøsen K
      Phenotypes and genotypes for CYP2D6 and CYP2C19 in a black Tanzanian population.
      • Relling 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.
      • Masimirembwa 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.
      • Mbanefo C
      • Bababunmi EA
      • Mahgoub A
      • Sloan TP
      • Idle JR
      • Smith RL
      A study of the debrisoquine hydroxylation polymorphism in a Nigerian population.
      The prevalence of rapid metabolizers of opioids has not been reported in Asian populations; estimates in African populations are high but variable (9%-30%).
      • Aklillu 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.
      • Bathum L
      • Skjelbo E
      • Mutabingwa TK
      • Madsen H
      • Hørder M
      • Brøsen K
      Phenotypes and genotypes for CYP2D6 and CYP2C19 in a black Tanzanian population.
      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 opioid metabolizers may experience increased opioid effects with a usual dose of codeine because their rapid metabolism generates a higher concentration of morphine.
      • Lötsch J
      • Skarke C
      • Liefhold J
      • Geisslinger G
      Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives.
      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.
      • Foster A
      • Mobley E
      • Wang Z
      Complicated pain management in a CYP450 2D6 poor metabolizer.
      • Susce MT
      • Murray-Carmichael E
      • de Leon J
      Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer.
      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.
      • Heiskanen T
      • Olkkola KT
      • Kalso E
      Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.
      However, individual cases of reduced oxycodone efficacy
      • Susce MT
      • Murray-Carmichael E
      • de Leon J
      Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer.
      or increased toxicity
      • Foster A
      • Mobley E
      • Wang Z
      Complicated pain management in a CYP450 2D6 poor metabolizer.
      in CYP2D6 poor metabolizers have been reported.

      Phase 2 Metabolism

      Morphine, oxymorphone, and hydromorphone are each metabolized by phase 2 glucuronidation
      and therefore have little potential for metabolically based drug interactions. Oxymorphone, for example, has no known pharmacokinetic drug-drug interactions,
      and morphine has few.
      Of course, pharmacodynamic drug-drug interactions are possible with all opioids, such as additive interactions with benzodiazepines, antihistamines, or alcohol, and antagonistic interactions with naltrexone or naloxone.
      However, the enzymes responsible for glucuronidation 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)
      • Coffman BL
      • King CD
      • Rios GR
      • Tephly TR
      The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268).
      • Bhasker CR
      • McKinnon W
      • Stone A
      • et al.
      Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance.
      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.
      • Hara Y
      • Nakajima M
      • Miyamoto K
      • Yokoi T
      Morphine glucuronosyltransferase activity in human liver microsomes is inhibited by a variety of drugs that are co-administered with morphine.
      Moreover, preliminary data indicate that UGT2B7 metabolism of morphine may be potentiated by CYP3A4, although the clinical relevance of this finding is unknown.
      • Projean D
      • Morin PE
      • Tu TM
      • Ducharme J
      Identification of CYP3A4 and CYP2C8 as the major cytochrome P450s responsible for morphine N-demethylation in human liver microsomes.
      • Takeda S
      • Ishii Y
      • Iwanaga M
      • et al.
      Modulation of UDP-glucuronosyltransferase function by cytochrome P450: evidence for the alteration of UGT2B7-catalyzed glucuronidation of morphine by CYP3A4.
      • Takeda S
      • Ishii Y
      • Mackenzie PI
      • et al.
      Modulation of UDP-glucuronosyltransferase 2B7 function by cytochrome P450s in vitro: differential effects of CYP1A2, CYP2C9 and CYP3A4.
      The activity of UGT2B7 shows significant between-patient variability, and several authors have identified allelic variants of the gene encoding this enzyme.
      • Coffman BL
      • King CD
      • Rios GR
      • Tephly TR
      The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268).
      • Bhasker CR
      • McKinnon W
      • Stone A
      • et al.
      Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance.
      Although 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.
      • Darbari DS
      • van Schaik RH
      • Capparelli EV
      • Rana S
      • McCarter R
      • van den Anker J
      UGT2B7 promoter variant -840G>A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease.
      • Duguay Y
      • Báár C
      • Skorpen F
      • Guillemette C
      A novel functional polymorphism in the uridine diphosphate-glucuronosyltransferase 2B7 promoter with significant impact on promoter activity.
      Moreover, research 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.
      • Toide K
      • Takahashi Y
      • Yamazaki H
      • et al.
      Hepatocyte nuclear factor-1α is a causal factor responsible for interindividual differences in the expression of UDP-glucuronosyltransferase 2B7 mRNA in human livers.

      Clinical Implications of Metabolic Pathways

      Most opioids are metabolized via CYP-mediated oxidation and have substantial drug interaction potential. The exceptions 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 monitoring, 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 understood. Because an individual patient's response to a given opioid cannot be predicted, it may be necessary to administer a series of opioid trials before finding an agent that provides effective analgesia with acceptable tolerability.
      • Grilo RM
      • Bertin P
      • Scotto di Fazano C
      • et al.
      Opioid rotation in the treatment of joint pain: a review of 67 cases.
      • Mercadante S
      Opioid rotation for cancer pain: rationale and clinical aspects.
      • Mercadante S
      • Bruera E
      Opioid switching: a systematic and critical review.
      • Quang-Cantagrel ND
      • Wallace MS
      • Magnuson SK
      Opioid substitution to improve the effectiveness of chronic noncancer pain control: a chart review.
      In some patients, the most effective and well-tolerated opioid will be one that undergoes CYP-mediated metabolism. 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 obtained in 40 (80%) of these patients.
      • Mercadante S
      • Casuccio A
      • Fulfaro F
      • et al.
      Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study.
      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 selection 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 4
      • Flockhart DA
      Drug interactions: cytochrome P450 drug interaction table. Indiana University School of Medicine.
      • Cone EJ
      • Caplan YH
      • Moser F
      • Robert T
      • Black D
      Evidence that morphine is metabolized to hydromorphone but not to oxymorphone.
      • Cone EJ
      • Heit HA
      • Caplan YH
      • Gourlay D
      Evidence of morphine metabolism to hydromorphone in pain patients chronically treated with morphine.
      • McDonough PC
      • Levine B
      • Vorce S
      • Jufer RA
      • Fowler D
      The detection of hydromorphone in urine specimens with high morphine concentrations.
      • Hutchinson MR
      • Menelaou A
      • Foster DJ
      • Coller JK
      • Somogyi AA
      CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes.
      • DrugBank Web site
      Departments of Computing & Biological Sciences, University of Alberta.
      • Oyler JM
      • Cone EJ
      • Joseph Jr, RE
      • Huestis MA
      Identification of hydrocodone in human urine following controlled codeine administration.
      • Oda Y
      • Kharasch ED
      Metabolism of methadone and levo-α-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): potential contribution of intestinal metabolism to presystemic clearance and bioactivation.
      • Reisfield GM
      • Salazar E
      • Bertholf RL
      Rational use and interpretation of urine drug testing in chronic opioid therapy.
      ). Altered metabolism 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.
      TABLE 4Major Opioid Metabolites
      OpioidInactive metabolitesActive metabolites identical to pharmaceutical opioidsActive metabolites that are not pharmaceutical opioids
      Morphine
      • Flockhart DA
      Drug interactions: cytochrome P450 drug interaction table. Indiana University School of Medicine.
      • Cone EJ
      • Caplan YH
      • Moser F
      • Robert T
      • Black D
      Evidence that morphine is metabolized to hydromorphone but not to oxymorphone.
      • Cone EJ
      • Heit HA
      • Caplan YH
      • Gourlay D
      Evidence of morphine metabolism to hydromorphone in pain patients chronically treated with morphine.
      • McDonough PC
      • Levine B
      • Vorce S
      • Jufer RA
      • Fowler D
      The detection of hydromorphone in urine specimens with high morphine concentrations.
      NormorphineHydromorphone
      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
      • Morphone-3-G glucuronide
      • Morphone-6-G glucuronide
      Hydromorphone
      Minor metabolitesNoneHydromorphone-3-glucuronide
      Hydrocodone
      • Hutchinson MR
      • Menelaou A
      • Foster DJ
      • Coller JK
      • Somogyi AA
      CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes.
      NorhydrocodoneHydromorphoneNone
      Codeine
      • DrugBank Web site
      Departments of Computing & Biological Sciences, University of Alberta.
      • Oyler JM
      • Cone EJ
      • Joseph Jr, RE
      • Huestis MA
      Identification of hydrocodone in human urine following controlled codeine administration.
      Norcodeine
      • Hydrocodone
        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
      • Morphine
      None
      Oxycodone
      NoneOxymorphoneNoroxycodone
      Oxymorphone
      Oxymorphone-3-glucuronideNone6-Hydroxy-oxymorphone
      Fentanyl
      NorfentanylNoneNone
      Tramadol
      NortramadolNoneO-desmethyltramadol
      Methadone
      • Oda Y
      • Kharasch ED
      Metabolism of methadone and levo-α-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): potential contribution of intestinal metabolism to presystemic clearance and bioactivation.
      2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine 2-Ethyl-5-methyl-3,3-diphenylpyrrolineNoneNone
      Heroin
      • Reisfield GM
      • Salazar E
      • Bertholf RL
      Rational use and interpretation of urine drug testing in chronic opioid therapy.
      NormorphineMorphine6-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.
      • Cone EJ
      • Caplan YH
      • Moser F
      • Robert T
      • Black D
      Evidence that morphine is metabolized to hydromorphone but not to oxymorphone.
      • Cone EJ
      • Heit HA
      • Caplan YH
      • Gourlay D
      Evidence of morphine metabolism to hydromorphone in pain patients chronically treated with morphine.
      • Oyler JM
      • Cone EJ
      • Joseph Jr, RE
      • Huestis MA
      Identification of hydrocodone in human urine following controlled codeine administration.

      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 metabolite
      • Susce MT
      • Murray-Carmichael E
      • de Leon J
      Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer.
      and in rapid metabolizers who form too much morphine.
      • Dalén P
      • Frengell C
      • Dahl ML
      • Sjöqvist F
      Quick onset of severe abdominal pain after codeine in an ultrarapid metabolizer of debrisoquine.
      • Gasche Y
      • Daali Y
      • Fathi M
      • et al.
      Codeine intoxication associated with ultrarapid CYP2D6 metabolism.
      In fact, a recent study found that adverse effects of codeine are present irrespective of morphine concentrations in both poor and rapid metabolizers,
      • Eckhardt K
      • Li S
      • Ammon S
      • Schänzle G
      • Mikus G
      • Eichelbaum M
      Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation.
      suggesting that a substantial proportion of patients with CYP2D6 allelic variants predisposing 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 unknown mechanism to produce hydrocodone in quantities reaching up to 11% of the codeine concentration found in urinalysis.
      • Oyler JM
      • Cone EJ
      • Joseph Jr, RE
      • Huestis MA
      Identification of hydrocodone in human urine following controlled codeine administration.
      The clinical effect of the hydrocodone metabolite 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-glucuronide (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 sulfate. A recent study found that a small proportion of morphine is also metabolized to hydromorphone,
      • McDonough PC
      • Levine B
      • Vorce S
      • Jufer RA
      • Fowler D
      The detection of hydromorphone in urine specimens with high morphine concentrations.
      although there are no data suggesting a meaningful clinical effect.
      Like morphine, M6G is a μ-opioid receptor agonist with potent analgesic activity. However, morphine has greater affinity than M6G for the μ2-opioid receptor thought to be responsible for many of the adverse effects of μ-receptor agonists,
      • Barkin RL
      • Iusco AM
      • Barkin SJ
      Opioids used in primary care for the management of pain: a pharmacologic, pharmacotherapeutic, and pharmacodynamic overview.
      • Hucks D
      • Thompson PI
      • McLoughlin L
      • et al.
      Explanation at the opioid receptor level for differing toxicity of morphine and morphine 6-glucuronide.
      most notably respiratory depression, gastrointestinal effects, and sedation.
      • Hucks D
      • Thompson PI
      • McLoughlin L
      • et al.
      Explanation at the opioid receptor level for differing toxicity of morphine and morphine 6-glucuronide.
      • Cann C
      • Curran J
      • Milner T
      • Ho B
      Unwanted effects of morphine-6-glucoronide and morphine.
      Although the affinities of morphine and M6G for the μ1-opioid receptor are similar, a study of low-dose morphine, M6G, and M3G found that morphine had greater analgesic efficacy.
      • Penson RT
      • Joel SP
      • Bakhshi K
      • Clark SJ
      • Langford RM
      • Slevin ML
      Randomized placebo-controlled trial of the activity of the morphine glucuronides.
      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.
      • Smith MT
      Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites.
      • Wright AW
      • Mather LE
      • Smith MT
      Hydromorphone-3-glucuronide: a more potent neuro-excitant than its structural analogue, morphine-3-glucuronide.
      • Wright AW
      • Nocente ML
      • Smith MT
      Hydromorphone-3-glucuronide: biochemical synthesis and preliminary pharmacological evaluation.
      In a clinical trial, however, low-dose M3G exhibited no analgesic effects, did not potentiate the analgesic effects of morphine or M6G, and did not produce adverse effects.
      • Penson RT
      • Joel SP
      • Bakhshi K
      • Clark SJ
      • Langford RM
      • Slevin ML
      Randomized placebo-controlled trial of the activity of the morphine glucuronides.
      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.
      • Klepstad P
      • Borchgrevink PC
      • Dale O
      • et al.
      Routine drug monitoring of serum concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide do not predict clinical observations in cancer patients.
      • Quigley C
      • Joel S
      • Patel N
      • Baksh A
      • Slevin M
      Plasma concentrations of morphine, morphine-6-glucuronide and morphine-3-glucuronide and their relationship with analgesia and side effects in patients with cancer-related pain.
      Moreover, in patients with impaired renal function, the pharmacokinetics of morphine appear to be less affected than that of its M6G and M3G metabolites, which were found to accumulate.
      • Angst MS
      • Buhrer M
      • Lötsch J
      Insidious intoxication after morphine treatment in renal failure: delayed onset of morphine-6-glucuronide action.
      • Hagen NA
      • Foley KM
      • Cerbone DJ
      • Portenoy RK
      • Inturrisi CE
      Chronic nausea and morphine-6-glucuronide.
      • Osborne R
      • Joel S
      • Grebenik K
      • Trew D
      • Slevin M
      The pharmacokinetics of morphine and morphine glucuronides in kidney failure.
      • Osborne RJ
      • Joel SP
      • Slevin ML
      Morphine intoxication in renal failure: the role of morphine-6-glucuronide.
      Although M6G appears to be better tolerated than morphine, increased toxicity in patients with reduced clearance was primarily related to the accumulation of the M6G metabolite.

      Hydromorphone

      The production of active metabolites is also an issue with hydromorphone. The primary metabolite of hydromorphone, hydromorphone-3-glucuronide, has neuroexcitatory potential similar to
      • Smith MT
      Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites.
      • Wright AW
      • Nocente ML
      • Smith MT
      Hydromorphone-3-glucuronide: biochemical synthesis and preliminary pharmacological evaluation.
      or greater than
      • Wright AW
      • Mather LE
      • Smith MT
      Hydromorphone-3-glucuronide: a more potent neuro-excitant than its structural analogue, morphine-3-glucuronide.
      the M3G metabolite of morphine. Clinical data on the neuroexcitatory potential of hydromorphone during long-term therapy are unavailable. However, hydromorphone is available only in short-acting formulations and extended-release formulations are recommended in patients with chronic pain requiring long-term therapy.
      • AGS Panel on Persistent Pain in Older Persons
      The management of persistent pain in older persons.
      • American Pain Society

      Tramadol

      Like codeine, tramadol requires metabolism to an active metabolite, O-desmethyltramadol (M1), to be fully effective. The parent compound relies on both CYP3A4 and CYP2D6, with metabolism of M1 relying on CYP2D6.
      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.
      • Halling J
      • Weihe P
      • Brosen K
      CYP2D6 polymorphism in relation to tramadol metabolism: a study of Faroese patients.
      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. Although M1 has more potent activity at the μ-opioid receptor,
      • Gillen C
      • Haurand M
      • Kobelt DJ
      • Wnendt S
      Affinity, potency and efficacy of tramadol and its metabolites at the cloned human μ-opioid receptor.
      tramadol is the more potent inhibitor of serotonin and norepinephrine reuptake and the more potent promoter of serotonin and norepinephrine efflux.
      • Driessen B
      • Reimann W
      Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro.
      • Driessen B
      • Reimann W
      • Giertz H
      Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro.
      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.
      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 are governed primarily by the parent drug, with a negligible contribution from its circulating oxidative and reductive metabolites.
      • Lalovic B
      • Kharasch E
      • Hoffer C
      • Risler L
      • Liu-Chen LY
      • Shen DD
      Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites.
      Oxymorphone is present only in small amounts after oxycodone administration, making the clinical relevance of this metabolite questionable. Although the CYP2D6 pathway is thought to play a relatively minor role in oxycodone metabolism, at least 1 study has reported oxycodone toxicity in a patient with impaired CYP2D6 metabolism.
      • Foster A
      • Mobley E
      • Wang Z
      Complicated pain management in a CYP450 2D6 poor metabolizer.
      The authors of this report suggested that failure to metabolize oxycodone to oxymorphone may have been associated with accumulation 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. Fentanyl is predominantly converted by CYP3A4-mediated N-dealkylation to norfentanyl, a nontoxic and inactive metabolite; less than 1% is metabolized to despropionylfentanyl, hydroxyfentanyl, and hydroxynorfentanyl, which also lack clinically relevant activity.
      • Feierman DE
      • Lasker JM
      Metabolism of fentanyl, a synthetic opioid analgesic, by human liver microsomes: role of CYP3A4.
      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.
      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 receptors
      • Inturrisi CE
      Pharmacology of methadone and its isomers.
      ; 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.
      • Bush E
      • Miller C
      • Friedman I
      A case of serotonin syndrome and mutism associated with methadone.
      • Ito S
      • Liao S
      Myoclonus associated with high-dose parenteral methadone.
      • Sarhill N
      • Davis MP
      • Walsh D
      • Nouneh C
      Methadone-induced myoclonus in advanced cancer.

      ADHERENCE MONITORING: THE IMPORTANCE OF ACTIVE METABOLITES

      Opioids that produce active metabolites structurally identical 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 compounds. 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, the patient may be taking heroin or ingesting morphine in addition to codeine. CYP2D6 rapid metabolizers may have an unusually high morphine-to-codeine ratio, making interpretation of the morphine-to-codeine ratio challenging.
      • He YJ
      • Brockmöller J
      • Schmidt H
      • Roots I
      • Kirchheiner J
      CYP2D6 ultrarapid metabolism and morphine/codeine ratios in blood: was it codeine or heroin?.
      However, in patients taking only codeine, the codeine-to-morphine ratio is less than 6, even in rapid metabolizers.
      • He YJ
      • Brockmöller J
      • Schmidt H
      • Roots I
      • Kirchheiner J
      CYP2D6 ultrarapid metabolism and morphine/codeine ratios in blood: was it codeine or heroin?.
      • Kirchheiner J
      • Schmidt H
      • Tzvetkov M
      • et al.
      Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication.
      Additionally, morphine alone may be detectable in the urine 30 hours after ingestion of a single dose of codeine.
      • Cone EJ
      • Welch P
      • Paul BD
      • Mitchell JM
      Forensic drug testing for opiates, III: Urinary excretion rates of morphine and codeine following codeine administration.
      • Solomon MD
      A study of codeine metabolism.
      • Dutt MC
      • Lo DS
      • Ng DL
      • Woo SO
      Gas chromatographic study of the urinary codeine-to-morphine ratios in controlled codeine consumption and in mass screening for opiate drugs.
      • Posey BL
      • Kimble SN
      Simultaneous determination of codeine and morphine in urine and blood by HPLC.
      The urine of patients treated with morphine may contain small amounts of hydromorphone (≤2.5% of the morphine concentration).
      • Cone EJ
      • Caplan YH
      • Moser F
      • Robert T
      • Black D
      Evidence that morphine is metabolized to hydromorphone but not to oxymorphone.
      • Cone EJ
      • Heit HA
      • Caplan YH
      • Gourlay D
      Evidence of morphine metabolism to hydromorphone in pain patients chronically treated with morphine.
      Similarly, those treated with hydrocodone may test positive for both hydrocodone and hydromorphone, making it difficult to determine whether the parent opioid was taken as prescribed or a second opioid is being abused.
      Clinicians may find it easier to monitor patients for adherence and abuse if the opioid prescribed does not produce active metabolites similar to other opioid medications. If abuse is suspected, choosing opioids such as fentanyl, hydromorphone, methadone, or oxymorphone may simplify monitoring. Sometimes an inactive metabolite provides a more reliable test of adherence than does the parent opioid. Urinary concentrations of methadone depend not only on dose and metabolism but also on urine pH. In contrast, the concentration of an inactive metabolite of methadone (via N-demethylation), 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, is unaffected by pH and is therefore preferable for assessing adherence to therapy.
      • George S
      • Braithwaite RA
      A pilot study to determine the usefulness of the urinary excretion of methadone and its primary metabolite (EDDP) as potential markers of compliance in methadone detoxification programs.

      POPULATION PHARMACOKINETICS

      Opioid metabolism differs with individual opioids in populations stratified according to age, sex, and ethnicity (Table 5
      ). Reduced clearance of morphine,
      codeine,
      fentanyl,
      and oxymorphone
      has been reported in older patients. Oxycodone concentrations are approximately 25% higher in women than in men after controlling for differences in body weight, making it important for physicians to consider the patient's sex when prescribing this opioid.
      Chinese patients have higher clearance and lower concentrations of morphine.
      Similarly, codeine is a prodrug that exerts its analgesic effects after metabolism to morphine. Morphine concentrations were shown to be reduced in Chinese patients treated with codeine, providing confirmation of altered morphine metabolism in this large population.
      • Caraco Y
      • Sheller J
      • Wood AJ
      Impact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects.
      As already stated, altered opioid metabolism in ethnic populations is also a byproduct of allelic variants of the gene encoding CYP2D6,
      • Bathum 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.
      • Løvlie 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.
      • Foster A
      • Mobley E
      • Wang Z
      Complicated pain management in a CYP450 2D6 poor metabolizer.
      particularly in African populations.
      • Aklillu 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.
      • Bathum L
      • Skjelbo E
      • Mutabingwa TK
      • Madsen H
      • Hørder M
      • Brøsen K
      Phenotypes and genotypes for CYP2D6 and CYP2C19 in a black Tanzanian population.
      • Relling 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.
      • Masimirembwa 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.
      • Mbanefo C
      • Bababunmi EA
      • Mahgoub A
      • Sloan TP
      • Idle JR
      • Smith RL
      A study of the debrisoquine hydroxylation polymorphism in a Nigerian population.
      Ethnic differences in the gene encoding UGT2B7 have also been identified, but these have not been associated with clinical differences in enzyme activity.
      • Bhasker CR
      • McKinnon W
      • Stone A
      • et al.
      Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance.
      TABLE 5Demographic/Medical Factors Influencing Opioid Metabolism
      OpioidAgeSexEthnicityHepatic impairmentRenal impairment
      Morphine
      Clearance may be reduced in older patientsNo effectChinese patients have higher clearance of morphineDose adjustment recommendedDose adjustment recommended
      Codeine
      Caution recommended in older patientsNo effectCYP2D6 allelic variants may alter metabolism, more common in populations of Asian or African descentDose adjustment recommendedDose adjustment recommended
      Hydrocodone
      Caution recommended in older patientsNo known effectCYP2D6 allelic variants may alter metabolism, more common in populations of Asian or African descentMost frequently administered in combination with acetaminophen; liver function monitoring is advised during treatment in patients with hepatic impairmentMost frequently administered in combination with acetaminophen; renal function monitoring is advised during treatment in patients with severe renal impairment
      Oxycodone
      Concentrations nominally higher in older patientsConcentrations ∼25% higher in women than in menNo effectDose adjustment recommendedDose adjustment recommended
      Methadone
      Dose adjustment may be necessary in elderly patientsNo effectNo effectDose adjustment recommended in patients with severe impairmentDose adjustment recommended in patients with severe impairments
      Tramadol
      Effects of age on pharmacokinetics have not been studiedNo significant effectNo effectPharmacokinetics significantly altered in patients with severe hepatic impairmentPharmacokinetics significantly altered only in patients with severe renal impairment
      Fentanyl
      Clearance may be reduced in older patientsNo effectNo effectDose adjustments may not be necessary in patients with hepatic impairmentDose adjustments may not be necessary in patients with renal impairment
      Hydromorphone
      No effectCmax 25% higher in women than in men with similar AUC0-24No effectDose adjustment recommendedDose adjustment recommended
      Oxymorphone
      Steady-state concentrations ∼40% higher in patients aged ≥65 yConcentrations the same in men and women after controlling for body weightNo effectContraindicated in patients with moderate or severe hepatic impairmentDose adjustment recommended
      AUC0–24 = area under the plasma concentration vs time curve; Cmax = maximum plasma concentration; CYP = cytochrome P450.
      In most cases, altered opioid metabolism in older patients, women, or specific ethnic groups can be addressed by careful dose adjustment. For example, morphine,
      codeine,
      fentanyl,
      and oxymorphone
      should be initiated at lower doses in older patients, and physicians prescribing oxycodone to women may consider starting at a lower dose relative to men. Morphine or codeine dose reductions may also be necessary in Asian populations. Given the genetic variability of metabolism in specific ethnic populations, it may make sense for patients with an unexplained history of poor response or an inability to tolerate a particular opioid to be switched to an opioid that relies on a different metabolic pathway.
      • Ahdieh H
      Regarding CYP450 2D6 poor metabolizers [letter].

      Foster A. In response to Dr. Ahdieh [published online ahead of print May 26, 2008]. Pain Pract. doi:10.1111/j.1533-2500.2008.00218_2.x.

      MEDICAL CONDITIONS

      Hepatic Impairment

      The liver is the major site of biotransformation for most opioids (Table 4). It is therefore not surprising that the prescribing information for most frequently prescribed opioids recommends caution in patients with hepatic impairment.
      For example, in patients with moderate to severe liver disease, peak plasma levels of oxycodone and its chief metabolite noroxycodone were increased 50% and 20%, respectively, whereas the area under the plasma concentration-time curve for these molecules increased 95% and 65%.
      Peak plasma concentrations of another active metabolite, oxymorphone, were decreased by 30% and 40%, respectively. Although oxymorphone itself does not undergo CYP-mediated metabolism, a portion of the oxycodone dose is metabolized to oxymorphone by CYP2D6. Failure to biotransform oxycodone to oxymorphone may result in accumulation of oxycodone and noroxycodone, with an associated increase in adverse events.
      • Foster A
      • Mobley E
      • Wang Z
      Complicated pain management in a CYP450 2D6 poor metabolizer.
      The differential effect of hepatic impairment on the metabolism of oxycodone relative to its active metabolite illustrates the complexities associated with opioids that have multiple active metabolites.
      Hepatic impairment may also affect metabolism of opioids that undergo glucuronidation rather than CYP-mediated metabolism, such as morphine and oxymorphone. In a 1990 study, the elimination half-life and peak plasma concentrations of morphine were significantly increased in 7 patients with severe cirrhosis.
      • Hasselström J
      • Eriksson S
      • Persson A
      • Rane A
      • Svensson JO
      • Säwe J
      The metabolism and bioavailability of morphine in patients with severe liver cirrhosis.
      The bioavailability of morphine in these patients was 101% compared with approximately 47% observed in healthy participants. The ratio of morphine to its inactive metabolite M3G was significantly higher in cirrhotic patients than in controls. In another study, morphine hepatic extraction was compared in 8 healthy participants and 8 patients with cirrhosis. Hepatic extraction was 25% lower in patients with cirrhosis.
      • Crotty B
      • Watson KJ
      • Desmond PV
      • et al.
      Hepatic extraction of morphine is impaired in cirrhosis.
      This reduction was attributed to reduced enzyme capacity rather than to impairment in blood flow. The authors of that study suggested that cirrhosis affected the metabolism of morphine less than other high-clearance oxidized drugs, perhaps indicating that cirrhosis has less of an effect on glucuronidation relative to CYP-mediated metabolism.
      Currently, no comparable data exist on metabolism of oxymorphone in patients with cirrhosis. However, hepatic disease may certainly have significant effects on oxymorphone pharmacokinetics. Specifically, the bioavailability of oxymorphone increased by 1.6-fold and 3.7-fold in patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment, respectively, compared with healthy controls. In 1 patient with severe hepatic impairment (Child-Pugh class C), the bioavailability was increased by 12.2-fold.
      The pharmacokinetics of fentanyl
      • Haberer JP
      • Schoeffler P
      • Couderc E
      • Duvaldestin P
      Fentanyl pharmacokinetics in anaesthetized patients with cirrhosis.
      and methadone,
      • Novick DM
      • Kreek MJ
      • Fanizza AM
      • Yancovitz SR
      • Gelb AM
      • Stenger RJ
      Methadone disposition in patients with chronic liver disease.
      2 of the frequently used opioids, are not significantly affected by hepatic impairment. Although dose adjustments for these opioids may not be required in certain patients with hepatic impairment, clinicians should nonetheless be extremely cautious when prescribing any opioid for a patient with severe hepatic dysfunction.

      Renal Impairment

      The incidence of renal impairment increases significantly with age, such that the glomerular filtration rate decreases by an average of 0.75 to 0.9 mL/min annually beginning at age 30 to 40 years.
      • Lindeman RD
      • Tobin J
      • Shock NW
      Longitudinal studies on the rate of decline in renal function with age.
      • Rowe JW
      • Andres R
      • Tobin JD
      • Norris AH
      • Shock NW
      The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study.
      At this rate, a person aged 80 years will have approximately two-thirds of the renal function expected in a person aged 20 or 30 years.
      • Lindeman RD
      • Tobin J
      • Shock NW
      Longitudinal studies on the rate of decline in renal function with age.
      • Rowe JW
      • Andres R
      • Tobin JD
      • Norris AH
      • Shock NW
      The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study.
      • Anderson S
      • Brenner BM
      Effects of aging on the renal glomerulus.
      Because most opioids are eliminated primarily in urine, dose adjustments are required in patients with renal impairment.
      However, the effects of renal impairment on opioid clearance are neither uniform nor clear-cut. For example, morphine clearance decreases only modestly in patients with renal impairment, but clearance of its M6G and M3G metabolites decreases dramatically.
      • Milne RW
      • Nation RL
      • Somogyi AA
      • Bochner F
      • Griggs WM
      The influence of renal function on the renal clearance of morphine and its glucuronide metabolites in intensive-care patients.
      • Pauli-Magnus C
      • Hofmann U
      • Mikus G
      • Kuhlmann U
      • Mettang T
      Pharmacokinetics of morphine and its glucuronides following intravenous administration of morphine in patients undergoing continuous ambulatory peritoneal dialysis.
      • Wolff J
      • Bigler D
      • Christensen CB
      • Rasmussen SN
      • Andersen HB
      • Tønnesen KH
      Influence of renal function on the elimination of morphine and morphine glucuronides.
      Accumulation of morphine glucuronides in patients with renal impairment has been associated with serious adverse effects, including respiratory depression, sedation, nausea, and vomiting.
      • Angst MS
      • Buhrer M
      • Lötsch J
      Insidious intoxication after morphine treatment in renal failure: delayed onset of morphine-6-glucuronide action.
      • Hagen NA
      • Foley KM
      • Cerbone DJ
      • Portenoy RK
      • Inturrisi CE
      Chronic nausea and morphine-6-glucuronide.
      • Dubs A
      • Wiedemeier P
      • Caduff B
      Morphine poisoning in chronic kidney failure: morphine-6-glucuronide as a pharmacologically active morphine metabolite [in German].
      Similarly, patients with chronic renal failure who receive 24 mg/d of hydromorphone may have a 4-fold increase in the molar ratio of hydromorphone-3-glucuronide to hydromorphone.
      • Babul N
      • Darke AC
      • Hagen N
      Hydromorphone metabolite accumulation in renal failure [letter].
      Conversely, in patients treated with oxycodone, renal impairment increases concentrations of oxycodone and noroxycodone by approximately 50% and 20%, respectively.
      Although renal impairment affects oxycodone more than morphine, there is no critical accumulation of an active metabolite that produces adverse events.
      Thus, selecting an opioid in patients with renal impairment requires an understanding not only of the anticipated changes in concentrations of the opioid and its metabolites but also of the differential effects of parent compounds and metabolites when they accumulate.
      As in liver disease, methadone and fentanyl may be less affected by renal impairment than other opioids. Methadone does not seem to be removed by dialysis
      • Furlan V
      • Hafi A
      • Dessalles MC
      • Bouchez J
      • Charpentier B
      • Taburet AM
      Methadone is poorly removed by haemodialysis [letter].
      ; in anuric patients, methadone excretion in the feces may be enhanced with limited accumulation in plasma.
      • Kreek MJ
      • Schecter AJ
      • Gutjahr CL
      • Hecht M
      Methadone use in patients with chronic renal disease.
      However, for patients with stage 5 chronic kidney disease, the prudent approach remains to begin with very low doses, monitor carefully, and titrate upward slowly. Fentanyl is metabolized and eliminated almost exclusively by the liver; thus, it has been assumed that its pharmacokinetics would be minimally altered by kidney failure.
      • Dean M
      Opioids in renal failure and dialysis patients.
      However, despite limited pharmacokinetic data, hepatic clearance and extraction of drugs with high hepatic extraction ratios (eg, fentanyl) could potentially be inhibited by uremia
      • Koehntop DE
      • Rodman JH
      Fentanyl pharmacokinetics in patients undergoing renal transplantation.
      ; the theoretical potential for accumulation of fentanyl in patients with hepatic impairment makes caution advisable when prescribing opioids to these patients.

      CLINICAL IMPLICATIONS OF MEDICAL CONDITIONS

      The selection of an opioid analgesic may be affected by comorbidities and diminished organ reserve. Health care professionals need to be especially cautious when dealing with patients with diminished metabolic capacities due to organ dysfunction. In general, dose reduction and/or prolongation of dose intervals may be necessary depending on the severity of organ impairment. Moreover, clinicians should adopt a “start low and go slow” approach to opioid titration when hepatic or renal impairment is a factor.
      Although metabolism of drugs undergoing glucuronidation rather than oxidation may be less affected by hepatic impairment, this does not appear to be a major advantage with respect to opioids. Morphine clearance and accumulation of its M3G metabolite are increased in cirrhosis, making dose adjustments advisable. Oxymorphone, which also undergoes glucuronidation, is contraindicated in patients with moderate or severe hepatic dysfunction.
      Among opioids undergoing CYP-mediated metabolism, fentanyl
      • Haberer JP
      • Schoeffler P
      • Couderc E
      • Duvaldestin P
      Fentanyl pharmacokinetics in anaesthetized patients with cirrhosis.
      and methadone
      • Novick DM
      • Kreek MJ
      • Fanizza AM
      • Yancovitz SR
      • Gelb AM
      • Stenger RJ
      Methadone disposition in patients with chronic liver disease.
      appear to be less affected by liver disease. Nonetheless, data on these opioids are limited, making caution and conservative dosing advisable in this population.
      In patients with substantial chronic kidney disease (stages 3-5), clinicians should carefully consider their options before choosing morphine. Nausea, vomiting, profound analgesia, sedation, and respiratory depression have been reported in patients who have kidney failure and are taking morphine.
      • Angst MS
      • Buhrer M
      • Lötsch J
      Insidious intoxication after morphine treatment in renal failure: delayed onset of morphine-6-glucuronide action.
      • Hagen NA
      • Foley KM
      • Cerbone DJ
      • Portenoy RK
      • Inturrisi CE
      Chronic nausea and morphine-6-glucuronide.
      • Dubs A
      • Wiedemeier P
      • Caduff B
      Morphine poisoning in chronic kidney failure: morphine-6-glucuronide as a pharmacologically active morphine metabolite [in German].
      • Chauvin M
      • Sandouk P
      • Scherrmann JM
      • Farinotti R
      • Strumza P
      • Duvaldestin P
      Morphine pharmacokinetics in renal failure.
      • Sear JW
      • Hand CW
      • Moore RA
      • McQuay HJ
      Studies on morphine disposition: influence of renal failure on the kinetics of morphine and its metabolites.
      Several authors have suggested that fentanyl and methadone are preferred in end-stage renal disease
      • Dean M
      Opioids in renal failure and dialysis patients.
      • Murtagh FE
      • Chai MO
      • Donohoe P
      • Edmonds PM
      • Higginson IJ
      The use of opioid analgesia in end-stage renal disease patients managed without dialysis: recommendations for practice.
      ; however, this advice needs to be tempered by the challenges inherent in dosing potent opioids in patients with poor renal function.

      CONCLUSION

      Patient characteristics and structural differences between opioids contribute to differences in opioid metabolism and thereby to the variability of the efficacy, safety, and tolerability of specific opioids in individual patients and diverse patient populations. To optimize treatment for individual patients, clinicians must understand the variability in the ways different opioids are metabolized and be able to recognize the patient characteristics likely to influence opioid metabolism.

      Acknowledgments

      Jeffrey Coleman, MA, of Complete Healthcare Communications (Chadds Ford, PA) provided research and editorial assistance for the development of the submitted manuscript, with support from Endo Pharmaceuticals (Chadds Ford, PA).

      REFERENCES

        • World Health Organization
        Cancer Pain Relief: With a Guide to Opioid Availability. 2nd ed. WHO Office of Publication, Geneva, Switzerland1996
      1. Practice 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: 1573-1581
        • AGS Panel on Persistent Pain in Older Persons
        The management of persistent pain in older persons.
        J Am Geriatr Soc. 2002; 50: S205-S224
        • American Pain Society
        Guideline for the Management of Pain in Osteoarthritis, Rheumatoid Arthritis and Juvenile Chronic Arthritis. 2nd ed. American Pain Society, Glenview, IL2002: 184
        • Andersson GB
        Epidemiological features of chronic low-back pain.
        Lancet. 1999; 354: 581-585
        • Grilo 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: 491-494
        • Mercadante S
        Opioid rotation for cancer pain: rationale and clinical aspects.
        Cancer. 1999; 86: 1856-1866
        • Mercadante S
        • Bruera E
        Opioid switching: a systematic and critical review.
        Cancer Treat Rev. 2006 Jun; 32 (Epub 2006 Apr 19.): 304-315
        • Quang-Cantagrel ND
        • Wallace MS
        • Magnuson SK
        Opioid substitution to improve the effectiveness of chronic noncancer pain control: a chart review.
        Anesth Analg. 2000; 90: 933-937
      2. Duragesic (fentanyl transdermal system) [package insert]. Janssen Pharmaceuticals, Inc, Titusville, NJ2008
      3. OxyContin (oxycodone HCl controlled-release tablets) [package insert]. Purdue Pharma LP, Stamford, CT2007
        • Coffman 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: 73-77
      4. Codeine Contin (codeine controlled-release tablets) [product monograph]. Purdue Pharma, Pickering, Ontario, Canada2006
      5. Hydrocodone [package insert]. Watson Laboratories, Corona, CA2004
      6. Methadone hydrochloride tablets [package insert]. Mallinckrodt, Inc, Hazelwood, MO2004
      7. Ultram ER (tramadol hydrochloride) [package insert]. Ortho-McNeil, Raritan, NJ2008
      8. Dilaudid-HP injection 10 mg (hydromorphone hydrochloride) full prescribing information. Abbott Laboratories, North Chicago, IL2008
      9. OPANA ER (oxymorphone hydrochloride extended-release tablets) [package insert]. Endo Pharmaceuticals Inc, Chadds Ford, PA2008
        • Foster 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: 403-412
        • Totah 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.): 389-399
        • Wang JS
        • DeVane CL
        Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro.
        Drug Metab Dispos. 2003; 31: 742-747
        • Li Y
        • Kantelip JP
        • Gerritsen-van Schieveen P
        • Davani S
        Interindividual variability of methadone response: impact of genetic polymorphism.
        Mol Diagn Ther. 2008; 12: 109-124
        • Crettol 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: 668-681
        • Zhou 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: 687-710
        • Zhou SF
        Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4.
        Curr Drug Metab. 2008; 9: 310-322
        • Girennavar 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-C421
        • Huber 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: 1230-1238
        • Flockhart DA
        Drug interactions: cytochrome P450 drug interaction table. Indiana University School of Medicine.
        (Accessed March 5, 2009.)
        • Evans 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: 102-105
        • Heiskanen T
        • Olkkola KT
        • Kalso E
        Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.
        Clin Pharmacol Ther. 1998; 64: 603-611
        • Bertilsson 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: 388-397
        • Bathum 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: 119-123
        • Løvlie 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: 30-34
        • Sohn 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: 504-507
        • Aklillu 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: 441-446
        • Bathum 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: 395-401
        • Relling 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: 308-313
        • Masimirembwa 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: 713-719
        • Mbanefo 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: 811-818
        • Lötsch J
        • Skarke C
        • Liefhold J
        • Geisslinger G
        Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives.
        Clin Pharmacokinet. 2004; 43: 983-1013
        • Foster A
        • Mobley E
        • Wang Z
        Complicated pain management in a CYP450 2D6 poor metabolizer.
        Pain Pract. 2007 Dec; 7 (Epub 2007 Nov 6.): 352-356
        • Susce MT
        • Murray-Carmichael E
        • de Leon J
        Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer.
        Prog Neuropsychopharmacol Biol Psychiatry. 2006 Sep 30; 30 (Epub 2006 Apr 24.): 1356-1358
      10. Kadian (morphine sulfate extended-release capsules) [package insert]. Alpharma, Piscataway, NJ2008
        • Bhasker CR
        • McKinnon W
        • Stone A
        • et al.
        Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance.
        Pharmacogenetics. 2000; 10: 679-685
        • Hara Y
        • Nakajima M
        • Miyamoto K
        • Yokoi T
        Morphine glucuronosyltransferase activity in human liver microsomes is inhibited by a variety of drugs that are co-administered with morphine.
        Drug Metab Pharmacokinet. 2007; 22: 103-112
        • Projean D
        • Morin PE
        • Tu TM
        • Ducharme J
        Identification of CYP3A4 and CYP2C8 as the major cytochrome P450s responsible for morphine N-demethylation in human liver microsomes.
        Xenobiotica. 2003; 33: 841-854
        • Takeda S
        • Ishii Y
        • Iwanaga M
        • et al.
        Modulation of UDP-glucuronosyltransferase function by cytochrome P450: evidence for the alteration of UGT2B7-catalyzed glucuronidation of morphine by CYP3A4.
        Mol Pharmacol. 2005; 67 (Epub 2004 Dec 20.): 665-672
        • Takeda S
        • Ishii Y
        • Mackenzie PI
        • et al.
        Modulation of UDP-glucuronosyltransferase 2B7 function by cytochrome P450s in vitro: differential effects of CYP1A2, CYP2C9 and CYP3A4.
        Biol Pharm Bull. 2005; 28: 2026-2027
        • Darbari DS
        • van Schaik RH
        • Capparelli EV
        • Rana S
        • McCarter R
        • van den Anker J
        UGT2B7 promoter variant -840G>A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease.
        Am J Hematol. 2008; 83: 200-202
        • Duguay Y
        • Báár C
        • Skorpen F
        • Guillemette C
        A novel functional polymorphism in the uridine diphosphate-glucuronosyltransferase 2B7 promoter with significant impact on promoter activity.
        Clin Pharmacol Ther. 2004; 75: 223-233
        • Toide K
        • Takahashi Y
        • Yamazaki H
        • et al.
        Hepatocyte nuclear factor-1α is a causal factor responsible for interindividual differences in the expression of UDP-glucuronosyltransferase 2B7 mRNA in human livers.
        Drug Metab Dispos. 2002; 30: 613-615
        • Mercadante S
        • Casuccio A
        • Fulfaro F
        • et al.
        Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study.
        J Clin Oncol. 2001; 19: 2898-2904
        • Cone EJ
        • Caplan YH
        • Moser F
        • Robert T
        • Black D
        Evidence that morphine is metabolized to hydromorphone but not to oxymorphone.
        J Anal Toxicol. 2008; 32: 319-323
        • Cone EJ
        • Heit HA
        • Caplan YH
        • Gourlay D
        Evidence of morphine metabolism to hydromorphone in pain patients chronically treated with morphine.
        J Anal Toxicol. 2006; 30: 1-5
        • McDonough PC
        • Levine B
        • Vorce S
        • Jufer RA
        • Fowler D
        The detection of hydromorphone in urine specimens with high morphine concentrations.
        J Forensic Sci. 2008; 53: 752-754
        • Hutchinson MR
        • Menelaou A
        • Foster DJ
        • Coller JK
        • Somogyi AA
        CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes.
        Br J Clin Pharmacol. 2004; 57: 287-297
        • DrugBank Web site
        Departments of Computing & Biological Sciences, University of Alberta.
        (Accessed March 5, 2009.)
        • Oyler JM
        • Cone EJ
        • Joseph Jr, RE
        • Huestis MA
        Identification of hydrocodone in human urine following controlled codeine administration.
        J Anal Toxicol. 2000; 24: 530-535
        • Oda Y
        • Kharasch ED
        Metabolism of methadone and levo-α-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): potential contribution of intestinal metabolism to presystemic clearance and bioactivation.
        J Pharmacol Exp Ther. 2001; 298: 1021-1032
        • Reisfield GM
        • Salazar E
        • Bertholf RL
        Rational use and interpretation of urine drug testing in chronic opioid therapy.
        Ann Clin Lab Sci. 2007; 37: 301-314
        • Dalén P
        • Frengell C
        • Dahl ML
        • Sjöqvist F
        Quick onset of severe abdominal pain after codeine in an ultrarapid metabolizer of debrisoquine.
        Ther Drug Monit. 1997; 19: 543-544
        • Gasche Y
        • Daali Y
        • Fathi M
        • et al.
        Codeine intoxication associated with ultrarapid CYP2D6 metabolism.
        N Engl J Med. 2004; 351: 2827-2831
        • Eckhardt K
        • Li S
        • Ammon S
        • Schänzle G
        • Mikus G
        • Eichelbaum M
        Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation.
        Pain. 1998; 76: 27-33
        • Barkin RL
        • Iusco AM
        • Barkin SJ
        Opioids used in primary care for the management of pain: a pharmacologic, pharmacotherapeutic, and pharmacodynamic overview.
        in: Boswell MV Cole BE Weiner's Pain Management: A Practical Guide for Clinicians. 7th ed. CRC Press/Taylor & Francis Group, New York, NY2006: 789-804
        • Hucks D
        • Thompson PI
        • McLoughlin L
        • et al.
        Explanation at the opioid receptor level for differing toxicity of morphine and morphine 6-glucuronide.
        Br J Cancer. 1992; 65: 122-126
        • Cann C
        • Curran J
        • Milner T
        • Ho B
        Unwanted effects of morphine-6-glucoronide and morphine.
        Anaesthesia. 2002; 57: 1200-1203
        • Penson RT
        • Joel SP
        • Bakhshi K
        • Clark SJ
        • Langford RM
        • Slevin ML
        Randomized placebo-controlled trial of the activity of the morphine glucuronides.
        Clin Pharmacol Ther. 2000; 68: 667-676
        • Smith MT
        Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites.
        Clin Exp Pharmacol Physiol. 2000; 27: 524-528
        • Wright AW
        • Mather LE
        • Smith MT
        Hydromorphone-3-glucuronide: a more potent neuro-excitant than its structural analogue, morphine-3-glucuronide.
        Life Sci. 2001; 69: 409-420
        • Wright AW
        • Nocente ML
        • Smith MT
        Hydromorphone-3-glucuronide: biochemical synthesis and preliminary pharmacological evaluation.
        Life Sci. 1998; 63: 401-411
        • Klepstad P
        • Borchgrevink PC
        • Dale O
        • et al.
        Routine drug monitoring of serum concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide do not predict clinical observations in cancer patients.
        Palliat Med. 2003; 17: 679-687
        • Quigley C
        • Joel S
        • Patel N
        • Baksh A
        • Slevin M
        Plasma concentrations of morphine, morphine-6-glucuronide and morphine-3-glucuronide and their relationship with analgesia and side effects in patients with cancer-related pain.
        Palliat Med. 2003; 17: 185-190
        • Angst MS
        • Buhrer M
        • Lötsch J
        Insidious intoxication after morphine treatment in renal failure: delayed onset of morphine-6-glucuronide action.
        Anesthesiology. 2000; 92: 1473-1476
        • Hagen NA
        • Foley KM
        • Cerbone DJ
        • Portenoy RK
        • Inturrisi CE
        Chronic nausea and morphine-6-glucuronide.
        J Pain Symptom Manage. 1991; 6: 125-128
        • Osborne R
        • Joel S
        • Grebenik K
        • Trew D
        • Slevin M
        The pharmacokinetics of morphine and morphine glucuronides in kidney failure.
        Clin Pharmacol Ther. 1993; 54: 158-167
        • Osborne RJ
        • Joel SP
        • Slevin ML
        Morphine intoxication in renal failure: the role of morphine-6-glucuronide.
        Br Med J (Clin Res Ed). 1986; 292: 1548-1549
        • Halling J
        • Weihe P
        • Brosen K
        CYP2D6 polymorphism in relation to tramadol metabolism: a study of Faroese patients.
        Ther Drug Monit. 2008; 30: 271-275
        • Gillen C
        • Haurand M
        • Kobelt DJ
        • Wnendt S
        Affinity, potency and efficacy of tramadol and its metabolites at the cloned human μ-opioid receptor.
        Naunyn Schmiedebergs Arch Pharmacol. 2000; 362: 116-121
        • Driessen B
        • Reimann W
        Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro.
        Br J Pharmacol. 1992; 105: 147-151
        • Driessen B
        • Reimann W
        • Giertz H
        Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro.
        Br J Pharmacol. 1993; 108: 806-811
        • Lalovic B
        • Kharasch E
        • Hoffer C
        • Risler L
        • Liu-Chen LY
        • Shen DD
        Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites.
        Clin Pharmacol Ther. 2006; 79: 461-479
        • Feierman DE
        • Lasker JM
        Metabolism of fentanyl, a synthetic opioid analgesic, by human liver microsomes: role of CYP3A4.
        Drug Metab Dispos. 1996; 24: 932-939
        • Inturrisi CE
        Pharmacology of methadone and its isomers.
        Minerva Anestesiol. 2005; 71: 435-437
        • Bush E
        • Miller C
        • Friedman I
        A case of serotonin syndrome and mutism associated with methadone.
        J Palliat Med. 2006; 9: 1257-1259
        • Ito S
        • Liao S
        Myoclonus associated with high-dose parenteral methadone.
        J Palliat Med. 2008; 11: 838-841
        • Sarhill N
        • Davis MP
        • Walsh D
        • Nouneh C
        Methadone-induced myoclonus in advanced cancer.
        Am J Hosp Palliat Care. 2001; 18: 51-53
        • He YJ
        • Brockmöller J
        • Schmidt H
        • Roots I
        • Kirchheiner J
        CYP2D6 ultrarapid metabolism and morphine/codeine ratios in blood: was it codeine or heroin?.
        J Anal Toxicol. 2008; 32: 178-182
        • Kirchheiner J
        • Schmidt H
        • Tzvetkov M
        • et al.
        Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication.
        Pharmacogenomics J. 2007 Aug; 7 (Epub 2006 Jul 4.): 257-265
        • Cone EJ
        • Welch P
        • Paul BD
        • Mitchell JM
        Forensic drug testing for opiates, III: Urinary excretion rates of morphine and codeine following codeine administration.
        J Anal Toxicol. 1991; 15: 161-166
        • Solomon MD
        A study of codeine metabolism.
        Clin Toxicol. 1974; 7: 255-257
        • Dutt MC
        • Lo DS
        • Ng DL
        • Woo SO
        Gas chromatographic study of the urinary codeine-to-morphine ratios in controlled codeine consumption and in mass screening for opiate drugs.
        J Chromatogr. 1983; 267: 117-124
        • Posey BL
        • Kimble SN
        Simultaneous determination of codeine and morphine in urine and blood by HPLC.
        J Anal Toxicol. 1983; 7: 241-245
        • George S
        • Braithwaite RA
        A pilot study to determine the usefulness of the urinary excretion of methadone and its primary metabolite (EDDP) as potential markers of compliance in methadone detoxification programs.
        J Anal Toxicol. 1999; 23: 81-85
      11. Levine B Principles of Forensic Toxicology. 2nd ed. AACC Press, Washington, DC2003: 385
        • Caraco Y
        • Sheller J
        • Wood AJ
        Impact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects.
        J Pharmacol Exp Ther. 1999; 290: 413-422
        • Ahdieh H
        Regarding CYP450 2D6 poor metabolizers [letter].
        Pain Pract. 2008; 8: 329
      12. Foster A. In response to Dr. Ahdieh [published online ahead of print May 26, 2008]. Pain Pract. doi:10.1111/j.1533-2500.2008.00218_2.x.

        • Hasselström J
        • Eriksson S
        • Persson A
        • Rane A
        • Svensson JO
        • Säwe J
        The metabolism and bioavailability of morphine in patients with severe liver cirrhosis.
        Br J Clin Pharmacol. 1990; 29: 289-297
        • Crotty B
        • Watson KJ
        • Desmond PV
        • et al.
        Hepatic extraction of morphine is impaired in cirrhosis.
        Eur J Clin Pharmacol. 1989; 36: 501-506
        • Haberer JP
        • Schoeffler P
        • Couderc E
        • Duvaldestin P
        Fentanyl pharmacokinetics in anaesthetized patients with cirrhosis.
        Br J Anaesth. 1982; 54: 1267-1270
        • Novick DM
        • Kreek MJ
        • Fanizza AM
        • Yancovitz SR
        • Gelb AM
        • Stenger RJ
        Methadone disposition in patients with chronic liver disease.
        Clin Pharmacol Ther. 1981; 30: 353-362
        • Lindeman RD
        • Tobin J
        • Shock NW
        Longitudinal studies on the rate of decline in renal function with age.
        J Am Geriatr Soc. 1985; 33: 278-285
        • Rowe JW
        • Andres R
        • Tobin JD
        • Norris AH
        • Shock NW
        The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study.
        J Gerontol. 1976; 31: 155-163
        • Anderson S
        • Brenner BM
        Effects of aging on the renal glomerulus.
        Am J Med. 1986; 80: 435-442
        • Milne RW
        • Nation RL
        • Somogyi AA
        • Bochner F
        • Griggs WM
        The influence of renal function on the renal clearance of morphine and its glucuronide metabolites in intensive-care patients.
        Br J Clin Pharmacol. 1992; 34: 53-59
        • Pauli-Magnus C
        • Hofmann U
        • Mikus G
        • Kuhlmann U
        • Mettang T
        Pharmacokinetics of morphine and its glucuronides following intravenous administration of morphine in patients undergoing continuous ambulatory peritoneal dialysis.
        Nephrol Dial Transplant. 1999; 14: 903-909
        • Wolff J
        • Bigler D
        • Christensen CB
        • Rasmussen SN
        • Andersen HB
        • Tønnesen KH
        Influence of renal function on the elimination of morphine and morphine glucuronides.
        Eur J Clin Pharmacol. 1988; 34: 353-357
        • Dubs A
        • Wiedemeier P
        • Caduff B
        Morphine poisoning in chronic kidney failure: morphine-6-glucuronide as a pharmacologically active morphine metabolite [in German].
        Dtsch Med Wochenschr. 1999; 124: 896-898
        • Babul N
        • Darke AC
        • Hagen N
        Hydromorphone metabolite accumulation in renal failure [letter].
        J Pain Symptom Manage. 1995; 10: 184-186
        • Furlan V
        • Hafi A
        • Dessalles MC
        • Bouchez J
        • Charpentier B
        • Taburet AM
        Methadone is poorly removed by haemodialysis [letter].
        Nephrol Dial Transplant. 1999; 14: 254-255
        • Kreek MJ
        • Schecter AJ
        • Gutjahr CL
        • Hecht M
        Methadone use in patients with chronic renal disease.
        Drug Alcohol Depend. 1980; 5: 197-205
        • Dean M
        Opioids in renal failure and dialysis patients.
        J Pain Symptom Manage. 2004; 28: 497-504
        • Koehntop DE
        • Rodman JH
        Fentanyl pharmacokinetics in patients undergoing renal transplantation.
        Pharmacotherapy. 1997; 17: 746-752
        • Chauvin M
        • Sandouk P
        • Scherrmann JM
        • Farinotti R
        • Strumza P
        • Duvaldestin P
        Morphine pharmacokinetics in renal failure.
        Anesthesiology. 1987; 66: 327-331
        • Sear JW
        • Hand CW
        • Moore RA
        • McQuay HJ
        Studies on morphine disposition: influence of renal failure on the kinetics of morphine and its metabolites.
        Br J Anaesth. 1989; 62: 28-32
        • Murtagh FE
        • Chai MO
        • Donohoe P
        • Edmonds PM
        • Higginson IJ
        The use of opioid analgesia in end-stage renal disease patients managed without dialysis: recommendations for practice.
        J Pain Palliat Care PharmacoTher. 2007; 21: 5-16

      Linked Article

      • Contemporary Clinical Opioid Use: Opportunities and Challenges
        Mayo Clinic ProceedingsVol. 84Issue 7
        • Preview
          Opiate analgesics have been used by humans for thousands of years and are the longest continuously used class of medications. The recent increased interest in opiates (drugs derived from opium) and opioids (more generally, any natural or synthetic drug that binds to an opioid receptor) has evolved largely from 5 directions: (1) advances in the design of new opioid receptor agonist and antagonist drugs; (2) expansion and innovation in methods of drug delivery; (3) increased public awareness of pain management options and the appropriateness of aggressively treating pain (eg, declaration of pain as the “fifth vital sign”1 and pain relief as a fundamental human right2); (4) growing recognition of the serious consequences of opioid misuse, misadventure, and addiction; and (5) medicolegal aspects of practitioners' prescribing practices and legal prosecution for “overprescribing.” These and related issues are addressed in 4 articles and 1 additional editorial in the current issue of Mayo Clinic Proceedings.
        • Full-Text
        • PDF