REVIEWOpioid Metabolism
Section snippets
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,
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
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
PRODUCTION OF ACTIVE METABOLITES
Some opioids produce multiple active metabolites after administration (Table 410, 11, 16, 17, 18, 28, 43, 53, 54, 55, 56, 57, 58, 59, 60). 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.
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.82 An active metabolite of oxymorphone, 6-hydroxy-oxymorphone, makes up less than 1% of the administered dose excreted in urine and
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
POPULATION PHARMACOKINETICS
Opioid metabolism differs with individual opioids in populations stratified according to age, sex, and ethnicity (Table 510, 11, 13, 14, 15, 16, 17, 18, 43). Reduced clearance of morphine,43 codeine,13 fentanyl,10 and oxymorphone18 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.11 Chinese
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.10, 11, 13, 14, 17, 18, 43 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
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
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 (116)
Epidemiological features of chronic low-back pain
Lancet
(1999)- et al.
Opioid rotation in the treatment of joint pain: a review of 67 cases
Joint Bone Spine
(2002) - et al.
Opioid switching: a systematic and critical review
Cancer Treat Rev
(2006 Jun) - et al.
Effects of coffee and its chemopreventive components kahweol and cafestol on cytochrome P450 and sulfotransferase in rat liver
Food Chem Toxicol
(2008) - et al.
Ultrarapid metabolizers of debrisoquine: characterization and PCR-based detection of alleles with duplication of the CYP2D6 gene
FEBS Lett
(1996) - et al.
Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer
Prog Neuropsychopharmacol Biol Psychiatry
(2006 Sep 30) - et al.
Morphine glucuronosyltransferase activity in human liver microsomes is inhibited by a variety of drugs that are co-administered with morphine
Drug Metab Pharmacokinet
(2007) - et al.
Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation
Pain
(1998) - et al.
Hydromorphone-3-glucuronide: a more potent neuro-excitant than its structural analogue, morphine-3-glucuronide
Life Sci
(2001) - et al.
Hydromorphone-3-glucuronide: biochemical synthesis and preliminary pharmacological evaluation
Life Sci
(1998)
Chronic nausea and morphine-6-glucuronide
J Pain Symptom Manage
Gas chromatographic study of the urinary codeine-to-morphine ratios in controlled codeine consumption and in mass screening for opiate drugs
J Chromatogr
Fentanyl pharmacokinetics in anaesthetized patients with cirrhosis
Br J Anaesth
Cancer Pain Relief: With a Guide to Opioid Availability
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
The management of persistent pain in older persons
J Am Geriatr Soc
Opioid rotation for cancer pain: rationale and clinical aspects
Cancer
Opioid substitution to improve the effectiveness of chronic noncancer pain control: a chart review
Anesth Analg
Duragesic (fentanyl transdermal system) [package insert]
OxyContin (oxycodone HCl controlled-release tablets) [package insert]
The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268)
Drug Metab Dispos
Codeine Contin (codeine controlled-release tablets) [product monograph]
Hydrocodone [package insert]
Methadone hydrochloride tablets [package insert]
Ultram ER (tramadol hydrochloride) [package insert]
Dilaudid-HP injection 10 mg (hydromorphone hydrochloride) full prescribing information
OPANA ER (oxymorphone hydrochloride extended-release tablets) [package insert]
Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4
Br J Clin Pharmacol
Enantiomeric metabolic interactions and stereoselective human methadone metabolism
J Pharmacol Exp Ther
Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro
Drug Metab Dispos
Interindividual variability of methadone response: impact of genetic polymorphism
Mol Diagn Ther
ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment
Clin Pharmacol Ther
Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring
Ther Drug Monit
Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4
Curr Drug Metab
Potent inhibition of human cytochrome P450 3A4, 2D6, and 2C9 isoenzymes by grapefruit juice and its furocoumarins
J Food Sci
Drug interactions: cytochrome P450 drug interaction table. Indiana University School of Medicine
A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population
J Med Genet
Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone
Clin Pharmacol Ther
Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin
Clin Pharmacol Ther
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
Metoprolol oxidation polymorphism in a Korean population: comparison with native Japanese and Chinese populations
Br J Clin Pharmacol
Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles
J Pharmacol Exp Ther
Phenotypes and genotypes for CYP2D6 and CYP2C19 in a black Tanzanian population
Br J Clin Pharmacol
Lower prevalence of the debrisoquin oxidative poor metabolizer phenotype in American black versus white subjects
Clin Pharmacol Ther
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
A study of the debrisoquine hydroxylation polymorphism in a Nigerian population
Xenobiotica
Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives
Clin Pharmacokinet
Complicated pain management in a CYP450 2D6 poor metabolizer
Pain Pract
Kadian (morphine sulfate extended-release capsules) [package insert]
Cited by (563)
Scholarly literature on nurses and pharmacogenomics: A scoping review
2024, Nurse Education TodayMechanisms of pain in aging and age-related conditions: Focus on caregivers
2024, Ageing Research ReviewsImpact of a Community Pharmacy Pharmacotherapy Follow-up (PTF) service in patients using opioid analgesic
2024, Exploratory Research in Clinical and Social Pharmacy3-Methoxy-2-phenylimidazo[1,2-b]pyridazines highly active against Mycobacterium tuberculosis and Mycobacterium marinum
2023, European Journal of Medicinal ChemistryAversion-associated drug and alcohol seeking in females
2023, Frontiers in Neuroendocrinology
This article is freely available on publication.