Opioid Metabolism | Free Full Text PubMed article
This article explains the intricate details of how opioids are metabolized:
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.
Altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified.
Pharmacodynamic and pharmacokinetic differences underlie this variability of response.
Pharmacodynamics refers to how a drug affects the body. 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.
Pharmacokinetics describes how the body alters the drug. 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.
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.
FACTORS INFLUENCING OPIOID METABOLISM
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 CYP2D6 enzyme is entirely responsible for the metabolism of hydrocodone, codeine, and dihydrocodeine to their active metabolites (hydromorphone, morphine, and dihydromorphine, respectively)
Clinical Implications of Metabolic Pathways
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
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.
PRODUCTION OF ACTIVE METABOLITES
Some opioids produce multiple active metabolites after administration:
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.
This is the problem with untrained interpretation of Urine Drug Tests. Simply looking at what drugs show up on the screen is NOT indicative of what drugs were ingested.
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.
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.
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)
A recent study found that a small proportion of morphine is also metabolized to hydromorphone,55 although there are no data suggesting a meaningful clinical effect.
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
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
Oxycodone is metabolized by CYP3A4 to noroxycodone and by CYP2D6 to oxymorphone
The central opioid effects of oxycodone are governed primarily by the parent drug, with a negligible contribution from its circulating oxidative and reductive metabolites
OPIOIDS WITHOUT CLINICALLY RELEVANT ACTIVE METABOLITES
Fentanyl, oxymorphone, and methadone do not produce metabolites that are likely to complicate treatment.
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
The urine of patients treated with morphine may contain small amounts of hydromorphone (≤2.5% of the morphine concentration).
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.
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.