This is a long and detailed medical paper explaining how individuals metabolize opioids, why individuals have such a wide variety of responses to opioids, and why drug tests give ambiguous results.
Abstract: 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.
This fact of individual variability is deliberately ignored by the CDC Guidelines and all the other restrictions on opioid prescriptions.
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.
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.
Experienced clinicians are aware that the efficacy and tolerability of specific opioids may vary dramatically among patients
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.
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.
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
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.
Numerous individuals with EDS (and without it) have genetic variations in this particular cytochrome.
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
- 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
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
The complex interplay of methadone with the CYP system, involving as many as 6 different enzymes, is accompanied by considerable interaction potential.
The CYP2D6 enzyme is entirely responsible for the metabolism of hydrocodone, codeine and dihydrocodeine to their active metabolites (hydromorphone, morphine, and dihydromorphine, respectively)
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
Phase 2 Metabolism
Morphine, oxymorphone, and hydromorphone are each metabolized by phase 2 glucuronidation
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
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.
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, 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 (Dilaudid), methadone, or oxymorphone (Opana) 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.