Though this article is a decade old by now, the biological processes of opioid metabolism haven’t changed, so it’s still entirely valid. It points out several reasons why prescribing standard doses of opioids is not a valid medical practice.
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 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.
Experienced clinicians are aware that the efficacy and tolerability of specific opioids may vary dramatically among patients…
I would have thought that the CDC would listen to “experienced clinicians”, not just self-appointed “experts”, to confirm that standard doses for opioids are not medically appropriate, no matter how politically desirable (and idiot-proof) they may be.
…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.
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 is another factor that makes standard doses an ignorant political stance that has nothing do to with the practice of medicine.
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.
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.
- Phase 1 metabolism typically subjects the drug to oxidation or hydrolysis. It involves the cytochrome P450 (CYP) enzymes.
- Phase 2 metabolism conjugates the drug to hydrophilic substances, such as glucuronic acid, sulfate, glycine, or glutathione.
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.
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 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).
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.
Metabolic Pathway/Enzyme Involvement
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).
Cytochrome P450 3A4 Substrates, Inhibitors, and Inducers
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.
Cytochrome P450 2D6 Substrates, Inhibitors, and Inducers
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.
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.
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.
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) is UGT2B7.
The activity of UGT2B7 shows significant between-patient variability, and several authors have identified allelic variants of the gene encoding this enzym
…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.
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.
This is why standard doses of opioids are so stupid and medically inappropriate. Of course, this doesn’t prevent ignorant politicians from coming up with their own uninformed ideas about some “standard” regulations.
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
In some patients, the most effective and well-tolerated opioid will be one that undergoes CYP-mediated metabolism.
In short, for some patients, selecting an opioid without considerable potential for drug interactions may not be possible.
Again, it’s clear that there are no standard rules possible because our bodies are all so different.
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
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 a huge problem with urine drug screens because the opioid you are prescribed may show up as a different one in the drug screen after it’s been metabolized.
Major Opioid Metabolites
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 and in rapid metabolizers who form too much 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).
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
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
The primary metabolite of hydromorphone, hydromorphone-3-glucuronide, has neuroexcitatory potential similar to or greater than the M3G metabolite of morphine.
hydromorphone is available only in short-acting formulations and extended-release formulations are recommended in patients with chronic pain requiring long-term therapy.
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
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 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.
Fentanyl is predominantly converted by CYP3A4-mediated N-dealkylation to norfentanyl, a nontoxic and inactive metabolite
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
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
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.
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.
As already stated, altered opioid metabolism in ethnic populations is also a byproduct of allelic variants of the gene encoding CYP2D6.
Demographic/Medical Factors Influencing Opioid Metabolism
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.
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.
The pharmacokinetics of fentanyL and methadone, 2 of the frequently used opioids, are not significantly affected by hepatic 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.
Because most opioids are eliminated primarily in urine, dose adjustments are required in patients with renal impairment.
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.
This is nothing new since that’s how opioids should always be prescribed: tailored to the individual patient. Only lately has the misguided idea of “standardization” invaded the medical treatment of pain.
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.
This information directly contradicts any standardization of opioid dosages, but that hasn’t stopped more and more politicians and “medical groups” from implementing policies that reject, and sometimes forbid outright, the proper medical care for pain.