Much of the literature and discussions in the pain management field these days are so focused on prescription opioid misuse, abuse, and addiction that other safety concerns relating to prescribing seem to be overlooked. Far more prevalent problems, and ones that can be more readily controlled, involve potentially harmful interactions between opioids and other medications or substances. Prior research has observed that 70% of patients taking an opioid analgesic also take at least one nonprescription drug or substance and a majority also are prescribed one or more adjunctive medications. Such polypharmacy can set in motion physiologic processes that are a recipe for trouble; so, prudent practitioners must understand and be alert for opioid-drug interactions.
Complex Opioid Pharmacokinetics
Drug-drug interactions may be defined as two or more drugs affecting each other in such a way that the metabolism, elimination (clearance), effectiveness, and/or toxicity of one or all of the drugs are changed; often for the worse. A special concern is with drugs metabolized and cleared via the cytochrome P450 (CYP450) enzyme system, primarily in the liver. While this is a complex subject, and there are dozens of different CYP450 genes in humans, relatively few of the gene-encoded enzymes play a role in drug metabolism; most prominently involved are the CYP1, CYP2, CYP3 families and the CYP3A4 and CYP2D6 isoforms.
When taken concurrently, two or more drugs metabolized by the same enzyme(s) may compete against each other with the “winner,” so to speak, attracting more of the needed enzyme(s) for metabolism and clearance. Certain drugs may increase (ie, induce) or decrease (ie, inhibit) the actions of select enzymes and this can alter metabolism of coadministered drugs that are dependent on those enzymes. Some patients may be sensitive to even mild enzyme inducers or inhibitors. Further complicating the picture there can be genetic variations of the enzymes (polymorphisms) affecting their activity, which can alter drug metabolism in affected patients: some patients may be very rapid metabolizers of particular drugs; whereas, other patients may clear those same drugs much more slowly leading to possible toxic accumulations.
When it comes to opioid analgesics, several are largely unaffected by CYP450 metabolism, such as morphine, hydromorphone, and oxymorphone. However, most others — including, codeine, hydrocodone, oxycodone, tramadol, fentanyl, and methadone — are metabolized via CYP3A4 and CYP2D6 (plus CYP2B6 for methadone). Exposures to other drugs that rely on those same enzymes for metabolism, or are inducers or inhibitors of those enzymes, may incur opioid-drug interactions of some sort; although, it must be emphasized that not every such opioid-drug exposure results in a harmful interaction.
Still, opioid-drug interactions and/or individual genetic differences, often may account for why two patients with the same pain condition and prescribed identical opioid-analgesic regimens may have entirely different experiences; one patient may be overmedicated, perhaps extremely so, while the other complains of inadequate analgesic effect. Urine or serum drug testing in such cases may detect an excess of opioid in one patient, while the drug is barely detectable, if at all, in the other patient — even though they are both compliant with the prescribed regimen and taking exactly the same daily amount of opioid.
Concerns About Harmful Opioid-Drug Exposures
Researchers writing in Pain Practice recently reported using a retrospective analysis of large commercial and Medicare databases to evaluate opioid-drug exposures having potential to cause drug interactions among patients treated for chronic low back pain [Pergolizzi et al. 2010]. Overall, they identified 100,159 long-term patients taking opioid analgesics metabolized via CYP450 enzyme pathways, of whom 27% also were prescribed other CYP450-metabolized drugs that might cause an interaction.
Thus, more than 1 in 4 patients were exposed to potentially harmful drug interactions, with such exposures higher in women than men — 30.6% vs. 22%, respectively — and younger patients (ages 35-54) were 70% more likely to have an opioid-drug exposure of concern. The majority of potentially harmful exposures were with concomitant medications known to inhibit the action CYP2D6 enzymes, which might dangerously increase levels of the respective opioids. Unfortunately, the researchers were unable to determine how many of the opioid-drug exposures actually resulted in harmful opioid-drug interactions; however, this study suggests that such exposures are alarmingly common, at least in patients with chronic low back pain, and they should be equally of concern in the treatment of all other pain conditions for which opioids are prescribed.
Opioid prescribers who do not take potential opioid-drug interactions into account may incur problematic and even tragic consequences. Fishbain and colleagues , writing in Pain Medicine, describe forensic reports involving allegations of medical malpractice resulting from opioid prescribing for pain. In one case, a 50-year-old male patient being treated for chronic pain, and treated separately by a psychiatrist for depression and posttraumatic stress disorder, had been maintained without incident on opioid therapy (oxycodone in this case) for 18 months but was suddenly found dead at home from alleged opioid toxicity. Subsequently, the patient’s family brought legal action against both the opioid-prescribing physician and the psychiatrist.
In all, the patient had been prescribed 3 medications besides oxycodone. Unknown to the physician, 2 weeks earlier the psychiatrist had increased the patient’s dose of fluoxetine (a strong CYP2D6 inhibitor) by 50%, which may have robustly potentiated opioid adverse effects. It is important to note that effects of CYP enzyme inhibition can take some time to develop; perhaps weeks as in this case. However, cases of suspected opioid overdose such as this are complicated by the fact that ranges of therapeutic serum levels compared with toxic serum levels of many drugs, including most opioids, overlap. Although the medical examiner proclaimed there were “high toxic levels” of oxycodone present in the patient at the time of death it could not be determined with certainty that this was the cause of death — especially since the patient already had no doubt developed considerable opioid tolerance during 18 months of prior therapy. In fact, it was ultimately unknown whether cause of death was accidental opioid poisoning due to drug interaction, accidental overdose (the patient taking more oxycodone than prescribed), or suicide by drug overdose.
Fishbain et al. note that in cases where opioid-drug interactions are known to result from coadministration of a metabolism-inhibiting medication (eg, fluoxetine in the above case), prescribing an opioid at otherwise normal doses might be viewed by the courts as excessive or inappropriate dosing. Healthcare providers are expected to know about and understand the interactive potential of drugs that they prescribe; furthermore, inappropriate prescribing due to ignorance of what other providers are already prescribing for the same patient can be difficult to defend. In the case above, both the physician and psychiatrist were deemed culpable for not sharing information with each other about medications and doses the patient had been prescribed and, subsequently, for not taking the possible opioid-drug interactions into account.
What Can Opioid Prescribers Do?
Fishbain and coauthors  stress that the vast majority of patients with chronic pain prescribed opioids are also taking other drugs for associated comorbidities, such as antidepressants and anticonvulsants, or are prescribed these adjunctive medications for their pain. Therefore, polypharmacy is generally the rule rather than the exception in pain management and the patient can be subject to significant opioid-drug exposure and possible interaction risk. They suggest a number of risk-mitigation strategies that we have modified and expanded as follows (however, this list is not all-inclusive):
- Be aware of which medications or other substances are metabolized via the CYP450 enzyme system and may interact with opioid analgesics [see resources below].
- At each visit, review with the patient every medication being taken and document the drug and dose. This also should include over-the-counter medications, supplements, herbal remedies, alcohol, and other substances (including illicit drugs if possible).
- Advise patients that they must tell you if they themselves or any healthcare providers have made any additions or changes to their medication or substance use and document that patients have been advised to do this.
- Educate patients about any potential adverse or lethal effects of prescribed medications and document that patients have been advised of this.
- Educate patients that street drugs — eg, cannabinoids (even where legal), cocaine, etc. — and alcohol can exacerbate opioid-drug interactions and document that this information has been provided.
- Initiate any CYP450-affected opioid analgesic at low dose (especially in the presence of a CYP inhibitor agent) and only increase the opioid dose gradually after carefully assessing the patient’s response.
- Keep the dose of any co-prescribed CYP450 inhibitor as low as possible or if absolutely necessary to increase the dose, do so very gradually, recognizing that it can take some time before effects of metabolic inhibition are exhibited.
- When possible, consider co-prescribing drugs that are metabolized via other pathways or by multiple CYP450 enzymes rather one.
- The type and amount of opioid may not be most important; a small supply of a short acting opioid or an ongoing prescription for a long-acting opioid could be equally problematic if there is a significant opioid-drug interaction.
- Opioid prescribers should not assume that potential opioid-drug interactions will be detected by the pharmacist and the patient warned when the prescription is purchased. It cannot be expected that the pharmacy will have a record of all drugs and other substances that the patient is taking.
Fishbain et al. further observe that there has been some discussion about the value of quantitative therapeutic drug monitoring (TDM) and genotyping for CYP450 polymorphisms that may affect opioid metabolism. Both approaches are being promoted by some commercial laboratories but neither is currently considered a “standard of care.” From a safety perspective, quantitative TDM can be inconclusive since, as noted above, there are overlapping ranges for opioid serum concentrations considered either therapeutic or toxic, and there are variable factors affecting individual response to opioids (such as established tolerance level or variable CYP enzyme activity). Genotyping, such as for CYP2D6 polymorphisms, can be useful but it is still a specialized procedure and may not be practical, accessible, or cost effective in typical pain management settings.
Clinically, it is important to assess if a patient appears to be overly sensitive to low doses of a CYP-metabolized opioid (eg, signs of overmedication), which could indicate the presence of an unknown CYP inhibitor or a synergistic effect of concurrently taking substances affecting the central nervous system. Conversely, a patient complaining of continuing pain or opioid withdrawal even at reasonably high opioid doses may be a rapid metabolizer of the particular medication (possibly due to CYP2D6 polymorphisms or concomitant use of a CYP inducer) or fully tolerant of the current dose. All of these effects should be fully documented in the patient record and, with patient consent, shared with other medication prescribers who treat the patient.
Many practitioners rely on urine drug testing (UDT) to assess patient compliance and response to opioid therapy. However, as we have described previously [here], there are a number of pitfalls and without very cautious interpretation UDT may provide misinformation rather than helpful guidance regarding opioid dosing and drug interactions. Another consideration is caution during rotation from one opioid to another, which we have discussed [here]. For example, switching from a non-CYP-metabolized opioid (eg, morphine) to one affected by CYP metabolism (eg, methadone) in the presence of other CYP-metabolized medications could have unexpected, possibly harmful, interactive effects.
Admittedly, opioid-drug interactions is a complex subject, requiring considerable knowledge and circumspection whenever prescribing opioid analgesics. However, neglecting the various concerns may incur significant risk of unexpected and undesirable outcomes. There are further resources available to help prescribers, and their patients, understand and control such risks — see below.
> Up-to-date tables of drugs metabolized via CYP450 enzymes, including inhibitor and inducer agents, can be accessed [here].
> The ePocrates Rx online drug-drug interaction checker has been recommended by some authors and can be accessed [here]. Free registration is required.
> A research review for healthcare providers further describing pharmacokinetic drug interactions, with an emphasis on methadone, may be downloaded [here]
> The Opioids911-Safety website — http://opioids911.org/ — provides education for patients and their caregivers on opioid safety, including how to prevent, identify, and manage emergency situations.
> A handout for patients/caregivers on opioid safety, including what to watch for in opioid overmedication versus overdose, and what to do, can be downloaded [here]
> Education for patients/caregivers on opioid withdrawal and its signs/symptoms can be accessed [here].
> We have previously discussed the potential life-saving value of take-home naloxone prescribed for patients and their home-caregivers to avert opioid overmedication and overdose [here]. A new paper on this subject also is now available [here].
> Many foods and beverages can interact with opioids and other drugs. A guidebook for patients titled “Avoid Food-Drug Interactions” is available from the National Consumers League and the U.S. Food and Drug Administration [PDF here].
> Fishbain DA, Lewis JE, Gao J. Allegations of Medical Malpractice in Chronic Opioid Analgesic Therapy Possibly Related to Collaborative/Split Treatment and the P-450 Enzyme System: Forensic Case Report. Pain Med. 2010(Sep);11:1419-1425 [abstract here].
> Pergolizzi JV, Labhsetwar SA, Puenpatom RA, et al. Prevalence of Exposure to Potential CYP450 Pharmacokinetic Drug–Drug Interactions among Patients with Chronic Low Back Pain Taking Opioids. Pain Practice. 2010(Aug); online ahead of print [abstract here].