Stay Alert for Opioid Interactions

Roughly 30% of patients taking an opioid chronically are on interacting meds...and dangerous combos often go unrecognized.

You may feel stuck between a rock and a hard place...especially when patients have been on risky combos for a while.

But patient or med factors may tip the balance at any time. Be ready with a practical approach to manage interactions.

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Consider the patient. Review for factors that may increase opioid risks, such as changes in kidney or liver function. Stay alert for clues, such as a new Rx from a nephrologist, patients on phosphate binders, etc.

Be extra careful in patients who have other risks for respiratory depression...COPD, sleep apnea, etc.

Keep in mind, opioid use in older adults can also lead to falls or delirium...and certain meds (gabapentin, etc) in combo increase risks.

Evaluate meds. Continue to discourage using opioids with benzos OR other CNS depressants...such as sleep meds (zolpidem, etc), muscle relaxants (cyclobenzaprine, etc), gabapentinoids, or alcohol.

Lean away from combining a serotonergic opioid...tramadol, fentanyl, meperidine, or methadone...with other serotonergic meds (SSRIs, etc).

Pay close attention to interaction alerts with methadone. For instance, avoid methadone with other meds that prolong the QT interval (macrolides, quinolones, etc).

Watch for many CYP450 interactions. For example, CYP3A4 inhibitors (itraconazole, ritonavir, etc), may increase levels of certain opioids, such as hydrocodone, fentanyl, or oxycodone.

Help mitigate risk. Try to avoid situations where you see risky combos stacking up...and switch one of the interacting meds if possible.

Continue to emphasize nondrug measures and non-opioid options.

For acute pain, emphasize limiting opioids to the lowest dose and shortest duration possible.

Discuss tapering long-term opioids, especially with patients at increased risk of overdose or having side effects.

Or if patients are unable to taper full opioid agonists, consider a switch to buprenorphine. It may cause less euphoria and constipation compared to full agonists...and have less potential for misuse and overdose.

Recommend a med for opioid overdose...naloxone or nalmefene...with each opioid Rx, especially if they’re on an interacting med.

Use our resource, Appropriate Opioid Use, for help managing expectations, tapering tips, the role of urine drug testing, etc.

Key References

  • Matos A, Bankes DL, Bain KT, et al. Opioids, Polypharmacy, and Drug Interactions: A Technological Paradigm Shift Is Needed to Ameliorate the Ongoing Opioid Epidemic. Pharmacy (Basel). 2020 Aug 25;8(3):154.
  • Davison SN. Clinical Pharmacology Considerations in Pain Management in Patients with Advanced Kidney Failure. Clin J Am Soc Nephrol. 2019 Jun 7;14(6):917-931.
  • Overholser BR, Foster DR. Opioid pharmacokinetic drug-drug interactions. Am J Manag Care. 2011 Sep;17 Suppl 11:S276-87.
  • Dowell D, Ragan KR, Jones CM, et al. CDC Clinical Practice Guideline for Prescribing Opioids for Pain - United States, 2022. MMWR Recomm Rep. 2022 Nov 4;71(3):1-95.
Pharmacist's Letter. June 2024, No. 400602

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