Drug–Drug Interactions between Methadone and Apixaban

Dear Editor:

As new medications are developed and introduced into practice, it is important to recognize the potential for drug–drug interactions and their implications on symptom management. Given that a number of analgesic medications are metabolized via P-450 pathways, drug–drug interactions are of particular importance in medication selection and in monitoring the efficacy and potential side effects. Clinicians must recognize that drugs that affect these pathways may lead to elevated or inadequate serum levels of selected analgesics and analgesic failure depending on nature of the interaction.

Direct thrombin inhibitors and factor-Xa inhibitors represent an exciting development in the management of various coagulopathic conditions and have shown to be beneficial for the treatment and prevention of thromboembolic events.^1,2 Growth in the prescription of these novel anticoagulants is likely to climb. However, little is known about their potential drug–drug interactions, especially with medications that utilize the CYP3A4 pathway.

Apixaban is one such anticoagulant that has been shown to provide benefit. Apixaban is metabolized through the CYP3A4/5 and P-gp pathways; however, it is not known to be an inducer or inhibitor of CYP3A4. Drug insert information recommends dose titration of apixaban if used concomitantly with strong inhibitors of CYP3A4 and P-gp and recommends against apixaban use concomitantly with strong inducers. However, specific pharmacodynamics studies have not been reported, particularly with regard to interactions with analgesics using the same metabolic pathway.

We report on two cases of middle-aged patients with end-stage renal disease requiring hemodialysis and coagulopathy requiring warfarin. Both patients were admitted for workup and treatment of ulcerations consistent with calciphylaxis. Warfarin was discontinued in favor of apixaban. Pain was initially treated with short-acting opioids with appropriate titration and addition of long-acting opioids. Both patients ultimately were transitioned to methadone using calculations of mean equivalent oral morphine dose from the Ayonrinde rotation guidelines. ³ Despite this transition, severe pain persisted and a decrease in oral short-acting opioid requirement was not seen. Methadone doses were increased with only minimal improvement. Ultimately, these patients required methadone dosing roughly three times the initial calculated methadone dose using the Ayonrinde rotation guidelines. ³

The lack of pain relief was surprising, given the initial mean equivalent oral morphine requirements. Methadone is a mixed opioid agonist and N-methyl-d-aspartase antagonist with potent analgesic effects. Methadone is metabolized primarily through the CYP3A4, 2B6, and 2C19 pathways and is also a substrate of P-gp. ⁴ Our observations lead to the hypothesis that apixaban could be acting in vivo as a strong inducer of the CYP-3A4 system, leading to a therapeutic failure of methadone. Alternatively, this could be a drug–drug interaction involving P-gp. A literature search revealed no known evidence of such interactions.

Conclusion

It is important to recognize potential drug–drug interactions between analgesics and non-vitamin K antagonist oral anticoagulants to allow for safe and timely pain control via titration of analgesics. These cases outline that the interaction between methadone and apixaban may be one of these important drug–drug interactions and warrants further investigation into apixaban's effects at these pathways.