Levorphanol and Methadone: Considering the Alternatives

Methadone is not just your classic opioid. It also has NMDA receptor activity which has been postulated to help decrease the development of opioid tolerance. It’s also postulated to have more of a benefit in patients with neuropathic pain. Methadone is available in tablet or solution formulations, and is the only extended release tablet that’s an opioid that can be crushed without breaking the long-acting mechanism of action. You can dose it every 8 or 12 hours, and so depending on the patient and what their needs are, there is some flexibility there. But there are some drawbacks, including drug-drug interaction. It’s metabolized primarily through CYP3A4 and 2B6. It has a lot of CYP enzymes through which lots of other medications are metabolized as well. In patients who have a risk for QTC prolongation, EKG monitoring is sometimes required, and that can be cumbersome. Then there are the variable pharmacokinetics. Its half-life can be anywhere from five to 60 hours. Some patients it might not last very long, but in some other patients we can get into trouble if we adjust the dose. So, for the primary care provider considering methadone, if you don’t have clinical experience, it’s really important to speak to a colleague or perhaps a clinical pharmacist on your team to make sure that you’re dosing correctly. To be sure you’re converting or starting the dose out appropriately. You’re not titrating it too quickly. You also need to be looking at the drug interactions, and getting the EKG monitoring and cardiac assessment that you might need.

Levorphanol has a similar mechanism of action compared to methadone.  It has the mu opioid agonist activity and it also has the NMDA receptor antagonist activity which is helpful for neuropathic pain; but it does not have as many CYP3A4 drug interactions. It also doesn’t have any effect on the QTC interval. Those are some of the major advantages. On the other side, we certainly don’t have as much clinical experience with levorphanol.  Manufacturer availability of levorphanol is pretty scarce compared to methadone. Not as many clinicians have familiarity with levorphanol, and a concern would be patients who end up going to the ER or urgent care especially on the weekends. We also don’t have a lot of data in terms of equianalgesic dosing. When you’re converting someone from another opioid to levorphanol, it’s really a guessing game based on what’s out there.  We don’t have a lot of good information. And levorphanol is dosed every eight hours or three times a day automatically. Thus, we perhaps don’t have the same dosing flexibility that we do with methadone.