Why Not Methadone?

With this newsletter moving to Substack, it felt like the right moment to return to Pain & Symptom Management. Much of my work begins when “the usual” approaches fall short, where standard strategies don’t bring the relief patients need. Let’s take a closer look at the role of methadone in these complex cases.

Nowadays, I’m known at work for how frequently I suggest trying methadone for patients who appear to have refractory neuropathic pain.  But that wasn’t always the case.

Almost 20 years ago, one of our fellows and I cared for a patient who had breast cancer invading her brachial plexus. He had seen signs of opioid toxicity in similar patients whom we had initially treated with SR oxycodone, gabapentin and dexamethasone for severe neuropathic pain.  When they showed signs of neurotoxicity, we would rotate them to methadone with good effect, often being able to stop the adjuvants altogether.  As we created an initial treatment recommendation for this patient he asked, “Why not methadone?”.  And of course he was right—why not START with methadone?!

That has been my “mantra” ever since—when I see a patient with cancer who I think has severe neuropathic pain, we start with methadone. Who are these patients?  Most commonly, those with infiltration of a nerve plexus like the brachial plexus or the celiac plexus. But also, patients with retroperitoneal adenopathy especially from solid tumors, where the nerves are infiltrated by the tumor as they exit the spinal cord.  The lumbosacral plexus can be infiltrated with recurrence of colorectal cancers. The perineal plexus is often involved in patients with rectal or gynecologic cancers. The pain can be excruciating. Methadone may save these patients the need for an intrathecal pump. 

Less well-known neuropathic pains are mucositis and ischemic ulcers of patients with peripheral vascular disease. Mucositis that is refractory to standard PCA opioid therapy and severe skin manifestations of active GVHD are also partially neuropathic pains; they often respond to low doses of methadone, which leads to less sedation than conventional opioids. So do ischemic leg ulcers of patients with peripheral vascular disease. As little as 1 or 2 mg of methadone twice a day can relieve that pain. I’ve treated patients in their 80s with no adverse effects.

Methadone is structurally unrelated to the morphine family of drugs and to meperidine and fentanyl, and it can be used in the rare case of true allergy to these agents. It is also good for patients with renal insufficiency because it has no known active metabolites and does not accumulate. 

Why is methadone particularly effective for patients with neuropathic pain? When a patient has neuropathic pain, NMDA receptors, which attenuate the effect of opioid receptors, appear on the spinal cord.  Much higher doses of traditional opioids are needed, therefore, to overcome that blockade. Methadone contains d- and l-isomers one of which acts as opioid receptor agonist and the other as a NMDA receptor antagonist. Since methadone blocks the NMDA receptors and binds the opioid receptors, much lower opioid doses are needed. We are usually called to see patients already on another opioid that isn’t working for them. We convert them to oral methadone. For example, a 50-year-old patient with normal hepatic function, normal QTc, and severe brachial plexus pain receiving a 1 mg/hr infusion of hydromorphone, and taking 6 mg in rescue doses in a 24-hour period would have used 30 (24+6) mg IV hydromorphone, or 600 oral morphine equivalents. The equivalent in methadone is ~30 mg in 24 hours. Depending on whether she would be more distressed by ongoing pain or some degree of sedation, I would start with 5-10 mg of methadone po q8h. Avoid adding any agents that prolong the QTc, especially quinolone antibiotics. And be aware that the “azole” antifungals, like fluconazole, compete with methadone for metabolism. If fluconazole is needed, the methadone dose needs to be cut in half. Other common medication interactions can be found here.

But since I don’t expect the methadone to reach steady state for 3-5 days, I don’t stop the hydromorphone infusion right away. Usually, 24 hours after the methadone is started the patient has required many fewer opioid PRN doses. We decrease the opioid infusion by 50% at that point. If at 48 hours, the patient has not increased their need for PRN opioids, we stop the infusion then and continue IV or oral PRN breakthrough doses.  If you stop the hydromorphone infusion the same day you start the methadone, the patient’s pain will escalate, and they will usually refuse to continue the methadone.

For more information about methadone and how to use it clinically, there are several Resources on my website, JanetAbrahm.com:

• A curated series of papers here.
• A free chapter from my book (Comprehensive Guide to Supportive and Palliative Care for Patients With Cancer, 4^th edition, 2022). In this chapter you will find:
  • A full discussion of methadone on pages 256-262. 
  • A sample conversion chart from traditional opioids to methadone (page 260).
  • A clinical Case describing a day-by-day technique to convert an outpatient (“Josh”) from their traditional opioid to methadone (pages 261-262). 

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