For many years I was an internist, addiction medicine doc, and specialist in medication management for chronic pain. Around this time of year, when patients were in the “donut hole” of their medical insurance and now had to pay out of pocket for their own medications, I used to spend a lot of time converting some of them from whatever expensive opioid they were on – OxyContin®, MSContin®, OpanaER®, etc. – to methadone. Towards the beginning of the next year though, most were happy to get back on their original drug. I was willing to do this because it was the only way they could continue getting relief from their legitimate pain. But it meant a lot of extra work for me.
Switching between most opioids simply means knowing the conversion ratio. (and initially, reducing the new drug by about 50% of the calculated equivalent to minimize the risk of overdosing). For example oxycodone is generally 1.3 to 1.5 times as potent as morphine, so that 15 mg of morphine is equianalgesic to 10 mg oxycodone; 60 mg of morphine is equianalgesic to 40 mg of oxycodone; 300 of morphine is equianalgesic to 200 mg of oxycodone. See Opioid Calculator page on this Website. The same is not true of methadone – the higher the morphine-equivalent dose, the relatively higher is the ratio of morphine to methadone. The table on the right shows these ratios in various schematics.1
Dr. Fudin recently developed a mathematical model for calculating this which appears on the Website (Methadone Dose Conversion Unscrambled) and the table herein, but there is still uncertainty for individual patient conversion and significant variations by population due to polymorphic differences. This means more frequent visits and phone calls, longer explanation to the patients about the conversion process, and also dealing with the particular characteristics of methadone.
Methadone is an effective analgesic. It is a synthetic mixture of d- and l-isomers. The d-isomer has NMDA receptor antagonist activity. According to research by Dr. Charles Inturrisi, the d-isomer attenuates the development of morphine tolerance and NMDA-induced hyperalgesia.2 Methadone may be more effective than other opioids in treating neuropathic pain. Because of its very long serum half-life (24-36 and upwards to 60 hours for outliers), a single daily dose prevents withdrawal symptoms, which is why it is historically connected with treating heroin addicts. Of course, the addiction connection sometimes frightens patients when I suggest treating their pain with methadone. There’s also confusion about who can prescribe methadone and for what. According to the FDA, only methadone clinics can prescribe methadone for addiction treatment, but any prescriber with a DEA license that includes Schedule II substances can prescribe methadone for pain (even in a patient whose methadone concurrently treats their addiction). [Online MPA Degrees has an excellent schematic of commonly prescribed medications/pharmacological classes which succinctly clarifies DEA Schedules I through V.] It is important, however, to write the words “for pain” on every prescription of methadone for pain.
Working with methadone can be tricky. The FDA has issued multiple warnings about methadone-related deaths, which usually occur in the first few days of using the drug. In an opioid-naïve patient, any opioid needs to be initiated at a low dose and titrated upwards to adequate pain relief. This gives the patient an opportunity to develop tolerance to the sedation and nausea-inducing side effects, which rapidly resolve (unlike constipation, which persists). With most opioids, whose serum half-life is about 4 hours, the dose can be safely increased within a couple of days (after about 5 half-lives until steady state). If the prescriber allows a few extra doses, generally the patient will become sleepy until the drug wears off. But because of the long serum half-life of methadone, increasing the dose every 2 days (rather than 5-7 days as recommended), will cause accumulation of the drug in the body, with possible resulting overdose and death. That’s why starting methadone requires caution, conservative upward titration, and maintaining contact with the patient. In a patient who is being switched to methadone from another opioid, one way to deal with the risks of upward methadone titration is to transition it in stages, leaving the patient on some of the previous opioid so that they continue to get reasonable pain relief. Doctors Lynn Webster and Perry Fine have addressed this issue nicely in this commentary.
In the past, some patients were referred to me from methadone clinics because they also had chronic back or other pain. (These were patients considered very reliable by the methadone clinic, at a low risk of addiction relapse). Typically, these patients would explain that they had good pain relief in the morning, after their daily dose, but by the end of the day the pain had returned. Why? It’s because despite its long terminal half-life, methadone is not a long-acting or extended release analgesic as with other pharmaceutically prepared agents. The solution therefore is to divide the patient’s daily dose into 3 or 4 doses, often with a slight increase. For example, a patient on 80 mg methadone would be put on 30 mg three times daily or 20mg four times daily.
What about breakthrough pain in patients on methadone? In patients with an addiction history, no matter what opioid they’re on for pain, I prefer not to prescribe an immediate-release opioid such as hydrocodone [Vicodin® or oxycodone/APAP (Percocet®)]. What gives a person a sense of euphoria (or just a “good” feeling) is not the concentration of a drug in the blood stream, but rather the rate of increase of that drug in the brain. This is often the reason that recreational users of marijuana prefer to smoke it rather than ingest it in brownies. Similarly, I believe that Vicodin® or Percocet® are more likely to induce CNS effects compared to sustained-release preparations of the same or other opioids, or methadone, which has stable serum levels because of its long half-life.
I remember that many years ago, one of the first patients I treated with methadone for chronic pain required an unusually high dose – 200 mg/day. (A typical dose for addiction in a methadone clinic is about 80 mg/day, and doses for chronic pain vary widely). The patient insisted that lower doses weren’t helpful, so I slowly titrated upwards. She was taking the methadone for chronic headaches related to a head injury, from which she also had seizures. At around that time, serum methadone levels became available, so I shipped off her blood. To my surprise, her serum level was much lower than expected; she was a very compliant patient, so diversion of some of her medication was not a likely explanation. That’s when I learned that Tegretol® (carbamazepine), which the patient was taking for her seizures, increases the metabolism of methadone, thus reduced its serum level (up to 60%) and its efficacy. Unlike most opioids, methadone has multiple drug-drug interactions, some of which reduce its serum levels and therefore its efficacy, while others increase it. These interactions are due to Cytochrome P450 iso-enzymes in the liver that are responsible for metabolizing methadone and many other drugs that undergo similar metabolic pathways. So the prescriber needs to know every other drug the patient is taking and whether that drug interacts with methadone. See Treatment of Neuropathic Pain: the Role of Unique Opioid Agents and Drug Interactions Among HIV Patients Receiving Concurrent Antiretroviral and Pain Therapy. Both are listed on the Resources/Suggesting Readings section of this Website.
One other potential problem with methadone is that high doses can affect cardiac conduction, lengthening the Q-T interval on the EKG and potentially inducing a fatal arrhythmia, torsades de pointes. This is uncommon, but just to be sure, I would get an EKG in patients who were on 80 mg of methadone per day or more. I can say that I never saw a case methadone-induced of Q-T prolongation, but such cases have been reported. EKG’s should be obtained on any patients who receive methadone if they have a family history of Q-T prolongation or if they are on other medications that prolong Q-T interval, especially tricyclic antidepressants.
In summary, methadone is an inexpensive very effective opioid analgesic, but its use requires knowledge of its particular characteristics. I prescribe it often in my practice and it can be used in patients who have the dual diagnosis of pain and substance abuse disorder; but in the latter case it must be made explicitly clear in the record that it is being prescribed for pain.
- Fudin J, Marcoux MD, Fudin JA. Mathematical Model For Methadone Conversion Examined. Practical Pain Management. 2012 September; 12(8): 46-51.
- Note: Although this article is marked “Copyrighted”, a free copy is available at http://www.minervamedica.it/en/journals/minerva-anestesiologica/article.php?cod=R02Y2005N07A0435. Additionally, since NIH, a government agency was involved in funding the research and article “Pharmacology of methadone and its isomers”, certain Copyright laws allow public access and may notg apply. Please review these prior to distribution or reproduction.
Jennifer P. Schneider, M.D., Ph.D., is a physician certified in Internal Medicine, Addiction Medicine and Pain Management. She is the author of 9 books and numerous articles in professional journals. She is a compassionate professional committed to educating others in her fields of specialty. She is a nationally recognized expert in two addiction-related fields: addictive sexual disorders and the management of chronic pain with opioids. Aside from her own practice, her professional activities include writing; lecturing at conferences; serving as an expert witness in legal settings; and appearing as a media guest on television and radio.