TAMPA – Methadone is an excellent choice for pain management when the prescribing complexities are understood, said two experts at the annual meeting of the American Academy of Hospice and Palliative Medicine and the Hospice and Palliative Nurses Association.
“While it's probably the best opioid analgesic out there, it's also probably the most dangerous,” said Dr. Jane E. Loitman, who is the medical director for the palliative care service at Barnes-Jewish Hospital in St. Louis.
Methadone, a synthetic opioid that is available in the United States as a racemic mixture of two isomers, has several advantages over other opioid analgesics.
“Methadone is the only opioid that acts as an NMDA [N-methyl-D-aspartate] receptor antagonist as well as acting as a mu-[opioid] agonist,” said Dr. Gail Gazelle of Harvard Medical School, Boston. Other opioids work only as mu-opioid agonists. “Methadone also acts as a mu agonist but has this unique property, unlike all of the other opioids, that blocks NMDA receptors.” This action on NMDA receptors makes methadone an excellent choice for the treatment of neuropathic pain. And methadone does not appear to carry the same risk of respiratory depression as other opioids because of NMDA-receptor blockade, Dr. Gazelle said. There is also some evidence that because of the NMDA-receptor antagonism property, methadone has an antitussive action.
In addition, NMDA activity “may mean that it reduces some of the cross-tolerance that we see with patients being converted from another opioid to methadone,” she said. Because NMDA antagonism is one of the mechanisms to prevent tolerance and inhibit neuronal excitation, “methadone may be the drug of choice as an opioid analgesic for someone who has hyperalgesia,” Dr. Loitman said.
Methadone typically has very little euphoric effect, which can be advantageous when there is a concern about diversion. Methadone has no known active metabolites and blocks serotonin/norepinephrine uptake. Another “important advantage of methadone is that it is the only opioid that is fecally excreted. So it's an excellent medication to use for patients with known chronic renal insufficiency,” she said.
Methadone also has fewer of the neuroexcitatory side effects of opioids, such as myoclonus and delirium, and may be associated with a lower incidence of constipation than other opioids. The drug can be given orally, rectally, sublingually, intravenously, subcutaneously, and transdermally. It has a very high potency when used after another opioid, and its oral bioavailability is very high (85%), compared with roughly 35% for morphine.
“If you have a DEA license to prescribe other schedule II medications, you can prescribe methadone,” Dr. Loitman said. No special license is required, and one doesn't need to be a pain specialist to prescribe this drug. But “before you start someone on methadone, you need to understand the pharmacology, the side effects, the advantages and disadvantages, the myths, and who you're prescribing it for,” she said.
Despite methadone's attractiveness for the treatment of pain, it's a complicated drug to prescribe. Methadone is difficult to dose and equianalgesia is a particular problem, because the analgesic and biologic half-lives don't match. While the biologic half-life of methadone can range from 18 to almost 100 hours (average, about 24 hours), the analgesic half-life ranges from 6 to 12 hours. “So the steady state of methadone–because of its long half-life–can take a while to reach,” Dr. Gazelle said. Reaching a steady state takes about five biologic half-lives, she said.
Methadone also has a risk of cumulative toxicity because of its long and unpredictable biologic half-life, and it's necessary to titrate this drug more slowly than other opioids. Because methadone is lipophilic, it can be difficult to titrate the drug in elderly patients, who have a greater percentage of adipose tissue.
Another complication is that methadone is metabolized through the cytochrome P450 system, which is induced by a number of other drugs, including phenytoin and rifampin. Larger doses of methadone might be needed when a patient is also on one of these drugs. “It's almost impossible to get therapeutic levels of methadone in patients on rifampin,” Dr. Gazelle said. Other medications, including azole antifungal agents and macrolide antibiotics, might inhibit the cytochrome P450 system and require decreased doses of methadone. Therefore, it is important to review all of the drugs that a patient is on before prescribing methadone.
In 2006, the Food and Drug Administration issued a public health advisory for methadone, in part because of reports of QTc interval prolongation and serious arrhythmia (torsades de pointes) that had been observed during treatment with methadone. Most of these cases involved patients in pain who were receiving large, multiple daily doses.