Methadone as an Analgesic: How Dangerous Is It?

Whenever I attend a lecture on the use of opioids, the speaker almost invariably notes that methadone is an excellent analgesic, but then provides a list of reasons for why it is far more dangerous to prescribe than other long-acting (LA) opioids. Although I agree with the first part of the statement regarding efficacy, I disagree with the second part, which warns of the comparative danger of the agent. As I noted in a recent blog on LA opioids, I believe that methadone should certainly be considered when one of these medications is indicated.

One of the great benefits of methadone is that unlike the other µ-opioid receptor agonists available in LA forms (morphine, hydromphone, fentanyl, oxycodone, and oxymorphone), it has a secondary analgesic mechanism. Methadone is also an N-methyl-d-aspartate receptor antagonist-the same mechanism by which drugs such as ketamine and dextromethorphine appear to produce analgesia. Thus, in prescribing methadone you are essentially offering the benefits of 2 different analgesic classes in a single medication.

Methadone has another benefit that is little mentioned. Because its long-acting effects are the result of the drug’s intrinsic pharmacology and not of how it is formulated (ie, using extended-release technology) methadone cannot be manipulated by crushing or melting as can most of the other LA opioids. Users therefore cannot all at once ingest a dose that is supposed to be slowly released over an extended period. It is true that as tamper-resistant forms of the other LA opioids come on the market, this may be less of a concern, but we still don’t know how effective these formulations will be in preventing abuse.

Finally, methadone is very inexpensive. Thus, even patients who have limited or no insurance coverage for medications can usually afford it. It should be noted, however, that because they often find that there are limited requests for it, many drugstores in the community do not stock methadone. Therefore, if you are going to prescribe it and do not have an outpatient hospital pharmacy readily available for your patients, you need to identify stores that do carry it and direct patients to them.

There are some special properties of methadone about which prescribers need to be aware to ensure its efficacy and avoid adverse events:
• There is a marked difference between the half-life of methadone and the length of its analgesic effect. The half-life is approximately 16 to 30 hours which is why when it is used for the treatment of opioid addiction it only needs to be given once a day to prevent withdrawal. However, its analgesic effects last only 6 to 8 hours requiring it to be prescribed on a q8h or q6h around-the-clock schedule for it to provide optimal analgesia.  
• Methadone is metabolized by the liver and excreted through the kidneys so repeated dosing in patients with hepatic and renal impairment may result in a toxic build-up of methadone. Also, multiple medications can interfere with the metabolism of methadone thereby increasing the risk of toxicity.  
• Methadone can prolong the QT interval resulting in cardiac arrhythmia and has been shown to cause cardiac arrest. However, these events have generally occurred in patients taking methadone for treatment of opioid dependence at dosages of 100 mg or more per day. It is very rare for patients who take methadone for chronic pain to require anything close to this dose. If it is felt that a patient is at potential risk for this problem, however, an ECG should be obtained before starting the drug. In my experience, virtually all patients with chronic pain have had extensive workups to rule out potential underlying pathology. I doubt I’ve ever seen a patient with chronic pain who hadn’t undergone at least one ECG.
• There is no short-acting form of methadone. Patients are usually taking a short-acting opioid when the decision is made to switch to methadone as the LA agent and conversion from one to the other is required. The standard equivalent dosage charts for opioids provide only very rough estimates for a switch between agents, thus there is less guidance for the initial dose of methadone. However, this potential problem can be minimized by starting with a low dose of methadone and gradually increasing it over time.

All these concerns would suggest that methadone would probably be associated with higher mortality than the other LA opioids. However, a recent study contradicts this widespread belief.

Krebs and colleagues¹ utilized Department of Veteran Affairs health care databases to compare mortality rates of patients taking methadone and LA morphine for chronic pain. Patients taking methadone for opioid dependence and abuse were excluded. The study population was large with 28,554 of those studied taking methadone and 79,938 taking morphine.

Instead of methadone use resulting in a greater mortality risk than morphine, the study found that methadone actually was associated with a reduced risk. As the authors note: “Our findings were unexpected and challenge the widespread concern that prescribed methadone is associated with excess risk of death compared with other prescribed opioids.”¹ One explanation they offer for the apparent contradiction between their results and others on methadone is that most previous studies mixed patients who were taking methadone illicitly with those for whom it was prescribed appropriately for a medical problem and who were being followed up by physicians.

This study in no way downplays the potential problems associated with methadone and any physician considering prescribing it needs to be aware of them. However, as the authors also state: “Because all opioids are associated with potentially serious adverse effects, all should be prescribed and monitored cautiously.”¹

Reference
1. Krebs EE, Becker WC, Zerzan J, et al. Comparative mortality among Department of Veterans Affairs patients prescribed methadone or long-acting morphine for chronic pain. Pain. 2011;152:1789-1795.