Methadone as an Analgesic

Methadone differs from other opioids in several ways-some positive and some negative. On the positive side, it provides analgesia by at least 2 mechanisms. Like the other commonly used opioids, including morphine (MS Contin, Kadian), fentanyl (Duragesic), oxycodone (OxyContin, Percolone, Roxicodone), and hydrocodone (Lorcet, Lortab, Vicodin), it is a µ-opioid receptor agonist. However, methadone also appears to provide analgesia by a second mechanism-it is an N-methyl-d-aspartate receptor antagonist.¹ This is the mechanism by which drugs such as ketamine and dextromethorphine appear to exert their analgesic effects.

Methadone is a naturally occurring, long-acting medication in contrast to extended- or controlled-release formulations of short-acting opioids such as morphine, fentanyl, oxycodone, and oxymorphone (Opana ER). An advantage of long-acting opioids is that they provide consistent pain relief throughout the day without the peaks and valleys that can occur with immediate-release formulations.

Methadone has a long elimination half-life of approximately 16 to 30 hours in most people, which is why it only needs to be given once daily when used for opioid addiction. However, its analgesic effects last only 6 to 8 hours; thus, it often needs to be taken 3 or 4 times daily. I usually start methadone treatment with a 3-times-daily dosing schedule and then increase the dosing schedule to 4 times daily if the patient reports significant decline in relief 1 to 2 hours before the next dose is scheduled.

There are many potential problems that can occur in a person taking methadone. In November 2006, the FDA issued a public health advisory titled "Methadone Use for Pain Control May Result in Death and Life-Threatening Changes in Pain and Heart Beat."² The advisory reported that the FDA had received "reports of death and life-threatening side effects in patients taking methadone," primarily in patients who had just begun taking the drug. The report noted that this was related to its long half-life and the possibility that it could accumulate in the body, or that it could lead to drug-drug interactions or to patients taking too high a dose. However, the FDA did not oppose the use of methadone or create new restrictions on its prescription. The advisory only recommended that patients taking methadone should do so as prescribed, that they should not start or stop taking other medications or dietary supplements without talking to their health care provider, and that health care professionals and patients should be aware of the signs of methadone overdose.

The FDA presents valid concerns that should always be kept in mind when prescribing methadone. Methadone is primarily metabolized by the hepatic cytochrome P-450 3A4 enzyme by N-demethylation and to a lesser extent by the 1A2 and 2D6 enzymes.³ Thus, physicians must be especially cautious in prescribing methadone for patients with hepatic disease and for those taking other medications that can affect these isoenzyme systems. It should be noted that despite these drawbacks, methadone has the advantage of having no active metabolites.

Regarding the potentially life-threatening problems mentioned in the advisory's title, all opioids, including methadone, can cause respiratory depression, and this is the most common cause of opioid-related deaths. The cardiac concerns about methadone are primarily related to the fact that it can prolong the corrected QT interval.⁴ Both these problems are, in most cases, related to methadone overdose.

Many physicians are uncertain about methadone dosing and there appears to be a tendency to prescribe more than necessary.⁵ The equianalgesic doses of methadone and other opioids remain unclear.⁶ Most standard conversion tables indicate that the equianalgesic dose of methadone to immediate-release morphine is to 2 to 3:1. More recent research indicates that it is probably closer to 4 to 7:1.⁷

I would recommend that for a patient who is not already taking another opioid, treatment with methadone should be started at a dosage of no more than 5 mg every 8 hours. For some geriatric patients, I have even started treatment at a dosage of 2.5 mg every 8 hours. When changing from another opioid to methadone, the starting maximum dosage should only be 30 to 40 mg/d in divided doses. When starting any long-acting opioid, a short-acting opioid such as hydromorphone (Dilaudid) should also be prescribed as needed for breakthrough pain. This avoids the need for the patient to suffer if the starting dose is too low. In addition, because of its long half-life, methadone can take 3 to 5 days to attain optimal analgesic effects. Therefore, I usually wait at least 5 to 7 days before considering an increase in methadone dosage.

As with all long-acting opioids, methadone must be prescribed on a fixed schedule for maximal efficacy.

There are 3 additional caveats that should be kept in mind when considering methadone:

• Most patients have only heard of methadone as a treatment for narcotic addiction and are unaware of its analgesic properties. They may assume that if it is prescribed, it is for the former purpose. It is therefore vital to explain that it is for pain and not because the patient is thought to be abusing drugs.
• Unfortunately, because of the lack of widespread use of methadone as an analgesic, many pharmacies do not routinely stock it; therefore, it may be difficult to find. If you do intend to prescribe it, it is important to identify nearby pharmacies that have it and direct patients there.
• Many physicians believe that a special license is required to prescribe methadone. When methadone is prescribed as an analgesic, the legal requirements are the same as with any other Drug Enforcement Administration Schedule II opioid.

Because of these many different requirements, it is especially important to clearly document the reason methadone is being prescribed.

References:

References

1.

Ballantyne JC, Mao J. Opioid therapy for chronic pain.

N Engl J Med.

2003;349:1943-1953.

2.

FDA public health advisory. Methadone use for pain control may result in death and life-threatening changes in breathing and heart beat. US Food and Drug Administration Web site. November 27, 2006. Available at:

http://www.fda.gov/cder/drug/advisory/methadone.htm

. Accessed October 2, 2007.

3.

Fishman SM, Wilsey B, Mahajan G, et al. Methadone reincarnated: novel clinical applications with related concerns.

Pain Med.

2002;3:339-348.

4.

Kornick CA, Kilborn MJ, Santiago-Palma J, et al. QTc interval prolongation associated with intravenous methadone.

Pain.

2003;105: 499-506.

5.

Sandoval JA, Furlan AD, Mailis-Gagnon A. Oral methadone for chronic noncancer pain.

Clin J Pain

. 2005;21: 503-512.

6.

Fredheim OM, Borchgrevink PC, Klepstad P, et al. Long term methadone for chronic pain: a pilot study of pharmacokinetic aspects.

Eur J Pain.

2007;11:599-604.

7.

Walker PW, Bruera E, Pei B, et al. Switching from methadone to a different opioid: what is the equianalgesic dose ratio?

J Clin Oncol.

2006;24(Jun 20 supplement): 8617.