Introduction to Methadone:

Methadone is a synthetic (man-made) pain medication, which was developed in the 1940s by scientists in Europe. During the 1950s, methadone emerged as a maintenance or replacement drug for patients addicted to opioids, mostly as a substitute for heroin. Methadone has remained the primary therapy for this condition for more than forty years and there are thousands of patients on methadone maintenance programs today.

About fifteen years ago, however, scientists and physicians found that methadone was particularly effective in controlling cancer pain. This soon led to further studies and methadone was found to be very effective in other chronic (long-standing) pain conditions also. Over the past ten years, pain specialists have found that methadone is better tolerated and has fewer side effects than many other pain medications. Recent pharmacokinetic studies and a better understanding of the NMDA receptor site have propelled methadone usage in cancer hospital, pain clinics and hospice.

In this CareMatters we will only be introducing you to the basic facts and characteristics of methadone.

Methadone Positive Characteristics:

The key positive differences between methadone and other opioids are four: (1) highly lipophilic nature (2) inactive metabolites (3) NMDA receptor antagonist (4) unique pharmacodynamics. Those are all big words so let’s break those down:

Highly Lipophilic

Methadone is highly lipophilic. This simply means it dissolves easily when exposed to fats when compared to other opioids. This characteristic results in better absorption and less constipation when compared to other opioids. For instance, methadone is 80% absorbed in the GI tract – that’s about three times as much as other opioids. This lipophilic characteristic also insures better absorption in all other routes – sublingual, rectal, etc. (However, the subcutaneous route should be avoided because of tissue irritation.)

Inactive Metabolites

Methadone is metabolized by the liver into inactive metabolites, which are excreted by the kidneys and intestines. Therefore, no adjustment is needed for patients with renal failure and there is less neurotoxicity (confusion, hallucinations, delirium, myoclonus and seizures).

NMDA Receptor Antagonist

Without getting into the complexities of pain fibers in the spinal cord, NMDA receptor antagonists are effective in neuropathic pain and have less tolerance, hyperanalgesia and allodynia. Hyperanalgesia (an increased response to a stimulus that is normally painful) and allodynia (pain due to a stimulus that does not usually provoke pain) are common in patients on very high dosages of opioids.


Methadone is characterized by a rapid and extensive distribution phase (2-3 hours), which is followed by a slow elimination phase. In the initial distribution phase, methadone produces an immediate analgesic effect – similar to other opioids. But the slow elimination phase means it hangs around a lot longer. Methadone’s half-life is 190 hours or about 8 days. Compare this with morphine’s half-life of 2 hours. This long half-life can lead to drug accumulation and overdose – especially in the elderly or if the dose is increased too rapidly.

Methadone Negative Characteristics

Because of the unique properties outlined above, methadone is more difficult to titrate, has more drug interactions and there is larger inter-individual variability. In addition, switching to methadone from a different opioid is more complex. Because of these challenges, methadone is usually used as a second or even third-line opioid – only after other opioids have failed. All of this makes it important for physicians to be very familiar and experienced with methadone before prescribing it. Finally, methadone has a negative connotation in the minds of many patients and families because of its historic use in the management of opioid addiction.

The Bottom Line: Situations Where You Should Think About Using Methadone

In the hands of an experienced physician and hospice nurse, methadone should be considered in the following clinical situations: complex pain syndromes (mixed), neuropathic pain, hyperanalgesia, allodynia, opioid tolerance, patients with side effects on other opioids – nausea, confusion, myoclonus or seizures, patients with renal failure, when there is a need for a long-acting liquid opioid (methadone works well in PEG tubes), and when there is a need for inexpensive pain control (methadone typically averages one-tenth the cost of other opioids).

Switching to Methadone

There are many acceptable ways to switch patients from another opioid to methadone. Each physician needs to review the literature and come up with his or her own system and protocol for switching patients to methadone. Obviously, methadone is more complicated than our standard opioids and, therefore, methadone conversions should only be done with the close collaboration of an experienced physician. You may also want to consider transferring the patient to a hospice inpatient unit or putting in continuous care if the patient is on high doses of their opioids – especially if compliance is questionable or caregivers are marginal. But the good news is this: once a patient is on methadone and stable, side effects are uncommon and the need to switch to another opioid is rare.

Stigmatization Due to Its Use in the Management of Opioid Addiction

I believe that every patient on methadone deserves a detailed discussion about methadone and why it is being prescribed. Stigmatization due to its history in the management of opioid addiction is the “elephant in the room” that cannot and should not be ignored. Every patient, in my view, should be given a copy of our FamilyMatters entitled “Methadone.” It is a patient-friendly one-page sheet, developed by AseraCare Hospice, that can help answer many of the questions that patients and their families are thinking about. This one-page handout has increased compliance, fostered understanding, and helped to destigmatize the use of methadone for our AseraCare Hospice patients and it is available free from your local AseraCare Hospice team.