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Maximizing Safety with Methadone and Other Opioids

Risks associated with opioids can be safely and effectively managed while providing life-saving analgesia to chronic pain patients.
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This article is reprinted with permission from Pain Treatment Topics,

Opioids provide life-saving analgesia for the millions of Americans who suffer with chronic pain, yet overdose deaths are rising at an alarming rate, with methadone implicated to a disproportionate degree.1,2 Methadone’s relative increase in poisoning deaths outpaces that of all other drugs; in 1999, methadone was mentioned in 4% of all US drug-related deaths, but only five years later methadone’s share rose to 13%— a record 3,849 people died of methadone-related overdose in 2004.3

At least some of the deaths appear to be associated with methadone prescribed for pain. The increase in deaths involving methadone (213%) is comparable to the increase in its use for pain management (175%) but not to the increase for opioid-addiction treatment programs (43%).1 The US Substance Abuse and Mental Health Services Administration (SAMHSA) agrees that the increase in overdose deaths corresponds to supplies of methadone prescribed for pain, not to the methadone issued for addiction treatment,4 and a Utah study using multiple public health data sources reached the same conclusion.5

Finding solutions is critical. On November 27, 2006, the FDA issued a public health advisory warning of dangers associated with methadone and endorsing more conservative prescribing guidelines.6 Yet many professionals in the medical community who administer methadone for pain remain largely unaware of the need for extraordinary safety measures.

These developments highlight the immediate need to focus a rigorous investigation into the exact prevalence, causes, and risk factors for death associated with methadone and other opioids prescribed for pain. But because methadone’s popularity as a drug to treat pain is rising, education efforts cannot wait for research to answer all questions.

The nonprofit organization LifeSource ( was created to help address these concerns. The first educational initiative from LifeSource—started in 2006 and still ongoing—is the Zero Unintentional Deaths campaign ( This features seminars and media appearances to alert healthcare providers, chronic pain sufferers, and communities to the seriousness of the risk of overdose deaths.

In addition to education that widely disseminates known safety measures for initiating and titrating methadone for pain, a second component of the Zero Intentional Deaths campaign is research. This examines the root causes underlying the recent increases in deaths related to prescription opioids, particularly meth-adone. These two initiatives—education and research—go hand in hand.

Gaps in Clinical Knowledge

The increase in mortality associated with methadone may have many causes:

  • Patients overuse the medication in an effort to escape pain.
  • Patients are mixing methadone with benzodiazepines, street drugs, alcohol or other medications.
  • Clinicians are initiating methadone at too high a dose, escalating doses too rapidly, placing misguided faith in published conversion tables when switching from another opioid to methadone, and are unaware of contributory risks such as sleep apnea and concomitant benzodiazepines.
Clinicians who prescribe methadone for pain and patients themselves may be underestimating risks of respiratory depression associated with methadone.

It appears that clinicians who prescribe methadone for pain and the patients themselves may be underestimating the risk of respiratory depression associated with methadone. Certain research has found that tolerance to respiratory depression is incomplete and outpaced by tolerance to other opioid effects such as euphoria, even in long-term opioid users. Australian researchers White and Irvine,7 who examined the pharmacologic basis of respiratory depression following opioid administration, found that tolerance to the respiratory-depressant effects of methadone was incomplete as related to the hypoxia-sensitive chemoreceptor mechanism; this contrasted with the carbon dioxide-sensitive chemoreceptor mechanism, which research suggests was complete.

The pharmacologic properties of methadone have enormous safety implications. Methadone is eliminated from the body at a slower rate than many other medications; its long, variable half-life averages 20 to 35 hours with a range of 5 to 130 hours.8 However, analgesia often lasts only about 4 hours. This disparity makes methadone particularly prone to dangerous toxic buildup with potential for respiratory depression.

The Trouble With Conversion Tables

Another problem is over-reliance on published conversion tables for meth-adone. The doses recommended by conversion tables fail to account for the accumulated toxicity and polydrug interactions that can occur with around-the-clock methadone. Most conversion tables use a ratio to estimate the equianalgesic dose of one opioid to another. It is often assumed that the tolerance achieved by a patient on a current regimen of opioids allows the clinician to begin methadone at a rate equal to the exact morphine equivalent.

However, cross tolerance is incomplete even for individuals currently prescribed high doses of other opioids. These tables—which are designed for a single use, not for chronic administration—may imply no upper limit exists for the starting methadone dose. One table suggests a conversion rate of 5% to 10% of the oral morphine dose, which may be far too high. For example, if an opioid-tolerant individual were taking up to 500mg of morphine-equivalent opioids per day, the starting methadone dose could be as high as 50mg a day. Consider also that prior to the recent FDA advisory, package insert guidelines had allowed for a starting methadone dose as high as 80mg. Initial doses like these could prove dangerously high due to methadone’s wide variability of half-life and the accumulation that occurs with multiple doses.

The Need for Research

To stop the deaths, we must understand clearly what is causing them. The reasons are likely multi-faceted and poorly articulated to date. No systematic analysis so far has determined what percentage of decedents were A) taking methadone correctly as prescribed for pain, B) taking more methadone than prescribed while chasing greater pain relief or seeking to relieve a comorbid mental disorder, C) mixing methadone with other prescription drugs, street drugs, or alcohol, or D) taking methadone recreationally to seek a high.

The data gap invites a scare response among members of the public who may be taking methadone for pain or who have loved ones who are doing so. It also may foster ill-considered action from well-meaning individuals, such as:

Last updated on: February 28, 2011
First published on: April 1, 2008