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7 Articles in Volume 8, Issue #3
CES in the Treatment of Pain-Related Disorders
Commonsense Opioid-Risk Management in Chronic Non-cancer Pain
Injection Needle Injury of Oral Sensory Nerves
Maximizing Safety with Methadone and Other Opioids
Personality Disorders and the Bipolar Spectrum
Protecting Pain Physicians from Legal Challenges: Part 2
Technology in Pain Medicine

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.

This article is reprinted with permission from Pain Treatment Topics, Pain-Topics.org

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 (www.lsource.org) 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 (www.zero deaths.org). 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:

  1. Action from legislators and regulators seeking to limit or even ban methadone for pain. In West Virginia, legislators held hearings to try to limit who can prescribe the drug. More states can be expected to follow suit. Considering the lack of appropriate scientific data, sweeping regulatory changes at this time could hurt far more than help.
  2. Lawsuits and boycotts from people who have lost loved ones to methadone-related deaths. One bereaved family member organized supporters via the Internet and campaigned for strict regulatory changes that included:
    • A requirement that doctors receive special certification to prescribe methadone.
    • Inpatient stays for patients during methadone maintenance treatment (MMT) induction for addiction.
    • Eliminating all take-home doses for MMT program patients.
    The grief of losing a loved one is a powerful motivator; however, it is not a credential for regulating medical practice. Only evidence-based science should underpin regulatory change.
  3. Misinformation distributed via professional seminars, government agencies, and, in particular, the main-stream media. For example, methadone’s relation to cardiac toxicities needs further clarification but is addressed in lectures and in the recent FDA advisory. This is just one instance of how the communication cart gets ahead of the evidence horse. Furthermore, physicians commonly lecture at national meetings that metha-done is a safe and “benign” opioid without discussing its unique pharmacologic properties.

    Conversely, the mass media frequently portray methadone as a deadly street drug, calling it “highly addictive.”9 Often, it goes unreported that many people whose pain would otherwise go uncontrolled use methadone and other opioids safely and effectively. And, thousands treated in MMT programs have literally been saved as a result of methadone.

  4. Eventual compromised access to methadone and other opioids for pain therapy. The motivation to hold someone accountable frequently arises even in the absence of all the facts. This dynamic was clearly observed in the media and regulatory frenzy that surrounded OxyContin abuse earlier in this decade. It is reasonable to forecast a similar direction for the dialogue concerning methadone. This possibility dramatically underscores the urgent need for quality data.

Research Goals and Concerns

When we begin to ask the right questions, we will start to get useful answers. The current LifeSource research goal is to study decedent data in selected regional areas when death certificates mention opioids, including methadone. The objectives are to distinguish, to the extent possible, methadone’s precise contribution to the deaths and to isolate risk factors in methadone decedents. Based on the literature, patient characteristics that may have contributed to methadone-related deaths include: pain condition and intensity, presence of concurrent opioids or other medications, gender, age, body mass index, and presence of cooccurring disorders such as sleep apnea or cardiac problems. For instance, in Utah, more prescription- drug deaths occurred among people who were overweight than among those who were not.10 Sleep apnea is of particular interest, and early research found a dose response relation of sleep apnea to methadone and benzodiazepines in chronic pain patients.11 In addition, middle age appears to be a vulnerable period for overdose involving prescription drugs.

The analysis must be carefully performed. It is difficult to determine a cause of death from postmortem methadone blood levels alone. A wide range of postmortem concentrations of methadone are given as fatal, and bias may exist toward assigning an opioid as the cause of death whenever it is present in a toxicology report. Difficulty exists in pinpointing a blood level of methadone that would be toxic in most individuals.12-16 The undertaking is even more complicated when pain patients are involved, since levels of methadone typically reported as a cause of death may actually be at therapeutic levels in some chronic pain patients on long-term methadone therapy. When a polydrug interaction is documented, benzodiazepines and alcohol are frequent co-causes of death. The exact mechanisms of the interaction of benzodiazepines with methadone, whether additive or synergistic, have been studied14,15 but need to be better understood. In addition to their sedative effects, some benzodiazepines can alter the rate at which methadone is metabolized in the system. This drug interaction can make interpretation of postmortem results difficult.15

Another question is whether cost issues are driving medical decision making. Methadone is less expensive than many other medications for pain. So, it is worth asking whether patients without insurance are frequent consumers of methadone and also whether some insurance companies require that methadone be tried because of its lower cost. If so, payers may be pressuring physicians who are unfamiliar with methadone to prescribe it ahead of other opioids, and patients may be using methadone solely because they can afford nothing else. Along with that, it also is possible that a subset of patients who are likely to be noncompliant are gaining greater access to methadone. Or perhaps, when more methadone is prescribed it simply translates into more methadone available for misuse (and to potentially be misprescribed). These questions must be asked so we can gain accurate and helpful answers.

The Need for Education

Patients and the public need to know how to protect themselves and their loved ones from overdose if methadone is used. Practitioners should counsel patients and family members as to methadone’s potential for respiratory depression and the absolute necessity of never taking a non-prescribed extra dose of methadone or mixing it with unauthorized substances.

Patients should be counseled as follows:

  1. Never take a prescription painkiller unless it is prescribed for you.
  2. Do not take pain medicine with alcohol.
  3. Do not take more doses than prescribed.
  4. Mixing pain medicines with sedative or anti-anxiety medications can be dangerous.
  5. Follow doctor directions carefully.
  6. Avoid using opioids to facilitate sleep.
  7. Lock up prescription painkillers away from children, other family members and visitors.

Cautions for prescribers:

Methadone’s pharmacologic properties necessitate a conservative approach even for the most opioid-tolerant patients. Careful monitoring of the individual patient’s response is key, as well as some precautions:

  1. Do not use conversion tables to determine the initial dose. At present, the safest course is to consider your patient as opioid naïve for purposes of introducing methadone.
  2. Safe practice supports starting the conversion with a ceiling dose of no more than 20mg/day (10mg/day for elderly or infirm patients).
  3. Adjust other medications down slowly, while titrating methadone up slowly as a concurrent process
  4. Dose changes should not occur more often than weekly to allow steady state blood levels of methadone to develop and for the peak side effects to become clear.
  5. If patients are taking concomitant benzodiazepines, the starting dose and speed of methadone titration may need to be adjusted downward.2

These initial dosing guidelines may appear overly cautious to pain practitioners and are even more conservative than new dosing guidelines published by the FDA.6 But more aggressive pain control may follow once the mechanisms underlying the increases in overdose deaths are further researched and better understood.

Take-Away Message

Methadone mentions in overdose deaths have increased with its wider availability to treat pain. Because elimination of preventable deaths is of paramount importance, the medical establishment must urgently respond to any clinical misapplications of opioids. The goal is Zero Unintentional Deaths, which is also the name of an education campaign designed to spread the message that opioids entail risks, but those risks can be managed.

Methadone for pain incurs unique safety risks if incorrectly prescribed. It has a long elimination half-life, with analgesia that may last 4 to 8 hours and respiratory depression effects that linger closer to 2 days on average. Its properties heighten the risk for drug-drug-interactions and the introduction of a too-high initial dose, among other dangers.

A primary goal of the Zero Unintentional Deaths Campaign is to keep methadone available to patients who need it. Methadone is an effective opioid for pain, it has excellent bioavailability, is a good match with most short-acting opioids used to treat breakthrough pain, and is very affordable. Its continued value as an analgesic depends on educating all practitioners who use methadone to treat pain on its unique properties.

Opioid therapy entails risks, but those risks can be effectively and safely managed. Patients and the public need education on how to avoid methadone overdose. Practitioners should provide appropriate counseling.

Not only methadone but all opioids must be respected as powerful medications. Careless prescribing and consuming of opioids can be lethal. Patients need to know that methadone and other opioids should not be treated like aspirin or ibuprofen, to be increased at will. Finally, because many people are still undertreated for pain, these problems must be swiftly addressed.


Medical Editor: Stewart B. Leavitt, MA, PhD, is the Publisher/ Editor-in-Chief of Pain Treatment Topics and was the founding editor of Addiction Treatment Forum in 1992. He has served as a consultant to the US Center for Substance Abuse Treatment and as an officer in the US Public Health Service, stationed at the National Institutes of Health. He has more than 25 years experience as a medical researcher/ writer.


Pain Treatment Topics (Pain-Topics.org), the source of this article, is supported by an unrestricted educational grant from COVIDIEN/Mallinckrodt, St. Louis, Mo., a manufacturer of generic opioid anal-gesics. However, the sponsor did not participate in the conception, research, development, or revision of this paper. The author and editor have no conflicts of interest to declare relating to the subject of this paper or its contents.

Last updated on: February 28, 2011
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