Vital Signs: Risk for Overdose from Methadone Used for Pain Relief — United States, 1999–2010

Leonard J. Paulozzi, MD; Karin A. Mack, PhD; Christopher M. Jones, PharmD


Morbidity and Mortality Weekly Report. 2012;61(26):493-497. 

In This Article

Conclusions and Comment

The primary advantages of using methadone over other opioids for pain treatment are its long duration of action, relatively low cost, and availability in liquid formulation for oral use. Its primary disadvantages are its long and unpredictable half-life and associated risk for accumulating toxic levels leading to severe respiratory depression; its multiple interactions with other drugs, including frequently abused drugs such as antianxiety agents; and its ability to cause major disturbances of cardiac rhythm.[12]

Increased use of methadone since 1999 might have been prompted by growing costs of treating pain with opioids and increasing reports of abuse of other, more expensive, extended-release opioids.[1] Overdose reports and interventions by FDA and DEA might have resulted in declines in the amount of methadone distributed and methadone-related fatal overdoses in 2008, although the number of methadone prescriptions did not decline. The parallel trends in the amount of methadone distributed for use as a pain reliever and in the methadone mortality rate are consistent with methadone prescribed as a pain reliever being the primary determinant of methadone mortality rates.[1,3]

Data suggest that some of the current uses of methadone for pain might be inappropriate. According to an analysis conducted by FDA, the most common diagnoses associated with methadone use for pain in 2009 were musculoskeletal problems (such as back pain and arthritis) (46%), headaches (17%), cancer (11%), and trauma (5%). Most methadone prescriptions were written by primary care providers or mid-level practitioners (e.g., nurse practitioners) rather than pain specialists. Nearly a third of prescriptions appear to have been dispensed to patients with no opioid prescriptions in the previous month (i.e., opioid-naïve patients).[10]

The findings in this report are subject to at least five limitations. First, vital statistics underestimate the number of overdose deaths from specific drugs because the type of drug is not specified on many death certificates. Second, medical examiners in the DAWN system might have varying definitions of drug-related deaths. However, individual medical examiners likely apply the same definitions to all types of opioid analgesics. Third, assigning responsibility to any single drug in multidrug overdoses is difficult. However, this is not an issue in single-drug deaths, among which the highest risks for methadone were observed. Fourth, some deaths might have resulted from methadone provided in take-home doses by opioid treatment programs, but adjusting for such deaths in this analysis did not change the overall results. Finally, ARCOS data reflect distributions to retail outlets by state, but some drugs might have been used by residents of neighboring states.

This study and others suggest that methadone remains a drug that contributes disproportionately to opioid pain reliever overdoses and associated medical and societal costs. Additional warnings to prescribers about dosage are likely to have limited effect, given the high prevalence of use without a prescription among persons who overdose. The public health goal now should be to mount a concerted effort to reserve methadone for those pain-related conditions for which the benefits likely outweigh the risks to patients and society, such as use for cancer-related pain or palliative care. This will reduce the amount of methadone available for diversion and nonmedical use.

Methadone and other, extended-release opioids should not be used for mild pain, acute pain, "breakthrough" pain, or on an as-needed basis. For chronic noncancer pain, methadone should not be considered a drug of first choice. This is especially true for conditions for which the benefits of opioids have not been demonstrated, such as headache and low back pain. Only a small fraction of patients with intractable chronic headache treated with opioids experience long-term pain reduction or functional improvement.[13] Evidence that any opioids are effective in chronic low back pain is limited.[14] Additionally, methadone should not be prescribed to opioid-naïve patients, and, whenever possible, should not be prescribed to patients taking benzodiazepine antianxiety agents because of an increased risk for severe respiratory depression. Health-care providers who choose to prescribe methadone should have substantial experience with its use and follow consensus guidelines for appropriate opioid prescribing.[15] Providers should instruct patients about the potential risks of methadone and how to store and dispose of it properly.

Public and private insurers and health-care systems can ensure that prescribers of methadone follow dosage guidelines by requiring authorization for starting doses for pain that exceed the recommended upper limit of 30 mg per day.[5] Insurance formularies should not list methadone as a preferred drug for the treatment of chronic noncancer pain. Pharmaceutical companies should introduce a 2.5-mg formulation of methadone to facilitate treatment with the lowest recommended dosage.

Although interventions related to methadone use are urgently needed, government agencies, health-care providers, insurers, and other stakeholders must combine these interventions with measures that will address the problems of misuse and abuse of all opioid pain relievers. Interventions such as the use of prescription drug monitoring programs, appropriate screening and monitoring before prescribing opioid pain relievers, regulatory and law enforcement efforts, and state policies (e.g., "pill mill" laws) aimed at providers and patients involved in diversion of these drugs continue to be essential elements in addressing this public health emergency.


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