Deaths Higher With Methadone vs Morphine in Chronic Pain

Pauline Anderson

January 29, 2015

Patients receiving methadone for noncancer pain had a 46% increased risk for death compared with patients receiving morphine sustained release (SR), a new study shows.

The increased risk occurred even with methadone doses as low as 20 mg/d.

The study results support the message that doctors should reconsider prescribing methadone for noncancer pain, said study author C. Michael Stein, MB ChB, Dan May Professor of Medicine and Pharmacology, Vanderbilt Medical School, Nashville, Tennessee.

"Apart from thinking about the overall risks and benefits of chronic opioid use, I think prescribers should also think about the specific drugs they choose, and methadone should not be the drug of first choice for chronic noncancer pain," Dr Stein told Medscape Medical News.

The study was published online January 19 in JAMA Internal Medicine.

Long Half-Life

While methadone is as effective as other long-acting opioids, it has an advantage in that it has a long elimination half-life and is relatively inexpensive. However, it has been linked to unintentional overdoses; in 2006, the US Food and Drug Administration issued a public health advisory that using methadone for pain control may result in death and life-threatening changes in breathing and heartbeat.

To compare out-of-hospital deaths, researchers conducted a retrospective cohort study of Tennessee Medicaid enrollees aged 30 to 74 years who filled a prescription for methadone or morphine SR between January 1, 1997, and December 31, 2009.

Dr C. Michael Stein

The analysis included 32,742 patients with a prescription for morphine SR and 6014 patients with a prescription for methadone. Their median age was 48 years, and about 58% were female. Almost 90% of patients were taking the opioid for back pain or other musculoskeletal pain. The study excluded patients with cancer and other serious illnesses.

Median doses prescribed were 90 mg/d for morphine and 40 mg/d for methadone. About 65.4% of patients receiving morphine SR were also receiving a nonstudy opioid compared with 47.7% of the methadone group.

The primary endpoint was death outside the hospital. Deaths were classified into three subgroups: sudden unexpected deaths consistent with opioid overdose or life-threatening arrhythmias, other respiratory or cardiovascular deaths for which opioid involvement was possible but less certain, and deaths less likely to be related to opioid toxic effects.

Researchers further classified sudden unexpected deaths as meeting the definition for opioid overdose only, meeting the definition for sudden cardiac death only, and meeting both definitions.

Increasing Doses

There were 477 deaths during 28,699 person-years of follow-up. Of these, 72.5% of the deaths were sudden unexpected deaths, 11.1% were other respiratory/cardiovascular deaths, and 16.4% were other deaths.

After adjustment for covariates, patients receiving methadone had a 46% increased risk for death vs those receiving morphine SR (hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.17 - 1.83; P < .001). For sudden unexpected death, there was also an increased risk (HR, 1.47) among patients taking methadone.

For deaths meeting the definition of opioid overdose, patients who had received methadone had more than a 2-fold increased risk vs morphine SR (HR, 2.54; 95% CI, 1.33 - 4.84; P = .005).

The risk for death rose with increasing doses for both opioids. Patients receiving methadone with doses below the median (as low as 20 mg/d) had a significantly greater risk for death than similar patients receiving morphine (HR, 1.70; 95% CI, 1.23 - 2.34; P = .001). For doses above the median, risk was increased for methadone users but not significantly so.

The risks were increased significantly in analyses restricted to subgroups, including new users of the study opioid, younger patients, and follow-up restricted to first year of using a study opioid.

Although the paper doesn't address why patients taking methadone have a higher risk for death, researchers speculate that there may be two possible reasons, said Dr Stein.

The first is that blood concentrations of methadone vary substantially among people taking the same dose. "So perhaps some patients accumulate the methadone and inadvertently have an overdose," he speculated.

Another reason is that while all opioids suppress the drive to breathe, it seems that in the case of methadone, this lasts longer than the ability to suppress pain. "In other words, a patient may take a second dose early because of pain even though the harmful effects on breathing have not yet worn off, which could cause an inadvertent overdose," said Dr Stein.

The findings differ from those of another study in Veterans Affairs patients (Pain. 2011;152:1789-1795) that reported an adjusted overall mortality in patients receiving methadone that was 44% lower than that in patients receiving morphine SR.

Dr Stein explained that the designs of the two studies differed; the Veterans Affairs study included patients with life-threatening illnesses, such as cancer.

"Our study focused on people dying outside of hospital, and we excluded people with serious underlying illness. So I think it represents deaths that were relatively sudden and unexpected and a population that was being treated for noncancer pain."

Several lines of evidence suggest that findings of the current study weren't the result of confounding. Because it excluded patients with serious illnesses, 84% of the deaths were potentially related to opioid toxic effects, said the authors. As well, patients in the two groups were similar in terms of indications for opioids, prescribed doses, and use of cardiovascular and other medications, and the study adjusted for 196 potential confounders, they note.

Because patients vary in their response to drugs, some might do better with methadone than alternative drugs, but Dr Stein stressed that methadone should not be the drug of first choice for chronic noncancer pain.

Starting Dose Too High?

Asked to comment on this new research, Lynn Webster, MD, vice president, scientific affairs, PRA Healthsciences, Salt Lake City, Utah, and immediate past president, American Academy of Pain Medicine, said it highlights the fact that methadone is far more dangerous than most clinicians appreciate. 

"There are many deaths with starting doses because of the huge variability in its metabolism and excretion," he said.

According to the package insert, a starting dose for the drug can be up to 30 mg/d. "This is too high," said Dr Webster. "Some patients will die if they are started on even 20 mg per day."

After methadone is started, the drug will accumulate and have maximum respiratory depression in 4 to 10 days after each dose increase, added Dr Webster. "Too frequent and too high dose increases can cause an overdose and respiratory depression."

This is not the first time that research has linked methadone to overdose deaths. According to a 2012 report in the Centers for Disease Control and Prevention's Vital Signs, an early release of the Morbidity and Mortality Weekly Report, methadone contributed to almost 1 in 3 prescription painkiller deaths in 2009.

The report also showed that 6 times as many people died of methadone overdose in 2009 as did a decade earlier, and that every year about 5000 people die of overdoses related to methadone, most of which are unintentional.

And in 2010, researchers at a meeting of the American Academy of Pain Medicine reported on a national review showing that a disproportionate number of unintentional overdose deaths were related to methadone use. According to the review, 30% of unintentional overdose deaths involve methadone, whereas only 5% of the nation's opioid prescriptions are written for methadone, the researchers said.

The researchers noted that the problems appeared to center on patients prescribed methadone for pain and not to treat addiction.

The study was supported by a grant from the National Heart, Lung, and Blood Institute; the National Institute of Arthritis and Musculoskeletal and Skin Diseases; and a Vanderbilt Physician Scientist Development award. The study authors have disclosed no relevant financial relationships.

JAMA Intern Med. Published online January 19, 2015. Abstract


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