High-Dose Methadone Boosts Cardiovascular Risk

Allison Gandey

Patients taking high doses of methadone have more cardiovascular risk, warn researchers.

"There is a dose-dependent effect on QTc interval in patients taking more than 120 mg per day," presenter Ricardo Cruciani, MD, from Beth Israel Medical Center in New York City, said here at the American Pain Society 30th Annual Scientific Meeting.
Investigators grouped chronic pain patients according to methadone dose and found the highest-dose group showed significantly more QTc prolongation. Lower doses ranged from 10 to 120 mg.
Dr. Cruciani's team considered a QT corrected for heart rate prolongation of more than 500 milliseconds as a definite risk for the potentially fatal arrhythmia torsades de pointes. Men with prolongations of more than 430 and 450 and women with increases of 450 and 470 were considered at risk.
According to the Centers for Disease Control and Prevention (CDC), the number of fatal poisonings caused by opioid overdoses has tripled in recent years. Leading the pack among analgesic-related deaths is methadone.

Rising Death Rate

"Our interpretation is the doses for methadone used to be low," Dr. Cruciani told Medscape Medical News. "For many years it has been used as substitution therapy in treatment programs for patients with opioid addiction. However, in the last decade, methadone to treat chronic pain patients became more common."
Dr. Cruciani suggests the increasing popularity can be attributed to the efficacy, long duration of action, and low cost. Many questions remain about the cause of methadone deaths, but some researchers suggest cardiac toxicity is at play.
In the CDC report led by Diane Makuc, DrPH, the team from the National Center for Health Statistics points out the drug is a long-acting opioid and requires a complex dosing schedule. "Methadone relieves pain for 4 to 8 hours but remains in the body for up to 59 hours. A lack of knowledge about the unique properties of methadone was identified as contributing to some deaths."
Another national review of unintentional overdose deaths involving opioids came to a similar disturbing conclusion — a disproportionate number of poisonings are related to methadone.
Presenting at last year's American Academy of Pain Medicine Annual Meeting, investigators reported 30% of deaths involved methadone even though the drug represents only 5% of the nation's opioid prescriptions.
The researchers, led by Lynn Webster, MD, founder of the Salt Lake City, Utah–based Life Source Foundation, which funded the study, said the problems appeared to center on methadone prescribed for pain not addiction.
In this new study, Dr. Cruciani's team focused on chronic pain patients and especially those older than 50 years, considered at higher cardiovascular risk. Investigators looked at 39 patients taking methadone and wanted to compare the effectiveness of a single electrocardiogram vs a 24-hour Holter monitor in detecting abnormal QT.

Torsades de Pointes

They found a single electrocardiogram detected fewer patients with QTc interval prolongations compared with a 24-hour Holter monitor (15 vs 20). However, the 2 approaches detected the same number of patients at risk for torsades de pointes.
Of note, Holter monitoring detected twice as many patients with QTc prolongations at noon compared with electrocardiogram. "This suggests that a single test might not be sufficient in identifying patients at risk," Dr. Cruciani said.
Despite the growing concerns over cardiac toxicity, many investigators suggest methadone deaths are a multipronged problem.
Dr. Webster's team studied malpractice cases in the United States, searched the literature, and reviewed other local and federal sources of information and found many reasons for the rising death toll.
"There's not one thing that caused this," Dr. Webster said when first presenting the results of his study. "There are multiple things that all add up."
A chief reason, his team suggests, is that conversion tables — used by physicians to transition patients from one opioid to another — recommend too much methadone for most patients. For example, Dr. Webster pointed out, through 2006, the US Food and Drug Administration recommended a starting dose of 80 mg per day. That recommendation has since been changed to 30 mg a day.
"For most individuals, starting them at 80 mg per day, they would die," Dr. Webster said.
"We used to regularly see doses of 40 or 60 mg," Dr. Cruciani told Medscape Medical News. "This was when methadone was used primarily for addiction, but now that we use it for chronic pain we choose much higher doses."

courtesy: http://www.medscape.com/