Amid fentanyl crisis, first-of-its-kind study to evaluate expanded methadone access

Ever since fentanyl entered the U.S. drug supply, many Americans seeking treatment for opioid addiction have found that only a single medication is effective at easing cravings and withdrawal: methadone.

But even though the drug is widely considered to be safe and effective, there’s not much data about how methadone stacks up against its main alternative, buprenorphine. And since methadone treatment is only available at specialized clinics known as opioid treatment programs, or OTPs, it’s even more of a mystery how patients might fare when it’s prescribed in a doctor’s office.

Now, amid calls to dramatically expand methadone access, a team of addiction researchers is looking for answers. A new clinical trial, set to launch this year, will attempt to directly compare patients’ ability to remain in treatment when prescribed buprenorphine or methadone in an office setting — the first study of its kind in the fentanyl era.

“While we do have hints from the scientific literature that methadone has better outcomes with respect to retention in treatment and decreases in illicit drug use, we actually don’t have that literature in patients who are primarily using fentanyl,” said David Fiellin, the director of Yale Medical School’s Program in Addiction Medicine and the researcher overseeing the trial.

The trial is well-timed: Since the proliferation of fentanyl, many patients have found that buprenorphine treatment induces intolerable withdrawal symptoms, essentially eliminating it as an option. And with opioid overdose deaths hovering at an all-time high, many lawmakers, public health experts, and advocates have increasingly argued that methadone should be accessible like other medications — via doctors and pharmacies. OTPs, by comparison, often require patients to show up in person daily to receive a single dose of medication.

Opponents, meanwhile, have argued that expanding methadone could have unintended consequences. The drug is itself an opioid, and can cause overdose when used in excess or in combination with alcohol or other drugs.

Given the magnitude of the current overdose crisis, however, advocates argue that allowing doctors to prescribe methadone directly to their patients would do dramatically more good than harm.

Doctors, in fact, are already allowed to prescribe methadone in a traditional primary-care setting — but only when it’s used as a treatment for pain, not as a treatment for opioid use disorder. Calls to let doctors prescribe methadone as an addiction treatment as well are gaining steam.

Sens. Ed Markey (D-Mass.) and Rand Paul (R-Ky.) introduced a bill last year that would have allowed doctors to prescribe methadone directly to patients, who’d be allowed to pick it up at a pharmacy. The American Medical Association has indicated support for doctors to prescribe methadone in at least some circumstances, and the American Society of Addiction Medicine has endorsed the Markey-Paul proposal directly.

The U.S. system of restricting methadone treatment to OTPs, experts argue, is both unique and unnecessary.

“Australia, the U.K., and Canada all do a combination of office-based methadone and specialty treatment programs, so you have an option,” said Noa Krawczyk, a professor at the NYU Grossman School of Medicine whose research focuses on drug use and addiction care. “They’ve had it for many years and it works very well.”

While past studies have attempted to compare the effectiveness of methadone and buprenorphine head-to-head, they’ve only analyzed patients who were already in stable recovery at the time the clinical trial began.

The new trial will be the first to focus on relatively less stable patients who have not yet entered treatment. In many ways, that group represents a more meaningful study population, given that the first weeks and months of opioid addiction treatment are typically seen as a bigger challenge than continuing medication treatment for patients in long-term recovery.

Given the momentum surrounding expanded methadone access, Fiellin said the trial is being conducted in anticipation of increased flexibility in the future.

“The relative efficacy of these two medications when coordinated out of a primary care practice or office-based setting is really not known — or at least, not known in the United States,” he said. “We want to be able to conduct research now that will inform clinician decisions when office-based and pharmacy-dispensed methadone is available.”

The trial hasn’t yet begun enrolling patients. Its lead investigators are currently in the early stages of selecting six sites for the study, each of which will have two doctors who prescribe methadone and a partner pharmacy that dispenses it.

The clinical trial’s sponsors expect to receive special research exceptions from the Drug Enforcement Administration, the government agency that regulates controlled substances. Fiellin said that DEA officials have indicated the agency plans to cooperate with the study and grant two types of exceptions: One that would allow doctors to prescribe the drug, and another that would allow retail pharmacies to dispense the medication.

The trial is unlikely to yield results for several years, Fiellin said, given the timeline for selecting sites, receiving regulatory approvals, enrolling hundreds of patients, and measuring their outcomes over time.

Both the study and the proposed policy changes, Krawczyk said, are long overdue.

“We know that a lot of people actually need methadone because they can’t use buprenorphine,” Krawczyk said. “Yet methadone is only available through this very restrictive OTP system, so having the option of getting methadone in an office-based setting is going to be really life-changing for a lot of people.”

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