Long- and Short-Acting Opioid Addiction Meds Equally Effective

Alicia Ault

November 16, 2017

Extended-release naltrexone (XR-NTX) (Vivitrol, Alkermes) and buprenorphine/naloxone (BUP-NX) (Suboxone, Indivior) were similarly efficacious in preventing relapse for patients with opioid use disorder, although naltrexone therapy was more difficult to initiate, new research shows.

The protocol for the randomized, controlled, multisite study required that patients achieve complete withdrawal from opioids before beginning therapy with XR-NTX. When patients could not follow the study protocol, results favored BUP-NX, with lower relapse rates, better relapse-free survival, and more opioid-abstinent days.

The study was published online November 15 in the Lancet.

Evidentiary Void Filled

"The good news is we filled the evidentiary void, and also learned that for those who were able to initiate treatment, the outcomes were essentially identical, as were adverse events," lead investigator John Rotrosen, MD, said in a statement issued by the National Institute on Drug Abuse (NIDA).

"This is important data for guiding usual use of Vivitrol and helping people understanding the two choices," Joshua D. Lee, MD, study investigator and associate professor of population health, New York University School of Medicine, New York City, told Medscape Medical News. Now there is evidence that "Vivitrol, despite its limitations, is a decent option," he said.

"These findings should encourage clinicians to use medication protocols, and these important results come at a time when communities are struggling to link a growing number of patients with the most effective individualized treatment," NIDA Director Nora D. Volkow, MD, said in a statement.

In 2015, nearly 600,000 Americans had a heroin use disorder, and close to 13,000 died of a heroin overdose, said NIDA.

The study results will not change the practice landscape for Andrew Saxon, MD, chairman of the American Psychiatric Association's Council on Addiction Psychiatry, who told Medscape Medical News that he was very familiar with the positives and negatives of each medication. Dr Saxon is professor of psychiatry and behavioral sciences at the University of Washington, Seattle.

"What the study did confirm is that there are a lot of challenges to getting on the extended-release naltrexone and that makes it difficult for both patients and physicians to use that medication," said Dr Saxon, who ran one of the study's treatment sites in Seattle but did not participate in the designing the study or analyzing or reporting the results. But, once someone has fully withdrawn from opioids, XR-NTX "seems to be as effective as the other medications we have," said Dr Saxon.

"This is a very exciting study," Cory Waller, MD, FACEP, DFASAM, chair of the legislative advocacy committee of the American Society of Addiction Medicine, told Medscape Medical News.

He noted that head-to-head studies are rare. "Now we have the ability to dispel a lot of myths and just look at the science," said Dr Waller, who is a fellow at the National Center for Complex Health and Social Needs, Camden, New Jersey.

Two Effective, Safe Options

The study authors determined that almost all patients who had failed to begin therapy with a study drug experienced an early relapse. XR-NTX was more difficult to initiate; in the intent-to-treat analysis, for those in that treatment group, the rate of relapse-free survival was lower, owing to the failure to start treatment. For those who did begin treatment with either medication, XR-NTX and BUP-NX were similarly effective.

"Thus, if induction to either medication is successful, XR-NTX and BUP-NX were comparably effective and safe options," the authors note.

In the study, 570 patients were randomly assigned to receive either XR-NTX or BUP-NX. The timing of the initiation of treatment was flexible; patients generally either initiated treatment early, during a methadone or buprenorphine taper while undergoing detoxification, or later, after detoxification was completed. Completion of detoxificaiton was verified by screening of urine.

The primary outcome was time to relapse, defined as use of nonstudy opioids at any time after 20 days from initiation of treatment; at the start of 4 consecutive weeks of opioid use; or at the start of 7 consecutive days of self-reported opioid use.

A use-week was further defined as at least 1 day of nonstudy opioid use, having a urine sample that tested positive for nonstudy opioids, refusing to provide a urine sample, or missing an appointment for collecting a urine sample. Of the study enrollees, 82% were dependent on heroin, and 16% were dependent on pain medications.

Of 570 opioid-dependent adults, 283 were randomly assigned to the XR-NTX group, and 287 were assigned to the BUP-NX group. Patients were followed for up to 24 weeks of outpatient treatment.

Among the 204 patients in the XR-NTX group, treatment failed for 79; of the 270 BUP-NX patients, treatment failed for 17. These 474 patients were included in the per-protocol analysis, which found that 52% of the XR-NTX group experienced a relapse event, compared to 56% of the BUP-NX group. The authors found no difference in the relative hazard of relapse over time (hazard ratio, 0.92; 95% confidence interval, 0.71 - 1.18).

For the intent-to-treat analysis, 185 (65%) of the 263 X-NTX patients experienced an opioid-relapse event, compared with 163 (57%) of the 287 BUP-NX patients.

The difference between the two analyses "was largely accounted for by high occurrence of early relapse among XR-NTX induction failures," the authors note.

Dr Waller said the study shows that "the difference is not which medication we put you on, but how we get you on it."

Patients and clinicians can determine which medication is best, given the fact that full detoxification is necessary before starting XR-NTX, he added.

Overdose Data

"This study highlights the importance of detoxification for initiating treatment with Vivitrol," agreed Craig Hopkinson, MD, chief medical officer and senior vice-president of clinical development and medical affairs at Alkermes, in a statement.

The company "is working alongside prominent researchers in the field to determine effective, safe and efficient detoxification strategies for successful induction onto Vivitrol, in order to help healthcare providers manage their patients through this critical transition period," said Dr Hopkinson.

"The clinician would have to take into account the situation of the patient," said Dr Saxon. For the average patient in an outpatient setting, "the most expeditious treatment is probably going to be the buprenorphine/naloxone combination," he added.

Although the study recorded overdoses, it was not powered to detect significant differences. Twenty-eight overdoses were reported in 23 study participants: 18 among those receiving XR-NTX, and 10 in the BUP-NX group.

Eight of the 18 overdoses in the naltrexone group were among patients who did not initiate therapy with a study medication. One patient in the 10 BUP-NX group did not initiate therapy with a study medication. Five overdoses were fatal ― three among patients in the BUP-NX group, and two among those in the XR-NTX group. Most of the overdoses occurred long after the last dose of study drug had been given.

NIDA said the overall overdose rates, including nonfatal overdoses, were low compared to what would be expected in this population. NIDA supported the conclusion that medication protects against overdose.

Mortality and overdose risk is high for patients taking naltrexone, buprenorphine, and methadone in the period immediately after these drugs are withheld, said Dr Saxon. He also noted there had been some concern that naltrexone may increase the risk for overdose after withdrawal of the drug of dependence, because its mechanism would lower the user's tolerance to opioids.

The Lancet study "didn't show that there's more overdose risk with naltrexone than with going off buprenorphine," he said. "So to me, it gives me a little extra edge of comfort that by using naltrexone, I'm not putting them at more risk than putting them on buprenorphine or methadone," said Dr Saxon.

However, the study did demonstrate the challenge of keeping patients on treatment once they have started. "We don't have all the answers in engaging people in care and keeping them in care," said Dr Lee.

"Despite the efficacy of the three currently available medications, they are not effective for all patients, and each has drawbacks," said Dr Volkow in an editorial that accompanied the study.

She noted that two monthly extended-release formulations of buprenorphine are under review by the US Food and Drug Administration. Research is needed on how to optimally initiate XR-NTX "and on how to reduce dropout rates, which remain high for all medications," she said.

The evidence shows that medication-assisted treatment works, said Dr Volkow and Dr Saxon. "If the purpose of medical interventions is to save lives, the medical treatment for opioid use disorder is at the top of the list of what we can do to save lives," said Dr Saxon.

Patients discontinue treatment for many reasons, which include financial and emotional factors. "For most patients, the most convenient and easiest medication to get on is going to be the buprenorphine, and we've been aware of that for a while," Dr Saxon said.

The study was supported by grants from the National Drug Abuse Treatment Clinical Trials Network of the National Institute on Drug Abuse. The authors' relevant financial relationships are listed in the original article.

Lancet. Published online November 15, 2017. Abstract, Editorial

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