Extended-release naltrexone (Vivitrol) has been more popular than methadone or buprenorphine in the corrections field. So who better than Kevin Fiscella, M.D., M.P.H., liaison from the American Society of Addiction Medicine (ASAM) to the National Commission on Correctional Health Care (NCCHC), to question the way clinicians decide what medication to use in the treatment of opioid use disorders (OUDs). In prisons and jails, there has been a bias against the agonists methadone and buprenorphine. The NCCHC last month posted its position statement on the treatment of substance use disorders in correctional facilities, which includes a strong recommendation for treatment with methadone or buprenorphine, and also refers to the use of naltrexone.

In a Letter to the Editor in the November-December issue of the Journal of Addiction Medicine, Fiscella raises the issue of the standard of evidence for naltrexone compared to methadone or buprenorphine. He said that based on the evidence, naltrexone should not be a first-line medication for treatment of OUDs; rather, buprenorphine or methadone should be the first-line medication. In addition, he said naltrexone should only be for highly motivated patients. It’s important to note that much of the evidence about naltrexone refers to the oral form, as extended-release naltrexone — only available as Vivitrol — has little evidence. With oral naltrexone, even if patients are highly motivated, administration should be observed to make sure patients are compliant, Fiscella suggested.

Fiscella’s letter referred to a paper by Alex Harris, Ph.D., and colleagues entitled “Specifying and Pilot Testing Quality Measures for the American Society of Addiction Medicine’s Standards of Care,” published in the May/June issue of the Journal of Addiction Medicine. The paper looked at three measures: pharmacotherapy for alcohol use disorder, pharmacotherapy for opioid use disorder and detoxification. Fiscella’s letter focused on how quality measures should be used in selecting between the three medications approved for the treatment of OUD: methadone, buprenorphine and naltrexone. (Naltrexone is also used for the treatment of alcohol use disorders.)

“Evidence regarding effectiveness and outcomes supports recommendations for methadone and buprenorphine as first-line drugs for OUD under most circumstances,” concluded Fiscella’s letter. “Naltrexone should be reserved for highly motivated, supervised patients. Guidelines and quality measures should reflect this evidence.”

Harris responds

Harris and the co-authors of the original study responded to Fiscella’s letter, agreeing in many areas, in particular on the evidence supporting the effectiveness of methadone and buprenorphine. The difference, however, is that ASAM does not take a position on “first-line” drugs. “The current ASAM guidelines cite the same facts and recommendations, but do not take the step of distinguishing first-line and other medications,” said the Harris letter. However, Harris was welcoming of the dialogue and cited the importance of transparency in developing quality measures.

Harris noted that the ASAM OUD guideline required at least one of the following criteria for recommending a medication: (1) FDA approval for the indication or (2) effectiveness for the indication supported by high-quality meta-analysis. There is “weak meta-analytic support” for naltrexone for OUDs, said Harris in the letter.

“A possible downside of Dr. Fiscella’s proposal is that some patients who are less motivated or not supervised might prefer or benefit from naltrexone, but might not receive it under more prescriptive guidelines and measures,” said Harris. On the other hand, the science supporting methadone and buprenorphine as more effective is there. “A downside to being less prescriptive is that clinicians and patients might not appreciate the underlying science,” said Harris. “We hope in the next revision of the guidelines, discussion will focus on the benefits and potential pitfalls of distinguishing methadone and buprenorphine as first-line drugs for OUD, and carefully specifying the condition under which naltrexone should be considered.”

The Lee study vs. real life

We asked H. Westley Clark, M.D., Dean’s Executive Professor of Public Health at Santa Clara University, to comment on the discussion.

Clark said that both Fiscella and Harris, in assessing evidence, need to consider two key aspects of a paper they both rely on — the paper by Joshua Lee, M.D. (published in the New England Journal of Medicine this spring; see ADAW, April 4) that found that Vivitrol was better than usual treatment — which was no medication — at preventing relapse. Why the Lee paper may not be relevant to the real-world criminal justice system: Lee’s subjects were voluntary participants and not facing criminal sanction for not taking the medication, and — importantly — they stopped taking the medication after the trial was completed, most likely because they couldn’t afford to pay for it.

In the Lee study, the control group (no medication) received the same range of incentives as the Vivitrol group, including encouragement to access other treatment, including buprenorphine or methadone, if preferred, both during the trial and after the treatment phase. Visits were scheduled every two weeks; 79 percent of the Vivitrol group and 75 percent of the treatment as usual group attended these visits.

No participants in the Lee trial continued Vivitrol after the treatment phase. At the time, Vivitrol may not have been accessible to patients relying on public-sector funding, noted Clark.

“In regard to the notion of incentives, the population in the Lee paper did not have the negative incentive of parole, probation or other criminal justice–related remand,” noted Clark. “All the subjects were voluntary. Thus, the idea or notion of incentives, whether positive or negative, is not appropriate for a discussion involving Lee et al.”

So the Lee paper did not address how Vivitrol applies to a real-life criminal justice population, which is faced with consequences of relapse such as reincarceration.

Fiscella concluded that the evidence is lacking that most patients with OUD will continue to show up on their own for monthly injections, without the leverage of the criminal justice system. Clark said this conclusion is “true but fuzzy” because the criminal justice system only concerns itself with the period of supervision, not what happens afterward. “The criminal justice system has leverage in terms of return to incarceration, which is an incentive to return for monthly injections,” said Clark. “The only issue then would be cost and who would pay the cost.”

In addition, one paper cited as evidence that naltrexone has worse outcomes dealt with oral, not extended-release, naltrexone, noted Clark, adding that Fiscella’s conclusion that “higher deaths among those prescribed naltrexone reflected greater nonadherence and relapse” does not seem to be applicable.

Harris and colleagues propose a decision rule that places “effectiveness for the indication supported by high-quality meta-analysis” above FDA approval in rank, noted Clark. But waiting for this meta-analysis is not a good idea during this crisis, he said. “The real-world criminal justice context is unique because it carries with it the threat of sanctions, including loss of freedom,” he said. “Waiting for permission to do the ethical studies in sufficient quantities to generate appropriate meta-analysis could deprive individuals of an alternative to methadone or buprenorphine.” However, if the question of who is paying for the treatment isn’t addressed, the issue of effectiveness can’t be addressed either, said Clark. “What I fear is that the poor under the supervision of the criminal justice system will have a more narrow list of treatment options, given the cost. Or, the poor will be given a Hobson’s choice — pay for extended-release naltrexone or continue in incarceration.”

Next steps for the guideline

“Our hope is that ASAM members and other stakeholders continue to discuss the benefits and risks of these and other alternatives,” said Harris. “Dr. Fiscella has made a reasoned and concise proposal for summarizing current evidence into concrete standards.” However, even assuming that only patients with high motivation and supervised administration should receive oral naltrexone for OUD, there is no data that exists on these concepts, he said. “Thus, we are again stuck with unsatisfying choices, all with attendant risks and benefits,” he said. “We can give credit for giving naltrexone or not, but we have no way of assessing motivation or capacity for supervision.”

The ASAM National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use was released last year (see ADAW, June 15, 2015) and published in the May/June 2015 issue of the Journal of Addiction Medicine.

For the new NCCHC position statement on treatment of substance use disorders in correctional facilities, go to http://www.ncchc.org/filebin/Positions/Substance-Use-Disorder-Treatment-2016.pdf. Dr. Fiscella discussed the need to prevent withdrawal deaths in prisons and jails in an interview this summer (see ADAW, July 25).

Bottom Line…

Vivitrol is more popular than methadone or buprenorphine among most corrections officials, but a top corrections medical expert says it should be second-line only.