Two key medications for opioid addiction have finally been compared in a head-to-head, randomized study. But the first major trial to pit a buprenorphine/naloxone combination (daily Suboxone sublingual film) against a newer drug, extended-release naltrexone (monthly Vivitrol injection) does not answer key questions—including whether the newer medication actually increases death risk following treatment and which medication is best for which patients. In the face of an ever-rising toll of overdose deaths, these data are urgently needed.
The study, which was published this week in The Lancet, does provide some useful information for patients and families who are considering treatment options. Researchers led by Joshua Lee, an associate professor in the departments of medicine and population health at New York University, used data from 570 participants at eight inpatient treatment centers who were randomly assigned to either the buprenorphine film or the naltrexone injection. They found that both medications performed equally well—at least, for those who were able to be started on them. Around half of each group avoided relapse during the six-month trial.
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Importantly, however, far fewer people were able to start extended-release naltrexone, which requires enduring at least three days of withdrawal symptoms, compared to buprenorphine, which can be started the day those symptoms arise. Four times more patients in the trial failed to start long-acting naltrexone, compared to those randomized to buprenorphine.
Multiple headlines about the paper said the drugs were equally effective, but that’s not entirely true. As Sarah Wakeman, assistant professor of medicine at Harvard Medical School and medical director of the Massachusetts General Hospital Substance Use Disorder Initiative, told STAT News, “The take-home from this study is that buprenorphine is more effective.”
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Most of the overdoses during the study (64 percent) occurred among people assigned to Vivitrol; eight of these involved people who didn’t succeed in starting the drug, while 10 occurred among people who had taken it at least once. During treatment, the most common occasions for overdose are when medications are missed, leading to relapse.
The overdose death rate for both groups, however, was statistically equivalent: two people who took extended-release naltrexone died, compared to three in the buprenorphine group. Unfortunately, the research did not have enough participants to actually determine exactly how each medication affects overdose death risk—a crucial issue for obvious reasons.
There is reassuring data on that point from other studies on buprenorphine and methadone, which both act in the brain in similar ways. Both medications been shown repeatedly to cut overdose death rates by half or more, so long as patients stay in treatment. Based on existing data, they are clearly the safest choice. Since these medications are themselves opioids, they maintain tolerance by activating opioid receptors; this reduces overdose risk, but does not produce impairment as long as patients are prescribed an appropriate dose and take them at the same time every day.
We don’t, however, have similar long-term data on Vivitrol, which was only approved for opioid treatment in 2010. (Suboxone was approved as a pill in 2002 and as a dissolvable film in 2010.) Pharmacologically, naltrexone has the opposite effect of the other medications: it prevents opioids from activating their receptors. Which means it could potentially produce the opposite of tolerance, that is, sensitization. In other words, when people stop Vivitrol, they might be at even higher risk of dying from overdose than they would be if they end treatment with methadone or buprenorphine.
Research here shows real reason for concern: Australian studies of the short-acting pill form of naltrexone found that those who ended treatment with this drug were eight times more likely to overdose and nearly four times more likely to die compared those who stopped buprenorphine or methadone. Proponents argue that this risk is only relevant for the short-acting drug because it’s related to people failing to take the drug every day, which can’t happen with Vivitrol—a shot that lasts for a month. But right now, we simply don’t have the evidence either way.
To get this data, patients taking Vivitrol need to be tracked after treatment—as I reported for VICE in July, at least half a dozen deaths are already known to have occurred immediately following Vivitrol cessation, and since that story posted, I’ve heard from two additional families who lost a child in this way. Given this, the increasing use of legal coercion to get people to use the drug in criminal justice settings also needs to be reconsidered, especially since those who are not ready to quit often try to overcome the effects of Vivitrol by using higher doses of opioids or adding cocaine or methamphetamine.
This doesn’t mean, however, that Vivitrol is not a good option for some. Different people are likely to benefit from different approaches—after all, some medications that produce depression in some people relieve it in others. And in addiction treatment, simply having a choice of treatment options actually improves outcomes.
As in every other area of medicine, treatment needs to be tailored—something that is currently denied people in many drug courts, jails and prisons, which only permit Vivitrol. The rationale is that opioids like buprenorphine and methadone can be misused or diverted to others— however, data on the rare facilities that do allow them shows that it can be done safely.
Indeed, many in the field suspect that the criminal justice preference for Vivitrol is actually due to its manufacturer’s intense marketing pressure and because courts prefer giving people with addiction a medication that is unlikely to make them feel good. (A long-acting injectable version of buprenorphine is expected to be approved by the FDA next year, which will obviate the “diversion” argument for disallowing it.)
In any event, this study adds further weight to the expert consensus that people with addiction in any setting should have access to all FDA-approved medications. If we really believe that addiction is a medical problem, evidence—not the preferences of police, jailers, and judges—needs to determine appropriate treatment. And so far, the evidence still favors buprenorphine or methadone in most cases.
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