The Vivitrol vs Suboxone Debate

Researchers say they found a "data blunder" in a landmark 2018 study that concluded Vivitrol was equally effective as Suboxone.

In 2018, The Lancet published a landmark trial that compared two drugs that are FDA-approved to treat opioid use disorder: buprenorphine (Suboxone) and naltrexone (Vivitrol). The original study concluded no statistically significant difference in overdose between the naltrexone and buprenorphine groups. “Both medications were equally safe and effective,” the researchers concluded.

Four years later, a group of researchers are challenging these results. Upon re-analysis of the original 2018 paper, researchers found more overdose events that were not originally included, which led them to conclude that patients in the naltrexone group had a higher overdose risk than patients in the buprenorphine group. According to the re-analysis, the overdose risk among patients taking extended-release naltrexone was 2.4 times higher than those taking buprenorphine.

Now, more than 180 researchers, clinicians, and other advocates have signed on to a letter demanding The Lancet either correct or retract the original 2018 study.

Dr. Joshua Lee, who led the 2018 trial, says he and his team stand by their original conclusions.

Of the re-analysis, Lee said, “Their findings are interesting but inconclusive.” Lee added, “We stand by all of it, while also agreeing that those same methods were never perfect. In subsequent and current trials, we've been working at tracking overdose events differently, using newer instruments and more detailed and specific event reporting.”

The main conflict between the two groups concerns the counting of overdose events. Before unraveling all of that, let’s take a look at the differences between the two drugs that were studied.

Naltrexone vs Buprenorphine

Both buprenorphine (Suboxone) and naltrexone (Vivitrol) are FDA-approved medications for opioid use disorder. Buprenorphine is a partial-opioid agonist, which means it eases the pain of withdrawal by partially activating opioid receptors, which curbs cravings for other opioids like heroin. Patients on buprenorphine tend to report a markedly improved quality of life. On top of that, research shows buprenorphine can dramatically reduce the risk of all-cause mortality, including fatal overdose. Famously, after France made buprenorphine widely available in the mid-1990s, overdoses plummeted.

A huge decline in overdoses in France after making buprenorphine available

Unlike buprenorphine and methadone, naltrexone is an opioid receptor antagonist. That means instead of activating receptors to ease withdrawal and satiate cravings, naltrexone works as a receptor blocker, preventing opioids like heroin from taking effect. The overall efficacy of naltrexone, including in the 2018 trial in question, are much more mixed.

There have been a couple different versions of naltrexone on the market. An oral version to be taken daily didn’t really work out so well for opioid addiction. A 2005 Australian study found the mortality rate for oral natrexone was four times higher than methadone, as well as substantially higher than buprenorphine. The Australian reseachers emphasized that naltrexone significantly diminishes one’s tolerance, leaving patients ultra-sensitive to opioid doses they think are safe, putting them at heightened risk for overdose.

In the U.S. today, people with opioid use disorder instead recieve an extended-release version of naltrexone that gets adminstered via a monthly injection. This is the version of naltrexone (called Vivitrol) that was compared to buprenorphine in the 2018 trial.

Research shows the extended-release version works better than the daily oral version. Prior to the 2018 paper, naltrexone was only ever compared to placebo in trials that took place in Russia. Those results—not so shockingly—showed naltrexone worked better than no treatment. Critics of the Russian trials point out that Alkermes, the manufacturer of Vivitrol, only went to Russia in the first place because that country bans agonist therapies like methadone and buprenorphine. Critics say the ideal Vivitrol trial would have compared it to the gold-standards of care: methadone and buprenorphine. Results from the Russian trial showed that a year after people stopped taking Vivitrol, the rate of relapse was the same for those on the placebo.

Multiple clinicians also report that the Vivitrol injection does not always last the full month as advertised. Toward the end of each month, the Vivitrol shot could wear off and receptors are no longer blocked. This creates at least one potential scenario where people are at risk of an overdose.

How do these two very different drugs compare to each other?

Writing in Harvard’s Health Blog, Dr. Sarah Wakeman summed up the 2018 findings published in The Lancet paper that has become a lightning rod for debate:

“Before a person can start taking [extended-release] ER naltrexone, they must be completely off opioids for seven to 10 days. Only 72% of the group assigned to ER naltrexone even got the first dose, and among those who were randomized during the detoxification process, only 53% started the medication. In contrast, 94% of the group assigned to buprenorphine started the medication.”

Dr. Wakeman is saying it’s hard for people to get on naltrexone in the first place. Those initial seven to 10 days are a high hurdle to clear, depending on how bad the withdrawal is. Now that illicit fentanyl has taken over the street opioid market, withdrawals come on very fast and can be especially hellish, making Vivitrol a tough sell for people looking for fast relief.

Once people did manage to get on naltrexone, the relapse rate in that group was higher compared to the buprenorphine group. By day 21 in the 2018 study, 25 percent of the naltrexone group relapsed compared to 3 percent of those in the buprenorphine group. “Researchers learned that relapse was significantly more likely in the extended-release naltrexone group (65% compared to 57% in the buprenorphine group),” Dr. Wakeman writes. Finally, out of 144 days, Suboxone patients reported 81 opioid abstinent days and Vivitrol 39 abstinent days. Put differently, a patient in the Suboxone group had a 36 percent higher odds of avoiding relapse that week than people on Vivitrol.

For all the above reasons, addiction medicine professionals tend to favor buprenorphine and methadone over naltrexone. The leader of the 2018 trial agrees with his critics on this point. “Accessing buprenorphine or methadone is a safer bet,” Dr. Lee said by email.  “Agonists are easier to start and they are very effective OUD treatments with solid retention.”  

Below is a handy visual aid to retain all of this:

via Recovery Research Institute

There certainly are people who benefit from Vivitrol, especially patients who are highly motivated to not use illicit substances. In America, there’s also a lot of stigma over remaining “dependent” on a substance like methadone or buprenorphine. For those who are adamant that they don’t want to be on an opioid, for whatever reason, they’re more likely to opt for Vivitrol.

Tha’s why researchers and clinicians say it’s important for patients to have options and for them to be well informed of which option is best for them. For opioid addiction there’s only three options, which is rather pitiful. People with depression, for instance, have dozens of drugs to choose from. In jails, prisons, and drug courts, some people don’t get to choose their treatment at all.

“Vivitrol Courts”

There’s a broader political-ideological context to the Suboxone vs Vivitrol debate that’s important to get into.

Alkermes, the company that makes and sells Vivitrol, has been accused of cynical, misleading, and aggressive marketing practices, particularly the way the company has courted police, judges, and jailers.

In 2017, investigative reporter Alec McGillis published an exposé in ProPublica that revealed how Alkermes convinced drug court judges to favor its drug over methadone and buprenorphine. Alkermes targeted drug court judges who started prescribing Vivitrol from the bench, turning their drug courts into “Vivitrol courts.”

This approach is rather bizzare. Typically, pharma companies pitch their medicine to doctors and, in America, directly to patients. But with Vivitrol, Alkermes took a different route. “If the usual route of selling medications — pitching them to physicians and directly to patients — wasn’t going to work, the company had to find another way,” McGillis wrote. “And so it did. It began focusing on a market where consumer choice was less relevant: drug courts.”

McGillis continues:

“Over the past five years, Alkermes has persuaded hundreds of [drug courts] to favor Vivitrol injections. The judges say they don’t force anyone to take a particular medicine. But in effect, they give addicts a choice: the shot, or jail.”

“Thanks in great part to these judges, and to an explosive epidemic that only seems to be accelerating, some 30,000 people are now receiving Vivitrol shots. In the first quarter of 2017, sales totaled $58 million, a 33 percent increase over the year before. The company is ramping up manufacturing capacity, enough so that it could soon handle $800 million in annual sales, which it projects it will reach by 2020.”

Vivitrol has fallen well short of that $800 million in annual sales. In 2021, Alkermes netted $344 million in sales from Vivitrol. That’s still a lot.

McGillis reports that part of Alkermes’s success hinged on exploiting well-worn biases and stigma against methadone and buprenorphine, especially in their pitch to the criminal justice system. Many jails and prisons do not offer either drug because they are opioids. That is, unless they’re sued and forced to offer them. The Department of Justice argues denying buprenorphine or methadone to people with opioid use disorder is a violation of the Americans with Disabilities Act. The DOJ has won several such cases.

Fears of “diversion,” “misuse,” and “getting high” have been used to justify witholding of buprenorphine and methadone. “The Suboxone zombies aren’t getting any better,” one drug court judge told McGillis. Buprenorphine and methadone also run up against misguided myths that are popular in the culture of 12-steps and AA meetings: These drugs are merely trading one addiction for another. There remain to be widely held notions like: You can’t be in recovery if you still take an opioid, even if it is part of a treatment prescribed by a doctor.

All of this is part of the critique from the research group that conducted the re-analysis of the paper and sparked the letter campaign to The Lancet. Past research combined with the drug’s political-ideological context make for a lot of skeptics of Vivitrol.

“Vivitrol offers the illusion of being able to say you are drug free,” said Nabarun Dasgupta, an epidemiologist and statistican at University of North Carolina, a critic of the 2018 trial who organized the letter campaign to The Lancet. “Because the idea of a blocker is so appealing to so many people, the pharma company that makes Vivitrol marketed it to the courts. Brilliant, opportunistic, and disgusting. But, business as usual.”

The FDA has also admonished Alkermes. In 2019, the FDA issued a warning letter to Alkermes for omitting “overdose risk” in its marketing materials. The FDA demanded Alkermes to “immediately cease advertising practices that misbrand Vivitrol.”

To balance the scales here, the manufacturer of Suboxone also engaged in shady and illegal practices. In 2020, Indivior Solutions pleaded guilty to making false statements to promote the film version of Suboxone. Indivior’s scheme was less about branding and efficacy of the drug and more about evergreening their patent to retain market share by kneecaping cheaper generics.

Both of these companies, in their own way, offer up examples of Big Pharma’s shameless pursuit of profits. Business as usual, indeed.

Correct and Retract?

Back to the disagreement over The Lancet study. The paper is four years old and debate over its results has been brewing for about as long.

So, what does all of it mean?

I’ve talked to and listened to both sides of the conflict. As a non-statistican, the arguments being made are fairly technical, concerning statistical methods, study design, outcome measures, etc. My original thoughts went like: This one paper from 2018 should not matter all that much.

Alas, it does matter. The Lancet is the most influential medical journal in the world. The media widely covered the results of the trial, sometimes without important nuances. Pharma companies like Alkermes seized on the conclusions for its own marketing. And then institutions like drug courts set bad policies. So, it’s all a big mess, which is par the course for American drug policy and addiction treatment.

Looking back at the 2018 trial, it wasn’t really designed to track overdose events in the first place. And that’s what this debate is all about. The primary outcome measures deal mostly with relapse rates, not overdose rates. The numbers of overdose events are fairly small. And if there is one thing I do know about statistics, it’s that small numbers tend to mess things up.

The whole study follows 570 people who were randomly assigned to either the naltrexone (n=283) or buprenorphine group (n=287). Out of all these people, the re-analysis found 28 overdose events among the groups. The original analysis found 23 overdose events among the groups. The re-analysis used a broader search for overdoses and found more overdose events that were not included in the original analysis.

In the narrow academic sense, the two research groups are essentially arguing over which methods should be used for counting overdoses (both fatal and non-fatal) in a National Institutes of Health funded clinical trial. The fact that overdose deaths were not a primary outcome measure seems to me to be a flaw in the design of the study. To compare two drugs that treat opioid addiction, one would think counting overdoses would be top of mind.

Here is what Dr. Lee said about all of this to me:

“If [the trial] had been 10x the size, designed to track overdose as a primary outcome, and the same basic 2:1 ratio of events held, it may have or would have likely shown a much clearer difference in overdose events favoring buprenorphine.  That would be a reasonable bet and my working hypothesis if you gave me tens of millions of dollars to repeat the X:BOT trial. But the trial wasn’t that big, it wasn’t designed to more finely examine overdose events, and as is, it didn’t show that much of a difference.”

Lee is sort of saying to his critics: This is the trial that was conducted. I get that you wish it was different.

The researchers are sort of saying to Lee et al.: We know that naltrexone is an inferior drug, so why did you conclude that it isn’t?

And maybe this gets at the real argument between the two research teams. The letter opposing the trial says:

“With more than 100,000 overdose deaths annually, clinicians must make treatment decisions based on information that is accurate. Naltrexone use, based on the fallacy that it is as safe as buprenorphine in terms of risk of subsequent overdose, may be contributing to the opioid overdose epidemic rather that effectively treating OUD.”

This group sees naltrexone (Vivitrol) as not only less effective than buprenorphine and methadone, but also as a less safe and inherently more risky option. People can and do disagree with their view. But it is not entirely unfounded. Patients on methadone and buprenorphine retain a higher tolerance for opioids than patients on naltrexone. And during an overdose crisis like the one we’re in, tolerance is everything.

Tolerance to opioids is protective against an overdose. The other day I spoke to researcher and anthropologist Jennifer J. Carroll, who signed the letter criticizing the 2018 trial, and she said: Overdose is primarily a mismatch between dose and tolerance: A person uses an amount their body cannot handle, and they literally over-dose. If more people are on a stable dose of an opioid and keep their tolerance, they are far less likely to overdose.

Naltrexone/Vivitrol simply does not retain a tolerance. Thus, addiction experts view the drug as fundamentally risky.

Perhaps this why the FDA issued such a strong letter to Alkermes in 2019, which concerned how the company downplayed overdose risk in its marketing campaign.

So I’ll end all of this with what the FDA wrote to Alkermes:

“Those utilizing Vivitrol for the treatment of opioid dependence should be made aware of the vulnerability to potentially fatal overdose at the end of a dosing interval, after missing a dose, or after discontinuing Vivitrol treatment. Attempts to overcome blockade may also lead to fatal overdose.”

The Lancet did not respond to a request for comment. I’ll update the post if they do respond.