How Fentanyl Is Forcing Providers to Go Rogue

Healthcare providers who treat addictions are having to try new things thanks to the arrival of illicit fentanyl over the last decade. While pharmaceutical fentanyl is an effective prescribed pain treatment, illegally manufactured fentanyl has taken over the illicit opioid market, largely replacing heroin.

This shift has transformed the addiction treatment landscape. Now, patients seeking treatment for an opioid problem may be advised to continue their illicit opioid for a few days as they taper onto buprenorphine, the first-line treatment.

According to the Centers for Disease Control, the death rates from overdoses are at an all-time high due to illicit fentanyl, whose high potency makes it extremely dangerous. But this drug also poses treatment challenges when people who become addicted want to stop.

Specifically, protocols that used to work for the initiation of buprenorphine, a widely-used treatment for opioid use disorder, are not working as they used to because of fentanyl’s unique pharmacological profile. Increasingly, providers are preferring to use new initiation methods informed by anecdotes and a few case series over established protocols.

“It was very confusing in the beginning,” says Rifka Stern, community addiction treatment physician in New Mexico and member of the Bernalillo County Addiction Treatment Advisory Board. She said that providers would initiate patients on buprenorphine using old protocols and put them into precipitated withdrawals. “We just didn’t understand what was going on,” says Stern.

For providers like Stern, there has been nowhere to turn for answers. The evidence base has not had time to catch up.

“It’s like the wild west again,” says Snehal Bhatt, Division Chief, Addictions Psychiatry, University of New Mexico. “For a long time, we knew exactly what to do and now it’s… like we’re all just trying things.”

Buprenorphine for Opioid Use Disorder: A Primer

Overwhelming evidence indicates that opioid use disorder is best treated with medications—often taken for months or years—which prevent craving and relapse back to use, instead of therapy alone. These medications reduce mortality and help people get back to their lives.

There are several options, but buprenorphine is the “first-line” option because of its safety and convenience. The downside of buprenorphine is that it can be hard to initiate because it will trigger withdrawal—called precipitated withdrawal—if taken when opioids are still in the system. Protocols have been designed to ease the transition onto this life-saving treatment, but they are no longer working like they should, with fentanyl.

Initiation of Treatment: A Critical Window

Treating withdrawal is a critical part of treatment. The physical and emotional discomfort is time-limited, but, if too prolonged, can send people right back out to using, sometimes for months or years.

Stern, referencing a local detox center survey, recalls that, in the early days of fentanyl under old protocols, less than 10 percent stayed the full seven days because of precipitated withdrawal from buprenorphine. “They just kept leaving."

In response, providers have been tabling old evidence-based protocols and innovating.

Why Are Fentanyl and Buprenorphine Like Oil and Water?

Buprenorphine binds to opioid receptors in the brain. Unlike heroin or fentanyl, though, which are full agonists—meaning they fully activate opioid receptors—buprenorphine has both activating and blocking effects. If given too soon after a full agonist, buprenorphine knocks opioids off receptors and triggers withdrawal symptoms. But if it is given when someone is in opioid withdrawal, it relieves symptoms.

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People need to have some abstinence time and to be in some opioid withdrawal before taking their first dose of buprenorphine. With heroin, that is usually 12 hours, and with pain pills, it is longer.

With her fentanyl patients, Stern saw something unusual. “They’d show all the signs of being in withdrawal, and then we would give them buprenorphine and they’d come back feeling terrible, and the only thing they could do was use more because they were in withdrawals.” Bhatt and other providers across the country saw the same thing, and soon published reports validating their experiences.

One reason for this is that fentanyl stays in the body a lot longer than heroin, because it is rapidly re-distributed into fat cells after use, where it is slowly released and takes many days to clear.

What About Methadone or Naltrexone?

There are two other medication options that prevent relapse and are taken long-term.

Methadone is one option, and it does not pose initiation challenges like buprenorphine, because it does not have any opioid receptor-blocking properties. For many, it is still the best option.

Unfortunately, it has some downsides, including a higher risk of overdose. Plus, it is dispensed from specialized clinics at which daily visits are required for dosing. Research from animal studies also raises concerns that methadone will not prevent relapse to fentanyl as well as it does to other opioids.

A long-acting injectable form of naltrexone—Vivitrol—is another treatment option. It is a full blocker at the opioid receptor and prevents both relapse and overdose if someone goes back to using. Unfortunately, Vivitrol is even harder to start than buprenorphine, requiring people to stay abstinent even longer before dosing.

Fentanyl might also be able to overcome naltrexone’s opioid blockade, rendering it inert. “Now it doesn’t seem like Vivitrol is cutting it, and that’s scary,” says Paul Tucker, Director of Turning Point Recovery Center in Albuquerque, New Mexico, who reports a recent overdose death in one of their Vivitrol patients.

What Are People Doing Now?

Because buprenorphine is such a great option, providers are working hard to find ways to get people on the medication before they drop out of treatment.

One novel protocol, according to Bhatt and Stern, is “microdosing,” where patients are asked to cross-taper from their illicitly abused opioid to buprenorphine, taking progressively lower doses of the illicit opioid while slowly escalating doses of the buprenorphine—starting at much lower doses than is standard—over 7 to 10 days.

If the patient has not used fentanyl in several days or longer, Bhatt has been using another approach: build up to higher doses of buprenorphine much more quickly than is standard. Bhatt believes that these adaptations have mitigated, if not eliminated, the dropout problem in their clinic and feels—“anecdotally, without doing statistical tests”—that although dropout rates are still higher, they are making some headway and keeping more people in treatment.

Once they get on buprenorphine, people who use fentanyl can do as well as patients did in the past with other opioids, and do not appear to show higher relapse rates or risk of overdose.

“I think the initiation is critical and if you can get them on and over that hump… I think you can retain patients,” Bhatt says, especially if they are maintained on higher doses than they were taking in the past.

He feels these new ways of starting buprenorphine are becoming the standard of care. Although the new methods are based on anecdotal evidence and not clinical trial results, numerous published case series have begun to suggest what providers have started to believe: the new way works better and saves more lives.

Clearly, many questions still remain. Microdosing and other variations (named ultra-microdosing or rapid micro-dosing) have reportedly shown success, but clinical trials are needed to determine the best way to start buprenorphine in this new, rocky era.

This article also appears in Science in the News.