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Doctors are reporting a troubling trend when it comes to fentanyl.

The powerful drug, they say, isn’t just causing overdoses — it’s also making it more difficult to begin addiction treatment. In particular, fentanyl appears more likely to cause severe withdrawal symptoms for patients put on buprenorphine, a key medication used to treat opioid use disorder.


The development adds yet another layer of crisis to the country’s drug epidemic, which killed nearly 108,000 Americans last year. Even as fentanyl sends overdose deaths soaring, it threatens to make the world’s most-prescribed addiction drug inaccessible to the increasing number of patients who need it.

“It’s the clinical challenge of my career,” said Sarah Kawasaki, an addiction doctor and psychiatry professor at Pennsylvania State University. Inductions, or the process of starting patients on buprenorphine treatment, have become “progressively more difficult” in the past five years, she said, as fentanyl has spread throughout the drug supply.

To make matters worse, Kawasaki added, buprenorphine is one of just two medications commonly prescribed to treat opioid addiction. The other, methadone, is highly regulated; patients can only access it at specialized clinics that typically require them to appear in person each day to receive a single dose.


“We have 20 different ways to treat strep throat, but two medications that work well in the treatment of opioid use disorder,” Kawasaki said. “When you eliminate one and make the other really hard to get, it is a setup for failure.”

While doctors across the U.S. and Canada, where fentanyl is also pervasive, have reported that buprenorphine inductions have become more difficult in recent years, the phenomenon is hard to measure or explain. Theories include fentanyl’s raw potency, or that it is lipophilic — it sticks to fat molecules — and remains in the body for longer than other opioids.

Buprenorphine is what’s known as a partial agonist, meaning that it binds tightly but incompletely to the same brain receptors that give a euphoric effect when opioids bind to them. But it binds to the receptor awkwardly, like a puzzle piece that doesn’t quite fit. As a result, patients with opioids already in their system can feel what’s known as “precipitated withdrawal” as the addiction medication shoves the fentanyl aside.

As a result, it’s normal for doctors to wait several hours until patients start experiencing withdrawal symptoms before they administer buprenorphine. At that point, the “bupe,” as it is known, helps to treat withdrawal symptoms like anxiety or gastrointestinal distress, as well as eliminate future opioid cravings.

With fentanyl, however, doctors are sometimes forced to wait a full day, if not longer, to make sure buprenorphine doesn’t cause severe discomfort. In some cases, even patients experiencing withdrawal because they refrained from drug use for many hours — typically ideal candidates for buprenorphine — find that their symptoms get worse, not better, once they begin using the medication. Many don’t come back for another dose, known in doctors’ parlance as a “failed induction.”

Doctors warn those failed attempts can be dangerous — not just because they risk patients returning to fentanyl use, but also because those patients might feel so miserable that they refuse to ever try buprenorphine again.

Some clinicians report that patients have become more likely to request methadone, despite its inconveniences. Kawasaki, who works at a clinic that offers both methadone and buprenorphine, said she’s had trouble enrolling patients in a clinical trial about buprenorphine induction because her patients are opting for the drug less likely to cause withdrawal symptoms.

Though the phenomenon is widespread, doctors haven’t reached a consensus about how to move forward. Nor have they received much guidance from medical societies and local health officials, leaving doctors to rely informally on word of mouth, email chains, and new scientific papers.

One recent set of recommendations from the Substance Abuse and Mental Health Services Administration did little beyond acknowledge the issue, warning that patients using fentanyl long-term and at high doses “may not be appropriate for buprenorphine.”

“There’s a patchwork of induction strategies at this point,” said David Fiellin, an addiction physician and the director of Yale University’s Program in Addiction Medicine. “In a lot of ways, we’re in an area without much science.”

The knowledge gap led Fiellin to issue a recent call in the Journal of Addiction Medicine for “rapid research” analyzing the relationship between the type and quantity of drugs used and difficulties beginning buprenorphine treatment.

In the meantime, however, doctors are employing strategies that vary dramatically. Some have begun administering radically larger amounts of buprenorphine in an effort to overcome withdrawal symptoms by brute force — as much as 32 milligrams, or four times a typical first dose.

Some doctors, like Kawasaki, also use common medications to treat any remaining symptoms of physical discomfort and anxiety, including antihistamines, ibuprofen, and drugs to combat nausea and gastrointestinal problems.

Others have tried the opposite approach: “microdosing” buprenorphine in increasing amounts over the course of several days, avoiding a moment where a sudden, large buprenorphine dose causes immediate withdrawal. Samantha Young, a doctor and researcher at the British Columbia Centre for Substance Use, said she sometimes prescribes shorter-acting opioids typically used for pain, like hydromorphone, to help alleviate withdrawal symptoms as patients build up to larger buprenorphine doses.

“When I teach residents and medical students about buprenorphine, I tell them it’s an art based on the science,” Young said.

Others, still, have tried the controversial approach of administering naloxone, a drug used to reverse opioid overdoses, even to patients who are not overdosing. The result is a very short period of intense withdrawal, setting the patient up for a first buprenorphine dose that alleviates discomfort instead of causing it.

Any strategy that works is promising, Fiellin said. But the fact that it’s become harder for doctors to prescribe buprenorphine is concerning in its own right. While the medication is highly effective, it’s also tightly regulated, meaning convincing doctors who aren’t addiction specialists to prescribe it has long been challenging. The newfound difficulties, he said, risk reversing recent progress.

“There was a period of 10 or 15 years where bupe initiation was not seen as a challenge, so it was much more common that nonspecialists would take on buprenorphine prescribing,” Fiellin said. “Unfortunately, we’re in a situation where now initiation is seen as a huge challenge, and I worry that’s going to set us back with respect to expanding the number of clinicians who are prescribing buprenorphine.”

Still, some physicians remain optimistic. And patients who want to begin buprenorphine treatment shouldn’t despair, they say. Ultimately, buprenorphine induction for people using fentanyl is still possible, despite its difficulties. The pervasiveness of fentanyl in the North American drug supply “does make the induction a bit more challenging,” Young said. “But just so people know: We’ve developed a lot of methods — if you want to get on bupe, and you use fentanyl, great! We can definitely do that for you, without you being in withdrawal.”

STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies. Our financial supporters are not involved in any decisions about our journalism.

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