Probuphine: Promises and Problems

buprenorphineEver wish you could improve treatment compliance among your patients who receive buprenorphine? Ever wish you could offer them the benefit of sublingual buprenorphine while avoiding the risk of diversion and abuse? Well, now you can—maybe. In May of this year, the FDA approved Probuphine, an implantable form of buprenorphine that lasts up to six months. Probuphine’s manufacturer points to improved adherence, lower risk of diversion, and less frequent office visits as advantages over traditional buprenorphine treatment. But behind the fanfare are hidden costs and risks, and the jury’s still out on whether the trade-off is worth it for patients and prescribers. Read on for an overview.

Probuphine: What is it?

Probuphine is an implantable rod, measuring about one inch in length, that consists of a polymer matrix impregnated with buprenorphine. The efficacy of buprenorphine for treating opioid use disorder has, of course, been established by multiple randomized clinical trials (RCT). But while most buprenorphine patients adhere to a daily dosing schedule, Probuphine—after delivering an initial loading “pulse”—releases a constant low dose of the medication. This eliminates the fluctuating plasma levels seen with sublingual dosing, and in theory should reduce the periodic craving and withdrawal symptoms that result from those peaks and troughs. Four Probuphine rods, implanted in the subcutaneous tissue of a patient’s upper arm, deliver the equivalent of about 8 mg of daily sublingual buprenorphine over a period of 24 weeks.

What does the research say?

So far there have been just two RCTs comparing implantable to sublingual buprenorphine, and both have been so-called “non-inferiority” trials. This means they were designed to establish whether the buprenorphine implant was at least as good as sublingual buprenorphine. In the first RCT, 287 subjects were inducted on sublingual buprenorphine and then randomized to either the buprenorphine implant, a placebo implant, or sublingual buprenorphine/naloxone for 24 weeks. The buprenorphine implant was found non-inferior to sublingual buprenorphine at reducing the frequency of illicit opioid use, as measured by urine testing (Rosenthal RN et al, Addiction 2013;108(12):2141– 2149). A limitation of the study is that while the implant conditions were double-blind, the sublingual buprenorphine arm was open-label (meaning both doctors and patients knew they were getting the active sublingual drug).

The second RCT, published earlier this year, had 177 participants and used a double-blind design for both implant and sublingual treatment conditions. Like the first study, it found that implantable buprenorphine was non-inferior to the sublingual formulation over a 24-week study period. Furthermore, results suggested that Probuphine may be better than sublingual treatment at both relapse prevention and patient retention (Rosenthal RN et al, JAMA 2016;316(3):282–290. doi:10.1001/jama.2016.9382).

A limitation of the second study is that it may not be generalizable to a typical buprenorphine patient. Recruited subjects were predominantly white, employed, and addicted to prescription opioids rather than heroin. Moreover, at the time of enrollment they had been abstinent for at least 90 days on 8 mg or less of sublingual buprenorphine, and the median length of time they had received buprenorphine prior to study enrollment was 3 years. Finally, subjects in the Probuphine arm had greater withdrawal symptoms compared to those in the sublingual buprenorphine group, suggesting implants may not be appropriate for patients requiring higher buprenorphine doses.

What about the downside?

Disadvantages of Probuphine fall into two major categories: clinical and practical. On the clinical side, risks of bleeding, infection, scarring, nerve damage, and other adverse outcomes must be managed as with any surgical implant. Other disadvantages, however, are less obvious. For example, patients with the most severe opioid use disorder often require indefinite opioid replacement therapy, but current FDA rules allow only 1 year of Probuphine treatment. What will happen to these patients when that year is up? Will they have to go back to the oral version? Will the FDA raise the duration of allowed treatment? Patients will want answers to these questions.

Another issue is the frequency of visits. One of the nice things about sublingual buprenorphine is the need to come to appointments for refills; it presents a good incentive to check in with the clinic where patients can also get drug counseling and other psychosocial treatments. If they have six months of drug in their system, it will be harder to ensure frequent appointments. Finally, patients on Probuphine may still need sublingual buprenorphine for “breakthrough” craving or withdrawal symptoms. For patients who require breakthrough dosing, many of the expected benefits of implantable buprenorphine will be lost, at least temporarily.

This article originally appeared in The Carlat Addiction Treatment Report -- current coverage of topics in addiction medicine.
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If you’re like most addiction specialists, adding Probuphine to your practice will require a major change in practice structure and a significant financial investment. First of all, Probuphine can’t be picked up at the corner pharmacy— prescribers must purchase Probuphine kits themselves, at a cost of nearly $5,000, and may need to negotiate with patients or insurance companies over reimbursement. Second, you’ll need a room and sterile equipment to do the procedure. Third, the FDA requires you to enroll in the Probuphine Risk Evaluation and Mitigation Strategy (REMS)—and become specially trained and certified—before you can prescribe or implant Probuphine.

According to FDA rules, you can be certified to prescribe Probuphine, to insert it (the manufacturer uses the term “insert”), or both. If you become certified to prescribe only, you must enter a practice agreement with another physician who is certified to insert the implant before you can prescribe it. You don’t have to be a surgeon to insert the drug, but according to the company website (, you must have performed a surgical procedure within the past 90 days to be eligible for insertion training—a significant obstacle for most psychiatrists. For those who are eligible, training and certification include both lecture and hands-on content and take about a day to complete.

CATR VERDICT: Probuphine promises several advantages as a long-acting alternative to sublingual buprenorphine. Unfortunately, the most compelling research has been limited mainly to employed patients with prescription opioid dependence who had already been stable on low-dose sublingual buprenorphine for a long time. It’s not yet clear that Probuphine will work for the majority of our real-world patients.

Probuphine: Promises and Problems

This article originally appeared in:

The Carlat Addiction Treatment Report
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This article was published in print September/October 2016 in 4:7.


APA Reference
Sonkiss,, J. (2017). Probuphine: Promises and Problems. Psych Central. Retrieved on May 28, 2020, from


Scientifically Reviewed
Last updated: 20 Dec 2017
Last reviewed: By John M. Grohol, Psy.D. on 20 Dec 2017
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