When the Food and Drug Administration (FDA) approved Probuphine, a six-month buprenorphine implant, this spring, there were strict indications (see ADAW, June 6). Now, the sponsor, Braeburn Pharmaceuticals, has moved forward into commercialization, starting with the process of training physicians in surgically placing the implant. The FDA, in its approval, required that such training be done by Braeburn.
This leaves two main groups of Probuphine providers — prescribers and inserters, or surgeons. However, there is probably going to be an overlap, if prescribers — who are likely to be addiction experts — learn minor surgery, and if surgeons decide to treat addiction.
The National Institute on Drug Abuse (NIDA), which developed buprenorphine-naloxone for the treatment of opioid use disorders, supported the use of Probuphine in an editorial published July 19 in The Journal of the American Medical Association (JAMA). In the editorial, NIDA Director Nora Volkow, M.D., and Deputy Director Wilson Compton, M.D., point to research by Richard N. Rosenthal, M.D., and colleagues, published in JAMA the same day, showing that the implant is effective at achieving long-term opioid abstinence for stable patients already on low doses of oral buprenorphine.
In Rosenthal’s double-blind double-dummy study, 86 percent of patients receiving implants were abstinent from opioids for six months, compared to 72 percent of patients on sublingual buprenorphine. The long-term implant could make treatment more accessible to new populations who were previously difficult to reach, including those in the criminal justice system and rural areas, according to the NIDA editorial.
Rosenthal, who is medical director of addiction psychiatry at the Mount Sinai Institute of Mental Health in New York City, receives funding from Braeburn. The study published in JAMA and praised by NIDA was also funded by Braeburn.
Nonsurgeons doing surgery
The JAMA study described the implant as a “10- to 15-minute in-office procedure” in which “4 subdermal implants were inserted one at a time through a single 2.5- to 3-mm incision in the inner upper arm using an applicator designed for the implants.” The patient received a local anesthetic first. “The incision was closed with steri-strips, and a pressure bandage was applied for 24 hours,” according to the study.
“Nonsurgeons have been trained and are doing well with the procedure,” said Behshad Sheldon, executive director, president and CEO of Braeburn Pharmaceuticals. “Patients have been implanted by nonsurgeons and are doing well.” As of last week, 2,342 physicians have been certified to provide Probuphine, she said.
“Physicians are supposed to behave within their scope of practice,” said Rosenthal, who does not think the procedure is that complicated. “There are psychiatrists who are much more hands-on primary care–type people,” he told ADAW. “If they have the skill set, they can do minor office surgery.”
However, it’s also possible for a psychiatrist to refer patients to a hospital or surgeon for the procedure, said Rosenthal. “You need to have a relationship with someone who has gone through the training,” he said. Performing the procedure the way Braeburn — and the FDA — want it done “increases the efficacy and lowers the adverse effects,” he said.
For the most recent study, Rosenthal himself did not do the insertion, although he wanted to. He couldn’t because of the double-blind double-dummy nature of the study — the active implant and the placebo looked a little different, and he knew it. However, he found an obstetrician-gynecologist who was comfortable with the procedure, having done Norplant insertions, who did the insertions for his study.
Prescriber gets trained
Prescribers don’t have to be trained in insertion, but H. Westley Clark, M.D., a psychiatrist who was formerly director of the federal Center for Substance Abuse Treatment at the Substance Abuse and Mental Health Services Administration, wanted the training, and so he signed up. He doesn’t think most prescribers, who are addiction physicians or primary care physicians who do not do minor surgery, will be inserters, but said the training was “interesting.”
The company provides the insertion kit and the removal kit for about $30, but the insertion process itself is “labor-intensive,” said Clark. “I got to practice palpating, cutting, inserting and suturing on proxy material,” he told ADAW. “A great experience for a psychiatrist who doesn’t cut. Fortunately, I won’t have to do this in real life.”
However, many addiction doctors also are primary care physicians of some kind, “so minor surgical procedures fall within their bailiwick,” said Clark. In addition, some addiction physicians are surgeons and have the skills to perform the insertion, he said.
Obviously, patients don’t want to have someone cutting, inserting and suturing who isn’t qualified, and Braeburn only requires that one minor surgery have been performed in the last three months. “If there is a problem, it would be the physician who does not have sufficient skills with minor surgery and who overestimates his or her skills after the basic training offered by Braeburn,” said Clark. “This would include any physician who misrepresents prior experiences.”
Qualifying procedures, according to Braeburn, are “those performed under local anesthesia using aseptic technique, and include, at a minimum, making skin incisions, or placing sutures.”
Physicians who undertake this procedure do assume the risks of any such procedure, noted Clark, including local migration of the implants, protrusion and expulsion, infections and nerve damage.
The FDA required Risk Evaluation and Mitigation Strategies both on implantation and after implantation. The Braeburn insertion training is part of that, although Rosenthal doesn’t understand why trained surgeons need to go through specialized training. “They’re being overly cautious,” Rosenthal said of the FDA. “My opinion is after a couple of years, in which there are no bad outcomes, they’ll back up a little bit. Anybody with decent office-based skills should be able to do this readily.”
Adverse events related to the insertion that were found in the first study were eliminated in the second, said Rosenthal. “We did simple things like changing the retraction and applying a 24-hour pressure bandage,” he said.
The study was conducted on patients who had been on stable doses of 8 milligrams or less a day of buprenorphine, over a course of three months. These are very stable patients. That dosage represents 25 percent of buprenorphine prescriptions, said Rosenthal, noting that this shows that the Probuphine implant is meant for a specific subset of patients, he said. “Unlike people who are often in these studies, who are on the street, these subjects were referred from physician practices, were more highly educated, more likely to be employed,” he said.
Why would people need to get the implant if they are doing well on the oral dose? According to Rosenthal, patients who are “likely to forget” to take their pill are ideal, giving as examples “people who might travel a lot, or have ADD.”
However, Rosenthal said buprenorphine — either in implant form or oral — is not by itself a cure. “Until I see evidence to the contrary, you still need to learn how to move forward without using opioids as your primary coping mechanism,” he said. “As far as I’m concerned, most people need psychosocial therapies.”
“Counseling and drug testing are part of an overall treatment plan that is defined by each treating physician,” said Sheldon of Braeburn.
Even so, Braeburn itself is leaving the treatment up to the physician. While oral buprenorphine was approved by clinical trials that did utilize counseling, Probuphine was approved based on treating already stable patients. And there is always the fact that physicians are free to treat off-label — in other words, inserting more than four rods. Braeburn, however, does not encourage off-label use and does encourage counseling.
According to NIDA, future research is needed to determine whether the implant improves treatment adherence over time.
The Probuphine implant requires both prescribers and inserters, but there needs to be coordination, and in some cases, the provider may do both.