Last week, the FDA’s advisory committee voted to approve Titan Pharmaceutical’s Probuphine. This is an implantable form of buprenorphine, a drug more commonly known under the brand names of the sublingual forms Suboxone and Subutex.
Probuphine is a slender rod, as pictured above, containing buprenorphine that is released into the body over time. Probuphine is meant to be inserted a few days after the patient has stabilized on sublingual buprenorphine. Four of the Probuphine rods are inserted under the skin of the inner upper arm in a fan formation, just like birth control implants such as Norplant. Four rods contain 320mg of buprenorphine, released over six months.
Probuphine has been touted as the answer to this country’s problem with Suboxone and Subutex drug diversion. Even though studies show most people who buy Suboxone off the black market use it to stay out of withdrawal and not to get high, many officials are appalled at how the medication, intended to treat opioid addiction, seems to be a new favorite street drug. But implantable Probuphine, for obvious reasons, is highly unlikely to be diverted to anyone besides the patient for whom it was intended. With this implantable form of the medication, pediatric exposures would be practically non-existent.
Safety data of the implants appears acceptable. Even minor surgical procedures can cause infection and bleeding, and these were the main problems with insertion. A fair number of patients also had irritation over the implants, possible from the medication.
But how effective is Probuphine? For me, the study results are underwhelming. It did outperform placebo in double-blind randomized controlled trials, but not as well as I expected. In Titan’s two studies, 40% and 60% of patients given active Probuphine also required supplemental sublingual buprenorphine. If patients continued to require extra sublingual buprenorphine, a fifth Probuphine rod was inserted.
Even worse, 35% of the Probuphine patients did not complete the twenty-four week study, and only 8% of Probuphine patients had 80% or more of their urine drug screens negative for illicit opioids. So the Probuphine did outperform placebo, but not robustly. Only a few of the Probuphine patients were negative for opioids at the end of the study.
The surprisingly low blood levels of buprenorphine produced by Probuphine may have caused these disappointing results. Researchers found that blood levels from four rods of Probuphine gave only 31% of the blood levels of patients dosing with 16mg of sublingual buprenorphine. Many of the patients may have been under-dosed. To get the same blood level, I’m assuming it would take 12 implants, too many to be practical.
The FDA Advisory Committee also mentioned other concerns. Obviously, the doctors implanting the medication need to be trained to do so. In the past, sub dermal implants like Norplant were inserted by doctors with training in surgical procedures, like OB/GYN doctors. With buprenorphine, around 21% of patients are treated by psychiatrists, with little training in surgery. The other doctors treating addiction with buprenorphine tend to be like me – minimal experience with surgical procedures. Titan Pharmaceutical has a plan for teaching doctors how to do this procedure, but is it enough to make us proficient?
Do I want to learn to do this procedure, or would I prefer referring patients to a general surgeon? Would the local surgeons be interested in doing these implants? Who follows the patients afterward?
I have no doubt I could learn how to do the implants if I wanted to. But that’s the question…do I want to? I’ve done minor surgical procedures during my years in primary care, like suturing lacerations, incising and draining pustules and abscesses and the like. But I don’t really enjoy doing that kind of thing. I’m slow at it, tend to be nervous, and I don’t like pus. I’m an accomplished quilt maker and I can handle a needle & thread, but memories of surgery rotations during medical school haunt me.
My surgical rotations weren’t the disaster that my OB rotation was, but that’s not much of a horse race. Actually, I did fine in my OB/GYN rotations as long as I didn’t watch any babies being born, but that was kind of hard to avoid. And I got “Honors” in my two-week rotation in Cardiothoracic Surgery, but not because I was brilliant. I was an idiot savant when it came to holding retractors, largely because I was too scared of the surgeons to move a millimeter. These were prototypic 1980’s cardiothoracic surgeons; they threw things and swore, and called the nurses “honey.” They liked me because they didn’t have to keep telling me to hold still and pull on the retractors. I could stand like a statue, for hours, literally scared stiff.
My other surgery rotations were not much better; I did my general surgery rotation at an urban trauma center in a big Ohio city. On my first day, my resident commanded me to record the history of the trauma victims arriving in the Emergency Department. So I would sidle up to a fresh trauma patient, blood spraying, body parts partially amputated, clear my throat to ask, “Um, can you tell me what happened?” The answers were usually short and colorful. Eventually I learned to ask the EMS workers, and confirm with the patients after they were out of surgery.
I didn’t enjoy that month. I saw young people die in quick and brutal ways, forcing my 24-year old self to realize that I wasn’t immortal. I’ve been a careful driver ever since, and always, always, ALWAYS wear my seatbelt.
So do I want to risk re-activation of my medical school post-traumatic stress disorder?
Titan Pharmaceutical’s answer to the FDA’s demand for a Risk Evaluation and Management Strategy (REMS) for Probuphine includes plans for a closed distribution system. This means that the drug company will only ship Probuphine directly to providers who have been trained to implant the cylinders, and are approved to prescribe buprenorphine. This means I would have to store medication in my office. I’d need a system of accounting for controlled substance medication. I wouldn’t be too hard to implement in my small office, but it’s another bit of work for me, and I don’t like the idea of having controlled substances on the premises.
I assume I would have to buy the implants, and then ask my patient to pay me for the implants, the surgical procedure, and my time and expertise. That’s a big financial risk for a bare-bones operation such as mine. I can only have one hundred buprenorphine patients at any one time, so I keep my overhead very low in order to survive financially. This expense does not fit into my business plan.
If I find a surgeon to implant the Probuphine, there are even more barriers to the process. The REMS says not only would I have to store Probuphine until the implantation procedure, but I also have to be present for the implantation procedure, and also for explantation six months later, when the rods are taken out.
Are you kidding me?? This is not practical in my world. And is the patient going to pay for the time of not one doctor, but two? Would health insurance pay for both doctors’ time? I know the answer to that.
I’ve saved the big question for last: how do you get patients with Probuphine implants to keep counseling appointments? Yes, some patients, hungry for recovery, will go to great lengths to get counseling. And others won’t go at all. With our present system, the prescription for sublingual buprenorphine is the leverage used for counseling. Many doctors won’t continue to prescribe unless the patient goes for counseling. But after a patient gets a Probuphine implant, she can decide she doesn’t need counseling doesn’t want counseling, and what’s the doctor going to do about it? Surely not go dig the implant out of her arm.
Probuphine is a great idea, and may work for some patients. But in the real world, I see problems: limited efficacy, muddled plan for implantation and explantation, financial and reimbursement issues, and no way to leverage patients into counseling. This idea needs more work.