Posts Tagged ‘implantable buprenorphine’

Probuphine: the Injectable Suboxone

aaaaaapro

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.

Probuphine Update: Implantable Buprenorphine

At present, only the sublingual (under the tongue) forms of buprenorphine are approved to treat opioid addiction. But recently I’ve been reading more about the long-acting buprenorphine (active ingredient in Suboxone) implants that are undergoing Phase 3 tests. The brand name of this product is Probuphine and it’s marketed by Titan Pharmaceuticals.

This medication is composed of small cylinders consisting of ethylene-vinyl acetate and buprenorphine, to be implanted under the skin of the upper arm. The cylinders release buprenorphine slowly over six months, given a constant level of medication in the body. After six months the medication is depleted, so they must be replaced if the patient needs to stay on buprenorphine.

Last year we saw from study results published in the Journal of the American Medical Association (1) that Probuphine is superior to placebo, but the real question is this: how does it compare to sublingual Suboxone? (See my post from October 13, 2010)

From data obtained and recently released, in the drug’s Phase 3 trials, it appears implanted buprenorphine is “non-inferior” to sublingual buprenorphine. That’s doctor speak for saying implants appear to work at least as well as sublingual forms. In this study of 114 patients given Probuphine versus 119 patients given Suboxone, both groups had around 35% of their drug screens negative for illicit opioids. Additionally, both groups had the same amount of improvement on a scale of global severity of opioid dependence and overall patient improvement.

To me, 35% negative of urine drug screens negative for illicit opioids doesn’t sound all that great. I’d estimate at least 90% of my sublingual Suboxone patients have urine drug screens negative for illicit opioids, but I need to remember that most of them have been in treatment for quite some time. Many of them I “inherited” from another doctor, and these patients have been doing well for more than five years.

So if it appears that the implants work as well as sublingual Suboxone, what will this mean? I don’t know for sure, but I have a few predictions.

I don’t think patients will like the implants. Just look at the difficulty many had switching from the tablets to the film: go to any forum and read some of the very negative comments about the film. Plus, patients with addiction like to take drugs, particularly early in treatment. I try to get my patients to take their dose of Suboxone all at one time, and many say they prefer to divide the dose. Part of that, I believe, is the habit of taking drugs. With an implant, it may be easy for the disease of addiction to convince patients that the medication isn’t working, when it’s actually doing exactly what it should.

Some patients will love it, because they’ll like that it frees them from having to think about taking drugs. These folks may be further along in their recovery, or their addiction isn’t as bad.

Suboxone doctors will have to learn to do the minor surgical procedure to place the implants, or refer their patients to general surgeons. Then there will be great difficulty getting patients to make and keep follow up appointments with both doctors and therapists. If they already have the medication in their system, many won’t want to keep doctor and counseling appointments. That prescription is leverage to get the patient into the office.

Diversion will plummet, if we can get most patients on the implantable form of buprenorphine. How can you divert something that gets implanted into your arm? It’s not going to be impossible, but much more difficult. No more black market Suboxone.

There are other advantages. For patients on Suboxone who have to be incarcerated, they can’t be denied their medication since it will be implanted! No more jail house withdrawals. And no more awful taste in your mouth after the sublingual forms of medication.

As a way to force patients to get the implants rather than prescribed sublingual buprenorphine, I won’t be surprised if some states, or even the whole nation, reclassify sublingual buprenorhpine to a Schedule II drug, and allow buprenorphine implants to be Schedule III. Under the DATA 2000 Act, this would make sublingual forms only available at opioid treatment centers. This may not be a bad idea, given the rampant diversion of buprenorphine. You only need to read some of the posts on this blog by active addicts to see how addicts are misusing the present medication.

Doctors like me are wondering if we can remain in practice seeing only buprenorphine patients. Since we’ve only been allowed 100 buprenorphine patients anyway, I think most addictionologists already see other types of patients. For me,  the upcoming changes may mean going back into primary care, which I don’t enjoy nearly as much as addiction medicine.

  1. Ling, W et. al, “Buprenorphine implants for opioid dependence: A randomized controlled trial,” Journal of the American Medical Association, October 13, 2010, Vol 304, No. 14, pp 1576-1583.