Posts Tagged ‘Probuphine’

New Way to Dose Buprenorphine

FluidCrystal technology

 

 

We all know that Probuphine in now available. It’s a depot preparation of buprenorphine that can be implanted beneath the skin to release buprenorphine for six months. It finally came to market last year, and we are awaiting news of how well it is working.

Soon we may have another choice: weekly and monthly depot injections of buprenorphine. I blogged about this in an entry posted July 30, 2013.

In essence, this new subcutaneous injection of buprenorphine was invented by Camarus Pharmaceuticals, a small Swedish company that invented a nanoscale drug delivery system, as they say on their website. This “Fluidcrystal” injection containing buprenorphine comes in preparations of varying doses, and can be dosed once per week or once per month, depending on the preparation.

The liquid substance containing buprenorphine is injected subcutaneously (under the skin), where it forms a gel. Then a capsule-type substance surrounds it, allowing buprenorphine to be released into the body over time. Started weekly, the dose can be adjusted to meet patient needs. Eventually, the patient can move to once-monthly injections. The matrix of material is biodegradable, and eventually completely absorbed by the body.

This subcutaneous injection of medication has a very low viscosity, meaning it can be given with small needles that cause less pain to the patient. The medication is already pre-mixed, making it convenient for medical providers, and it is stable at room temperature for up to three years.

Initial trials of this medication have been intriguing; they show a fast delivery of medication, giving rapid onset and a steady blood level over one week or one month, depending on the preparation given. Safety data was pretty good; other than some headache and a low rate of inflammation at the injection site, it was well-tolerated. Because of the Fluidcrystal technology, if an addict attempts to inject this substance into a vein, it will form a deposit at the injection site, blocking the vein.

I’m excited by this medication. First, with daily buprenorphine dosed sublingually, some patients relapse. They may decide to stop taking the buprenorphine for a few days so that they can use their opioid of choice and get high again. True, they have to do a little more planning to relapse than if they were not on buprenorphine, but relapse rates are still too high. The depot forms make relapse less likely, I think, because compliance is assured once the medication is injected.

Second, with the depot forms of buprenorphine, the patients don’t have to think about taking something to treat their addiction. They don’t have to think about their medication at all, and their addiction doesn’t have the chance to urge them to take more of their medication than prescribed. Thankfully with buprenorphine there is a ceiling to its opioid effect, so that patients already on a blocking dose of sublingual buprenorphine won’t usually feel any intoxication from taking more of their medication.

Third, we’ve seen increases in the amount of buprenorphine being diverted to the black market, as the total amount prescribed has increased. Politically, this diversion threatens buprenorphine availability. One only need to look at regulations like what was passed by Virginia’s medical board to see the limits being placed on this life-saving medication, due to concerns about diversion. Law enforcement officials and politicians believe buprenorphine is a desirable street drug. Of course, research shows most people using illicit buprenorphine are trying to prevent withdrawal, and not using it to get high.

With this subcutaneous injection, I think it’s highly unlikely to be diverted, or at least much less likely that film or tablet to be diverted.

Because the dosing interval is every one week to every one month, medical providers can still see the patient once per month, and can provide counseling as a condition of continued treatment. With the six-month depot placement of Probuphine, it’s unlikely the patient will voluntarily return monthly for counseling visits, once they get the medication implanted. The more frequent and simpler administration of this form of buprenorphine appears ideal to me.

According to the Drug Addiction Treatment Act of 2000, the FDA must give approval to any form of buprenorphine that’s to be used to treat opioid addiction. At present, the sublingual form of buprenorphine and the implantable form of buprenorphine known as Probuphine have FDA approval. Other forms of buprenorphine in patch (Butrans) or injectable form are illegal for a doctor to prescribe to treat opioid addiction. this new subcutaneous injection of buprenorphine therefor must be approved by the FDA before it can be legally used to treat patients with opioid use disorder.

According to the manufacturer’s website, Phase 3 trials are concluded. According to a company press release, a double-blind, double dummy controlled trial of the weekly and monthly injections were found to be “non-inferior” to sublingual buprenorphine. That phrase is something drug manufacturers have to prove before a new drug is allowed to be approved by the FDA. The new drug must show it’s at least as good as the old drug. Additional data is rumored to show that it’s superior to sublingual buprenorphine, though I haven’t been able to find and read the original data yet.

This is a medication I would be excited to use in my practice. Instead of a surgical procedure, all I would need to do would be give a subcutaneous injection of this new product. How easy! My patient could see me as often as needed, and could see her counselor the same day she gets the injection, thus remaining established in a counseling program, too.

I am eager for the FDA to review this drugs study and approve it, if appropriate.

Updates

Empty board

 

Prisoner death from drug withdrawal:

In my blog entry on October 20, 2015, I discussed the horrible death from drug withdrawal suffered by David Stojcevski in the Macomb County, Michigan, jail. I’ve been scouring the internet looking for updates on the lawsuit the family has filed against the county, but haven’t found anything. However, I’m pleased to find many news stories about this awful incident, which helps to keep the issue of medical treatment of prisoners in the news. This is something we must change. Incarcerated people should not be allowed to die from drug withdrawal!

http://www.newsjs.com/ca/cops-arresting-man-in-murder-probe-leave-him-locked-on-bus-with-passengers/diV1CbLR9C6B0bMHAlNf4Wk68k_mM&authuser=0/

Bad legislation:

On April 12, 2015, I blogged about NC bill S297, which is legislature intended to make drug use by a pregnant woman a criminal act. Regrettably, this sorry and misguided piece of legislation was passed on its first reading in the NC senate. It’s now been referred to the Committee on Rules and Operations of the Senate. If you live in NC, when you vote, remember that Republican Brent Jackson presented this bill, which I believe will keep pregnant women from seeking medical care during pregnancy if they have the disease of addiction. This bill is not good for society, pregnant women, and especially not good for fetuses.

Probuphine:

I’ve written a few blog entries (September 2, 2011; March 30, 2013; May 21, 2013; and November 7, 2015), about Probuphine, implantable small rods that deliver buprenorphine into a patient’s bloodstream over six months.

In January of 2016, an advisory committee to the FDA voted to recommend Probuphine for approval by the FDA for the treatment of opioid addiction. The FDA is expected to hold its vote at the end of this month. You will recall that despite a similar recommendation last year, the FDA did not approve this implant, stating more study was needed, especially on patients who were stable at lower dose of buprenorphine.

This time, Titan Pharmaceuticals is seeking approval in patients who are stable on 8mg of the sublingual buprenorphine or less per day.

Of the minority of people on the advisory panel who voted no to the recommendation, concerns were expressed about identifying appropriate patients for this medication, and risks of both implantation and removal of the rods.

I’m still not clear if there will be changes to the rules for implantation and removal of the Probuphine rods. For a buprenorphine prescriber to be able to offer Probuphine, she would have to take a training class for the procedures for implantation and removal. This requires time away from work, to meet an uncertain demand for this product. Not all doctors who prescribe buprenorphine will want do this procedure anyway.

If I want to do this procedure in my office, how to I get the implants? Do I have to buy them, and wait for the patient to pay me back? Do I write a prescription and have the patient pick them up at the pharmacy? Will insurance cover the medication and the procedure? If yes, how long would I have to wait for payment from these companies? I’ve been able to stay in business at my private office by keeping overhead pared to a minimum, so if Probuphine requires an investment by me, I may decide it’s not worth my time and effort.

Hepatitis C treatment

As described in my July 3, 2015 blog entry, the CDC recently reported a surge in the numbers of U.S. citizens who have contracted Hepatitis C. Now another drug has entered the market to treat Hep C, but remains extremely expensive. Earlier this year, Merck pharmaceutical company launched a new Hep C drug called Zepatier. It’s an oral drug that costs an estimated $54,000 for a twelve week course, compared to $80,000 for a similar course of Harvoni. However, early reports say Zepatier cure rates may not be as high as Harvoni’s, so we await more information.

Many health insurance systems can’t afford to pay this much money for treatment of their insured, and so many people infected with Hep C have found their insurer refuses to pay for this new treatment that cures Hep C in most patients. Without insurance, few people could shoulder that expense themselves.

So we have another treatment option, and a little bit less expensive. Let’s hope this trend continues.

ALKS 5461

In my blog post from January 17.2015, I reported a new drug on the horizon that was hoped to be a novel treatment for resistant depression. This medication, known as ALKS 5461, contains buprenorphine (just like Suboxone, Subutex) and samidorphan, a new opioid receptor blocker. The medication was theorized to treat depression by the buprenorphine’s antagonistic action on the kappa receptors, and the samidorphan would serve to block the effect of buprenorphine on opioid receptors, so that the patient would not develop an opioid dependency.

Unfortunately, ALKS 5461 failed to show benefit in two phase III clinical trials, leading Alkermes stock to fall when this data was announced in January of 2016. Despite these results, Alkermes is reported to be continuing research into this potential new medication for depression.

Probuphine Update

aaaaaaaapro

About a month ago, the FDA accepted the re-submission of Probuphine, an implantable preparation of buprenorphine, for review. New Phase III studies apparently showed this form of buprenorphine to be “non-inferior” to existing products presently on the market.

As you may recall from my previous blog entry from May 21, 2013, Probuphine is an implantable form of buprenorphine that releases the medication over six months. The FDA rejected this form of buprenorphine in 2013 because the implanted rods impregnated with buprenorphine didn’t produce an adequate blood level of buprenorphine. The FDA also wanted more information about how physicians would be trained to implant the medication.

A double-blind, double-dummy phase 3 trial was completed in May of 2015 which apparently showed Probuphine did as well as the present sublingual buprenorphine products now available. I’ve searched the internet for this information but haven’t found the actual data. I’ve seen some information saying the Probuphine implant was compared to sublingual buprenorphine patients dosing at 8mg per day or less. If so, this would mean the company set the bar lower than the last study, when it was compared to patients on 16mg or less.

The process of Probuphine implantation may be cumbersome; doctors who wish to do this procedure must have a DATA 2000 waiver, and most of these doctors are not surgeons. Will general medicine doctor and psychiatrists presently prescribing buprenorphine want to learn this surgical procedure? I don’t know.

Unless the regulations are changed, if DATA 2000-waived physicians prefer to let surgeons implant the rods, we still must be physically present with the surgeon during both implantation, and explanation six months later. Will the patient’s insurance pay for the time and expertise of two doctors? I don’t see that happening.

What do I think about Probuphine? I think it’s an excellent method to reduce diversion. I think it would probably reduce opioid overdose deaths. However, I think it will make it more difficult to get patients to engage in the psychosocial counseling that’s so necessary for long-term change and recovery.

At present, the need to get new buprenorphine prescriptions keeps patients coming back to healthcare providers. We can, in a way, hold the prescription hostage until our patient engages in counseling. With an implantable form, we have no such leverage.

Probuphine could be an ideal treatment for incarcerated patients. If opioid-addicted patients are sent to jail, they could agree to have Probuphine implanted in order to reduce opioid craving and withdrawal symptoms. These patients would still need the psychosocial counseling for the treatment of addiction, but the Probuphine would be a humane comfort measure for these pateints.

If any of my readers have more information about Probuphine, please chime in.

And buprenorphine patients, what do you think about getting buprenorphine implanted every six months? Would this be something you’d be interested in, if it were covered by insurance?

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.