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.

9 responses to this post.

  1. I, like you, feel that this would be great because no special training is required as subq injections are very easy to give and even easier than Vivitrol which is IM and cumbersome to inject. I hope they approve this soon!!


  2. Posted by Maximilian Alexander on April 5, 2017 at 1:57 am

    I wonder how the subjective experience of buprenorphine will differ when it has steady state plasma levels as a result of the implant / depot injections.


  3. Posted by Knothead on April 6, 2017 at 3:07 pm

    Do you have any concern that the injectable cannot be removed? For example, the risk of a major, unplanned surgery that the patient would need an opioid pain killer for? Or are there other pain relievers that could be an easy substitution?

    Also, is there no risk of drug dumping in the event of trauma? The capsule-like substance that surrounds the gel is not subject to any risk of being punctured?


    • Good questions. The same issue rises with the six-month buprenorphine implant, Probuphine. I think the buprenorphine can be over-ridden, with larger doses and closer monitoring than usual. The drug dumping issue is something I hadn’t thought of. I will ask about this at the next addiction medicine conference. My guess is that even if the drug is dumped, the ceiling effect of the medication may prevent overdose but that would depend on the patient’s tolerance. I suspect it certainly wouldn’t be as dangerous as a full opioid in the same situation.


  4. Posted by Knothead on April 7, 2017 at 6:13 pm

    Thanks for following up. I know probuphine has been a huge failure so far, which surprised me because many thought it would provide benefits for a certain class of patient. As Braeburn is only funded to the extent its venture capital investors continue to provide funds, I’m concerned that the failure might persuade Braeburn Pharmaceuticals to just drop the injectable program as well and focus on its other development projects.


    • I think the weekly and monthly injections will be successful if they are priced within reach of patients.
      Doctors like that patients have to have contact to stay on the medication – whether it’s weekly or monthly.
      Much easier to provide counseling.


  5. Posted by Knothead on April 10, 2017 at 2:48 pm

    Well, the good news is Indivior is developing a competing injectable, and that should prevent Braeburn from being able to set an artificially high price. Probuphine has no competition, and so it’s been priced very high in my opinion. However, my understanding is that insurance coverage has been available for probuphine, and so I don’t know if price has really been a material impediment to its adoption.

    I’ve heard the argument from a number of doctors that sublingual or now injectables are better for the patient over an implant, but I’ve never really understood it logically. While its true a patient has to return to the doctor to get another injection, isn’t there a heightened risk of patients not coming back, relapsing, and starting the cycle all over? I thought the certainty of compliance provided with an implant (plus the fact that the patient must return to the doctor to remove the implant, and make an affirmative decision not to have a replacement implant) would outweigh the risk of missing counseling appointments (although the probuphine REMS requires continued appointments). But it appears a lot of doctors don’t agree. I’d love to understand why.


    • Yes, the implant ensures the patient gets the medication, but there’s no way to “lure” them to counseling appointments. With the injections, we can ask that they get counseling before we give the dose of medication. If the patient doesn’t come back to get the counseling, they don’t get their medication, which motivates many patients to return.
      You may not like that way of thinking. I don’t completely like it either, but I get judged on how much counseling I’m able to provide to my patients with opioid use disorder, like it or not.
      If we were a completely harm-reduction oriented society, we’d offer buprenorphine whether or not the patient wanted counseling. If we were really serious about preventing overdose no matter what, maybe outreach workers would be handing our buprenorphine tablets on the street corners. But that’s not now and probably never will be the U.S. approach.


  6. Posted by Knothead on April 12, 2017 at 9:12 pm

    Thanks for the thoughtful reply. I’ve lost a few friends over the last year to opioid addiction, and I can only imagine the challenges involved…thanks for your work.


Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: