by Peter R. Coleman, MD
Titan Pharmaceuticals has been developing their long lasting Buprenorphine implant for about 10 years now. They have been trying to get the FDA approval for many years. They have made a lot of progress and have come close to getting FDA approval a couple of times, but this month they got another delay. The FDA has some reservations about allowing this drug on the market, and wants at least another 6 months to study all of the ramifications. Right now, we are living through a serious epidemic of opiate addiction. There are reportedly 2.5 million people in the US with an opiate addiction and fatalities are at an all-time high. It is clear that we need to have multiple tools at our disposal to combat the disease. It may well be that Probuphine will be an effective tool.
Probuphine® is an implant which contains Buprenorphine, the active ingredient in Suboxone®, Subutex and Bunavail®. The implant is inserted under the skin and delivers a dose of the medicine for about 6 months. Buprenorphine tablets and film have been available since 2000 and they have become a very popular treatment - about 1.5 Billion dollars in sales last year. Buprenorphine products relieve a lot of the withdrawal and cravings for opiates - so patients like taking this medicine. But, one of the problems with any product containing Buprenorphine is that the drug is highly addictive. Buprenorphine relieves the withdrawal and cravings for opiates because it attaches to the same opiate receptors similar to heroin and OxyContin®. In fact, it binds so tightly that most patients have more trouble getting off Suboxone® than they do getting off heroin. The withdrawal symptoms off any Buprenorphine product last so long that most patients go back on their drug or they go back to using street drugs.
Two other problems that have become very apparent with Suboxone® and the other Buprenorphine products - diversion and misuse of the drug. Many patients will admit they frequently divert their medicine. They sometimes use less of the drug than they are prescribed, or they sometimes skip some doses in order to sell their “extra” doses to other people. There is quite a street value for Suboxone® because it is cheaper than heroin and prescription opiates. It can tide heroin addicts over if they can’t find or afford their drug of choice. Some people also misuse their Buprenorphine products by injecting them. More commonly, people misuse their treatment by skipping a few days so that they can then feel a stronger high from using heroin - not exactly what was intended by the FDA when they approved these medicines to help patients get into recovery.
Probuphine® has the potential to relieve both of these problems. Once patients receive their implants they will not be able to skip doses or sell their medicine, and it will be lot harder to override their treatment. There are other potential benefits from this treatment. A six-month implant will make it more likely that patients remain in treatment for at least 6 months. It has also been said that an implant can break the cycle of having to take a pill each day. This may help patients feel more normal and less like a drug addict. There is also less likelihood of children accidentally taking the medicine and suffering from an overdose.
The big question of course is what are the downsides of this treatment, and the truth is that at this point, we do not know. We won’t know all of the problems with Probuphine® until it is used in clinical practice, and I think this is why the FDA is being quite cautious about allowing its introduction.
One issue is the amount of Buprenorphine that are delivered - are they appropriate levels, and are they consistent over time? In fact, the implants deliver quite high doses of Buprenorphine initially, but over the 6-month life span of the implants, the amount delivered drops off somewhat. It is not clear if this presents a problem. There could be a problem because the loser doses of Buprenorphine will cause an increased number of relapses as the dose goes down. Alternatively, it could be a good method of weaning off the Buprenorphine as patients recover. Another issue is what happens if people use extra drugs - either more Suboxone®, or street drugs. In the earlier studies, patients who got implants were also allowed to use extra Suboxone® tablets for cravings - which many people did. But using extra doses of Suboxone® while on the implant defeats the purpose of the implant, as far as diversion goes - people will still have “emergency” doses around that they can sell or use themselves. Another question is how effective the treatment is. In the original studies, only about 65% of the patients completed the 6 month program, so there was a high dropout rate. Also, in the early studies, most patients continued to abuse opiates. In fact, around 60% of the patient with implants still continued to use street opiates. It is clear these implants are not a cure for addiction.
Another issue concerns what to do after the treatment is over. The implants have to be removed after the 6-month period and questions remain about how easy they will be to remove. Another question arises for the patients who don’t come back to have the implants removed and what effect it will have on their long term health if the implant stays in for an extra year or two.
Finally, it is not clear what will happen to patients when they want to stop their implant treatment. After the implant loses its effectiveness, patients will definitely go into major withdrawal. Withdrawal off Buprenorphine is much worse to recover from prescription opiates or Heroin. Presumably, the intention will be for the patients to transition back to oral Buprenorphine products and then detoxify from those.
Here at TCI, we are seeing more and more patients who get onto Suboxone® or other Buprenorphine treatment and are unable to stop taking it. They cannot stand the long and intense withdrawal symptoms coming off these products. Fortunately, our Accelerated Opiate Detox program works very well for these patients.
So, it may be that Probuphine® implants do have a place in the treatment of opiate dependence. There are a lot of questions, and as mentioned, we will likely have to wait for the product to be released before we really see how well it helps and what are the related problems. At TCI, we have been using Naltrexone implants, as opposed to Buprenorphine Implants, for more than 17 years. These Naltrexone implants block all opiates and dramatically reduce cravings, helping patients stay off opiates. I have to say that when I look at the research on Buprenorphine implants, I am more and more confident and satisfied with our treatment protocols. Our patients usually report no cravings at all. They are able to concentrate on their therapy and their recovery program. Many are able to use the Naltrexone implants to achieve long term recovery.