What new treatments for opioid use disorder were on the way?
In June 2021, I spoke with Adam Bisaga, MD, a research psychiatrist, professor of clinical psychiatry at Columbia University, and the author of Overcoming Opioid Addiction. We focused on research: implants, injections, and other long-acting forms of the medications already used for opioid use disorder.
This is an archive episode, recorded when the show covered addiction and recovery broadly. We also talked about how hard it can be to start naltrexone, how fentanyl has changed the first days of buprenorphine, and whether the brain heals during long-term treatment.
Why does a medication that lasts for weeks or months matter?
I opened with Probuphine, the buprenorphine implant placed as small rods in the arm, whose training course I had attended. At 0:43, Dr. Bisaga explained that the manufacturer had discontinued it. In his view, its low dose and the surgery to place and remove it limited its use.
Still, he said the product filled a real gap. Buprenorphine works very well, yet many people do not take it as prescribed, and they go on having cravings and using illicit opioids. A medication taken once a week, once a month, or less often would take the daily decision away. Of course, he noted, many people feel fantastic on a daily dose.
What was it like to use the monthly injection in practice?
At 5:30, I described the year we provided Sublocade, the monthly buprenorphine injection, to patients. It worked very well for them. Our problems were all logistics, from specialty pharmacies and insurance companies to a package that had to be kept cold. One shipment sat in a delivery truck for a week and spoiled.
From 7:19, I asked about Brixadi, which had been held up for years. Dr. Bisaga explained that a patent dispute had delayed it in the United States. In his account, it would offer weekly and monthly doses and would not need refrigeration.
What is a dissolving naltrexone implant?
Later in that answer, Dr. Bisaga turned to his own work. The monthly naltrexone injection, Vivitrol, had improved how well people stayed with treatment compared with the daily pill. Yet, he said, the average patient stayed on the injection for only a few months, while he believed treatment should ideally last a year or two, or longer.
So his division at Columbia, with a grant from the National Institute on Drug Abuse and an Australian manufacturer, was studying a naltrexone implant. He described early work in healthy volunteers as very encouraging, with patient studies due to begin that summer. The implant releases medication steadily for many months, and the material holding it together dissolves, much like dissolvable sutures.
At 16:08, I said that would be a big deal for doctors. In the Probuphine training, we practised finding implants that a butcher had hidden in a piece of pork, and we learned that rods could migrate or break. Not having to go fishing for pieces is a real improvement.
Why do so many people stop treatment too soon?
At 17:27, I said that, as I saw it, the main reason is not forgetting doses. It is stigma and social pressure from family, friends, support meetings, and society in general, even when the doctor keeps telling the patient they are on the right path.
Dr. Bisaga agreed. To someone who does not understand the condition, a daily dose can look like still taking a drug every day. A treatment given once or twice a year would be discreet, he said, and would end the fear of running out.
Why is starting naltrexone so hard?
At 19:43, I compared the three medications. A person can usually start methadone the same day and buprenorphine after about a day, but naltrexone means waiting much longer. Someone waiting alone at home reaches the worst of withdrawal and has every reason to give up.
Dr. Bisaga described a large multicenter study of a short inpatient protocol, and he considered an inpatient setting the safest. Unfortunately, he said, most providers still send patients home to wait, which is an impossible task for most of them.
How has fentanyl changed the start of buprenorphine?
At 23:40, I described a problem we were seeing. Patients waited the usual time, felt ready, took their first dose of buprenorphine, and still went into precipitated withdrawal. I asked whether the fentanyl in street heroin was behaving differently.
Interestingly, Dr. Bisaga said the reports varied by region. The difficulty seemed concentrated in outpatient settings in parts of the East Coast. One answer many colleagues had developed was to start buprenorphine at a very low dose, sometimes while the person was still using, and build up slowly. He was clear that this had not yet been tested in a controlled way.
Does blocking the opioid system take away everyday pleasure?
At 28:56, I asked about a worry some patients raise: that long-term buprenorphine or naltrexone might dull natural rewards like a runner’s high.
In his view, the concern was mostly promoted by people with little experience using these medications, and controlled studies do not support it. If anything, he said, mood improves. He stressed shared decision-making, because no test yet predicts who will do better on which medication.
Does the brain heal during long-term treatment?
At 34:33, I described what I see when people taper off buprenorphine after a year or more. Many have some withdrawal symptoms to get through, but they typically no longer have opioid cravings. It looks to me like healing.
Dr. Bisaga agreed that the brain changes and remodels, although good studies comparing recovery with and without medication do not yet exist. In his view, some people will stop medication, some will stay on a low dose for a long time, and all of those outcomes are acceptable. Learning new behaviors, he said, probably matters more than waiting for the brain to heal.
Who is Adam Bisaga, MD?
Adam Bisaga, MD, is a research psychiatrist and professor of clinical psychiatry at Columbia University, where his division was leading research on a naltrexone implant when we spoke. He is the author of Overcoming Opioid Addiction, a book written for patients, families, and healthcare professionals.
What can listeners take away from this conversation?
The medications we already have work, and the research Dr. Bisaga described was aimed at the places where people fall away: the daily dose, the hard start, and the pressure to stop early. As I said near the end, at 44:50, patients can be confident sticking with what works now, knowing that more options are coming.
How do I approach this today?
My thinking has kept developing since this conversation was recorded. Today my practice is built on one idea that runs through all of it: when the body has adapted to a substance, the safest way off is usually gradual, with the smallest steps the person’s nervous system can tolerate. Physical dependence is not addiction.
For opioid dependence I prescribe buprenorphine, which steadies the body so a person can rebuild their life without the cycle of withdrawal. Visits are monthly, or weekly when needed. Some people stay on it for a long time, and that is a legitimate choice. Others later taper slowly, using the same gradual approach I use for every other medication.
I believe medication for opioid dependence should be available wherever people need it. I prescribe in Florida only.
Call 911 or go to an emergency department if there is a seizure, confusion or hallucinations, or thoughts of self-harm. For thoughts of suicide or any mental health crisis, you can also call or text the 988 Suicide and Crisis Lifeline.
This page is educational. It is not medical advice, and listening to the episode or reading this page does not create a doctor-patient relationship. Decisions about starting, continuing, or tapering any medication should be made with your own physician.
Full transcript
A note from Dr. Leeds: my guests speak from their own experience and expertise, and the terminology they use is their own. Whatever the topic, this show holds to one distinction: physical dependence on a prescribed medication is not addiction. This transcript is educational content, not medical advice, and nothing here creates a doctor-patient relationship.
Read the full transcript (46 minutes)
Dr. Mark Leeds [00:01] Dr. Adam Bisaga is a research psychiatrist and professor of clinical psychiatry at Columbia University. He is the author of Overcoming Opioid Addiction, the definitive book for patients, family, and healthcare professionals on the subject of effective treatment for opioid dependence. Yeah, so let’s start with as far as long-term medication-assisted treatment for opioid use disorder. There was on the market a product named Probuphine. Probuphine, the six-month implant, which was buprenorphine, four rods usually were implanted in a person’s arm. And I went to the training. It was really interesting. And my understanding is now that product is off the market.
Adam Bisaga, MD [00:43] Right. The product was discontinued by the manufacturer. So there is no way to insert new rods. However, of course, if patients have already rods, they should be removed. So this was an interesting product, and certainly we’ve learned a lot from that. It was a relatively low-dose product, probably equivalent to 8 mg or less per day of the sublingual preparation. Because it was low dose, it really didn’t have an overwhelming clinical benefit. Certainly had some benefits, but kind of limited. So a lot of patients had to take supplemental sublingual buprenorphine in order to have benefits, full benefits, decreasing cravings, and all that. So the product ended up being approved only for stable patients who are maintained on low doses. So you had to be on sublingual for some time, very stable on a relatively low dose, and then you would be eligible for the implant to kind of make it much easier for you to remain on the medication without having to worry about daily taking. There were some barriers to, of course, it had to be surgically implanted and surgically removed afterwards. It was a non-dissolvable polymer EVA. First of all, indications, access to physicians, the relatively low dose kind of made it, I think, difficult to have a widespread use. And I’m not really sure about all the reasons why the company pulled, but certainly we have learned a few lessons from this product. It was still, I think, an attractive product for some, and there were certainly patients that were looking for that. I’m not sure about you, but I certainly have been on the list and I’ve been getting one a month kind of call to see if I was offering this product. But anyway, the product like that are clearly filling the gap that we have in the treatment, right? We have a highly effective medications like buprenorphine. The issue is that many patients, maybe up to half of the patients that are prescribed are not adherent with the medication. And because they don’t take medication as prescribed, the doses as prescribed, they continue to have cravings, they continue to use illicit opioids, which limits their full benefits, full recovery, and they often drop out of treatment, right? So you know that about 40 to 50% of patients relapse or stop taking medication and resume regular use within six months. If we only had a way to offer for patients to take medications not twice a day or once a day, but maybe once a week or once a month or maybe once every six months, it looks like those preparations would be much more effective. And actually, there is a study that came out this week published in JAMA from Australia that do compare sublingual buprenorphine with buprenorphine monthly injection and show that patient satisfaction and patient benefits are much greater from the long-acting preparation. So, of course, we have to talk to the patients and it’s important to consider their voices in terms of what kind of treatment would be most acceptable for them. But it does appear that at least for some patients, there is huge benefits from the medicine that you don’t need to think about taking every day. You don’t need to make a decision about taking medicine or maybe thinking about using, right, on a daily basis, which is a challenge for some patients. You know, not for all. There are many patients that feel fantastic on daily medication. They have no craving surges, no interest in resuming kind of illicit opioid use. And those patients are great. But there is a lot of patients, maybe half of all the patients, right, that struggle with daily adherence. They think about, you know, when to take, how much to take, whether to take only a little bit in the morning, when maybe take at night. And people have busy lives. Sometimes they have disorganized lives. They may have ADHD or other psychiatric problems that make it difficult for them to think and remember about medications. And those people clearly are at very high risk of relapse. And extended release preparations would fill, I think, a very important niche, right, or gap that we have right now in these medications. What’s your sense about long-acting preparations and how useful those may be?
Dr. Mark Leeds [05:30] I agree. They’re definitely helpful, and some patients do very well with them. We were providing Sublocade to patients for about a year. For the first year it was available. And it worked very well for our patients. I spoke to another doctor who said that he did have to give some supplementation of sublingual medication in the beginning with the patient, but I didn’t have that experience. Our patients did very well. Our biggest problem was with logistics, getting the medication shipped on time, dealing with the specialty pharmacies that the insurance companies would cover, patients complaining that their copay was changing and a FedEx driver is not dropping off the package. And the fact that the package had to be kept cold. And we had one issue where a FedEx driver refused to give it to a courier and it sat in the truck for a week and spoiled. So, yeah, we did have issues, but the issues were not with the medication or the treatment or patient satisfaction. It was all with issues with the pharmacies, the insurance companies and the shipping companies.
Adam Bisaga, MD [06:26] Right, right. Absolutely. So those issues are hopefully solvable, although not easy. But certainly when it comes to patient perspective, many patients feel that this is a better option for them and many families. Right. And also there are some treatment settings which really cannot administer medication every day. Some residential programs, of course, criminal justice systems where they cannot really have controlled substances stored and given every day, where clearly extended release preparations are treatment of choice. And have now hopefully two extended-release buprenorphine. There’s another one coming any day to the market, which will be both weekly as well as monthly dose. And it will have more doses than Sublocade, which only has monthly and only two doses, which will then hopefully allow doctors to use it.
Dr. Mark Leeds [07:19] We’ve been waiting for that for a long time and apparently it doesn’t need to be kept cold. I think you’re talking about Brixadi. And I thought that was going to be approved a year ago or two years ago. And do we know why that’s being held up so long? Because a patient told me that it’s available in other countries and just not in the U.S. Yet.
Adam Bisaga, MD [07:36] That’s correct. That’s correct. So it’s held in the U.S. Because of the patent dispute with Sublocade. It was fought in court. It was held up for several years. But there was a citizen petition last year and it was actually accepted. So the product will be available in 2021. And again, it will give you a wider range of doses. It doesn’t need to be refrigerated. It actually will be a smaller volume so it will be a little bit easier to administer and you will have many more subcutaneous areas that medication can be administered. We have to see for the patients what they tell us but it kind of promises hopefully an advance, some advantages over existing. But both will be, I think, clearly play a role. So we’re excited about buprenorphine. There is also in the works a pill that you swallow once a week of buprenorphine. And this is still research, but that certainly could be also an interesting addition that you don’t have to keep under your tongue. You’ll just swallow once a week. And I hear a little bit about other versions of implants, but I’m not sure where those are. What I’m involved is working on the extended-release naltrexone, right? As we know, extended-release injection naltrexone has been available for the past 14 years, approved in 2006 for alcohol dependence and 2010 for opioid use disorder. Vivitrol, which is an injection that is given into the muscle. So not like buprenorphine is given under the skin. This is an intramuscular, deep intramuscular injection, which is supposed to maintain therapeutic level of naltrexone for about three to four weeks with some individual variability, which clearly increased, doubled actually the rates of treatment adherence and abstinence over the daily pill to the point that we kind of no longer really recommend daily naltrexone tablet for patients with opioid use disorder. We still recommend and use it for patients with alcohol use disorder, but with opioid use disorder, injection is far superior. Again, it allows patients to remain about 50 to 60% of patients are abstinent on medicine six months. So it’s comparable with buprenorphine, right? But still, average patient remains on injection for two to three months. So it is a challenge to keep patients for longer. And, you know, we don’t have to probably mention here is that patient needs to stay on medication for much longer than six months, right? Ideally, one, two years would be really the kind of optimal or even longer duration of treatment. So if we could have a medicine that could be taken twice a year or once a year and remain in your system for that long, it will be hopefully a very useful addition. And so that’s why we’ve been kind of working on naltrexone implant, which has been used in Australia for many, many years. Many iterations of the product have been introduced and used in thousands and thousands of patients. So we have actually received a grant from National Institute of Drug Abuse, the HEAL grant, which is, again, one of this recent pool of money to develop new treatments, to then partner with the drug company, an Australian manufacturer called Go Medical. So NIH, NIDA is involved, Go Medical provides medication, and our division substance use disorder Columbia is actually leading this research effort. And we were able to characterize, we have administered implants to healthy controls to characterize how long the implant lasts, what are the blood levels, how stable those blood levels are, what is the individual variability, how safe it is, how difficult is the implantation procedure, what may be possible adverse effects, how you manage that. So we have done all this preliminary work and the results are very, very encouraging. So we received just this year additional money to study this in patients now and we’ll be starting recruitment this summer. So naltrexone implant, there is one implant approved. It’s actually improved in Russia. It’s called Prodetoxon. It’s a different preparation of the implant. The good news is that both implants don’t need to be removed. They dissolve gradually once the medication is released. The polymer, which is a matrix that holds the medicine together, gradually dissolves. It’s the same polymer that it’s used for dissolvable sutures and other biological materials that are used routinely. So it’s pretty safe from that perspective. And it does seem to provide very stable blood levels for many, many months, up to six months, some patients much longer, some patients maybe one, two months shorter, but there is no burst release. So medication is very stable, controlled release, maintains therapeutic blood levels comparable with Vivitrol. There is a hope that once this medication is fully tested and approved by the FDA, it will be a very attractive treatment options to patients that prefer to be detoxified and treated with naltrexone to prevent relapse. A lot of exciting developments. There are other extended release naltrexone or nalmefene, which is another opioid antagonist, in the works funded by NIH. So there are two-month or even a six-month-long injections. There are other implants. So there is a lot of exciting new developments that hopefully will make to the clinicians like yourself and others who are open to try different treatment options with their patients.
Dr. Mark Leeds [13:58] One question that I get sometimes with, even with just daily suboxone and naltrexone and definitely with the longer-acting preparations and injections and implants, a question that would come up in the mind of a lot of patients is what happens if they need an emergency surgery or even a planned surgery? Would that be a problem if the person has that naltrexone implant as far as still being able to effectively treat them during a surgical procedure?
Adam Bisaga, MD [14:24] Right. So that’s a common concern. It tends to be much more of a concern than actual reality. So those occurrences are rare. They certainly do happen. But anesthesiologists are very well trained to manage pain in acute situation, right? They put people to sleep. They can give them high doses of very potent opioid, monitor their breathing or supportive breathing, oxygenation, and administer sufficient doses to override the blockade. You know, anesthesiologists all the time have to treat pain in patients who have a very high level of tolerance, right? They need to give them much, much higher doses than people who are non-tolerant given, right? This can be certainly managed in acute situation when you need acute surgery. The advantage of the implant is that, of course, it can be removed. It may be easier to remove the first one to two months, a little bit more difficult to remove later, but theoretically it can be removed. Naltrexone injection cannot be really removed, so then you have to wait or try to override. But remember that we have learned a lot about non-opioid pain management. Right? So people figure out how to decrease opioid exposure and treatment. And we’ve learned a lot of non-opioid ways of managing pain, whether locally or systemically with various non-opioid options. So these days, I think anesthesiologists have a lot of options to provide treatment to someone that may be taking these medicines. But it is true. It is a limitation. You are making decision to not rely on opioids for kind of day-to-day pain management, but you can settle in emergency situation, manage that. There are guidelines.
Dr. Mark Leeds [16:08] The dissolving implant, that’s a big deal. And I think for doctors, it’s going to be a big deal because I went through the training course for Probuphine. One of the scariest parts was when they told us how we have to look for the implant and they can migrate. Sometimes you can’t find it and you have to search around and they can break in pieces. And they give us some really difficult, they would give us a piece of pork that we had to dig around and a butcher had placed the implant and they made them difficult to find and then you have to know to send the patient for MRI or ultrasound after to look for these migrated and possibly broken pieces of implant. That would be a major improvement to not have to go fishing around for the pieces of implant when treatment is over.
Adam Bisaga, MD [16:47] Right, right. That sounds like everybody agrees that’s the progress. Those implants may be a little bit more kind of variability, but certainly there is new technologies. There are nanotechnologies that are in the works that will use a dispersed material. There is hopefully if there is interest, there is certainly plenty of technology to support extended release or controlled, what is called controlled release medication. As we know, contraceptive implants are widely used and very popular treatment options. Extended release antipsychotic medications, there’s certainly plenty of clinical situations in which those medicines can be very useful.
Dr. Mark Leeds [17:27] It seems like the major reason why patients discontinue medication early, it’s not so much that they forget to take the medication or that kind of thing. But overwhelmingly, it seems like it’s stigma and social pressure, pressure from family members, maybe pressure from support meetings and friends and family and just even just society in general. Patients, even on their own, get in their mind that, you know, I feel better. I don’t want to do this for a year. I don’t even want to do it for two months. And even with the doctor educating them and repeatedly telling them you’re doing the right thing, you’re on the right path, you need to stick with this. It seems like the social pressure and stigma is a major reason why most people fail treatment or end treatment too soon.
Adam Bisaga, MD [18:07] Absolutely. And I think there is something about taking medication every day that for many people, it’s confusing. You know, what do you mean is helping you? You’re still taking a drug quote unquote every day, right? So when someone doesn’t really understand the nature of the disease, meaning how the daily heroin disorganize your life, they can be very confused and look only at the surface, you’re still taking something every day. So if this can be eliminated, if the treatment can be discreet, right? You go to your doctor twice or once a year, get this medicine in you, and then no one really knows what you’re doing and you feel well, this could be hopefully a huge game changer for the patient, for the family, for other people around. Of course, there are other barriers to taking daily medications, right? Like traveling, it’s not easy to travel abroad with the controlled substance. Many countries would not allow you in. You have to worry that if you lose your supply of medicine, right, and you find yourself in a different city, obviously patients panic. And just as you’re saying, you know, just the apprehension, am I going to get the medicine in time, for some patients is very destabilizing because it kind of reminds them how they had to struggle with securing daily supply of their opioids when they were addicted to it. So there are certainly many dimensions in which we hope that patients will benefit from that, but we have to ask the patients, right? Some patients may prefer daily security, safety of daily dose, and some patients may not want to do that. Having more choices ultimately will be beneficial to everybody.
Dr. Mark Leeds [19:43] As far as like between the, you know, there’s the three major medications for opioid use disorder, for MAT. There’s methadone, buprenorphine, and naltrexone. And the major differences, it seems like, or like one of the key differences between each of those, if someone says, which is best for me? Well, methadone, you know, say if someone quits heroin, they can go to the methadone clinic that same day and get their first dose of methadone without really having to go into withdrawal. Then buprenorphine, it’s a little bit more difficult. They have to wait at least a day in most cases, sometimes more depending on what they’re taking. And then naltrexone being the most difficult as far as you have to wait at least a week, I think. And that puts the person, you know, they have to go through the worst part of withdrawal. If they’re not taking anything for withdrawal, you know, if they’re home alone waiting to be able to take naltrexone, by the third day of withdrawal, they’re at a peak where they’re having severe cravings and probably having a lot of reservations and second thoughts. And so what would be the best environment for someone to start the naltrexone implant?
Adam Bisaga, MD [20:41] Right. Absolutely. This is very real. So it is true that patients have to go through the withdrawal at the beginning. Now, some patients prefer the detox. Some patients like the whole concept of just detox, getting rid of opioids and then starting anew. But it is a challenge. There is a lot of confusion how to best do that. Obviously, for many people, they remember how they were trying to quit at home by themselves. And that was very, very traumatic, aversive experience. Right. But we certainly have developed a very effective ways of alleviating the withdrawal, treating the withdrawal. And for most part, there are protocols that can really minimize the withdrawal, waiting for naltrexone initiation, which are not that more severe than the withdrawal you need to go through to wait for buprenorphine, right? Except that it just lasts a few more days. So actually, we’re now in the middle of the very large multicenter study where we are training and comparing five, six-day inpatient protocol to switch someone from heroin or fentanyl to Vivitrol. And we compare it with the standard method, which is a week of buprenorphine taper followed by the week of washout. And again, we have done this studies in one side, but we’re now doing in a community programs. And we’re hoping that we’ll have some kind of protocols available and experience from community programs available for providers to do it over a week. I think inpatient setting is still probably the safest and the best because you can then administer relatively higher doses of medications to eliminate most of the withdrawal, right? To keep patients comfortable during this week when they are washing their body of opioids and getting ready for naltrexone. And you can do it on an outpatient basis, but then you have to have someone really adherent. You know, you have to probably want to have significant other or family kind of being involved. You want to see them often to prescribe medications and the medicine certainly may have some side effects, which you then need to recognize and manage. But in the inpatient setting, it’s relatively easy to administer medication to eliminate most of the withdrawal as your body goes through this period of adjustment from daily heroin or fentanyl to then being able to accept naltrexone without any further withdrawal. So we’re hoping that we’ll have pathways to naltrexone available. Unfortunately, at this point, most providers don’t really have this experience, and they’re basically asking patients to go home and wait. And as you say, this is an impossible task for most patients to go home, go through the mild withdrawal, and wait day after day. And most patients, you’re right, ultimately have the thought that they should just postpone the trial, just use it for now, make themselves feel better, and not have to go through that. So making it faster, it’s absolutely a way to go.
Dr. Mark Leeds [23:40] When you do a study and you do a study where you transition someone from heroin, fentanyl on the streets onto naltrexone, something that we’ve had a lot of difficulty with recently is the nature of street heroin, which seems to all have fentanyl. And it seems to not be pharmaceutical fentanyl. And it acts differently. Patients have this issue where they wait the right amount of time. They feel like they’re in the proper moderate withdrawal and we’re ready to administer their first dose of buprenorphine. And then they go into precipitated withdrawal, you know, even 24 hours out and sometimes even further out, maybe even 48 hours. You know, and I’ve heard some different theories. One I’ve heard was that the fentanyl gets sequestered in fat cells and takes more time to come out of the system. I was wondering if you’ve had issues with that and if that creates an issue in your studies. Are you using maybe a more controlled form of heroin or do you know or not know what mix of opioid the person has when they transition? Can.
Adam Bisaga, MD [24:36] So there’s a lot of anecdotal reports like the ones you just cited from your experience. But our talking and listening to a lot of colleagues from around the country, what we’ve noticed first, there are regional variations, right? So where it’s in Massachusetts, in Baltimore, maybe in New York, Pennsylvania, there is certainly a type of heroin slash fentanyl on the street that makes the induction very difficult. But then we hear from the Western United States, from somewhat Midwest, Texas, where this is not an issue. Interestingly, in emergency rooms, emergency room doctors don’t, most of them don’t seem to report that. I don’t know what it is, but a lot of buprenorphine, as you now know, are initiated in the emergency room. And those ER doctors don’t really report that because they have patient in the control setting for, I don’t know, half a day, and they make sure that patients are abstinent. I don’t know. Or they can just manage and administer medications to alleviate withdrawal. But there’s less issue. There’s less issue on inpatient units, although sometimes we do hear some inpatient units have trouble. I think that for outpatients, especially the Eastern seaboard of the United States, that seems to be a problem. And one way that I think many colleagues have developed a way to manage this is to start buprenorphine at a very low dose. I’m sure you’ve heard about the concept of microdosing, right? Where you are initiating buprenorphine in someone who is unable to stop and go through even mild withdrawal, right? So those are patients who just cannot stop taking heroin for more than a few hours. And you can introduce buprenorphine in those patients by starting very low, like a quarter milligram, while they are still taking heroin. So you can do quarter milligram the first day. You can give two or three quarters the second day. You can go one milligram. And slowly, you can build up buprenorphine to about eight, 16 milligrams. And then they stop heroin and they feel fine. So this technique of microdosing has been used to transition pain patients who cannot really stop their pain medications, right? So patients who take high doses of pain medicines, you can transition them to buprenorphine using this technique. And then you can also do people using heroin. And the same technique can be used to initiate buprenorphine in people who use fentanyl. So we started initiating buprenorphine at half milligram as a test dose. Whenever you have doubts about fentanyl, they’re not in withdrawal 24, 36 hours later, you can give half a milligram of buprenorphine, observe their reaction for one hour or two, can give them another half a milligram. And if they take one to two milligrams, they’re usually fine to tolerate higher doses. So that’s the technique. Now, it hasn’t been really tested in a controlled way. We are actually collecting the experience to at least be able to say whether there’s a difference in people who are fentanyl positive versus negative in terms of the delay to the first dose and the total first dose and all that. You probably also don’t want to give too much buprenorphine on the first day. Overall. Some colleagues I know are pushing buprenorphine to, you know, 16 or 24 in the first 24 hours. I don’t have experience with that. We usually give like a six milligrams the first day. And then if the patient continues to have craving the next day, we can give higher dose. We use adjunctive medications, right? So we certainly use clonidine. You can use lofaxidine. You can use other anxiolytic, sedating medications, hypnotic medications to help with this first day. And of course, psychoeducation, support. Patients are confused, don’t know what’s happening. They hear horror stories and they, I think, are bringing a lot of apprehension to the treatment, which then makes it more difficult for them. So, yes, fentanyl has changed how we initiate buprenorphine and then again, how we reverse overdose, how we do maintenance. But certainly, we’re learning to adapt. It doesn’t mean that it will not continue to be a challenge as new fentanyl or even non-fentanyl synthetic opioids become available. Those are new substances that we don’t really fully understand.
Dr. Mark Leeds [28:56] There’s been some concern, not a lot, but occasionally a patient brings this up as far as blocking the natural endorphin opioid system in the body for long periods of time. If that’s in any way detrimental to a person, whether they’re taking buprenorphine or naltrexone on a daily basis or with an implant and they have that long-term blockage. And some people might say, well, when they go for a run, they don’t get the same runner’s high or they don’t get that same reinforcement of good habits that they might get otherwise. Is there anything to that? I mean, my experience of seeing patients on buprenorphine long-term is that there’s no issue, They function very well. But that has come up. Is that anything that people should be concerned about?
Adam Bisaga, MD [29:40] This is a common concern. And it’s usually, I think, promoted by people who don’t have much experience using medication, especially using antagonists. So this concern is dominant with critics of antagonist-based relapse prevention treatment following detoxification with naltrexone. So there seems to be really, this seems to be a very robust system. Opioid systems is very robust. It has a lot of type of receptors in multiple configurations all around the body. And blocking mu opioid receptors at 100% almost or 98% of the occupancy with naltrexone doesn’t seem to have any major effect. Now, there are some subtle differences in some kind of experimental paradigms, like a social relatedness paradigm. But in terms of having a major impact on day-to-day life experiences, this is really not supported by control studies. The same effect on mood. If anything, mood improves. And there are studies that show that mood on naltrexone improves as good or maybe even slightly better than mood on buprenorphine. So clearly blocking or stimulating opioid receptors doesn’t seem to have any major impact. But naltrexone, as you know, certainly is an effective medicine to help with variety of pathological cravings or pathological rewarding reinforcing situations. We know that naltrexone helps some people not experience pleasure from alcohol and allows them to have controlled alcohol intake. It’s certainly, there’s a small group of patients that have anorexic effects with naltrexone. Naltrexone, as you know, is one of this medicine that is in use and is actually an approved medicine for a treatment of overeating in combination with another agent. It’s used to treat gambling. It’s used to treat other behavioral addictions, so-called, like hypersexual behavior or self-injurious behavior. So naltrexone certainly can help extinguish or block the kind of pathological cravings, pathological, very intense reward-oriented behavior, but it doesn’t seem to have any discernible effect on day-to-day pleasures of food, running, sex, or anything else that keeps us going from day to day. One thing that I have to just mention, that there is certainly a small group of patients that may have a mood effect with naltrexone, and which seems to be a little bit more pronounced than with buprenorphine. So people who get depressed, maybe even suicidal, maybe 4% of people treated with naltrexone versus 2% of people treated with buprenorphine. So there is a slight, there is the type of patients that probably don’t feel well on naltrexone and they should not really be on naltrexone. They should be offered treatment with agonist and vice versa. There are people who don’t feel well on buprenorphine and should be offered antagonist treatment. So as you were saying at the beginning of our conversation is that we would like to have a way to match patients to treatment based on some kind of testing, genetic testing. We don’t have it yet, but it is very clear that there are some patients who feel well on antagonist and some patients who feel better on agonist. And we cannot really predict who it is. We don’t really have any any good predictors who’s going to respond to agonist versus antagonist. And what we have to do is to have a shared decision-making, talk to the patient about pluses and minuses of each treatment option and help them make a choice. The medication that is best works for them, is consistent with their long-term goals, their day-to-day life. And if one doesn’t work, then offer them another like we do in the rest of the medicine, right? There isn’t really any discernible negative effects. If anything, we see majority beneficial effects, right? The mood is improved, the craving is improved, the illicit drug use stops, and all the negative consequences, your life, your sleep improves, your cognition improves, and it’s comparable for antagonist and agonist. We continue to collect evidence, but it is very clear that the medications, any of those three medications are far, far superior to a treatment without medications, that it’s unpredictable, difficult, and often fails. And knowing how risky is a failure in this treatment of this disorder, when the failure can meet overdose and death, that there is really no reason to suggest that it is worth for people to try recovery without medicine, at least at the early recovery the first few years. That seems to be an overwhelming consensus from people who have been providing treatment for many, many years.
Dr. Mark Leeds [34:33] Now, my experience with giving people buprenorphine for a long enough period of time where they take it for at least a year, and in some cases, a year and a half, two or three years, and then when they stop taking it, they taper off and they discontinue. In a lot of cases, they do have withdrawal symptoms and they have to get past that, but typically they don’t have opioid cravings after that period of time. Are there studies or any evidence that the brain is healing during that time period? Because that’s what it seems like to me, that the brain, whatever changes have happened in the brain leading up to opioid addiction, it seems that there’s a healing process happening during that long-term treatment with medication, whether it be buprenorphine or naltrexone.
Adam Bisaga, MD [35:10] Absolutely. The brain changes. If you don’t use drugs, your brain gradually changes, right? You’re learning new ways of interacting with the world, both positive and negative interaction, new ways of dealing with stress, new words of experiencing positive experiences, your brain remodels all the time and new pathways get formed. So the brain changes, the brain heals, the brain no longer reacts to stress or cues reminding them of drug availability with the cravings and urges, right? We see it very well. What patients describe, there is always brain function that’s parallel to the behavior that we observe. Now, we don’t fully understand. I don’t think there are good studies showing compare brains in long-term abstinence, brain of people without medicine, with people on buprenorphine and people on naltrexone. It would be great to know what is the nature of recovery. Does it go beyond just the new behaviors that you learn? Or is there some kind of basis that makes brain recovered on medicine versus brain recovered spontaneously different. So we don’t have this. There is a study going on now. It’s a large discontinuation study when people who’ve been stable on medicine for many months can enter the discontinuation phase. So this is a study funded by CTN, again, Clinical Trials Network, the HEAL community funding project that will observe those people, what happens to them after they’ve stopped taking buprenorphine for several months. It will collect some of this data, but those studies, the long-term studies are difficult to conduct, expensive. And I think for the time being, we just have to rely on the clinical observations from clinicians like yourself who accumulate experience, right? I’ve seen that many of patients who stop buprenorphine. Yes, they continue to have sleep problems, anxiety, restlessness, but they had enough of the skills that they’ve acquired during the treatment to cope with them. They no longer have cravings. They have full lives. They’re engaging with other rewards. They have support networks. They have recovery community. They have hobbies. So they can get through that and continue their life in recovery without medicine and feeling much better, which is certainly a pathway. This is a goal for many people now probably not everybody will achieve that goal. Some people will remain on low dose of medications for a long time. Some people will require a higher dose of medicines. All those solutions are fine, acceptable. I don’t think there is one that is better, quote unquote, than the other. Everybody’s recovery is their own personal, unique pathway to recovery and should be accepted and applauded as such. And the brain will go along. But I think behaviors are learning new behaviors is probably more important than waiting for your brain to heal.
Dr. Mark Leeds [38:09] Yeah, definitely. There’s someone doing a study and they’re claiming this will be the first genetically targeted treatment that they’re testing people genetically to see if they have some kind of a serotonin transport system that not everybody has. And if they do have it, then this medication may be useful for opioid use disorder, maybe even alcohol and cocaine and other kinds of addictions.
Adam Bisaga, MD [38:28] Right. So there’s a study of ondansetron, low dose, so much lower dose, than the one you have in Zofran in people with alcohol use disorder. And I think if I remember correctly, they did post hoc analysis and have shown that people with one version of the serotonin transporter genes had a very pronounced response to this medicine, which was not there for people who had a different variant of the genes, right? So there was this theory that there is a genetic profile that makes people very responsive to this medication. This was for people with alcohol use disorder. So this was done by Dr. Johnson, who I think was in Virginia at that time. And I think he then went on to continue prospectively now planned comparison in people with this genetic variant versus without it to see if they’ll have a benefit. Now, we’ve always, always wanted to have the genetic test to tell us, yes, you have the right genes, this is a medication for you, the way that oncologists have, right? We envy oncologists that they have to genotyping and then they have a right medicine for everybody. But all the attempts have been unfortunately not successful. There was a lot of excitement with the opioid receptor gene for alcohol use disorder, right? OPRM118 that did not really, in prospective studies, planned comparison didn’t prove to be actually predictable treatment response. So I don’t know. We’re excited to applaud those studies, waiting for the results. I know the company and I know that they do attempt to offer medication that would promise to be very effective for people with this genetic variant. But as we know, in psychiatry, you know, we’ve been testing people, genotyping up and down. And except for a few circumstances when we can predict side effects, we haven’t really been able to have a reliable genetic testing to predict response to the medication. There’s a lot of excitement in research, and maybe this study will lead us somewhere. Yeah.
Dr. Mark Leeds [40:31] You know, patients are definitely very interested in new research being done on various psychedelic drugs, and some research is being done in the U.S., but occasionally patients ask the question, should I fly to Mexico and go do this Ibogaine treatment? And of course, my answer is no. It’s outside of the U.S. It’s not FDA approved. It’s outside of the scope of anything I know about. And from what I do know that it has some cardiac risk and I don’t know under what controlled situations they’re administering this kind of a treatment. You know, I heard one patient report back, they were put in a hotel room and told it was a hospital room and put in an IV. I mean, which is a scary thing, but like, what do you, what do you tell patients when they say, I want to go do this experimental treatment in another country. And, you know, rather than be stuck on buprenorphine long-term or naltrexone, you know, what would be a good response for that?
Adam Bisaga, MD [41:18] Right, right. No, you have to empathize with people that they wish for the magic cure. They wish for the silver bullet, right? They wish kind of one simple solution that will solve all their problems. And patients maybe with addiction have even more of a – all of us are susceptible to that. And patients with addictive disorders and their families are very susceptible and are willing to put out a lot of money if there is a promise of some kind of miracle cure. And unfortunately, a lot of people take advantage of those patients. So I tell them the same thing you’re saying, is that yes, ibogaine, there are some reports saying that medication can be very effective. Single episode of treatment can have lasting effects, not only relieving withdrawal, but also protecting against relapse. But there are also reports of not such a good effect, and there are certainly reports of deaths in people who have done those treatment in hotel rooms, whether it’s in Amsterdam or in Mexico. So ibogaine, I think, is pretty well established. It does have some kind of rare but pretty devastating adverse effects. So there is a version of this ibogaine, one of its analog, that has been in development for quite some time, 18 MC. So noribogaine, one of the analogs of the metabolite that has been under FDA oversight. I don’t know where this research is at this point, but you are absolutely right that we have seen a revival of psychedelic medicine in psychiatry, starting with ketamine for depression and now going to psilocybin, MDMA, and LSD in treatment of a whole bunch of psychiatric disorders, including addictive disorders. And there is certainly some evidence that those medicines like psilocybin can be useful to help people quit smoking, quit stimulants, and maybe even quit opioids. So I think there will be definitely data coming up in the next one, two years that will give us some confidence that this is a viable, safe option that we can recommend for our patients. There is certainly promise in psychedelics. In medicine, we don’t fully understand whether this has something to do with pure neuropharmacology or is that more about medication-assisted psychotherapy, right? Whether this is replicable in any hands or it has to really be done by a very experienced team of psychotherapies that can guide, prepare, and then guide the patient through the experience and debrief them after the experience, which is more like a therapy. We do know that people recover spontaneously from addictions, right? Because of their spiritual experience. We hear those stories all the time when people suddenly woke up one day and saw the world in a different light and never went back to use drugs. And maybe having the experience of therapy under the influence of these medications, maybe we’ll do that. So there are studies of ketamine, psilocybin for addictive disorders, and I am very excited. And I would caution patients in the meantime to try proven and effective life-saving FDA-approved medications while we are waiting for these new medicines. There may be clinical trials going on in the neighborhoods. They can certainly enroll in those trials. And if they desire this type of treatment, so that could be an earlier avenue. And again, one more reason to be very excited about the future of addiction treatment in this country. We have a lot of, I think, new options that we haven’t really had in the past 10 years. A lot of excitement on the horizon.
Dr. Mark Leeds [44:50] It definitely is very exciting what’s coming in the future. And I agree patients can be confident in sticking with what we have now, which is very effective, knowing that in the next maybe three years, five years, there’s going to be new things coming out. And so they don’t have to worry if this doesn’t give them the results. And it will give them good results. But say a few years down the road, they’re worried about what happens when I come off of naltrexone or buprenorphine. We may have something ready for them at that time, if needed, to go forward. Exactly. Thank you, Dr. Bisaga. Thank you for joining me today on the podcast.
Adam Bisaga, MD [45:23] Oh, my pleasure, Khalid. And hopefully we can connect next year or in the future. And all the best in your efforts to popularize this and reach a wide audience. And I certainly applaud you and wish you all the best. Thank you.
