This material covers changes in the clinical use of buprenorphine that have occurred within the last several years. We're going to begin by reviewing the standard induction protocols. We've asked in the past that patients show signs of mild to moderate opiate withdrawal, that you use an opiate withdrawal scale to measure that, that you begin with either a two or a four milligram buprenorphine naloxone dose. Patients can be re-dosed in two hours if opiate withdrawal has not been diminished by the first dose. Our target dose for the first day was eight milligrams, but we could go to 12 milligrams in areas where patients were using fentanyl. And then it would be possible the second day to increase the dose to 12 milligrams as the target dose of induction. We initially recommend that patients come back and be seen the second day and the dose be adjusted according to patient need. Most of the patients are going to stabilize using this model between 12 or 16, but you're probably going to have to go higher in areas where fentanyl is being used. FDA has approved buprenorphine in a dose range of up to 24 milligrams daily. And whenever you hear me using the word buprenorphine, I'm really referring to the buprenorphine naloxone combination. So we're talking here about a combination of 24 milligrams buprenorphine and six milligrams naloxone. Now, our early recommendations for induction included specific detail depending on what drug the patient was addicted to. If they were using heroin, we recommended that they abstain from any drug use for 16 hours before you initiate the buprenorphine. If they were using opioid pharmaceuticals, we recommended that you sustain from any drug use for a full 24 hours before attempting induction. And if they've been on methadone for any period, we're suggesting that the methadone dose be reduced slowly, and you may have to work with a methadone clinic to gradually bring them down to 30 milligrams. Once they're stabilized on 30 milligrams, and that usually would take about one to two weeks at that dose, then switch them to an initial dose of 15 milligrams for the first day, no methadone the next day. So you got one day at 15 milligrams, no methadone for one day, and then the next day you can begin the induction of buprenorphine. So you gradually reduce the methadone, get it down, miss one day, and then start the buprenorphine. We're recommending that the patient have a moderate cow score of 8 to 10 before they receive the first dose of buprenorphine. For patients who've been using fentanyl, we recommend that a cow score of at least 13 to 15 would be a safer target before you begin to initiate buprenorphine, and that it would avoid precipitating withdrawal if you make sure that the cow score is in the moderate range or higher. You can rapidly escalate the dose to at least 12 milligrams if needed by the end of day one. So these were our earlier recommendations. In the next couple of slides, I'll get to the sections on high-dose and low-dose protocols, which are the revised recommendations for induction. I also would mention home inductions. These were relatively infrequent five or ten years ago. Now they're becoming very common. And it's been our experience that home induction can be considered with almost any patient, particularly those who've had any prior experience taking buprenorphine. In this situation, we would recommend a rapid induction to medications. That should be a high priority. You would continue with weekly office visits as possible until the patient is stable in treatment. So you would see them at home or send them home, maintain telephone contact with them over the next couple of days, see them back in your office weekly until their treatment, and in the meantime, continue monitoring with telephone calls. Many practices are using home inductions in the pandemic, and they have found that they work extremely well. I think over the last ten years, the patient population has become much more familiar with using buprenorphine, so patients are relatively experienced on how the drug works, and you need, of course, to review the issues of precipitated withdrawal and how to take buprenorphine correctly, but patients generally are not naive about buprenorphine, so it's easier to proceed with a home induction. We'll now get to the procedures for high-dose and low-dose initiation. This has probably been the most radical change in induction procedures in the last few years. Low-dose induction, or something that is called microdosing, was first developed in Bern, Switzerland, in 2010. It's sometimes referred to as the Bernese method. It's initiation of low-dose methadone while the patient is still using opioids or the dose of a full agonist, so the patient really does not have to experience withdrawal, and it can be a way of switching them from their street drugs or prescribed pharmaceuticals on to buprenorphine without requiring that they go through withdrawal. It's accomplished by a gradual increase of buprenorphine starting at a very low dose, and I'll give you more details on that in a second. Once you have a sufficient accumulation, usually by the seventh day in most protocols, you can switch to buprenorphine just in the standard dosing mechanism, starting with BID dosing, and you can stop all the illicit or other prescribed opioids. Now, this is an example of European protocols. They are available to clinicians in Europe, and they have lower doses of buprenorphine tablets available or sublingual tablets available, so you can see they're able to start with a 0.2-milligram tablet on one day, repeat that the second day, go to 2.8 tablets the third day, 4.8 the fourth day, the fifth day up to 5 milligrams, up to 7 milligrams, then 8 milligrams for two days, the seventh and eighth day, and then on the ninth day they're up to 12 milligrams. So we see a rapid increase of buprenorphine over a 12-day period, and here the patients were using heroin, and you can see that they continued using the heroin they were on for the first two days, then they were asking the patients to reduce the heroin they were using, getting that down to 0.5 milligrams a day by the fifth day, and then stopping it completely. So what you've basically done is start with a low dose of buprenorphine, increase it rapidly to a 12-milligram dose at the end of nine days, and at the same time reduce heroin gradually over a five-day period, and then stop the heroin. And with this method they described no particular problem with withdrawal symptoms. So this is a very effective way to initiate buprenorphine. Now this is a U.S. protocol because in this country we do not have the pharmaceutical availability of such a low dose of buprenorphine, and here they were using film strips, and people have either done initiations of taking these sublingual tablets and splitting them into small pieces, which may be a little bit more difficult to do, or using the smallest film strip available and cutting that into thirds or quarters. But the effort was to begin with 0.5 milligrams once a day, and then go to 0.5 twice a day, then 1 milligram a day, then 2 milligrams a day, and then 3 milligrams, 4 milligrams, and up to 12 milligrams by day seven. Here the fentanyl was being used. Now SAMHSA does not endorse telling a patient to keep using fentanyl, but this is what clinicians were seeing, that if the patient continued using their street drugs for several days, they were able to do that. At this point, where you're getting to a full buprenorphine dose, they can stop the heroin or fentanyl, and they should not experience withdrawal symptoms. Now this slide describes high dose or macro dosing. This procedure has become very common in the last year. It's primarily used in emergency rooms, so it's not done in a private office setting, at least the bulk of experience looking at it has been the induction of patients in the emergency room in hospitals that are well prepared to deal with opiate-related problems. You give a large dose of buprenorphine, larger than you would use in conventional dosing, often beginning at 4 milligrams, rapidly going to 16, or even in some cases beginning with 16 milligrams. Rapid increase of the dose is the T, is the target. In some cases, the target dose is 24 milligrams. In other situations, it's been as high as 32 milligrams or higher. I would have to say with both the micro dosing protocols and the macro dosing protocols, there is no one standard protocol that is accepted. Nothing has been officially endorsed by SAMHSA or the FDA. We're describing here what people have done in a variety of settings using a variety of protocols. The success that people are reporting suggests that there's a lot more flexibility in this process of both high-dose and macro dosing and low-dose initiation than we initially thought. The only caveat that I'm aware of regarding high-dose initiation is that it does not appear to work well with patients who have been consistently using methadone. I would not use this with any patient on methadone that you are attempting to use to switch to buprenorphine, but they would be a candidate for a micro dosing initiation, as I described previously. This slide just shows you some other protocols for the emergency room algorithm. This was one study where they aimed at trying to get patients treated in the emergency room. They looked for the presence of at least a cows higher than eight if the cows were lower than eight, they did not attempt initiation. If it was higher than eight, they separated the group into standard induction protocols versus the high-dose induction protocols. They observed the patients, they repeated doses if they needed to, and they were able to successfully treat most of the patients. The second box on the slide here just shows you the dose ranges that were used by advanced practice practitioners and physicians. Seemingly a little bit more enthusiasm with the advanced practice prescribers compared to the physicians, but it was acceptable in both groups. This study was done in emergency rooms that were inducing patients and had experience using these protocols to induce people rapidly. A total of 1,200 patients with opiate use disorder and a cows greater than four were seen in 28 different emergency departments over a two-year period. Almost 70% of this population had urine drug screens that were positive for fentanyl. So by and large, we're talking about treating a patient group with a very serious severe opiate use disorder problem. In this study, the patients were randomized to either a sublingual buprenorphine initiation. If the cows was greater than eight, they usually began with eight milligrams of lingual buprenorphine and discharged them that day with 16 milligrams a day. If the cows was lower, that is in the four to seven range, they were given a home induction. They were told how to handle it. They were instructed to get the dose ingested up to 12 milligrams the first day and then go to 16 milligrams. This was compared to a group with a seven day induction or with the sub cue injection of buprenorphine of 24 milligrams. What they were looking at was how could this sub cue induction versus the sublingual induction work with patients seen in the emergency room with severe withdrawal symptoms. And their concern was if you try to rapidly increase buprenorphine and get patients stabilized in this circumstance, would you run the risk of precipitated withdrawal if the patients had high evidences withdrawal scores? These were the outcome of those 1200 patients. There were only nine patients less than 1% who had precipitated withdrawal. All of these patients were using fentanyl. The way they ingested the fentanyl varied. Three were intranasal. Three were smoking. Three were IV. The baseline cows in these patients ranged from eight to 29. Peak cows was seen within 20 minutes to 120 minutes. But all the patients were successfully treated and were discharged from the emergency room in less than 24 hours. So even if precipitated withdrawal occurred, which was extremely rare, all these patients could be treated successfully and discharged within 24 hours. So this is very positive news. I think people have been very reluctant to try to initiate buprenorphine in patients using fentanyl or highly addicted patients. And the fear was that precipitated withdrawal would be a common occurrence. But this data shows that precipitated withdrawal is very rare and that it can be managed well. Now, this slide is going to compare different protocols for buprenorphine initiation. I have to thank Dr. Basaga for sharing this data. First of all, we see the traditional dosing here, but what I described is more a low-dosing protocol. Here we see patients getting symptomatic treatment, that is, non-opioid treatment. The patient was on fentanyl. They stopped the fentanyl. They went two days without any medications other than the symptomatic drugs. And then they, using the low-dose protocols, rapidly increased buprenorphine from a very low dose over the next two days into a therapeutic dose of 16 milligrams a day. This visually describes a high-dose mechanism here. We begin with the patients on fentanyl. They're getting that for the last day. There's a 24-hour period where they get no medications. And then on the next day, they are started with a high-dose protocol onto buprenorphine, so they're very rapidly increased up to a therapeutic buprenorphine dose. And they may get symptomatic medications at the same time, but it permitted these patients to, within two days, get to a therapeutic dose of buprenorphine. And lastly, this is a crossover technique, also using microdosing. Here you can see the patient remained on fentanyl, and they've gone for six days taking their fentanyl. Buprenorphine was begun with a very, very low dose, but rapidly increased to a therapeutic range within seven days. So I'm showing you here three different protocols that would permit the transition from fentanyl to buprenorphine, either very rapidly, a little bit longer in this protocol, and longer in this protocol, but all of them really should have minimal problems with opioid withdrawal. Now I want to talk about protocols or recommendations for patients who are on prescribed drugs, and we have to make transitions to buprenorphine. The traditional recommendations for patients on methadone was that you taper their methadone dose down to 30 milligrams a day, that you stop that. One mechanism was to have them stop that on a Friday, no dose on Saturday or Sunday, begin the buprenorphine on Monday. With the low-dose technique, the protocols have been very different. Some of them have tried to reduce buprenorphine. Some of them left buprenorphine to higher ranges of around 100. I would not recommend attempting anything like this on patients who were anything higher than 60 milligrams, but it would enable you to keep the patient on their dose. You're using the transdermal patch or the sublingual formulation. I would note here the transdermal patch is approved by the FDA in the U.S. for treating pain problems. It is not approved for treating opiate use disorders, so there are issues with whether you can use the transdermal patch since it does not have FDA approval for doing it. In either situation, the patient is not subjected to a tapering dose or opiate withdrawal, and there's decreased risk of withdrawal in this process. However, there's no general agreement on the protocols. This is one sample protocol using the transdermal patch. Again, I note it's not approved by the FDA for this use, but in this model, patients received 20-microgram patch. One patch was applied, which lasted for two days. They were at 100% of their methadone dose. On day three, they were given two patches. Their methadone dose was cut to 60 milligrams. On day five, they were increased to three patches and got 30 milligram doses, 33% of their methadone dose. And then on day seven, they were switched to sublingual buprenorphine in the range of 8 to 16 milligrams, and the methadone was stopped completely. I would refer you to this article for references given at the end of this talk for more details, but it would permit you to transition patients from a higher methadone dose to buprenorphine using this process. I'd also like to speak about extended release naltrexone or Vivitrol. This is a long-acting injectable formulation. It was approved by the FDA in 2010. Patients are given an injection of 380 milligrams every 28 days. NIDA funded the XBOT study to demonstrate the compatibility and efficacy between sublingual buprenorphine and the injectable buprenorphine. It was an open-label randomized controlled trial. The issue in the trial was that about 25% of the patients dropped out of the study who were in the extended release naltrexone arm. So the concern when you looked at the data, the extended release naltrexone clearly did not work as well as the buprenorphine. But when you looked at the patient groups who actually got onto naltrexone and got onto buprenorphine, you can see that once the patients were on either of those drugs, the outcome was fairly similar. Both safety issues were fairly similar and retention for the study itself was fairly similar. So I think the takeaway from this is that extended release naltrexone can be an effective treatment for opiate use disorder if the patient can get onto the medication. So the problem is initiating the medication. But there's also a problem in retention. Extended release naltrexone works well, but you have to continue taking the drugs. And the way it's used in the United States at present, for reasons that are not totally clear, the average use is only about two months. I think this audience is well aware that two months is generally accepted as an ineffective period for treating opiate use disorder. So it's, I think, something we need to work with as a group of clinicians to try and understand why patients are not continuing on the drug and looking at what we can do to increase their retention. The retention data in general shows that the drug that is most effective at retaining patients is methadone. Buprenorphine is successful, but not as good as methadone. And extended release naltrexone is the least successful of the group. Interestingly enough, better retention has been associated with patients with psychiatric comorbidity, patients who are monitored closely, white patients, and patients who participate in counseling and NA or AA. So I think here the take home is that patients stay with the medication and do better if they're given ancillary services. And if you're treating their psychiatric comorbidity. The drug by itself is not as likely to be successful. Now another slide by Dr. Basaga showing some of this data. This slide compares the initiation of naltrexone. There are two phases of treatment, the withdrawal treatment and then naltrexone induction. As I mentioned earlier, current FDA approved method involves a seven day washout period between the two phases of treatment. That is there's seven days of no medication between the last day of the opioid and the first day of naltrexone. This has proved to be a difficult process for many patients. And that leads us to these other options that are described below. This first slide shows the FDA recommended initial approach. That is they stay on buprenorphine. They stop their buprenorphine. They go seven days without any medication. And then you begin the naltrexone. What Dr. Basaga has proposed, one initial model was you taper them off the buprenorphine. So you're getting buprenorphine, then you go for seven days with a combination of clonidine and benzodiazepines. You wait a day with no medication and then you begin the naltrexone. So here you provide the requisite seven days without any opioids, but you're providing supplemental treatment to ease the withdrawal symptoms that the patient will be experiencing. And lastly, we're looking at this alternative protocol. Here we're seeing one day of buprenorphine followed by six days of the medications of clonidine and benzodiazepine. But instead of waiting to begin the naltrexone later, you begin with microdosing of naltrexone. So you begin very low doses of naltrexone. You rapidly increase that over six days so that by the end of that six-day period, you've reached a full blocking dose of naltrexone. So the models in this area avoid putting the patient through long periods of withdrawal and avoid patient dropout. So I would expect that we should watch for continued protocols for beginning naltrexone to avoid the need for extended periods of withdrawal. Now, I want to finish our discussions today by focusing on more current management of acute and chronic pain. How do we handle acute pain in patients who are being maintained on buprenorphine? Buprenorphine is thought to block the opioid receptor. And the understanding in the beginning was that you could not use other opioids because a buprenorphine would block the use of those drugs. It's turned out that that was an inadequate understanding of the pharmacology of the situation. And the initial perception was that it would be very hard to provide analgesia for buprenorphine patients. So what people were initially were recommending that a non-opioid alternative be a first line for pain management during this period because you would run into difficulty with full agonists. With moderate pain, it was suggested that patients take their buprenorphine but divide it up into multiple doses given every six to eight hours. And if that is inadequate, you can add a short-acting opioid agonist or a supplemental low dose of buprenorphine during the pain period. So we keep them on a divided dose. We supplement that a small amount and we manage the pain. Now, based on our original understanding of how buprenorphine worked, it was surprising that adding that short-acting agonist would be effective, but it turns out to be effective. However, I think there was a lot of concern about potential relapse if either you stopped the buprenorphine or you reduced it and were not providing adequate pain care. And there was some concern if you stopped the buprenorphine and then added short-term prescription of other opioids during this period that you simply would trigger a relapse. Now we've got protocols for handling severe acute pain in patients. These are patients on buprenorphine who end up in the hospital perhaps needing to undergo surgery or have had an accident and need treatment. There are multiple protocols available. There's no general consensus on the best approach, but I want to describe several things that have been done. I think the most important point is to avoid stopping the buprenorphine and avoid any periods with no medication. I think the biggest risk to the patient both in terms of relapse and poor pain management is stopping their medication. Most of these protocols now recommend that you continue the buprenorphine and in some cases increase it to handle the pain. In other cases, you cut it back to either 8 milligrams a day or 12 milligrams a day in divided doses and that you supplement that with a full agonist. It doesn't seem to matter too much which agonist you're using. It turns out that this combined dosing of both buprenorphine and the full agonist in this model works fairly well. If you have to, you can also use non-opioid analgesia such as regional blocks or NSAIDs. You can always argument dosing with short-acting opioids. You ought to make sure that they're receiving multidisciplinary treatment to handle their pain and that this is coordinated with their other providers. Now, what about patients who are on the subcutaneous buprenorphine? That is, they've been given their buprenorphine shot. It will be effective for the next several weeks, but they suddenly need surgery. If it's elective surgery, the recommendation has been to consider converting the patient from the subcutaneous buprenorphine to sublingual buprenorphine, and that be done about a month before the surgery. And then you could use the approaches that I described in the previous slide. For non-elective surgery, that is emergency surgery, you might rely on regional blocks or NSAIDs. For patients on buprenorphine that require higher doses, just understand that patients who've been maintained, and I would say this is true with methadone as well as buprenorphine, usually will require higher doses of opioids for pain management and not lower doses. Their doses for maintenance do not provide adequate analgesia, and particularly if they're getting their medication as a single daily dose, they do not get adequate coverage for analgesia for 24 hours. And lastly, a few comments about chronic pain patients. There's now clearly a reexamining of our management for chronic nonmalignant pain. It used to be that opioids were recommended for chronic use in these situations. The agreement now is that we generally would try to avoid opiates in these patients. If we do use opiates, we want a treatment agreement with the patient that only one physician and one pharmacy be involved, there be regular monitoring with urine toxic screens. The patient agrees to a pill count when asked, we monitor medication levels and they're frequent, that we monitor the use of refills and are careful about just not making it too easy for patients to get large supplies of drugs, that we make it too easy for patients to get large supplies of drugs with refills without being monitored, and that we include in the treatment agreement what violations or misuse of the medication will produce, and they're not going to be using alcohol or other medications or other drugs. We also understand at this point that chronic pain with significant opioid use disorder may do better on methadone if the pain is quite severe and long term. If more moderate pain is involved, it appears that they do well on buprenorphine, but that it has to be provided in divided doses. These are the references that I will put up for a second here so that people can see them and continue to look at them if there's any other information that they need. This finishes our section. Thank you very much for participating.

clinical use

buprenorphine

induction protocols

opioid withdrawal

transitioning protocols

pain management

extended-release naltrexone