This talk is going to focus on the primary issues related to the clinical use of buprenorphine that will cover induction, stabilization, maintenance, and withdrawal treatment. We'll begin by covering stabilization and maintenance. To find the dose when you induce someone on buprenorphine, you're looking for the dose that is going to avoid opiate withdrawal symptoms, that will help the patient reduce or stop the use of illicit opioids. The patient should experience no cravings and there should be minimal side effects. There are two questions that should be resolved before you begin treatment. You can do this in two ways. One of which is to write a prescription and give the patient the prescription, ask them to fill it, and bring it back to the office. The other is to maintain a supply of medication in the office and to use it for induction. If you decide to go with that option, you need to understand that you're going to be required to maintain records that can be reviewed by the state or federal authorities that cover how you store these drugs and how you administer and keep track of them. These records can be audited by the DEA. If you go with the second option, you will give the patient a prescription for the first day or two of their dosing. You're going to have the patient fill that and bring it back to the office. That means there may be some delay in starting the first day's dosing and there's a risk that the patient may not return with the prescription. That's very rare. I've had that happen once in 15 some years, so that's nothing I think you should be concerned about. I would strongly recommend that you begin the treatment on Monday or Tuesday, the beginning of the week, and start at the beginning of the day, so 8 or 9 o'clock in the morning is ideal. You want to really leave yourself enough time to see the patient multiple times. You should also consider whether the patient is appropriate for home induction. Patients who've been inducted on buprenorphine before and are familiar with how the drug works can often handle that at home with directions and monitoring by the physician. Many patients will have used buprenorphine on the street and are familiar with the drug and in some cases if they appear to be knowledgeable and responsible, home induction may also be an alternative to consider. It's important that the patient understand how to appropriately take a sublingual tablet. They need to be told to start with a moist mouth, not a dry mouth. They should avoid any acidic beverages, so no coffee or no fruit juices. Once the tablet is in their mouth, they don't talk. They need to keep it under the tongue until it is completely dissolved, and during that time they should not swallow any saliva, and until the tablet is completely dissolved, they can't really begin to swallow saliva again. You need to instruct the patient before you begin induction that it's very important that they arrive at the office in a state of mild opiate withdrawal. That is necessary before they can receive the first dose of buprenorphine. That's primarily to avoid precipitating withdrawal. That is really the only complicated issue around induction, and that's the key to successful induction. If the patient has been using short-acting opioids such as heroin, they should be instructed to wait 16 hours before they arrive for their induction. If they've been using long-acting opioid pharmaceuticals such as oxycontin or methadone, the directions are going to be different. For most opiate pharmaceuticals, 24 hours waiting before the induction will work. For methadone, which is a particularly long-acting drug, you want them to wait 36 hours before you begin induction. If someone has been on a methadone clinic and you're going to transfer them from methadone to buprenorphine, you need to work with the methadone clinic to have them gradually reduce their dose down to 30 milligrams of methadone a day. I would recommend that the patient stabilize on that dose for at least a week, if not two weeks. On the last day, I recommend that they cut that dose in half to 15 milligrams, so that's their last dose of methadone. The following day, they will receive no methadone. The day after that, they can arrive first thing in the morning, and almost always they will be in moderate withdrawal at that point, and you can begin induction at that point. When you do the induction, and before you start, you need to document their state of opiate withdrawal. The easiest way to do this is to use the COWS or the Clinical Opiate Withdrawal Scale. This slide shows you the items that are covered in the scale. Pulsing pulse, sweating, restlessness, pupil size, and various other symptoms that you're familiar with for opiate withdrawal. Each of these symptoms are scored. The items will be scored on a four to five point scale. What you're aiming for is mild opiate withdrawal. That patient should score somewhere between five and 12 on the COWS. Moderate withdrawal is 13 to 24, or moderately severe withdrawal 25 to 36, and over 36 is very severe. One caveat in some cases for patients who've been using potent long-acting opioids like fentanyl, we find that you may need to wait for a higher level of opiate withdrawal before you start, so look for withdrawal in the range of 13 to 15 on the COWS score. If the patient is not in opiate withdrawal when they arrived at the office, you need to carefully assess the last time that they used an opiate. You need to consider whether you're going to have them wait in the office, and that's why you want them to come early in the day, so that gives you maximum time to see them again and reassess them, or whether you're going to tell them to go home and come back and try again tomorrow. It's obvious that you should avoid that latter option, and if at all possible, have the patient wait long enough to see withdrawal so that you can begin induction that day. Your first dose is going to be two to four milligrams of buprenorphine naloxone. You want to monitor the patient in your hour for about an hour after that first dose. That does not mean they need to sit in your office with you during that time. They can certainly sit in the waiting room, and then you can reassess them an hour later. You want to see signs that you're seeing some relief of opiate withdrawal symptoms from the buprenorphine. That should begin to happen within 30 to 45 minutes after the first dose. You can re-dose again two to four hours later if opiate withdrawal symptoms subside and then become evident again. You're going to aim for a total dose of eight milligrams that first day, and you'll probably send the patient home with a small supply of medication. You may instruct the patient to take another two milligram tablet later in the evening if the symptoms return, or if they wake up early at night with significant symptoms, it's OK to take another two milligrams. One thing you're going to be concerned about, though, is precipitated opiate withdrawal. This happens if there's still significant opioids in the system, and they get their first dose of buprenorphine, and you really precipitate a severe syndrome. The severity of opiate precipitated withdrawal is going to be worse for one to four hours after the dose, and then it will begin to decrease. What do you do if the patient has precipitated opiate withdrawal? There are a couple of options. One approach is to give additional doses of buprenorphine and attempt to override using the agonist effect of buprenorphine to suppress the withdrawal symptoms. The other option is to simply stop induction at that point, give symptomatic medication for withdrawal symptoms, and then tell the patient to return the next day. We strongly recommend that you follow the first option. There's always a risk that if you send the patient home and they're still feeling sick, they're likely to use, or they may just decide not to return because of a negative experience. You really want to have the patient feeling better before you send them home that first day. Now what about day two for opioid induction? Ideally, you would like to have the patient return to your office so you can assess exactly what's happened. You want to make sure that you've controlled their symptoms, but you also want to find out whether they used any opiates after the induction and whether they have any more significant symptoms of opiate withdrawal. You're going to adjust the dose accordingly. If they're still having opiate withdrawal symptoms or significant craving, you're going to increase the dose. In the rare circumstances that the patient may seem sedated or overly medicated, you may want to adjust the dose down. You will continue adjusting the dose in two to four milligrams until you've reached a target dose of 12 to 16 milligrams by the end of day two. And in most cases, at that point, you have really completed the induction phase of treatment. You should be familiar with the various formulations in generic tablets, the formulation doses for the suboxone film, or the News Upsolve tablets. You can refer to this chart so that you know what the equivalent doses are of these different formulations. So what happens after day two? You may have patients who will request increased doses three or four days after beginning induction. It's not necessary to do that quickly. Buprenorphine has a long half-life. The drug will accumulate over the next several days, and it may be four or five days after initial dosing before you see the full effect of the original dose. Most patients, as I said before, are going to stabilize between 12 and 16 milligrams, and you may just have to wait until they see the full benefit of that dose and realize that they are comfortable with that dose. If you've waited seven days, the patient is still uncomfortable and still has craving, then you may want to consider increasing the dose. Any time you increase the dose, I would do a modest two milligram increase and then wait another four to five days to see how the patient reacts. The standard dose range approved by the FDA is eight to 24 milligrams. There have been reported experience with doses as high as 32 milligrams, but it is unlikely that most patients will require a dose in that range. Now to give you some examples of another model for induction. These are patients who are not currently physically dependent and therefore are not going to show any signs of opiate withdrawal. So who would these individuals be? These are patients who have a history of opiate use disorder, but now are at high risk for starting or relapse again. This might be someone who's been in jail for several months, so they're now returning to the community and are at high risk for relapse. This may also be someone who's been on buprenorphine and was tapered off, and now they're starting to use again, or they have really intense craving and they decide that they want to continue on treatment. If someone has used once or twice in the last week, you don't really want to send them home and tell them to wait until they're really fully dependent and return then for induction. That person is not currently physically dependent, but is perfectly appropriate for reinduction on buprenorphine because they still meet DSM-5 criteria for opiate use disorder. So how do you proceed with this patient? You begin with a two milligram dose, and that's probably the only amount you're going to need to use on that first day. You will monitor them for an hour or two after that dose just to see how they react to it, and then tell them to come back. Over the next several days, you're probably going to increase the dose by about two milligrams a day. You may wait a day or two in between doses. That depends on how much craving the patient has and how much risk they are, because still at a low dose like that, they may be at risk for using. But you go up slowly. I would aim for at least a minimum of eight milligram dose. And depending on the patient's history and situation, you may want to gradually increase them back to the dose range of 12 to 16 milligrams. But you go slowly. There's no need to rush up, and if the patient has no existing tolerance, going too quickly may have them overly sedated and may not be appropriate. So what happens after you've achieved the initial dose that controls withdrawal symptoms and manages the patient? We're now at the stabilization phase. You can expect, as I said, that the dose is probably going to be somewhere between eight to 24 milligrams. Most patients are not going to require more than 16 milligrams a day. If patients are taking higher doses, you may be prescribing two or three pills for them to take in the beginning of each day. It's important to instruct them to take these pills sequentially and not all at one time. Absorption is poor if there are multiple tablets in the mouth and under the tongue. So you instruct the patient to wait until the first tablet is dissolved and then take the next tablet. You also might consider alternative dosing. If a patient has a long half-life, it's certainly possible to adequately dose patients with doses on Monday, Wednesday, Friday, or Monday and Thursday, for example. This pattern is probably not reasonable for most patients in regular outpatient therapy. Clinically, I think it's better for the patients to take a dose every day. I think you may be setting yourself up for problems if the patients have to decide on any given day whether this is the day they take meds or not. It may be too easy for them to skip a dose and then move in the direction of having too low a dose, which may make it possible for them to use opiates on top of the buprenorphine or set themselves up for relapse. The only time where this actually makes a lot of sense are for patients who are being treated within a methadone maintenance program. And in that situation, they may be coming to the clinic every day to pick up their buprenorphine. So if they're on a Monday, Wednesday, Friday schedule, that means they only have to come to the clinic three days a week. So that's much more convenient for the patient. And pharmacologically, that dosing pattern is adequate to control their opiate withdrawal symptoms. Now buprenorphine can also be used for medication withdrawal from opiates. The research on this topic is considerably less than the research that's available on long-term maintenance treatment. So I think we're looking at some protocols. We don't have a lot of information as to the ideal protocol. We are using a lot of the information we've gained from methadone withdrawal protocols. And there are some studies that have generally indicated that withdrawal from buprenorphine is less intense than withdrawal from methadone and more comfortable for the patient. The patients need to understand that they will have withdrawal symptoms. And in some cases, they may be extremely uncomfortable. Now this is one protocol for a very rapid medication withdrawal done over three days. Here you induce the patient as you would if you were starting longer-term treatment. So you're aiming to get an 8 to 12 milligrams a day the first day. The second day, you repeat that dose or stabilize the dose at 12 milligrams. And then on the third day, you're going to cut that dose in half. And then that's the last dose. So you've completed the withdrawal and the patient has now finished the treatment. We do not recommend this rapid detox. We don't recommend withdrawal treatment in general because the rates for relapse are very high within this patient group. What about a more extended withdrawal? In many cases, people have recommended anything from 4 to 30 days. There are few studies that have looked at this approach. We do know that this is effective in reducing withdrawal symptoms. We know that using buprenorphine this way is more effective than clonidine over the same period. But the long-term efficacy is not known. And particularly, there's no evidence that a slow taper like this guarantees that the patient is going to remain drug-free once you have completed the treatment. This is a protocol that was developed by the National Institute of Drug Abuse Clinical Trials Network. It spreads dosing over 13 days. You can see that over the first three days, the doses gradually increased up until 16. And then it's tapered off slowly over the rest of the period. Again, this is just one model for a slightly longer taper schedule. What about withdrawal that goes beyond 30 days? This is not a well-studied topic. We know from our experience with methadone that very slow protracted withdrawals will work. And in some cases, patients do better because you're able to do it with very minimal withdrawal symptoms. But the literature is fairly scarce. You can taper more slowly until you get, or rather, you can taper a little bit more rapidly until you get to 8 milligrams. But at that point, we would recommend that you go much more slowly with the taper. And the lower you go, the lower the dose, you can still have significant withdrawal symptoms even if you're going from 2 milligrams to 1 milligram or to 0. So in summary, when you're starting to do buprenorphine treatment, you need to consider your office logistics. And that primarily has to do with whether you're going to store the medication in your office or whether you're going to send the patient to a pharmacy with a prescription. We recommend the latter. At the current time, most pharmacies stock buprenorphine, so patients should not have any difficulty having that prescription filled. You want to instruct the patient carefully so that they arrive in the office in moderate to mild opiate withdrawal. And that's the key to making sure you don't precipitate withdrawal with the first dose. You want to be doubly sure by measuring the cows. You want to document that in the medical records so it's clear that the patient was in withdrawal and that you've measured it. You're aiming for a score on the cows of 8 to 10 before you give the first dose of buprenorphine. And it's very important to keep the patient in your office after that first dose to evaluate how they have responded to treatment. As we mentioned towards the end of this talk, buprenorphine is used for more rapid withdrawal from opiates. The ideal protocols are not well established. The long-term outcome for such taper and withdrawal is also not well documented. But it probably will work best if you conduct withdrawal over longer periods rather than shorter periods. Thank you.

clinical use

buprenorphine

induction

stabilization

maintenance

withdrawal treatment