CATR: Dr. Capurso, given your role as an expert on various things related to addiction and the editor-in-chief of The Carlat Addiction Treatment Report, we’ve had several discussions about buprenorphine treatment. To begin with the basics, why use buprenorphine at all?
Dr. Capurso: Buprenorphine binds to the mu-opioid receptor, the very same receptor bound by commonly misused opioids. As a partial agonist, it can provide enough agonism to prevent craving and withdrawal but does so with a much lower risk of overdose. The effects of partial agonists plateau at high doses, which is what provides a higher safety margin. We call this a “ceiling effect.” Another property of buprenorphine that makes it helpful is its long half-life. Drugs that take effect quickly and leave the body quickly, what I like to call “quick on, quick off,” tend to be more reinforcing of addiction behavior. Buprenorphine’s long half-life prevents cycles of intoxication, withdrawal, craving, and return to use. A single dose can prevent withdrawal and cravings for an entire day, or even several days, so patients usually just take it as a daily medication. It’s a “slow on, slow off” medication, though not as “slow off” as methadone.

CATR: And how does it compare to methadone?
Dr. Capurso: Both are highly effective treatments for opioid use disorder. Pharmacologically, the difference is that buprenorphine is a partial agonist while methadone is a full agonist. This means methadone does not have the same “ceiling effect” and is therefore not as safe in terms of overdose. In fact, there are some data to suggest that overdose risk actually goes up for a few weeks after methadone is started, likely because its long half-life requires some time to titrate up to an effective dose (Kelty E et al, Am J Drug Alcohol Abuse 2019;45(3):285–291).

CATR: If buprenorphine and methadone are binding the same receptor, aren’t we just substituting one addiction for another?
Dr. Capurso: No, but this is a reasonable question and one that patients ask all the time, so it’s important to address. Illicit opioid use is associated with the DSM’s criteria for substance use disorder: disrupted social relationships, use in hazardous situations, giving up activities, etc. This is what we think of when we think of addiction—substance use being harmful to your body and your ability to live life. But medication for opioid use disorder (MOUD) is all about preventing these detrimental outcomes. Other than tolerance and withdrawal, which is a purely physiologic phenomenon, these medications allow people to live lives in which substances are not getting in the way of relationships, employment, or activities. These are medications prescribed by professionals; they are much safer than anything bought off the street from a drug dealer. I tell patients about a famous study that followed a group of young men with opioid addiction, average age 25. After 33 years, more than half were dead or incarcerated, and more than one in 10 were totally lost to follow-up (Hser YI et al, Arch Gen Psychiatry 2001;58(5):503–508). Those are terrible statistics. Outcomes for patients on MOUD are much better than that.

CATR: What kind of outcomes are you talking about here?
Dr. Capurso: Well, I think the most important outcome is mortality, and we have very good data to show that MOUD saves lives (Pearce LA et al, BMJ 2020;368:m772). MOUD also retains patients in treatment, decreases illicit opioid use, reduces criminal activity, and decreases incidence of HIV and hepatitis C (www.tinyurl.com/9n28w5am).

CATR: OK, so we have this great medication: buprenorphine. Why do we need extra training and a special DEA waiver to be allowed to prescribe it, and why are there federal laws dictating the numbers of patients that can be treated?
Dr. Capurso: The answer has very little to do with pharmacology. At the end of the day, buprenorphine is much safer than many of the other medications that have no special requirements or training for prescribers. The requirements for buprenorphine prescribing are the result of a legislative fight that occurred between the FDA and DEA when buprenorphine was first approved. The FDA tried to regulate buprenorphine as a medication, while the DEA worried it could become the next big street drug. Their compromise was the cumbersome legislation that we have today, though it has been adjusted several times since then. It’s certainly true that buprenorphine can be diverted, but most of the buprenorphine that winds up on the street is taken to avoid withdrawal or maintain abstinence rather than to get high (Cicero TJ et al, Drug Alcohol Depend 2018;193:117–123). In my opinion, it’s an example of legislative stigmatization of addiction. I recommend an episode of the podcast Planet Money that dives into this further: www.tinyurl.com/xawawae9.

CATR: Is that why buprenorphine comes packaged with naloxone?
Dr. Capurso: Yes, exactly. The naloxone prevents misuse through injection. Pure buprenorphine (Subutex) should be reserved for pregnant patients or those with adverse reactions to naloxone.

CATR: Many providers find prescribing buprenorphine intimidating. The process of starting it even has a special name, “induction.” Why is it tricky to start buprenorphine?
Dr. Capurso: The trickiness comes from two of its pharmacological properties: the high receptor affinity and the partial agonism. Let’s say a patient who’s recently used heroin comes into your office. Their opioid receptors are occupied by morphine molecules (remember that heroin is a morphine prodrug), which are sending full agonist signals. If your patient immediately takes buprenorphine, it will kick the morphine off the receptor since buprenorphine has a much higher affinity for opioid receptors than morphine.

CATR: So now you have one opioid that is replacing another opioid on the receptor. What’s the big deal? Either way, their opioid receptors are being activated, right?
Dr. Capurso: Not exactly. The buprenorphine is not a full agonist, but rather a partial agonist, and therefore those opioid receptors will suddenly be sending much less of a signal. The result is instant opioid withdrawal and all the discomforts that go along with that. That’s called precipitated withdrawal. The way around this is for your patient to wait long enough since their last heroin use to have some mild to moderate withdrawal symptoms. Patients will be very familiar with these symptoms—things like runny nose, chills, anxiety, craving. These can be measured with the Clinical Opiate Withdrawal Scale (COWS). I usually administer buprenorphine once the patient reaches a COWS of 8 or more. One sign I like to look for is pupil size; dilated pupils usually mean that the patient is ready for a dose of buprenorphine.

CATR: What you’re describing is what happens in a clinic or emergency room. These days, a lot of inductions are happening at home, are they not?
Dr. Capurso: They are. We don’t have numbers of how many in-office inductions are done versus at home, but home inductions are becoming more and more common. Personally, I’ve had many patients with successful home inductions, and studies show they work just as well as in-office inductions (Lee JD et al, J Gen Intern Med 2009;24(2):226–232).

CATR: How do you determine if a patient is a candidate for home versus in-office induction?
Dr. Capurso: The first distinction is whether the patient presents in withdrawal or not. If the person shows up to the office already withdrawing, they are a good candidate for an in-office induction; you’re able to give the medication, see the response, and monitor. This is a common scenario in an emergency room. But it’s pretty rare that someone walks into an outpatient clinic in the throes of withdrawal. Usually they say, “I used a few hours ago and I’ll likely go into withdrawal in 12 to 24 hours.” Well, maybe the clinic won’t be open then, or maybe the patient won’t be able to come back, or maybe they have every intention of coming back, but they end up using again in the meantime. The patient is in the clinic now, so you should try to seize the opportunity and engage them in treatment. This is a perfect time for a home induction.

CATR: What are the differences between in-office and home induction?
Dr. Capurso: At the end of the day, there actually aren’t many differences. The dosing strategies are the same. I’ll run through the nuts and bolts of buprenorphine induction, then point out some considerations for when it’s done at home. The induction protocol is laid out nicely in the Substance Abuse and Mental Health Services Administration’s Treatment Improvement Protocol series, which is a great free resource that I highly recommend (www.ncbi.nlm.nih.gov/books/NBK82999/). As we discussed, the first buprenorphine dose should be taken once the patient is in mild to moderate withdrawal. I recommend a first dose of 2 mg for a patient using small amounts of opioids, or 4 mg for patients using large amounts of opioids, such as a bundle or more of heroin daily (which is the equivalent of 10 bags or approximately half a gram). Doses can be repeated every 1–2 hours for a total of 8 mg in the first 24 hours. On rare occasions, a patient might require 12 mg. The dose can be increased to a total of 16 mg on day 2 (spaced throughout the day) and up to 24 mg on day 3.

CATR: It’s the same dosing whether the patient is in the office or at home, correct?
Dr. Capurso: Yes, that’s right. In the clinic, the severity of withdrawal is determined with COWS, and the timing of the first buprenorphine dose is up to the prescriber or nurse. At home, the patient decides when to take the first dose. For home inductions, I review the symptoms of opioid withdrawal with the patient and then provide them with a Subjective Opiate Withdrawal Scale (SOWS) printout, which is available for free online (www.tinyurl.com/7s9d77km). The SOWS is very similar to the COWS and allows patients to give their withdrawal severity a score. I tell them to take a 2–4 mg dose once their symptoms cross into the “moderate” category. They should start feeling relief pretty quickly. I tell them, “You’ll start feeling better in 15 minutes or so. After an hour, if you’re still feeling uncomfortable and your score on the SOWS is 10 or more, take a second dose.”

CATR: Do patients who are withdrawing actually fill out the SOWS? I’d be nervous that someone with free access to buprenorphine would take it too early, throw themselves into withdrawal, and make things a whole lot worse.
Dr. Capurso: That’s actually pretty rare. I say, “The longer you wait, the better your relationship with this medication is going to be.” Whether patients actually fill out the SOWS is variable. Honestly, most patients have experienced withdrawal, and many have taken buprenorphine, either from the street or prescribed. Many patients know what it feels like when it is safe for them to take buprenorphine, and for these patients I don’t worry too much about the exact SOWS score. And for our more tech-savvy patients, the Buprenorphine Home Induction app can be helpful (available through Apple App Store and Google Play).

CATR: OK, you’ve walked us through the first 24 hours. Now what?
Dr. Capurso: Whatever amount patients took on the first day, I have them take that same amount when they wake up on day two. It’s repetitive after that—wait a few hours, take another 2–4 mg if still in withdrawal, and repeat up to a total of 16 mg. Then the whole thing again, for the third 24 hours, with a total up to 24 mg. I should mention that there are other approaches being developed called “microdosing” or “microinduction.” These strategies are not standard practice, but preliminary studies are encouraging (Editor’s note: See our research update “Buprenorphine Induction Without Withdrawal” on page 8).

CATR: And what guides dosing? Do you have a preset target, or are you just going symptomatically?
Dr. Capurso: Dosing is guided by symptoms, but the symptoms you are treating depends on the patient’s goals. Do they want ongoing buprenorphine treatment or just a detoxification? I always strongly recommend ongoing buprenorphine treatment. Detoxification is not adequate addiction treatment, and patients need to understand this. Nonetheless, if the patient insists on just a detox, your target is to minimize physiologic symptoms—diarrhea, rhinorrhea, aches, nausea, etc—and 8 mg of buprenorphine is usually enough to treat these symptoms. The dose is then tapered over a few days. For ongoing treatment, the target is to minimize opioid cravings, which requires higher doses of buprenorphine—usually 16 mg or above (Mattick RP et al, Cochrane Database Syst Rev 2014;2:CD002207). So if a patient is interested in long-term treatment, I recommend at least 16 mg daily initially. Cravings are a moving target, especially at first. I want to aggressively treat cravings because the early period has the highest risk of returning to use. So I tell patients, “If you are feeling cravings, it’s OK to take an extra 4 mg; just keep track of how much you take.”

CATR: Are there any other differences to keep in mind between home and in-office induction?
Dr. Capurso: Only one. There are two general approaches to detoxification: 1) using an opioid like buprenorphine or methadone, and 2) symptomatic treatment with clonidine, dicyclomine, loperamide, etc. In an office setting, I advocate for not mixing the two. If you’re using buprenorphine, for example, you should give that for withdrawal symptoms—giving clonidine is just going to muddy the waters. But with home inductions, I’m a little less dogmatic. I recommend taking buprenorphine at the doses we discussed, but if patients are still feeling breakthrough symptoms, there is no harm in providing a little ondansetron, loperamide, or clonidine.

CATR: What about follow-up? How often to do you see home induction patients?
Dr. Capurso: For the first few days, you’d ideally see the patient daily, or at least have a phone call with them. Sometimes that’s not possible, so you can go two or even three days, though I don’t like doing that. For patients starting ­ongoing treatment, once the dose is stable, I see them weekly for a few weeks. As long as they are doing OK, meaning showing up to appointments, having negative urine drug screens, and taking the medication as prescribed, I’ll space them out to every two weeks, and then monthly. That’s pretty standard.

CATR: We’ve covered how to prescribe buprenorphine—what else should providers be thinking about?
Dr. Capurso: Buprenorphine is just one piece of the puzzle. Granted, it’s the most important piece—treatment plans that don’t incorporate MOUD don’t have good outcomes. But these encounters are also an opportunity for psychoeducation and motivational interviewing. I always try to work in some basic behavioral strategies like deleting drug dealers’ numbers, getting rid of any drugs in the house, avoiding the “people, places, and things” that can lead to drug use. And I recommend using harm reduction strategies (see CATR January/February 2020): prescribe naloxone, offer testing for HIV and hepatitis, refer to primary care if they don’t have a PCP, or refer to case management services if that’s an option. Some of these patients might benefit from a referral to therapy for comorbid mental health issues; others might benefit from apps such as reSET-O (see CATR November/December 2020). For many of these patients, especially ones just receiving withdrawal management, your visit might be one of their very few encounters with the health care system. Make it count.

CATR: Thank you for your time, Dr. Capurso.