CATR: We’ve got methadone, buprenorphine, and naltrexone; all treat opioid use disorder (OUD) but have opposing mechanisms of action. How does that work?

Dr. Hermes: It’s a big and important question that’s about opioid receptors themselves and their role in regulating responses to reward. Normally, we can balance underlying hedonic responses emerging from our limbic system with our executive function. But long-term opioid use upends that capacity. Remember, opioid receptors are fundamental in regulating so many physical functions throughout our body, as well as mood, affect, and cognition. This complexity of action means that thinking of these medications as either turning on or shutting off the opioid system is overly simplistic. We don’t fully understand all the interconnections. The different mechanisms of action may mean that the subjective experience of taking these medications is quite different. But the overall goal remains the same: to decrease cravings and overwhelming euphoric effects, reduce withdrawal risk, reduce adverse health consequences, and most fundamentally keep people alive.

CATR: Let’s quickly review the evidence, starting with methadone.

Dr. Hermes: Treatment of OUD with methadone started in 1947, so it’s by far the most established. There was a 1965 JAMA study that was really a watershed moment in the history of the field (Dole VP and Nyswander M, JAMA 1965;193:646–650). But since then, there have been a lot of studies supporting its use, notably a 2009 Cochrane review showing that patients taking methadone had 33% fewer opioid-positive drug tests and were over four times more likely to stay in treatment compared to controls (Mattick RP et al, Cochrane Database Syst Rev 2009;2009(3):CD002209). So, methadone treatment significantly improves outcomes in the context of counseling or not. There’s a huge evidence base when it comes to methadone, so I’m really just glossing over it. I’d point readers to the National Institute on Drug Abuse website, which I have drawn on routinely—it reviews the evidence for each of these drugs in much more detail (www.tinyurl.com/5n7zv36p).

CATR: And buprenorphine?

Dr. Hermes: Buprenorphine is a partial opioid agonist that came onto the market in 2002 and is currently available in a couple of forms, including a monthly injection (Editor’s note: See CATR Jul/Aug 2020 for more about buprenorphine formulations and CATR Jan/Feb/Mar 2023 for more about the long-acting injection). We have a lot of evidence for buprenorphine, though not quite as much as with methadone. We’ve seen that patients on 16 mg or more a day were twice as likely to stay in treatment compared to placebo and the number of opioid-positive drug tests was reduced by 15% (Mattick RP et al, Cochrane Database Syst Rev 2014;(2):CD002207). One challenge with buprenorphine is that nonspecialist prescribers may be wary about using it or prescribe it improperly. There is a dose response, with higher doses tending to work better, and many patients treated in the community wind up on subtherapeutic doses. For most patients, 16 mg seems to be an effective dosage—some need more, some less, but that’s a good general dosage target. By the way, that dose for methadone is around 90 mg a day.

CATR: And finally, we have naltrexone.

Dr. Hermes: Naltrexone has less of an evidence base. It’s a full antagonist, so it has none of the rewarding benefits of buprenorphine or methadone. Initially, naltrexone was approved as a daily pill, but adherence was very low and outcomes were not that great. But a shift to an injectable form (Vivitrol) meant that patients could be on medication for an entire month without having to think about it, and the outcomes were much better. There’s a double-blind placebo-controlled trial from 2010 that showed higher treatment retention in the extended-release naltrexone (XR-NTX) group vs placebo (58% vs 42%), while subjective drug craving and relapse were both decreased (0.8% vs 13.7%; Krupitsky E et al, Lancet 2011;377(9776):1506–1513). SAMHSA has a good introductory overview of injectable naltrexone for OUD that I’d point readers to (www.tinyurl.com/yc6yxkmk).

CATR: But these medications have benefits beyond just treatment retention and opioid use.

Dr. Hermes: Yes. A core principle and goal of treatment has always been about more than just not using the drug anymore. Dating back to that 1965 study by Nyswander and Dole, we’ve looked at outcomes that have to do with function in society and quality of life. And there is considerable evidence that methadone and buprenorphine reduce overdose risk, overdose mortality, infectious disease transmission, and criminal behavior; there is also evidence that they improve employment (Kampman K and Jarvis M, J Addict Med 2015;9(5):358–367). The evidence base for naltrexone is still catching up.

CATR: Can you talk a bit about side effects?

Dr. Hermes: Sure. As a full agonist, methadone acts on so many systems of the body. It can cause respiratory depression, especially if the dose is escalated quickly or is out of proportion to the patient’s tolerance. It can affect the rhythmicity of the heart and can cause sexual dysfunction by lowering testosterone levels. It slows the gastrointestinal system, causing potentially serious constipation; patients need to be on bowel regimens. Buprenorphine has many of these same side effects, though typically to a lesser degree due to its partial agonism and inherent ceiling effect. Respiratory depression is less of a risk than methadone, though it can be an issue if mixed with other central nervous system depressants like benzodiazepines. The constipation side effect can be profound. Starting buprenorphine can be tricky given the possibility of precipitated withdrawal (Editor’s note: See CATR Nov/Dec 2021 for buprenorphine induction details). The other issue with buprenorphine is that the maximum dose is 24 mg in most settings, which is where we encounter a ceiling effect. But this still may not be enough for some patients; some people need the full agonism of methadone to relieve opioid cravings.

CATR: What about cardiac effects with buprenorphine?

Dr. Hermes: Buprenorphine does have QT-prolonging effects, though not to the same degree as methadone.

CATR: Naltrexone is generally very well tolerated, but there are some additional barriers to treatment.

Dr. Hermes: Yes, that’s right. XR-NTX is very expensive, which could limit access for many patients. The other big issue is that it requires patients to withdraw completely from opioids before it can be started, and that is hard for people to tolerate. But choosing between these options really needs to be anchored in the patient’s experience with the opioids and their experience with the medication. I personally have had very few patients who choose naltrexone—only a few out of several thousand.

CATR: Why do you think that is?

Dr. Hermes: I think there are a few reasons. First, it’s just a huge shift for people who have used opioids over long periods of time to go from a full agonist to a full antagonist. It can be difficult to tolerate. And then there is the time before starting that people need to be off all opioids, which can be challenging outside of a controlled setting. There was an important trial that found outcomes with naltrexone were comparable to buprenorphine, but only once the medication was started. Taking initiation into account, the buprenorphine group did better than the naltrexone group (Lee JD et al, Lancet 2018;391(10118):309–318). And finally, because it’s not taken daily, people can forget it’s there. The month comes and goes, and people don’t go and get reinjected.

CATR: How do you sort through which medications are best for which patients?

Dr. Hermes: The evidence base is always evolving, so what I’m about to say is rooted in current research as well as my own personal experience. I’ve found that methadone is ideal for patients with a long history of daily high-dose use. It is also ideal for those who could benefit from additional support provided in the methadone clinic; this benefit cannot be overstated. A methadone clinic is a highly interprofessional team of individuals with huge levels of expertise in their own specialized areas. Patients can receive daily psychosocial support, so it can be an ideal place for individuals who are homeless, are in unstable relationships, don’t have a place to store medication safely, or otherwise have difficult living circumstances. The clinic is also suited for those with cognitive issues since medication is directly dispensed. In many instances, it is the best choice for our patients who are facing incarceration. Methadone is more uniformly available in prison systems.

CATR: Who does best with buprenorphine?

Dr. Hermes: Most broadly, I’ve found that buprenorphine works best for people with a shorter history of use. Typically, these are patients who have experienced fewer sequelae from substance use. It is ideal for a patient for whom methadone is contraindicated, such as somebody with a cardiac history or who’s had bad side effects in the past. Access to methadone clinics is not uniform, so buprenorphine is also the medication of choice where there aren’t methadone clinics. I will also say that many patients come in with an idea of what they want, and we listen closely to that. Methadone and buprenorphine are available on the street, and many of our patients already have a sense of what might work for them. They even sometimes come in and tell us the dose.

CATR: And naltrexone?

Dr. Hermes: I’ve found that people who do best with naltrexone have a high level of motivation. And it can be a good option for people with comorbid alcohol use disorder or severe sedative hypnotic use disorders where you might want to avoid furthering respiratory depression. Those who are being supervised by the legal system often get triaged into naltrexone. Because of the withdrawal management requirement before starting, it is much easier to use after a patient has been in a supervised addiction treatment setting. Access is important too; until December 2022, there were restrictions on prescribing buprenorphine. We’ll see how the lifting of the X-Waiver restriction ultimately affects access, but so long as a person has insurance, XR-NTX is probably the easiest of the three to get for now. Finally, naltrexone is the least stigmatized of all the treatments. Many feel backed into a corner at the first mention of a methadone clinic. There are ways to address the stigma directly, but sometimes naltrexone is the only treatment someone is willing to accept.

CATR: How do you address stigma?

Dr. Hermes: We must understand that globally, the level of social acceptance for these treatment modalities is extremely low. Patients risk derisive comments from family and friends; they risk losing employment; they risk bias at work. And most importantly, there can be an overwhelming confrontation with self; a patient’s decision to take medications acknowledges that there is something about themselves that works differently than the way it works in other people: “No one else needs to take methadone; why do I need it?” So, I anchor the conversation not in human fallibility and moral weakness but in biology and make a clear distinction between a physiological dependence on a medication and addiction. I’ll start by saying, “This is a brain-based illness that we can treat. It isn’t your fault, but you need assistance to solve this, and we are here to give you that assistance. That involves medication, support from us, and hard work from you.” And if we focus on that, we can start to address the biggest risk, which is that people don’t show up.

CATR: What else are you careful to do when starting treatment?

Dr. Hermes: I always tell patients about the medical benefits we covered here. But I start very simply. Alexithymia, meaning inability to describe feeling states, is a big issue with many of our patients; they have numbed their emotions for years with substances, and many are traumatized. Think about it: Trying to treat somebody who can’t describe their feelings or response to medication is a problem. So, I start with the basics: “How are you feeling?” Often people don’t know the answer to that, which is informative in itself. But I offer some words to them: “Are you feeling uncertain? Are you feeling afraid? Are you feeling small? Are you feeling overwhelmed?” And this begins to open up language that they can use to describe what they’re feeling when they first arrive in a methadone clinic and progress through treatment.

CATR: How can we ensure that a patient will continue in care?

Dr. Hermes: We often forget the basics, which are crucial to treatment success. “Do you have transportation?” is a key question so many of us forget to ask. Methadone treatment entails coming into clinic every day, though that universal requirement is changing, and if that means getting up at 4 in the morning and dealing with multiple bus transfers, the possibility of treatment succeeding is that much lower. You’ve just identified an important barrier that you might be able to address.

CATR: What other basics do you cover?

Dr. Hermes: Assessing support outside of the clinic is key. I ask, “What is your experience with your family?” “What about support systems in the community?” In my experience, patients do better if they have support, so it’s good to know how much is available to them already and what we might be able to supplement. And then, of course, I gather a detailed history of use, which guides what medication to recommend. Once I decide which way to go, I’ll say, “You’ve used such and such a drug in this way for this length of time. We’ve found that for people like yourself, this is the best medication—what do you think?” I believe strongly that “minds are more powerful than medications,” so trying to get a patient to understand and collaborate with your rationale is essential.

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