Comparing medications to treat opioid use disorder

Using medications to treat opioid use disorder is a lifesaving cornerstone of treatment — much like insulin for type 1 diabetes. The flawed but widely held view that medications like methadone or buprenorphine are “replacing one addiction for another” prevents many people from getting the treatment they need. In actuality, people successfully treated with these medications carefully follow a prescribed medication regimen, which results in positive health and social consequences — as in patients with many types of chronic medical conditions.

However, even among those who embrace treating opioid use disorder (OUD) with medication, there is a difference of opinion as to which medications are most effective. A new study offers important insight into the advantages and disadvantages of the two medications for OUD that can be prescribed in a doctor’s office (that is, on an outpatient basis). These medications are buprenorphine and extended-release (ER) naltrexone. This study was widely covered in the press, and many of the sound bites and headlines reporting the two treatments to be equally effective were a bit misleading.

The advantages and disadvantages of buprenorphine (Suboxone, Subutex, Zubsolv, Probuphine, Sublocade)

Buprenorphine is a partial opioid agonist medication. This medication activates the same receptors in the brain as any opioid, but only partly. Because its effects are long-lasting, it can be taken once a day to relieve cravings, prevent withdrawal, and restore normal functioning in someone with opioid use disorder. Because it is a partial agonist, it has a ceiling effect. This means once all the receptors are occupied by the medication, even if a person takes 20 more tablets she wouldn’t feel any additional effect or be at risk of overdose.

Any doctor who has completed special training (a primary care provider, addiction specialist, OB/GYN, etc.) can prescribe buprenorphine. The advantage is, theoretically, that a person with OUD could receive treatment from any provider he or she might see for a routine health issue. I say theoretically because, despite its availability, only about 4% of physicians have done the necessary training to be able to prescribe it. The research on buprenorphine is robust, with multiple studies showing it reduces the risk of death by more than 50%, helps people stay in treatment, reduces the risk that they will turn to other opioids (like heroin), and improves quality of life in many ways.

The advantages and disadvantages of naltrexone (Vivitrol, Revia)

Naltrexone is a pure opioid antagonist. It sticks to an opioid receptor, but instead of activating it to relieve craving and withdrawal it acts as a blocker, preventing other opioids from having any effect. The research on naltrexone has been mixed. Naltrexone in pill form is basically no better than placebo because people simply stop taking it. Studies on extended-release naltrexone are more promising and have shown it to be better than no medication at all. However, there has never been a US trial comparing extended-release naltrexone to either methadone or buprenorphine, until this study.

The X-BOT study: Comparing buprenorphine and extended-release naltrexone

This study enrolled individuals with opioid use disorder who had voluntarily gone to a detoxification program. Researchers then randomly assigned them to either daily buprenorphine or monthly extended-release naltrexone. Both groups were followed for 24 weeks, to see how many people relapsed.

One of the most important things investigators learned is just how hard it was to get participants onto extended-release naltrexone, revealing a potential barrier to its usefulness. Before a person can start taking ER naltrexone, they must be completely off opioids for seven to 10 days. Only 72% of the group assigned to ER naltrexone even got the first dose, and among those who were randomized during the detoxification process, only 53% started the medication. In contrast, 94% of the group assigned to buprenorphine started the medication.

The other important finding was what happened with relapses. The researchers analyzed their data using an “intention to treat analysis.” This means that once a person is randomly assigned to a treatment (or placebo), their data counts even if they don’t stick with the treatment. Here’s why this is important: if you don’t include that data, then you miss other important outcomes that influence how effective a treatment really is. Thanks to this type of analysis, researchers learned that relapse was significantly more likely in the extended-release naltrexone group (65% compared to 57% in the buprenorphine group).

Immediate relapses were even more likely in the naltrexone group due to failures to start the medication — 25% of the naltrexone group had a relapse on day 21, compared to 3% in the buprenorphine group. Overall there were more overdoses in the naltrexone group, but no difference in fatal overdoses between the groups. Most of the overdoses occurred after the study medication was stopped, highlighting the lifesaving importance of getting on, and staying on, treatment. The naltrexone group also had a longer length of stay in inpatient detoxification programs, which may be an important consideration when we think about overall healthcare costs.

So, why did many headlines claim extended-release naltrexone was as effective as buprenorphine? Well, that was the finding of a separate analysis that looked only at people who successfully started each medication. When the data was viewed that way, there was no difference between the two medications, but that’s just part of the picture. If it’s harder to get a person to successfully start and stick with a medication, that should factor in evaluating its “effectiveness.”

Take-home messages from X-BOT

This is an incredibly important study. The findings are generally consistent with what I see in my clinical practice. Overall buprenorphine is a more effective treatment for opioid use disorder, in part because it’s easier to get patients started on it and they are more likely to stick with it. Extended-release naltrexone may be as good for people who can successfully complete the detoxification required before starting on it. Both medications have a place, but as with so many conditions and treatments, one size does not fit all.


  1. Debra Kate

    Just a comment. NPs who complete additional 24 hour training can also prescribed buprenorphine which increases the number of providers offering this service.

  2. Daniel Mccarty

    Wish it helped people like me that have all my medical records of spinal injury’s and how it has effected. I’ve had a perfect record taking my meds and never took anything my doctor didn’t give me. One pharmacy is all I ever use an my records clean there too. But my doctor told me he can’t write my pain medication anymore. I’ll have to go to a pain clinic. I’ve already been to those had 9 steroid or whatever they are called. No relief. Had all kinds of therapy. Test MRI milagram exrays I can’t count how many. But still my doctor refused to write meds. So I eat Tylenol and ibruprofen and suffering with constant pain. I don’t want anymore shots in my back I had a headache 2 yrs after the last rounds and hole in my tailbone that leaked when I got home! The clinic is 30+miles away I can’t ride that far without getting out 2 times for relief and all they say is have to do shots. No more just another point of view from a 55yr old disabled man. Sorry to take all the space here thanks for reading my story! DM

    • Eliot

      Dear Mr. McCarty,

      I thank your for your post. It highlights the difficulty actual patients have and must work thru and endure regardless of factors as varied as the exigencies of local,state, Federal regulators and the “current climate” – a cheap and blanket term I despise.

      Physical assault left me in 2011 with bi-lateral Renal Calculi that painfully pass or do not pass on their own, along with a spinal fracture. As you alluded to, OTC ibuprofen and Tylenol only do so much (which is not enough) to live pain free or “pain functioning” . NSAIDS also required me to receive more than 3 transfusions in 2017 as they affected the gastric lining, bleeding ulcers and anemia, as well as drive down renal function.

      Newer Medications, such as Nucynta, are even In the current months Issue and discussion of Men’s Health, purportedly showing less potential for misuse than traditional meds such as Hydrocodone, or Oxycodone generics. Unfortunately, a months supply of Nucynta (the non Extended Release formulation) Is several thousand U.S. Dollars with even the free of charge GoodRX 70% off.,

      Physical assault left me in 2011 with bi-lateral Renal Calculi that painfully pass or do not pass on their own, along with a spinal fracture. As you alluded to, OTC ibuprofen and Tylenol only do so much (which is not enough) to live pain free or “pain functioning” . NSAIDS also required me to receive more than 3 transfusions in 2017 as they affected the gastric lining, bleeding ulcers and anemia, as well as drive down healthy Renal Function.

      Epileptic nerve blockers such as Gabapentin made me gain 30-40 pounds in less than a Fiscal Quarter – and I would not advise -ever – that medication. There is one consistent and much worse side effect to Gabapentin that a cursory Google search would reveal to be a tragically common occurrence. Tramadol affects Serotinin levels in the brain and very rapidly can cause symptoms of serotonin toxicity so do be careful regarding that medication… A known contraindication to Tramadol is Zofran, (for nausea) and it is shocking to see the the frequency with which they can be sent to patients in a busy E.R.

      I don’t believe anyone truly wakes up one day having envisioned themselves with such health/conditions to navigate either personally or with a loved one.

      Advocacy, Understanding, and Dialogue is a responsibility of a patient to provider, and reciprocal honesty is a patients right as well. Communication should never be stigmatized or erroneously threatened as a label of “drug seeking” behavior or dialogues in approach to care.

      I am blesssed to come from a family of good genes with no hereditary correllations or health issues before a physical assault In Jan. 2011. i share my thoughts for others, and was inspired to do so and again i thank you Mr. McCarty, and to Harvard Health for hosting this forum.

      To All,
      Best In Health In 2018, and forever more…


      Eliot Carr, Tennessee, 32y.o.

  3. James

    You’re review fails to acknowledge the disadvantages of buprenorphine, which is one of this most significant sources of contraband in prisons, given it too is an opioid.

  4. Matthew Keene, MD

    This is an excellent review of X-BOT, that cuts through the PR sound-bites and dives into the actual data and how that impacts real-world clinicians.

    My only suggestion is that the author lists every available buprenorphine product approved to treat opioid use disorder with the exception of Bunavail. Perhaps this was an oversight, or perhaps Bunavail was excluded as it has a relatively small presence in this space. But for those of us knee-deep in treating this population, it is perhaps the best option available, as it uses the least amount of buprenorphine per dose to achieve similar plasma levels, allows patients to speak and swallow while dosing, and has a much lower likelihood of abuse/diversion.

  5. Kurt

    Thank you for this nice review of X-BOT. I’m always happy to see scientific and evidence-based reporting in this space since there is so much misinformation being purported by patients and physicians alike.

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