Pregnant Women with Opioid Use Disorder: Treatment with Combination Buprenorphine/naloxone versus Buprenorphine Monoproduct









Browsing through my copy of the May/June 2020 issue of the Journal of Addiction Medicine, I started reading an article titled, “Buprenorphine and Naloxone Versus Buprenorphine for Opioid Use Disorder in Pregnancy: A Cohort Study.” Then I happened to read the authors’ names and discovered it was written by physicians and scientists from Asheville, NC. I was pleased to see a submission in this major journal by people I knew in my state and read it with interest.

In their introduction, the authors of this article gave some basic facts about opioid use disorder and pregnancy. They quoted statistics from the 2017 NSDUH report, saying 8.5% of pregnant women reported that they had used an illicit substance within the past month, and 1.4% reported the use of some sort of opioid, either heroin or prescription opioid pain medications.

In our nation, opioid use disorder during pregnancy quadrupled between 1999 and 2014, at a rate of 6.5 per 1000 pregnant women. In North Carolina, our rate was 7.8 per 1000 pregnant women. Along with this increased use of opioids, the U.S. has seen a five-fold increase in neonatal abstinence syndrome between 2009 and 2012.

The authors point out that medication (methadone and buprenorphine products) for stabilization of opioid use disorder during pregnancy is the recommended standard of care, endorsed by the World Health Organization, The American College of Obstetrics and Gynecology, the American Society of Addiction Medicine, and the Substance Abuse and Mental Health Services Administration.

Prior to DATA 2000, these pregnant women could only get this treatment at opioid treatment programs, with methadone. Since DATA 2000, these patients also can get treatment with buprenorphine products at office-based practices as well as at opioid treatment programs. All of the patients in this study received buprenorphine product prescriptions from office-based practices, either at the community-based OB/GYN residency program or community-based providers.

Past studies (MOTHER trial, 2010, Jones et al –  another great scientist from North Carolina, at University of North Carolina) showed buprenorphine worked as well as methadone for pregnant patients with opioid use disorders, and over the past ten years, more moms-to-be have chosen buprenorphine over methadone.

This present study was done in order to compare outcomes of moms (and their babies) treated with buprenorphine monoproduct compared to those treated with the combination product, buprenorphine/naloxone.

In the past, pregnant women were usually treated with buprenorphine monoproduct because of fears the fetus could be exposed to naloxone if the combination product was used. However, over the past ten years, more physicians have prescribed the combination product for pregnant women, after some small studies reported no adverse effects. Prescribers were hesitant to prescribe the monoproduct buprenorphine because it is more often misused, and can be injected. The monoproduct has a higher street value than the combination product in most areas, underlining its popularity on the black market.

This retrospective cohort study looked at pregnant patients with opioid use disorder treated from January of 2014 to July 2018. Of the 226 women who met criteria for the study, 108  women taking the buprenorphine monoproduct delivered locally and could be included in the study. Eighty-five women taking the combination product delivered locally and were able to be included in the study.

At the end of the study, the women who had taken the combination product, buprenorphine/naloxone, had outcomes that were not worse than those of the women who had taken the monoproduct. Therefore, this article reassures providers that they can treat pregnant women safely with the combination product.

But hold on…there’s another interesting finding…

The incidence of neonatal abstinence syndrome (NAS) was significantly lower in babies born to moms on the combination product as compared to the monoproduct.

Thirty-five percent of the babies born to moms on the combination product had neonatal abstinence syndrome severe enough to need treatment. However, 55% of babies born to moms on the monoproduct buprenorphine had NAS severe enough to need treatment. That difference was found to be statistically significant.

There were some other differences between the two groups of women that didn’t meet statistical significance, such as age, race, insurance type, presence of chronic pain diagnoses, mental health diagnoses, buprenorphine dose prescribed, and other physical health problems. Interestingly, prescribers working at the residency program were more likely to prescribe the combination buprenorphine/naloxone product than community prescribers.

Intriguing though this finding is, this present study can’t show cause and effect. That is, the most we can say is that the combination buprenorphine is associated with lower neonatal abstinence rates in the babies, but not that the combination buprenorphine product causes lower neonatal abstinence rates. To determine a causal relationship, a different kind of study must be done.

The authors have some ideas about possible factors that could explain these findings. For one thing, there may have been selection bias in which medication was started. This was not the type of study where patients were randomly assigned the monoproduct versus combo product. Selection bias means that perhaps some unknown factor made the study subjects or their prescribers pick one form of medication over the other, and this factor is responsible for the difference in NAS rates.

The authors also suggested that there’s been a trend toward lower NAS rates in recent years compared to earlier years, and that coincided with the trend towards prescribing the combination product instead of the monoproduct. Maybe since both of those things happened at the same same time, it made it appear that the combination product was associated with lower NAS rates.

However, is it possible that the mothers on the combination product actually do absorb more naloxone that we have thought in the past? Is it possible that there’s enough naloxone in those moms’ bloodstream to affect the risk of withdrawal in the newborns?

We know some patients (not necessarily pregnant) complain of low-grade withdrawal symptoms when they take combination products of buprenorphine/naloxone. Some patients report headaches, persistent nausea, and body aches when taking the combination buprenorphine/naloxone sublingual products. These patients’ symptoms resolve on the monoproduct.

Many providers assume such patients are lying, trying to scam them to get monoproduct buprenorphine for some illicit intent. But perhaps sublingual naloxone in the combination product is more active physiologically than we think, causing withdrawal symptoms in susceptible patients, and causing less opioid effect in utero, and reduction of the risk of withdrawal in the newborn.

This issue desperately needs more study, both for pregnant patients with opioid use disorder, and for the patients who describe withdrawal symptoms with the combination product buprenorphine/naloxone.


7 responses to this post.

  1. Posted by Zac Talbott on July 26, 2020 at 8:06 pm

    Regarding, “Past studies (MOTHER trial, 2010, Jones et al – another great scientist from North Carolina, at University of North Carolina) showed buprenorphine worked as well as methadone for pregnant patients with opioid use disorders, and over the past ten years, more moms-to-be have chosen buprenorphine over methadone,” It is important to note that outcomes were similar for those mothers who *remained in treatment.* Additionally, the selection of buprenorphine at a growing rate compared to methadone has much to do with what is available. The reality we’ve added more new OTPs across the country in the last 5 years than we have at any other time in the field’s history since the early 70’s is encouraging, but methadone continues to simply be less widely accessible than buprenorphine due to any prescriber who has a DEA registration and takes an 8 hour online course (4 hours of which is often “self study”) being able to prescribe buprenorphine for OUD. Methadone for OUD continues to be provided in a setting that requires behavioral health accreditation and access to comprehensive psychosocial support services for patients. Both medications have their place, and both demand our full support, but the realities that more pregnant women are initiating Buprenorphine vs Methadone treatment now is nuanced and must be explored. One should not infer it’s because that’s the patient’s preference. It might just be the medication that is available. It could be because so many X-waivered buprenorphine prescribers still carry significant stigma against methadone, and some patients are never given objective information on the similarities and differences of the two.

    Of critical importance is the conclusion by the MOTHER Study and several other studies not specific to pregnant patients that document retention in treatment is notably better for patients enrolled in methadone treatment than it was with buprenorphine treatment. That’s critical. Evidence does not show that methadone and buprenorphine are equal substitutes for each other across the OUD population, and one of the most important factors for treatment effectiveness and long-term positive outcomes, along with adequate and individualized medication dosing, is that a patient actually remains in treatment. Retention is something that has to be a part of the risk v. benefits analysis and patient education when a provider is in dialogue with a patient regarding which medication may be the best fit for them.

    Similarly, we also know that the overwhelming majority of patients who do well on buprenorphine will also do well on methadone. On the flip side, we simultaneously know that the numbers of those who do well on methadone will not be as high when it comes to also doing well on buprenorphine. As more powerful and potent fentanyl and other synthetic opioid analogs continue growing in prevalence and potency in the illicit opioid supply, there’s never been a greater need for a long-acting full agonist like methadone as an accessible and encouraged option alongside the partial agonist/antagonist buprenorphine.

    Lastly, when it comes to the entire buprenorphine mono product versus buprenorphine/naloxone combo product debate, I struggle to understand why so much time, energy, and other resources are spent on running down this topic. Buprenorphine itself has an amazing safety profile, and there is no objective evidence or data that shows the combo product is any less misused or diverted than the mono product. There was an international poster research report at the AATOD Conference in NYC (which has been 5 years ago now) that really drove home how silly this ongoing topic is… The combo product just isn’t a “thing” in the vast majority of other countries where Pharma lobbyists aren’t involved in health policy and practitioner education. We know the Pharma patent holder for the first combo product sold a lot of smoke & mirrors when it came to the combo product being an effective diversion tool and other myths that continue to this day (how else do we describe the obsession with the combo product by 3rd party payers, state regulators, the DEA, and even addiction medicine physicians?). The predecessor company of that initial combo product patent just plead guilty to misleading the FDA on the claims made regarding the Suboxone film within the last week! Among other things, Naloxone’s affinity for the mu receptor is lower than that of buprenorphine, and Naloxone (like pretty much all other agonists and antagonists except perhaps Fentanyl) is just not going to win the fight with buprenorphine. The entire combo product push is smoke and mirrors that are not related to treatment outcomes or patient safety. Subjective patient reports even suggest the combo strips are preferred for IV buprenorphine users because they dissolve so easily compared to the process of breaking down a sublingual tablet…. and the inclusion of the Naloxone does not make the user sick or other deter diversion or misuse.

    The ongoing obsession with combo products in the U.S. is further kept as an assumed best practice (it is not – best practices must be rooted in data and objective evidence from systematic research while considering a patient’s values and preferences) by the ongoing flood of new combo formulations that equal very profitable patents for the Pharma companies. Even generic sublingual tablet combo products are significantly more expensive than the mono product, and that unnecessarily drives up treatment fees, significantly increases the dollars spent by Medicaid and Medicare on MAT at the pharmacies, and is an example of the practices that continue to drive up premiums for commercial health insurance.

    ::steps off his soap box::

    Sorry my comment ended up so long! I didn’t set out with that as my intention.


    • Heh heh. You can step up on the soapbox anytime, Zac.

      I agree with you when you say the combo/monoproduct debate is smoke & mirrors. Well said.
      Re: MOTHER study…although the buprenorphine group had worse retention in treatment on buprenrophine, they fortunately weren’t lost to treatment. Many of those patients were successfully transitioned to methadone. This underlines the importance of having BOTH medications available and easily accessible.


      • Posted by Zac Talbott on August 22, 2020 at 7:11 pm

        Yes! We must support both medications. Any argument of one being better than the other is a disservice to our efforts in effectively combatting OUD and opioid overdose. Keep up the great work!


  2. Posted by william taylor on July 26, 2020 at 8:57 pm

    The rates of neonatal withdrawal are suspiciously high. My postpartum patients tell me that hospitals are overreactive when they deliver on buprenorphine, and bias on the part of treating pediatricians especially towards patients on monoproduct, would be a concern. Also, monoproduct use is often driven by financial concerns; it would not surprise me if there are substantial confounding differences between the monoproduct group and the combination product group.

    As you say, you can’t simultaneously believe that the naloxone has no biological activity when taken as prescribed, and that it is a powerful agent that can reduce neonatal withdrawal.


    • To be fair, the authors of this study didn’t say bupe/nal products reduce neonatal withdrawal. They know this type of study can’t determine the cause of the differences between the two groups. Their only conclusion was that moms & babies didn’t have any worse outcomes if the mothers were dosed with bupe/nal compared to bupe monoproduct.


  3. Posted by Matthew C. McClure on July 27, 2020 at 7:09 pm

    Of the 20 or so gravids the past 5 years that I have assisted, I bet 18 of them live 60 miles or more from a OTP. Methadone was not an option. Much of my state is a methadone wasteland without access.
    Zac is spot on with his rant. If a recall Jana posted about using mono product IV several years ago? The pictures in the article struck me.
    I agree with William Taylor and bias against new moms. Interesting, I have noticed that moms that are followed by Family Practice and particularly waiver approved residents, they rarely end up weaning newborns.


  4. Posted by soraya kamran on November 14, 2020 at 2:56 pm

    The bioavailability of naloxone taken SL or orally is well-documented I believe – and those test are easily reproducible – administer in controlled setting and measure. I agree some patients do respond better to the monoproduct, could be a placebo effect, I do not know. However, in regards to pregnancy or breastfeeding I think the bioavailability of oral naloxone in plasma has been shown to be low, and low data in breastmilk.


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