Pregnant patients with opioid use disorder (OUD) who received subcutaneous extended-release buprenorphine had higher rates of abstinence from illegal opioids than those who received the sublingual formulation, according to a noninferiority randomized trial in JAMA Internal Medicine.

Neonatal outcomes were similar between groups. Injectable buprenorphine was first approved in the US in 2018 but is not widely used in hospitals or other care settings, in part due to concerns that the formulation leads to higher exposure to the drug and may not be safe for infants.

The findings “give us more options for treatment, and more options are certainly better in pregnancy,” said Stephen Patrick, MD, MPH, MS, a professor of pediatrics at the Rollins School of Public Health, Emory University in Atlanta, who has researched the impact of substance use disorder on pregnant women and infants. Patrick was not involved with the new study.

OUD in pregnancy is associated with adverse maternal and neonatal outcomes such as preeclampsia and small for gestational age, and often triggers the involvement of child protective services. But only about half of pregnant women receive medication treatment for OUD.

Sublingual buprenorphine, in tablet or film form, is a standard treatment for peripartum patients. The drug can come with drawbacks, however. Because of increases in metabolism and other changes during pregnancy, absorption and blood levels can vary throughout a day, increasing the likelihood of cravings and withdrawal. A weekly or monthly extended-release injection can be a better option for some patients.

“Having multiple formulations available may help improve engagement in care and ultimately support better outcomes for both mothers and infants,” said T. John Winhusen, PhD, a professor of psychiatry and behavioral neuroscience at the University of Cincinnati, Cincinnati, who led the study. “For clinicians, the key takeaway is that weekly extended-release buprenorphine may be considered another evidence-based option for treating OUD during pregnancy.”

But research has shown among substance use and mental health care centers, only roughly one third offer the injection. Facilities that offered outpatient and integrated primary care services had an increased likelihood of prescribing the treatment.

Winhusen and colleagues sought to test the safety and efficacy of the extended-release injection in pregnant patients.

At 12 outpatient perinatal treatment sites in the US between July 2020 and October 2024, 140 pregnant participants with moderate or severe OUD were included in the study (69 extended-release, 71 sublingual). Randomization occurred between 6 and 30 weeks of gestation. Patients were excluded if they had physiologic dependence to alcohol or sedatives requiring medically managed withdrawal, had a psychiatric or medical condition that would make study participation difficult, or were receiving methadone or naltrexone treatment.

Most sites were obstetric and gynecologic programs affiliated with academic health centers. Both groups attended weekly visits to collect urine during pregnancy and for 1 year following birth.

Researchers evaluated illicit opioid abstinence, defined as a negative urine screen for fentanyl, morphine, codeine, ethylmorphine, and heroin. Postpartum abstinence was also assessed, along with treatment for neonatal opioid withdrawal syndrome, and maternal and infant safety through the study period.

During pregnancy, extended-release dosing was typically at 32 mg/wk, or the equivalent of 18-24 mg of sublingual buprenorphine. Sublingual dosing averaged 18.8 mg/d, and more than 80% of these participants took smaller doses multiple times a day. After birth, patients received monthly sublingual or injection dosing. Medication was discontinued by 12% in the extended-release group and 9% in the sublingual group during pregnancy.

The extended-release group showed higher proportions of negative urine samples for illicit opioids during pregnancy (82.5% vs 72.6%; 95% CI, 1.72-17.95; P = .009). Rates of illicit opioid abstinence fell in the postpartum period and were similar between groups (60.2% vs 59.5%; P = .45). Serious maternal adverse events were less common with extended-release treatment during pregnancy (8.7% vs 26.8%; P = .007) and through 12 months postpartum (6% vs 18.6%; P = .04). The most common serious event was initial or prolonged hospitalization.

Although there were concerns that higher buprenorphine exposure with depot formulations might worsen neonatal outcomes, the trial showed no significant differences in opioid treatment for neonatal opioid withdrawal syndrome (30.2% vs 26.5%; P = .64). The mean days infants were treated after birth also did not differ significantly. Infants exposed to the sublingual version had slightly more serious adverse events, the most common being prolonged hospitalization.

Uptake

Sublingual buprenorphine can be easier to prescribe to patients because of many factors, said Drew Herbert, MSN, MA, NP, RN, a doctoral student at the University of Missouri in Columbia, Missouri, who researches OUD in pregnant women and has previous experience treating this population.

He said he mostly prescribed sublingual buprenorphine due to cost. Without insurance, this formulation can cost as low as $37 a month, while the injection without insurance can cost $500 a week per injection. Many state Medicaid programs cover both formulations at low or no cost.

“Buprenorphine itself is a relatively inexpensive medication as a mono tablet,” Herbert said. “The injectable in this study is significantly more expensive than that, which is a consideration depending on how someone’s paying.”

Insurance requirements can also be a barrier to access. One study found a little over one third of Medicaid formularies required prior authorization for the injectable compared to 5% for other buprenorphine formulations. Care facilities must also be registered in the Risk Evaluation and Mitigation Strategy program by the FDA to dispense the drug. Any clinician who can prescribe Schedule III drugs can prescribe sublingual buprenorphine, with no mandatory specialized training.

Although the trial showed that subcutaneous buprenorphine is as safe as the sublingual version, Herbert said one confounding factor that may have improved rates of abstinence were weekly appointments for both groups.

“Weekly appointments for someone with a substance use disorder, in itself, is great: just the ability for frequent check-ins, frequent support, frequent reassurance, question answering,” Herbert said. “I think that just affirms that in addition to the medication, there are other important things that we can and should be doing in the treatment of opioid use disorder.”

Patrick said, while having another option for treatment is important, a much larger problem looms for pregnant patients who need treatment. One study showed pregnant women were 17% less likely to r eceive an appointment with a clinician who prescribed buprenorphine.

“Where women often find themselves is with an obstetrician who may not be comfortable with addiction, or an addiction medicine doc who is not comfortable with pregnancy,” he said.

Research has shown overall low rates of buprenorphine prescribing by ob/gyns, with less than 6% of ob/gyns prescribing the drug in one study.

“The big picture is we still have a profound access problem,” Patrick said. “The more we get OBs that are comfortable caring for addiction, the better.”

Herbert said any form of the drug can lead to positive outcomes.

“I find buprenorphine changes people’s lives. They describe a sense of relief for not having to pay for nonprescribed opioids. They feel a sense of relief that they no longer feel stigmatized by other people. They describe feeling reconnected with family,” Herbert said.

The study was supported by grants from the National Drug Abuse Treatment Clinical Trials Network. Pharmaceutical company Braeburn donated extended-release buprenorphine. Various study authors reported receiving grants, consulting fees, honorarium, and contract support from the National Institutes of Health, Gilead Sciences, Koko Medical, and Alydia/Organon, among others.

Karina M. Sasin, MD, MBA, is a freelance writer based in Europe.