Weekly Injectable Buprenorphine Outperforms Daily Oral Treatment for Opioid Use Disorder in Pregnancy

The first randomized clinical trial testing extended-release buprenorphine injections during pregnancy has found the weekly formulation significantly outperforms the standard daily sublingual treatment in keeping pregnant patients abstinent from illicit opioids—while also producing fewer serious adverse events. The results, published March 16 in JAMA Internal Medicine, could reshape how clinicians approach one of the most medically complex intersections in addiction medicine.

The multicenter trial, led by T. John Winhusen, PhD, director of the University of Cincinnati/UC Health Addiction Center, enrolled 140 pregnant adults and randomized them to receive either weekly subcutaneous injections of extended-release buprenorphine or the conventional daily sublingual buprenorphine tablets or films, with or without naloxone. Supported by the National Institute on Drug Abuse Clinical Trials Network as part of the NIH Helping to End Addiction Long-term Initiative, it represents the kind of rigorous evidence that has been conspicuously absent from maternal addiction care for years.

A Gap in the Evidence That Mattered

Sublingual buprenorphine has long been the frontline medication for treating opioid use disorder during pregnancy. It works, and it has meaningfully reduced the catastrophic risks that untreated addiction poses to both mother and child—fatal overdose for the pregnant patient, neonatal opioid withdrawal syndrome for the infant, and a cascade of complications from preterm birth to placental abruption.

But the daily oral formulation carries well-documented limitations. Blood levels of the medication fluctuate through each 24-hour cycle, creating peak-trough effects that can leave patients vulnerable to breakthrough cravings and withdrawal symptoms during the troughs. Adherence is a persistent challenge: remembering to take medication every morning while navigating the chaos that often accompanies active substance use disorder is difficult under any circumstances, and pregnancy adds its own layer of medical appointments, physical discomfort, and anxiety.

There is also the question of diversion risk. Sublingual buprenorphine can be misused or diverted, a reality that has historically made some prescribers cautious about initiating or maintaining treatment—sometimes to the detriment of patients who need it.

Extended-release injectable buprenorphine was already known to produce superior abstinence outcomes in non-pregnant adults. The weekly formulation delivers steady medication levels without the daily peaks and troughs, eliminates adherence burden by shifting responsibility from the patient to a once-weekly clinic visit, and removes diversion risk entirely since the medication is administered by a healthcare provider and absorbed slowly from a subcutaneous depot.

The problem was that no one had tested it in pregnancy. Pregnant patients are routinely excluded from clinical trials, and the resulting evidence vacuum left clinicians relying on case reports and clinical intuition rather than randomized data. Winhusen's trial fills that gap directly.

What the Trial Found

Urine drug screens during pregnancy showed significantly higher rates of illicit opioid abstinence among participants receiving the weekly injectable compared to those on sublingual buprenorphine. During the postpartum period, the injectable formulation was non-inferior—meaning it performed at least as well, though the difference narrowed.

The safety profile was notable. While non-serious adverse events occurred at similar rates between groups, those in the injectable arm were more often rated as medication-related during pregnancy—largely injection site reactions and similar localized effects. More importantly, serious maternal adverse events were less common in the extended-release group throughout the entire trial period.

Neonatal opioid withdrawal syndrome outcomes did not differ between treatment groups, an important finding that addresses one of the primary concerns clinicians might have about switching formulations. The babies born to mothers in both groups experienced similar rates and severity of withdrawal symptoms, suggesting the different pharmacokinetic profiles of the two formulations do not meaningfully change neonatal outcomes.

"It is exciting to share the results of this trial, which have immediate clinical application," Winhusen said. "This longer-acting medication can safely and more effectively support treatment and recovery in pregnant patients."

Nora D. Volkow, MD, director of the National Institute on Drug Abuse, framed the results in the context of the broader crisis: "These findings are clinically valuable, for they show us that this injectable extended-release buprenorphine formulation is safe to use in pregnancy and results in better opioid abstinence outcomes compared to sublingual buprenorphine. This is especially relevant in the context of the ongoing opioid overdose crisis and public health emergency."

Why Steady Blood Levels Matter in Pregnancy

The pharmacokinetic advantage of extended-release buprenorphine takes on particular significance during pregnancy. The physiological changes of pregnancy—expanded blood volume, altered liver metabolism, increased renal clearance—affect how medications are processed. For sublingual buprenorphine, these changes can accelerate metabolism and reduce effective blood levels, sometimes requiring dose adjustments that are difficult to calibrate in real time.

Weekly injections bypass this problem by maintaining more consistent medication levels regardless of metabolic fluctuations. The subcutaneous depot releases buprenorphine gradually, smoothing out the peaks and troughs that make daily dosing unreliable for some patients. For a pregnant patient already managing the physical upheaval of gestation, that pharmacological stability can mean the difference between sustained abstinence and relapse during a period when the consequences of illicit opioid use are magnified for two lives.

The structured weekly clinic visits also create a natural scaffold for the kind of comprehensive prenatal care that this population needs. Each injection appointment becomes an opportunity for obstetric monitoring, counseling, social service referrals, and the relational continuity that builds trust between patient and provider—trust that is frequently damaged or absent among people with substance use disorder histories.

The Scale of the Problem

Opioid use disorder during pregnancy remains one of the most underdiscussed dimensions of the overdose crisis. While national attention has rightly focused on the overall death toll—now declining toward pre-pandemic levels after peaking above 111,000 in 2023—the maternal and neonatal consequences of untreated addiction continue to devastate families.

Neonatal opioid withdrawal syndrome affects thousands of infants each year, requiring extended hospital stays, specialized medical management, and follow-up care that strains neonatal intensive care units already operating at capacity. The mothers themselves face elevated risks of overdose death during pregnancy and in the postpartum period, when the physiological and psychological stresses of new parenthood converge with the ongoing challenges of recovery.

Despite the availability of effective medications, many pregnant patients either cannot access treatment or are discouraged from seeking it by stigma, legal concerns in states that criminalize substance use during pregnancy, and a healthcare system that too often treats addiction and obstetrics as separate domains requiring separate providers in separate buildings.

The 2023 elimination of the federal X-waiver requirement expanded the number of clinicians authorized to prescribe buprenorphine, but uptake in obstetric settings has been slow. Many obstetricians remain uncomfortable prescribing addiction medications, and many addiction specialists lack the obstetric training to feel confident managing pregnant patients. The result is a coordination gap that the patients themselves are left to navigate.

What Comes Next

The Winhusen trial provides the randomized evidence that treatment guidelines have been waiting for. Whether that evidence translates into changed clinical practice depends on several factors beyond the data itself.

The weekly injectable formulation requires a clinical setting for administration—a healthcare provider must perform each injection. For patients in rural areas where addiction treatment providers are already scarce, adding a weekly in-person visit to the treatment regimen could present logistical challenges that daily at-home sublingual dosing does not.

Insurance coverage and reimbursement for extended-release buprenorphine in pregnancy will also need to catch up. While monthly injectable buprenorphine has gained traction in non-pregnant populations, the weekly formulation used in this trial may face separate prior authorization hurdles or formulary restrictions that vary by state and payer.

Still, the trial's results are unambiguous: weekly injectable buprenorphine is safe during pregnancy and produces better abstinence outcomes than the current standard of care, with fewer serious adverse events. For a population that has been historically underserved by clinical research and systematically excluded from innovation in addiction medicine, that clarity matters enormously.

The NIH HEAL Initiative, which funded the trial, was designed to accelerate practical solutions to the overdose crisis. Winhusen's work represents precisely the kind of finding the initiative was built to produce—actionable evidence that can improve outcomes for patients who need it most, delivered at a moment when the tools to fight the crisis are finally beginning to match its scale.