NIH Trial Shows Weekly Buprenorphine Injections Outperform Daily Pills for Pregnant Women with Opioid Use Disorder

The first randomized clinical trial testing extended-release buprenorphine for opioid use disorder during pregnancy has delivered results that could reshape how doctors treat one of the most vulnerable patient populations navigating addiction. Published this week in JAMA Internal Medicine, the NIH-supported study found that weekly injectable buprenorphine led to significantly higher rates of abstinence from illicit opioids during pregnancy compared to the current standard treatment—daily sublingual tablets placed under the tongue.

For 140 pregnant adults enrolled across multiple medical centers, the difference wasn't marginal. Those receiving weekly subcutaneous injections of extended-release buprenorphine showed superior abstinence rates throughout pregnancy, as measured by urine drug screens. The benefit persisted postpartum, where injectable treatment remained non-inferior to daily pills. Perhaps most striking: serious adverse events occurred less frequently in the extended-release group, challenging assumptions that newer formulations might carry unknown risks for pregnant patients.

"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," said Dr. Nora D. Volkow, director of NIH's National Institute on Drug Abuse (NIDA). "This is especially relevant in the context of the ongoing opioid overdose crisis and public health emergency."

The Stakes for Pregnant Women with OUD

Untreated opioid use disorder during pregnancy carries catastrophic risks. Illicit opioid use raises the chance of fatal overdose for the mother—a threat compounded by pregnancy's physiological changes affecting drug metabolism and respiratory function. For the baby, exposure can lead to neonatal opioid withdrawal syndrome (NOWS), a condition requiring weeks of intensive medical management as the infant's nervous system adjusts to the absence of opioids after birth.

Medication-assisted treatment with buprenorphine, a partial opioid agonist that reduces cravings and withdrawal without producing euphoria, has long been the evidence-based answer. Sublingual buprenorphine, typically dissolved under the tongue once or twice daily, allows pregnant individuals to stabilize their opioid use disorder while minimizing fetal exposure and improving prenatal care engagement. The approach works—but not always well enough.

Daily sublingual dosing comes with practical and pharmacological limitations. Adherence suffers when patients face housing instability, work schedules incompatible with daily clinic visits, or transportation barriers. There's also the risk of diversion, where prescribed medication is sold or shared. And crucially, sublingual buprenorphine creates peak-trough blood level fluctuations throughout the day: medication levels spike shortly after dosing, then gradually decline until the next dose. For some patients, those troughs trigger cravings and withdrawal symptoms severe enough to drive continued illicit opioid use.

Extended-release formulations sidestep these problems by delivering steady medication levels over days or weeks through a single injection. The question was whether that benefit—already established in non-pregnant adults—would translate to pregnancy, where medication safety is scrutinized with particular intensity.

Trial Design and What It Measured

The NIDA Clinical Trials Network study, conducted as part of the NIH Helping to End Addiction Long-term Initiative (NIH HEAL Initiative), randomized 140 pregnant adults to receive either weekly subcutaneous extended-release buprenorphine injections or daily sublingual buprenorphine (with or without naloxone, an opioid antagonist added to some formulations to deter misuse).

Participants receiving injections could transition to a monthly formulation postpartum if they weren't breastfeeding. The trial's primary outcomes focused on illicit opioid abstinence during pregnancy and postpartum, measured through urine drug screens. Secondary measures tracked maternal adverse events and neonatal opioid withdrawal syndrome severity.

Dr. John Winhusen, principal investigator and professor of Psychiatry and Behavioral Neuroscience at the University of Cincinnati College of Medicine, emphasized the trial's novelty: "We knew that injectable extended-release buprenorphine leads to superior rates of illicit opioid abstinence in non-pregnant adults, but there had been no completed randomized clinical trial testing its use during pregnancy."

The study filled that evidence gap with findings carrying immediate clinical implications.

Higher Abstinence, Fewer Serious Harms

Urine drug screens revealed significantly higher abstinence rates among pregnant participants receiving weekly extended-release buprenorphine. The treatment's effectiveness didn't fade postpartum; abstinence rates remained non-inferior to sublingual treatment after delivery, suggesting the benefits extend through a critical transition period when relapse risk typically spikes.

Maternal adverse events told a more nuanced story. Non-serious events—minor side effects like injection site reactions, nausea, or headache—occurred at similar rates in both groups but were more commonly attributed to the medication itself in the extended-release arm. That makes sense: an injection creates a visible, localized reaction, while sublingual medication's side effects may be harder to distinguish from pregnancy symptoms.

What matters more is serious adverse events—hospitalizations, life-threatening complications, events requiring medical intervention. These were less common in the extended-release group throughout the trial. The finding directly contradicts concerns that a longer-acting formulation might pose heightened risks if complications arose, since the medication can't be immediately stopped like a daily pill can.

Neonatal outcomes showed no difference in NOWS severity between treatment groups. Babies born to mothers on extended-release buprenorphine faced the same withdrawal challenges as those whose mothers took sublingual medication—neither better nor worse. That parity matters because it confirms that achieving superior maternal abstinence didn't come at the cost of infant health.

Why Weekly Dosing Changes the Equation

Extended-release buprenorphine addresses structural barriers that sublingual treatment can't overcome. A patient without reliable transportation doesn't need daily clinic access when a single weekly visit covers medication. Someone in unstable housing doesn't risk losing medication or having it stolen between doses. The pharmacokinetic profile—steady blood levels rather than peaks and troughs—means cravings and withdrawal remain suppressed around the clock, not just for a few hours after dosing.

For pregnant individuals juggling prenatal appointments, potential bed rest requirements, work obligations, and childcare for existing children, reducing treatment from seven weekly interactions to one removes friction from an already overwhelming equation. The same holds postpartum, when newborn care competes with recovery priorities.

The trial's allowance for monthly formulations postpartum (for non-breastfeeding participants) points toward even greater flexibility. A mother discharged from the hospital with a newborn faces weeks of sleep deprivation, pediatrician visits, and adjustment to new routines. Monthly dosing could be the difference between sustained recovery and relapse triggered by logistical exhaustion rather than lack of motivation.

Unanswered Questions and Implementation Challenges

The study leaves critical questions unresolved. How does extended-release buprenorphine perform across different stages of pregnancy? The trial enrolled participants at various gestational ages; whether initiation during the first trimester versus the third trimester affects outcomes remains unclear. Cost and insurance coverage pose another barrier—extended-release formulations are expensive, and prior authorization requirements often delay or deny access even when clinically indicated.

Provider availability matters too. Administering subcutaneous injections requires trained staff and clinic infrastructure. Rural areas already facing OUD treatment deserts may lack the capacity to offer weekly injection appointments, even if the medication itself becomes more widely prescribed. And while the trial demonstrated safety and efficacy, not every pregnant patient will prefer injections over pills. Shared decision-making requires options; adding extended-release to the toolkit expands choice but shouldn't eliminate sublingual treatment for those who prefer it or can't access injections.

The breastfeeding restriction on monthly formulations also deserves scrutiny. The trial's postpartum protocol limited monthly injections to non-breastfeeding participants, reflecting caution about prolonged medication exposure through breast milk. But breastfeeding itself improves maternal-infant bonding and may reduce NOWS severity; forcing a choice between optimal medication dosing and breastfeeding creates an unnecessary trade-off if further research establishes safety.

What the Results Mean for Policy and Practice

Dr. Winhusen called the findings "exciting" with "immediate clinical application," and that's not hyperbole. The trial provides Level 1 evidence—the gold standard of randomized controlled trials—supporting extended-release buprenorphine as safe and superior to sublingual treatment for pregnant individuals with OUD. Clinicians who've hesitated to prescribe extended-release formulations during pregnancy due to limited data now have peer-reviewed evidence from a multicenter trial published in a top-tier journal.

Insurance companies and Medicaid programs, which often restrict coverage of extended-release buprenorphine to patients who've "failed" sublingual treatment, face pressure to revise those policies. Requiring pregnant patients to try and fail a less effective treatment before accessing superior care contradicts both the evidence and basic ethical principles around maternal-fetal health.

State and federal policymakers navigating opioid settlement spending should take note. Expanding access to extended-release buprenorphine during pregnancy requires infrastructure investment—training providers, equipping clinics, negotiating bulk purchasing agreements, and ensuring Medicaid reimbursement covers the full cost without prior authorization delays. Settlement dollars could fund pilot programs in high-need regions, demonstrating feasibility and building the case for sustained state budget support.

The trial also underscores the value of the NIH HEAL Initiative, which funded this research as part of a broader strategy to accelerate addiction science and translate findings into practice. At a moment when federal addiction funding faces political uncertainty, the study offers a reminder that rigorous clinical research generates actionable knowledge that saves lives.

A Tool, Not a Panacea

Extended-release buprenorphine won't solve every challenge pregnant individuals with OUD face. Stigma from healthcare providers, child welfare systems, and communities persists regardless of medication formulation. Many states still lack robust prenatal care integrated with addiction treatment, forcing patients to navigate fragmented systems. And buprenorphine—whether daily or weekly—remains just one component of comprehensive care that should include counseling, social support, housing assistance, and trauma-informed services.

But tools matter. A medication that improves abstinence rates, reduces serious adverse events, and eases logistical burdens expands what's possible for patients who've often been told their options are limited. The trial's findings suggest that for many pregnant individuals struggling with opioid use disorder, weekly injections could offer a pathway to recovery that daily pills don't.

The next step is ensuring that evidence translates to access—that the patients who could benefit from extended-release buprenorphine can actually get it, without insurance denials, geographic barriers, or provider hesitation standing in the way. The research has done its job. Now the healthcare system has to do its own.