JAMA Internal Medicine · March 2026
Extended-Release vs Sublingual Buprenorphine in Pregnancy
A Randomized Clinical Trial Through 12 Months Post Partum
Winhusen TJ et al. JAMA Intern Med. doi:10.1001/jamainternmed.2026.0057
Background
Why Consider Extended-Release Buprenorphine?
Challenge 1
💊
Diversion & Misuse
Daily sublingual tablets carry risk of diversion and non-prescribed use.
Challenge 2
📉
Adherence Barriers
Daily dosing during pregnancy is associated with poor adherence rates.
Challenge 3
🔄
Peak-Trough Effects
Plasma levels fall during pregnancy, inadequately suppressing cravings.
Extended-release buprenorphine (Brixadi/CAM2038) provides stable plasma levels via weekly subcutaneous injection — potentially addressing all three challenges.
Methods
Trial Design
1
Enrollment
Adults with OUD, singleton pregnancy 6–30 wks GA
2
Randomization
1:1 allocation · Balanced on site & GA
3
Pregnancy Phase
Weekly ER-BUP injection vs daily SL-BUP
4
Delivery
Infant NOWS monitoring & outcomes
5
Post Partum
12-month follow-up · Monthly visits
Extended-Release (n=69)
Brixadi 24 mg/wk SC injection during pregnancy; monthly option post partum if not breastfeeding
Sublingual (n=71)
Generic buprenorphine tablets or buprenorphine/naloxone film; target 16 mg/day
Open-label, noninferiority RCT · 13 US outpatient peripartum OUD treatment sites · July 2020 – October 2024
Study Population
Participant Characteristics
Mean Age
31.2 yrs
SD 4.6 · Range 18–41
Mean GA at Enrollment
21.1 wks
SD 6.5
Already on Buprenorphine
98.6%
Clinically stable population
OUD (DSM-5, past 12 mo)
75.7%
Moderate or severe
Polysubstance Use
85%
Cotinine positive; 14% amphetamine
Study Completion
81%
Through 12 months post partum
82.9% White · 7.1% Black · 7.1% Hispanic · 10% Additional groups
Primary Outcome · Pregnancy
Illicit Opioid Abstinence During Pregnancy
Extended-Release
82.5%
Negative urine samples
Superior · P = .009
vs
Sublingual
72.6%
Negative urine samples
Noninferiority was demonstrated; superiority testing confirmed ER-BUP advantage.
Buprenorphine adherence was high and similar in both groups (~85%).
Primary outcome: proportion of weekly UDS negative for fentanyl, morphine, heroin, oxycodone, and other illicit opioids. Missing samples imputed as positive.
Key Secondary Outcome · Post Partum
Illicit Opioid Abstinence Post Partum
Extended-Release
60.2%
Negative urine samples
No Difference · P = .45
vs
Sublingual
59.5%
Negative urine samples
Postpartum Adherence
ER-BUP: 69.3% · SL-BUP: 75.5%
Difference not significant (P = .30)
Medication Discontinuation
35% postpartum vs 10% during pregnancy
Custody demands & CPS involvement cited
90% of participants retained maternal custody · 36% had open CPS cases
Infant Outcomes
Neonatal Opioid Withdrawal Syndrome (NOWS)
| Outcome |
ER-BUP (n=66) |
SL-BUP (n=69) |
P Value |
| Treated for NOWS |
30.2% |
26.5% |
.64 |
| Opioid treatment duration |
10.9 days |
14.8 days |
.28 |
| Hospital length of stay |
8.5 days |
9.5 days |
.54 |
| Peak Finnegan score |
10.4 |
10.0 |
.45 |
| Head circumference at birth |
34.0 cm |
33.4 cm |
.049 ✓ |
| 12-month developmental issues |
17.3% |
15.4% |
.79 |
Only 28% of infants required opioid treatment for NOWS — lower than historical rates of 39–48%. All infants had live birth and were discharged alive.
Maternal Safety
Adverse Events & Safety Outcomes
Serious Adverse Events
During Pregnancy
8.7% vs 26.8% P=.007
Post Partum
6.0% vs 18.6% P=.04
Hospitalizations (pregnancy)
8.7% vs 26.8%
Postpartum Pain Management
Any pain medication
85.7% vs 98.5% P=.03
Opioid pain medication
30.2% vs 50.0% P=.02
HADS Anxiety score (PP)
5.8 vs 6.8 P=.04
Non-Serious AEs (Pregnancy)
Any non-serious TEAE
63.8% vs 66.2%
Medication-related
26.1% vs 7.0% P=.003
GI-related (mild/moderate)
Higher in ER group
Injection Site Reactions (ER only)
Severity
Primarily mild–moderate
Overdose events
Rare; associated with medication discontinuation
Critical Appraisal
Strengths & Limitations
Strengths
- ✅ First RCT of ER-buprenorphine in pregnancy
- ✅ 13 geographically diverse US sites
- ✅ High study completion (98% through pregnancy)
- ✅ Comprehensive effectiveness & safety data
- ✅ Pragmatic, real-world clinical settings
- ✅ Polysubstance use population
Limitations
- ⚠️ Open-label design (no blinding)
- ⚠️ Clinically stable population (most already on BUP)
- ⚠️ Supply disruption affected 16 postpartum participants
- ⚠️ Sample predominantly White, non-Hispanic
- ⚠️ Some secondary outcomes underpowered
- ⚠️ Variation in Finnegan scoring across hospitals
Funded by NIH HEAL Initiative · Extended-release buprenorphine donated by Braeburn (CAM2038/Brixadi)
Conclusions & Clinical Implications
What This Trial Tells Us
Weekly extended-release buprenorphine produced
significantly higher illicit opioid abstinence during pregnancy
compared to sublingual buprenorphine (82.5% vs 72.6%; P = .009),
with fewer serious adverse events and
less postpartum opioid pain medication use.
NOWS outcomes were comparable between groups.
-
🟢
ER-buprenorphine is an effective, guideline-supportable option for OUD treatment during pregnancy.
-
🟡
Postpartum advantage is not sustained — both groups show similar abstinence rates after delivery.
-
🔵
Infant safety profile is reassuring; no increase in NOWS severity or developmental delay at 12 months.
Winhusen TJ et al. JAMA Intern Med. Published online March 16, 2026. doi:10.1001/jamainternmed.2026.0057