Extended-release buprenorphine in pregnancy
Abstract
Background and Objectives
The relative safety and efficacy of monthly extended-release buprenorphine (XR-BUP) has not been fully evaluated in pregnant persons.
Methods
Case report of two pregnant individuals receiving XR-BUP while pregnant.
Results
Both patients had positive experiences and healthy infants.
Discussion and Conclusions
Sparse data regarding the use of XR-BUP in pregnant patients limits shared decision-making. Additional evidence will support the growing population of pregnant patients exposed to XR-BUP.
Scientific Significance
Positive patient experiences using XR-BUP during pregnancy have been previously unreported. This report will contribute to discussions of risks and benefits for future patients using XR-BUP during pregnancy.
INTRODUCTION
The rates of opioid use and opioid use disorder (OUD) in pregnant people are rising. From 1999 to 2014, the rates of OUD increased fourfold from 1.5 per 1000 hospital births to 6.5 in the United States, affecting an estimated 14.6 per 1000 deliveries in patients insured by Medicaid.1 From 2017 to 2020, pregnancy-associated overdose deaths involving fentanyl and other synthetic opioids increased from 5.73 to 9.47 deaths per 100,000.2 Significant health complications for the birthing person and the pregnancy have been associated with perinatal OUD.3 The current recommendation for perinatal OUD is treatment with medications for opioid use disorder (MOUD): methadone or buprenorphine, both of which have been shown to reduce the rates of non-prescribed opioid use and its complications.4
An extended-release buprenorphine (XR-BP) formulation (Sublocade®, formerly RBP-6000 [Individor Inc.]) was approved by the FDA for treatment of OUD in 2017.5 XR-BUP is a monthly injection demonstrating high levels of retention and treatment satisfaction and increased rates of drug-free patients.6, 7 Most recent data maintain improved results through 18 months of treatment.8 Not much is known about its use in pregnancy, although a survey of 98 pregnant and postpartum people indicated interest in the use of XR-BUP as an alternative to a daily dosed medication (45.6%) and to help avoid opioid withdrawal symptoms between daily dosing (29.1%).9 XR-BUP provides relatively more stable serum levels of buprenorphine, compared to sublingual formulations.5 This could prove beneficial for pregnant patients, as changes in metabolism often lead to dose changes and recurrence of cravings and withdrawals.10
Our literature search identified two published case reports of XR-BUP use in pregnancy.11, 12 In the first case report, two pregnant people were receiving monthly XR-BUP injections when pregnancy was identified, and both decided to terminate buprenorphine treatment at that time. At delivery, there were no patient withdrawal symptoms, no signs of neonatal opioid withdrawal syndrome (NOWS), and no identified birth abnormalities. In the second report, three patients who were previously stable on sublingual buprenorphine daily were switched to XR-BUP while pregnant. Within days of the initial injections, they developed undesirable side effects which included euphoria, withdrawal symptoms and cravings. Additional doses of sublingual buprenorphine were administered to minimize symptoms of withdrawal and cravings, and patients were subsequently switched back to sublingual buprenorphine alone for maintenance treatment. No patient opted to receive a second XR-BUP injection. The authors cautioned against further use of XR-BUP in pregnant women until further studies are carried out.12 In addition, other concerns have been raised about the potential for the monthly injection excipient, N-methyl-2-pyrrolidone (NMP), to cause adverse fetal developmental effects5, 13 and ongoing research is examining treatment in pregnancy using a weekly extended-release formulation that does not include this same excipient.14 As Bernstein et al. discuss in their reply to Cleary et al. shared-decision making needs to consider the lack of significant research on this topic and avoid condemning its use based on “the negative experiences of three patients.” Our report adds to the data on pregnancy that is achieved while already taking XR-BUP and may help guide patient-centered discussions for those patients hoping to maintain or initiate the medication in pregnancy.
Both patients signed an agreement for publication of their case reports and engaged in multiple, extensive conversations regarding risks and benefits of treatment.
CASE PRESENTATION
Patient 1
A 27-year-old G2P0020 patient with a past medical history of OUD, ADHD, and tobacco use disorder initially presented to the emergency department for treatment of opioid withdrawal. She had a 2-year history of intravenous heroin and fentanyl use and had a negative pregnancy test (HCG) at that time. She completed induction with sublingual buprenorphine-naloxone but noted nausea and vomiting. Within 1 month, she received a 300 mg XR-BUP injection and her nausea/vomiting resolved. The day of her second injection she was noted to have a pregnancy test which was positive. At this time, the risks of XR-BUP were discussed including the lack of safety data in pregnancy. Included in shared-decision making was the patient's improved tolerance of XR-BUP compared with sublingual buprenorphine. She subsequently received 100 mg doses on schedule for the next 2 months with no reported withdrawal symptoms. After discussing with the patient, a plan was made to change the frequency of XR-BUP injections to 6 weeks instead of the typical 4 weeks, to minimize risk to the unborn fetus from excipient NMP and to limit potential discomfort from injections into the gravid abdomen. No opioid use throughout the pregnancy was identified, and no withdrawal symptoms or cravings were noted. After delivery, the newborn was cared for in the Neonatal Intensive Care Unit (NICU) for 5 days due to NOWS. The newborn received no medication for withdrawals and did not have abnormalities or further medical concerns at the time of hospital discharge. At 1 year post-delivery, there are no identified health concerns for the patient or infant. The infant is reported to be meeting all developmental milestones and the patient remains drug-free with ongoing use of XR-BUP.
Patient 2
A 35-year-old G2P1011 patient with a history of opioid, sedative, and methamphetamine use disorders, anxiety, chronic back pain, and Hepatitis C with no active viral load had been successfully maintained on XR-BUP at 100 mg monthly for a 4-year duration. The patient contacted clinic staff regarding a new diagnosis of pregnancy in the context of her XR-BUP treatment. At that time, shared-decision making was employed with a discussion of risks and benefits. The patient expressed concerns for her ongoing recovery with possible cessation of XR-BUP. A longer duration between injections was discussed as an option to decrease medication and excipient NMP exposure. Additional discussion explored the option of a lower dose regimen due to lower extremity edema, a chronic side-effect of previous XR-BUP injections. During the first trimester the injection dose was decreased to 50 mg. She received injections monthly throughout the pregnancy except one incident when the patient required supplemental buprenorphine tablets for mild withdrawal symptoms when her XR-BUP was delayed due to inclement weather.
During pregnancy the patient underwent a normal and complete anatomic survey ultrasound with normal fetal growth throughout her pregnancy. She experienced an uncomplicated full-term delivery. The neonate was hospitalized for 2 days without NICU admission and did not have any evidence of NOWS. At 1 month after delivery, the infant was meeting all milestones and the patient remained on XR-BUP prescribed 50 mg monthly with no evidence of return to non-prescribed opioid use. Her swelling resolved after delivery and has not returned with continued use of this lower dose.
Both patients experienced uncomplicated pain management and were breastfeeding consistently from birth through time of manuscript submission.
DISCUSSION
Despite the potential benefits of XR-BUP, there is limited knowledge about its use in pregnancy. As more patients are treated with monthly injectable XR-BUP, there will be an increase in patients that become pregnant while taking this medication. Counseling of nonpregnant but reproductive potential patients is imperative to confirm that contraception is utilized if pregnancy is not desired while taking XR-BUP given the limited safety data.
The benefits of XR-BUP outside of pregnancy include improvements in treatment retention, quality of life, and drug-free incidence. It would be reasonable to expect these benefits to translate to pregnant persons.6-8 Additionally, it is important for pregnant individuals who are taking buprenorphine to be closely monitored by a healthcare provider to ensure the safety of both the mother and the baby. These individuals would access healthcare more often to receive monthly injectable XR-BUP, and therefore would have more opportunities for prenatal care and supporting any co-occurring substance use that may persist despite the benefits of buprenorphine.
The patients in this case discussion were both counseled extensively about the risks and benefits involved with XR-BUP use in pregnancy. Topics reviewed included the theoretical risk of perinatal excipient exposure causing fetal malformations as well as the lack of information available to fully evaluate the risks and benefits. Discussions included the risks and benefits associated with all patients taking buprenorphine during pregnancy, such as higher rates of NOWS and lower risk of returning to opioid use. In both cases, shared-decision making resulted in patient decisions to continue XR-BUP. Both patients identified the benefits of XR-BUP to include the ease of management, the perceived lack of side-effects compared with sublingual daily dosing, and the ability to avoid daily medication administration.
It is important to note that pregnancy occurred after initiating XR-BUP for both patients—these reports will not reflect the initiation of XR-BUP in a confirmed pregnancy. Additionally, more robust data is necessary to assess the clinical outcomes of XR-BUP in pregnant patients.
An ongoing multisite analysis, the RECOVER study, is currently examining the efficacy of the newer weekly injectable XR-BUP in pregnant patients and is enrolling over 200 patients.14 This formulation does not contain an excipient that could cause fetal developmental concerns. While awaiting this evidence, providers are encouraged to balance the limited existing data with the potential risks and benefits of XR-BUP in pregnancy for the patient and their ongoing recovery.
ACKNOWLEDGMENTS
The authors alone are responsible for the content and writing of this paper.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
