Pharmacokinetics and Breast Milk Transfer to Infants of Subcutaneous Extended-Release Buprenorphine for the Treatment of Individuals with Opioid Use Disorder

Abstract

Background:

Extended-release buprenorphine (XR BUP) is commonly used for individuals with opioid-use disorder (OUD), however, with limited experience in pregnancy. N-methyl-2-pyrrolidone (NMP), an excipient of monthly XR BUP formulations, is a developmental toxicant. No information is available on pharmacokinetics or breast milk transfer in lactating individuals receiving XR BUP.

Methods:

Samples of maternal plasma, infant plasma, and breast milk were collected from lactating individuals between 0 and 6 months postpartum receiving monthly XR BUP. All samples were analyzed for BUP and NMP concentrations using a validated liquid chromatography–tandem mass spectrometry assay.

Results:

Three lactating individuals provided a total of nine maternal plasma, six infant plasma, and five breast milk samples. Mean BUP concentrations were 6.0 ng/mL (standard deviation [SD] 1.6) in maternal plasma, 8.9 ng/mL (SD 6.6) in breast milk, and below the lower limit of quantitation for all infant plasma samples. We estimated the relative infant dose (RID) of BUP to be 1%. NMP was detectable in maternal plasma (mean 5.43 μg/mL, SD 4.56) and breast milk (mean 3.83 μg/mL, SD 5.07) only from samples measured between 1 and 5 hours after dosing. NMP was not detected in infant plasma.

Conclusions:

Among lactating individuals receiving XR BUP, BUP was present in low levels in maternal plasma (similar to nonlactating individuals on XR BUP) and breast milk of lactating individuals receiving XR BUP (similar to lactating individuals on sublingual BUP), resulting in a low RID. NMP passes into breast milk, however, was not present in infant plasma. Additional data are needed before definitive conclusions can be made.

Introduction

The rate of opioid use disorder (OUD) during pregnancy in the United States increased by 131% between 2010 and 2017 to 8.2 per 1,000 deliveries.¹ While pregnancy is a motivating time for individuals to abstain from nonprescribed drug use, the postpartum period is associated with an increased risk for relapse and overdose.² This risk is mitigated by the receipt of pharmacotherapy for OUD.² First-line treatment during pregnancy and the postpartum period is methadone or any formulation of sublingual buprenorphine (SL BUP).³ An extended-release monthly formulation of BUP (Sublocade) was approved by the Food and Drug Administration for nonpregnant adults with OUD in 2017.⁴ There are currently very little data assessing the safety and efficacy of extended-release BUP (XR BUP) during pregnancy and the postpartum period.

XR BUP administered by subcutaneous injection provides a slow release of BUP from the subcutaneous depot throughout a prolonged time period, such as over a 28-day interval.⁴ XR BUP formulations have less variability in plasma levels than SL BUP, which could be particularly beneficial for stability in perinatal people.^5,6 Two formulations are currently in use in nonpregnant patients, including Sublocade and Brixadi®.^6,7 In nonpregnant patients, XR BUP has been shown to be as effective as SL BUP at decreasing return to nonprescribed opioid use.⁸ There is concern for use of some XR BUP formulations during pregnancy due to the presence of NMP (N-methyl-2-pyrrolidone), a biodegradable solvent that allows for the sustained-release of drugs from the injection site.^4,9 Both human and animal studies show a dichotomy of findings regarding the safety of NMP. A clinical trial utilizing oral NMP found no adverse events in doses up to 1 g/day.¹⁰ However, rodent studies have shown that NMP can cause fetal abnormalities at high doses.⁹ Moreover, a case report of a chronic workplace exposure to high levels of NMP via inhalation and direct skin exposure of a pregnant individual was associated with an occurrence of stillbirth at 31 weeks.¹¹

Also of importance in postpartum individuals is the safety of medications used for the treatment of OUD during lactation. Prior studies have demonstrated the safety of SL BUP formulations during lactation.^12–15 BUP and its primary metabolite nor-BUP were detected in low levels in breast milk after exposure to SL BUP with undetectable concentrations in infant plasma. Infants were estimated to be exposed to an estimated relative infant dose (RID) of less than 1% consistent with safety during lactation.^12,16 There have been no prior studies examining NMP in lactating individuals.

Several survey studies of pregnant and postpartum individuals have indicated an interest in use of XR BUP formulations.^4,16 An initial study of XR BUP during pregnancy has not demonstrated any major adverse effects.¹⁷ Despite the potential advantages of use of these formulations in the high-risk perinatal period, there is limited research evaluating the safety of XR BUP formulations on the developing fetus and during lactation.^4,18 The objective of this study was to begin to fill these knowledge gaps by evaluating maternal, breast milk, and infant concentrations of BUP and NMP in lactating individuals receiving XR BUP and their infants.

Materials and Methods

This was a prospective cohort study that took place at Boston Medical Center (BMC), a substudy of a larger study, the MOM NEST Study (NCT03718104). The study was approved by the Boston University Medical Campus Institutional Review Board. To be eligible, individuals had to be ≥18 years of age, between 0 and 6 months postpartum, have had a singleton pregnancy, English-speaking, willing to complete study visits at BMC, receiving prescribed monthly XR BUP (Sublocade formulation) as part of their clinical care for the treatment of OUD, and be currently breastfeeding. Those individuals who did not have current custody of their infant and those with severe psychiatric conditions were excluded. Participants were enrolled between September 2022 and June 2023.

The study aimed to complete paired maternal blood, infant blood, and breast milk samples at three time points in the postpartum period at any point between enrollment and 12 months postpartum if still breastfeeding. Participants pumped breast milk just before the visits, with blood samples collected during their visit. Date and time of sample collection, current XR BUP dose, most recent maternal weight, date and values of most recent serum creatinine and liver function tests, date and time of last two XR BUP injections, and days postpartum at time of collection were recorded.

Participants completed questionnaires at their baseline visit, including demographics, medical and psychiatric history, and substance-use disorder histories. Participants also completed questionnaires with each breast milk collection about their infant’s current intake of breast milk and formula in the prior 24 hours. Their electronic medical records were reviewed over the course of their study participation.

Laboratory methods

Breast milk and plasma sample were stored in 0.5–1 mL aliquots at −80°C until batched shipments to the University of California San Diego laboratory. Calibrators were prepared in human plasma and quality control materials were matrix matched in plasma and breast milk from certified reference material: BUP (Cat#: B-044; Cerilliant); NMP (Cat#: 78769; Sigma Aldrich); and NMP-d9 (Cat#:615854; Sigma Aldrich). For BUP, internal standards were prepared from certified reference material: BUP-d4 (Cat#: B-901; Cerilliant). Calibration standards were prepared in Mass Spect Gold standard plasma (Cat#: MSG7000; Golden West Diagnostics) and breast milk and were used to generate an external 8-point calibration curve (0.5, 1, 5, 10, 25, 50, 100, and 250 ng/mL) using linear regression (1/× weighting) to plot the peak area ratio versus concentration. For NMP, calibration standards prepared in Mass Spect Gold standard plasma (Cat#: MSG7000; Golden West Diagnostics) and blank breast milk were used to generate an external single-point calibration curve (100 ng/mL).

Quantitative determination of BUP and NMP in specimens was determined by liquid chromatography multiple reaction monitoring spectrometry on a Waters TQ-XS triple quadrupole mass spectrometer coupled to an Acquity I-class FTN liquid chromatography system. Chromatography was obtained using an Acquity BEH C18 column (50 mm length × 2.1 mm I.D; 1.7-µm particle size, Cat#: 1860002350, Waters Corporation).

Statistical methods

Descriptive statistics for baseline characteristics and pregnancy outcomes were calculated. BUP and NMP concentrations by specimen type were summarized utilizing means (standard deviations [SD]) and medians (25th and 75th percentiles). The mean time after the XR BUP dose in days was determined for each sample type. The volume of breast milk consumed per day at each sample collection time point was collected. The RID from breast milk was calculated based on maternal and infant weights and typical breast milk intake (150 mL/kg/day).

Results

A total of five participants were enrolled in the study; however, only three provided biological samples due to discontinuation of breastfeeding by the time of their study visits in the other participants. All three were receiving 300 mg of XR BUP subcutaneously monthly. Two of the patients delivered preterm at 33 0/7 and 34 6/7 weeks and one at 37 1/7 weeks of gestational age. All transitioned to XR BUP after delivery with an average of two doses before first timing of sampling. All participants were mix-feeding with breast milk and formula, with a mean 68.8% (SD 20.0%) breast milk consumption reported in the 24 hours before each sampling time point (Table 1). The estimated volume of breast milk consumption per day was determined based on reported breastfeeding sessions and pumped breast milk volume in the 24 hours before sample collection and averaged 29.6 (SD 11.8) ounces per day.

Table 1.

Characteristics of Three Mother–Infant Dyads with Extended-Release Buprenorphine Exposure

Variable	N (%) or mean (SD)
Maternal age at enrollment (years)	30.3 (7.4)
Maternal ethnicity
Non-Hispanic	3 (100)
Hispanic	0 (0)
Maternal race
White	2 (66.7)
Black	1 (33.3)
Maternal health insurance
Medicaid	2 (66.7)
Private insurance	1 (33.3)
Medication for opioid use disorder (MOUD) at delivery
Sublingual buprenorphine-naloxone	1 (33.3)
Sublingual buprenorphine	1 (33.3)
Extended-release buprenorphine CAM2038	1 (33.3)
Infant gender
Female	2 (66.7)
Male	1 (33.3)
Birth weight (grams)	2248 (653)
Sample timing summary
Maternal weight (kg) at time of first sampling	84.4 (10.8)
Dose of XR BUP at time of sampling (mg/dose)	300
Weeks postpartum of sample collection	16.5 (5.4)
Direct breastfeeding frequency per day at time of sampling	6.4 (2.9)
Estimated breast milk volume of intake at time of sampling (ounces/day)	29.6 (11.8)
Percent breast milk intake per day at time of sampling	68.8 (20.0)

XR BUP, extended-release buprenorphine.

A total of nine maternal plasma, six infant plasma, and five breast milk samples were collected. Samples were taken at a mean of 16.5 (SD 5.4) weeks postpartum and a mean of 16.5 days after the last dose of XR BUP. Maternal plasma concentrations (mean 6.0 ng/mL, SD 1.6) were similar to those previously reported in nonpregnant individuals on XR BUP and postpartum individuals on SL BUP. Breast milk concentrations of BUP after XR BUP were a mean 8.9 ng/mL (SD 6.6) with an RID of 1% with a mean milk-to-plasma ratio of 1.2 (SD 0.6), similar to previously reported levels in SL BUP. BUP was below the lower limit of quantitation (<0.5 ng/mL) for all infant plasma samples (Table 2). NMP was detectable in maternal plasma (mean 5.43 μg/mL, SD 4.56) and breast milk (mean 3.83 μg/mL, SD 5.07) from samples measured between 1 and 5 hours after dosing, with levels less frequently detected when measured between 5 and 35 days after dosing. NMP was not detected in any infant plasma samples (Table 3). The mean milk-to-plasma ratio for NMP was 1.4 (SD 0.4).

Table 2.

Buprenorphine Concentrations in Mother–Infant Dyads in Maternal Plasma, Breast Milk, and Infant Plasma

Paired sample number	Dyad number	Time since last injection	Maternal plasma concentration (ng/mL)	Breast milk concentration (ng/mL)	Infant plasma concentration (ng/mL)	Milk: Plasma ratio
1	3	1 hour	4.4	No sample available	No sample available	NA
2	1	1 hour	5.9	No sample available	ND	NA
3	2	5 hours	5.6	7.0	ND	1.3
4	1	5 days	6.3	7.3	ND	1.2
5	2	13 days	9.3	21.4	ND	2.3
6	1	13 days	7.2	7.0	ND	1.0
7	3	15 days	ND	No sample available	No sample available	NA
8	2	27 days	No sample available	No sample available	ND	NA
9	1	29 days	4.8	1.7	ND	0.4
10	3	35 days	4.2	No sample available	No sample available	NA
Mean (SD)			6.0 (1.6)	8.9 (6.6)	NA	1.2 (0.6)

The lower limit of quantification for buprenorphine (BUP) was 5 ng/mL.

ND, not detected.

Table 3.

N-Methyl-2-Pyrrolidone Concentrations in Mother–Infant Dyads in Maternal Plasma, Breast Milk, and Infant Plasma

Paired sample number	Dyad number	Time since last injection	Maternal plasma concentration (ng/mL)	Breast milk concentration (ng/mL)	Infant plasma concentration (ng/mL)	Milk: Plasma ratio
1	3	1 hour	8,750	No sample available	No sample available	NA
2	1	1 hour	1,931	No sample available	ND	NA
3	2	5 hours	1,100	1,100	ND	1.0
4	1	5 days	ND	ND	ND	NA
5	2	13 days	ND	ND	ND	NA
6	1	13 days	48	85	ND	1.8
7	3	15 days	ND	No sample available	No sample available	NA
8	2	27 days	No sample available	No sample available	ND	NA
9	1	29 days	ND	394	ND	NA
10	3	35 days	ND	No sample available	No sample available	NA
Mean (SD)			5432.2 (4562.0)	3826.3 (5074.1)	NA	1.4 (0.4)

The lower limit of quantification for N-methyl-2-pyrrolidone (NMP) was 5 ng/mL.

ND, not detected.

Discussion

In this pilot study, we found that BUP is present in low levels in breast milk of lactating individuals receiving XR BUP with nondetectable levels in infant plasma. NMP passes into breast milk after XR BUP dosing, yet was not detected in infant plasma. Over the past decade, clinical interest for pregnant and lactating individuals in utilizing XR BUP formulations has grown significantly, with patients citing advantages of not having to remember to take sublingual dosing multiple times a day.^16,17 This pilot study provides additional data to inform best practice clinical care recommendations for lactating individuals with OUD on XR BUP.

BUP levels in maternal plasma were above the target BUP plasma concentration of 2 ng/mL and comparable with exposures reported in nonpregnant individuals taking XR BUP.⁵ Specifically, prior studies reported that 300 mg of monthly XR BUP resulted in plasma levels of BUP between 5 and 10 ng/mL, comparable with our maternal plasma mean of 6.0 ng/mL.⁵ Levels of BUP in breast milk, maternal plasma, and infant plasma were also similar to levels reported in lactating individuals taking SL BUP. We found mean breast milk concentrations of 8.9 ng/mL and nondetectable infant plasma levels with an RID of 1%. One study following seven lactating individuals receiving SL BUP found a similar BUP RID of <1%.¹² Another study of 10 lactating individuals receiving SL BUP found low levels (median 1.2–2.4 ng/mL) in maternal plasma and breast milk (median 1.4–4.8 ng/mL) over the first 30 days postpartum, and nondetectable infant plasma levels on day of life 14.¹³ SL BUP-naloxone was also studied in four lactating individuals over the first 30 days postpartum with maternal plasma BUP concentrations ranging from 3.1 to 10.3 ng/mL and breast milk concentrations ranging from 2.4 to 8.4 ng/mL, again with nondetectable infant BUP levels on day 14.¹⁵

Our study is the first to our knowledge to report measurable NMP concentrations in maternal plasma and breast milk. There are conflicting reports as to the risks of NMP exposure in pregnancy. A study during which rats absorbed NMP through the skin found that it was not teratogenic at low doses, but resulted in both less maternal weight gain and teratogenic effects of fewer live fetuses at a dose of 750 mg/kg.¹⁹ Other animal studies suggest that NMP can negatively impact the development of the fetus.²⁰ A human case report of a pregnant individual who worked three to four 12-hour shifts per week in a laboratory with NMP exposure reported an association with preterm delivery of a stillborn baby at 31 weeks of gestation.¹¹ Around her 16th week of gestation, the individual cleaned up a NMP spill during which her gloves dissolved. The individual also experienced intrauterine growth restriction and a small placenta for gestational age.¹¹

We found detectable concentrations of NMP in breast milk shortly after XR BUP dosing, but not in infant plasma. Prior studies have shown that oral NMP in nonpregnant adults at doses between 100 and 400 mg orally per day is not associated with adverse effects.^10,20 However, NMP is a developmental toxicant and a safe exposure in infants has not been established. Although we did not detect NMP in plasma of breastfeeding infants, it cannot be ruled out that NMP could be transferred via breast milk to infants, with unknown safety consequences.

The strengths of this study include that it is the first study to examine the pharmacokinetics of XR BUP in lactating individuals, and the first measuring NMP in maternal plasma, breast milk, and infant plasma. However, this study has a few limitations, primarily related to our small sample size and limited number of sampling time points after dosing, which did not allow for comprehensive pharmacokinetic analyses. We are also limited in that time of breast milk sampling at the last infant feeding was not collected. In addition, we did not conduct sampling during pregnancy or shortly after delivery to determine if concentrations vary over time in the postpartum period.

Conclusions

Our study found that BUP is present in low levels in breast milk of lactating individuals receiving XR BUP resulting in a low RID. NMP passes into breast milk shortly after XR BUP dosing but was not detected in infant plasma. While this initial study is overall reassuring about the use of XR BUP in this population, additional data are needed before definitive clinical care management recommendations can be made.

Footnotes

Acknowledgment

The authors acknowledge Anchiao Cheng, Aneya Sousa, and Chloe Deflorimonte for their contributions to this study.

Authors’ Contributions

A.N.-R.: Writing—original draft (lead) and reviewing and editing (supporting). K.S.: Conceptualization (equal) and reviewing and editing (equal). X.X.: Data acquisition, writing (supporting), and reviewing and editing (equal). J.M.: Data analysis (lead), writing—original draft (supporting), conceptualization (equal), and reviewing and editing (equal). D.M.S.: Reviewing the editing (equal) and conceptualization (supporting). E.M.W.: Conceptualization (lead), writing—original draft (equal), and reviewing and editing (lead).

Disclosure Statement

The authors have no conflicts of interest to disclose.

Funding Information

We received funding from the NIH (3R01HD96798-05S1 to E.M.W.) for the conduct of this study.

References

Hirai

, Ko

, Owens

, et al. Neonatal abstinence syndrome and maternal opioid-related diagnoses in the US, 2010-2017. JAMA, 2021; 325(2):146–155; doi: 10.1001/jama.2020.24991

Schiff

, Nielsen

, Terplan

, et al. Fatal and nonfatal overdose among pregnant and postpartum women in Massachusetts. Obstet Gynecol, 2018; 132(2):466–474; doi: 10.1097/AOG.0000000000002734

Gilmour

, Honeybul

, Lewis

, et al. Scoping review: Mapping clinical guidelines and policy documents that address the needs of women who are dependent on drugs during the perinatal period. BMC Pregnancy Childbirth, 2024; 24(1):84; doi: 10.1186/s12884-023-06172-6

Hubbell

, Aghenta

, Jones

, et al. Extended-release buprenorphine in pregnancy. Am J Addict, 2024; 33(3):354–356; doi: 10.1111/ajad.13518

Jones

, Ngaimisi

, Gopalakrishnan

, et al. Population pharmacokinetics of a monthly buprenorphine depot injection for the treatment of opioid use disorder: A combined analysis of Phase II and Phase III trials. Clin Pharmacokinet, 2021; 60(4):527–540; doi: 10.1007/s40262-020-00957-0

Lofwall

, Young

, Hansen

, et al. What to expect with pregnant or postpartum prescribing of extended-release buprenorphine (CAM2038). J Clin Gynecol Obstet, 2023; 12(3):110–116; doi: 10.14740/jcgo919

Laffont

, Lapeyra

, Mangal

, et al. A single-dose study to evaluate the relative bioavailability, safety, and tolerability of monthly extended-release buprenorphine at alternative injection locations in adult participants with opioid use disorder. Clin Drug Investig, 2024; 44(12):939–949; doi: 10.1007/s40261-024-01406-7

Marsden

, Kelleher

, Gilvarry

, et al. Superiority and cost-effectiveness of monthly extended-release buprenorphine versus daily standard of care medication: A pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trial. EClinicalMedicine, 2023; 66:102311; doi: 10.1016/j.eclinm.2023.102311

Jouyban

, Fakhree

MAA

, Shayanfar

. Review of pharmaceutical applications of N-methyl-2-pyrrolidone. J Pharm Pharm Sci, 2010; 13(4):524–535; doi: 10.18433/j3p306

10.

Galettis

, Cheah

, Davis

, et al. A phase 1 clinical trial of the repurposable acetyllysine mimetic, n-methyl-2-pyrrolidone (NMP), in relapsed or refractory multiple myeloma. Clin Epigenetics, 2023; 15(1):15; doi: 10.1186/s13148-023-01427-7

11.

Solomon

, Morse

, Garbo

, et al. Stillbirth after occupational exposure to N-methyl-2-pyrrolidone. A case report and review of the literature. J Occup Environ Med, 1996; 38(7):705–713; doi: 10.1097/00043764-199607000-00014

12.

Lindemalm

, Nydert

, Svensson

, et al. Transfer of buprenorphine into breast milk and calculation of infant drug dose. J Hum Lact, 2009; 25(2):199–205; doi: 10.1177/0890334408328295

13.

Jansson

, Spencer

, McConnell

, et al. Maternal buprenorphine maintenance and lactation. J Hum Lact, 2016; 32(4):675–681; doi: 10.1177/0890334416663198

14.

Ilett

, Hackett

, Gower

, et al. Estimated dose exposure of the neonate to buprenorphine and its metabolite norbuprenorphine via breastmilk during maternal buprenorphine substitution treatment. Breastfeed Med, 2012; 7:269–274; doi: 10.1089/bfm.2011.0096

15.

Jansson

, McConnell

, Velez

, et al. Buprenorphine-naloxone maintenance and lactation. J Hum Lact, 2024; 40(1):113–119; doi: 10.1177/08903344231209304

16.

Lai

, Bowman

, Charles

, et al. Pregnant and postpartum individuals’ knowledge, attitudes, and perceptions of extended-release buprenorphine for treatment of opioid use disorder. J Addict Med, 2023; 17(3):342–345; doi: 10.1097/ADM.0000000000001100

17.

Kanervo

, Tupola

, Nikkola

, et al. Extended-release versus oral buprenorphine as opioid maintenance treatment during pregnancy-maternal and neonatal outcomes. Eur J Obstet Gynecol Reprod Biol, 2024; 297:106–110; doi: 10.1016/j.ejogrb.2024.04.003

18.

Harris

, Schiff

, Saia

, et al. Academy of breastfeeding medicine clinical protocol #21: Breastfeeding in the setting of substance use and substance use disorder (Revised 2023). Breastfeed Med, 2023; 18(10):715–733; doi: 10.1089/bfm.2023.29256.abm

19.

Becci

, Knickerbocker

, Reagan

, et al. Teratogenicity study of N-methylpyrrolidone after dermal application to Sprague-Dawley rats. Fundam Appl Toxicol, 1982; 2(2):73–76; doi: 10.1016/s0272-0590(82)80117-6

20.

Akesson

, Jönsson

. Major metabolic pathway for N-methyl-2-pyrrolidone in humans. Drug Metab Dispos, 1997; 25(2):267–269.