An evidence-based recommendation to increase the dosing frequency of buprenorphine during pregnancy

Abstract

Background Dose-adjusted plasma concentrations of buprenorphine are significantly decreased during pregnancy compared to the non-pregnant state. This observation suggests that pregnant women may need a higher dose of buprenorphine than non-pregnant individuals in order to maintain similar drug exposure (plasma concentrations over time after a dose). The current dosing recommendations for buprenorphine during pregnancy address the total daily dose of buprenorphine to be administered but the frequency of dosing is not clearly addressed. Based on buprenorphine’s long terminal half-life, once daily or twice daily dosing has generally been suggested. Objective To assess the impact of dosing frequency on buprenorphine plasma concentration time course during pregnancy. Study Design We have utilized three data sources to determine an optimal frequency for dosing of buprenorphine during pregnancy: data from a pharmacokinetic study of 14 pregnant and post-partum women on maintenance buprenorphine in a supervised clinical setting; data from pregnant women attending a buprenorphine clinic; and data from a physiologically based pharmacokinetic (PBPK) modeling of buprenorphine pharmacokinetics in non-pregnant subjects. Results Among the fourteen women participating in the pharmacokinetic study during and after pregnancy, plasma concentrations of buprenorphine were < 1ng/ml (the theoretical concentration required to prevent withdrawal symptoms) for 50–80% of the 12 hour dosing interval while at steady state. Among 62 women followed in a opioid agonist treatment program, where dosing frequency is determined in part by patient preference, 10 (16 %) were on once daily dosing, 10 (16%) were on twice daily dosing, 28 (45%) were on thrice daily dosing and 14 (23%) were on four times daily dosing. A physiologic based pharmacokinetic (PBPK) model in non- pregnant subjects demonstrated that dosing frequency impacts the duration over which the plasma concentrations are below a specified plasma concentration threshold. Conclusion(s) A more frequent dosing interval i.e. TID or QID dosing may be required in pregnant women to sustain plasma concentrations above the threshold of 1ng/ml to prevent withdrawal symptoms and to improve adherence.

Gestational changes in buprenorphine exposure: A physiologically‐based pharmacokinetic analysis

“…The model predictions are in agreement with the current clinical practice in pregnant women. At the Pregnancy Recovery Center at Magee‐Womens Hospital, among 62 pregnant women followed up in an opioid agonist treatment programme, 68% of the patients chose a three or four times dosing per day to maximally suppress craving/withdrawal symptoms .…”

“…We have demonstrated in a small cohort of pregnant women that plasma concentrations of BUP and the corresponding BUP exposure is significantly reduced during pregnancy compared to the postpartum state [19]. We have suggested that more frequent dosing of buprenorphine will reduce the time that treated women are likely to be subtherapeutic during pregnancy [19,20]. Our observations may at least in part explain the report of Jones et al [21], who in a large clinical trial reported higher study withdrawal rates in subjects assigned to BUP compared with methadone.…”

Methadone or buprenorphine? The choice of substitution therapy in pregnant opioid dependent women

“…Volume of distribution and increased clearance during pregnancy compared to the postnatal period, causes even 50% reduction of the drug's concentration, frequently to subtherapeutic dose levels [44]. The latest pharmacokinetic studies suggest that apart from the need to increase the daily buprenorphine dosage, its frequency also needs to be increased to three-four times per day [45]. Buprenorphine was confirmed as a substitution therapy drug later than methadone and there are fewer reports on its influence on pregnant women Wyniki szeregu badań dotyczących relacji między dawkami metadonu stosowanymi w późnym okresie ciąży a częstością występowania i nasileniem NAS nie doprowadziły do ustalenia jednoznacznych wniosków.…”

“…Objętość dystrybucji i zwiększenie klirensu podczas ciąży, w porównaniu z okresem poporodowym, powodują nawet 50-procentową redukcję stężenia leku, często do dawek subterapeutycznych [44]. Ostatnie badania farmakokinetyczne sugerują, oprócz potrzeby zwiększenia dziennej dawki buprenorfiny, zwiększenie częstotliwości dawkowania trzy do czterech razy dziennie [45]. Buprenorfina została zatwierdzona do terapii substytucyjnej później niż metadon i dlatego jest mniej doniesień na temat jej wpływu na kobiety w ciąży i ich potomstwo.…”

Medication treatment for opioid use disorder in expectant mothers (MOMs): Design considerations for a pragmatic randomized trial comparing extended-release and daily buprenorphine formulations

“…Relative to methadone, BUP-SL offers the advantages of lower NOWS severity in infants [9] and greater convenience for pregnant women by removing the requirement of near-daily clinic visits for dosing [10]. BUP-SL limitations include risk for diversion [11], potential for non-adherence [11], poor retention [12][13][14], and daily peak-trough effects [15], with evidence that BUP-maintained pregnant women may be at sub-therapeutic doses for most of their dosing interval [16].…”