Randomized controlled trials in pregnancy: scientific and ethical aspects. Exposure to different opioid medications during pregnancy in an intra‐individual comparison

Abstract

Background Chronic medical conditions such as opioid dependence require evidence-based treatment recommendations. However, pregnant women are underrepresented in clinical trials. We describe the first within-subject comparison of maternal and neonatal outcomes for methadone vs. buprenorphine exposed pregnancies. Though methadone is the established treatment of pregnant opioid dependent women, recent investigations have shown a trend for a milder neonatal abstinence syndrome (NAS) under buprenorphine. However, it is not only the choice of maintenance medication that determines the occurrence of NAS, other factors such as maternal metabolism, illicit substance abuse and nicotine consumption also influence its severity and duration and represent confounding factors in the assessment of randomized clinical trials. Case series description Three women who were part of the European cohort of a randomized, double-blind multicenter trial with a contingency management tool [the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study], each had two consecutive pregnancies and were maintained on either methadone or buprenorphine for their first and then the respective opposite, still-blinded medication for their second pregnancy. Birth measurements, the total neonatal abstinence score, the total amounts of medication used to treat NAS and the days of NAS treatment duration were assessed. Results Both medications were effective and safe in reducing illicit opioid relapse and avoiding preterm labour. Methadone maintenance yielded to a significantly higher neonatal birth weight. Data patterns suggest that buprenorphine-exposure was associated with lower neonatal abstinence syndrome (NAS) scores. Findings from this unique case series are consistent with earlier reports using between-group analyses. Conclusions Buprenorphine has the potential to become an established treatment alternative to methadone for pregnant opioid dependent women. Under special consideration of ethical boundaries, psychopharmacological treatment during pregnancy must be addressed as an integral part of clinical research projects in order to optimize treatment for women and neonates.

Statement of the American Society of Addiction Medicine Consensus Panel on the Use of Buprenorphine in Office-Based Treatment of Opioid Addiction

“…Several studies have recently been published that have demonstrated that buprenorphine offers a substantial efficacy advantage over the current standard of care with oral morphine (Kraft et al, 2011;Unger et al, 2011). Several studies have recently been published that have demonstrated that buprenorphine offers a substantial efficacy advantage over the current standard of care with oral morphine (Kraft et al, 2011;Unger et al, 2011).…”

Neonatal Abstinence Syndrome: Update on Diagnostic and Therapeutic Strategies

“…This indicates that fetal exposure does not necessarily result in NAS symptoms. Compared with methadone‐exposed neonates, buprenorphine‐exposed neonates usually experience a milder NAS course and a reduced need for pharmacotherapy . This clinical heterogeneity may result from the complex interplay of genetic, physiologic, and environmental factors.…”

A National Survey Investigating Methadone Treatment for Pregnant Opioid Dependent Women in England and Wales

“…The Royal College of General Practitioners', using evidence from a comparison of two self-selected Scottish groups (Hepburn, 1997), suggest that methadone detoxification can be carried out 'at any speed and at any stage' during pregnancy (Ford et al, 2005). Others highlight nevertheless the poor maternal treatment outcomes observed following opioid detoxification, such as the high rate of relapse back to illicit drug use (Kashiwagi, Arlettaz, Lauper, Zimmermann, & Hebisch, 2005), which has been widely observed to be detrimental to neonatal outcomes (Hulse, Milne, English, & Holman, 1997;Unger et al, 2011). In this survey the likelihood of a CDTS recommending inpatient detoxification was doubled (0R = 2.28) when neonatologists, were involved in patient care.…”