The Effects of Maternally Administered Methadone, Buprenorphine and Naltrexone on Offspring: Review of Human and Animal Data

Abstract

Most women using heroin are of reproductive age with major risks for their infants. We review clinical and experimental data on fetal, neonatal and postnatal complications associated with methadone, the current "gold standard", and compare these with more recent, but limited, data on developmental effects of buprenorphine, and naltrexone. Methadone is a -opioid receptor agonist and is commonly recommended for treatment of opioid dependence during pregnancy. However, it has undesired outcomes including neonatal abstinence syndrome (NAS). Animal studies also indicate detrimental effects on growth, behaviour, neuroanatomy and biochemistry, and increased perinatal mortality. Buprenorphine is a partial -opioid receptor agonist and a -opioid receptor antagonist. Clinical observations suggest that buprenorphine during pregnancy is similar to methadone on developmental measures but is potentially superior in reducing the incidence and prognosis of NAS. However, small animal studies demonstrate that low doses of buprenorphine during pregnancy and lactation lead to changes in offspring behaviour, neuroanatomy and biochemistry. Naltrexone is a non-selective opioid receptor antagonist. Although data are limited, humans treated with oral or sustained-release implantable naltrexone suggest outcomes potentially superior to those with methadone or buprenorphine. However, animal studies using oral or injectable naltrexone have shown developmental changes following exposure during pregnancy and lactation, raising concerns about its use in humans. Animal studies using chronic exposure, equivalent to clinical depot formulations, are required to evaluate safety. While each treatment is likely to have maternal advantages and disadvantages, studies are urgently required to determine which is optimal for offspring in the short and long term.

Acupuncture for analgesia in the emergency department: a multicentre, randomised, equivalence and non‐inferiority trial

“…Much of the information about the effects of opioids on neonates comes from pregnant patients who abuse opioids or who are on maintenance programs for drug dependence. Maternal opioid use can have significant developmental effects in the fetus, although social and environmental factors (eg other drugs, smoking) may also have an impact (Farid et al, 2008;Winklbaur et al, 2008). Neonatal abstinence syndrome (NAS) requiring treatment occurs in over 60% to 90% of infants exposed to opioids in utero (Farid et al,…”

“…Outcomes tend to be better in mothers on maintenance therapy rather than heroin (Farid et al, 2008 Level IV), and although initial studies suggested an advantage of buprenorphine over methadone (Farid et al, 2008 Level IV), a recent trial (Bakstad et al, 2009 Level III-2) and a meta-analysis (Minozzi et al, 2008 Level I) reported no difference in maternal or neonatal outcome with methadone, buprenorphine or oral morphine. A small study suggested that neonatal outcome was better in mothers receiving opioids for chronic pain rather than addiction, although differences in dose and other environmental factors may contribute (Sharpe & Kuschel, 2004 Level III-2).…”

Buprenorphine with, or without, Naloxone for Pregnant Women?–Review of Current Evidence and Practice in Massachusetts

“…Moreover, long-acting naltrexone injections present similar problems with adequate emergent analgesia and anaesthesia as buprenorphine. Notwithstanding the detoxification and withdrawal, the pure opiate antagonist naltrexone otherwise appears to be reasonably safe for foetal development [33].…”

“…Naloxone's potential for teratogenicity has also been questioned but to our knowledge, never corroborated by evidence [34]. The exact physiologic effects of various opioid receptor agonists and antagonists, especially in long-term use have not been fully elucidated either in pregnancy or in addiction treatment in general [33,35].…”

Behavioural outcomes of four-year-old children prenatally exposed to methadone or buprenorphine: a test of three risk models

“…Several theoretical and empirical studies have claimed that prenatal exposure to methadone or buprenorphine in combination with lifestyle-related factors such as maternal smoking and illicit drug use during pregnancy directly influence child development (for reviews, see Farid, Dunlop, Tait, & Hulse, 2008;Konijnenberg & Melinder, 2011). Prenatal exposure to opioids such as methadone and buprenorphine causes neonatal abstinence syndrome (NAS) in approximately half of all prenatally-exposed infants (Jones et al, 2010).…”