Related article, page 83 .
In this issue of the Journal, Towers et al describe the pregnancy and neonatal outcomes in a prospectively enrolled cohort of pregnant women with an opioid use disorder. These women were given the option of receiving either medication-assisted treatment (n=109) with 1 of the opioid agonists methadone or buprenorphine or undergoing medically supervised withdrawal followed by the opioid antagonist naltrexone (n=121). This study provides important information on the safety and effectiveness of naltrexone in pregnancy.
Naltrexone binds to the opioid receptor; however, as a reversible antagonist, it does not elicit a pharmacologic response but rather competes with exogenous and possibly endogenous opioids. Naltrexone has been used in individuals with opioid use disorders who wish to eliminate opioid use entirely. At least 7–10 days must elapse from the last dose of opioids because naltrexone can initiate withdrawal symptoms if opioids are still present in the body. Naltrexone decreases reactivity to drug-conditioned cues and decreases opioid cravings, potentially reducing the risk for relapse and any associated complications. Naltrexone does not have abuse potential, is well tolerated, does not appear to cause any specific malformation, and does not alter pregnancy course. Despite these advantages, naltrexone has not been embraced because of high discontinuation rates and the unknown potential long-term effects on the developing fetal brain. Naltrexone is available as an oral and injectable formulation (Vivitrol) ; the oral dose is 50 mg daily with a half-life of approximately 13 hours; the injectable form has a half-life of 2–3 weeks. The injectable naltrexone is Food and Drug Administration–approved for both opioid and alcohol use disorders. Naltrexone has also been used extensively to treat alcohol dependence; therefore, it has an extensive history of use, and its safety profile in nonpregnant subjects is well-characterized.
The data provided by Towers et al add substantially to the limited number of reported cases of naltrexone use in pregnancy and begin to address some of the concerns related to this treatment. These concerns have been thoughtfully and systematically summarized by Jones et al and the accompanying commentaries and include relapse during induction and the potential consequences of relapse such as dropping out of prenatal care, resuming risky behaviors, suicide and overdose risk from enhanced sensitivity to opioids, fetal safety that includes fetal withdrawal, modification of fetal opioid receptor–mediated functions, and altered fetal growth and behaviors. The findings reported by Towers et al address some of these concerns. Data are provided on 121 pregnant women who chose to receive naltrexone during some part of their pregnancy. Additionally, data are provided on maternal:cord plasma concentrations of naltrexone and its metabolites. The data indicate that, during pregnancy, the fetus and mother tolerated the medication well, that no major malformations were reported with first trimester exposure, and that the risk of Neonatal Abstinence Syndrome was reduced markedly in those women who completed the program successfully. Furthermore, neonatal head circumference did not appear to be affected adversely. Pregnancy outcomes were not significantly different from those who underwent traditional medication-assisted treatment. Similar encouraging results have been reported by Hulse et al in a series of reports from the University of Western Australia. The data provided by Towers et al were not obtained from a randomized trial; therefore, outcomes by treatment (medication-assisted treatment vs medically supervised withdrawal and maintenance with naltrexone) cannot be compared statistically; however, the rates of maternal and fetal/neonatal outcomes provide fundamental pharmacologic information similar to that obtained in phase 1 or phase 2 trials.
Currently, naltrexone is not recommended in pregnancy because of both the required 7- to 10-day period of opioid abstinence and the potential for relapse as well as concerns for fetal well-being from that period of abstinence and the unknown fetal effects. The American Society of Addiction Medicine, the American College of Obstetricians and Gynecologists, and the Society for Maternal Fetal Medicine have decried the lack of data to enable any meaningful recommendations to be made for this medication during pregnancy. The findings reported by Towers et al and by Hulse et al and others may alleviate some of the concerns raised by these entities. Clearly, a key component of concern is the risk of relapse during the 7- to 10-day period of abstinence that is required to eliminate residual opioids from the mother’s brain. Rates of relapse in nonpregnant subjects is very high, 72% in a recent systematic review, and obviously are affected by a multitude of factors such as the method of detoxification, the motivation of the subject, and the extent and history of opioid usage. In the report of Towers et al, subjects were given the option to try opioid agonist dose reduction or total withdrawal. Amazingly, none of those women who chose to eliminate opioid agonist treatment relapsed during the period before receiving naltrexone; they had the option of resuming medication-assisted treatment, reducing the dose, or eliminating all opioid agonists. Regardless of their choice and their subsequent treatment, they stayed in the program and received the full programmatic support offered to all women. Once started on naltrexone, the percentage of women who used illicit opioids was 12%, similar to the 15% rate of those on medication-assisted treatment. These results are surprising, given the high relapse rates reported previously with the oral formulation. In nonpregnant individuals, the high relapse rate has led to the use of long-lasting injectable or implantable formulations, which appear to have higher rates of adherence.
The excellent response to medically supervised withdrawal clearly addresses 1 of the major concerns raised with the naltrexone-based approach. Additional data are needed before this therapy can be embraced fully; however, because many of the expressed concerns about naltrexone use in pregnancy have not been validated, a more permissive perspective seems reasonable, particularly in those women already receiving naltrexone before pregnancy. In the excellent summary by Jones et al that defines the issues surrounding naltrexone use, a discussion by McCullough et al addressed ethical considerations regarding the type of studies that should be considered for this treatment option. They suggested that insufficient data exist to consider a randomized trial but recommended that more information should be obtained from phase 1 and 2 studies such as that reported in this Journal by Towers et al. Given that naltrexone and other opioids (which include buprenorphine and methadone) cross the placental barrier, it is also important to focus on neonatal neurodevelopment in those who are exposed to these medications. We commend Towers et al for this important contribution and encourage funding agencies to consider supporting such undertakings that can provide another alternative to pregnant women with an opioid use disorder.
The authors report no conflict of interest.
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