In this randomized, double-blind trial, infants who had prenatal exposure to buprenorphine required significantly less morphine for the treatment of NAS, a significantly shorter period of NAS treatment, and a significantly shorter hospital stay than did infants with prenatal exposure to methadone. The superiority of buprenorphine over methadone did not extend to differences in the number of neonates requiring NAS treatment, peak NAS score, head circumference, any other neonatal outcome, or any maternal outcome.
Although buprenorphine was superior for two of the five primary outcomes among women who completed treatment, women who were taking buprenorphine were more likely to discontinue treatment. If patients with more severe opioid dependence were more likely to leave the buprenorphine group than the methadone group, this factor could have accounted for better outcomes in the buprenorphine group. However, the absence of significant between-group differences in baseline characteristics and in previous and current substance-use characteristics, both for women who completed treatment and for those who did not, suggests that differences in the rates of treatment completion are unlikely to explain the results. In addition, the significant differences between groups in the amount of morphine required for the treatment of NAS and the duration of the hospital stay remained significant in post hoc analyses that excluded participants receiving 100 mg or more of methadone daily.
Methadone has been the recommended standard of care for opioid-dependent pregnant women, and our double-blind study provides critical data on the outcomes of methadone treatment. Our findings support the safety and usefulness of methadone treatment for opioid dependence during pregnancy, and they also show that the treatment of opioid-dependent pregnant women with buprenorphine results in a clinically meaningful reduction in the severity of NAS in their neonates, as compared with methadone. The mechanisms responsible for this effect remain elusive; variability in the MDR1
genotype may influence the transport of methadone or buprenorphine to the fetus and thus the combination of NAS symptoms exhibited.38,39
Our finding that there was no significant difference between the treatment groups in rates of opioid use during treatment is consistent with observations in previous randomized trials involving nonpregnant patients that methadone and buprenorphine cause similar reductions in illicit opioid use.32
Moreover, the low levels of concomitant use of alcohol and illicit drugs, in combination with the nonsignificant differences in other maternal outcomes between the methadone and buprenorphine groups, suggest that these two medications, in the context of comprehensive care, do not differ markedly in terms of their effect on maternal treatment outcomes at delivery. Thus, the less severe NAS in neonates exposed to buprenorphine as compared with those exposed to methadone cannot be attributed to different effects of these agents on the outcomes of maternal opioid treatment.
These results must be considered in light of the markedly different rates of attrition, which were largely due to greater patient dissatisfaction with buprenorphine than with methadone. Although this finding is similar to the results of trials in nonpregnant patients receiving doses within similar acceptable therapeutic ranges,12
the reasons for the difference in attrition rates are unknown. It is possible that withdrawal was inadequate before the first dose of buprenorphine was administered or that buprenorphine induction was too slow.40,41
In both cases, administering the initial induction dose in smaller increments throughout the day might reduce the dropout rate.42
It is also possible that there is individual variation in the absorption of sublingual buprenorphine tablets. Another possible explanation is that an abrupt cessation of treatment may be more comfortable for patients taking buprenorphine than for those taking methadone because of the milder effects of withdrawal with buprenorphine.43
Buprenorphine may have less potent agonistic effects than methadone in mitigating craving and other symptoms of withdrawal, especially in patients who are highly dependent on opioids. Whatever the reasons, the fact that two primary outcomes remained significant in post hoc analyses omitting participants whose methadone dose at delivery exceeded 100 mg lends support to our general conclusions, particularly given the lost power associated with removing 19% of our sample (25 of 131 participants).
The greater rate of satisfaction with methadone affirms the important role it plays in treating pregnant women who are dependent on opioids. Moreover, given the partial agonistic activity of buprenorphine and its ceiling effect at maximal doses, it will not be the optimal treatment for all pregnant patients with a dependency on opioids. Further research is needed to assess the effectiveness of methods intended to reduce buprenorphine-specific attrition and to examine factors that may predict maternal and neonatal responses to each medication (e.g., pharmacogenomics44
), making it feasible to identify subpopulations of pregnant patients who are more likely to have a response to one medication than to the other.
In summary, our findings are consistent with the use of buprenorphine as an alternative to methadone for the treatment of opioid dependency during pregnancy. Although there were no significant differences in overall rates of NAS among infants exposed to buprenorphine and those exposed to methadone, the benefits of buprenorphine in reducing the severity of NAS among neonates with this complication suggest that it should be considered a first-line treatment option in pregnancy. In selecting a course of treatment, however, clinicians should take into account the possibility of reduced adherence and the ceiling effect of this medication as compared with methadone.