Kraft and colleagues'  evaluation of buprenorphine as a therapeutic agent for alleviating neonatal abstinence syndrome (NAS) in prenatally opioid-exposed neonates has advanced the thinking in the field of addiction medicine. This commentary reflects on some ‘lessons learned’ from Kraft et al.  to further our field's approach to both research on and treatment of NAS.
First and foremost, Kraft et al. are to be thanked for their pioneering efforts to evaluate buprenorphine as a new therapeutic agent for NAS treatment. Their findings suggest that, in fact, buprenorphine has the necessary initial safety and efficacy data to be subjected to rigorous randomized double-blind controlled trial testing relative to morphine, the most commonly used medication to treat NAS . As second-generation studies intended to evaluate novel medications to treat NAS are designed, they face several questions that Kraft et al. have posed to our field.
First, a primary focus of future research should be the conduct of comparative efficacy studies of buprenorphine and morphine, as Kraft et al.  did not equate dosages or examine the degree of treatment impact of these two medications (other than determine if the MOTHER NAS score of a neonate exceeded a cut-point). As a Phase IB trial, such a limitation is certainly understandable. However, this limitation greatly tempers the strength of any conclusions about the relative merits of buprenorphine over morphine. As Kraft et al. note, a double-blind randomized controlled trial is the next step in addressing the question of relative efficacy.
Secondly, Kraft et al., in combination with the large volume of published NAS research, reminds us that current NAS assessment measures burden staff in terms of ambiguity of item definition, as well as length of training and administration time. With the advent of new medications intended to treat NAS, the field must also refine and examine NAS measures. These measures should focus upon the different expressions of NAS that occur in response to opioids alone and in combination with other substances such as tobacco, benzodiazepines and/or alcohol. Ideally, one NAS measure will be able to differentiate reliably between prenatal exposure to opioids, alcohol, benzodiazepines, tobacco, stimulant drugs and any combination thereof. Future NAS measures require the inclusion of items with clear, quantifiable definitions that require minimal staff training time, and can be administered without undue burden on the neonate, mother and/or hospital staff. Such measures would also need to be subject to rigorous psychometric testing to establish reliability and validity, particularly predictive validity.
A third issue that Kraft et al. raise is the need for standardized evidence-based treatment guidelines for NAS using single, or a combination of, pharmacotherapeutic approaches. Again, the protocol developed by Kraft et al. is a step in that direction. However, the lengths of hospital stay in both medication conditions are longer than providers or payers find ideal, and future studies need to examine how to shorten the length of hospital stays safely with symptom- rather than weight-based protocols for NAS treatment. Such an approach might also have the benefit of exposing the neonate to less total NAS medication . Moreover, it may also be productive to think of the use of additional medications such as phenobarbitol not as ‘rescue’ therapies, but as the stepping-board to integrative pharmacological treatment. Future NAS pharmacological treatments may also benefit from the inclusion of non-pharmacological interventions that focus on strengthening the maternal–infant bond, in addition to medication(s) . The evaluation of comprehensive interventions based not only on pharmacological agents but also on nurturance and care-giving may serve as the focus of the ‘third generation’ of controlled trials examining NAS treatment.
Finally, although NAS places considerable stress on neonates, their families and medical care providers, Kraft et al. remind us that NAS can be assessed and treated effectively. If treated effectively, NAS is a short-term resolvable condition. Neither NAS nor the exposure to NAS medications appears to be a major contributor to any long-term adverse outcomes.
In conclusion, Kraft et al. are to be commended for expanding the possible boundaries for treatment options for neonates requiring medication to alleviate NAS. Building upon this work, our field must continue to work to understand NAS, its expression and its treatment—and, importantly, concomitant maternal and in utero developmental factors that may serve to reduce or exacerbate NAS.