As someone with an interest in neonatal abstinence (NAS) I am surprised that I missed this study back in May. Anyone who says they aren’t interested in NAS research must be turning a blind eye to the North American epidemic of patients filling neonatal units or postpartum wards in need of treatment for the same. News feeds such as CNN have covered this story many times with concerning articles such as this published “Opioid Crisis Fast Facts” even the Trump White House has officially declared it as an emergency at this point. With NICU resources stretched and care providers fatigue levels wearing thin (these patients are typically very challenging to take care of due to the crying and agitation with neurological excitability that is at the core of the symptoms, something needs to be done. The vast majority of neonatal care providers treat such patients with an approach that promotes first non pharmacologic strategies such as keeping mom and baby together when possible, breast feeding and disturbing these infants as little as possible to name a few points. For those patients though who require pharmacologic support though, the mainstay has been oral morphine. At least in our units though once a patient is admitted and undergoes treatment we are still looking at anywhere from 3-4 weeks on average that they will occupy a hospital bed. If only there was a better way.
Could Buprenorphine do the trick?
While morphine is widely used to treat NAS symptoms unresponsive to other non pharmacologic methods of control, buprenorphine has a similar profile as an opioid but has less risk of respiratory depression as a partial agonist. A small but important trial has been published directly comparing the use of morphine to buprenorphine for treatment of NAS symptoms with the primary outcome being days of treatment and the second important point being length of stay. The trial, Buprenorphine for the Treatment of the Neonatal Abstinence Syndrome.by Kraft WK et al was entitled the BBORN trial for short. This was a single centre trial in which a double blind/double dummy approach was used. By double dummy this meant that after randomization those babies randomized to morphine received morphine plus a buprenorphine placebo and the other arm received a buprenorphine dose and a morphine placebo. In total 33 infants were randomized to buprenorphine and 30 to morphine (hence my comment about this being a small study). Their power calculation had called for 40 infants per arm to detect a 28% difference in the primary end point of duration of treatment but in the end that didn’t matter so much as they found a significant difference exceeding their estimate anyway. A lack of power would have become important mind you had they not found a difference as they wouldn’t have actually had the numbers to do so.
A strength of the study up front was that all care providers scored NAS symptoms the same way (need to take into account there is some subjectivity in scoring altogether though) and escalations and decreases of medication were done following a strict protocol both ways. In both arms, once a maximal dose of 60 mcg/kg of body weight for buprenorphine and 1.2 mg/kg for morphine was reached phenobarbital was added. When comparing the two groups at the outset there were no significant differences in characteristics so two generally similar populations of infants were being treated.
The Results Were Indeed Impressive
Before launching into the table, there were 21 babies in both groups that were bottle fed and 12 in the burprenorphine group and 9 in the morphine group that breastfed.
Median days of treatment
Hospital stay in days
No difference was seen in those who needed phenobarbital. Looking at the table, a couple things really stand out to me. They were looking for a 28% reduction in days of treatment. The results came in far excess of that at a 46% reduction. Curiously, breastfeeding which has classically been associated with a reduction in scores and therefore faster weaning due to less symptoms seemed to have the opposite effect here. Does this imply that breastfeeding slows down both duration of treatment and length of stay as a result? With a study this small it is difficult to say with so few breastfed babies but if I had to guess I would suggest those mothers that worked at breastfeeding may have had longer stays.
Should we all jump on the buprenorphine train?
For now I would give this a big maybe. One of the concerns about burprenorphine is that it comes as a solution of 30% alcohol. Giving multiple doses (3 per day in this study) of such a solution could in part contribute to these results of lower NAS symptoms. Is giving alcohol to reduce symptoms a good idea here? Not sure if there are any long term effects and moreover if the cumulative dose of this medication would be of a concern. Definitely something to check with your local pharmacist before rolling this out. On the other hand if the dose of alcohol provided was truly significant I might have expected the burprenorphine group to be poorer feeders due to intoxication which we certainly did not see.
With increasing volumes of newborns afflicted with symptoms of NAS we do need to find a way to stem the tide. Ideally, primary preventative strategies would be best but until that solution is found could burprenorphine be the next step in tackling this epidemic?
I work in an NICU that is no different in at least one way than yours. We have been seeing a growing volume of Neonatal Abstinence Syndrome (NAS) in our units for the last number of years. In fact I recall one week on service last year where 10/24 patients in our unit or roughly 42% were suffering from this condition. When I use the word suffering I should also mention that the staff experience this too. These infants are resource intensive in that they cannot be left alone for too long and as part of their management demand or require frequent feeding to keep their scores down.
As the saying goes misery loves company and the following graph tells the story of NAS in North America very well. There has been a dramatic rise in admissions with a progressive increase in length of stay. Attempts to curtail use of these drugs in pregnancy by criminalizing the use of drugs for the unborn fetus has not gone well; Mandatory Drug-Testing in Pregnancy: Lesson Learned
The conclusions of this paper changed the practice in our own and from the data presented here other centres as around 2009 – 2010, the use of phenobarbital decreased while morphine rose consistent with the recommendations from this group. Morphine was selected as it appeared to reduce the incidence of seizures although I have to mention I have never seen a case myself, so I remain curious as to how common they really are. In the review they also commented however that the use of opiates for treatment was associated with a prolongation of hospital stay. The reasons for this are in part explained by practitioner reluctance to discharge an infant home on an opiate. Doing so on low dose phenobarbital would have a much greater comfort level due to the common use for seizure control over the years in a home setting. This may be reflected in the findings as well in this paper that the practice of discharging on medications for NAS control decreased during the period studied from 4% down to 1-2%. Given the large number of babies being seen, this would represent a lot more infants in hospital and therefore a longer stay.
It is also tempting to blame the drugs that the mothers were exposed to but it would appear that there really is no basis for this based on this graph from the supplementary appendix The percentage of infants exposed to methadone remained the same, so higher use can not be blamed (which has been associated with higher rates of NAS).
Compounding the problem of NAS is that there are competing demands in many areas of the country where higher birth rates demand more NICU beds which are quite often occupied with NAS babies. There is clearly work that is needed in the field to turn the tide and reduce NAS admissions and certainly length of stay. As for how to do this there are a few ideas.
2. Treat the approach to NAS the same as that for headaches. Get on top of it quickly! Although not published, our own centre’s experience was that when we switched to predominantly using morphine we found that many of the infants required not only morphine but phenobarbital and often clonidine to control their symptoms and had the mean length of stay increase dramatically to 3-4 weeks per patient. What we discovered thanks to a very dedicated nurse with a passion for NAS management was that we were not doing what we said we would. Specifically, once the infant qualified for treatment we were not giving loads of 0.1 mg/kg of morphine q2h until controlled but rather in many instances waiting a little longer and then using 0.05 mg/kg as loads. Since reinforcing that we need to get on top of the issue right away (like with a headache before it becomes entrenched) the use of morphine monotherapy has increased dramatically.
3. Never admit these children in the first place. We have an agreement with the postpartum ward that the initial monitoring for NAS can occur in the room with the parents. The lack of separation encourages breastfeeding which in and of itself has led to some infants being successfully managed without ever coming to the NICU. We still see infants coming but those that do have had 2 -5 days less time in the NICU decreasing the usage of NICU beds for this purpose with the added benefit of increasing maternal/infant bonding. Better yet there are models out there of mother-infant homes that these dyads can be discharged from hospital to. Having them out of the hospital environment may be the best thing for them altogether and avoid treatment with medications at all.
4. Consider discharging infants on morphine or other opiate. There is no question that during the acute phase these children need to be in hospital as there are significant side effects from morphine not the least of which is respiratory depression. Once a patient in weaning from the morphine and has successfully decreased the dosing or interval by 30 – 50% it is exceedingly unlikely that on the lower daily dosage they will start having symptoms. In the presence of a reliable family with good supports that has been screened by a social worker such treatment can be completed outside the hospital. Some may be worried about what could happen if the medication is taken by an older child or parent but as you know the amount of drug that would be sent home when dosed at 0.05 mg/kg or less for a few doses would not impact such larger individuals.
I am grateful to NEJM for publishing this article as it shows we are not alone. Your suspicions that NAS is on the rise are accurate. NAS is here and it’s not going anywhere. The question is what are you going to do about it?!