Sublingual Buprenorphine Treatment for Neonatal Abstinence Syndrome - Pilot Study

The Problem: Infants who are born to mothers taking or abusing opiates frequently suffer
from neonatal abstinence syndrome (NAS) after birth. They often have withdrawal symptoms
which can be life threatening if untreated. The American Academy of Pediatrics recommends
opioid replacement for the treatment of these symptoms in newborns. Buprenorphine (BNP) has
gained widespread use in the treatment of adult opioid dependence. One of the reasons BNP is
so appealing is because of its safety profile in comparison to the other drugs in its class
(opiates). It has less respiratory depression and a lower level of physical dependence than
the other opioids. BNP has recently been trialed, in its sublingual form, as a treatment for
newborns with NAS. In two trials by the same group, there was a significant reduction in
both the length of treatment and in-patient hospital days in infants treated with BNP in
comparison to infants treated with morphine.

In both of these studies, mother/infant pairs were excluded if the mother was dual dependent
on opiates and benzodiazepines (BZDs). This is not an insignificant population. BZDs are
frequently prescribed during pregnancy to treat anxiety and panic disorder in women who are
taking methadone or BNP for opioid replacement therapy. BZDs are also common drugs of abuse.
It has been estimated that 22-47% of mothers whose infants are diagnosed with NAS used both
BZDs and opiates during the pregnancy. These infants have a protracted NAS with longer
hospitalization in comparison to infants exposed to an opioid alone. There are conflicting
reports in the literature regarding the safety of concomitant use of BNP and BZDs. In both
adults and children the combination of BNP and BZD prolongs respiratory depression in
non-drug abusers. In addition, autopsy findings in six adults who were drug abusers were
linked to concomitant use of BNP and BZD by analysis at autopsy. On the other hand in adult
tapering trials comparing BNP with methadone in dual-dependent adults there were no adverse
events in the BNP group, opiate withdrawal scores were lower and the adults were more likely
to complete treatment. Thus while treatment of NAS with BNP may be desirable and efficacious
in opiate tapering protocols, it is imperative that we look specifically at this group of
infants with dual exposure to opioids and BZDs. This is a single site, un-blinded
observational safety study. Study participants will be recruited from eligible participants
who are born at Bayfront Medical Center Baby Place and subsequently admitted to the neonatal
intensive care unit (NICU) at All Children's' Hospital (ACH) for treatment of NAS. Data from
this pilot safety trial will be used to apply for NIH funding to conduct a large randomized
double-blind trial to determine the efficacy of BNP versus morphine for the treatment of
NAS.

The Research Hypothesis: BNP can be used safely to treat NAS in the subgroup of infants
whose mothers were taking both an opiate and a BZD in the week prior to delivery.

The Importance of the Research: BNP is emerging as a "safer" and more efficient drug for
adult detoxification and maintenance programs and is showing promise for the treatment of
neonatal abstinence syndrome (NAS). In the most recent published trial comparing BNP to
morphine in infants with NAS, the length of stay (LOS) was decreased by 40% in the BNP group
(from an average of 38 days in the morphine group to 23 days in the BNP group). No major
adverse effects were reported in either treatment group. As is common in early trials, the
experimental group was restricted - specifically maternal BZD use was an exclusion criteria.
The rational given was that length of stay is known to be longer for infants whose mothers
were also using BZDs. However, this is not an insignificant population. It has been reported
that 22-47% of opiate users are co-using BZDs. At ACH, the incidence of infants exposed to
both classes of drugs has ranged from 15-35%. Before BNP becomes the standard of care it is
important to look closely at this group of infants and either caution the use of BNP or
demonstrate its safety. This pilot trial is designed to determine if infants who have dual
in-utero exposures to opiates and BZDs can be safely treated with BNP.

Inclusion Criteria:

- Newborns ≥ 35 0/7 wks. Gestation undelivered or < 12 hours of age at enrollment and
within the 72 hrs. after birth at the time of transfer to ACH for pharmacologic
treatment for moderate to severe NAS

- Newborns ≥ 2 kg weight at birth (10th % for a 35 0/7 wk. newborn)

- Informed parental

Exclusion Criteria:

- Newborns <35 0/7 wks. gestation OR older than 72 hrs. of life at time of transfer to
ACH for pharmacologic treatment for moderate to severe NAS

- Major congenital anomalies

- Major concomitant medical illness including antibiotic treatment for greater than 3
days

- Any illness that precludes oral or sublingual medication use

- Infants who have received any drug other than "study drug" to treat their NAS

- Infants requiring drug therapy with any high or moderate CYP3A4 inhibitor or inducer
(Appendix A)

- Breastfeeding infants.

- Infants in significant pain requiring medication for comfort (for example those with
a fracture).