This study is the first reported use of buprenorphine for the treatment of NAS. The feasibility of using sublingually administered buprenorphine for this indication was demonstrated. Administration was technically easy, and a decreased interval of dosing was convenient for nursing staff. With regard to safety, buprenorphine has a theoretical potential to precipitate withdrawal due to its partial agonist/antagonist activity. With the exception of a seizure in the second child treated, treatment with buprenorphine was uneventful. The etiology of the seizure in the second child treated with buprenorphine remains cryptic. Undertreatment of NAS due to underdosing is unlikely, given improved control of NAS symptoms in the day preceding the event. Buprenorphine-induced toxicity is also unlikely due to lack of reports of seizure induction in adults and a post-dose drug concentration of 0.35 ng/ml in this patient. While future investigations with the use of buprenorphine in this population will need to remain vigilant for this adverse event, it is possible that this seizure will be amongst the 10% classified as idiopathic at this age. (25
A secondary endpoint of the study was an examination of efficacy compared to the standard of care treatment at our institution. Buprenorphine use was associated with a 31% reduction in length of treatment and a 29% reduction in the length of stay. However, the variance seen in both treatment arms was large and the two treatments were not statistically different. A mechanism to explain this suggestion of improved efficacy is not immediately apparent, but a longer half-life and greater affinity for the mu opioid receptor are plausible explanations. It should be noted that this feasibility study employed an unblinded design. Though the same nursing and physician teams made assessments of Finnegan scoring in both treatment arms, there was no blinding of staff or parents. We believe treatment allocation did not influence assessment of abstinence symptoms; however, occult bias in scoring or in weaning decisions cannot be definitively excluded. There was a higher percentage of males in the buprenorphine (10/13) compared to the NOS (7/13) groups. This imbalance is not expected to have biased treatment toward the buprenorphine group, as a recent investigation suggested that male neonates may have more severe NAS than females. (26
The case report of Marquet describes a buprenorphine serum concentration of 1.9 ng/ml in a newborn of 20 hours age whose mother was maintained on 4 mg/day of buprenorphine. (18
) Dose selection for this clinical trial employed a monoexponential pharmacokinetic model with a target steady state concentration of 2 ng/mL. With the exception of three outliers, actual concentrations observed during the trial were <0.6 ng/ml, with many samples below the limit of quantification of 0.1 ng/ml. It is notable that in 9 of 12 completed patients there was good control of withdrawal symptoms at these concentrations. This is surprising, as amelioration of adult signs of withdrawal is estimated to occur at 0.7 ng/ml and above. (27
) This differential pharmacodynamic response based upon age may represent an additional safety margin for concentration-dependent adverse events associated with opioid agonists.
Given the necessity of a limited sampling regimen in those otherwise healthy newborns and large proportion of samples below the limits of quantification, formal pharmacokinetic parameters could not be generated. While the study population as a whole had measured buprenorphine and norbuprenorphine concentrations that remained within a relatively narrow range, there was significant dose-to-dose intra-subject variability that could not be explained solely by developmental ontogeny of metabolic enzymes. It is more likely that the variability noted was a reflection of variability of extent of sublingual dosing. Variability did not decrease as the study progressed. It is anticipated that some of the dose was swallowed, and that the amount swallowed and metabolized pre-systemically would vary from dose to dose. Morphine pharmacokinetics in neonates are also quite variable, (28
) and ultimately clinical efficacy rather than fully characterized pharmacokinetic parameters will primarily drive dose selection. The ratio of buprenorphine to norbuprenorphine was between 0.47–8.1 in samples that had both analytes. These are higher than those calculated from the data presented by Huang et al. of 0.165 to 1.40. (29
) That and the finding that norbuprenorphine was not present in two thirds of the samples suggest impaired N-dealkylation of buprenorphine in the newborn.
The need for phenobarbital rescue in three children randomized to buprenorphine suggests that the maximal dose used in the trial may not be high enough for the control of NAS. This theory is supported by the plasma concentrations observed and the inherent safety margin in adults, as well as that observed in this trial. An investigation using higher doses of buprenorphine is presently underway. The use of 30% ethanol solution was mandated by the Food and Drug Administration, and a future goal will be the reduction of ethanol administered. Benzodiazepine use was an exclusion criteria, which limits the generalizability of results to all infants exposed in utero
to opioids. The rationale for this exclusion was anecdotal evidence of decreased therapeutic index of buprenorphine in adults who also abused benzodiazapines. Benzodiazepines cross into the placenta, (30
) though maternal confounders have made it difficult to estimate adverse effects specific to in utero exposure of benzodiazepine. (32
) Having established a safety parameter, future investigations should also include neonates born to poly-drug abusing mothers. Breastfeeding was also an exclusion criteria. However, thought should be given to revisiting this exclusion, particularly in buprenorphine-maintained mothers, given suggestions of improved neonatal outcomes compared to formula fed infants. (33
). As the abuse potential of buprenorphine is less than that of morphine and the dosing interval is longer, it is possible that buprenorphine may facilitate the treatment of NAS in care settings of lower acuity. Home administration in highly selected patients with visiting nursing care could be explored.
Research of optimal drug use in pregnant females and their infants has traditionally lagged that in other populations. (34
) The present study could constitute the first major advance in decades in the treatment of NAS, particularly in view of the increasing use of buprenorphine in the maintenance of opioid-dependent pregnant females, particularly in Europe. (35
) Incidence of NAS in the offspring of buprenorphine maintained mothers appears similar to that of mothers maintained on methadone. (36
) The use of buprenorphine for the treatment of these children is attractive.
In conclusion, we have demonstrated in this pilot study that the treatment of NAS with sublingual buprenorphine is feasible and has an acceptable safety margin. Confirmation of safety will require further study. A seizure occurred in one subject in the buprenorphine arm, but a direct causal relation could not be established. Intra-dose variability of buprenorphine is high, but control of symptoms occurred at serum concentrations lower than the 0.7 ng/ml estimated as the threshold needed to ameliorate adult abstinence. There is a suggestion of improved efficacy in terms of length of stay and length of treatment, but will need to be confirmed in a larger double blind, properly-powered clinical trial.