Published online August 11, 2008
PEDIATRICS Vol. 122 No. 3 September 2008, pp. e601-e607 (doi:10.1542/peds.2008-0571)
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ARTICLE

Sublingual Buprenorphine for Treatment of Neonatal Abstinence Syndrome: A Randomized Trial

Walter K. Kraft, MDa, Eric Gibson, MDb,c, Kevin Dysart, MDb,c, Vidula S. Damle, MSb,c, Jennifer L. LaRusso, DOa, Jay S. Greenspan, MDb,c, David E. Moody, PhDd, Karol Kaltenbach, PhDb and Michelle E. Ehrlich, MDb,c,e

Departments of a Pharmacology and Experimental Therapeutics
b Pediatrics
e Neurology, Jefferson Medical College, Philadelphia, Pennsylvania
c A.I. DuPont Hospital for Children, Wilmington, Delaware
d Center for Human Toxicology, University of Utah, Salt Lake City, Utah


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. In utero exposure to drugs of abuse can lead to neonatal abstinence syndrome, a condition that is associated with prolonged hospitalization. Buprenorphine is a partial µ-opioid agonist used for treatment of adult detoxification and maintenance but has never been administered to neonates with opioid abstinence syndrome. The primary objective of this study was to demonstrate the feasibility and, to the extent possible in this size of study, the safety of sublingual buprenorphine in the treatment of neonatal abstinence syndrome. Secondary goals were to evaluate efficacy relative to standard therapy and to characterize buprenorphine pharmacokinetics when sublingually administered.

METHODS. We conducted a randomized, open-label, active-control study of sublingual buprenorphine for the treatment of opiate withdrawal. Thirteen term infants were allocated to receive sublingual buprenorphine 13.2 to 39.0 µg/kg per day administered in 3 divided doses and 13 to receive standard-of-care oral neonatal opium solution. Dose decisions were made by using a modified Finnegan scoring system.

RESULTS. Sublingual buprenorphine was largely effective in controlling neonatal abstinence syndrome. Greater than 98% of plasma concentrations ranged from undetectable to ~0.60 ng/mL, which is less than needed to control abstinence symptoms in adults. The ratio of buprenorphine to norbuprenorphine was larger than that seen in adults, suggesting a relative impairment of N-dealkylation. Three infants who received buprenorphine and 1 infant who received standard of care reached protocol-specified maximum doses and required adjuvant therapy with phenobarbital. The mean length of treatment for those in the neonatal-opium-solution group was 32 compared with 22 days for the buprenorphine group. The mean length of stay for the neonatal-opium-solution group was 38 days compared with 27 days for those in the buprenorphine group. Treatment with buprenorphine was well tolerated.

CONCLUSIONS. Buprenorphine administered via the sublingual route is feasible and apparently safe and may represent a novel treatment for neonatal abstinence syndrome.

Key Words: neonatal abstinence syndrome • buprenorphine • sublingual drug administration • morphine

Abbreviations: NAS—neonatal abstinence syndrome • NOS—neonatal opium solution

Neonatal abstinence syndrome (NAS) is a complex of signs and symptoms in the postnatal period associated with the sudden withdrawal of maternally transferred opioids. Cardinal manifestations include increased muscle tone, autonomic instability, irritability, poor sucking reflex, and impaired weight gain. In epidemiologic studies, maternal opioid abuse is common, with toxicologic evidence of use in ~1% of births.1 This includes methadone and, increasingly, buprenorphine, which is used to treat women with physical dependence to opioid agonists. In aggregate, NAS occurs in 55% to 94% of infants who are born to opioid-dependent mothers.2

The optimal treatment for NAS has not been established. This is reflected in the considerable heterogeneity in the pharmacologic treatment of NAS among different institutions.3,4 Cochrane reviews suggest lack of high-quality evidence to support any specific treatment,5,6 although expert opinion places opioids as the class of agents that possesses the greatest efficacy.7 Specific opioid agents that are used include morphine sulfate, morphine in the form of neonatal opium solution (NOS) or deodorized tincture of opium, and methadone. Although values vary considerably between institutions, treatment for NAS is associated with long inpatient treatment stays. Administration of morphine or NOS has been reported to have lengths of treatment of 8 to 79 days,8–11 although a consensus duration is ~30 days. This length of hospitalization is suboptimal because of interference with maternal bonding, potential for nosocomial infection, and resource use. There is a need for improved therapeutic agents that would safely decrease the length of inpatient hospitalization.

Buprenorphine is a partial µ-opioid receptor agonist with an extended half-life that has found increasing use in the treatment of adult opiate addiction.12 The drug has a large first-pass metabolism in adults and is administered via the sublingual route. Buprenorphine has a number of characteristics that would make it an attractive agent in the treatment of NAS. As an agonist/antagonist, buprenorphine has a ceiling effect for respiratory depression.13 There is a lack of the cardiovascular liability associated with methadone14 as well as an established safety profile in adults. The long half-life and duration of action prevents the rapid change in receptor occupancy that can precipitate withdrawal symptoms.15 Finally, there is limited abuse liability, which makes consideration of outpatient treatment for NAS a possibility for carefully screened caregivers. Thus, buprenorphine is a candidate to fill the unmet need of improved NAS treatment and certainly as a useful alternative treatment.

There has been little experience with the use of buprenorphine in neonatal or pediatric populations.16 Published pharmacokinetic parameters are limited to a single investigation of preterm infants who required opioid analgesia.17 Quantitative drug determination in term infants has been reported only in a single case report involving placental transmission after maternal buprenorphine use.18 Finally, there is no information about the use of sublingual buprenorphine below the age of 4 years19 or, indeed, the use of any sublingual medications in the newborn. The primary goal of this trial was to test the hypothesis that buprenorphine administered via the sublingual route in term infants with the NAS is safe, tolerable, and feasible. Secondary goals were to explore buprenorphine efficacy compared with standard-of-care treatment with NOS on the basis of a priori end points of length of treatment and length of stay; however, this was a preliminary study that was not powered to detect differences in these efficacy end points. Another secondary aim was to explore buprenorphine pharmacokinetics within the limits of what can be accomplished in this sized otherwise healthy neonatal study population.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Design
This was a single-site, randomized, open-label trial conducted between April 2005 and January 2008. Twenty-six neonates were randomly assigned to treatment with either sublingual buprenorphine or NOS in a 1:1 ratio. NAS was graded by using a modified Finnegan scale, which is the standard instrument at Thomas Jefferson University Hospital.20,21 Initiation of treatment was based on any consecutive 3 scores that added up to ≥24. Inclusion criteria were ≥37 weeks' gestation, exposure to opioids in utero, and demonstration of signs and symptoms of NAS that required treatment. Exclusion criteria were major congenital malformations and/or intrauterine growth retardation,22 medical illness that required intensification of medical therapy, concomitant maternal benzodiazepine or severe alcohol abuse, maternal use of alcohol or of benzodiazepines in the 30 days before enrollment (as determined by self-report or intake urine drug screen), concomitant neonatal use of cytochrome P450 3A inhibitors or inducers before initiation of NAS treatment, seizure activity or other neurologic abnormality, breastfeeding, and inability of mother to give informed consent as a result of comorbid psychiatric diagnosis. Informed consent was obtained for each patient before any study procedures. The study protocol conformed to the ethical guidelines of the Declaration of Helsinki as reflected in approval by the institutional review board of Thomas Jefferson University. Computer-generated randomization was performed by the Hospital Investigational Drug Service.

Study Treatments
Patients who were randomly assigned to sublingual buprenorphine initially received 13.2 µg/kg per day in 3 divided doses. Buprenorphine solution was prepared by mixing buprenorphine for injection (Buprenex [Reckitt Benckiser, Richmond, VA]) in 100% ethanol USP (30% final concentration) and simple syrup (85 g sucrose per 100 mL). Final buprenorphine concentration was 0.06 mg/mL. The solution was administered under the tongue followed by insertion of a pacifier to reduce swallowing. Nursing staff were instructed in sublingual technique by means of in-service training with observed administration. Initial volumes were ~0.2 mL, and volumes of >0.5 mL were administered in 2 aliquots separated by 2 minutes. Dose escalation was a 20% increase for Finnegan scale scores of >24 total on either 2 or 3 measures or a single score of 12. Patients with inadequate control could be administered a rescue dose of 50% of the previous dose, after which the subsequent dose would be advanced 20%. After at least 3 days of dose stabilization, patients could begin weaning for scores of <8. Weaning was at intervals of 10% until cessation of dosing at or near the initial dose. When NAS was not controlled with maximally specified dose of 39 µg/kg per day, patients were administered phenobarbital with a goal serum concentration of 20 to 30 mg/dL (Fig 1). This protocol was designed on the basis of estimated buprenorphine pharmacokinetics and pharmacodynamics and thus took into account differences relative to morphine in terms of starting dose and weaning protocol.


Figure 1
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  		FIGURE 1 Study flow.

 
Standard-of-care treatment at Thomas Jefferson University Hospital consisted of an initial dose of morphine of 0.4 mg/kg per day (in the form of NOS) in 6 divided doses with dose escalation of 10% per day for Finnegan scale scores >24 total on either 2 or 3 measures or a single score of 12. The final alcohol concentration of NOS was 0.19%. Adjunctive treatment with phenobarbital was initiated when the dose of NOS reached 1 mg/kg per day. Infants were weaned from NOS once they demonstrated control of their NAS as measured by the Finnegan scale for 48 hours. Daily dose was weaned by 10% every 24 hours as tolerated. When an infant required rescue therapy, the equivalent of 1 extra dose of NOS was given. Regardless of treatment allocation to buprenorphine or NOS, all patients were observed for at least 2 days after the cessation of dosing. Dosing for all patients was based on birth weight. In both buprenorphine and NOS groups, use of adjunct phenobarbital was considered a treatment failure but not an adverse event.

Pharmacokinetics
Pharmacokinetic samples were drawn at predose, postdose, and midinterval times in neonates who were randomly assigned to buprenorphine. Pre- and postdose samples were drawn 15 to 45 minutes before or after a dose. Capillary blood was obtained via heel stick. There was a protocol-specified maximum blood volume of 12 mL per patient. Buprenorphine and its primary metabolite norbuprenorphine were measured essentially as described by Moody et al23 with the transition of norbuprenorphine as the acetonitrile adduct (and its internal standard) modified to m/z 455 (459) to 414 (417) at approximately –25 eV.24 This method was modified to accommodate the lower volume infant blood samples. Instead of the normal 1-mL aliquot used for plasma from adults, a 0.1-mL aliquot was used. For controlling for the smaller aliquot size, quality control samples were also run as 0.1-mL aliquots at concentrations of 0.25, 2.0, and 7.5 ng/mL. In any run at least two thirds of all quality controls had to be within ±20% of target and at least 1 of 2, or 2 of 3 at any concentration had to meet that acceptance criteria. The mean results for buprenorphine controls (N = 13, expressed as percentage of target) were 100.3%, 95.3%, and 98.5% at 0.25, 2.0, and 7.5 ng/mL, respectively. Those for norbuprenorphine were 94.3%, 94.8%, and 94.0%. The limits of quantification were 0.1 ng/mL for both analytes in most samples. The limits of quantification was 0.2 ng/mL in the 3% of the samples that had a small volume.

Statistics
This was a pilot study to examine the first use of sublingual administration of buprenorphine in neonates. In light of limited a priori knowledge of buprenorphine behavior in the neonatal population, sample size was not based on a formal power calculation. Group comparisons for continuous variables were made using the Student's t test or the Wilcoxon rank-sum test where appropriate. Statistical analysis was completed with JMP 5.1.2 (SAS Institute Inc, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
A total of 26 patients received treatment with either buprenorphine or NOS during the conduct of this trial. The buprenorphine and NOS groups were similar with regard to their gestational ages, birth weights, and Apgar scores (Table 1). All mothers were maintained on methadone. One patients who was randomly assigned to buprenorphine did not complete a course of treatment. Enrollment is presented in Fig 2.


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  		TABLE 1 Characteristics of Patients in the Trial

 

Figure 2
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  		FIGURE 2 Disposition of enrolled patients.

 
Pharmacokinetics
A total of 202 samples were analyzed. With the exception of 3 outliers, the maximum buprenorphine concentrations were 0.60 ng/mL. One outlier of 3.69 ng/mL buprenorphine occurred in an infant at the initial dose of 13.2 µg/mL. The outlier values of 1.80 and 0.85 ng/mL occurred in 1 patient at the maximum protocol specified dose of 39 µg/kg. The sample with 3.69 ng/mL buprenorphine had a norbuprenorphine concentration of 0.83 ng/mL; all other samples had <0.33 ng/mL norbuprenorphine. A significant portion of samples were below the limit of quantification (35.6% for buprenorphine and 68.9% for norbuprenorphine). Low values occurred even during collection times temporally close to a dose, at higher doses, and during periods of adequate control of abstinence symptoms, suggesting possible uncoupling of plasma and peripheral compartment buprenorphine concentrations. Overall, there was a high degree of intrasubject variability. The ratio of buprenorphine to norbuprenorphine in the 51 samples for which both were detected ranged from 0.47 to 8.1. Ratios were generally higher at peak compared with trough draws.

Adverse Events
The second patient who was randomly assigned to buprenorphine developed generalized seizures 78 hours after the initial dose. The infant had 4 up-titrations before this event but no alteration in dose in the 16 hours immediately preceding the event and had demonstrated improved symptomatic control during this period, with Finnegan scores between 6 and 8. Buprenorphine was halted and treatment was initiated with phenobarbital and NOS. Postevent evaluation revealed normal serum hematology, chemistry, C-reactive protein, and lumbar puncture indices and negative cultures. An interictal electroencephalogram was negative, and MRI of the brain revealed a small amount of dependent subdural hemorrhage within the posterior fossa likely related to the birthing process and deemed unlikely to be symptomatic, with no parenchymal abnormalities. Lack of maternal exposure to benzodiazepines was reconfirmed. This child's total length of stay was 28 days. At 1-year follow-up, the child was developmentally normal and seizure-free. A causal link of undertreatment of withdrawal or a dose-dependent effect of buprenorphine was not immediately apparent to the investigators. Independent review was performed, and it was recommended that the trial be resumed by using the established protocol. Another child who received buprenorphine developed a mild fungal paronychia judged to be unrelated to study drug.

Efficacy
Despite a trend toward lower values in the buprenorphine-treated group, the clinical outcome variables of length of treatment and length of stay were not significantly different between the 2 groups (Table 2). The patient who was discontinued from the buprenorphine arm was not included in the efficacy analysis. The length of stay for this infant was 28 days. The mean length of treatment for the NOS group was 32 days (n = 13; range: 14–60 days; SD: 16 days) compared with 22 days (n = 12; range: 11–47 days; SD: 11 days) for the buprenorphine group (P = .077; Fig 3). The mean length of stay for the NOS group was 38 days (n = 13; range: 19–66 days; SD: 16 days) compared with 27 days (n = 12; range: 17–51 days; SD: 11 days) for the buprenorphine group (P = .068). There was significant heterogeneity of response between patients (Fig 4). Supplemental treatment with phenobarbital was required for 3 patients in the buprenorphine arm who reached the maximum dose of 39 µg/kg per day and 1 patient in the NOS group.


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  		TABLE 2 Outcomes of Treatment With Buprenorphine and NOS

 

Figure 3
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  		FIGURE 3 Length of treatment for infants who were treated with NOS (•; n = 13) and sublingual buprenorphine ({blacksquare}; n = 12). One patient who was withdrawn from the buprenorphine group and had a length of treatment of 4 days of buprenorphine is not included. The small bars represent the SD, and the large bars represent the mean.

 

Figure 4
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  		FIGURE 4 Length of stay for infants who were treated with NOS (•; n = 13) and sublingual buprenorphine ({blacksquare}; n = 12). One patient who was withdrawn from the buprenorphine group and had a length of stay of 28 days is not included. The small bars represent the SD, and the large bars represent the mean.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
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 as a result of its partial agonist/antagonist activity. With the exception of a seizure in the second child treated, treatment with buprenorphine was uneventful. The cause of the seizure in the second child treated with buprenorphine remains cryptic. Undertreatment of NAS as a result of underdosing is unlikely, given improved control of NAS symptoms in the day before the event. Buprenorphine-induced toxicity is also unlikely because of lack of reports of seizure induction in adults and a postdose drug concentration of 0.35 ng/mL for this patient. Although 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 among the 10% classified as idiopathic at this age.25

A secondary end point of the study was an examination of efficacy compared with 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 2 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 µ-opioid receptor are plausible explanations. It should be noted that this feasibility study used an unblinded design. Although 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 that 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 boys in the buprenorphine group (10 of 13) compared with the NOS group (7 of 13). This imbalance is not expected to have biased treatment toward the buprenorphine group, because a recent investigation suggested that male neonates may have more severe NAS than female neonates.26

The case report of Marquet et al18 described a buprenorphine serum concentration of 1.9 ng/mL in a newborn of 20 hours age whose mother was maintained on 4 mg/d of buprenorphine. Dose selection for this clinical trial used a monoexponential pharmacokinetic model with a target steady-state concentration of 2 ng/mL. With the exception of 3 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, because amelioration of adult signs of withdrawal is estimated to occur at ≥0.7 ng/mL.27 This differential pharmacodynamic response on the basis of age may represent an additional safety margin for concentration-dependent adverse events that are 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. Although 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 intrasubject 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 presystemically would vary from dose to dose. Morphine pharmacokinetics in neonates are also 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 and 8.10 in samples that had both analytes. These are higher than those calculated from the data presented by Huang et al29 of 0.165 to 1.400. 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 for 3 children who were randomly assigned 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 that uses higher doses of buprenorphine is under way. 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 criterion, which limits the generalizability of results to all infants who are exposed in utero to opioids. The rationale for this exclusion was anecdotal evidence of decreased therapeutic index of buprenorphine in adults who also abused benzodiazepines. Benzodiazepines cross into the placenta,30,31 although 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 who are born to polydrug-abusing mothers. Breastfeeding was also an exclusion criterion; however, thought should be given to revisiting this exclusion, particularly for buprenorphine-maintained mothers, given suggestions of improved neonatal outcomes compared with formula-fed infants.33 Because 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 for 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 for other populations.34 This 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 seems similar to that of mothers who are maintained on methadone.36,37 The use of buprenorphine for the treatment of these children is attractive.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
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 additional study. A seizure occurred in 1 patient in the buprenorphine arm, but a direct causal relation could not be established. Intradose 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.


   ACKNOWLEDGMENTS
 
This project was supported by the Commonwealth of Pennsylvania Tobacco Fund and National Institute on Drug Abuse grant R21DA018207. Dr LaRusso is supported by National Institutes of Health postdoctoral training grant T32 GM08562. The authors would like to thank Drs Ed Johnson and Ashwin A. Patkar for their scientific input.


   FOOTNOTES
 
Accepted May 13, 2008.

Address correspondence to Walter K. Kraft, MD, 132 S 10th St, 1170 Main Building, Jefferson Medical College, Philadelphia, PA 19107. E-mail: walter.kraft{at}jefferson.edu

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health.

This trial has been registered at www.clinicaltrials.gov (identifier NCT00521248).

Dr Ehrlich's current affiliation is Departments of Pediatrics and Neurology, Mt Sinai School of Medicine, New York, New York.

The authors have indicated they have no financial relationships relevant to this article to disclose.


What's Known on This Subject

Neonatal abstinence syndrome of severity requiring pharmacologic treatment is associated with long hospitalization. Opioid replacement with morphine is the present preferred treatment. Improved treatment options would be a therapeutic advance.

 

What This Study Adds

Buprenorphine is a partial opioid agonist that is finding increasing use in adult abstinence but has never been used for neonatal abstinence syndrome. The safety, feasibility, efficacy, and pharmacokinetic profile of sublingual buprenorphine are described for the first time after this trial.

 


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics




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