October 13, 2010 — Sublingual buprenorphine is significantly more effective than oral morphine in treating infants with neonatal opioid abstinence syndrome (NAS), suggests a new randomized, open-label phase 1 study.
In fact, the length of treatment was 40% shorter and the length of hospital stay was 24% shorter for the infants given buprenorphine than for those receiving morphine, report the investigators.
"We were surprised that the sublingual administration of drugs was well tolerated by infants and that we were able to demonstrate a sizable advantage over standard therapy," lead study author Walter K. Kraft, MD, director of the Clinical Research Unit at Thomas Jefferson University and associate professor in the Department of Pharmacology and Experimental Therapeutics at Jefferson Medical College in Philadelphia, Pennsylvania, told Medscape Medical News.
"Given further study, such a beneficial drug could provide a new standard of treatment in a field where a well-defined therapeutic approach doesn't exist," added Dr. Kraft in a release. "Not only do we think it is an excellent choice to treat neonatal opioid withdrawal, but it may prove to also be cost effective."
He estimates that up to 16,000 infants each year are at risk for the syndrome. "If you assume the costs of this treatment are $2000 a day over an average 30 days of hospitalization, annual charges for this treatment can be up to $1 billion. If we were to reduce hospital stay by just 20%, that would save $150 million."
The investigators note, however, that more research is needed before firm comparative conclusions can be drawn.
The study was published online October 6 in Addiction.
Optimal Regimen Not Established
Past research has found that NAS symptoms, severe enough to require pharmacologic therapy, develop in 55% to 94% of infants exposed to opioids in utero.
Although several organizations, including the American Academy of Pediatrics, have recommended opioid replacement as "the ideal treatment" for these withdrawal symptoms, "the optimal pharmacologic regimen for NAS has not been established," write the study authors.
The most commonly used agent currently is morphine, but it is associated with prolonged treatment durations.
"This is a population that has been understudied for a while," said Dr. Kraft. "For them, pharmacologic therapy is oftentimes in an inpatient setting with length of stays of months.
"This means resource utilization and some maternal-infant bonding issues for children who are often otherwise healthy. Clearly, there's a need for better treatments," he added.
Buprenorphine is a "long-acting partial mu opioid receptor agonist used in the treatment of adult abstinence therapy," explain the researchers, who first published results from a cohort study of infants using buprenorphine in 2008.
For this study, a second cohort of 24 term infants with NAS, requiring pharmacologic treatment, were enrolled between February 2008 and January 2010. The mothers had all been maintained with methadone at the time of birth.
All infants were randomized to initially receive either 6 divided doses of 0.4 mg/kg/day of oral morphine, which is the standard of care treatment at Thomas Jefferson University Hospital (n = 12, 65% female), or 3 divided doses of 15.9 μg/kg/day of buprenorphine under the tongue, along with pacifiers to reduce swallowing of the solution (n = 12, 50% female).
"This is the only report of a sublingual drug used in infants," reported Dr. Kraft.
The morphine doses could be increased by 10% until symptoms were controlled, with phenobarbital added when the dose reached 1 mg/kg/day. The weaning dose was 10% per day as tolerated and cessation of therapy occurred when the infant was at 0.15 mg/kg/day.
The buprenorphine doses were increased by 25% until control of symptoms, and phenobarbital was added when the dose reached 60 μg/kg/day. Its weaning dose was also 10% per day, and cessation was when the newborn was within 10% of the initial dose.
"This was a follow-up pilot study to optimize the dose of sublingual buprenorphine in neonates," note the investigators.
Significant Buprenorphine Benefits
Results showed that the length of treatment was significantly less for those receiving buprenorphine than for those receiving morphine (23 vs 38 days, P = .01).
The length of hospital stay was also significantly less (32 vs 42 days, P = .05).
Only 1 buprenorphine-treated patient had a serious adverse event (prolonged reflux/poor feeding), but that was deemed "probably not related" to treatment.
This same infant also had the adverse events of paronychia of finger, cytomegalovirus (CMV) infection, and aminoaciduria (which were found to be "unrelated" to treatment) and elevated levels of transaminases (which were found to be "probably not related" to treatment).
"It is arguable that many signs and symptoms observed in the infant with CMV infection did not reflect severity of NAS but instead were manifestations of the multiorgan viral process," explain the study authors.
Adverse events recorded in those given morphine included oral thrush, conjunctivitis, and reflux. However, these were all found to be "unrelated" to treatment.
Phenobarbital was required in 3 of the patients in the buprenorphine treatment group compared with none of the morphine group.
Finally, the researchers note that "no infant in the study was re-admitted for withdrawal following discharge."
Limitations of the study include that preterm infants and those with benzodiazepine exposure were excluded, which may limit the results' generalizability, and the overall trial design. "A double blind, double dummy study would be required to fully evaluate any differential efficacy of buprenorphine over morphine," write the researchers.
Dr. Kraft added that nurses in the study used a checklist to make their assessments of how well the children were doing during treatment. "It was a semisubjective measurement. So it's possible that there was some occult bias."
However, "if these efficacy advantages hold up in a randomized trial that's blinded, there's potential to change standard based upon less time in the hospital and potentially even sending kids home on this therapy, because there's less of a chance for diversion," he said. "You don't have to give it every 4 hours. You can give it every 8 hours."
Dr. Kraft reported that his center is not currently using buprenorphine to treat for NAS. "That's because we're planning on doing a definitive study on this treatment. Until that happens, we're not going to change our practice yet.
"We've talked about saying this is what we're now going to treat our kids with. But that would probably remain a local practice and not a national practice. Whereas if we test this in a rigorous fashion, that's the type of evidence that standard setters would need to make a definitive recommendation," he explained.
If funding comes through, Dr. Kraft said he hopes to start this trial next summer.
First Step Study
"This is a good first step study, but it is important to remember that [it] was not powered to compare short-term and long-term outcomes in morphine-treated infants and buprenorphine-treated infants," Ashraf Hamdan, MD, clinical assistant professor in the Pediatric Department at Vanderbilt University and neonatologist with the Pediatrix Medical Group of Nashville, Tennessee, told Medscape Medical News.
Dr. Hamdan, who was not involved with this study, noted that buprenorphine has many characteristics that make it an attractive agent in the treatment of NAS, including "a ceiling effect" for respiratory depression and that it does not have the cardiovascular liability associated with methadone.
"There is a lower risk of abuse, addiction, and side effects compared to full opioid agonists because of its ceiling effect," explained Dr. Hamdan. "This makes it a possible good drug for outpatient treatment. However, safety, the ease, and the effectiveness of sublingual dosing in neonates are not known."
In addition, he said he was not sure about the feasibility of giving a liquid form sublingually and wondered how much is absorbed, how much is spit out, how much is swallowed, and how can one control for all of that.
"With a drug that has a 30% to 50% bioavailability from sublingual doses in adults, it is difficult to predict what it will be in neonates," said Dr. Hamdan. "It was [also] not mentioned whether they did serum levels in their buprenorphine group to see if the desired drug level was achieved."
He also pointed out that the length of stay for the morphine-treated infants in this study was longer compared with those at other institutions. "Many centers will wean the morphine by 10% to 20% once control is achieved. This might make the difference in the length of stay between the groups found in [this] study."
When asked what he considers the number 1 takeaway, Dr. Hamdan said it is that buprenorphine might be an alternative option for treatment of NAS in the future. For now, he said that it should not be used in this way until a large safety, feasibility, and effectiveness trial has been done comparing it to morphine and/or methadone.
"Buprenorphine should still be considered as a research drug in this group of infants," he concluded.
This study was funded by the Commonwealth of Pennsylvania Tobacco Fund and by a grant from the National Institute on Drug Abuse. The study authors and Dr. Hamdan have disclosed no relevant financial relationships.
Addiction. Published online October 6, 2010.
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Cite this: Sublingual Buprenorphine Relieves Symptoms of Neonatal Opioid Abstinence Syndrome - Medscape - Oct 13, 2010.