Project to Investigate Opiate Dependence in Neonates

Issue: 

Every year, approximately 350,000 to 400,000 infants are treated in a neonatal intensive care unit (NICU), according to a report put out by the Health Resources and Service Administration. Of those, between 50 and 80 percent become dependent on the opiates — such as the powerful analgesic morphine — they are prescribed for their pain.

Per the Drug Enforcement Agency, morphine “has a high potential for abuse,” but is also “one of the most effective drugs known for the relief of severe pain and remains the standard against which new analgesics are measured.” This means that clinicians trying to manage their patients’ pain know those same treatments that ease their pain could lead to dependence and difficult withdrawal later. Pain management is a Catch-22.

Following this, a 2010 paper published in Pediatrics on opioid tolerance and withdrawal in children notes prolonged opioid treatment “is associated with opioid withdrawal when opioids are weaned or discontinued.” Currently, the “mainstay of pharmacologic management is gradual opioid weaning,” the study’s authors write. Specifically, neonates are often weaned with the long-acting opioid methadone, pointed out The Children’s Hospital of Philadelphia’s Gordon A. Barr, PhD. Methadone is also “used to prevent withdrawal symptoms in patients who were addicted to opiate drugs,” according to the National Library of Medicine’s MedlinePlus site.

“There’s no good treatment,” for opioid dependence in infants, Dr. Barr said. “People have tried benzodiazepine, they’ve tried barbiturates, they’ve tried keeping the lights really low and dim and quiet — those environmental conditions help calm the baby, but they don’t slow the withdrawal process.” But the standard of care remains lowering the methadone dose gradually, he said.

Director of the Section of Acute and Chronic Pain Management in Children’s Hospital’s Department of Anesthesiology and Critical Care Medicine, Dr. Barr investigates early development transitions, with a particular focus on the mechanisms of pain and analgesics’ effect on development. Dr. Barr recently received a grant from the National Institute on Drug Abuse to examine the immune system’s role in opioid dependence during early development.

Over the course of this two-year, exploratory R21 award, Dr. Barr plans to look “at whether modulation of immune function has the same consequences for opiate actions in infancy as it does in adults,” he said. “And if so, how?”

Elucidating the Immune System’s Role

 This project grows out recent “attention paid to the interactions of the immune system and brain function in general, and opiates and immune function and brain function in particular,” Dr. Barr noted. In addition to relieving pain, opiates are known to act as immunosuppressors, but how they do so in neonates remains poorly understood and understudied. There is a paucity of literature on opiate action during early development, Dr. Barr pointed out.

“Given that premature babies and infants who are sick in the NICU are in pain and are being treated for pain with opiates, the concern is what are these drugs doing to the immune system, and how does the immune system alter the effectiveness drugs,” Dr. Barr said.

However, preliminary research by Dr. Barr’s laboratory shows that activating the immune system during treatment actually worsens opioid withdrawal, and that doing so in very young neonates (mice younger than seven days old, or full-term human babies) has no effect. With this investigation, Dr. Barr will be specifically be looking at the immune receptor toll-like-receptor 4 (TLR4). The interest in TLR4 stems from the work of the University of Colorado Boulder’s Linda R. Watkins, PhD, and Mark Hutchinson, PhD, of the University of Adelaide (Australia), who have published a number of papers on TLR4’s interaction with opioids.

Based on this work, Dr. Barr and his team’s hypothesis is that TLR4 in the nervous system is not functional in very young neonates, hence the lack of reaction observed when the immune system is activated during opioid treatment.

“So we’re looking at drugs that suppress the immune system — for one to see if that actually is the opposite what happens if you stimulate it — we’re looking drugs that block the TLR4 receptor specifically, and we’re looking at TLR4 knockout mice,” Dr. Barr said.

The investigators plan on evaluating a number of drugs, including some already approved for other uses and experimental drugs not yet on the market. Though pre-clinical, basic work, Dr. Barr’s hope with this project is that it will help inform clinical decisions in the future, and help to determine whether need exists for new drugs to be developed.

To read more about pain management, see the Department of Anesthesiology and Critical Care Medicine’s Pain Management Program. And for more information about research at Children’s Hospital, see The Children’s Hospital of Philadelphia Research Institute’s website.

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