Georgia State Study First to Confirm Long-Term Benefits of Morphine Treatment in Infants

A recent study conducted by researchers at Georgia State University is the first of its kind to demonstrate that administration of preemptive morphine prior to a painful procedure in infancy blocks the long-term negative consequences of pain in adult rodents. These studies have serious implications for the way anesthetics and analgesics are administered to neonates prior to surgery. Infant rodents that did not receive preemptive pain medication prior to surgery were less sensitive to the effects of morphine in adulthood. This means that infants undergoing invasive procedures at birth that do not receive any pain medicine will require more morphine in adulthood to modulate their pain.

This study -- conducted by Anne Z. Murphy, Ph.D., a Georgia State Professor of Neuroscience and member of the Center for Behavioral Neuroscience, and graduate student Jamie LaPrairie -- has serious clinical implications for the more than 400,000 human infants that are admitted to a newborn intensive care unit (NICU) in the United States each year.

Past studies have shown human infants born between 25-42 weeks gestation experience on average 14 painful procedures per day during the first two weeks of life with fewer than 35 percent receiving appropriate analgesic therapy.

“While such surgical procedures in preterm infants are clearly necessary, the resulting pain and inflammation has been shown to lead to negative behavioral consequences later in life,” Murphy said. “Our previous studies have shown that, just as in humans, neonatal inflammation in rodents (that did not receive preemptive pain medication) results in an increase in sensitivity to pain, stress, and decreased reaction to morphine as adults.

While evidence exists that morphine is efficacious in neonatal rodents, this is the first study to confirm the long-term behavioral benefits.

In this study, published online in Pediatric Research, a group of rat pups received an injection of morphine sulfate on the day of birth prior to inducing inflammation; another group received a saline injection instead. The groups were then raised identically and received identical procedures during a 60-day period. Rodents that received preemptive morphine behaved normally while those rats that received saline showed significant increases in pain sensitivity and were resistant to the pain relieving effects of morphine in adulthood.

“This tells us that morphine doesn’t work very well in human children and adults that were formally in the NICU and didn’t receive preemptive pain treatment, and since morphine is still the primary drug used to treat severe pain, this means that there is an entire subpopulation for which morphine doesn’t work efficiently,” Murphy said. “These results suggest that there are long-term benefits of providing all newborns with some sort of pain relieving medicine prior to the initiation of an invasive procedure.”

Murphy’s work was supported by the National Institutes of Health, the Center for Behavioral Neuroscience, and the Georgia State Brains and Behavior Program.

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Note to Pediatricians: Taper Meds in Kids with Stable Asthma

A study of how pediatricians prescribe asthma medications suggests that while most would readily increase a child’s medication if needed, many are reluctant to taper off drug use when less might be best. A report on the study, led by Johns Hopkins Children’s Center researchers, appears in the July issue of Pediatrics.

“Asthma medications can have serious, albeit infrequent, side effects, and while under-treatment is undeniably a big problem, not stepping down treatment when a child is doing well may be too,” says lead investigator Sande Okelo, M.D., an asthma specialist at Hopkins Children’s.

In the research, conducted among 310 pediatricians nationwide, 40 percent said they would not step down high-dose treatment even if a child’s symptoms were well controlled and infrequent.

“If a child is doing well and her symptoms are well under control, why not take that chance and see if a smaller dose would do the trick?” says senior investigator Gregory Diette, M.D., M.H.S., a lung specialist at Hopkins.

Beyond side effects, Okelo says, a failure by pediatricians to taper off drugs may also lead parents to do so on their own by skipping doses or decreasing them.

“Past research shows that when parents are concerned about side effects and their child is doing well, they may take action without a doctor’s approval,” Okelo says.

For the study, the pediatricians were asked to devise treatment plans using different patient scenarios, describing various elements, including whether a child had been hospitalized recently, how bothersome and frequent a child’s symptoms were, whether symptoms had recently intensified or lessened and whether the child had wheezing on a physical exam. Most doctors reported they would step up treatment in patients with:

recent hospitalizations
frequent symptoms
parents who said they were bothered by their child’s symptoms
those who had wheezing on exam
While current treatment guidelines focus on symptom frequency, nearly all pediatricians reported using multiple factors in their decision-making, including quality of life and how bothered parents were by their child’s symptoms.

Okelo says pediatricians might greatly benefit from a step-by-step, “frontlines” tool that tells them how to specifically apply treatment guidelines and how to use different dimensions of the disease in their day-to-day practice.

Because asthma is an unstable disease and can change often and unpredictably, it is essential that children with asthma get regular follow-up exams every three to six months even in the absence of symptoms, researchers recommend.

Asthma is the most common pediatric chronic illness, affecting 6.5 million children in the United States, according to the Centers for Disease Control and Prevention.

The study was funded by the National Heart, Lung and Blood Institute.

Other Hopkins investigators on the study: Cecilia Patino, M.D., Kristin Riekert, Ph.D., Barry Merriman, M.A., Andrew Bilderback, B.S., Nadia Hansel, M.D., M.P.H., Kathy Thompson, R.N., Jennifer Thompson, M.P.H. and Cynthia Rand, Ph.D. Other institutions involved in the study include Howard University, Washington, D.C.

FDA, European Medicines Agency to Consider Additional Test Results When Assessing New Drug Safety

In the first use of a framework allowing submission of a single application to the two agencies, the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) worked together to allow drug companies to submit the results of seven new tests that evaluate kidney damage during animal studies of new drugs. The tests measure the levels of seven key proteins or "biomarkers" found in urine that can provide additional information about drug-induced damage to kidney cells, also known as renal toxicity.

The new biomarkers are KIM-1, Albumin, Total Protein, β2-microglobulin, Cystatin C, Clusterin, and Trefoil Factor-3. For decades, both FDA and EMEA have required drug companies to submit the results of two blood tests, called blood urea nitrogen (BUN) and serum creatinine, to evaluate renal toxicity. In addition to those tests, the FDA and EMEA will now consider results from the seven new tests as part of their respective drug review processes. Although a decision by the sponsor to collect information using the new tests is voluntary, if collected, it must be submitted to FDA.

"The development of these and other biomarkers can result in important tools for better understanding the safety profile of new drugs," said Janet Woodcock, M.D., director of FDA's Center for Drug Evaluation and Research. "We hope these biomarkers will lead to human tests that detect drug-induced kidney injury in people earlier than is now possible, and help health care professionals better manage potential kidney damage from drugs."

Woodcock added that such human tests could one day open the door to the approval of more powerful drugs, especially for diseases where renal toxicity currently prevents promising experimental drugs from being approved. With more sensitive tests for renal toxicity, FDA could approve such drugs because health care professionals could closely monitor patients and halt the drug if early signs of renal toxicity appear.

Development of the new biomarkers was led by the Predictive Safety Testing Consortium (PSTC), whose members include scientists from 16 pharmaceutical companies. The PSTC was organized and led by the Critical Path Institute, a nonprofit organization that works to support FDA research collaborations that improve the development of medical products.

Researchers from Merck & Co., Whitehouse Station, N.J., and Novartis AG, Basel, Switzerland, identified the new biomarkers, tested them to prove their accuracy and usefulness, and then shared their findings with the other consortium members for further study. The consortium then submitted applications for use of the biomarkers to FDA and EMEA.

The project is the first in which a group of drug companies has worked together to propose and qualify new safety tests and then present them jointly to the FDA and EMEA for consideration. The FDA and EMEA laid the groundwork for these specific joint-agency biomarker reviews in 2004 when they developed a framework called the Voluntary Exploratory Data Submission review process.

The new process allowed the PSTC to submit a single biomarker data application to both regulatory agencies, and then to meet jointly with scientists from both agencies to discuss it in detail and to address additional scientific questions posed by the regulators. Each regulatory agency then reviewed the application separately and made independent decisions on use of the new biomarkers.

FDA scientists believe that the seven new tests may provide important advantages over the BUN and creatinine tests. For example, in experiments using rats, the two traditional tests can only detect kidney damage a week after it has begun to occur. The new tests, however, are more sensitive and can detect cellular damage within hours. And while BUN and serum creatinine show that damage has occurred somewhere in the kidneys, the new tests can pinpoint which parts of the kidney have been affected.

The seven new tests were developed and will be carried out initially in rats. These tests were selected because other studies have shown that identical biomarkers are produced in human kidney cells. While the FDA and EMEA will consider these biomarkers in rat studies initially, the PSTC has begun work to further qualify the biomarkers for use in human studies. If successful, the PSTC will present a new biomarker data application to the two agencies to seek acceptance of the human biomarkers.