Single injection could treat pain days, weeks, maybe even months

Researchers at Children's Hospital Boston have developed a slow-release anesthetic drug-delivery system that could potentially revolutionize treatment of pain during and after surgery, and may also have a large impact on chronic pain management.

In NIH-funded work, they used specially designed fat-based particles called liposomes to package saxitoxin, a potent anesthetic, and produced long-lasting local anesthesia in rats without apparent toxicity to nerve or muscle cells. The research was published online April 13 by the Proceedings of the National Academy of Sciences .

"The idea was to have a single injection that could produce a nerve block lasting days, weeks, maybe even months," explains Daniel Kohane, MD, PhD, of the Division of Critical Care Medicine in the Department of Anesthesiology at Children's, and the report's senior author. "It would be useful for conditions like chronic pain where, rather than use narcotics, which are systemic and pose a risk of addiction, you could just put that piece of the body to sleep, so to speak."

Previous attempts to develop slow-release anesthetics have not been successful due to the tendency for conventional anesthetics to cause toxicity to surrounding tissue. Indeed, drug packaging materials have themselves been shown to cause tissue damage. Now, Kohane and colleagues report that if saxitoxin is packaged within liposomes, it is able to block nerve transmission of pain without causing significant nerve or muscle damage.

In lab experiments, the researchers evaluated various formulations -- various types of liposomes containing saxitoxin with or without dexamethasone, a potent steroid known to augment the action of encapsulated anesthetics. The best liposomes produced nerve blocks lasting two days if they contained saxitoxin alone and seven days if combined with dexamethasone.

Cell culture experiments and tissue analysis confirmed that the formulations were not toxic to muscle or nerve cells. Furthermore, when the team examined expression of four genes known to be associated with nerve injury, they found no up-regulation.

"If these long-acting, low-toxicity formulations of local anesthetics are shown to be effective in humans, they could have a major impact on the treatment of acute and chronic pain," says Alison Cole, PhD, of the NIH's National Institute of General Medical Sciences, which partially funded the work. "This slow-release technology may also have broader applications in drug delivery for the treatment of a variety of diseases."

Kohane is currently optimizing the formulation to make it last even longer, while avoiding local and systemic toxicity. "It is conceivable we could have a formulation that is suitable for clinical trials before too long," he says.

The study was supported by the National Institute of General Medical Sciences (www.nigms.nih.govwww.nigms.nih.gov>). Hila Epstein-Barash, PhD, was first author on the paper.

To access the study, visit: http://www.pnas.org/content/early/2009/04/13/0900598106.abstract.

Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 396-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School.