Highlights

Mounting a lasting blockade against pain

Boston Children's researchers work on novel treatment to stop neuropathic pain before it starts

Langer_Kohane_liposomes

A cut, a bruise, a scrape…these can all cause pain that, while unpleasant, usually passes quickly. But for an estimated 3.75 million people in the United States with neuropathic pain, the pain is debilitating for life. With neuropathic pain, the damaged nerve signals to the central nervous system that something’s wrong, causing the sensation of pain. There are therapies to control neuropathic pain, like lifestyle changes and a range of medications, but they don’t target it at its source.

Multiple efforts are underway at Boston Children’s to not just treat the symptoms caused by the disease, but attack the root of the problem and reverse the condition. One effort by Boston Children’s Hospital’s Daniel Kohane, MD, PhD, along with collaborator Robert Langer, ScD, at the Massachusetts Institute of Technology, aims to do just that and even stop pain before it starts using a novel treatment--microscopic beads full of a neurotoxin found in shellfish.

“There has been significant interest in using powerful local anesthetics to block aberrant nerve discharges from the site of injury to prevent the onset of neuropathic pain,” says Dr. Kohane, who works in Boston Children’s Department of Anesthesia. “Others have tried with varying degrees of success to do this in animal models using a variety of methods. But if applied clinically, those methods would require surgical intervention or could be toxic to tissues. We want to avoid both of those concerns.”

Dr. Kohane’s solution uses a fat-based microspheres called liposomes filled with saxitoxin, a powerful local anesthetic derived from paralytic shellfish toxin (think red tide). The liposomes—which are only about five and a half micrometers wide, or a bit smaller than a red blood cell—also contain dexamethasone, a steroid that helps the saxitoxin’s effects last longer.

Dr. Kohane and Langer first tried out their saxitoxin dexamethasone liposomes (SDLs) in 2009, showing they could, in an animal model, reduce short-term pain without causing additional damage. In the recent Proceedings of the National Academy of Sciences, the pair (along with postdoctoral fellow Sahadev Shankarappa, MBBS, MPH, PhD, and others) reported the next step: using SDLs to block local nerve signaling at the site of nerve injury and delay neuropathic pain’s appearance.

In their model, one dose of SDLs right after injury had only a mild effect, delaying the onset of neuropathic pain by a couple days compared to untreated animals. However, three doses spread out over 12 days delayed the pain by a month, suggesting that the SDLs could indeed keep the injured nerve quiet.

Another positive, the study showed that the SDLs’ effects extended to the animals’ dorsal horn—a part of the spine that relays pain signals from the body to the CNS. When the team examined the dorsal horn five or 60 days after injury, they found no sign that it was registering pain from the injury site; the SDLs had completely blocked the signals.

This is not the first Boston Children’s project to have positive effects using neurotoxins like saxotoxin to treat pain. Thirteen years ago, Dr. Kohane, along with Charles Berde, MD, Chief, Division of Pain Medicine, Gary Strichartz, PhD at Brigham and Women’s Hospital and Langer, found that by combining tetrodotoxin with local anesthetics they could prolong a nerve blockade from 8 hours to periods of two to four days in animals with minimal local or systemic side effects. Since this initial study, Boston Children’s researchers have teamed up with Proteus SA in Chile to further the development of NeoSTX (a novel saxotoxin formulation) as a long lasting anesthetic to treat postoperative pain. The group is now preparing for a phase one clinical trial. Dr. Kohane has already begun working on the next steps.

“We’re trying to refine our methods so that we can get individual injections to last longer and figure out how to generalize the method to other models of neuropathic pain,” he says. “We also need to see whether it is safe to block nerve activity in this way for this long. We think that this approach could be fruitful for preventing and treating what is really a horrible condition.”

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