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August 10, 2017

Sound-Sensitive On-Demand Pain Relief

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    Illustration showing ultrasound triggering liposomes to release local anesthesia. [Mary O'Reilly]

    Imagine a small hand-held device that could be directly placed on the skin and with the press of a button localized pain would vanish. Sound like something you would see in an episode of Star Trek, right? If a team of investigators, led by scientists at Boston Children’s Hospital have it their way, it will become a reality very soon, as they have just reported on a new way to noninvasively relieve pain at local sites in the body. Findings from the new study—published today in Nature Biomedical Engineering in an article entitled “Ultrasound-Triggered Local Anesthesia”—could one day improve pain management by replacing addictive opioids and short-lasting local anesthetics.

    "Opioid abuse is a growing problem in healthcare," explained senior study investigator, Daniel Kohane, M.D., Ph.D., a senior associate in critical care medicine at Boston Children's and professor of anesthesiology at Harvard Medical School. "In the future, this system could potentially combat that by giving patients access to nonopioid, effective nerve-blocking drugs."

    In the new study, the research team developed a novel system that uses ultrasound to trigger the release of nerve-blocking agents—injected into specific sites of the body ahead of time, when and where pain relief is needed most. Ultrasound is commercially available and widely used in various clinical and therapeutic settings, making it an attractive technology to use as a drug "trigger."

    "One of the most interesting aspects of this system is that the degree of nerve block can be controlled just by adjusting the duration and intensity of the ultrasound,” noted lead study investigator Alina Rwei, a graduate researcher in Dr. Kohane's laboratory. "We envision that patients could get an injection at the hospital and then bring home a small, portable ultrasound device for triggering the nerve-blocking agent. This could allow patients to manage their pain relief at-will, noninvasively."

    To create the ultrasound-triggered pain relief system, Kohane's team developed liposomes—phospholipid encased sacs that are micrometers in size—and filled them with a nerve-blocking drug. The walls of the liposomes contain small molecules called sono-sensitizers, which are sensitive to ultrasound.

    "Once the drug-filled liposomes are injected, ultrasound can be applied to penetrate tissue and cause the sensitizers to create reactive oxygen species, which react with lipids in the walls of the liposomes," Dr. Kohane remarked. "This opens the surface of the liposomes and releases the nerve-blocking drug into the local tissue, reducing pain."

    “On insonation [treatment with ultrasound], the encapsulated sonosensitizer protoporphyrin IX produced reactive oxygen species that reacted with the liposomal membrane, leading to the release of the potent local anesthetic tetrodotoxin,” the authors wrote. “Repeatable ultrasound-triggered nerve blocks were achieved in vivo, with the nerve-block duration depending on the extent and intensity of insonation. There was no detectable systemic toxicity, and tissue reaction was benign in all groups.”

    The small sono-sensitizer molecules that the research team built into the liposomes are the active component of an already-FDA-approved drug that is currently used in photodynamic therapy. Right now, the pain treatment system developed by Dr. Kohane's team can be activated by ultrasound up to three days after injection of liposomes, making it well-positioned for future translation as a postoperative pain management strategy.

    "Out of all the particle delivery systems, I think liposomes are one of the most clinically acceptable and customizable options out there," Ms. Rwei concluded. "Our research indicates that liposomes can be tailored to respond to near-infrared light, ultrasound, and even magnetic triggers."

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