Preclinical studies demonstrate effectiveness of laser technologies for local pain control

A pair of preclinical studies reveals two methods for using a laser to trigger on-demand release of a local anesthetic to provide repeatable, long-lasting pain management, either directly at the site of an injury or by blocking pain signals transmitted from an injury.

Both studies, conducted by researchers in the Laboratory for Biomaterials and Drug Delivery (LBDD) at Boston Children's Hospital (MA) and at the Massachusetts Institute of Technology (MIT; Cambridge, MA), point to ways to provide patients with durable, localized, and personalized control of surgical, traumatic, or chronic pain.

Daniel Kohane, MD, Ph.D., director of the LBDD and a physician in the Division of Anesthesiology, Perioperative and Pain Medicine at Boston Children's and senior author on both studies, explains that current approaches to postoperative pain rely on systemic analgesics such as narcotics, which come with side effects and risks of tolerance, addiction, and diversion. Kohane adds that current targeted drug delivery technologies cannot be adjusted or repeatedly triggered to provide a desired, durable level of analgesia, so his research team's goal was to engineer an approach to pain control that, once administered, could be triggered as needed.

Both technologies rely on lipid microspheres carrying tetrodotoxin, a potent local anesthetic, and a laser producing a focused beam of near-infrared (NIR) light, which is able to penetrate tissues without causing direct injury. In the technology reported in the Proceedings of the National Academy of Sciences (PNAS), the microspheres also contained a photosensitizing agent that, when exposed to laser light, produces molecules of reactive oxygen. The microspheres in the Nano Letters report were instead embedded with gold nanorods that heat up when targeted with the laser.

In both cases, the microspheres' surface becomes permeable when exposed to the laser, allowing the drug to escape. Once the laser is turned off, the microspheres reseal, retaining the rest of their drug payload for later triggering.

In the PNAS study, lead author Alina Rwei, a graduate student in the LBDD and the MIT Department of Materials Science and Engineering, successfully blocked hindpaw pain in rats by injecting the photosensitizer-containing microspheres near the sciatic nerve (which transmits pain signals from the lower limbs to the brain) and testing the animals' reactions when stepping on a heat source. Rwei's team found they could tune the level and duration of pain blockade by changing how frequently and for how long they exposed the injected microspheres to the laser beam, as well as the intensity of the beam. For instance, by repeatedly triggering the microspheres, they found they could block pain signals for approximately 24 hours. In addition, they found that the microspheres could be triggered for up to two days after injection.

In the Nano Letters study, lead author Changyou Zhan, Ph.D., a fellow in the LBDD, injected gold nanorod-modified microspheres containing both tetrodotoxin and dexmedetomidine (which prolongs the effects of tetrodotoxin) directly into the footpads of rats and testing the animals' reaction to mechanically induced pain. As with Rwei's experiment, Zhan and his colleagues found they could trigger pain control by repeatedly exposing the rats' nanosphere-injected paws to the NIR laser for up to five days.

In neither study did the investigators find any signs of tissue damage caused by the laser, the microspheres, or tetrodotoxin itself.

Kohane noted that while both technologies need to be refined and optimized, both represent significant steps to addressing an unmet medical need for patient-adjustable local pain relief. In his vision, patients who have undergone surgery or who suffer chronic pain would receive an injection of anesthetic-loaded microspheres at the site of pain and be sent home with a laser device. Upon experiencing discomfort, the patient would use the laser to trigger anesthetic release until he/she achieves a desired level of pain relief.

Both studies were supported by the National Institutes of General Medical Sciences (grant number GM073626). The Technology and Innovation Development Office at Boston Children's has filed a patent application covering both technologies.

For details of the work in PNAS, please visit http://www.pnas.org/content/early/2015/12/03/1518791112. For Nano Letters, please visit http://dx.doi.org/10.1021/acs.nanolett.5b01325.

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