Could a local anesthetic that doesn’t impair motor function be within reach?

(Press-News.org) All current local anesthetics block sensory signals — pain — but they also interrupt motor signals, which can be problematic. For example, too much epidural anesthesia can prevent mothers in labor from being able to push. Prolonged local anesthesia after orthopedic surgery can leave patients unable to participate in rehab.

Researchers at Boston Children’s Hospital now report an alternative local anesthetic, 2',6'-pipecolylxylidine (PPX), in the journal Anesthesiology, the peer-reviewed journal of the American Society of Anesthesiologists. Unlike the conventional anesthetics from which it’s derived, PPX selectively blocks pain while leaving motor function intact.

“Current local anesthetics all do much the same thing: interrupt conduction of nerve impulses from the periphery to the central nervous system and back,” says study leader Daniel Kohane, MD, PhD, in the department of Anesthesiology, Critical Care and Pain Medicine at Boston Children’s Hospital. “What we developed is a local anesthetic that blocks only the sensory nerves. While conventional local anesthetics are used safely every day, they can have serious toxicities. This new agent is less toxic than conventional anesthetics.”

Striking a balance

PPX’s sensory specificity is believed to lie in its basic chemistry and the anatomy of motor and sensory nerves. While motor nerves have a fatty myelin coating, pain fibers — sensory nerves — have little or no myelin. Most local anesthetics have a combination of hydrophobicity and lipophilicity, properties that affect their ability to get through the myelin sheath and access both motor and sensory nerves.

“The trick is to find a local anesthetic that is hydrophobic enough to get down to the sensory nerves, but not so hydrophobic as to penetrate the myelin sheath on motor nerves,” says Kohane, who also directs the Laboratory for Biomaterials and Drug Delivery at Boston Children’s.

PPX seems to have struck that balance. In rats, it blocked pain without impairing motor function when injected at the sciatic nerve or given intrathecally (into the spinal fluid). Local tissue toxicity was similar to that with conventional local anesthetics, with minimal damage to muscle tissue. There were also fewer signs of systemic neurotoxicity and cardiotoxicity than with ropivacaine, one of the less-toxic commercially available local anesthetics.

A known quantity

Since PPX is a metabolite of conventional local anesthetics, people have already been exposed to it, further indicating its safety. Prior clinical studies have found it to have less toxicity than conventional anesthetics when given intravenously and intraperitoneally.

“Anyone who’s received any of the structurally similar conventional local anesthetics has received PPX,” says Kohane. “People have known about PPX for decades, but have thought of it as a metabolite. No one thought of it as a potentially active agent itself.”

Kohane and his colleagues are starting tests of PPX in large animals and are developing encapsulated formulations that would enable long-term, slow-release delivery for applications such as chronic pain and postoperative pain relief. PPX could also potentially be delivered through an indwelling catheter or implantable pump.

“If people had longer-lasting pain relief, they might be able to use less opioids or even avoid them altogether,” Kohane says.

Claire A. Ostertag-Hill, MD, and Shuanglong Chen, MS, in the Laboratory for Biomaterials and Drug Delivery were co-first authors on the paper. Yueqin Cheng, in the State Key Laboratory of Natural Medicines at China Pharmaceutical University; Nanjing, was co-corresponding author.

To inquire about the technology, please contact Eugenia Park, PhD, in the Technology and Innovation Development Office.

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