Selective local anaesthetic can block pain without patient also losing their motor ability

Researchers at Boston Children’s Hospital have identified a metabolite of existing anaesthetics that can block sensory nerves while not impairing motor function

Existing local anaesthetics block pain signals by suppressing nerve conduction while at the same time causing temporary paralysis by also interrupting motor nerve impulses. For example, in childbirth, excessive epidural anaesthesia can prevent mothers from being able to push with their contractions. And prolonged local anaesthesia after orthopaedic surgery can leave patients temporarily unable to begin their rehabilitation.

Researchers at Boston Children’s Hospital, Massachusetts, USA, have now reported an alternative local anaesthetic – 2′,6′-pipecolylxylidine (PPX) –  which unlike the conventional anaesthetics from which it is derived it can selectively block pain while leaving motor function intact.

“Current local anaesthetics all do much the same thing: interrupt conduction of nerve impulses from the periphery to the central nervous system and back,” said Professor Daniel Kohane, MD, PhD, in the Department of Anaesthesiology, Critical Care and Pain Medicine at Boston Children’s Hospital.

“What we developed is a local anaesthetic that blocks only the sensory nerves. While conventional local anaesthetics are used safely every day, they can have serious toxicities. This novel agent is less toxic than conventional anaesthetics,” he said.

The chemical properties of PPX’s selective action appear to depend on the structural differences between motor and sensory nerves. Motor nerves are encased in a fatty myelin sheath while sensory pain fibres have little or no such insulation. Conventional anaesthetics are both hydrophobic and lipophilic allowing them to penetrate the myelin sheath and affect both nerve types.

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

In animal studies, PPX appears to achieve this balance. In rats, it blocked pain without impairing movement when injected near the sciatic nerve or administered intrathecally, into the spinal fluid. Local tissue toxicity was comparable with that of conventional anaesthetics and caused minimal muscle damage. Signs of systemic neurotoxicity and cardiotoxicity were fewer than with ropivacaine, one of the least-toxic commercially available current anaesthetics.

Because PPX is a metabolite of conventional anaesthetics, many patients have already been exposed to it, which further supports its safety profile. Earlier clinical research has shown PPX to be less toxic than traditional anaesthetics when administered intravenously or into the peritoneum.

“Anyone who’s received any of the structurally similar conventional local anaesthetics has received PPX,” said Professor Kohane.

“People have known about PPX for decades but have thought of it [only] as a metabolite. No one thought of it as a potentially active agent itself.”

Kohane and his colleagues have begun testing PPX in larger animal models and are developing encapsulated formulations for sustained, slow-release delivery, suitable for chronic or postoperative pain management. The team has also proposed that PPX could be administered via an indwelling catheter or an implantable pump.

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

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

For further reading please visit: 10.1097/ALN.0000000000005679