Chronic Pain: Lidocaine Metabolite May Help and Open New Avenues of Treatment

Lidocaine metabolite N-ethylglycine (EG) relieves hyperalgesia and allodynia in animal models for chronic pain, suggests a study in Pain. The finding is an indicator that use of Glycine transporter 1 substrates might constitute a new drug target for the modulation of glycinergic inhibition in pain signaling.

Unraveling the mysterious mechanisms behind chronic pain is in many ways the Holy Grail of pain management. While this discovery is unlikely to revolutionize the field, it does provide a significant step forward in understanding how glycinergic inhibition takes place — opening up a potential new avenue of nonpharmacologic treatment.

“Current recommendations for the management of patients suffering from neuropathic pain include the treatment with tricyclic antidepressants, dual reuptake inhibitors for serotonin and norepinephrine, calcium channel α2δ ligands, opioids, and topical application of lidocaine or capsaicin,” the study authors noted. “In addition to significant adverse effects, all known pharmacological approaches typically show only limited efficacy in the majority of patients.”

It has been well-established in clinical research that lidocaine results in a long-lasting general antinociceptive effect and possibly an anti-inflammatory effect, although the mechanism by which it works has remained a mystery.

“In this study, we provide evidence that the antinociceptive effect seen after long-term treatment with lidocaine can be mimicked by systemic application of the lidocaine metabolite EG, which acts as an artificial substrate specifically on glycine transporters of the GlyT1 subtype, suggesting a novel additional route of action for systemically applied lidocaine,” the authors explained.

The team found that systemic EG was dose-dependently antinociceptive in chronic, but not acute, pain. They noted that the reduction of the glycine uptake capacity of GlyT1 might constitute a general treatment strategy for diseases associated with a diminished inhibitory neurotransmission in caudal regions of the CNS, such as chronic pain with central sensitization.

According to the researchers, the data suggest that “…after continuous application of lidocaine, EG can accumulate and reach plasma concentrations that are sufficient for a significant glycine transport inhibition in vitro and antinociceptive effects in vivo. These results strongly suggest that the antinociceptive effects of systemic lidocaine are caused by EG accumulation that results in elevated glycine levels at synapses of spinal inhibitory circuits.”

The takeaway is that there was no effect on motor coordination or the development of inflammatory edema, and no adverse neurological effects were observed after repeated high-dose application of EG.

“Our results demonstrate that competitive inhibition of GlyT1 by application of GlyT1 substrates like EG is a promising strategy for the therapy of chronic pain conditions. Future investigations are needed to determine the precise molecular mechanisms behind the antinociceptive action,” the study authors concluded.