Optimized Electrical Stimulation of C-Nociceptors in Humans Based on the Chronaxie of Porcine C-Fibers

Classically, to electrically excite C-nociceptors, rectangular pulses are used with a duration close to the estimated chronaxie of C-fibres (about 2 ms). Recent results using slow depolarizing stimuli suggest longer chronaxies. We therefore set out to optimize C-fiber stimulation based on recordings of single C-nociceptors in-vivo and C-fiber compound-action-potentials (C-CAP) ex-vivo using half-sine shaped stimuli of durations between 1 and 250ms. Single fiber (n = 45) recording in pigs revealed high chronaxie values for C-touch fibers (15.8 ms), polymodal- (14.2 ms) and silent-nociceptors (16.8 ms). Activation thresholds decreased 2 to 3-fold in all fibre classes when increasing the duration of half-sine pulses from 1 to 25 ms (P < .05). C-CAPs strength-duration curves of the pig saphenous nerve (n = 7) showed the highest sensitivity for half-sine durations between 10 and 25 ms. Half-maximum currents for C-CAPS were reduced 3-fold compared to rectangular pulses (P < .01) whereas the opposite was found for A-fiber compound action potentials. Psychophysics in humans (n = 23) revealed that half-sine stimulus durations >10 ms reduced detection thresholds, pain thresholds, and stimulus current amplitudes required to generate a pain rating of 3 on an 11-point Numeric Rating Scale (NRS) as compared to 1 ms rectangular pulses (P < 0.05). Increasing the duration from 1 to 25 ms led to a 4-fold amplitude reduction for pain-thresholds and stimuli caused an axon-reflex flare. Excitability of single polymodal nociceptors in animals paralleled human psychophysics and we conclude optimized half-sine pulses facilitate C-nociceptor activation. PERSPECTIVE: Electrical stimulation with longer lasting half-sine wave pulses preferentially activates C-nociceptors and changes in the strength duration curve may identify nociceptor hyperexcitability in patients with neuropathic pain.