Contact heat and cold, mechanical, electrical and chemical stimuli to elicit small fiber-evoked potentials: merits and limitations for basic science and clinical use.

Laser-evoked potentials are the most extensively validated method to objectively assess nociceptive pathway function in humans. Here, we review merits and shortcomings of alternative techniques using different principles of stimulus generation to stimulate Aδ- or C-fibers. Fast ramp contact heat stimuli yield reproducible responses; however, stimulus location needs to be changed to reduce peripheral habituation, and the limited steepness of temperature ramps may result in response jitter and absence of averaged responses even in some healthy subjects. Inverse temperature ramps can serve to evoke cool evoked potentials to specifically test the cold pathway; the clinical impact of such findings is promising but uncertain to date, and availability of devices optimized for this purpose is currently limited. Mechanical stimuli excite low- or high-threshold mechanoreceptors depending on both the probe surface and the applied force. Electrical stimuli can be used to excite nerve fibers directly in the epidermis, the mucosa of the gut, or the tooth pulp. Principle limitation of the applicability of mechanical and electrical stimuli is the inevitable co-excitation of tactile (Aβ-) fibers. The nasal mucosa can be stimulated using pulsed-CO(2) air streams, which excite chemo-nociceptors; although these stimuli are specific to excite thin trigeminal afferents, their use is limited as it is restricted to a relatively small region. Current data do not allow a comparative analysis on their respective diagnostic values. Quantification of analgesic efficacy in healthy subjects has been established and may be useful in phase I and IIa clinical trials.