Background: This preclinical study in humans was designed to selectively induce delayed nociceptive pain responses to individually titrated laser stimulation, enabling separate bedside intensity scoring of both immediate and delayed pain. Methods: Forty-four (fourteen female) healthy volunteers were subjected to repeated nociceptive dermal stimulation in the plantar arc, based on ultra-short carbon dioxide laser with individually titrated energy levels associated with mild pain. Results: Data was analysed in 42 (12 female) subjects, and 29 of them (11 females) consistently reported immediate and delayed pain responses at second-long intervals to each nociceptive stimulus. All single pain responses were delayed and associated with lower levels (p = 0.003) of laser energy density (median 61; IQR 54-71 mJ/mm 2 ), compared with double pain responses (88; 64-110 mJ/mm 2 ). Pain intensity levels associated with either kind of response were readily assessable at bedside. Conclusions: This study is the first one to show in humans that individually titrated ultra-short pulses of laser stimulation, enabling separate pain intensity scoring of immediate and delayed responses at bedside, can be used to selectively induce and evaluate delayed nociceptive pain, most likely reflecting C-fibre-mediated transmission. These findings might facilitate future research on perception and management of C-fibre-mediated pain in humans.
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