A multicentre randomized double-blind placebo-controlled study of lacosamide, pregabalin, and tapentadol on spinal pain biomarkers

Introduction: Chronic pain is a major public health issue due to limited treatment efficacy. Within the IMI-PainCare project, we aimed to identify spinal biomarkers reflecting nociceptive processing and responsive to analgesics. Standardization and pharmacological validation are key for advancing analgesic development and improving care. Methods: In a multi-center, randomized, double-blind, placebo-controlled crossover trial in healthy subjects, we assessed single doses of tapentadol (primary endpoint), lacosamide, and pregabalin (secondary endpoints) on two spinal biomarkers: RIII flexion reflex area and N13 somatosensory evoked potentials (N13-SEP), after hyperalgesia induction via high-frequency stimulation (HFS). Exploratory analyses included RIII reflex threshold and pain ratings. Results: Twenty-four participants were enrolled. Tapentadol and pregabalin reduced the RIII flexion reflex area on the HFS sensitized side, 60 min after drug, compared to placebo, but the predetermined level of significance (p = 0.025) was not reached. No drug affected N13-SEP amplitude. All drugs significantly increased RIII threshold vs. placebo. Tapentadol and pregabalin also reduced RIII pain ratings. Conclusions: Although primary and secondary endpoints were not met, tapentadol and pregabalin reduced the RIII flexion reflex area with medium, non-significant effect sizes. Exploratory analysis showed all drugs significantly increased the RIII threshold in HFS-induced hyperalgesic condition. N13-SEP amplitudes remained unchanged, questioning its reliability as a spinal biomarker. Significance: Our findings support the RIII threshold as an objective spinal biomarker to assess antihyperalgesic drug effect. This study informs future choices of biomarkers, optimal timing, and analysis strategies in analgesic research.