No relevant modulation of TRPV1-mediated trigeminal pain by intranasal carbon dioxide in healthy humans

BACKGROUND: Nasal insufflation of CO(2) has been shown to exert antinociceptive respectively antihyperalgesic effects in animal pain models using topical capsaicin with activation of TRPV1-receptor positive nociceptive neurons. Clinical benefit from CO(2) inhalation in patients with craniofacial pain caused by a putative activation of TRPV1 receptor positive trigeminal neurons has also been reported. These effects are probably mediated via an activation of TRPV1 receptor - positive neurons in the nasal mucosa with subsequent central inhibitory effects (such as conditioned pain modulation). In this study, we aimed to examine the effects of intranasal CO(2) on a human model of craniofacial pain elicited by nasal application of capsaicin. METHODS: In a first experiment, 48 healthy volunteers without previous craniofacial pain received intranasal capsaicin to provoke trigeminal pain elicited by activation of TRVP1 positive nociceptive neurons. Then, CO(2) or air was insufflated alternatingly into the nasal cavity at a flow rate of 1 l/min for 60 sec each. In the subsequent experiment, all participants were randomized into 2 groups of 24 each and received either continuous nasal insufflation of CO(2) or placebo for 18:40 min after nociceptive stimulation with intranasal capsaicin. In both experiments, pain was rated on a numerical rating scale every 60 sec. RESULTS: Contrary to previous animal studies, the effects of CO(2) on experimental trigeminal pain were only marginal. In the first experiment, CO(2) reduced pain ratings only minimally by 5.3% compared to air if given alternatingly with significant results for the main factor GROUP (F(1,47) = 4.438; p = 0.041) and the interaction term TIME*GROUP (F(2.6,121.2) = 3.3; p = 0.029) in the repeated-measures ANOVA. However, these effects were abrogated after continuous insufflation of CO(2) or placebo with no significant changes for the main factors or the interaction term. CONCLUSIONS: Although mild modulatory effects of low-flow intranasal CO(2) could be seen in this human model of TRPV-1 mediated activation of nociceptive trigeminal neurons, utility is limited as observed changes in pain ratings are clinically non-significant.