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

Nasal insufflation of CO₂ 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 CO₂ 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 CO₂ on a human model of craniofacial pain elicited by nasal application of capsaicin.

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, CO₂ 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 CO₂ 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.

Contrary to previous animal studies, the effects of CO₂ on experimental trigeminal pain were only marginal. In the first experiment, CO₂ 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 CO₂ or placebo with no significant changes for the main factors or the interaction term.

Although mild modulatory effects of low-flow intranasal CO₂ 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.