Reply to: Noxious cold stimulation: pro–con perspectives on the hypothermic effect on experimentally evoked cough

Reply to S. Zhong and co-workers:

We thank S. Zhong and co-workers for their interest and thoughtful letter in response to our manuscript, “The effect of pain conditioning on experimentally evoked cough: evidence of impaired endogenous inhibitory control mechanisms in refractory chronic cough” [1]. In this study we demonstrated that a painful cold stimulus, applied to the hand, inhibited cough responses to capsaicin in humans, and that this phenomenon (known as conditioned pain modulation, CPM) was impaired in patients with refractory chronic cough. Interestingly, the recent study performed by Dong et al. [2] also investigated the effects of cold on the cough reflex. They found placing guinea pigs in a cold environment had the opposite effect, heightening cough responses to cinnamaldehyde in animals repeatedly exposed to citric acid; the citric acid exposure being an attempt to emulate the hyperexcitability of the cough reflex observed in patients with chronic cough.

There are fundamental differences between these studies that may account for the conflicting results. These include different species, cough challenge agents and the relevance of the citric acid exposure model to refractory chronic cough. However, in our opinion, the disparity in findings highlights that the reflex responses evoked by a localised painful cold stimulus, i.e. descending inhibitory controls, are quite distinct from those activated when the whole body or majority of the skin surface is exposed to cold air, which provokes systemic acute physiological responses to cold. Similar contrasting observations have been made in the context of chronic pain. For example, the cold pressor test used in our study is the most commonly used paradigm for demonstrating inhibition of pain through CPM and impaired pain inhibition is well-established in patients with chronic pain syndromes [3]. However, this conflicts with studies reporting the enhancement of pain on exposure to cold environments and observations that humans working in cold conditions are at greater risk of chronic pain [4, 5].

A study comparing five different methods for inducing CPM found the cold pressor test and ischaemic occlusion produce similar CPM effects, but the cold pressor test was the most effective at inducing pain, and the CPM effect was greater [6]. The cold pressor test also has better repeatability between visits compared with ischaemic occlusion [7]. For these reasons, we adopted the cold pressor test in our study, and we would not predict any difference in the outcomes if an alternative conditioning stimulus, such as ischaemic pressure, was used. However, the cold pressor test does require specialist equipment and, therefore, ischaemic occlusion is more easily applied in clinical as opposed to research settings.

The authors also expressed their concern about tachyphylaxis occurring in our study. Tachyphylaxis does occur in all capsaicin cough challenges and is most marked when high concentrations of capsaicin are inhaled, especially if then followed by a lower concentration [8]. The use of a single concentration (ED50) of capsaicin (inhaled four times) helps to avoid excessive tachyphylaxis when repeated measures of cough responses are required, as the overall exposure of subjects to capsaicin is much less than when doubling concentrations are used to measure a standard C5 (concentration evoking five coughs). Moreover, for a 90-s cold-water immersion it would be impossible to measure a C5 in such a short time frame. As can be seen from our no intervention data a small (but not statistically significant) reduction in the number of coughs was seen in our study due to tachyphylaxis, but as this effect is the same for all the experimental conditions, this not a confounding factor and does not influence the results.

Finally, S. Zhong and co-workers also commented that the “change of coughing during cold water immersion” was not provided. We only measured cough frequency at baseline in this study, to characterise the patients, but did not collect further data on the intervention days. This was because the interventions only lasted for 90 s and so it would have been impossible to see changes in cough frequency during such a short time-period and unlikely that such a brief intervention would change cough frequency over the remainder of the 24 h period.

The mechanisms underlying chronic cough remain poorly understood; however, using established experimental paradigms to explore processes thought to be important in chronic pain, may be a route to improving our knowledge.

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