In the study, gabapentin eliminated or attenuated the cough in about two-thirds of patients with CRC, and achieved a comparable therapeutic success with the previous researches5, 7, 8. Central nervous system-related side effects were common for the therapy although they were tolerable and rarely resulted in the treatment interruption. Moreover, HARQ might be a useful predictor of the therapeutic efficacy of gabapentin in treating CRC.
Cough hypersensitivity in patients with CRC is characterized by clinical features including abnormal laryngeal sensations in the throat (laryngeal paresthesia), the exaggerated cough response to the threshold or subthreshold-level exposure to a known tussigen (hypertussia) and cough triggered by non-tussive stimuli (allotussia) 20, 21. Therefore, to restore normal cough sensitivity and inhibit pathological cough under the premise of preserving the protective effect of cough reflex are an ideal therapeutic strategy. The rationale for gabapentin treating CRC is the similar central hypersensitivity of chronic cough to neuropathic pain and the proven efficacious effectiveness of gabapentin in chronic pain 22–25. Our study has supported that gabapentin is an effective regimen for CRC, as indicated by a favorable response to gabapentin in the majority of recruited patients.
HARQ has originally been designed as an aid to diagnosis rather than a quality-of-life tool for cough hypersensitivity syndrome. Several lines of evidence have shown HARQ can detect cough hypersensitivity with a high sensitivity and specificity, and clearly separate the coughers from the non-coughers when adopting cutoff values as ≥ 12.75–139−11, 26. However, CRC does not differ from the other common etiologies of chronic cough except for cough due to reflux in cough hypersensitivity identified by HARQ9, reflecting a single coherent clinical entity of chronic cough27. In the study, we have demonstrated that HARQ may be helpful to screen patients with CRC suitable for gabapentin therapy as it had a moderate good ability to predict the therapeutic efficacy of gabapentin when adopting 21.5 as a cutoff point.
The central and peripheral components of cough hypersensitivity vary among the individual patient with chronic cough, and both can develop as a part of CRC. Considering the centrally acting nature of gabapentin, CRC patients with predominant central cough sensitization should have a higher possibility to respond to gabapentin. Although HARQ cannot definitely measure central sensitization, some items may imply central cough hypersensitivity. Itchy throat, a common trigger to cough28, is involved in laryngeal sensory neuropathy and indicates laryngeal hypersensitivity as the sensitization of the central neural circuit helps to regulate chronic itchy sensation29. Therefore, it is not surprising that the HARQ items of “A tickle in your throat, or a lump in your throat” and “Cough with eating”, the respective manifestation of laryngeal paresthesia and allotussia representing central hypersensitivity20 scored higher in gabapentin responders than in non-responders, and were identified as two independent predictors of gabapentin efficacy. Our study has confirmed central cough hypersensitivity was a crucial factor predicting the therapeutic success of gabapentin in patients with CRC.
Gastroesophageal reflux can be a determinant of CRC since about 36% of patients with cough due to reflux are resistant to anti-reflux medicinal treatment15 and need the neuromodulators as add-on therapy7, 16, 30. The underlying mechanisms include incomplete acid suppression, non-acid reflux, transient lower esophageal sphincter relaxations and esophageal hypersensitivity30, which are generally associated with peripheral sensitization of cough reflex. However, the reflux reaching the proximal esophagus and laryngopharynx is often accompanied by laryngeal sensory neuropathy, a sign of central sensitization31. Despite the fact that cough due to reflux was excluded by negative findings of esophageal impedance-pH monitoring and failure to the subsequent trial of anti-reflux medicinal therapy, reflux as a precipitating factor of CRC was possible since the HARQ items of “Cough with eating” and “Cough when you get out of bed in the morning” hint airway reflux induced by gaseous reflux32 in addition to cough hypersensitivity. When considering gabapentin resolves CRC associated with reflux8, the two HARQ items became the therapeutic predictive factors of gabapentin has a potential reasonability.
Among the three independent predictors corresponding to HARQ items, the individual importance was almost equal. In fact, the findings in our study may reflect the multiple facets and non-prominent recognition features of central cough hypersensitivity27. Therefore, anyone of these factors alone is not powerful enough to select appropriate patients with CRC most likely responsive to gabapentin and to predict therapeutic success. With the established multivariate logistic regression equation, the overall prediction of the three independent factors for the therapeutic success of gabapentin can be more accurately estimated, leading to a convenient clinical decision making. When calculated P is ≥ 0.5714, more than 80% of the treatment success rate of gabapentin can predictably be achieved by the equation. By prior screen with HARQ, the treatable traits of CRC will be easy to be identified for gabapentin and the experienced adverse effects of the therapy without benefit will be minimized.
There were several limitations in the study. The cough hypersensitivity assessed by HARQ was inevitably affected by the subjectivity of the questionnaire, which limits the reliability of results. Since the determination of predictors for the therapeutic efficacy of gabapentin was performed by post-hoc analysis, we think the subjective inherence of the HARQ will not decrease the power of the conclusion because participants were blinded to the HARQ utilization, which was further supported by the preliminary results of our consequent revalidating study. Although the placebo effects of gabapentin cannot be ruled out, the study aimed to identify the therapeutic predictors of gabapentin, rather than to confirm its effectiveness in CRC. In fact, the usefulness of gabapentin for CRC has been fully established2, 6. The established logistic regression equation is indeed imperfect since it has only a moderate ability to predict the therapeutic success of gabapentin. However, it may significantly enhance the therapeutic efficacy of gabapentin from 66.5–83.7%. We hope the prediction model will be persistently improved by further clinical study and practice in the future.