Discussion
In the patients with presumptive GERC whose cough persists despite proton pump inhibitors therapy, three possibilities arise to explain the continuing cough: 1. the gastric acid may be incompletely suppressed, and the patients are having continuing acid reflux that causes cough by microaspiration or esophageal-tracheobronchial reflex [
1]. 2. non-acid (weakly acidic or alkaline) reflux is producing cough. It is proposed that cough due to non-acid reflux is resistant to proton pump inhibitors since they only reduce the pH of the refluxate but not the amount and the rate of reflux episodes [
2]. 3. the ongoing cough is not related to any continuing reflux. It has been reported that only 40.8% of the patients with the positive findings of 24 hour esophageal pH monitoring were responsive to the high dose of omeprazole [
3]. In all the three patients, MII-pH uncovered the abnormal acid or nonacid reflux and the temporal association between reflux and cough. Therefore, GERC could be established since the other common causes of chronic cough such as upper airway cough syndrome, cough variant asthma and eosinophilic bronchitis were excluded with the previous investigation procedure and specific therapies. The diagnosis of GERC was finally confirmed by the favorable response to the subsequent antireflux treatment containing omeprazole and baclofen even though the initial standard antiacid medical treatment failed.
In theory, the therapeutic options available for refractory GERC resistant to proton pump inhibitors include prokinetic agents, transient lower esophageal sphincter relaxation inhibitors and antireflux surgery because they all have the ability to reduce the frequency of reflux and volume of refluxate. At present, the efficacy of prokinetic agents has not been ascertained, which can explain the failure of the initial antireflux therapy containing domperidone. Antireflux surgery should not be the preferred choice when a cause and effect relationship between reflux and chronic cough is not definitely established. We selected baclofen, a potent inhibitor of transient lower esophageal sphincter relaxation, as an add-on trial for GERC unresponsive to proton pump inhibitors since it has been proposed in the management of difficult to treat gastroesophageal reflux disesase [
4]. To our knowledge, this is the first report for the successful resolution of refractory GERC with baclofen.
Baclofen modulates the transient lower esophageal sphincter relaxations mediated by vagal reflex pathways through the activation of gamma-aminobutyric acid B receptor. Considering transient lower esophageal sphincter relaxations account for the vast majority of reflux events [
5], it is predictable that baclofen may be helpful for refractory GERC by the inhibition of both acid and nonacid reflux. The limited studies have shown that it decreased the frequency of transient lower esophageal sphincter relaxations by 40-60% and acid or non-acid reflux episodes by 43% [
6‐
8]. Vela has illustrated that baclofen reduced the symptoms related to acid reflux by 72% and related non-acid reflux by 21% in a small cohort of patients with heartburn [
9]. In addition, baclofen has also been recognized for a long time to have a nonspecific antitussive activity both in animals [
10] and in humans [
11,
12]. There have been several lines of evidence illustrating baclofen can treat the cough caused by angiotensin-converting enzyme inhibitors [
13] and refractory chronic cough with unknown cause [
14]. Our observations revealed that 2–4 week course of baclofen was needed for the significant alleviation of cough, and the complete resolution was generally achieved in the 2–3 months. Because MII-pH is an invasive procedure, our patients refused to undergo a repeated examination after the cough was resolved. Therefore, we were unable to directly evaluate the inhibitory efficacy of baclofen on acid or non-acid reflux in the patients. Nevertheless, it can be speculated that baclofen may play a therapeutic role through the effective blockade of all types of reflux events as well as the nonspecific antitussive effect.
A variety of central nervous system-related side effects can be produced by Baclofen, including somnolence, dizziness, fatigue, weakness and trembling. The other adverse reactions consist of dry mouth, nausea, vomiting, diarrhea or constipation. These side effects usually occur in the early or high-dose phase of treatment, and often limit the utility of baclofen in clinical practice [
4]. In our patients, there was only slight dizziness and sleepiness in patient 2 and 3 respectively, which did not interrupt the treatment of baclofen. The lack of obvious side effects may be attributed to the well tolerance of the patients to the drug.
In conclusion, baclofen may be a viable option for refractory cough due to gastroesophageal reflux. Further study is needed to validate its therapeutic efficacy for GERC in the future.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
XX was in charge of collection of cases and writing the manuscript. QC, SL and HL took part in the collection of cases and review of the manuscript. ZQ was in charge of design and coordination of the program, review and correction of the manuscript. All authors read and approved the final manuscript.