Xu XH, Yang ZM, Chen Q, Yu L, Liang SW, Lv HJ, Qiu ZM. Therapeutic efficacy of baclofen in refractory gastroesophageal reflux-induced chronic cough. World J Gastroenterol 2013; 19(27): 4386-4392 [PMID: 23885151 DOI: 10.3748/wjg.v19.i27.4386]
Corresponding Author of This Article
Dr. Zhong-Min Qiu, Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, No. 389 Xincun Road, Shanghai 200065, China. qiuzhongmin@tongji.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Brief Article
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Xiang-Huai Xu, Zhong-Min Yang, Qiang Chen, Li Yu, Si-Wei Liang, Han-Jing Lv, Zhong-Min Qiu, Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
ORCID number: $[AuthorORCIDs]
Author contributions: Xu XH recruited the patients, performed experiments and statistical analysis of data, and wrote the manuscript; Yang ZM, Chen Q, Yu L, Liang SW and Lv HJ took part in the recruitment of patients and review of the manuscript; Qiu ZM designed and coordinated the program, and revised the manuscript.
Supported by National Natural Science Foundation of China, No. 81170079; Shanghai Shenkang Hospital Development Center Project, No. SHDC12012211
Correspondence to: Dr. Zhong-Min Qiu, Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, No. 389 Xincun Road, Shanghai 200065, China. qiuzhongmin@tongji.edu.cn
Telephone: +86-21-66111286 Fax: +86-21-56050502
Received: February 6, 2013 Revised: May 3, 2013 Accepted: June 5, 2013 Published online: July 21, 2013 Processing time: 164 Days and 23.6 Hours
Abstract
AIM: To evaluate the efficacy and safety of baclofen for treatment of refractory gastroesophageal reflux-induced chronic cough (GERC) unresponsive to standard anti-reflux therapy.
METHODS: Sixteen patients with refractory GERC were given an 8-wk course of baclofen 20 mg three times a day as an add-on therapy to omeprazole. Changes in the cough symptom score, cough threshold to capsaicin, reflux symptom score and possible adverse effects were determined after treatment. The variables of multi-channel intraluminal impedance combined with pH monitoring were compared between responders and non-responders to baclofen.
RESULTS: Twelve of 16 patients completed treatment. Cough disappeared or improved in 56.3% (9/16) of patients, including 6 patients with acid reflux-induced cough (66.7%) and 3 patients with non-acid reflux-induced cough (33.3%). With baclofen treatment, the cough symptom score began to decrease at week 2, was clearly decreased at week 6 and reached a minimum at week 8. At the end of therapy, the lowest concentration of capsaicin required for induction of ≥ 2 and ≥ 5 coughs increased from 0.98 (1.46) to 1.95 (6.82) μmol/L (Z = -2.281, P = 0.024) and from 1.95 (7.31) to 7.8 (13.65) μmol/L (Z = -2.433, P = 0.014), respectively, and the reflux symptom score decreased from 8.0 ± 1.6 to 6.8 ± 0.8 (t = 2.454, P = 0.023). The number of acid reflux episodes was significantly lower in responders than in non-responders. The main adverse effects were somnolence, dizziness and fatigue.
CONCLUSION: Baclofen is a useful, but suboptimal treatment option for refractory GERC.
Core tip: This study evaluated the efficacy and safety of baclofen in a cohort of patients with refractory gastroesophageal reflux-induced chronic cough (GERC) unresponsive to 8 wk of standard anti-reflux therapy consisting of omeprazole twice daily and domperidone. Baclofen is found to be a useful, but suboptimal treatment option for refractory GERC.
Citation: Xu XH, Yang ZM, Chen Q, Yu L, Liang SW, Lv HJ, Qiu ZM. Therapeutic efficacy of baclofen in refractory gastroesophageal reflux-induced chronic cough. World J Gastroenterol 2013; 19(27): 4386-4392
Gastroesophageal reflux-induced chronic cough (GERC) is a clinical syndrome manifested predominantly by chronic cough caused by the backflow of gastric acid or other gastric contents into the esophagus[1]. Acid suppression by proton pump inhibitors alone or in combination with prokinetic agents is currently considered as the standard therapy for GERC, and can improve or eradicate reflux-related cough in the majority of patients, even though there is controversy on the therapeutic effects of these agents[2,3]. Unfortunately, some patients do not respond to standard therapy. Refractory GERC can be defined as cough due to reflux which does not respond to 8 wk of standard anti-reflux treatment with proton pump inhibitors alone twice daily before meals or in combination with prokinetic agents[4]. The management of refractory GERC remains a challenge.
Although anti-reflux surgery such as fundoplication may be an option and benefit some patients in this situation, its role has not been clearly defined and its application is restricted[5]. At present, intensified medical therapy is still the major treatment for refractory GERC. Baclofen, an inhibitor of transient lower esophageal sphincter relaxations (TLESRs)[6], can inhibit both acid and non-acid reflux and is now used in the treatment of refractory gastroesophageal reflux disease[7]. We previously showed in a case report that baclofen was helpful in resolving cough in patients with GERC resistant to standard anti-reflux medical therapy[4]. However, more clinical data are needed for the accurate assessment of its therapeutic efficacy.
Therefore, a prospective and open interventional clinical investigation was performed to evaluate the efficacy and safety of baclofen in a cohort of patients with refractory GERC.
MATERIALS AND METHODS
Patients
Sixteen patients with suspected refractory GERC were recruited from our respiratory clinic between October 2010 and November 2011, including 3 patients reported previously[4]. Their clinical characteristics are shown in Table 1. The inclusion criteria were as follows: (1) chronic cough with or without typical upper gastrointestinal symptoms such as regurgitation, heartburn and chest pain; (2) multi-channel intraluminal impedance combined with pH monitoring (MII-pH) confirmed abnormal acid or non-acid reflux, as shown by a DeMeester score of ≥ 14.72 and/or syndrome association probability (SAP) for acid or non-acid reflux of ≥ 95%[8]; (3) cough fails to improve with 2 mo of standard anti-reflux treatment consisting of omeprazole 20 mg twice daily plus domperidone 10 mg three times a day; and (4) other causes of chronic cough such as upper airway cough syndrome, cough variant asthma and eosinophilic bronchitis were excluded.
Table 1 Demographic characteristics of 16 patients with refractory gastroesophageal reflux-induced cough.
Variables
Value
Sex (male/female)
9/7
Age (yr)
47.8 ± 11.6
Cough duration (mo)
36.0 (27.7)
FEV1 (% predictive value)
93.3 ± 8.3
FVC (% predictive value)
98.1 ± 11.1
FEV1/FVC (%)
80.3 ± 6.1
Cough symptom score
Daytime
3 (0)
Nighttime
1 (1)
DeMeester score
33.1 ± 10.7
SAP (%)
SAP for acid reflux
73.1 (28.2)
SAP for non-acid reflux
71.2 (37.6)
This study was approved by the Ethics Committee of Tongji Hospital and was registered with the Chinese Clinical Trials Register (http://medresman.org) number ChiCTR-ONC-13003123. All patients gave informed consent before entering the study.
Cough severity was rated using the cough symptom score described by Hsu et al[9]. Cough sensitivity to inhaled capsaicin was determined according to a previously described method[10]. Cough threshold was defined as the lowest concentration of capsaicin required for the induction of ≥ 2 (C2) and ≥ 5 coughs (C5). Reflux-related symptoms were scored by a Chinese version of the gastroesophageal reflux diagnostic questionnaire (GerdQ) provided by the designer[11].
MII-pH was performed to evaluate the probability of GERC prior to the commencement of standard anti-reflux treatment as previously described by us[12]. Briefly, a 2.1-mm diameter combined MII-pH catheter with a six impedance channel sensor (K6011-E10632, MMS, Switzerland) and an antimony pH electrode (819100, MMS, The Netherlands) was inserted transnasally into the patient’s esophagus, with the impedance channel sensor located at 3, 5, 7, 9, 15 and 17 cm above the manometrically located proximal border of the lower esophageal sphincter, and the pH electrode positioned at 5 cm above the proximal border of the lower esophageal sphincter. The catheter was connected to a portable data logger (Ohmega, MMS, The Netherlands) which recorded data from all seven channels (six impedance and one pH) with a frequency of 50 Hz over 24 h. Using appropriate software (Database soft, 8.7 version, Medical Measurement System BV, The Netherlands), the data were manually analyzed for reflux episodes, and classified as liquid, gas and mixed reflux on the basis of impedance values, or categorized as acidic (pH < 4.0), weakly acidic (pH 4.0-7.0) or weakly alkaline reflux (pH > 7.0). Combined with diary cards, SAP for acid or non-acid reflux was calculated respectively[13]. The DeMeester score was automatically calculated as described previously[14]. Furthermore, the number of reflux episodes, proximal reflux episodes, time of bolus exposure, time of bolus clearance and time of acid clearance were analyzed.
Procedures
Initial assessments included the collection of patients’ general information and recording of the cough symptom score, reflux symptom score, cough sensitivity to capsaicin and study of MII-pH. The 16 patients with GERC resistant to standard anti-reflux treatment were then given an 8-wk course of baclofen 20 mg three times a day as an add-on therapy to omeprazole 20 mg twice a day, but discontinued domperidone. The patients received weekly follow-up. Responses to therapy, the cough symptom score and possible side effects were evaluated at each follow-up. When treatment was complete, reflux symptom score and cough sensitivity to capsaicin were repeated once more. Cough was considered controlled when it disappeared completely, improved when the cough symptom score decreased by one or more, and failed when the cough worsened or was not alleviated to a noticeable degree[15,16]. The patients who responded favorably to baclofen continued on this therapy for 1 mo and then the dose of baclofen was decreased by 10 mg every month with the lowest maintenance dose of 20 mg daily, while patients who did not improve with baclofen moved to the intensified acid suppression trials and given double dose of omeprazole (40 mg twice a day) for 4 wk and double dose of omeprazole combined with ranitidine 150 mg twice a day for 4 wk in a sequential manner. Refractory GERC was determined if the cough was controlled or improved by treatment with either baclofen, double dose of omeprazole or the combination of ranitidine with double dose of omeprazole.
Statistical analysis
Data with normal distribution were expressed as mean ± SD, or as median (25%-75% interquartile) if the distribution was skewed. A comparison of pre- and post-treatment was made using paired t tests for the data with normal distribution or with the Mann-Whitney U test for the data with skewed distribution. Software (SPSS version 17.0, Chicago, IL, United States) was used for statistical calculation. A P value of < 0.05 was considered significant.
RESULTS
Treatment efficacy
Of 16 patients, 4 withdrew from therapy due to intolerable and persistent nausea and diarrhea following the initiation of baclofen for a week (n = 1) and deterioration or no improvement in cough in the third week (n = 3). Among 12 patients who completed the treatment course of baclofen, cough was controlled in 7 patients (58.3%), improved in 2 patients (15.7%) and failed to improve in 3 patients (25.0%). The overall therapeutic efficacy of baclofen was 56.3% (9/16). Cough in patients responsive to baclofen was considered to be due to acid reflux in 6 (66.7%) and due to non-acid reflux in 3 (33.3%). In the remaining 7 patients who withdrew baclofen therapy (n = 4) or were resistant to treatment (n = 3), cough was resolved by subsequent therapies of double dose of omeprazole in 5 patients and double dose of omeprazole combined with ranitidine in 2 patients.
Changes in cough symptom score, cough threshold and reflux symptom score
With baclofen treatment, the cough symptom score was reduced at week 2, obviously decreased at week 6 and reached a minimum at week 8 (Figure 1). With the exception of 3 non-responders, baclofen treatment resulted in an increase in cough threshold to capsaicin in 9 patients. Cough threshold C2 increased from 0.98 (1.46) to 1.95 (6.82) μmol/L and C5 increased from 1.95 (7.31) to 7.8 (13.65) μmol/L (Figure 2). In contrast, the reflux symptom score reduced from 8.0 ± 1.6 to 6.8 ± 0.8 at the end of therapy (Figure 3).
Figure 3 Changes in gastroesophageal reflux diagnostic questionnaire score after treatment with baclofen.
GerdQ: Gastroesophageal reflux diagnostic questionnaire.
Comparison of variables in MII-pH between responders and non-responders to baclofen
Most MII-pH variables were comparable between the responders and non-responders to baclofen treatment (Table 2). However, the number of acid reflux episodes was lower in the responders than in the non-responders (Z = -2.277, P = 0.023).
Table 2 Comparison of variables in multi-channel intraluminal impedance combined with pH monitoring between patients responsive and unresponsive to baclofen.
The main adverse effects of baclofen were somnolence, dizziness and fatigue (Table 3). These adverse effects were usually tolerable and waned within 1-3 wk despite persistent somnolence and fatigue in 2 (12.5%) patients throughout the entire duration of treatment.
Table 3 Adverse effects in 16 patients during treatment with baclofen n (%).
Adverse effects
Frequency
Somnolence
5 (31.25)
Dizziness
2 (12.50)
Fatigue
3 (18.75)
Nausea
1 (6.25)
Diarrhea
1 (6.25)
DISCUSSION
To date, the definition of refractory GERC remains to be elucidated. According to a widely accepted definition for refractory gastroesophageal disease, cough due to reflux can be considered refractory when the patient does not respond to 4-8 wk of treatment with proton pump inhibitors twice daily[17,18]. However, attention should be paid to the limitations of the diagnostic standard for refractory gastroesophageal reflux disease. Unlike regurgitation and heartburn, cough is an atypical symptom of gastroesophageal reflux disease and can be caused by a number of diseases other than GERC. A temporal cause-effect relationship between reflux and cough established by MII-pH, as indicated by the positive SAP, does not mean that reflux is the true cause of cough and must be verified by specific anti-reflux therapy[1,19]. In our cohort of patients, cough did not improve with a standard course of acid suppression therapy, but resolved after adjustment of the anti-reflux regimen. Therefore, the diagnosis of refractory GERC in these patients was confirmed.
TLESRs refer to periods of spontaneous (not preceded by a swallow) relaxation of the lower esophageal sphincter lasting 10-60 s[20]. TLESRs play a physiological role in venting air from the stomach, but are also the main mechanism for gastroesophageal reflux[21]. In patients with gastroesophageal reflux disease, TLESRs are usually more frequent and are twice as likely to be associated with a reflux event[22]. Proton pump inhibitors can increase the pH value and reduce the volume of the refluxate, and even decrease reflux episodes in combination with prokinetic agents, and thus improve or resolve the symptom in patients with GERC[23]. However, they essentially have no ability to rectify dysfunction in the lower esophageal sphincter and eliminate reflux episodes. In addition, proton pump inhibitors are often ineffective for non-acid (weakly acid or weakly alkaline) reflux[8]. This might explain why patients with GERC failed to respond to initial standard anti-reflux therapy. In this case, inhibitors of TLESRs may help to control the cough. Inhibitors of TLESRs previously under development include gamma-aminobutyric acid B receptor agonists, metabotropic glutamate receptor 5 antagonists and cannabinoid receptors agonists[21]. Inhibitors of TLESRs have primarily been utilized as an add-on treatment for patients with gastroesophageal reflux disease who failed proton pump inhibitors[7,18].
Baclofen is a selective agonist of the gamma-aminobutyric acid B receptor and can inhibit TLESRs by modification of the vagal reflex pathway[24]. There are several lines of evidence to show that baclofen can reduce the frequency of TLESRs, decrease reflux episodes[6,25,26], and reduce acid reflux-related symptoms by 72% and non-acid reflux-related symptoms by 21%[27]. Moreover, baclofen has direct antitussive activity and has been used for the treatment of refractory chronic cough of unknown cause[28,29]. Our results showed that baclofen, as an add-on therapy, reduced cough severity and cough sensitivity to capsaicin in 56.3% of patients with refractory chronic cough due to acid as well as non-acid reflux, which partially confirms our previous observations in a case report[4].
Our results also revealed that the therapeutic efficacy of baclofen was suboptimal, as more than 40% patients with refractory chronic cough due to acid reflux were resistant to baclofen, as characterized by significantly more acid reflux episodes in non-responders than in responders, and further augmented acid suppression eliminated the cough in patients who failed baclofen. This may be explained by the incomplete inhibition of TLESRs by baclofen. There is evidence that baclofen at the dose currently used only reduced the frequency of TLESRs by 40%-60% and decreased the reflux episodes by 43%[6,25,26]. Although studies in dogs have shown that baclofen can abolish TLESRs at higher doses[30], such high doses cannot be administered to humans due to side-effects. In addition, reflux may be secondary to the reduced pressure difference between the stomach and esophagus due to the lower baseline pressure of the lower esophageal sphincter, and may be unrelated to TLESRs[31]. Baclofen and the GABAB agonist lesogaberan have consistently been demonstrated to increase basal pressure of the lower esophageal sphincter in humans[32], which may contribute to the reduction in reflux episodes, but not the absence of reflux episodes. Residual reflux can continue to stimulate sensors with increased sensitivity located at the mucosa in the distal esophagus and cause cough through esophageal-tracheobronchial reflexes[33].
The main side-effects of baclofen emanating from the central nervous system limited its value in the treatment of refractory GERC[34]. Other adverse effects include dry mouth, nausea, vomiting, diarrhea and constipation. Our findings showed that drug-related somnolence, fatigue and dizziness, although common, waned within 3 wk and did not influence treatment in most patients. Considering that the dose of baclofen is gradually increased for the treatment of spasticity in clinical practice, perhaps a similar increase in the dose of baclofen from 5 to 20 mg may help improve tolerance in patients and reduce severe adverse effects[21].
There are several limitations in the present study. First, only a small number of patients with refractory GERC were recruited, and this may have limited the strength of the study. A recent multi-center survey showed that GERC is relatively rare in China[35], and patients with refractory GERC account for a small number. Therefore, it is difficult to enroll a large number of patients. Second, we were unable to directly evaluate the inhibitory efficacy of baclofen on acid or non-acid reflux as the patients refused to undergo a repeat invasive MII-pH study at the end of the treatment period. Moreover, it is difficult to exclude the contribution of the nonspecific non-reflux-related antitussive activity of baclofen. Nevertheless, the obvious parallel reduction in GerdQ suggests that the improvement in cough, at least in part, can be attributed to the blockade of abnormal reflux. Finally, the broad utility of baclofen in clinical practice can be criticized as it only resolves the cough in partial patients with refractory GERC. Nevertheless, considering the negative impact of chronic cough on patient’s quality of life[36] and the difficulty in the management of refractory GERC, we believe that baclofen has its position in the treatment of refractory GERC, even though its effectiveness is limited.
In conclusion, baclofen may be useful for the treatment of refractory GERC. When a standard therapy for GERC fails, baclofen can at least be considered as a treatment option, even though its therapeutic efficacy is suboptimal.
COMMENTS
Background
Gastroesophageal reflux-induced chronic cough (GERC) is a special form of gastroesophageal reflux disease with a predominant chronic cough. Refractory GERC resistant to proton pump inhibitors alone twice daily or in combination with prokinetic agents is difficult to treat as there is currently no satisfactory therapy available.
Research frontiers
Baclofen, a selective agonist of the gamma-aminobutyric acid B receptor, can inhibit both acid and non-acid reflux by reducing the frequency of transient lower esophageal sphincter relaxations and is now used in the treatment of refractory gastroesophageal reflux disease. The authors previously showed in a case report that baclofen successfully resolved the cough in three patients with GERC as an add-on therapy to omeprazole. However, more clinical data are needed to assess its therapeutic efficacy.
Innovations and breakthroughs
In this prospective study involving 16 patients, the authors demonstrated that baclofen, as an add-on therapy to omeprazole, can eliminate or improve cough in 56.3% of patients with refractory GERC, and modify cough hypersensitivity to capsaicin. However, the study also revealed that the therapeutic efficacy of baclofen is suboptimal for the treatment of refractory GERC.
Applications
The study results suggest that baclofen may be considered as an option for the treatment of refractory GERC.
Terminology
Refractory GERC: Refractory GERC is defined as cough caused by reflux which persists despite 8 wk of standard anti-reflux treatment with the combination of proton pump inhibitors twice daily before meals with prokinetic agents.
Peer review
It is an interesting study and will add new information to the treatment of refractory cough due to reflux.
Footnotes
P- Reviewers Fouad YM, Lehmann A S- Editor Zhai HH L- Editor A E- Editor Li JY
Zhang Q, Lehmann A, Rigda R, Dent J, Holloway RH. Control of transient lower oesophageal sphincter relaxations and reflux by the GABA(B) agonist baclofen in patients with gastro-oesophageal reflux disease.Gut. 2002;50:19-24.
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