Chronic cough and esomeprazole: a double-blind placebo-controlled parallel study

Background and objective: Gastro‐oesophageal reflux has been implicated in the pathogenesis of chronic cough. Guidelines on management suggest a therapeutic trial of anti‐reflux medication. Esomeprazole is a proton pump inhibitor licensed for the long‐term treatment of acid reflux in adults and we compared the effects of esomeprazole and placebo on patients with chronic cough. Methods: This was a prospective, single‐centre, randomized, double‐blind, placebo‐controlled, parallel group study conducted over 8 weeks. Fifty adult non‐smokers with chronic cough and normal spirometry were randomized. Patients completed cough‐related quality‐of‐life and symptom questionnaires and subjective scores of cough frequency and severity at the beginning and end of the study. They also kept a daily diary of symptom scores. Citric acid cough challenge and laryngoscopic examination were performed at baseline and the end of the study. The primary outcome was improvement in cough score. Results: There were no differences in cough scores in the placebo and treatment arms of the study although some significant improvements were noted when compared to baseline. In the cough diary scores there was a trend towards greater improvement in the treatment arm in patients with dyspepsia. Conclusions: Esomeprazole did not have a clinically important effect greater than placebo in patients with cough. It suggests a marked placebo effect in the treatment of cough.     

Gastroesophageal reflux in asthmatics: A double-blind, placebo-controlled crossover study with omeprazole

STUDY OBJECTIVES: To investigate the prevalence of gastroesophageal reflux (GER) among patients with asthma and to determine the effect of omeprazole on the outcome of asthma in patients with GER. DESIGN: A double-blind, placebo-controlled crossover study. SETTING: Asthmatic patients who attended the pulmonary outpatient clinic of Turku University Central Hospital, Finland. PATIENTS: One hundred seven asthmatic patients. INTERVENTIONS: The patients who were found to have GER in ambulatory esophageal pH monitoring were randomized to receive either omeprazole, 40 mg qd, or placebo for 8 weeks. After a 2-week washout period, the patients were crossed over to the other treatment. Spirometry was performed at baseline and immediately after both treatment periods. Peak expiratory values, use of sympathomimetics, and pulmonary and gastric symptoms were recorded daily in a diary. RESULTS: Pathologic GER was found in 53% of the asthmatic patients. One third of these patients had no typical reflux symptoms. Daytime pulmonary symptoms did not improve significantly (p = 0.14), but a reduction in nighttime asthma symptoms (p = 0.04) was found during omeprazole treatment. In the patients with intrinsic asthma, there was a decline in [corrected] FEV(1) values (p = 0.049). Based on symptom scores, 35% of the patients were regarded as responders to 8-week omeprazole treatment. The reflux (time [percent] of pH < 4) was found to be more severe (p = 0. 002) in the responders. CONCLUSIONS: There is a high prevalence of GER in the asthmatic population. This reflux is often clinically "silent." After an 8-week omeprazole treatment, there was a reduction in nocturnal asthma symptoms, whereas daytime asthma outcome did not improve. There seems to be a subgroup of asthma patients who benefit from excessive antireflux therapy.     

Ranitidine in reflux oesophagitis. A double-blind placebo-controlled study

This study was designed to assess the effect of ranitidine on patients with symptomatic oesophageal reflux. In a double-blind comparative trial in 46 patients a twice daily dose of 150 mg ranitidine was compared with placebo. Relief of pain, endoscopic healing and histological improvement were significantly better in those treated with ranitidine. Thus, ranitidine is of value in the management of patients with reflux oesophagitis and may prevent the development of peptic stricture.     

Patients with functional dyspepsia responding to omeprazole have a characteristic gastro-oesophageal reflux pattern.

BACKGROUND: The effect of acid secretion inhibitors in patients with functional dyspepsia (FD) is equivocal. One previous trial showed an effect in patients with a characteristic gastro-oesophageal reflux pattern. This double-blind trial compares the number of reflux episodes in responders and non-responders to omeprazole. METHODS: Twenty-four patients (men/women, 11:13; mean age, 49 years) with FD were included; those with reflux as the main symptom were excluded. An upper endoscopy and a 24-h oesophageal pH measurement were performed before randomization to treatment with 10-20 mg omeprazole or placebo for 4 weeks. Patients who at questioning considered themselves to have achieved sufficient relief of dyspeptic symptoms after 4 weeks were characterized as responders. RESULTS: The number of responders in the omeprazole and placebo groups was 8 of 14 (57%) and 2 of 10 (20%), respectively (P = 0.07). The mean number of reflux episodes at the 24-h oesophageal pH measurement in responders and non-responders to omeprazole was 57 and 25, respectively (P < 0.003). In the omeprazole group the number of responders was 0 of 5 (0%) in those with < 32 reflux episodes and 8 of 9 (89%) in those with > 32 reflux episodes (P < 0.003). CONCLUSION: Patients with FD responding to omeprazole were characterized by many reflux episodes.     

Adult asthma and gastro-oesophageal reflux: the effects of omeprazole therapy on asthma

Background: Approximately 40–60% of patients with asthma have gastro-oesophageal reflux (GOR) and it has been postulated that this may worsen asthma severity. Aims: To investigate the effect of the potent gastric acid inhibitor omeprazole 40 mg orally daily on peak expiratory flow rate (PEFR), asthma symptoms and histamine bronchial responsiveness in adult patients with both asthma and GOR. Methods: This was a double blind, randomised, placebo controlled, crossover study. Upper gastrointestinal endoscopy, 24 hour oesophageal pH measurements, spirometry and histamine bronchoprovocation test (HIT) were performed prior to entry. Phase 1:2 week placebo run-in period, with baseline recording of PEFR, asthma and GOR symptoms, and use of inhaled p₂-agonist. Phase 2: patients randomised to receive either placebo or omeprazole 40 mg/d for four weeks. Phase 3: placebo for two weeks. Phase 4: patients crossed over to opposite treatment from that of phase 2. Spirometry, and diary cards were assessed at beginning and end of phases 2 and 4. HIT was performed at the end of phase 2 and at the beginning and end of phase 4. Results: Twenty patients (eight female and 12 male) completed the study. The evening but not morning PEFR (% predicted) were significantly higher on omeprazole vs placebo (82 ± 4% SEM vs 79 ± 4% SEM; p<0.05). No significant differences were found in FEVj, FVC, histamine bronchial responsiveness and diurnal variation of PEFR between placebo and omeprazole treatments. Similarly, there were no significant differences during placebo and omeprazole periods in day time wheeze, cough, breathlessness, p₂-agonist use or night time wheeze and breathlessness. Day and night heartburn symptoms were significantly better on omeprazole vs placebo (p<0.05). Conclusions: Omeprazole 40 mg daily improved evening PEFR in asthma patients with GOR. However, asthma symptoms, inhaled β₂-agonist use and histamine bronchial responsiveness did not change.     

Twelve months' follow-up after treatment with the EndoCinch endoscopic technique for gastro-oesophageal reflux disease: a randomized, placebo-controlled study

OBJECTIVE: The Bard EndoCinch plication technique has been reported to improve symptoms and reduce oesophageal acid exposure in patients with gastro-oesophageal reflux disease (GORD). However, no placebo-controlled studies have been published as yet. The purpose of this study was to evaluate the effects of the EndoCinch plication technique in a randomized, placebo-controlled setting. MATERIAL AND METHODS: Forty-six otherwise healthy subjects with objectively verified GORD requiring regular use of proton-pump inhibitors (PPIs) were enrolled in the study. Patients were randomized to the EndoCinch plication technique or a sham procedure. Pre- and post-procedure assessments included gastro-oesophageal endoscopy, oesophageal manometry and 24-h pH recording, quality of life (QoL) assessment and use of PPIs. RESULTS: Reflux-specific symptoms and use of PPIs (total intake as well as number of patients not taking PPIs) improved in both groups at 6 weeks and at 3 and 12 months post-procedure (p<0.05) with an increased improvement in the treatment group at 3 months compared to controls (p<0.05 versus sham). There were no inter- or intra-group differences in endoscopic findings, oesophageal manometry or acid exposure before or at 3 or 12 months post-procedure. Gastro-oesophageal endoscopy showed that 71% and 67% of sutures remained at 3 and 12 months, respectively. CONCLUSIONS: Although some short-term effects were achieved, it was found that there were no differences between the treatment and control groups after 12 months and the lack of reduction of oesophageal acid exposure suggests that, in its present form, the EndoCinch plication technique is not to be recommended for use in clinical practice. It is suggested that the lack of long-term effects is primarily due to detachment of the sutures.     

Prevention of duodenal ulcer relapse with omeprazole 20 mg daily: A randomized double-blind, placebo-controlled study

Abstract We report the first double-blind, placebo-controlled study that assesses the efficacy and safety of omeprazole 20 mg daily in the maintenance treatment of duodenal ulcer. For the healing phase, 128 patients with endoscopically proven active duodenal ulcer and a history of three or more relapses during the 2 years prior to the study were treated until healing with omeprazole 40 mg daily for 2 and up to 8 weeks. One hundred and twenty-three patients whose ulcers were healed were randomized to receive omeprazole 20 mg daily (n = 60) or placebo (n = 63) for 12 months as maintenance treatment. Patients were interviewed at 3, 6, 9 and 12 months, and endoscopy was performed at 3, 6 and 12 months and whenever symptoms recurred. The healing rates of the 124 patients completing the healing phase were 84, 98 and 100% at 2, 4 and 8 weeks, respectively. During the maintenance phase, eight and four patients discontinued treatment from the omeprazole and placebo groups, respectively. The proportion of patients in remission in the omeprazole group and placebo group after 12 months were 94 and 9% respectively (life table estimates, P < 0.0001). No significant clinical or laboratory changes were observed in patients on therapy with omeprazole. Patients with a history of frequent relapses thus continued to have a very high relapse rate without prophylactic treatment. Omeprazole 20 mg daily was effective and safe in maintaining such patients in remission.     

Irsogladine maleate and rabeprazole in non-erosive reflux disease: A double-blind,placebo-controlled study

AIM:To evaluate the efficacy of adding irsogladine maleate(IM) to proton-pump inhibitor(PPI) therapy in non-erosive reflux disease(NERD) treatment.METHODS:One hundred patients with NERD were recruited and randomized to receive rabeprazole plus IM(group I) or rabeprazole plus placebo(group P).The efficacy of the treatment was assessed using the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease(FSSG) and the short form(SF)-36 quality of life questionnaires after four weeks of treatment.We also assessed whether patients with NERD with minimal changes(grade M) had different responses to the therapies compared with patients who did not have minimal changes(grade N).RESULTS:Group I and group P showed significant improvements in their FSSG scores after the treatment(from 17.9 ± 7.9 to 9.0 ± 7.6, and from 17.7 ± 7.3 to 11.2 ± 7.9, respectively, P = 0.0001), but there was no statistically significant difference between the FSSG scores in group I and those in group P.Subgroup analysis showed that significant improvements in the FSSG scores occurred in the patients in group I who had NERD grade N(modified Los Angeles classification)(7.8 ± 7.4 vs 12.5 ± 9.8, P = 0.041).The SF-36 scores for patients with NERD grade N who had received IM and rabeprazole were significantly improved in relation to their vitality and mental health scores.CONCLUSION:The addition of IM to rabeprazole significantly improves gastroesophageal reflux diseasesymptoms and the quality of the lives of patients with NERD grade N.     

Rabeprazole is equivalent to omeprazole in the treatment of erosive gastro-oesophageal reflux disease: A randomised, double-blind, comparative study of rabeprazole and omeprazole 20 mg in acute treatment of reflux oesophagitis, followed by a maintenance open-label, low-dose therapy with rabeprazole

BACKGROUND: Previous studies have shown similar effects of rabeprazole and omeprazole, when used at the same dose in the treatment of reflux oesophagitis. However, such studies have been conducted as superiority studies but interpreted as equivalence ones. AIM: To properly assess the comparative efficacy of rabeprazole and omeprazole in inducing complete endoscopic healing and symptom relief in patients with reflux oesophagitis. METHODS: Patients (n=560) with Savary-Miller grade I-III reflux oesophagitis were randomised in a double-blind, double-dummy fashion to rabeprazole or omeprazole 20 mg once daily for 4-8 weeks. Then, patients endoscopically healed and symptomatically relieved were openly maintained with rabeprazole 10 mg or 2x10 mg once daily (in the event of clinical and/or endoscopic relapse) for a maximum of 48 weeks. RESULTS: After 4-8 weeks of treatment, healing (primary end-point) was observed in 228/233 (97.9%) patients in the rabeprazole group and in 231/237 (97.5%) in the omeprazole one (equivalence effect demonstrated by p<0.0001 at Blackwelder test and an upper confidence limit at 97.5% of 0.023). However, rabeprazole was faster in inducing heartburn relief than omeprazole (2.8+/-0.2 versus 4.7+/-0.5 days of therapy to reach the first day with satisfactory heartburn relief, p=0.0045 at log-rank test). In the maintenance phase, 15.2% of patients had an endoscopic and/or clinical relapse. CONCLUSION: Rabeprazole is equivalent to omeprazole in healing reflux oesophagitis, but shows a faster activity on reflux symptoms in the early treatment phase.     

Helicobacter pylori and gastro-oesophageal reflux disease: a cross-sectional epidemiological study

BACKGROUND: H. pylori infection is accompanied by a lower prevalence of reflux disease. There is still an ongoing debate as to whether H. pylori actually protects against the development of reflux oesophagitis or is merely an epiphenomenon. A cross-sectional study was performed to study the relation of H. pylori with reflux oesophagitis, hiatus hernia and Barrett's oesophagus. MATERIAL AND METHODS: Consecutive patients undergoing upper gastrointestinal endoscopy in a period of ten years were studied. Included were patients with active reflux oesophagitis and/or hiatus hernia and/or Barrett's oesophagus. As a reference group, patients without macroscopic abnormalities were included. H. pylori was detected applying routine diagnostic modalities. RESULTS: In the ten years 11,691 consecutive patients were studied. Reflux oesophagitis was seen in 1535 patients, 307 patients had Barrett's oesophagus and a hiatus hernia was present in 2116 patients. The reference group consisted of 5341 patients. H. pylori was significantly less often detected in patients with reflux oesophagitis or Barrett's oesophagus compared with the reference group, 20 vs 29% (p<0.001). Also presence of H. pylori was significantly lower in patients with hiatus hernia 20 vs 29% (p<0.0001). CONCLUSION: The present study confirms, in a very large group of patients studied in one single centre, the findings of earlier papers. Patients without H. pylori gastritis suffer more often from reflux disease. There is a relation between H. pylori and reflux disease. However, the consequence of this relation will not be the same in every patient.     

Genetic influences in gastro-oesophageal reflux disease: a twin study

BACKGROUND: A number of families have been described which include multiple members with symptomatic, endoscopic, or complicated gastro-oesophageal reflux disease (GORD). First degree relatives of patients with GORD are more likely to suffer with GORD symptoms. These observations raise the possibility of a genetic contribution to the aetiology of GORD. AIMS: To determine the relative contribution of genetic factors to GORD by evaluating GORD symptoms in monozygotic (MZ) and dizygotic (DZ) twins. METHODS: A total of 4480 unselected twin pairs, identified from a national volunteer twin register, were asked to complete a validated symptom questionnaire. GORD was defined as symptoms of heartburn or acid regurgitation at least weekly during the past year. RESULTS: Replies were obtained from 5032 subjects (56% response rate). A total of 1960 twin pairs were evaluable: 928 MZ pairs (86 male pairs, mean (SD) age 52 (13) (range 19-81) years) and 1032 DZ pairs (71 male pairs, mean age 52 (13) (20-82) years). The prevalence of GORD among both groups of twins was 18%. Casewise concordance rates were significantly higher for MZ than DZ twins (42% v 26%; p<0.001). Multifactorial liability threshold modelling suggests that additive genetic effects combined with unique environmental factors provide the best model for GORD. Heritability estimates suggest that 43% (95% confidence interval 32-55%) of the variance in liability to GORD is due to additive genetic factors. CONCLUSIONS: There is a substantial genetic contribution to the aetiology of GORD.     

Effect of sulindac on angiotensin converting enzyme inhibitor-induced cough: randomised placebo-controlled double-blind cross-over study

The effect of sulindac on ACE inhibitor-induced cough was studied in eight hypertensive subjects in a randomised placebo-controlled double blind cross-over trial. There was no significant improvement in cough or sense of well-being. Blood pressure, renal function, plasma renin and ACE activity were unchanged. Sulindac however, appears to be effective in some individuals in reducing ACE inhibitor-induced cough with acceptable tolerance and few side effects. Further work is needed to elucidate the mechanism of sulindac's interaction with ACE inhibitors.     

Effects of anti-reflux surgery on chronic cough and asthma in patients with gastro-oesophageal reflux disease

This two-group prospective study evaluated the effect of anti-reflux surgery (fundoplication) on 24 patients with severe gastro-oesophageal reflux disease (GORD) and concomitant asthma (n=13) or chronic cough (n=11). Twenty-four hour oesophageal pH monitoring and lung function tests (FEV1, FVC) were done before and within 1 year after anti-reflux surgery. A diary was kept by the patient during the 4-week period prior to surgery and during 4-week periods 6 and 12 months postoperatively, with daily monitoring of peak expiratory flow rate, respiratory and reflux symptoms and medication. In non-asthmatic patients, coughing was reduced by 47% and 80% during the day and night, respectively, 12 months after surgery (P < 0.01). Concomitant hoarseness and expectoration were also significantly reduced (P<0.05). No effect on lung function was seen. In patients with asthma, small, non-significant reductions in asthma symptom scores and consumption of rescue medication were seen. Twenty-two patients were completely free from their GORD symptoms after surgery. In conclusion, anti-reflux surgery in patients with GORD had a more favourable effect on concomitant cough than concomitant asthma.     

Chronic cough, asthma, and gastroesophageal reflux

Gastroesophageal reflux disease (GERD) causes chronic cough and triggers asthma. Mechanisms of reflux-associated chronic cough include micro- and macroaspiration, laryngeal injury, and a vagally mediated reflex. An empiric trial of a proton pump inhibitor in patients without other etiologies of cough found through diagnostic testing may be an effective diagnostic strategy for GERD-associated cough. In GERD-associated asthma, there is evidence of neurogenic inflammation. Medical or surgical therapy of GERD results in asthma symptom improvement in about 70% of patients. A 3-month empiric trial of omeprazole, 20 mg daily, followed by esophageal pH testing in drug nonresponders, is the most cost-effective way of diagnosing asthma triggered by GERD.     

Chronic cough caused by gastroesophageal reflux]

We reported a case of chronic cough due to gastroesophageal reflux (GER). The patient was a 29-year-old woman who had suffered from persistent chronic cough for more than 3 years. She had been treated with high doses of inhaled steroids, oral bronchodilators, and oral corticosteroids on a presumed diagnosis of asthma. However, her cough was not alleviated by these treatments, and the patient was referred to our hospital. She did not exhibit typical GER symptoms except for belch. Although esophagoscopy did not disclose reflux esophagitis, esophageal pH monitoring revealed acid reflux 7 to 8 times higher than the reference value. The patient was treated with a proton-pump inhibitor, which markedly alleviated her cough. Chronic cough due to GER was diagnosed. Although the incidence of chronic cough due to GER was thought to be rare in Japan, the findings in our case report underscored the importance of this association to the differential diagnosis of chronic cough.     

Acid gastro-oesophageal reflux and oesophageal pressure activity during postprandial and nocturnal periods. A study in subjects with and without pathologic acid gastro-oesophageal reflux

The aim of the investigation was to evaluate the relative quantity of acid gastrooesophageal reflux during different time periods in subjects with and without pathologic reflux. Twenty duodenal ulcer patients, 10 with and 10 without pathologic acid gastro-oesophageal reflux, and 26 asymptomatic volunteers were subjected to 12 h of simultaneous monitoring of pH and pressure activity in the oesophagus. The monitoring period was divided into a 3-h postprandial period, a night period of 6 h, and a 3-h period in the morning. The highest reflux frequency and the longest duration of oesophageal acid exposure were found in the postprandial hours (p less than 0.001). Thereafter, all groups had an even reduction in reflux rate. A greater absolute reduction in the duration of oesophageal acid exposure could be measured in patients with pathologic reflux as compared with the other groups (p less than 0.001). In spite of this, both reflux frequency and time with acid in the oesophagus were increased during the night in patients with pathologic reflux (p less than 0.001). Pathologic refluxers had in total 11 times as much reflux as normal subjects, and in addition 37.9% of the reflux took place during the 6 night hours. In contrast, only 5.4% of the reflux recorded in normal subjects occurred during this period. The pressure activity during periods with a normal intraoesophageal pH was reduced in all three groups during the night (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic cough and hoarseness in patients with severe gastroesophageal reflux disease

Gastroesophageal reflux may be responsible for atypical symptoms such as chronic cough and hoarseness. Our aim was to evaluate and treat patients with severe gastroesophageal reflux and chronic cough or hoarseness with intensive antireflux therapy. Twenty-seven patients with typical heartburn symptoms in addition to significant cough or hoarseness were treated with aggressive antireflux therapy. We recorded the response of each symptom to the antireflux therapy. Two patients were lost to follow-up. Twenty of the 25 (80%) patients showed some improvement in cough or hoarseness, nine (36%) had no atypical symptoms at follow-up. The response of heartburn to therapy was strongly predictive of successful therapy for the atypical symptoms. Cough and hoarseness improved in only two of the five patients with residual heartburn symptoms compared to 18 of 20 patients with no heartburn (P<0.04). Only patients with no heartburn symptoms at follow-up had complete resolution of atypical symptoms. There were no important differences on ambulatory pH monitoring between partial and complete responders. Improvement in atypical reflux symptoms, such as chronic cough and hoarseness, is common with aggressive antireflux therapy. There are no findings on ambulatory esophageal pH monitoring that uniquely identify patients who are likely to respond to antireflux therapy.     

Male hormonal contraception: a double-blind, placebo-controlled study

BACKGROUND: This study was performed to assess spermatogenesis suppression and safety of a new combination of an etonogestrel (ENG) implant combined with testosterone undecanoate (TU) injections for male contraception. This is the first large placebo-controlled study for male hormonal contraception. DESIGN AND STUDY SUBJECTS: In this double-blind, multicenter study, we randomly assigned 354 healthy men to receive either a low- or high-release ENG implant sc combined with im TU injections (750 mg every 10 or 12 wk or 1000 mg every 12 wk) or placebo implant and injections. Treatment duration was 42 or 44 wk and posttreatment follow-up at least 24 wk. RESULTS: Overall, spermatogenesis was suppressed to 1 million/ml or less at wk 16 in 89% of men, with approximately 94% in two high-release ENG groups. Suppression was maintained up to the end of the treatment period in 91% of men. For all men who completed the treatment period, 3% never achieved 1 million/ml or less. Median recovery time to a sperm concentration above 20 million/ml was 15 wk (mean 17 wk, 95% confidence interval 16-18 wk). Treatment was well tolerated. As compared with the placebo group, more men in the active treatment groups reported adverse events such as weight gain, mood changes, acne, sweating, or libido change. For both spermatogenesis suppression and safety, differences were small between the active treatment groups. CONCLUSIONS: The combination of an ENG implant with TU injections is a well-tolerated male hormonal method, providing effective and reversible suppression of spermatogenesis. Although the results are good, there is still room for improvement, possibly by adjusting the dose regimen or changing the mode of application.