Chronic cough and gastro-oesophageal reflux: a double-blind placebo-controlled study with omeprazole. Lansoprazole treatment of patients with chronic idiopathic laryngitis: a placebo-controlled trial. Comparison of the effect of a cornstarch thickened formula and strengthened regular formula on regurgitation, gastric emptying and weight gain in infantile regurgitation. Chronic cough. Effects of a prethickened formula on esophageal pH and gastric emptying of infants with GER. Efficacy of a pre-thickened infant formula: a multicenter, double-blind, randomized, placebo-controlled parallel group trial in 104 infants with symptomatic gastroesophageal reflux. Proton pump inhibitor therapy for chronic laryngo-pharyngitis: a randomized placebo-control trial. Double-blind, placebo-controlled trial with single-dose pantoprazole for laryngopharyngeal reflux. Evaluation of omeprazole in the treatment of reflux laryngitis: a prospective, placebo-controlled, randomized, double-blind study. Effect of pantoprazole on the course of reflux-associated laryngitis: a placebo-controlled double-blind crossover study. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. [Nocturnal spasmodic cough in the infant. Evolution after antireflux treatment]. A prospective evaluation of esophageal testing and a double-blind, randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough. Treatment of postnasal drip with proton pump inhibitors: a prospective, randomized, placebo-controlled study. Thickened feedings as a cause of increased coughing when used as therapy for gastroesophageal reflux in infants. Treatment of chronic posterior laryngitis with esomeprazole.
Gastro-oesophageal reflux (GOR) is an important cause of chronic cough. There has been a lack of placebo-controlled trials treating GOR related chronic cough with antireflux therapy. The aim of this study was to determine the efficacy of omeprazole on GOR related chronic cough. After excluding other common causes of cough, oesophageal pH monitoring was performed on 48 patients with chronic cough. Twenty-nine patients found to have GOR were randomized in a double-blind fashion to receive omeprazole 40 mg o.d. or placebo for 8 weeks. After a 2-week washout period, patients were crossed over to the other treatment. Symptoms were recorded daily in a diary. Twenty-one patients completed both treatment periods. Cough (p=0.02) and gastric symptoms (p=0.003) improved significantly during the omeprazole treatment in twelve patients who received placebo during the first and omeprazole during the second 8-week period. In nine patients who received omeprazole during the first 8-week period, amelioration in cough reached statistical significance only after cessation of omeprazole. Gastric symptoms also remained minor during placebo in these nine patients. Omeprazole 40 mg o.d. seems to improve chronic cough in patients with gastrooesophageal reflux and the effect of omeprazole in ameliorating both cough and reflux symptoms continues after treatment ceases. Previous uncontrolled studies suggested a therapeutic benefit for treating gastroesophageal reflux disease (GERD) among patients with laryngitis. The present study is the first randomized, placebo-controlled, double-blind study of gastric acid suppression among patients with laryngitis in the United States.
                Patients diagnosed with idiopathic chronic laryngitis were randomized to receive either lansoprazole 30 mg p.o. b.i.d. or a matching placebo for 3 months. Before randomization, all patients underwent upper endoscopy, dual probe ambulatory 24-h esophageal pH-metry, and laryngoscopy, as well as completing a symptom questionnaire for GERD and laryngitis. The primary outcome of treatment was the complete resolution of laryngeal symptoms.
                A total of 22 patients with symptoms and signs of chronic laryngitis were enrolled, 20 of whom completed the study. At baseline, there were no significant differences between the two groups with regards to GERD symptoms, erosive esophagitis, proximal and distal esophageal pH-metry, or laryngeal signs and symptoms. In an intention-to-treat analysis, six patients in the lansoprazole group (50%) and only one patient (10%) in the placebo group achieved a complete symptomatic response, p = 0.04. Apart from receiving lansoprazole, there were no significant differences between responders and nonresponders in any of baseline esophageal or laryngeal signs and symptoms.
                Empirical treatment with lansoprazole is efficacious in relieving symptoms of laryngitis compared to placebo. Such treatment can be considered as a first-line option in managing patients with idiopathic chronic laryngitis. The purpose of this study was to evaluate the efficacy of a specially selected cornstarch-supplemented formula on clinical symptoms, gastric emptying and weight gain in infants with regurgitation. We performed a prospective randomised trial evaluating the therapeutic efficacy of two different formula feedings (cornstarch-thickened formula, group A; 25% strengthened formula, group B) in 81 young infants with regurgitation/vomiting > or = 3 times/day. A Tc-99 m milk scintigraphy was performed at inclusion and after 2 months to quantify gastric emptying time; all studied infants underwent a 2-month period of clinical follow-up evaluating regurgitation and body weight gain. At inclusion, group A and B had a similar age and weight. After the 2-month period of intervention, regurgitation and vomiting had both greater decrease (both P < 0.001 at 1 and 2 months) in group A (from a score of 4.19 +/- 1.71 to 0.93 +/- 0.42) than in group B (from a score of 4.15 +/- 1.68 to 2.89 +/- 1.16). Non-regurgitation symptoms (irritability, cough, choking, night-waking) decreased (P = 0.045 at 1 month and 0.017 at 2 months) in group A (from a score of 18 at baseline to 3 after 8 weeks) as compared to group B (from a score of 18 at baseline to 11 after 8 weeks). Weight increased more in group A (29.1 +/- 3.9 g/day over 8 weeks) versus group B (23.6 +/- 3.5 g/day over 8 weeks) (P < 0.01 at 1 and 2 months) Gastric emptying improved significantly in group A as compared with group B (all P < 0.001 for T1/2, and residual volume at 60 and 90 min). Ingested feeding volume was significantly larger in the group receiving cornstarch-thickened formula, both at 4 weeks (109.4 +/- 24.5 vs. 98.5 +/- 23.6 mL/meal) (P: 0.042) and at 8 weeks (137.6 +/- 27.9 vs. 115.7 +/- 26.5 mL/meal) (P < 0.001). Cornstarch-thickened formula feeding decreases the frequency of regurgitation/vomiting, provides better body weight gain and has an accelerated gastric emptying in comparison to a 25% strengthened regular formula in infants with regurgitation. nan Advantages of prethickened formulas (AR) with regards to esophageal pH and gastric emptying were investigated in this study as compared with a regular formula (R).
                Seventy-four healthy infants, <6 months old, with gastroesophageal reflux were enrolled into the study. All infants underwent 24-hour esophageal pH monitoring while receiving R and AR, alternately. Electrogastrography was measured before and after feeding each study formula. Thereafter, the infants were randomly assigned to receive either R or AR for 1 month. Episodes of regurgitation, vomiting, coughing, crying, and bowel movements were recorded on a weekly interval.
                Reflux index (RI) of AR-fed infants were lower (5.64%) than the R-fed infants (7.77%) showing a significant difference (P<0.01) between the 2 groups, favoring AR. Eighty-seven percent of infants improved their RI while receiving the AR formula. Electrogastrography variables were not significantly different between the 2 study groups. A significant decrease (P<0.01) in the daily episodes of regurgitation and vomiting was observed in the AR-fed infants. No adverse events were reported during the study.
                Prethickened infant formula was effective in reducing clinical symptoms of uncomplicated gastroesophageal reflux and reducing RI. Prethickened formulas do not alter gastric emptying time and was very well tolerated. To evaluate a pre-thickened formula (Enfamil AR) for regurgitant gastroesophageal reflux, 104 infants were enrolled in a 5-week, multicenter, double-blind, randomized, placebo-controlled parallel group trial. The Enfamil AR group showed greater symptom reduction by the end of the first week: percent feedings with any regurgitation (p = 0.045), total regurgitation volume score (p = 0.035), and percent feedings with choke-gag-cough (p = 0.004). The most symptomatic infants at baseline had a reduction in trouble sleeping significantly with Enfamil AR by the end of the study (p = 0.030). This formula flows through a standard nipple, reduces regurgitation and choking-gagging-coughing within a week, and improves sleep in the most symptomatic babies by 5 weeks, without causing constipation. To determine the efficacy of proton-pump inhibitor (PPI) therapy for chronic laryngo-pharyngitis treated with lifestyle modification.
                Double-blind, randomized trial comparing two-month Rabeprazole (20 mg b.i.d.) to placebo control.
                Compared to baseline, both PPI and control patients had significant improvement in total reflux symptoms (P = 0.002 and P = 0.03 respectively), with significant improvement in "laryngo-pharyngeal" but not "typical" reflux symptoms. No significant difference was noted for change in reflux symptoms between PPI-treated and control patients (P = 0.44). Significant global improvement was noted by 50% of control and 53% of PPI-treated patients (P = 1.0). No significant differences were noted within or between treatment groups for change in health status or videostrobolaryngoscopy grade. Lifestyle modification compliance correlated significantly with global improvement.
                Compared to baseline, lifestyle modification for 2 months significantly improved chronic laryngo-pharyngitis symptoms. When compared to control, treatment with a PPI failed to demonstrate significantly greater improvement in reflux symptoms, health status, or laryngeal appearance. Results of randomized treatment trials for laryngopharyngeal reflux (LPR) are mixed. The cause and effect between gastroesophageal reflux and laryngeal symptoms remain elusive.
                To determine the efficacy of single-dose pantoprazole in newly diagnosed LPR and to correlate hypopharyngeal reflux with symptom improvement.
                Randomized, double-blind, placebo-controlled trial was performed with a 2-wk run-in, 12-wk treatment period (pantoprazole 40 mg q.a.m. or placebo), and 4-wk follow-up. Study criteria were laryngeal complaints >3 days/wk and a positive triple-sensor pH test. Laryngeal exam was graded using a reflux finding score before and after treatment. Repeat pH test was performed on study drug at week 12. Weekly diaries were kept on symptom severity and global assessment. Total laryngeal symptom score was defined as the sum of six laryngeal symptoms. Mann-Whitney U, Wilcoxon, and Pearson tests were used.
                Thirty-nine subjects (13 M/26 F, median age 39 yr) were randomized; 35 completed the study. During the treatment period, total laryngeal symptom scores significantly improved compared with pretreatment scores in both study groups, but there were no significant differences between them. Forty percent of pantoprazole group reported adequate relief at week 12, compared with 42% of placebo group (p= 0.89). No significant improvement in hypopharyngeal reflux was found in either study group. There were no significant correlations between laryngeal reflux finding scores and hypopharyngeal reflux episodes with symptom improvement.
                Response was similar between single-dose pantoprazole and placebo in newly diagnosed LPR. Our results suggested that laryngeal exam was not useful in following treatment response. Hypopharyngeal reflux may represent acid reflux or artifacts, but is not likely the underlying cause. Proton-pump inhibitors are often recommended in the treatment of laryngitis secondary to gastric reflux. Despite prospective treatment studies reporting high efficacy, only one previous report has been placebo-controlled and blinded. The objective of this study was to determine the efficacy of omeprazole in treating proven reflux laryngitis.
                Prospective, placebo-controlled, randomized, double-blind clinical trial.
                Fifty-three patients with one or more reflux laryngitis symptoms were recruited to undergo 24-hour dual-channel pH probe testing. Thirty patients with more than four episodes of laryngopharyngeal reflux were enrolled. By random assignment, 15 patients received 40 mg omeprazole twice a day and the other 15 received placebo for a period of 2 months. Symptoms (hoarseness, throat pain, lump in throat sensation, throat clearing, cough, excessive phlegm, dysphagia, odynophagia, and heartburn) and endoscopic laryngeal signs (erythema, edema, and mucus accumulation) were recorded initially, at 1 month, and 2 months.
                In general, most symptom scores improved over time for both the omeprazole and placebo groups. Hoarseness, when patients begin with low hoarseness symptom scores, and throat clearing improved significantly more in patients on omeprazole than in those on placebo during the 2-month study. Throat pain, lump in throat sensation, excessive phlegm, difficulty swallowing, pain with swallowing, and heartburn showed improvement in both treatment arms, signifying the possibility of a placebo effect. Endoscopic laryngeal signs did not change significantly over the course of the study for either treatment group.
                A placebo effect appears to exist in the treatment of reflux laryngitis. However, hoarseness, when initially scored low, and throat clearing resulting from reflux laryngitis are effectively treated by omeprazole. The optimal management of patients with reflux-associated laryngitis is unclear. We performed a placebo-controlled crossover trial in patients with proven reflux disease and associated laryngitis to determine the effect of pantoprazole and to gain information on the natural course of the disease.
                Sixty-two consecutive non-smoking patients with hoarseness and proven laryngitis were examined. Scores with respect to the larynx and for subjective complaints were determined and 24-h pH-metry to assess acid reflux in the lower oesophagus and pharynx was performed. Patients with pathologic reflux were given the chance to enter a double-blinded randomized crossover trial with pantoprazole 40 mg b.i.d. and placebo for a duration of 3 months each, separated by a 2-week washout period.
                Twenty-four of 62 patients showed pathological reflux; 21 patients were included in the study and 14 concluded all parts of the study. Both pantoprazole and placebo resulted in a marked improvement in laryngitis scores (decrease of 8.0 +/- 1.4 versus 5.6 +/- 2.6; no significant difference between the 2 treatments) and symptoms after the first 3 months (decrease of oesophageal symptom score of 2.2 +/- 1.4 versus 5.4 +/- 2.8; decrease of laryngeal scores of 8.3 +/- 3.6 versus 10.3 +/- 3.9; also no significant difference between the 2 treatments). A second pH-metry 2 weeks thereafter proved the persistence of reflux in most of these patients. Switching to pantoprazole led to a further improvement of scores. In the group switched to placebo there was recurrence only in a minority of patients. CONCLUSIONs: The self-limited nature of reflux-associated laryngitis in non-smokers is largely underestimated. Laryngitis improves despite the persistence of reflux. Pantoprazole may be helpful especially in relieving acute symptoms, but the advantage of long-term treatment over placebo has been greatly overestimated. To assess the efficacy and safety of lansoprazole in treating infants with symptoms attributed to gastroesophageal reflux disease (GERD) that have persisted despite a >or= 1-week course of nonpharmacologic management.
                This multicenter, double-blind, parallel-group study randomized infants with persisting symptoms attributed to GERD to treatment with lansoprazole or placebo for 4 weeks. Symptoms were tracked through daily diaries and weekly visits. Efficacy was defined primarily by a >or= 50% reduction in measures of feeding-related crying and secondarily by changes in other symptoms and global assessments. Safety was assessed based on the occurrence of adverse events (AEs) and clinical/laboratory data.
                Of the 216 infants screened, 162 met the inclusion/exclusion criteria and were randomized. Of those, 44/81 infants (54%) in each group were responders--identical for lansoprazole and placebo. No significant lansoprazole-placebo differences were detected in any secondary measures or analyses of efficacy. During double-blind treatment, 62% of lansoprazole-treated subjects experienced 1 or more treatment-emergent AEs, versus 46% of placebo recipients (P= .058). Serious AEs (SAEs), particularly lower respiratory tract infections, occurred in 12 infants, significantly more frequently in the lansoprazole group compared with the placebo group (10 vs 2; P= .032).
                This study detected no difference in efficacy between lansoprazole and placebo for symptoms attributed to GERD in infants age 1 to 12 months. SAEs, particularly lower respiratory tract infections, occurred more frequently with lansoprazole than with placebo. Several studies have shown the relationship between gastro-oesophageal reflux, bronchial asthma and chronic nocturnal cough and this should not be neglected, particularly in patients who present an unfavourable development in spite of conventional treatment. For diagnosis of gastroesophageal reflux, amongst other investigations, esophageal gammagraphy of swallowing, that detects alterations in the mobility of the oesophagus, secondary to a possible oesophagitis. The objective of this study was to evaluate the clinical progress and gammagraphy of a group of children with chronic predominantly nocturnal cough (with or without bronchial asthma) with initially pathological esophageal gammagraphy, after three months of treatment with gastrokinetic drugs (cisapride against domperidone) and postural dietetic limits, in comparison with a reference group who, although having followed the limits in question had not received the pharmacological treatment. From the clinical viewpoint, cough disappeared in 64.5% of cases without significant statistical differences between the two groups. Gammagraphy became normal in 20/55 cases, improved in 10/55 cases and was unchanged in 25/55. Although there was no significant difference, gammagraphy development was better in children who received domperidone. The agreement between clinical progress and gammagraphy was 60% with a large number of false positives in the gammagraphy. We believe that the simple introduction of the postural-dietetic measures may improve the clinical control in the type of patients who present with a chronic nocturnally predominant cough that does not yield to conventional treatment. Recent studies suggest an association between chronic cough and gastroesophageal reflux. Our study aims were 1) to define the prevalence of acid reflux induced cough in the general community, 2) to examine the ability of esophageal testing to identify gastroesophageal reflux related cough, and 3) to assess the utility of omeprazole in a chronic cough algorithm.
                Patients with chronic cough of unknown etiology, who were mostly from the community, were evaluated. Subjects underwent a chest x-ray, methacholine challenge test, and empiric trial of postnasal drip therapy, and completed daily cough symptom diaries subjectively evaluating cough frequency and severity on a graded scale of 0-4 (combined maximum 8). After excluding other causes of cough, the remaining patients underwent esophageal and pH testing. Those testing positive were randomized to omeprazole 40 mg b.i.d. or placebo for 12 weeks. Follow-up was 1 yr.
                A total of 71 patients were screened; 48 were excluded. Twenty-three patients were evaluated for gastroesophageal reflux disease; six (26%) were eventually determined to have an acid-related cough. Of these patients, 17 had a positive pH test, six (35%) of whom showed a striking improvement or resolution of their cough during omeprazole treatment which was sustained for up to 1 yr. Six had a negative pH test, none of whom responded to omeprazole therapy. No significant differences were seen between responders (n = 6) and nonresponders (n = 11) for demographic factors, baseline symptom frequency and duration, or physiological parameters (motility/pH).
                Acid-related chronic cough was present in 26% (six of 23) of patients evaluated for gastroesophageal reflux disease. Esophageal testing does not reliably identify patients with acid induced chronic cough responsive to proton pump inhibitor therapy. We suggest that the best diagnostic and therapeutic approach, after excluding asthma and postnasal drip syndrome, is empiric treatment for 2 wk with a high dose proton pump inhibitor. Patients commonly present with complaints of postnasal drainage (PND) without objective evidence to support a sinonasal or infectious etiology. PND has been attributed to extra-esophageal reflux (EER), and an empiric trial of antireflux medication often is used to treat PND and associated symptoms. This study was performed to (1) evaluate the relationship between symptoms of EER and PND and (2) assess the efficacy of proton pump inhibitors (PPIs) in the management of PND.
                Patients with a chief complaint of PND without objective evidence of sinonasal inflammatory disease were enrolled in a prospective, double-blinded, randomized placebo-controlled trial using rabeprazole, 20 mg, orally twice daily or placebo for 90 days. Subjects completed two-site 24-hour pharyngeal pH probe monitoring before treatment. Outcome measures included pre- and posttreatment visual analog scales for PND symptoms, reflux symptom index, and reflux finding score (RFS).
                Forty-seven patients were enrolled (mean age, 55 years)-21 patients in the PPI group and 26 in the placebo group. Fifty-six percent of subjects had pH probe confirmed EER using a cutoff of pH < 5.0. Baseline symptom measures between subjects with and without EER were not different. Compared with placebo, subjects receiving rabeprazole reported significant reduction in PND frequency (p = 0.0180), hoarseness (p = 0.0164), and chronic cough (p = 0.0204). The RFS decreased slightly in the placebo group (p = 0.1490) whereas it increased slightly in the PPI group (p = 0.5235). This difference between groups was significant (p = 0.0272).
                Although 50% of subjects had evidence of EER, there was no difference in baseline symptoms between subjects with and without. Our findings support the potential benefit of PPI therapy for reducing PND frequency, hoarseness, and chronic cough, and confirm a placebo effect for other laryngopharyngeal reflux symptoms. The effect on laryngeal findings is mixed and patients may experience symptomatic improvement before changes in laryngoscopic appearance. To determine whether thickening of infant formula feedings with rice cereal increases coughing, we studied 25 infants from birth to 6 months of age, referred for evaluation of gastroesophageal reflux. Coughing was blindly quantified after each of a pair of isocaloric meals (one thickened and one unthickened). Coughing was more frequent after thickened feedings than after unthickened feedings. To evaluate the efficacy of acid-suppressive therapy with the proton pump inhibitor esomeprazole on the signs and symptoms of chronic posterior laryngitis (CPL) in patients with suspected reflux laryngitis.
                Prospective, multicenter, randomized, parallel-group trial that compared twice-daily esomeprazole 40 mg with placebo for 16 weeks.
                Eligible patients had a history of one or more CPL symptoms (throat clearing, cough, globus, sore throat, or hoarseness) and laryngoscopic signs indicating reflux laryngitis based on CPL index (CPLI) scores measured during a screening laryngoscopy. Patients were randomized to treatment if their 7-day screening diary-card recordings showed a cumulative primary symptom score of 9 or higher and they had 3 or more days with moderately severe symptoms based on a 7-point scale. Efficacy was assessed by changes in symptoms as recorded by patients and investigators and by changes in CPLI scores based on laryngoscopic examinations.
                The patients' primary CPL symptom at final visit (primary efficacy end point) was resolved in 14.7% (14/95) and 16.0% (8/50) of patients in the esomeprazole and placebo groups, respectively (P=.799). Esomeprazole and placebo were not significantly different for change from baseline to the final visit in mean total CPLI (-1.66+/-2.13 vs. -2.0+/-2.55, respectively; P=.446) or any other secondary efficacy end points based on patient diary card or investigator assessments.
                This study provides no evidence of a therapeutic benefit of treatment with esomeprazole 40 mg twice daily for 16 weeks compared with placebo for signs and symptoms associated with CPL.
PPI is not efficacious for cough associated with GORD symptoms in very young children (including infants) and should not be used for cough outcomes. There is insufficient data in older children to draw any valid conclusions. In adults, there is insufficient evidence to conclude definitely that GORD treatment with PPI is universally beneficial for cough associated with GORD. Clinicians should be cognisant of the period (natural resolution with time) and placebo effect in studies that utilise cough as an outcome measure. Future paediatric and adult studies should be double-blind, randomised controlled and parallel-design, using treatments for at least two months, with validated subjective and objective cough outcomes and include ascertainment of time to respond as well as assessment of acid and/or non-acid reflux.