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Meta-analysis of the efficacy of proton pump inhibitors for the symptoms of laryngopharyngeal reflux.

Introduction

Laryngopharyngeal reflux (LPR) is the retrograde flow of gastric contents into the pharynx and larynx, causing a variety of symptoms. LPR has become a significant and increasingly prevalent disease seen in the otolaryngologist's office. The prevalence of LPR in outpatients is about 10% in the USA (1).

Most of the patients with LPR do not complain of heartburn and regurgitation, which are the classic gastroesophageal reflux disease (GERD) symptoms, and many studies have shown an association between GERD and LPR symptoms. The mechanisms for GERD-associated LPR are considered to be the acid stimulation of vagal afferent nerves and the direct laryngeal contact with gastroesophageal reflux (2). Compared with the esophageal mucosa, the mucosa of the pharynx and larynx are less resistant to the gastric acid effects (3). Small amounts of acid substance is possibly insufficient to cause esophageal symptoms, but may be sufficient to cause laryngeal symptoms.

As LPR is one of many extra-esophageal manifestations of GERD, medical treatment for reflux disease is recommended for LPR. The most common class of drugs prescribed for LPR is the proton-pump inhibitor (PPI), which has shown to benefit patients with LPR in some studies (4). However, most of the studies address empiric therapy, with few randomized, placebo-controlled trials (RCTs) addressing LPR therapy. The aim of the study was to conduct a meta-analysis in order to evaluate the effectiveness of PPI therapy in adult patients with LPR.

Material and Methods

Search strategy

A comprehensive search was done using Cochrane Library, EMBASE, Ovid EBM Reviews, and PubMed for English-language literature in September 2014. The following key words were used as search items: laryngeal reflux, pharyngeal reflux, laryngopharyngeal reflux, laryngopharyngeal reflux disease, laryngopharyngeal reflux diseases, LPR, LPRD, reflux laryngitis, reflux pharyngitis, hoarseness, throat clearing, throat mucus, postnasal drip, dysphagia, cough, dyspnea, dyspnea, globus, throat lump, rumination, vocal cord/fold edema, posterior laryngitis, vocal cord/fold granuloma, gastric aspiration(s), gastric regurgitation(s), extraesophageal reflux, extraesophageal reflux disease, gastropharyngeal reflux, GPR, proton pump inhibitor(s), PPI, proton pump antagonist, proton pump blocker, omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, acid suppressive therapy, and anti-reflux therapy.

Inclusion criteria: 1) patients with laryngeal or pharyngeal reflux lasting [greater than or equal to] 2 weeks; 2) adult patients aged [greater than or equal to] 18 years; 3) studies comparing PPIs and placebo interventions; 4) study personnel, clinicians and patients were blind to the treatment; 5) curative effect criterion; 6) randomized controlled trials (RCTs) or controlled clinical trials.

Exclusion criteria: 1) patients with laryngeal or pharyngeal reflux lasting <2 weeks; 2) children; 3) study without curative effect criterion; 4) single-/multi-intervention; 5) presence of several diseases; 6) duplicate publications; 7) reviews, case reports, single clinical trials, and expert opinions.

All titles and abstracts of the studies were reviewed, and the full text of the eligible studies was obtained for further review. The bibliography of the selected literature was reviewed to determine whether any relevant study had been missed.

Quality assessment

The level of evidence of the included literature was graded according to Oxford Centre for Evidence-Based Medicine 2011, as follows: level 1: systematic review of randomized trials or n-of-1 trials; level 2: randomized trial or observational study with dramatic effect; level 3: nonrandomized controlled cohort/follow-up study; level 4: case-series, case-control studies, or historically controlled studies; level 5: mechanism-based reasoning.

Results

The systematic search strategy produced 2420 possibly relevant English-language papers. Only 21 studies meeting the inclusion criteria were selected and their full texts obtained for further review. After reviewing the full texts, 8 papers (5-12) were identified and included in our analysis (Figure 1). Of the 8 studies, 7 were placebo-controlled, and 1 was a placebo-controlled, cross-over trial. Table 1 shows the characteristics of the studies included in the meta-analysis.

The total number of patients included in our analysis was 370, of which 210 and 160 patients took PPIs and placebo, respectively. As shown in Figure 2, the pooled effect of the difference between the effect of PPIs and placebo treatment in overall improvement of symptoms in adult patients with LPR was not statistically significant (RR=1.22; 95%CI=0.93-1.58; P=0.149).

Of the 8 studies, 3 contained data on cough improvement. The pooled effect analysis shows that the difference between PPIs and placebo groups in cough improvement was not statistically significant (RR=0.65; 95%CI=0.30-1.41; P=0.279) (Figure 3).

Discussion

The results of the meta-analysis showed that PPIs therapy had no significant advantage in improving or resolving LPR symptoms over placebo. Similarly, no significant difference between the PPIs and placebo was found towards cough improvement.

One of the 8 studies was a randomized controlled crossover trial (10), all other studies were randomized controlled trials. All patients were randomized into PPIs or placebo treatment groups. This is a critical issue regarding the quality of the present meta-analysis. The limitation is that different types of PPIs were used in the studies. The PPIs included omeprazole (12), lansoprazole (11), pantoprazole (7,10), rabeprazole (9), and esomeprazole (5,6,8). The daily dose of PPIs varied from 40 to 80 mg lasting at least 8 weeks, which was higher than that routinely used in GERD patients (13).

Most clinicians recommend PPIs for the treatment of LPR, and are convinced of their benefits. However, our study shows that PPIs have a similar effect as placebo in the improvement of LPR symptoms. The various symptoms of LPR include hoarseness, cough, globus, sore throat and dysphagia, which have been used as labels for the reflux symptom index (RSI) (14). The RSI and reflux finding score (RFS) (15), used in one study in our meta-analysis (6), have been widely used in evaluating LPR. The diagnosis of LPR is mainly dependent on symptom evaluation. In this study, we analyzed the improvement of symptoms in adult patients with LPR taking PPIs or placebo. Our results might have been different if symptoms were evaluated using the RSI and/or RFS scores.

Two previous meta-analysis evaluated the efficacy of PPIs for GERD-related laryngeal symptoms (16,17). Gatta et al. (16) reviewed 4 RCTs (8,9,11,12) and 1 randomized clinical control trial (10) in 2007, and found no difference between the effects of PPI therapy and placebo in laryngopharyngeal symptoms improvement or resolution. Qadeer et al. (17) reviewed 8 studies (7-11,18,19) in 2006 and reported that PPI therapy may offer a modest, but non-significant clinical benefit over placebo in GERD-related chronic laryngitis. Our study also found no difference in the effect of PPI therapy and placebo in the improvement of symptoms in adult patients with LPR.

PPI therapy was found effective for treating LPR in one study (20), and BID (twice daily) PPI appeared to be more effective than QD (once daily) PPI (21). In our study, BID PPI was used in seven studies (5,6,8-12), and QD PPI in one study (7).

We found a strong placebo effect, which may have been a result of the scoring performed by the patients. The symptoms of LPR are not correlated with its signs (22,23). Another explanation is a possible over-diagnosis of LPR, which is based on nonspecific symptoms found also in other diseases. Laryngopharyngeal pH testing can be used to define laryngopharyngeal reflux, but it is not used universally and lacks a gold standard criteria. A gold standard for LPR diagnosis should be developed in the future.

Most of the studies included into our meta-analysis had small sample sizes, ranging from 17 to 145 study participants. The small sample sizes could have resulted in Type II statistical errors. Large sample RCTs are needed to estimate the true effect of PPIs.

Our study suggests that PPIs and placebo therapy are similarly effective in improving LPR symptoms in adult patients. A better understanding and further study of the effect of PPIs on LPR is necessary.

References

(1.) Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 1991; 101: 1-78, doi: 10.1002/lary.5541011220.

(2.) Wong RK, Hanson DG, Waring PJ, Shaw G. ENT manifestations of gastroesophageal reflux. Am J Gastroenterol 2000; 95: S15-S22, doi: 10.1016/S0002-9270(00)01074-1.

(3.) Vardar R, Varis A, Bayrakci B, Akyildiz S, Kirazli T, Bor S. Relationship between history, laryngoscopy and esophagogastroduodenoscopy for diagnosis of laryngopharyngeal reflux in patients with typical GERD. Eur Arch Otorhinolaryngol 2012; 269: 187-191, doi: 10.1007/s00405-011-1748-y.

(4.) Sen P, Georgalas C, Bhattacharyya AK. A systematic review of the role of proton pump inhibitors for symptoms of laryngopharyngeal reflux. Clin Otolaryngol, 2006; 31: 20-24, doi: 10.1111/j.1749-4486.2006.01134.x.

(5.) Shaheen NJ, Crockett SD, Bright SD, Madanick RD, Buckmire R, Couch M, et al. Randomised clinical trial: high-dose acid suppression for chronic cough--a double-blind, placebo-controlled study. Aliment Pharmacol Ther 2011; 33: 225-234, doi: 10.1111/j.1365-2036.2010.04511.x.

(6.) Reichel O, Dressel H, Wiederanders K, Issing WJ. Double-blind, placebo-controlled trial with esomeprazole for symptoms and signs associated with laryngopharyngeal reflux. Otolaryngol Head Neck Surg 2008; 139: 414-420, doi: 10.1016/j.otohns.2008.06.003.

(7.) Wo JM, Koopman J, Harrell SP, Parker K, Winstead W, Lentsch E. Double-blind, placebo-controlled trial with single-dose pantoprazole for laryngopharyngeal reflux. Am J Gastroenterol 2006; 101: 1972-1978, doi: 10.1111/j.1572-0241.2006.00693.x.

(8.) Vaezi MF, Richter JE, Stasney CR, Spiegel JR, Iannuzzi RA, Crawley JA, et al. Treatment of chronic posterior laryngitis with esomeprazole. Laryngoscope 2006; 116: 254-260, doi: 10.1097/01.mlg.0000192173.00498.ba.

(9.) Steward DL, Wilson KM, Kelly DH, Patil MS, Schwartzbauer HR, Long JD, et al. Proton pump inhibitor therapy for chronic laryngopharyngitis: a randomized placebo-control trial. Otolaryngol Head Neck Surg 2004; 131: 342-350, doi: 10.1016/j.otohns.2004.03.037.

(10.) Eherer AJ, Habermann W, Hammer HF, Kiesler K, Friedrich G, Krejs GJ. Effect of pantoprazole on the course of reflux-associated laryngitis: a placebo-controlled double-blind crossover study. Scand J Gastroenterol 2003; 38: 462-467, doi: 10.1080/00365520310001860.

(11.) El-Serag HB, Lee P, Buchner A, Inadomi JM, Gavin M, McCarthy DM. Lansoprazole treatment of patients with chronic idiopathic laryngitis: a placebo-controlled trial. Am J Gastroenterol 2001; 96: 979-983, doi: 10.1111/j.1572-0241.2001. 03681.x.

(12.) Ours TM, Kavuru MS, Schilz RJ, Richter JE. A prospective evaluation of esophageal testing and a double-blind, randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough. Am J Gastroenterol 1999; 94: 3131-3138, doi: 10.1111/j.1572-0241.1999.01504.x.

(13.) Bak YT. Management strategies for gastroesophageal reflux disease. J Gastroenterol Hepatol 2004;19: S49-S53, doi: 10.1111/j.1440-1746.2004.03587.x.

(14.) Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the reflux symptom index (RSI). J Voice 2002; 16: 274-277, doi: 10.1016/S0892-1997(02)00097-8.

(15.) Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the reflux finding score (RFS). Laryngoscope 2001; 111: 1313-1317, doi: 10.1097/00005537-20010800000001.

(16.) Gatta L, Vaira D, Sorrenti G, Zucchini S, Sama C, Vakil N. Meta-analysis: the efficacy of proton pump inhibitors for laryngeal symptoms attributed to gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2007; 25: 385-392, doi: 10.1111/j.1365-2036.2006.03213.x.

(17.) Qadeer MA, Phillips CO, Lopez AR, Steward DL, Noordzij JP, Wo JM, et al. Proton pump inhibitor therapy for suspected GERD-related chronic laryngitis: a meta-analysis of randomized controlled trials. Am J Gastroenterol 2006; 101: 2646-2654, doi: 10.1111/j.1572-0241. 2006.00844.x.

(18.) Noordzij JP, Khidr A, Evans BA, Desper E, Mittal RK, Reibel JF, et al. Evaluation of omeprazole in the treatment of reflux laryngitis: a prospective, placebo-controlled, randomized, double-blind study. Laryngoscope 2001; 111: 2147-2151, doi: 10.1097/00005537-200112000-00013.

(19.) Langevin S, Ngo H. GERD-induced ENT symptoms: A prospective placebo controlled study with omeprazole 40 mg a day. Gastroenterology 2001; 120: A16, doi: 10.1016/S0016-5085(08)80080-7.

(20.) Chiba T, Kudara N, Abiko Y, Endo M, Suzuki K, Sugai T, et al. Effects of proton pump inhibitors in patients with laryngopharyngeal reflux disease. Hepatogastroenterology 2011; 58: 1580-1582.

(21.) Park W, Hicks DM, Khandwala F, Richter JE, Abelson TI, Milstein C, et al. Laryngopharyngeal reflux: prospective cohort study evaluating optimal dose of proton-pump inhibitor therapy and pretherapy predictors of response. Laryngoscope 2005; 115: 1230-1238, doi: 10.1097/01. MLG.0000163746.81766.45.

(22.) Qadeer MA, Swoger J, Milstein C, Hicks DM, Ponsky J, Richter JE, et al. Correlation between symptoms and laryngeal signs in laryngopharyngeal reflux. Laryngoscope 2005; 115: 1947-1952, doi: 10.1097/01.mlg.0000176547. 90094.ac.

(23.) Noordzij JP, Khidr A, Desper E, Meek RB, Reibel JF, Levine PA. Correlation of pH probe-measured laryngopharyngeal reflux with symptoms and signs of reflux laryngitis. Laryngoscope 2002; 112: 2192-2195, doi: 10.1097/00005537200212000-00013.

C. Liu [1], H. Wang [2] and K. Liu [3]

[1] Department of Otolaryngology, Ji'ning First People's Hospital of Shandong Province, Ji'ning, Shandong, China

[2] Department of Pediatric Dentistry, Ji'ning Stomatological Hospital of Shandong Province, Ji'ning, Shandong, China

[3] Department of Otolaryngology, Ping'du People's Hospital of Shandong Province, Ping'du, Shandong, China

Correspondence: C. Liu: <liuchunxiu0921@163.com>

Received November 4, 2015 | Accepted April 28, 2016

http://dx.doi.org/10.1590/1414-431X20165149

Caption: Figure 1. Study selection process.
Table 1. Characteristics of the studies included in the meta-analysis.

                      Design          Patients   Symptoms
                                        (n)

Ours et al.     placebo-controlled,   17         cough
1999 (12)       parallel groups

El-Serag et     placebo-controlled,   22         hoarseness, cough,
al. 2001 (11    parallel groups                  globus, sore throat

Eherer et       placebo-controlled,   20         sore throat, hoarse-
al. 2003 (10)   cross-over groups                ness, globus sensa-
                                                 tion, dysphonic
                                                 attacks, cough,
                                                 nocturnal cough

Steward et      placebo-controlled,   42         hoarseness, throat
al. 2004 (9)    parallel groups                  clearing nonproductive
                                                 cough, globus
                                                 sensation, sore throat

Vaezi et al.    placebo-controlled,   145        throat clearing,
2006 (8)        parallel groups                  cough, globus, sore
                                                 throat, hoarseness

Wo et al.       2 (placebo-           39         globus, cough, sore
2006 (7)        controlled,                      throat, hoarseness,
                parallel groups)                 throat clearing,
                                                 excessive throat mucus

Reichel et      placebo-controlled,   58         chronic cough,
al. 2008 (6)    parallel groups                  dysphagia, throat
                                                 clearing, globus
                                                 sensation, hoarseness,
                                                 sore throat

Shaheen et      placebo-controlled,   40         chronic cough
al. 2011 (5)    parallel groups

                     Medication

Ours et al.     Omeprazole (Prilosec)
1999 (12)       80 mg, 12 weeks

El-Serag et     Lansoprazole 60 mg,
al. 2001 (11    12 weeks

Eherer et       Pantoprazole 80 mg,
al. 2003 (10)   12 weeks

Steward et      Rabeprazole 40 mg,
al. 2004 (9)    8 weeks

Vaezi et al.    Esomeprazole 80 mg,
2006 (8)        16 weeks

Wo et al.       Pantoprazole 40 mg,
2006 (7)        12 weeks

Reichel et      Esomeprazole 40 mg,
al. 2008 (6)    12 weeks

Shaheen et      Esomeprazole 80 mg,
al. 2011 (5)    12 weeks

Figure 2. Forest plot showing the effect of PPIs on improvement in LPR
symptoms. See Table 1 for reference details.

                                    Risk ratio
Study                                (95% CI)         % Weight

Ours TM et al, 1999 (12)         0.22 (0.03,1.54)        8.1
El-Serag HB et al, 2001 (11)     1.94 (0.67,5.62)        5.7
Eherer AJ et al, 2003 (10)       1.50 (0.87,2.59)       10.4
Steward DL et al, 2004 (9)       1.07 (0.55,2.07)       14.2
Vaezi MF et al, 2006 (8)         0.92 (0.41,2.05)       18.2
Wo JM et al, 2006 (7)            0.95 (0.45,2.02)       14.2
Reichel O et al, 2008 (6)        1.86 (1.14,3.03)       19.8
Shaheen NJ et al, 2011 (5)       1.15 (0.44,3.00)        9.5
Overall (95% CI)                 1.21 (0.93,1.58)

Figure 3. Forest plot showing the effect of PPIs on cough
improvement. See Table 1 for reference details.

Study                        Risk ratio (95% CI)     % Weight

Ours TM et al, 1999 (12)       0.22 (0.03,1.54)        37.6
Vaezi MF et al, 2006 (8)       0.36 (0.04,3.35)        18.5
Shaheen NJ et al, 2011 (5)     1.15 (0.44,3.00)        43.9
Overall (95% CI)               0.65 (0.30,1.41)
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Author:Liu, C.; Wang, H.; Liu, K.
Publication:Brazilian Journal of Medical and Biological Research
Article Type:Report
Date:Jul 1, 2016
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