ORIGINAL ARTICLE
Proton Pump Inhibitor Therapy for the Treatment of
Laryngopharyngeal Reflux
A Meta-Analysis of Randomized Controlled Trials
Huaiyuan Guo, MM, Haijun Ma, MM, and Jinliang Wang, MD
Goals: To compare the treatment effect of proton pump inhibitor
(PPI) therapy and placebo for patients with laryngopharyngeal
reflux (LPR).
Study: PubMed, Cochrane Library, and EMBASE were searched
from the date of conception to August 2014. Randomized con-
trolled clinical trials (RCTs) were included in this meta-analysis if
they compared the treatment response of PPI therapy and placebo
among patients with LPR. The risk difference, the standard mean
difference (SMD), and their corresponding 95% confidence inter-
vals (CIs) were calculated for the endpoints evaluated.
Results: Fourteen eligible RCTs with 771 participants were iden-
tified and analyzed in this meta-analysis. By pooling all eligible
data, we found that patients treated with PPI therapy had a sig-
nificantly higher response rate than those who received placebo
(risk difference = 0.15; 95% CI, 0.01-0.30). Compared with pla-
cebo, PPI therapy could also improve the total reflux symptom
index significantly (SMD = 1.65; 95% CI, 0.15-3.14), but results of
the reflux symptom index varied for specific symptoms. However,
PPI therapy did not show any advantage over placebo in the
improvement of the reflux finding score (SMD = 0.62; 95% CI,
0.96-2.19).
Conclusions: In this meta-analysis of 14 eligible RCTs, we found
that in patients with LPR, PPI therapy could improve reflux
symptoms significantly compared with placebo.
Key Words: laryngopharyngeal reflux, proton pump inhibitor,
reflux symptoms, randomized controlled trials, meta-analysis
(J Clin Gastroenterol 2016;50:295–300)
L aryngopharyngeal reflux (LPR) is a contributing factor
for hoarseness, cough, globus, throat clearing, and many
other laryngeal pathologies.1 The etiology of LPR is cur-
rently elusive. For gastroenterologists, LPR is just a man-
ifestation of gastroesophageal reflux disease (GERD). In
Received for publication November 9, 2014; accepted March 12, 2015.
From the Department of Gastroenterology, First Affiliated Hospital to
Science and Technology University of Henan, Luoyang, Henan,
China.
H.G., H.M., and J.W. designed the study and wrote the paper. H.G.
and H.M. searched the databases, selected eligible trials, extracted
data, and analyzed the data.
The authors declare that they have nothing to disclose.
Reprints: Jinliang Wang, MD, Department of Gastroenterology, First
Affiliated Hospital to Science and Technology University of Henan,
24 Jinghua Road, Luoyang, Henan 471003, China
(e-mail: jlcn_wang@163.com).
Supplemental Digital Content is available for this article. Direct URL
citations appear in the printed text and are provided in the HTML
and PDF versions of this article on the journal’s Website,
www.jcge.com.
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J Clin Gastroenterol  Volume 50, Number 4, April 2016
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contrast, otolaryngologists believe that LPR and GERD
are completely different in mechanisms and clinical mani-
festations. It is estimated that between 5% and 10% of the
patients visiting otolaryngologists have atypical symptoms
attributed to LPR.2 The prevalence of heartburn (6% to
43%) and esophagitis3 is quite low among these patients.
Among Chinese patients with clinically suspected LPR, a
preliminary pH biprobe study identified positive results in
21% of the patients.4
For patients with LPR, the recommended treatment
is a proton pump inhibitor (PPI) twice a day for 3 to 6
months.5,6 In recent years, more resources have been allo-
cated to treat LPR-related problems. PPI therapy for LPR
treatment has been criticized because PPI therapy is based
on a poor level of evidence. Several randomized controlled
trials (RCTs) have been performed to investigate the
treatment efficacy of PPI therapy for LPR.7–10 However,
most of these RCTs had a relatively small sample size and
no unified criteria in the monitoring of the treatment
response. In 2006, Qadeer et al11 performed a meta-analysis
of RCTs to investigate this issue and found that PPI ther-
apy could not offer significant clinical benefit over placebo
in patients with GERD-related LPR. However, Qadeer’s
meta-analysis included only 8 eligible trials and only the
overall response rate was analyzed quantitatively. After
Qadeer’s reports, many RCTs have been conducted.7–10
For example, the clinical trial by Lam et al9 demonstrated
that PPI therapy improved reflux symptoms significantly
compared with placebo.
Therefore, we conducted this updated meta-analysis to
investigate the efficacy of PPI therapy for the treatment of
LPR compared with placebo. In addition, we sought to
analyze the improvement of reflux symptoms quantitatively.
MATERIALS AND METHODS
Searching Strategy
This meta-analysis was reported according to the
guidelines of the quality of reporting of meta-analyses
conference statement (QUOROM). The following online
databases were searched from the date of interception to
August 2014: MEDLINE (through PubMed), Cochrane
Library, and EMBASE (through Ovid). The combination
of the following medical subheadings (MeSH) and key
words was used for database searching: proton pump
inhibitors or PPI or esomeprazole or pantoprazole or ome-
prazole or rabeprazole or lansoprazole and laryngitis or
pharyngitis or laryngopharyngeal reflux or gastropharyngeal
reflux or LPR. Alternative spellings and abbreviations of
the above key words were also considered. An expanded
manual search for references of eligible trials and related
www.jcge.com | 295
Guo et al
reviews was also performed. The Web site of Clinical-
Trials.gov was also checked. There was no limitation on the
language or the publishing date.
Inclusion Criteria
RCTs that met the following criteria were included: (a)
RCTs published with full articles; (b) RCTs including adult
patients with LPR (18 y and above), and (c) RCTs com-
paring the treatment efficacy of PPI therapy and placebo.
LPR was defined by the presence of Z1 of the following
symptoms: hoarseness, globus sensation, frequent throat
clearing, excessive phlegm, chronic cough, and the presence
of GERD-attributed signs of laryngitis on laryngoscopy
including edema, erythema, contact ulcer, pachydermia,
and/or granuloma. A RCT was defined according to the
National Library of Medicine. Two investigators (H.G. and
H.M.) selected eligible trials according the inclusion criteria
independently. Disagreement was solved by discussion until
consensus was achieved.
Data Abstraction
Two investigators (H.G. and H.M.) extracted data
from eligible trials independently with a predesigned data
extraction form. Disagreement between 2 investigators was
discussed with another expert (J.W.) until consensus was
achieved. The following baseline characteristics were
abstracted from each including trial: the first author, the
publishing time, the country where the trial was carried out,
the number of patients evaluated, the mean age of patients,
the number of male participants, the symptoms evaluated,
PPIs, and the dose used. The primary endpoint was the
response rate, and for this purpose, we abstracted the
number of patients in each study who reported Z50%
reduction in laryngeal symptoms compared with baseline.
Secondary endpoints were the reflux symptom index (RSI)
and the reflux finding score (RFS). For RSI, both the total
RSI and the RSI of heartburn and hoarseness were
abstracted.
Validity Assessment
The methodology quality of eligible RCTs was also
assessed using the “risk of bias” tool recommended by the
Cochrane Handbook. Random sequence generation (selec-
tion bias), allocation concealment (selection bias), blinding of
participants and personnel (performance bias), blinding of
the outcome assessment (detection bias), incomplete outcome
data (attrition bias), selective reporting (reporting bias), and
other bias were assessed. On the basis of the methods
reported in each trial, each of above 5 components was
graded “yes,” “unknown,” or “no,” which meant a low risk
of bias, uncertain risk of bias, and a low risk of bias,
respectively.
A GRADE profiler (version 3.6, downloaded from the
Web site of Cochrane) was used to assess the quality of each
endpoint. Factors that will downgrade or upgrade the
quality of evidence were assessed, and the quality of each
endpoint was graded as “low,” “moderate,” or “high.”12
Statistical Analysis
For the response rate, relative risks (RR) and corre-
sponding 95% confidence intervals (95% CI) were calcu-
lated. The standard mean differences (SMD) and their 95%
CIs were calculated for RSI and RFS. An RR with a 95%
CI without1 was considered to be of statistical significance,
and RR > 1 shows that patients in the PPI group will have
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J Clin Gastroenterol  Volume 50, Number 4, April 2016
a higher response rate. The SMD with a 95% CI without 0
was considered to be of statistical significance, and patients
with an SMD > 0 show that the reflux symptom improved
more significantly in the PPI group. The fixed-effects model
was used for calculating RR and SMD unless the hetero-
geneity was significant across trials.13 The heterogeneity
was tested using the Q-statistic, and a P-value <0.1 indi-
cated that there was significant heterogeneity.13 In the
presence of heterogeneity, the reason for heterogeneity was
explored and a random-effects model was applied. A funnel
plot was used to test publication bias.14,15 All statistical
analyses were performed with the Review Manager soft-
ware (version 5.0.24, The Cochrane Collaboration).
RESULTS
Trial Flow
A total of 741 records from databases and references
of relative articles were retrieved. After the first screen by
abstracts, 17 full-text articles were retrieved for further
review.7–10,12,16–27 After rigorous selection, 3 trials were
excluded for the reason of not comparing with placebo. Thus,
14 eligible RCTs7–10,12,16–24 were included and analyzed, and
the detailed selection process is shown in Figure 1.
Characteristics of Eligible Trials
A total of 14 RCTs including 808 patients with LPR
were analyzed. Baseline characteristics of eligible studies
are shown in Table 1. Most patients were validated by
laryngoscopy or esophageal pH monitoring. The 14 trials
were conducted in different parts of the world, and most of
them were performed in the United States.
Validity of the Included Trials
“Risk of bias” assessment showed that all trials were
free from selective reporting, and withdraw was addressed
in all trials. Although patients were randomized into
treatment arms in each trial, none of them presented the
detail of sequence generation, blinding methods, and
sequence concealment. In summary, the risk of bias and the
methodology quality of the included trials were acceptable.
Meta-Analysis Results
Patients with >50% reduction in laryngeal symptoms
(which was classified as the response to treatment) were
extracted from each study. A total of 10 RCTs with 400
participants were included in this analysis. By pooling all
eligible trials, we found that patients who received PPI
treatment had a significantly higher response rate than
FIGURE 1. The flow chart of study selection.
J Clin Gastroenterol  Volume 50, Number 4, April 2016 PPI Therapy for Laryngopharyngeal Reflux

those who received placebo (Fig. 2; risk difference = 0.15;
95% CI, 0.01-0.30; heterogeneity, P = 0.01).
RSI is a self-administered outcome instrument and
RSI is a generally used measure of reflux symptoms. The
meta-analysis results showed that for patients who received
PPI therapy, the total RSI improved more significantly
than in those who received placebo (Fig. 3A; SMD = 1.65;
95% CI, 0.15-3.14; heterogeneity, P < 0.01). We further
investigated the RSI for specific reflux symptoms such as
hoarseness and throat clearing. Compared with placebo,
PPI therapy improved the symptoms of hoarseness sig-
nificantly (SMD = 0.77; 95% CI, 0.14-1.39; heterogeneity,
P = 0.02), but PPIs failed to provide better improvement
for throat clearing (SMD = 0.85; 95% CI, 0.39 to 2.08;
heterogeneity, P < 0.01).
Laryngoscopy is often used for the diagnosis of LPR
as LPR often leads to posterior laryngeal mucosal abnor-
malities. The RFS was also analyzed to evaluate PPIs’ effect
on the laryngeal mucosa. Pooled results showed that the
PPI could not provide better improvement of RFS than the
placebo (Fig. 3B; SMD = 0.62; 95% CI, 0.96 to 2.19;
heterogeneity, P < 0.01).
Publication Bias
The funnel plot for the comparison of the response
rate was visually symmetrical (Fig. 4), which indicated that
our meta-analysis was not affected by publication bias.
Funnel plots for other comparisons were also analyzed and
no publication bias was found (figures not shown).
The Quality of Evidence
Factors that will downgrade the quality of evidence
(including “risk of bias,” “inconsistence,” “indirectness,”
“imprecision,” and “publication bias”) and those that will
upgrade the quality of evidence (including “large effect,”
“plausible confounding,” and “dose-response gradient”)
were assessed exactly according to the GRADE system.
As shown in the GRADE profiler (Supplementary

TABLE 1. Baseline Characteristics of the Eligible Randomized Clinical Trials

Mean Study
Patients Patients Age PPI and Dose Duration
References Country Randomized Analyzed (y) Males Used Scales for Outcome Measure (wk)
Chappity India 234 117/117 36.9 115 Omeprazole Self-designed symptom response score 12
et al7 20 mg twice
daily
Steward USA 42 18/19 9.3 12 Rabeprazole Total reflux score, videostrobe grade 8
et al8 20 mg twice a
day for 2 mo
Lam et al9 China 82 42/20 46.8 23 Rabeprazole Reflux symptom index, reflux finding score 12
20 mg twice
daily for 12 wk
Fass et al10 USA 41 24/17 65.1 17 Esomeprazole Gastroesophageal reflux disease symptom 12
20 mg twice checklist, esophageal pH monitoring,
daily for 12 wk Health-Related Quality of Life
Questionnaires, videostroboscopy
Reichel UK 58 30/28 32 30 Esomeprazole Reflux symptom index, reflux finding score 12
et al16 20 mg twice
daily, 30 min
before meals
Wo et al17 USA 39 20/19 39 13 Pantoprazole Self-designed visual analog scales 12
40 mg qam for
12 wk
Vaezi USA 145 95/50 50.7 71 Esomeprazole Self-designed symptom scales, 16
et al18 40 mg twice pharyngoesophageal pH monitoring,
daily for 16 wk laryngopharyngeal reflux—health-
related quality of life
Eherer Australia 21 10/10 48 16 Pantoprazole Self-designed symptom scales, esophageal 12
et al19 40 mg bid for pH measurement
12 wk
Noordzi USA 30 15/15 49 16 Omeperazole Self-designed symptom scales, laryngeal 8
et al20 40 mg bid scope
El-Serag USA 22 11/9 48 5 Lansoprazole Reflux symptoms, esophageal pH 12
et al21 30 mg oral measurement
capsules bid
before meals
Shaheen USA 40 22/18 50 9 Esomeprazole Reflux finding score, CQLQ scores 12
et al22 40 mg twice
daily
Ours USA 17 8/9 54 NA Omeperazole Esophageal manometry and pH testing 12
et al12 40 mg bid
Havas Australia 15 8/7 54 7 Lansaprazole Laryngeal symptom score 12
et al23 30 mg bid
Langevin Canada 30 14/16 53 16 Omeprazole Global symptom score 12
and 40 mg once a
Ngo24 day

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Guo et al J Clin Gastroenterol  Volume 50, Number 4, April 2016

FIGURE 2. Comparison of response rates between PPI therapy and placebo. CI indicates confidence intervals; PPI, proton pump
inhibitor.

Information, Supplemental Digital Content 1, http://links.
lww.com/JCG/A178), the quality of all outcomes was
moderate because the endpoints were downgraded for the
reason of “imprecision” (explained in the Supplementary
Information in detail, Supplemental Digital Content 1,
http://links.lww.com/JCG/A178). In summary, the results
of this meta-analysis were reliable and creditable.
DISCUSSION
This meta-analysis of 14 RCTs showed that for
patients with LPR, PPI therapy could improve the overall
reflux symptoms significantly compared with placebo;
however, PPI therapy could not improve RFS. No pub-
lication bias was found.
Over the past decades, a lot of improvement in the
diagnosis and the treatment of LPR has been achieved.
Common LPR-related symptoms are hoarseness, chronic
throat clearing, excessive phlegm, dry cough, dysphagia,
and globus sensation.1,2 The diagnosis of LPR is commonly
based on the patient’s history and the physical examination
demonstrating posterior laryngeal inflammation; however,
these signs and symptoms are not necessarily specific for
GERD-mediated LPR, which are often found in the
healthy population.9 For the pathology of LPR, there are 2
hypotheses. The first theory proposes that gastric acid and
pepsin injure the larynx directly through the reflux of gas-
tric secretions.2,28 The other theory proposes that gastric
acid in the distal esophagus stimulates vagal-mediated
reflexes, resulting in chronic throat clearing and coughing,
which lead to laryngeal injury.29 Therefore, PPI therapy is
commonly recommended to improve LPR-related symp-
toms due to its effect of inhibition of gastric acids.
In 2006, Qadeer et al11 reported a meta-analysis based
on 8 eligible RCTs and found that PPI therapy may offer a
modest, but nonsignificant, clinical benefit over placebo in
suspected GERD-related chronic laryngitis. Compared
with Qadeer’s meta-analysis, we identified 6 newly

FIGURE 3. Comparison of the reflux symptom index (A) and the reflux finding score (B) between PPI therapy and placebo. CI indicates
confidence intervals; PPI, proton pump inhibitor.

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J Clin Gastroenterol  Volume 50, Number 4, April 2016
FIGURE 4. The funnel plot for the analysis of the response rate.
published eligible RCTs7,9,10,12,16,22 in this updated meta-
analysis and found that PPI therapy could improve reflux
symptoms significantly, as the response rate was higher
(risk difference = 0.15; 95% CI, 0.01-0.30) and the total
RSI (SMD = 1.65; 95% CI, 0.15-3.14) improved sig-
nificantly in patients treated with PPI therapy than in
patients with placebo. The possible reason might be that the
sample size was larger in our meta-analysis. For example,
we included additional 2 eligible trials, increasing the ana-
lyzed sample size to 400 for the analysis of the response
rate. In addition, we also conducted quantitative analyses
for the RFS and the RSI of specific symptoms. In contrast,
Qadeer and colleagues performed a metaregression to find
the possible clinical predictors of PPI response, whereas this
analysis was not conducted in this meta-analysis due to
limited information.
Although the total RSI was significantly improved by
PPI therapy, the conclusion could not be simply applied to
all reflux symptoms. Hoarseness and throat clearing are the
most common LPR-related laryngeal symptoms, but the
effect of PPI therapy on these 2 symptoms was different.
For the analysis of hoarseness and throat clearing, the
sample size was small as we included only 3 eligible trials. In
addition, these symptoms were affected easily by other
unrecorded factors, such as voice abuse and inflammation.
Thus, further studies are necessary to determine the detailed
effect on specific symptoms.
Limitations of this meta-analysis should be highlighted
and our findings should be interpreted with caution. First,
most included trials were small sized and there were no
high-quality, multicentered, RCTs. Thus, the overall evi-
dence level of our findings was low. Second, comparisons in
this meta-analysis consisted of heterogeneity. To minimize
the effect of heterogeneity and provide robust and reliable
results, we used the random-effects model to calculate the
pooled estimates. Third, only 2 specific reflux symptoms
were analyzed quantitatively, which may lead to the
potential bias of selective reporting. However, the outcome
measurement scales varied among eligible trials, and it was
difficult to pool the data for each reflux symptom. To
summarize, further studies are needed to validate our
findings.
In summary, in this updated meta-analysis of 14 eli-
gible RCTs, we found that PPI therapy could improve
reflux symptoms significantly in patients with LPR
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PPI Therapy for Laryngopharyngeal Reflux
compared with placebo. Further high-quality clinical trials
with a large sample size are warranted.
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