ARTICLE IN PRESS

The Use of Inhaled N-Acetylcysteine for Laryngopharyngeal

Reflux Disease: A Randomized Controlled Trial
Yong Seok Jo, Ick Soo Choi, and Yoon Kyoung So, Goyang, Republic of Korea

Summary: Objectives. Proton pump inhibitors (PPIs) are the mainstay of the medical treatment for laryngo-
pharyngeal reflux disease (LPRD). However, extraesophageal symptoms of LPRD, such as globus, are often
refractory to PPI treatment. Many kinds of adjunctive medications have been attempted to address those refrac-
tory cases. We aimed to study whether inhaled N-acetylcysteine (NAC), a mucolytic agent, has additive effects
for the treatment of LPRD when used in conjunction with PPIs.
Methods. Patients with reflux symptom index (RSI) greater than 13 and reflux finding scores (RFS) greater than
7 were prospectively enrolled and were randomly assigned to control or study group. Patients were treated with oral
rabeprazole in the control group and with oral rabeprazole and inhaled NAC in the study group. Patients were fol-
lowed once a month for 2 months with questionnaires and stroboscopic examination. At every follow-up, RSI and
RFS were checked. The extent of improvements of RSI and RFS were evaluated and compared between two groups.
Results. With treatment, the mean RSI changed from 21.0 to 7.6 (P < 0.001) in control group and from 19.7 to
4.5 (P < 0.001) in study group. The mean RFS also changed from 12.9 to 7.1 (P < 0.001) in control group and
from 13.5 to 6.9 (P < 0.001) in study group. For both RSI and RFS, the extents of improvement were not signifi-
cantly different between two groups. In patients whose RSI improved less than nine at the first follow-up (poor
early responders), RSI became significantly lower in the study group (4.6 § 2.0) than in the control group (9.5 §
4.6) at second follow-up (P = 0.019). In good early responders, however, RSI was not significantly different
between the two groups in the second follow-up.
Conclusions. In this study, there were no significant differences in the overall outcome between patients treated
with inhaled NAC and PPI and those with PPI alone. Interestingly, some additional therapeutic effect of NAC
appeared late for the patients with poor early response. Further studies are required to investigate the underlying
mechanism for this.
Key Words: Laryngopharyngeal reflux−GERD−Reflux−N-acetylcysteine−Globus−Proton pump inhibitors−
Mucolytics.

INTRODUCTION PPIs are attempted to address these refractory extraeso-

Laryngopharyngeal reflux disease (LPRD) is the result of phageal symptoms. N-acetylcysteine (NAC) is a represen-
reflux of gastric contents to the laryngopharyngeal region, tative mucolytic agent that has been used for many years
where it changes the laryngopharyngeal mucosa.1 The cili- for the treatment of patients with a variety of respiratory
ated respiratory epithelium in the laryngopharyngeal region conditions.6,7 Aerosolized inhaled NAC dissociates the
is vulnerable to the gastric reflux and easily induces mucosal disulfide bonds of mucin to reduce viscosity and help
changes and symptoms of LPRD. Patients with LPRD treat mucus stasis.8,9 In addition, it has some extent of
often present with symptoms such as globus sensation, antioxidant effect to tissue.10 There has been a trial that
throat clearing, and cough, without esophageal symptoms demonstrated the effect of taking oral NAC for the
of reflux.2 The treatment of LPRD consists of behavioral treatment of LPRD.11 The mucolytic activity of NAC,
and dietary changes and medical treatment.3,4 Proton pump however, can be increased when inhaled.
inhibitors (PPI) are the mainstay of the medical treat- In this study, we aimed to study whether aerosolized
ment.1,5 However, extraesophageal symptoms are generally inhaled NAC helps relieve the symptoms of LPRD and
more refractory to medical treatment than the esophageal have any additive effect for the treatment of LPRD when
symptoms of GERD and are sometimes a challenge to used alongside PPIs.
physicians. Therefore, LPRD usually requires more aggres-
sive and prolonged treatment than gastroesophageal reflux
MATERIALS AND METHODS
disease (GERD). Often adjunctive medications other than
Ethical considerations
Accepted for publication October 2, 2019. This study was approved by the institutional ethical com-
Declarations of interest: All authors declare that they have no conflict of interests. mittee in accordance with the Helshinki declaration (IRB
From the Department of Otorhinolaryngology-Head and Neck Surgery, Ilsan Paik
Hospital, Inje University College of Medicine, Goyang, Republic of Korea. file No. 2016-03-013). All patients enrolled in this study
Address correspondence and reprint requests to Yoon Kyoung So, Department of gave written informed consents.
Otorhinolaryngology-Head and Neck Surgery, Ilsan Paik Hospital, Inje University
College of Medicine, 170 Juhwa-ro, Ilsanseo-gu, Goyang-si, Gyeonggi-do 10380,
Republic of Korea. E-mail: [email protected]
Journal of Voice, Vol. &&, No. &&, pp. &&−&& Trial design
0892-1997
© 2019 The Voice Foundation. Published by Elsevier Inc. All rights reserved.
This prospective, randomized controlled trial was carried
https://doi.org/10.1016/j.jvoice.2019.11.017 out in single blind design on patients with LPRD at a
 ARTICLE IN PRESS
2 Journal of Voice, Vol. &&, No. &&, 2019

university hospital from June 2016 to August 2018. The Intervention and randomization
allocation of patients to either study or control group was Enrolled patients were randomly allocated to the control or
blinded to the researcher who had seen and evaluated the study group according to a random number table. Patients
patients. This study was registered in Clinical Research in the control group were treated with oral rabeprazole
Information Service (KCT0004099). 20 mg once daily before breakfast. Those in the study group
were treated with oral rabeprazole 20 mg once daily before
breakfast and inhaled NAC (N-acetylcysteine 20%, 4 ml)
Patients twice a day. In most cases, the solution was nebulized via
We prospectively enrolled patients with LPRD from June facial mask. During the inhalation of NAC, patients were
2016 to August 2018. Patients who visited the department instructed to breathe comfortably and make intermittent
of otolaryngology at Ilsan Paik Hospital, South Korea, vocalization for increase in laryngeal aerosol deposition.
with symptoms of LPRD were screened for enrollment. The Twelve patients were followed up once a month for about 2
symptoms of LPRD included globus (a sensation of a lump months with questionnaires (RSI) and stroboscopic exami-
in the throat), throat clearing, hoarseness, postnasal drip nation. At every follow-up, RSI and RFS were checked by
(PND) sense, and cough. Among screened patients, patients a single physician. Compliance and discomfort with medica-
with reflux symptom index (RSI)12 greater than 13 and tion were checked by the coordinator of this study at every
reflux finding scores (RFS)13 greater than 7 were included in visit. Patients were given a small notebook and recorded
this study. The exclusion criteria were as follows: patients their using oral medication and/or inhaler on the check table
with acute or chronic sinusitis or with symptoms of upper of drug use in the notebook every day. Also, patients were
respiratory infection at initial visit, patients with lower required to bring the used sheets of tablets, as well as left-
respiratory disease such as asthma, chronic obstructive pul- over tablets and ampules. Compliance was checked using
monary disease, pneumonia, or lung cancer, patients with these. Patients who were lost to follow-up were excluded
organic lesions in the pharynx, larynx, or oral cavity such as from the study. Patients with medication compliance less
malignancy, significant hypertrophy of palatine or lingual than 60% were also excluded from the study at the time of
tonsil, or huge vallecular cyst, patients who had psychiatric final analysis. The trial protocol is summarized in the CON-
history such as depression or insomnia or those taking psy- SORT flow diagram (Figure 1).
chiatric medication, patients older than 70 years (due to the
difficulty in manipulating the inhaler machine and handling
the ampules of NAC, as well as the risk of comorbid dis- Statistical analysis
eases), younger than 20 years, or pregnant, patients cur- Paired t-tests were used to analyze the response after medi-
rently taking PPI. Lastly, after a detailed explanation, those cation within each group. Independent t-tests were used to
who did not agree to participate in this study were excluded. compare the response between the control and study groups.

FIGURE 1. Consort trial flow diagram.

 ARTICLE IN PRESS
Yong Seok Jo, et al N-acetylcysteine for LPRD 3

We used IBM SPSS Statistics, version 24 (IBM Corp. New TABLE 1.

York) for all statistical calculations. P values <0.05 were Patients’ Characteristics
considered statistically significant.
Characteristic Value
Age (yr) 53.0 § 8.9*
RESULTS Gender 22/8
Patients’ characteristics (male/female)
Among the 42 patients initially enrolled, 10 patients (eight Chief complaint† Globus 24 (80.0 %)
Voice change 16 (53.3 %)
in control group and two in study group) were lost to fol-
Cough 9 (30.0 %)
low-up and two other patients (in study group) were Other (heartburn, 10 (33.3 %)
excluded from the analysis due to low compliance to medi- sore throat, etc.)
cation (less than 60%). Finally, 30 patients were analyzed in Accompanying Dry mouth 13 (43.3 %)
this study and 15 patients were assigned to the control and symptoms†
study group, respectively (Figure 1). The age of the analyzed Snoring 20 (66.7 %)
patients ranged from 29 to 66 years, with an average of Mouth breathing 11 (36.7 %)
53 years. Of the 30 patients, 22 were male and 8 were Reflux symptom Overall 20.4 § 5.6*
female. The most common complaints were globus (80%) index
and voice change (53.3%). The mean compliance to the oral (initial score) Control group 21.0 § 5.5*
medication (rabeprazole) was 92.6% in the control group (n = 15)
Study group 19.7 § 5.6*
and 88.3% in the study group. The mean compliance to the
(n = 15)
inhaled NAC was 80.3% in the study group (Table 1). P value (control 0.551
There was no significant difference in initial RSI and RFS vs. study)
before treatment between the control and study groups. The Reflux finding Overall 13.2 § 2.9*
initial RSI was 21.0 § 5.5 in the control group and 19.7 § score
5.6 in the study group (P = 0.551). Initial RFS was 12.9 § (initial score) Control group 12.9 § 3.2*
3.2 in the control group and 13.5 § 2.6 in the study group (n = 15)
(P = 0.549). Study group 13.5 § 2.6*
(n = 15)
P value (control 0.549
Overall response after treatment vs. study)
RSI and RFS showed significant improvement after treat- Compliance to Control group 92.6 %
treatment (oral medication)
ment in both control and study groups. In the control group,
Study group 88.3 %
the mean RSI was 21.0 at initial visit and improved to 10.7 (oral medication)
at first follow-up (P < 0.001) and 7.6 at second follow-up Study group 80.3 %
(P < 0.001). In the study group, the mean RSI was 19.7 at (nebulizer)
the initial visit and improved to 11.3 at first follow-up * Values are expressed as the mean § standard deviation.
(P < 0.001) and 4.5 at second follow-up (P < 0.001; Table 2). †
Multiple responses allowed.
In the control group, the mean RFS was 12.9 at the initial
visit and improved to 9.3 at first follow-up (P < 0.001) and
7.1 at second follow-up (P < 0.001). In the study group, The late effect of the N-acetylcysteine inhalation in
the mean RFS was 13.5 at the initial visit and improved to good or poor early responders
10.3 at first follow-up (P = 0.001) and 6.9 at second follow- At first follow-up, the improvement of RSI ranged from 0 to
up (P < 0.001; Table 2). 21, with an average of nine and a median of 9.4 in all
There was no significant difference in the extent of patients. Based on these values, we divided the patients into
improvement between the two groups (Table 3). At first two new groups. Patients with improvement in RSI of less
follow-up, the extent of improvement of RSI was 10.3 § 5.7 than nine at the first follow-up were classified as poor early
in the control group and 8.5 § 4.6 in the study group responders (n = 14). Those with an improvement of RSI
(P = 0.331). At second follow-up, the extent of improve- nine or more at the first follow-up were classified as good
ment of RSI was 13.4 § 5.1 in the control group and 15.2 § early responders (n = 16).
4.7 in the study group (P = 0.319). At first follow-up, the In the poor early responders, the study group
extent of improvement of RFS was 3.5 § 2.1 in the control (rabeprazole + NAC) showed greater late improvement
group and 3.2 § 2.9 in the study group (P = 0.722). At sec- than the control group (rabeprazole only; Figure 2a, c,
ond follow-up, the extent of improvement of RFS was 5.7 Table 5). The RSI score of the two groups were almost simi-
§ 2.8 in the control group and 6.7 § 3.1 in the study group lar at the initial visit (P = 0.980) and the first follow-up
(P = 0.390). Also, when we examined the degree of improve- (P = 0.866). However, the RSI was significantly lower in
ment of RSI in each item, there was no difference between study group (4.6 § 2.0) than in the control group (9.5 § 4.6)
study group and control group (Table 4). at second follow-up (P = 0.019). Also, the RFS scores of the
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4 Journal of Voice, Vol. &&, No. &&, 2019

TABLE 2.
Improvement of RSI According to Treatment
RSI* P value RFS P Value
(Initial vs. 2nd) (Initial vs. 2nd)
Initial 1st FU 2nd FU Initial 1st FU 2nd FU
All patients 20.4 § 5.7 11.0 § 5.4 6.1 § 3.3 <0.001 13.2 § 3.0 9.8 § 2.6 7.0 § 3.4 <0.001
Control group 21.0 § 5.7 10.7 § 4.9 7.6 § 3.7 <0.001 12.9 § 3.3 9.3 § 2.7 7.1 § 3.4 <0.001
Study group 19.7 § 5.8 11.3 § 5.9 4.5 § 1.8 <0.001 13.5 § 2.7 10.3 § 2.6 6.9 § 3.5 <0.001
* Values are expressed as the mean § standard deviation.
Abbreviations: FU, follow-up; RFS, reflux finding score; RSI, reflux symptom index.

TABLE 3.
The Extents of the Improvement of RSI and RFS at Every Follow-up
Extent of Improvement From Initial Value
RSI RFS
1st FU 2nd FU 1st FU 2nd FU
Control group 10.3 § 5.7 13.4 § 5.1 3.5 § 2.1 5.7 § 2.8
Study group 8.5 § 4.6 15.2 § 4.7 3.2 § 2.9 6.7 § 3.1
P value (control vs. study) 0.331 0.319 0.722 0.390
*Values are expressed as the mean § standard deviation.
Abbreviations: FU, follow-up; RFS, reflux finding score; RSI, reflux symptom index.

TABLE 4.
Differences Between Control and Study Group in the Improvement of RSI and RFS Items
The Extent of the Improvement From
Initial Visit to 2nd FU*
Control Group Study Group P Value
Reflux symptom index
1. Hoarseness or a problem with voice 2.1 § 1.2 1.5 § 1.5 0.287
2. Throat clearing 1.9 § 0.7 2.5 § 1.0 0.100
3. Excess throat mucus or postnasal drip 1.5 § 1.5 2.4 § 1.1 0.054
4. Difficulty swallowing food, liquids, or pills 1.0 § 1.4 1.1 § 1.6 0.902
5. Coughing after eating or after lying down 1.1 § 1.6 1.5 § 1.8 0.529
6. Breathing difficulties or choking episodes 1.1 § 1.2 0.8 § 1.3 0.553
7. Troublesome or annoying cough 0.7 § 1.1 1.3 § 1.7 0.318
8. Sensations of something sticking in your throat 2.2 § 1.5 2.6 § 1.1 0.410
or a lump in your throat
9. Heartburn, chest pain, indigestion, or stomach 1.9 § 2.1 1.6 § 1.3 0.682
acid coming up
Reflux finding score
1. Subglottic edema 0.7 § 1.0 0.8 § 1.0 0.716
2. Ventricular obliteration 1.3 § 1.0 1.6 § 1.1 0.493
3. Erythema/hyperemia 1.6 § 1.4 1.6 § 1.1 1.000
4. Vocal fold edema 0.3 § 0.5 0.4 § 0.7 0.083
5. Diffuse laryngeal edema 0.4 § 0.6 0.7 § 0.5 0.109
6. Posterior commissure hypertrophy 0.3 § 0.5 0.2 § 0.4 0.679
7. Granuloma/granulation tissue 0.1 § 0.5 0.0 § 0.0 0.334
8. Thick endolaryngeal mucus 1.1 § 1.0 1.1 § 1.0 1.000
* Values are expressed as the mean § standard deviations.
Abbreviations: FU, follow-up; RFS, reflux finding score; RSI, reflux symptom index.
 ARTICLE IN PRESS
Yong Seok Jo, et al N-acetylcysteine for LPRD 5

FIGURE 2. Effect of inhaled N-acetylcysteine (NAC) on late response according to early response. Patients with improvement of RSI of
less than 9 at the first follow-up were classified as poor early responders (n = 14), while those with the improvement of RSI 9 or more were
classified as good early responders (n = 16). For the poor early responders, the study group (rabeprazole + NAC) showed greater late
improvement than the control group (rabeprazole only) (2a and 2c). RSI was significantly lower in the study group (4.6 § 2.0) than in the
control group (9.5 § 4.6) at second follow-up (P = 0.019) (2a). RFS was slightly lower in the study group (6.9 § 3.0) than in the control
group (9.3 § 2.9), although it did not reach statistical significance (P = 0.152) (2c). For the good early responders, the control and study
groups did not show significant differences at every follow-up (2b and 2d). For good early responders, the RSI graphs of control and study
groups almost overlap and there was no significant difference between the two groups at second follow-up (P = 0.117) (2b). Also, there was
no significant difference between the RFS scores of the two groups at every follow-up (P = 0.515) in good early responders (2d).

TABLE 5.
Effect of Inhaled N-Acetylcysteine on Late Response According to Early Response
Initial 1st FU 2nd FU
Poor early responders RSI Control 19.8 § 5.1 14.7 § 4.2 9.5 § 4.6
Study 19.8 § 6.7 14.1 § 6.8 4.6 § 2.0
RFS Control 12.8 § 3.1 10.5 § 2.7 9.3 § 2.9
Study 13.3 § 3.0 10.0 § 2.5 6.9 § 3.0
Good early responders RSI Control 21.8 § 6.2 8.0 §3 .3 6.3 § 2.6
Study 19.7 § 5.1 8.0 § 2.3 4.4 § 1.7
RFS Control 12.9 § 3.6 8.6 § 2.6 5.7 § 2.9
Study 13.9 § 2.4 10.7 § 2.8 6.9 § 4.2
Values are expressed as the mean § standard deviation.
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6 Journal of Voice, Vol. &&, No. &&, 2019

TABLE 6. 50 %.16 A meta-analysis showed no significant symptom

Overall Improvement of RSI According to Various improvement with PPI treatment compared with placebo.18
Accompanying Factors Treatment difficulties mainly related to the vulnerability of
laryngeal mucosa, and LPRD generally require more
Improvement
aggressive and prolonged treatment than gastro-esophageal
of RSI at 2nd
reflux disease (GERD).19 In this context, several adjunctive
N FU† P Value
medications, including prokinetics, have been used and
Age <56yrs* 13 14.9 § 4.4 0.600 investigated for their efficacy. However, randomized con-
≥56yrs* 17 13.9 § 5.3 trolled trials on those adjunctive medications are still lack-
Sex Female 8 17.1 § 6.2 0.053
ing. For several decades, NAC has been used as a mucolytic
Male 22 13.3 § 4.0
Dry mouth Absent 16 12.9 § 3.8 0.075
agent to treat a variety of respiratory diseases.20 NAC
Present 13 16.2 § 5.7 breaks disulfide bonds in the high-molecular-weight glyco-
Snoring Absent 10 14.1 § 4.9 0.877 proteins of mucus, which decreases its viscosity and makes
Present 20 14.4 § 5.0 it easier to transport along the airway.21 This study evalu-
Mouth Absent 17 13.6 § 4.4 0.414 ated the efficacy of NAC as an adjunctive medication for
breathing LPRD.
Present 11 14.7 § 4.1 When evaluating the overall improvement of RSI and
* Median age of enrolled patients was 56 years. RFS, inhaled NAC did not show any additional effect on
†
Mean § standard deviation. LPRD in this study (Tables 2 and 3). When we compared
Abbreviations: FU, follow-up; RSI, reflux symptom index.
the degrees of improvement of the RSI and RFS individual
items in the two groups, we also could not find a significant
two groups were similar at the initial visit (P = 0.805) and difference between the two groups (Table 4). RSI 2, 3, 8,
first follow-up (P = 0.725). The RFS was slightly lower in and RFS 8, which are related to the laryngeal mucus, also
the study group (6.9 § 3.0) than in the control group (9.3 § showed no significant differences in the extent of improve-
2.9), although it did not reach statistical significance ment in the two groups. RSI 2 (“clearing your throat”) and
(P = 0.152). 3 (“excess throat mucus or PND”) showed slightly better
In good early responders, the control and study improvement in the study group, although the analysis did
groups showed no significant differences at any follow-up not reach statistical significance. Statistical insignificance
(Figure 2b, d, Table 5). In good early responders, the RSI could be due to the small size of the patient population and
graphs of the control and study groups almost overlap, and a further study is needed in larger patient population in
there was no significant difference between the RSI scores order to clarify this.
of the two groups at the initial visit (P = 0.490), the first fol- Interestingly, when patients with poor early response to
low-up (P = 1.000), or the second follow-up (P = 0.117). treatment were analyzed separately, the additional thera-
Also, there was no significant difference between the RFS peutic effect of NAC appeared late in the treatment
of the two groups at the initial visit (P = 0.553), the first (Figure 2 and Table 5). At the second follow-up, the RSI
follow-up (P = 0.131), or the second follow-up (P = 0.515). was significantly lower in the study group (4.6 § 2.0) treated
with PPI and NAC than in the control group (9.5 § 4.6)
treated with PPI only (P = 0.019). The RFS was also slightly
The improvement of RSI and various factors lower in the study group (6.9 § 3.0) than in the control
Patient age, gender, and accompanying symptoms such as group (9.3 § 2.9), although it did not reach statistical signif-
dry mouth had no significant influence on the improvement icance (P = 0.152).
of RSI (Table 6). RSI tended to improve to a greater extent The clinical efficacy of NAC for the treatment of chronic
in female patients than in male patients, although there was bronchitis and COPD has been documented in several clini-
no statistically significant difference (P = 0.053). Also, the cal trials and meta-analyses,9,22−24 but there was only one
improvement of RSI was rather greater in patients with dry study that evaluated the effect of NAC in LPRD.11 In that
mouth than in those without it, which also did not reach to study, NAC was orally administered at a dose of 600 mg.
a statistical significance (P = 0.075) They showed a significantly greater improvement after
3-month treatment in the PPI + NAC group than in
NAC + placebo group. However, oral NAC has low bio-
DISCUSSIONS availability8 and it is not found in airway secretions after
Reflux of gastric contents damages the laryngeal ciliated oral dosing.25 In contrast, we administered NAC via inhaler,
epithelium.14 The subsequent mucus stasis produces globus which could increase the bioavailability of NAC and its den-
and PND sensation which are the extraesophageal symp- sity in airway secretions. And we got the somewhat different
toms of LPRD. PPIs are the mainstay of the medical treat- results. Overall, PPI + NAC group did not have significantly
ment for the LPRD.1,5 However, the response of these improved response than PPI group. However, when we eval-
symptoms to PPI treatment was disappointing.15−17 In a uated only the poor early responders, some additional effect
study, the response rate was reported to be only about of NAC appeared late in the treatment.
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Yong Seok Jo, et al N-acetylcysteine for LPRD 7

The mucolytic activity of NAC could be the underlying 3. Katz PO, Castell DO. Medical therapy of supraesophageal gastro-
mechanism of its effect on the treatment of LPRD. How- esophageal reflux disease. Am J Med. 2000;108(Suppl 4a):170S–177S.
ever, considering that the effect of NAC is apparent after 4. Steward DL, Wilson KM, Kelly DH, et al. Proton pump inhibitor
therapy for chronic laryngo-pharyngitis: a randomized placebo-control
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There are some limitations in this study. Since NAC was ing future. Respiration. 1986;50(Suppl 1):26–30.
used from the beginning of the treatment in this study, it 8. Borgstrom L, Kagedal B, Paulsen O. Pharmacokinetics of N-acetylcys-
cannot be reasonable to confirm that NAC is effective to teine in man. Eur J Clin Pharmacol. 1986;31:217–222.
9. Decramer M, Rutten-van Molken M, Dekhuijzen PN, et al. Effects of
treat poor responders. Further study is needed to confirm
N-acetylcysteine on outcomes in chronic obstructive pulmonary disease
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designed such that only patients who do not improve with randomised placebo-controlled trial. Lancet. 2005;365:1552–1560.
PPI single treatment for one or two months will be enrolled 10. Aldini G, Altomare A, Baron G, et al. N-Acetylcysteine as an antioxi-
and divided into two groups according to further treatment dant and disulphide breaking agent: the reasons why. Free Radic Res.
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Acknowledgments prospective cohort study evaluating optimal dose of proton-pump
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tion of the mucolytic properties of acetylcysteine. Am Rev Respir Dis.
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