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The Use of Inhaled N-Acetylcysteine for Laryngopharyngeal Reflux Disease: A Randomized Controlled Trial
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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 laryngopharyngeal 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 refractory 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 followed 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 significantly 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 Laryngopharyngeal reflux disease (LPRD) is the result of reflux of gastric contents to the laryngopharyngeal region, where it changes the laryngopharyngeal mucosa.1 The ciliated respiratory epithelium in the laryngopharyngeal region is vulnerable to the gastric reflux and easily induces mucosal changes and symptoms of LPRD. Patients with LPRD often present with symptoms such as globus sensation, throat clearing, and cough, without esophageal symptoms of reflux.2 The treatment of LPRD consists of behavioral and dietary changes and medical treatment.3,4 Proton pump inhibitors (PPI) are the mainstay of the medical treatment.1,5 However, extraesophageal symptoms are generally more refractory to medical treatment than the esophageal symptoms of GERD and are sometimes a challenge to physicians. Therefore, LPRD usually requires more aggressive and prolonged treatment than gastroesophageal reflux disease (GERD). Often adjunctive medications other than Accepted for publication October 2, 2019. Declarations of interest: All authors declare that they have no conflict of interests. From the Department of Otorhinolaryngology-Head and Neck Surgery, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea. Address correspondence and reprint requests to Yoon Kyoung So, Department of 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. &&−&& 0892-1997 © 2019 The Voice Foundation. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jvoice.2019.11.017
PPIs are attempted to address these refractory extraesophageal symptoms. N-acetylcysteine (NAC) is a representative mucolytic agent that has been used for many years for the treatment of patients with a variety of respiratory conditions.6,7 Aerosolized inhaled NAC dissociates the disulfide bonds of mucin to reduce viscosity and help treat mucus stasis.8,9 In addition, it has some extent of antioxidant effect to tissue.10 There has been a trial that demonstrated the effect of taking oral NAC for the treatment of LPRD.11 The mucolytic activity of NAC, however, can be increased when inhaled. In this study, we aimed to study whether aerosolized inhaled NAC helps relieve the symptoms of LPRD and have any additive effect for the treatment of LPRD when used alongside PPIs. MATERIALS AND METHODS Ethical considerations This study was approved by the institutional ethical committee in accordance with the Helshinki declaration (IRB file No. 2016-03-013). All patients enrolled in this study gave written informed consents. Trial design This prospective, randomized controlled trial was carried out in single blind design on patients with LPRD at a
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university hospital from June 2016 to August 2018. The allocation of patients to either study or control group was blinded to the researcher who had seen and evaluated the patients. This study was registered in Clinical Research Information Service (KCT0004099). Patients We prospectively enrolled patients with LPRD from June 2016 to August 2018. Patients who visited the department of otolaryngology at Ilsan Paik Hospital, South Korea, with symptoms of LPRD were screened for enrollment. The symptoms of LPRD included globus (a sensation of a lump in the throat), throat clearing, hoarseness, postnasal drip (PND) sense, and cough. Among screened patients, patients with reflux symptom index (RSI)12 greater than 13 and reflux finding scores (RFS)13 greater than 7 were included in this study. The exclusion criteria were as follows: patients with acute or chronic sinusitis or with symptoms of upper respiratory infection at initial visit, patients with lower respiratory disease such as asthma, chronic obstructive pulmonary disease, pneumonia, or lung cancer, patients with organic lesions in the pharynx, larynx, or oral cavity such as malignancy, significant hypertrophy of palatine or lingual tonsil, or huge vallecular cyst, patients who had psychiatric history such as depression or insomnia or those taking psychiatric 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 diseases), younger than 20 years, or pregnant, patients currently taking PPI. Lastly, after a detailed explanation, those who did not agree to participate in this study were excluded.
Intervention and randomization Enrolled patients were randomly allocated to the control or study group according to a random number table. Patients in the control group were treated with oral rabeprazole 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) twice a day. In most cases, the solution was nebulized via facial mask. During the inhalation of NAC, patients were instructed to breathe comfortably and make intermittent vocalization for increase in laryngeal aerosol deposition. Twelve patients were followed up once a month for about 2 months with questionnaires (RSI) and stroboscopic examination. At every follow-up, RSI and RFS were checked by a single physician. Compliance and discomfort with medication were checked by the coordinator of this study at every visit. Patients were given a small notebook and recorded their using oral medication and/or inhaler on the check table of drug use in the notebook every day. Also, patients were required to bring the used sheets of tablets, as well as leftover tablets and ampules. Compliance was checked using these. Patients who were lost to follow-up were excluded from the study. Patients with medication compliance less than 60% were also excluded from the study at the time of final analysis. The trial protocol is summarized in the CONSORT flow diagram (Figure 1). Statistical analysis Paired t-tests were used to analyze the response after medication within each group. Independent t-tests were used to compare the response between the control and study groups.
FIGURE 1. Consort trial flow diagram.
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We used IBM SPSS Statistics, version 24 (IBM Corp. New York) for all statistical calculations. P values <0.05 were considered statistically significant. RESULTS Patients’ characteristics Among the 42 patients initially enrolled, 10 patients (eight in control group and two in study group) were lost to follow-up and two other patients (in study group) were excluded from the analysis due to low compliance to medication (less than 60%). Finally, 30 patients were analyzed in this study and 15 patients were assigned to the control and study group, respectively (Figure 1). The age of the analyzed patients ranged from 29 to 66 years, with an average of 53 years. Of the 30 patients, 22 were male and 8 were female. The most common complaints were globus (80%) and voice change (53.3%). The mean compliance to the oral medication (rabeprazole) was 92.6% in the control group and 88.3% in the study group. The mean compliance to the inhaled NAC was 80.3% in the study group (Table 1). There was no significant difference in initial RSI and RFS before treatment between the control and study groups. The initial RSI was 21.0 § 5.5 in the control group and 19.7 § 5.6 in the study group (P = 0.551). Initial RFS was 12.9 § 3.2 in the control group and 13.5 § 2.6 in the study group (P = 0.549).
Overall response after treatment RSI and RFS showed significant improvement after treatment in both control and study groups. In the control group, the mean RSI was 21.0 at initial visit and improved to 10.7 at first follow-up (P < 0.001) and 7.6 at second follow-up (P < 0.001). In the study group, the mean RSI was 19.7 at the initial visit and improved to 11.3 at first follow-up (P < 0.001) and 4.5 at second follow-up (P < 0.001; Table 2). 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 mean RFS was 13.5 at the initial visit and improved to 10.3 at first follow-up (P = 0.001) and 6.9 at second followup (P < 0.001; Table 2). There was no significant difference in the extent of improvement between the two groups (Table 3). At first follow-up, the extent of improvement of RSI was 10.3 § 5.7 in the control group and 8.5 § 4.6 in the study group (P = 0.331). At second follow-up, the extent of improvement of RSI was 13.4 § 5.1 in the control group and 15.2 § 4.7 in the study group (P = 0.319). At first follow-up, the extent of improvement of RFS was 3.5 § 2.1 in the control group and 3.2 § 2.9 in the study group (P = 0.722). At second follow-up, the extent of improvement of RFS was 5.7 § 2.8 in the control group and 6.7 § 3.1 in the study group (P = 0.390). Also, when we examined the degree of improvement of RSI in each item, there was no difference between study group and control group (Table 4).
TABLE 1. Patients’ Characteristics Characteristic Age (yr) Gender (male/female) Chief complaint†
Accompanying symptoms†
Reflux symptom index (initial score)
Reflux finding score (initial score)
Compliance to treatment
Value 53.0 § 8.9* 22/8 Globus Voice change Cough Other (heartburn, sore throat, etc.) Dry mouth
13 (43.3 %)
Snoring Mouth breathing Overall
20 (66.7 %) 11 (36.7 %) 20.4 § 5.6*
Control group (n = 15) Study group (n = 15) P value (control vs. study) Overall
21.0 § 5.5*
Control group (n = 15) Study group (n = 15) P value (control vs. study) Control group (oral medication) Study group (oral medication) Study group (nebulizer)
24 (80.0 %) 16 (53.3 %) 9 (30.0 %) 10 (33.3 %)
19.7 § 5.6* 0.551 13.2 § 2.9* 12.9 § 3.2* 13.5 § 2.6* 0.549 92.6 % 88.3 % 80.3 %
* Values are expressed as the mean § standard deviation. † Multiple responses allowed.
The late effect of the N-acetylcysteine inhalation in good or poor early responders At first follow-up, the improvement of RSI ranged from 0 to 21, with an average of nine and a median of 9.4 in all patients. Based on these values, we divided the patients into two new groups. Patients with improvement in RSI of less than nine at the first follow-up were classified as poor early responders (n = 14). Those with an improvement of RSI nine or more at the first follow-up were classified as good early responders (n = 16). In the poor early responders, the study group (rabeprazole + NAC) showed greater late improvement than the control group (rabeprazole only; Figure 2a, c, Table 5). The RSI score of the two groups were almost similar at the initial visit (P = 0.980) and the first follow-up (P = 0.866). However, the RSI was significantly lower in study group (4.6 § 2.0) than in the control group (9.5 § 4.6) at second follow-up (P = 0.019). Also, the RFS scores of the
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TABLE 2. Improvement of RSI According to Treatment RSI*
All patients Control group Study group
Initial
1st FU
2nd FU
20.4 § 5.7 21.0 § 5.7 19.7 § 5.8
11.0 § 5.4 10.7 § 4.9 11.3 § 5.9
6.1 § 3.3 7.6 § 3.7 4.5 § 1.8
P value (Initial vs. 2nd) <0.001 <0.001 <0.001
RFS Initial
1st FU
2nd FU
13.2 § 3.0 12.9 § 3.3 13.5 § 2.7
9.8 § 2.6 9.3 § 2.7 10.3 § 2.6
7.0 § 3.4 7.1 § 3.4 6.9 § 3.5
P Value (Initial vs. 2nd) <0.001 <0.001 <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
Control group Study group P value (control vs. study)
RFS
1st FU
2nd FU
1st FU
2nd FU
10.3 § 5.7 8.5 § 4.6 0.331
13.4 § 5.1 15.2 § 4.7 0.319
3.5 § 2.1 3.2 § 2.9 0.722
5.7 § 2.8 6.7 § 3.1 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
2.1 § 1.2 1.9 § 0.7 1.5 § 1.5 1.0 § 1.4 1.1 § 1.6 1.1 § 1.2 0.7 § 1.1 2.2 § 1.5
1.5 § 1.5 2.5 § 1.0 2.4 § 1.1 1.1 § 1.6 1.5 § 1.8 0.8 § 1.3 1.3 § 1.7 2.6 § 1.1
0.287 0.100 0.054 0.902 0.529 0.553 0.318 0.410
1.9 § 2.1
1.6 § 1.3
0.682
0.7 § 1.0 1.3 § 1.0 1.6 § 1.4 0.3 § 0.5 0.4 § 0.6 0.3 § 0.5 0.1 § 0.5 1.1 § 1.0
0.8 § 1.0 1.6 § 1.1 1.6 § 1.1 0.4 § 0.7 0.7 § 0.5 0.2 § 0.4 0.0 § 0.0 1.1 § 1.0
0.716 0.493 1.000 0.083 0.109 0.679 0.334 1.000
Reflux symptom index 1. Hoarseness or a problem with voice 2. Throat clearing 3. Excess throat mucus or postnasal drip 4. Difficulty swallowing food, liquids, or pills 5. Coughing after eating or after lying down 6. Breathing difficulties or choking episodes 7. Troublesome or annoying cough 8. Sensations of something sticking in your throat or a lump in your throat 9. Heartburn, chest pain, indigestion, or stomach acid coming up Reflux finding score 1. Subglottic edema 2. Ventricular obliteration 3. Erythema/hyperemia 4. Vocal fold edema 5. Diffuse laryngeal edema 6. Posterior commissure hypertrophy 7. Granuloma/granulation tissue 8. Thick endolaryngeal mucus * Values are expressed as the mean § standard deviations. Abbreviations: FU, follow-up; RFS, reflux finding score; RSI, reflux symptom index.
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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
Poor early responders
RSI RFS
Good early responders
RSI RFS
Values are expressed as the mean § standard deviation.
Control Study Control Study Control Study Control Study
Initial
1st FU
2nd FU
19.8 § 5.1 19.8 § 6.7 12.8 § 3.1 13.3 § 3.0 21.8 § 6.2 19.7 § 5.1 12.9 § 3.6 13.9 § 2.4
14.7 § 4.2 14.1 § 6.8 10.5 § 2.7 10.0 § 2.5 8.0 §3 .3 8.0 § 2.3 8.6 § 2.6 10.7 § 2.8
9.5 § 4.6 4.6 § 2.0 9.3 § 2.9 6.9 § 3.0 6.3 § 2.6 4.4 § 1.7 5.7 § 2.9 6.9 § 4.2
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TABLE 6. Overall Improvement of RSI According to Various Accompanying Factors
Age Sex Dry mouth Snoring Mouth breathing
N
Improvement of RSI at 2nd FU†
<56yrs* ≥56yrs* Female Male Absent Present Absent Present Absent
13 17 8 22 16 13 10 20 17
14.9 § 4.4 13.9 § 5.3 17.1 § 6.2 13.3 § 4.0 12.9 § 3.8 16.2 § 5.7 14.1 § 4.9 14.4 § 5.0 13.6 § 4.4
Present
11
14.7 § 4.1
P Value 0.600 0.053 0.075 0.877 0.414
* Median age of enrolled patients was 56 years. † Mean § standard deviation. Abbreviations: FU, follow-up; RSI, reflux symptom index.
two groups were similar at the initial visit (P = 0.805) and first follow-up (P = 0.725). The 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). In good early responders, the control and study groups showed no significant differences at any follow-up (Figure 2b, d, Table 5). In good early responders, the RSI graphs of the control and study groups almost overlap, and there was no significant difference between the RSI scores of the two groups at the initial visit (P = 0.490), the first follow-up (P = 1.000), or the second follow-up (P = 0.117). Also, there was no significant difference between the RFS of the two groups at the initial visit (P = 0.553), the first follow-up (P = 0.131), or the second follow-up (P = 0.515).
The improvement of RSI and various factors Patient age, gender, and accompanying symptoms such as dry mouth had no significant influence on the improvement of RSI (Table 6). RSI tended to improve to a greater extent in female patients than in male patients, although there was no statistically significant difference (P = 0.053). Also, the improvement of RSI was rather greater in patients with dry mouth than in those without it, which also did not reach to a statistical significance (P = 0.075) DISCUSSIONS Reflux of gastric contents damages the laryngeal ciliated epithelium.14 The subsequent mucus stasis produces globus and PND sensation which are the extraesophageal symptoms of LPRD. PPIs are the mainstay of the medical treatment for the LPRD.1,5 However, the response of these symptoms to PPI treatment was disappointing.15−17 In a study, the response rate was reported to be only about
50 %.16 A meta-analysis showed no significant symptom improvement with PPI treatment compared with placebo.18 Treatment difficulties mainly related to the vulnerability of laryngeal mucosa, and LPRD generally require more aggressive and prolonged treatment than gastro-esophageal reflux disease (GERD).19 In this context, several adjunctive medications, including prokinetics, have been used and investigated for their efficacy. However, randomized controlled trials on those adjunctive medications are still lacking. For several decades, NAC has been used as a mucolytic agent to treat a variety of respiratory diseases.20 NAC breaks disulfide bonds in the high-molecular-weight glycoproteins of mucus, which decreases its viscosity and makes it easier to transport along the airway.21 This study evaluated the efficacy of NAC as an adjunctive medication for LPRD. When evaluating the overall improvement of RSI and RFS, inhaled NAC did not show any additional effect on LPRD in this study (Tables 2 and 3). When we compared the degrees of improvement of the RSI and RFS individual items in the two groups, we also could not find a significant difference between the two groups (Table 4). RSI 2, 3, 8, and RFS 8, which are related to the laryngeal mucus, also showed no significant differences in the extent of improvement in the two groups. RSI 2 (“clearing your throat”) and 3 (“excess throat mucus or PND”) showed slightly better improvement in the study group, although the analysis did not reach statistical significance. Statistical insignificance could be due to the small size of the patient population and a further study is needed in larger patient population in order to clarify this. Interestingly, when patients with poor early response to treatment were analyzed separately, the additional therapeutic effect of NAC appeared late in the treatment (Figure 2 and Table 5). At the second follow-up, the RSI 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 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). The clinical efficacy of NAC for the treatment of chronic bronchitis and COPD has been documented in several clinical trials and meta-analyses,9,22−24 but there was only one study that evaluated the effect of NAC in LPRD.11 In that study, NAC was orally administered at a dose of 600 mg. 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 bioavailability8 and it is not found in airway secretions after oral dosing.25 In contrast, we administered NAC via inhaler, which could increase the bioavailability of NAC and its density in airway secretions. And we got the somewhat different results. Overall, PPI + NAC group did not have significantly improved response than PPI group. However, when we evaluated only the poor early responders, some additional effect of NAC appeared late in the treatment.
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The mucolytic activity of NAC could be the underlying mechanism of its effect on the treatment of LPRD. However, considering that the effect of NAC is apparent after long-term use, it is possible that this effect is related to the antioxidative activity of NAC. Further research is needed in this regard, about the mechanism that NAC improved the LPRD. It is especially important to investigate whether damaged ciliated mucosa can be recovered after NAC treatment in LPRD patients. There are some limitations in this study. Since NAC was used from the beginning of the treatment in this study, it cannot be reasonable to confirm that NAC is effective to treat poor responders. Further study is needed to confirm this additive effect of NAC. We proposed a future study designed such that only patients who do not improve with PPI single treatment for one or two months will be enrolled and divided into two groups according to further treatment (PPI + NAC vs. PPI alone). In addition, adding a placebo like inhaled saline in the control group will be helpful to rule out the effect of inhaler itself or humidification. CONCLUSION In this randomized controlled study, there were no significant differences in the overall outcome between patients treated with inhaled NAC and PPI and those with PPI alone. However, the additional therapeutic effect of NAC appeared late for patients with poor early response. Further studies are required to confirm the effect of NAC in patients with poor response to PPI and to investigate the mechanism underlying the effect of NAC. Acknowledgments This study was supported by Boryung Pharmaceutical Co., Ltd (16-018). The company had no role in the study design or interpretation of the data. The submission of this article was unrelated to any approval from the company. SUPPLEMENTARY MATERIALS Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j. jvoice.2019.11.017. REFERENCES 1. Ford CN. Evaluation and management of laryngopharyngeal reflux. JAMA. 2005;294:1534–1540. 2. Koufman J, Sataloff RT, Toohill R. Laryngopharyngeal reflux: consensus conference report. J Voice. 1996;10:215–216.
7 3. Katz PO, Castell DO. Medical therapy of supraesophageal gastroesophageal reflux disease. Am J Med. 2000;108(Suppl 4a):170S–177S. 4. Steward DL, Wilson KM, Kelly DH, et al. Proton pump inhibitor therapy for chronic laryngo-pharyngitis: a randomized placebo-control trial. Otolaryngol Head Neck Surg. 2004;131:342–350. 5. Berardi RR. A critical evaluation of proton pump inhibitors in the treatment of gastroesophageal reflux disease. Am J Manag Care. 2000;6:S491–S505. 6. Rogers DF. Mucoactive drugs for asthma and COPD: any place in therapy? Expert Opin Investig Drugs. 2002;11:15–35. 7. Ziment I. Acetylcysteine: a drug with an interesting past and a fascinating future. Respiration. 1986;50(Suppl 1):26–30. 8. Borgstrom L, Kagedal B, Paulsen O. Pharmacokinetics of N-acetylcysteine in man. Eur J Clin Pharmacol. 1986;31:217–222. 9. Decramer M, Rutten-van Molken M, Dekhuijzen PN, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. 2005;365:1552–1560. 10. Aldini G, Altomare A, Baron G, et al. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res. 2018;52:751–762. 11. Dabirmoghaddam P, Amali A, Motiee Langroudi M, et al. The effect of N-acetyl cysteine on laryngopharyngeal reflux. Acta Med Iran. 2013;51:757–764. 12. Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the reflux symptom index (RSI). J Voice. 2002;16:274–277. 13. Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the reflux finding score (RFS). Laryngoscope. 2001;111:1313–1317. 14. Hanson DG, Jiang JJ. Diagnosis and management of chronic laryngitis associated with reflux. Am J Med. 2000;108(Suppl 4a):112S–119S. 15. Napierkowski J, Wong RK. Extraesophageal manifestations of GERD. Am J Med Sci. 2003;326:285–299. 16. Frye JW, Vaezi MF. Extraesophageal GERD. Gastroenterol Clin North Am. 2008;37:845–858. ix. 17. Tsoukali E, Sifrim D. Investigation of extraesophageal gastroesophageal reflux disease. Ann Gastroenterol. 2013;26:290–295. 18. Vaezi MF, Richter JE, Stasney CR, et al. Treatment of chronic posterior laryngitis with esomeprazole. Laryngoscope. 2006;116:254–260. 19. Park W, Hicks DM, Khandwala F, 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. 20. Hurst GA, Shaw PB, LeMaistre CA. Laboratory and clinical evaluation of the mucolytic properties of acetylcysteine. Am Rev Respir Dis. 1967;96:962–970. 21. Balsamo R, Lanata L, Egan CG. Mucoactive drugs. Eur Respir Rev. 2010;19:127–133. 22. Gerrits CM, Herings RM, Leufkens HG, et al. N-acetylcysteine reduces the risk of re-hospitalisation among patients with chronic obstructive pulmonary disease. Eur Respir J. 2003;21:795–798. 23. Stey C, Steurer J, Bachmann S, et al. The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review. Eur Respir J. 2000;16:253–262. 24. Sutherland ER, Crapo JD, Bowler RP. N-acetylcysteine and exacerbations of chronic obstructive pulmonary disease. COPD. 2006;3:195–202. 25. Bridgeman MM, Marsden M, MacNee W, et al. Cysteine and glutathione concentrations in plasma and bronchoalveolar lavage fluid after treatment with N-acetylcysteine. Thorax. 1991;46:39–42.
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 laryngopharyngeal 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 refractory 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 followed 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 significantly 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 Laryngopharyngeal reflux disease (LPRD) is the result of reflux of gastric contents to the laryngopharyngeal region, where it changes the laryngopharyngeal mucosa.1 The ciliated respiratory epithelium in the laryngopharyngeal region is vulnerable to the gastric reflux and easily induces mucosal changes and symptoms of LPRD. Patients with LPRD often present with symptoms such as globus sensation, throat clearing, and cough, without esophageal symptoms of reflux.2 The treatment of LPRD consists of behavioral and dietary changes and medical treatment.3,4 Proton pump inhibitors (PPI) are the mainstay of the medical treatment.1,5 However, extraesophageal symptoms are generally more refractory to medical treatment than the esophageal symptoms of GERD and are sometimes a challenge to physicians. Therefore, LPRD usually requires more aggressive and prolonged treatment than gastroesophageal reflux disease (GERD). Often adjunctive medications other than Accepted for publication October 2, 2019. Declarations of interest: All authors declare that they have no conflict of interests. From the Department of Otorhinolaryngology-Head and Neck Surgery, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea. Address correspondence and reprint requests to Yoon Kyoung So, Department of 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. &&−&& 0892-1997 © 2019 The Voice Foundation. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jvoice.2019.11.017
PPIs are attempted to address these refractory extraesophageal symptoms. N-acetylcysteine (NAC) is a representative mucolytic agent that has been used for many years for the treatment of patients with a variety of respiratory conditions.6,7 Aerosolized inhaled NAC dissociates the disulfide bonds of mucin to reduce viscosity and help treat mucus stasis.8,9 In addition, it has some extent of antioxidant effect to tissue.10 There has been a trial that demonstrated the effect of taking oral NAC for the treatment of LPRD.11 The mucolytic activity of NAC, however, can be increased when inhaled. In this study, we aimed to study whether aerosolized inhaled NAC helps relieve the symptoms of LPRD and have any additive effect for the treatment of LPRD when used alongside PPIs. MATERIALS AND METHODS Ethical considerations This study was approved by the institutional ethical committee in accordance with the Helshinki declaration (IRB file No. 2016-03-013). All patients enrolled in this study gave written informed consents. Trial design This prospective, randomized controlled trial was carried out in single blind design on patients with LPRD at a
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university hospital from June 2016 to August 2018. The allocation of patients to either study or control group was blinded to the researcher who had seen and evaluated the patients. This study was registered in Clinical Research Information Service (KCT0004099). Patients We prospectively enrolled patients with LPRD from June 2016 to August 2018. Patients who visited the department of otolaryngology at Ilsan Paik Hospital, South Korea, with symptoms of LPRD were screened for enrollment. The symptoms of LPRD included globus (a sensation of a lump in the throat), throat clearing, hoarseness, postnasal drip (PND) sense, and cough. Among screened patients, patients with reflux symptom index (RSI)12 greater than 13 and reflux finding scores (RFS)13 greater than 7 were included in this study. The exclusion criteria were as follows: patients with acute or chronic sinusitis or with symptoms of upper respiratory infection at initial visit, patients with lower respiratory disease such as asthma, chronic obstructive pulmonary disease, pneumonia, or lung cancer, patients with organic lesions in the pharynx, larynx, or oral cavity such as malignancy, significant hypertrophy of palatine or lingual tonsil, or huge vallecular cyst, patients who had psychiatric history such as depression or insomnia or those taking psychiatric 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 diseases), younger than 20 years, or pregnant, patients currently taking PPI. Lastly, after a detailed explanation, those who did not agree to participate in this study were excluded.
Intervention and randomization Enrolled patients were randomly allocated to the control or study group according to a random number table. Patients in the control group were treated with oral rabeprazole 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) twice a day. In most cases, the solution was nebulized via facial mask. During the inhalation of NAC, patients were instructed to breathe comfortably and make intermittent vocalization for increase in laryngeal aerosol deposition. Twelve patients were followed up once a month for about 2 months with questionnaires (RSI) and stroboscopic examination. At every follow-up, RSI and RFS were checked by a single physician. Compliance and discomfort with medication were checked by the coordinator of this study at every visit. Patients were given a small notebook and recorded their using oral medication and/or inhaler on the check table of drug use in the notebook every day. Also, patients were required to bring the used sheets of tablets, as well as leftover tablets and ampules. Compliance was checked using these. Patients who were lost to follow-up were excluded from the study. Patients with medication compliance less than 60% were also excluded from the study at the time of final analysis. The trial protocol is summarized in the CONSORT flow diagram (Figure 1). Statistical analysis Paired t-tests were used to analyze the response after medication within each group. Independent t-tests were used to compare the response between the control and study groups.
FIGURE 1. Consort trial flow diagram.
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We used IBM SPSS Statistics, version 24 (IBM Corp. New York) for all statistical calculations. P values <0.05 were considered statistically significant. RESULTS Patients’ characteristics Among the 42 patients initially enrolled, 10 patients (eight in control group and two in study group) were lost to follow-up and two other patients (in study group) were excluded from the analysis due to low compliance to medication (less than 60%). Finally, 30 patients were analyzed in this study and 15 patients were assigned to the control and study group, respectively (Figure 1). The age of the analyzed patients ranged from 29 to 66 years, with an average of 53 years. Of the 30 patients, 22 were male and 8 were female. The most common complaints were globus (80%) and voice change (53.3%). The mean compliance to the oral medication (rabeprazole) was 92.6% in the control group and 88.3% in the study group. The mean compliance to the inhaled NAC was 80.3% in the study group (Table 1). There was no significant difference in initial RSI and RFS before treatment between the control and study groups. The initial RSI was 21.0 § 5.5 in the control group and 19.7 § 5.6 in the study group (P = 0.551). Initial RFS was 12.9 § 3.2 in the control group and 13.5 § 2.6 in the study group (P = 0.549).
Overall response after treatment RSI and RFS showed significant improvement after treatment in both control and study groups. In the control group, the mean RSI was 21.0 at initial visit and improved to 10.7 at first follow-up (P < 0.001) and 7.6 at second follow-up (P < 0.001). In the study group, the mean RSI was 19.7 at the initial visit and improved to 11.3 at first follow-up (P < 0.001) and 4.5 at second follow-up (P < 0.001; Table 2). 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 mean RFS was 13.5 at the initial visit and improved to 10.3 at first follow-up (P = 0.001) and 6.9 at second followup (P < 0.001; Table 2). There was no significant difference in the extent of improvement between the two groups (Table 3). At first follow-up, the extent of improvement of RSI was 10.3 § 5.7 in the control group and 8.5 § 4.6 in the study group (P = 0.331). At second follow-up, the extent of improvement of RSI was 13.4 § 5.1 in the control group and 15.2 § 4.7 in the study group (P = 0.319). At first follow-up, the extent of improvement of RFS was 3.5 § 2.1 in the control group and 3.2 § 2.9 in the study group (P = 0.722). At second follow-up, the extent of improvement of RFS was 5.7 § 2.8 in the control group and 6.7 § 3.1 in the study group (P = 0.390). Also, when we examined the degree of improvement of RSI in each item, there was no difference between study group and control group (Table 4).
TABLE 1. Patients’ Characteristics Characteristic Age (yr) Gender (male/female) Chief complaint†
Accompanying symptoms†
Reflux symptom index (initial score)
Reflux finding score (initial score)
Compliance to treatment
Value 53.0 § 8.9* 22/8 Globus Voice change Cough Other (heartburn, sore throat, etc.) Dry mouth
13 (43.3 %)
Snoring Mouth breathing Overall
20 (66.7 %) 11 (36.7 %) 20.4 § 5.6*
Control group (n = 15) Study group (n = 15) P value (control vs. study) Overall
21.0 § 5.5*
Control group (n = 15) Study group (n = 15) P value (control vs. study) Control group (oral medication) Study group (oral medication) Study group (nebulizer)
24 (80.0 %) 16 (53.3 %) 9 (30.0 %) 10 (33.3 %)
19.7 § 5.6* 0.551 13.2 § 2.9* 12.9 § 3.2* 13.5 § 2.6* 0.549 92.6 % 88.3 % 80.3 %
* Values are expressed as the mean § standard deviation. † Multiple responses allowed.
The late effect of the N-acetylcysteine inhalation in good or poor early responders At first follow-up, the improvement of RSI ranged from 0 to 21, with an average of nine and a median of 9.4 in all patients. Based on these values, we divided the patients into two new groups. Patients with improvement in RSI of less than nine at the first follow-up were classified as poor early responders (n = 14). Those with an improvement of RSI nine or more at the first follow-up were classified as good early responders (n = 16). In the poor early responders, the study group (rabeprazole + NAC) showed greater late improvement than the control group (rabeprazole only; Figure 2a, c, Table 5). The RSI score of the two groups were almost similar at the initial visit (P = 0.980) and the first follow-up (P = 0.866). However, the RSI was significantly lower in study group (4.6 § 2.0) than in the control group (9.5 § 4.6) at second follow-up (P = 0.019). Also, the RFS scores of the
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TABLE 2. Improvement of RSI According to Treatment RSI*
All patients Control group Study group
Initial
1st FU
2nd FU
20.4 § 5.7 21.0 § 5.7 19.7 § 5.8
11.0 § 5.4 10.7 § 4.9 11.3 § 5.9
6.1 § 3.3 7.6 § 3.7 4.5 § 1.8
P value (Initial vs. 2nd) <0.001 <0.001 <0.001
RFS Initial
1st FU
2nd FU
13.2 § 3.0 12.9 § 3.3 13.5 § 2.7
9.8 § 2.6 9.3 § 2.7 10.3 § 2.6
7.0 § 3.4 7.1 § 3.4 6.9 § 3.5
P Value (Initial vs. 2nd) <0.001 <0.001 <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
Control group Study group P value (control vs. study)
RFS
1st FU
2nd FU
1st FU
2nd FU
10.3 § 5.7 8.5 § 4.6 0.331
13.4 § 5.1 15.2 § 4.7 0.319
3.5 § 2.1 3.2 § 2.9 0.722
5.7 § 2.8 6.7 § 3.1 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
2.1 § 1.2 1.9 § 0.7 1.5 § 1.5 1.0 § 1.4 1.1 § 1.6 1.1 § 1.2 0.7 § 1.1 2.2 § 1.5
1.5 § 1.5 2.5 § 1.0 2.4 § 1.1 1.1 § 1.6 1.5 § 1.8 0.8 § 1.3 1.3 § 1.7 2.6 § 1.1
0.287 0.100 0.054 0.902 0.529 0.553 0.318 0.410
1.9 § 2.1
1.6 § 1.3
0.682
0.7 § 1.0 1.3 § 1.0 1.6 § 1.4 0.3 § 0.5 0.4 § 0.6 0.3 § 0.5 0.1 § 0.5 1.1 § 1.0
0.8 § 1.0 1.6 § 1.1 1.6 § 1.1 0.4 § 0.7 0.7 § 0.5 0.2 § 0.4 0.0 § 0.0 1.1 § 1.0
0.716 0.493 1.000 0.083 0.109 0.679 0.334 1.000
Reflux symptom index 1. Hoarseness or a problem with voice 2. Throat clearing 3. Excess throat mucus or postnasal drip 4. Difficulty swallowing food, liquids, or pills 5. Coughing after eating or after lying down 6. Breathing difficulties or choking episodes 7. Troublesome or annoying cough 8. Sensations of something sticking in your throat or a lump in your throat 9. Heartburn, chest pain, indigestion, or stomach acid coming up Reflux finding score 1. Subglottic edema 2. Ventricular obliteration 3. Erythema/hyperemia 4. Vocal fold edema 5. Diffuse laryngeal edema 6. Posterior commissure hypertrophy 7. Granuloma/granulation tissue 8. Thick endolaryngeal mucus * Values are expressed as the mean § standard deviations. Abbreviations: FU, follow-up; RFS, reflux finding score; RSI, reflux symptom index.
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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
Poor early responders
RSI RFS
Good early responders
RSI RFS
Values are expressed as the mean § standard deviation.
Control Study Control Study Control Study Control Study
Initial
1st FU
2nd FU
19.8 § 5.1 19.8 § 6.7 12.8 § 3.1 13.3 § 3.0 21.8 § 6.2 19.7 § 5.1 12.9 § 3.6 13.9 § 2.4
14.7 § 4.2 14.1 § 6.8 10.5 § 2.7 10.0 § 2.5 8.0 §3 .3 8.0 § 2.3 8.6 § 2.6 10.7 § 2.8
9.5 § 4.6 4.6 § 2.0 9.3 § 2.9 6.9 § 3.0 6.3 § 2.6 4.4 § 1.7 5.7 § 2.9 6.9 § 4.2
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TABLE 6. Overall Improvement of RSI According to Various Accompanying Factors
Age Sex Dry mouth Snoring Mouth breathing
N
Improvement of RSI at 2nd FU†
<56yrs* ≥56yrs* Female Male Absent Present Absent Present Absent
13 17 8 22 16 13 10 20 17
14.9 § 4.4 13.9 § 5.3 17.1 § 6.2 13.3 § 4.0 12.9 § 3.8 16.2 § 5.7 14.1 § 4.9 14.4 § 5.0 13.6 § 4.4
Present
11
14.7 § 4.1
P Value 0.600 0.053 0.075 0.877 0.414
* Median age of enrolled patients was 56 years. † Mean § standard deviation. Abbreviations: FU, follow-up; RSI, reflux symptom index.
two groups were similar at the initial visit (P = 0.805) and first follow-up (P = 0.725). The 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). In good early responders, the control and study groups showed no significant differences at any follow-up (Figure 2b, d, Table 5). In good early responders, the RSI graphs of the control and study groups almost overlap, and there was no significant difference between the RSI scores of the two groups at the initial visit (P = 0.490), the first follow-up (P = 1.000), or the second follow-up (P = 0.117). Also, there was no significant difference between the RFS of the two groups at the initial visit (P = 0.553), the first follow-up (P = 0.131), or the second follow-up (P = 0.515).
The improvement of RSI and various factors Patient age, gender, and accompanying symptoms such as dry mouth had no significant influence on the improvement of RSI (Table 6). RSI tended to improve to a greater extent in female patients than in male patients, although there was no statistically significant difference (P = 0.053). Also, the improvement of RSI was rather greater in patients with dry mouth than in those without it, which also did not reach to a statistical significance (P = 0.075) DISCUSSIONS Reflux of gastric contents damages the laryngeal ciliated epithelium.14 The subsequent mucus stasis produces globus and PND sensation which are the extraesophageal symptoms of LPRD. PPIs are the mainstay of the medical treatment for the LPRD.1,5 However, the response of these symptoms to PPI treatment was disappointing.15−17 In a study, the response rate was reported to be only about
50 %.16 A meta-analysis showed no significant symptom improvement with PPI treatment compared with placebo.18 Treatment difficulties mainly related to the vulnerability of laryngeal mucosa, and LPRD generally require more aggressive and prolonged treatment than gastro-esophageal reflux disease (GERD).19 In this context, several adjunctive medications, including prokinetics, have been used and investigated for their efficacy. However, randomized controlled trials on those adjunctive medications are still lacking. For several decades, NAC has been used as a mucolytic agent to treat a variety of respiratory diseases.20 NAC breaks disulfide bonds in the high-molecular-weight glycoproteins of mucus, which decreases its viscosity and makes it easier to transport along the airway.21 This study evaluated the efficacy of NAC as an adjunctive medication for LPRD. When evaluating the overall improvement of RSI and RFS, inhaled NAC did not show any additional effect on LPRD in this study (Tables 2 and 3). When we compared the degrees of improvement of the RSI and RFS individual items in the two groups, we also could not find a significant difference between the two groups (Table 4). RSI 2, 3, 8, and RFS 8, which are related to the laryngeal mucus, also showed no significant differences in the extent of improvement in the two groups. RSI 2 (“clearing your throat”) and 3 (“excess throat mucus or PND”) showed slightly better improvement in the study group, although the analysis did not reach statistical significance. Statistical insignificance could be due to the small size of the patient population and a further study is needed in larger patient population in order to clarify this. Interestingly, when patients with poor early response to treatment were analyzed separately, the additional therapeutic effect of NAC appeared late in the treatment (Figure 2 and Table 5). At the second follow-up, the RSI 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 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). The clinical efficacy of NAC for the treatment of chronic bronchitis and COPD has been documented in several clinical trials and meta-analyses,9,22−24 but there was only one study that evaluated the effect of NAC in LPRD.11 In that study, NAC was orally administered at a dose of 600 mg. 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 bioavailability8 and it is not found in airway secretions after oral dosing.25 In contrast, we administered NAC via inhaler, which could increase the bioavailability of NAC and its density in airway secretions. And we got the somewhat different results. Overall, PPI + NAC group did not have significantly improved response than PPI group. However, when we evaluated only the poor early responders, some additional effect of NAC appeared late in the treatment.
ARTICLE IN PRESS Yong Seok Jo, et al
N-acetylcysteine for LPRD
The mucolytic activity of NAC could be the underlying mechanism of its effect on the treatment of LPRD. However, considering that the effect of NAC is apparent after long-term use, it is possible that this effect is related to the antioxidative activity of NAC. Further research is needed in this regard, about the mechanism that NAC improved the LPRD. It is especially important to investigate whether damaged ciliated mucosa can be recovered after NAC treatment in LPRD patients. There are some limitations in this study. Since NAC was used from the beginning of the treatment in this study, it cannot be reasonable to confirm that NAC is effective to treat poor responders. Further study is needed to confirm this additive effect of NAC. We proposed a future study designed such that only patients who do not improve with PPI single treatment for one or two months will be enrolled and divided into two groups according to further treatment (PPI + NAC vs. PPI alone). In addition, adding a placebo like inhaled saline in the control group will be helpful to rule out the effect of inhaler itself or humidification. CONCLUSION In this randomized controlled study, there were no significant differences in the overall outcome between patients treated with inhaled NAC and PPI and those with PPI alone. However, the additional therapeutic effect of NAC appeared late for patients with poor early response. Further studies are required to confirm the effect of NAC in patients with poor response to PPI and to investigate the mechanism underlying the effect of NAC. Acknowledgments This study was supported by Boryung Pharmaceutical Co., Ltd (16-018). The company had no role in the study design or interpretation of the data. The submission of this article was unrelated to any approval from the company. SUPPLEMENTARY MATERIALS Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j. jvoice.2019.11.017. REFERENCES 1. Ford CN. Evaluation and management of laryngopharyngeal reflux. JAMA. 2005;294:1534–1540. 2. Koufman J, Sataloff RT, Toohill R. Laryngopharyngeal reflux: consensus conference report. J Voice. 1996;10:215–216.
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