Volume 8, Issue 9 , Pages 741-742, September 2010
Benefit of Acid-Suppressive Therapy in Chronic Laryngitis: The Devil Is in the Details
Article Outline
Gastroesophageal reflux disease is increasingly associated with ear, nose, and throat symptoms.1 The surge of referrals for presumed reflux-related throat symptoms in a group of patients who are not responsive to aggressive acid suppression has resulted in frustration in the gastroenterology community. This is in no small part owing to poor diagnostic or treatment options for this group of patients. Many argue that reflux is not the cause if patients do not respond to acid suppression while others argue the role of continued nonacid or intermittent acid reflux. A variety of tests are used to diagnose potential reflux-related laryngitis, including laryngoscopy, esophagogastroduodenoscopy, and the use of ambulatory pH and impedance monitoring. However, no currently available test serves as the gold standard given its lack of sensitivity and specificity for reflux disease. Thus, we are left with empiric therapy as the gold standard to determine if patients' symptoms or laryngeal findings at laryngoscopy are reflux related. Numerous trials have assessed the role of proton pump inhibitor therapy in patients with laryngopharyngeal reflux and most have revealed no benefit to acid suppression over placebo,2 thus complicating an already complex area of care in reflux-related disorders.
In this issue of Clinical Gastroenterology and Hepatology, Lam et al3 performed a prospective, randomized, double-blind, placebo-controlled study to investigate if aggressive acid suppression is beneficial to patients suspected of having reflux-related chronic laryngitis. Patients with chronic symptoms of hoarseness, globus, persistent throat discomfort, and throat clearing with videostroboscopic evidence of laryngitis were enrolled. The laryngeal findings were assessed objectively by the reflux finding score (RFS), and patients with a score of 7 or greater were candidates for inclusion. Participants also were evaluated prerandomization by upper gastrointestinal endoscopy, esophageal manometry, and pH monitoring. Patients were randomized in a 1:1 ratio to either rabeprazole 20 mg twice daily (n = 42) or a similar-appearing placebo (n = 40) for 12 weeks. The outcome assessed included symptom change using a validated questionnaire, the Reflux Symptom Index (RSI), and blinded evaluation of change in RFS by videolaryngoscopic examinations at 6 and 12 weeks of medication and 6 weeks after cessation of medication. Lam et al3 found a significant improvement in RSI, but not laryngeal findings, in patients receiving rabeprazole instead of placebo, concluding that acid suppression can result in improvement of chronic laryngitis symptoms if a more appropriate measure such as RSI is used.
Lam et al3 should be congratulated for a well-conducted study. The strengths of the study included the study design, the use of validated outcome tools, and a relatively large sample size. The blinding of the videolaryngoscopist to patient randomization status was an important component of this study to exclude an important bias. However, the result of this study as well as a recent placebo-controlled study by Reichel et al4 suggesting benefit to acid-suppressive therapy over placebo are in contrast to the previous studies and the recent meta-analysis published in this area.2 What is the explanation for such dichotomy? Closer examination of the outcomes measured in these trials is necessary to answer this question. The similarity between the study by Lam et al3 and Reichel et al4 is the use of RSI and RFS as the measured outcome whereas most other studies did not use this outcome. As suggested by Lam et al,3 is it possible that the other trials did not use the correct outcome measure? For example, the largest randomized controlled study to date in the area of chronic laryngitis and gastroesophageal reflux disease enrolled 145 subjects and found no difference between esomeprazole 40 mg twice daily and placebo in symptom or laryngeal sign improvement.5 In this study, the authors developed a chronic posterior laryngitis index for the evaluation of laryngeal findings at laryngoscopy. This was based on the severity of the top 10 laryngeal signs agreed on by the laryngoscopist to be important in the evaluation of the larynx for patients with gastroesophageal reflux disease–suspected chronic laryngitis. The resolution and/or improvement of primary throat symptoms and the chronic posterior laryngitis index were the outcomes measured.
Let us step back for a moment and remember that the role of laryngoscopy in patients with chronic throat symptoms is not to rule in reflux but it is to rule out malignancy. Laryngeal irritation is a common finding and in fact one may conclude it is normal because laryngeal irritation is present in 80% to 90% of healthy volunteers without throat symptoms.6 Thus, the driving force behind the diagnosis of reflux in patients with throat symptoms is not based on laryngeal signs known to be reflux related but it is based on the fact that we do not know what else it might be. Closer examination of the study by Lam et al3 shows that the reported improvement on proton pump inhibitor (PPI) therapy was influenced by improvement in symptoms known to respond to acid-suppressive therapy. The only symptoms that significantly improved at 6 weeks in the study by Lam et al3 were heartburn and sensation of something sticking in throat, both symptoms of typical reflux. At 12 weeks after therapy, again the significant improvement in RSI was owing to improvement in heartburn and postnasal drip. There was no significant difference between the treatment groups among symptoms commonly present in most patients with chronic laryngitis such as hoarseness, throat clearing, excess throat mucus, cough, or shortness of breath. Similarly, in the study by Reichel et al,4 the only reason there was a significant difference among PPI versus placebo groups was the improvement in heartburn. Thus, I would argue that the reported significant improvement on PPI therapy in both studies is not for symptoms for which most patients with chronic laryngitis complain but with symptoms known to respond to PPI therapy, such as heartburn and regurgitation.
The report by Lam et al3 further supports the lack of specificity of laryngeal findings for reflux disease. In this study RFS decreased over time in both the PPI- and placebo-treated groups, and acid suppression did not improve the observed laryngeal irritation. Again, highlighting the fact that laryngeal irritation is nonspecific and does not suggest reflux as the etiology. Furthermore, lack of correlation between RSI and RFS, in this study, further questions the usefulness of these indices as outcome measures for reflux-related laryngeal irritation or symptoms. In fact, recent data question the clinical utility of these 2 indices.7, 8 In a study of 57 patients with globus, Park et al7 found low specificity (19%–50%) for RSI and RFS and concluded that the 2 measures are not valid for the diagnosis of chronic laryngitis. Recently, Musser et al8 studied 72 patients with chronic throat symptoms (hoarseness, cough, throat clearing, globus, and difficulty swallowing) and 10 controls who underwent videoendoscopy and 24-hour pH monitoring. RSI and RFS were measured in all subjects. The study found poor agreement between the measures and suggested a lack of association between these 2 indices.
How do we put all the data together and what should we do? There is no clear answer to this question. However, what we do know is that most placebo-controlled studies in this area do not suggest a significant benefit from acid-suppressive therapy in patients with chronic laryngeal signs and symptoms.2 The studies that do suggest a benefit only do so because of improvement in heartburn symptoms and not throat symptoms.3, 4 Laryngoscopic evaluation in a patient with chronic throat symptoms is indicated to exclude malignancy and cannot diagnose reflux given its low specificity for this diagnosis. Empiric therapy initially with twice-daily PPIs for 1 to 2 months is a reasonable starting point in this group of patients.1 If patients' symptoms improve then tapering to once-daily PPI followed by reducing the dose or the interval of acid suppression is highly recommended. However, lack of improvement after 1 to 2 months of PPI therapy should start a search for diagnoses other than reflux. It is unlikely that continued acid suppression will result in dramatic symptom improvement in a patient completely unresponsive to 1 to 2 months of twice-daily PPI therapy. Any suggestions that reflux still may be playing a role in patients refractory to therapy, especially if suggested by nonspecific laryngeal findings, is a less than optimal use of resources and should be discouraged. The role of pH monitoring (distal and proximal, or hypopharyngeal) is to rule out reflux disease, which is most likely (95%–99%) in this group of patients when performed on PPI therapy.1, 9, 10 Whether or not the new Restech probe (Dx-pH Measurement System; Respiratory Technology Corp, San Diego, CA) positioned in the oropharynx has the needed sensitivity to detect liquid or vapors of acidic refluxate11 in this group of patients is unexplored and worthy of future investigation. Finally, the role of impedance monitoring in identifying the role of weakly acidic or nonacid reflux in PPI-unresponsive patients awaits controlled surgical outcome studies.
Thus, the story of chronic laryngitis and reflux disease is not complete yet. There are conflicting data but closer examination of each study with respect to design and outcome measure is a must and will help us better understand the subgroup of patients in whom reflux may be causal and in those in whom it is implicated erroneously. Therefore, we must examine all evidence closely because the devil is always in the details.
References
- . Laryngitis: from the gastroenterologist's point of view. In: Vaezi MF editors. Extraesophageal reflux. San Diego: Plural Publishing, Inc; 2009;p. 37–47
- Proton pump inhibitor therapy for suspected GERD-related chronic laryngitis: a meta-analysis of randomized controlled trials. Am J Gastroenterol. 2006;101:2646–2654
- Rabeprazole is effective in treating laryngopharyngeal reflux. Clin Gastroenterol Hepatol. 2010;8:xxx–xxx
- Double-blind, placebo-controlled trial with esomeprazole for symptoms and signs associated with laryngopharyngeal reflux. Otolaryngol Head Neck Surg. 2008;139:414–420
- Treatment of chronic posterior laryngitis with esomeprazole. Laryngoscope. 2006;116:254–260
- The prevalence of hypopharynx findings associated with gastroesophageal reflux in normal volunteers. J Voice. 2002;16:564–579
- Diagnosis of laryngopharyngeal reflux among globus patients. Otolaryngol Head Neck Surg. 2006;134:81–85
- A comparison of rating scales used in the diagnosis of extraesophageal reflux. J Voice. 2010;[Epub ahead of print]
- . The role of esophageal pH monitoring in symptomatic patients on PPI therapy. Am J Gastroenterol. 2005;100:283–289
- . The role of pH monitoring in extraesophageal gastroesophageal reflux disease. Gastrointest Endosc Clin N Am. 2005;15:319–331
- A new pH catheter for laryngopharyngeal reflux: normal values. Laryngoscope. 2009;119:1639–1643
Conflicts of interest The author discloses no conflicts.
PII: S1542-3565(10)00549-5
doi:10.1016/j.cgh.2010.05.024
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Volume 8, Issue 9 , Pages 741-742, September 2010
