Prokinetic agents and Laryngopharyngeal Reflux Disease: A Systematic Review Jordan T Glicksman1 MD, MPH; Paul T Mick2 MD, MPH; Kevin Fung1 MD; Thomas L Carroll3 MD 1
Department of Otolaryngology—Head and Neck Surgery, Western University, London,
Ontario, Canada; 2Division of Otolaryngology, University of British Columbia, Kelowna, British Columbia, Canada; 3Department of Otolaryngology, Tufts Medical Center, Boston, Massachusetts, USA Corresponding Author: Thomas L. Carroll, MD Director, The Center for Voice and Swallowing Tufts Medical Center, Department of Otolaryngology Assistant Professor Tufts University School of Medicine 800 Washington St. Box 850 Boston, MA 02111 Office: (617) 636-2887 Fax: (617) 636-1479 [email protected]
Key Words: Prokinetic agents, Laryngopharyngeal Reflux, Atypical Reflux, Gastroesophageal Reflux, Extraesophageal Reflux Word Count: 1545 Conflicts of Interests: None Financial Disclosures: None “This material has never been published and is not currently under evaluation in any other peer-reviewed publication” This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/lary.24738 The American Laryngological, Rhinological and Otological Society, Inc.
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Abstract Objectives: To systematically identify and evaluate prospective studies providing evidence for and against the use of prokinetic agents in the treatment of Laryngopharyngeal Reflux (LPR) disease. Data Sources: Pubmed, Embase, Biosis and Web of Science databases Review Methods: A systematic literature review was conducted to identify studies prospectively evaluating the effectiveness of prokinetic agents in the treatment of LPR. Data from eligible studies were independently extracted from each study by two authors. The primary outcome of interest was the improvement of LPR symptoms amongst study participants. Secondary outcomes included resolution of LPR physical signs and the development of side effects from therapy. Results: Amongst 724 unique articles identified four studies met inclusion criteria. These four investigations provided mixed evidence about the effectiveness of prokinetic agents in the treatment of LPR. The studies included in the review were deemed to be at high risk of bias. Three of the four investigations demonstrated a statistically significant difference in patient symptoms that favored the use of prokinetics in the management of LPR. The investigations were mixed in their report of improvement in physical examination findings amongst patients receiving and those not receiving prokinetic medical therapy. No significant adverse effects were described in any of these trials. Conclusions: Prokinetic agents may be a viable treatment option for LPR. The current body of literature is inadequate to make a recommendation for their use in this disease process. Further research should be conducted to assess the use of prokinetic medications in the management of LPR.
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Introduction: Laryngopharyngeal reflux (LPR) disease is a common condition with a negative impact on quality of life,1,2 affecting up to 10% of patients seen by otolaryngologists.3 It is defined as “the retrograde movement of gastric contents into the larynx, pharynx, and upper aerodigestive tract.”4 LPR is caused by retrograde flow of stomach contents via the esophagus into the larynx. Though it shares a similar pathophysiology to gastroesophageal reflux disease (GERD), LPR is a distinct entity, which can exist in patients with or without symptoms of GERD.5 Symptoms of LPR commonly include throat clearing, persistent cough, globus sensation and voice quality changes.6 Current treatment recommendations include lifestyle changes and antacid medications such as histamine-2 receptor antagonists (H2-antagonists) and proton pump inhibitors (PPI).7 In refractory cases surgical management with fundoplication procedures may be indicated.8,9 Promotility agents are a diverse group of drugs that promote anterograde movement through the gastrointestinal tract by a variety of mechanisms, including increasing lower esophageal sphincter pressure and enhancing peristalsis.10 They have been used with mixed results in patients with GERD.11 Given that GERD and LPR share similar underlying pathophysiology related to gastric motility it would be reasonable to expect that LPR patients could benefit from prokinetic agents. While used in the treatment of gastrointestinal motility disorders, prokinetic agents carry a risk of serious adverse events, such as extrapyramidal symptoms (e.g. metoclopramide)12 and potentially fatal cardiac arrhythmias (e.g. cisapride)13 as well as minor side effects, such as diarrhea.
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It is unclear if promotility agents provide benefit in the setting of LPR. Dosing, scheduling and patient selection protocols have not been established. A small number of randomized controlled studies (RCTs) had conflicting results. Uncontrolled retrospective studies demonstrated improved symptoms,14,15 but design limitations prevented drawing firm conclusions from the data. The purpose of this review is to systematically identify and evaluate prospective studies for evidence for and against the use of prokinetic agents in the treatment of LPR. Methods: A comprehensive systematic literature review was conducted using the Pubmed, Embase, Biosis and Web of Science databases. The search was limited to prospective studies of the treatment of LPR in human subjects. The search was comprehensive including the terms “Laryngopharyngeal Reflux,” “'Supraesophageal Gastric Reflux,” "Extraesophageal Reflux" or “Atypical Reflux” and “Treatment” or “Rand*.” Features such as MeSH terms (PubMed) and Explosion (EMBASE) were used to expand the articles available for inclusion. The searches included articles in the indices published between 1970 and the search date (February 25, 2013). No language restrictions were applied. Two authors (JTG and PTM) independently identified potentially relevant articles by reviewing the titles and abstracts of all retrieved studies. The full text of the selected studies were then analyzed to ensure that the following inclusion criteria were met: prospective study design; a patient population with a diagnosis of LPR; treatment arm including a prokinetic agent with or without the concomitant use of an antacid therapy (e.g. PPI or H2-Antagonist); presence of a comparison arm; and treatment outcomes
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available. References of the retained articles were reviewed to identify additional relevant articles that were not found with the initial search strategy. Data were independently extracted from each study by two authors and entered into a standardized database. Clinical data included treatment and control group demographic information, sample size, criteria for LPR diagnosis, intervention descriptions (e.g., doses and duration), and outcome parameters. Internal validity was assessed using the Cochrane risk of bias assessment tool for RCTs.16 The authors also assessed each study’s generalizability to other patient populations. The primary outcome of interest was metrics assessing the improvement of LPR symptoms. Secondary outcomes of interest included resolution of LPR physical signs and the development of side-effects from therapy. While we initially intended to perform a meta-analysis of the results, the low number of studies and heterogeneity in study design, patient selection criteria and study endpoints (type and timing) amongst them precluded meta-analysis. All discrepancies between authors were resolved by group discussion and consensus.
Results The initial searches yielded a total of 1277 titles (449 PubMed, 458 Embase, 90 Biosis and 280 Web of Science), among which, 724 were unique. 713 were excluded based on review of titles and abstracts, since they clearly did not meet inclusion criteria. 7 of the remaining 11 studies were excluded after full text review. The remaining 4 studies
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were included in the current systematic review (Figure 1).17-20 The characteristics of the 4 studies, including bias assessments, are described in Table 1. The included studies were comprised of 3 full-text articles and 1 conference abstract. There were 248 patients among the 4 studies. The investigations provided mixed evidence about the effectiveness of prokinetic agents in the treatment of LPR. Based on the Cochrane criteria all four studies demonstrated high-risk of bias. Since one study was published as a conference proceeding abstract, it lacked sufficient information for evaluation. The authors of this abstract were contacted to clarify methods used to address bias.17 Only one study used a placebo control to blind participants, and explained a clear method of blinding the study investigators.19 The generation of a randomization sequence and allocation concealment were concerns for all papers, as they were not clearly described. A summary of study findings is found in Table 2. All studies evaluated clinical symptoms in patients before and after treatment. Three studies used the Reflux Symptom Index (RSI)21 to characterize symptoms,18-20 whereas Bafutto et al. utilized a composite score from Likert scales.17 In addition to a patient-reported clinical symptom index, two authors also describe improvement in Reflux Finding Score (RFS) after treatment.4,18,19 Three investigations demonstrated a statistically significant difference in patient symptoms favoring the use of prokinetics,17,19,20 whereas one did not.18 Whereas Ezzat et al. demonstrated a significant difference in improvement in physical findings in favor of prokinetic use,19 Chun and Lee did not observe a significant difference in mean RFS improvement between groups.18 No significant adverse effects were described in any of the trials.
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Discussion Our systematic review identified four RCT’s that investigated the use of prokinetic agents in patients with LPR. Although three of the four studies suggested that prokinetics significantly reduced LPR symptoms, study limitations prevent drawing firm conclusions from the data. A common concern for potential bias among the investigations cited in this review was the lack of blinding in three of four papers.17,18,20 Additionally, the effectiveness of the randomization process was questionable in three of the investigations.17,19,20 Furthermore allocation concealment was not well-described in any of the papers.17-20 This raises concern for the possibility of residual confounding. In the case of one investigation,20 baseline characteristic differences and regression to the mean could account for the greater improvement in control patients when compared to the intervention group.22 Lifestyle modifications and medications such as H2-antagonists or PPI’s are the mainstay of treatment for patients with LPR. Fundoplication has been suggested, and is performed at some centers for patients with refractory LPR.8,23 This procedure is associated with significant morbidity in approximately 3% of cases.24,25 While prokinetic agents do have potential adverse effects, if effective at reducing symptoms of LPR, they may be an option for patients who do not achieve a satisfactory result with standard medical therapy. PPI’s act through irreversible blockade of H+/K+ ATPase transporters in the gastric mucosa, thereby reducing the acidity and volume of gastric secretions.26 By reducing the volume and acidity of secretions, there is less potential for esophageal and extra-
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esophageal reflux. While the larynx is vulnerable to damage from acidic refluxate, other components of refluxed material may contribute to LPR. Pepsin, a digestive enzyme secreted by chief cells in the stomach, has been isolated in the larynx of patients diagnosed with LPR.23 Animal studies suggest that the larynx is vulnerable to irritation and cell damage induced by this enzyme.27 While most active in acidic environments, pepsin activity is not completely attenuated at elevated pH levels.28 Therefore, reducing or eliminating laryngeal reflux of stomach contents is important, regardless of the pH of the refluxate. Activation or reactivation of refluxed pepsin (through subsequent acid reflux or an acidic diet) is likely the primary factor in the laryngeal and pharyngeal inflammation with acid playing a supporting role.29 Promotility agents may help accomplish this goal of reflux elimination in some patients. The prokinetic agents used in the trials we analyzed include itopride, tegaserod and domperidone. None of these medications are currently approved for sale in the United States. Although not marketable, Domperidone is approved for use for gastroesophageal reflux disease with upper GI symptoms, gastroparesis, and chronic constipation in patients who have failed conventional management through the FDA’s Expanded Access to Investigational Drugs program.30 It is available as a prescription medication in other countries, such as Canada. Metoclopramide is available in the United States. It can cause tardive dyskinesia in up to 20% of patients using it for greater than 12 weeks, and therefore prolonged use may be limited.31 Metoclopromide remains a management option for patients with GERD and underlying gastroparesis, and could be a consideration for LPR management in the United States.11
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Uniform diagnostic criteria were not described in the investigations included in our analysis. In order to adequately determine the effectiveness of an intervention on any disease process it is important to ensure the study population is actually affected by the condition of interest. The diagnosis and quantifying the severity of LPR can be a challenge, as the physical exam is subjective and reports on the significance of findings are conflicting.4 Furthermore, other disease conditions such as esophageal dysmotility present with similar symptoms (e.g. mucous, globus sensation and throat clearing). Future investigations should therefore contain clear inclusion criteria to allow for meaningful results. While the theoretical benefit of eliminating laryngeal reflux is clear, the benefit of using prokinetics to achieve this goal is less certain. Based on existing evidence from prospective RCTs, we cannot conclusively ascertain the effect of this group of medications on the clinical course of LPR. The literature examining the use of prokinetics for LPR management contains few studies, and those that exist have considerable limitations that may have introduced bias to their results. We feel that further research should focus on patients who fail treatment with antacid medications such as PPI’s as in the study designed by Baffuto et al. This methodology is clinically meaningful as the side effects of prokinetic drugs restrict their utility as a first-line treatment modality. Ultimately, the safety profile of currently available prokinetic agents may deem a study such as this useful only when comparing the prokinetic medication side effect risk profile to the risks of anti-reflux surgery. Conclusion
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Prokinetic agents may be a viable treatment option for LPR. The current body of literature is inadequate to make a conclusive recommendation for their use in this disease process. Further research should be conducted to assess the benefit and risk profile of prokinetic medication use in the management of LPR.
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Figure Legend Figure 1: Search Strategy Table 1: Study Characteristics and Assessment of Bias Table 2: Summary of Outcomes
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References 1. 2. 3. 4. 5. 6. 7.
8.
9. 10.
11.
12. 13.
14.
15.
Siupsinskiene N, Adamonis K, Toohill RJ. Quality of life in laryngopharyngeal reflux patients. The Laryngoscope. 2007;117:480-4. Cheung TK, Lam PK, Wei WI, et al. Quality of life in patients with laryngopharyngeal reflux. Digestion. 2009;79:52-7. Madani A, Sowerby L, Gregor JC, Wong E, Fung K. Detecting the other reflux disease. Journal of Family Practice. 2010;59:102-7. Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the reflux finding score (RFS). The Laryngoscope. 2001;111:1313-7. Koufman JA. Laryngopharyngeal reflux is different from classic gastroesophageal reflux disease. Ear, Nose and Throat Journal. 2002;81:7-9. Book DT, Rhee JS, Toohill RJ, Smith TL. Perspectives in laryngopharyngeal reflux: an international survey. The Laryngoscope. 2002;112:1399-406. Koufman JA, Aviv JE, Casiano RR, Shaw GY. Laryngopharyngeal reflux: position statement of the committee on speech, voice, and swallowing disorders of the American Academy of Otolaryngology-Head and Neck Surgery. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2002;127:32-5. Van Der Westhuizen L, Von SJ, Wilkerson BJ, et al. Impact of Nissen fundoplication on laryngopharyngeal reflux symptoms. American Surgeon. 2011;77:878-82. Ford CN. Evaluation and management of laryngopharyngeal reflux. JAMA : the journal of the American Medical Association. 2005;294:1534-40. Champion MC. Prokinetic therapy in gastroesophageal reflux disease. Canadian journal of gastroenterology = Journal canadien de gastroenterologie. 1997;11 Suppl B:55B-65B. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. American Journal of Gastroenterology. 2013;108:308-28. Kataria M, Traub M, Marsden C. Extrapyramidal side-effects of metoclopramide. The Lancet. 1978;2:1254-5. Wilhelms M, Rombach C, Scholz EP, Dossel O, Seemann G. Impact of amiodarone and cisapride on simulated human ventricular electrophysiology and electrocardiograms. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2012;14 Suppl 5:v90-v6. Oridate N, Takeda H, Mesuda Y, Nishizawa N, Asaka M, Fukuda S. New approach to the treatment of laryngopharyngeal reflux symptoms using rikkunshito (Japanese herbal medicine TJ-43) in patients who responded poorly to acid suppression therapy. Gastroenterology. 2008;134:A170. Ishoo E. Role of Tegaserod in treatment of laryngopharyngeal reflux. Otolaryngology - Head and Neck Surgery. 2007;137:P233-4.
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16.
17.
18.
19.
20.
21.
22. 23.
24.
25.
26. 27.
28.
29. 30.
Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. 2011; www.cochrane-handbook.org. Accessed March 15, 2013. Bafutto M, Leite NV, Rezende Filho J. Effects of Combined Therapy with Esomeprazol and Tegaserod in Patients with Extra-Esophageal GERD Not Responsive to Esomeprazol. Gastroenterology. 2009;136:A434. Chun BJ, Lee DS. The effect of itopride combined with lansoprazole in patients with laryngopharyngeal reflux disease. European archives of otorhino-laryngology : official journal of the European Federation of Oto-RhinoLaryngological Societies (EUFOS) : affiliated with the German Society for OtoRhino-Laryngology - Head and Neck Surgery. 2013. Ezzat WF, Fawaz SA, Fathey H, El Demerdash A. Virtue of adding prokinetics to proton pump inhibitors in the treatment of laryngopharyngeal reflux disease: prospective study. Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale. 2011;40:350-6. Hunchaisri N. Treatment of laryngopharyngeal reflux: a comparison between domperidone plus omeprazole and omeprazole alone. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2012;95:73-80. Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the reflux symptom index (RSI). Journal of voice : official journal of the Voice Foundation. 2002;16:274-7. James KE. Regression toward the mean in uncontrolled clinical studies. Biometrics. 1973;29:121-30. Wassenaar E, Johnston N, Merati A, et al. Pepsin detection in patients with laryngopharyngeal reflux before and after fundoplication. Surgical endoscopy. 2011;25:3870-6. Wendling MR, Melvin WS, Perry KA. Impact of transoral incisionless fundoplication (TIF) on subjective and objective GERD indices: a systematic review of the published literature. Surgical endoscopy. 2013. Bergman S, Mikami DJ, Hazey JW, Roland JC, Dettorre R, Melvin WS. Endolumenal fundoplication with EsophyX: the initial North American experience. Surg Innov. 2008;15:166-70. Yang YX, Metz DC. Safety of proton pump inhibitor exposure. Gastroenterology. 2010;139:1115-27. Bulmer DM, Ali MS, Brownlee IA, Dettmar PW, Pearson JP. Laryngeal mucosa: its susceptibility to damage by acid and pepsin. The Laryngoscope. 2010;120:777-82. Ali MS, Parikh S, Chater P, Pearson JP. Bile acids in laryngopharyngeal refluxate: will they enhance or attenuate the action of pepsin? The Laryngoscope. 2013;123:434-9. Samuels TL, Johnston N. Pepsin as a marker of extraesophageal reflux. Annals Otology, Rhinology and Laryngology. 2010 Mar;119:203-8. Food and Drug Administration. Drugs: Domperidone- How to Obtain. 2014; http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDe
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31.
velopedandApproved/ApprovalApplications/InvestigationalNewDrugINDAp plication/ucm368736.htm. Accessed April 11, 2014. Food and Drug Administration. Safety: Reglan (metoclopramide) tablets, ODT (Orally Disintegrating Tablets), and injections. 2010; http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm170934.htm. Accessed April 11, 2014.
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Search Strategy 117x91mm (72 x 72 DPI)
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Table 1: Study Characteristics and Assessment of Bias Study
Design
Prior Treatment Status No treatment within past month
Chun and Lee, 2013
RCT (U)
Hunchaisri, 2012
RCT (U)
Unspecified
Ezzat et al., 2011
RCT (B)
Unspecified
Bafutto et al., 2009
RCT (U)
Patients had failed a trial with a PPI
Comparison Itopride & Lansoprazole vs. Lansoprazole only1 Domperidone & Omeprazole vs. Omeprazole only1 Itopride & Pantoprazole vs. Pantoprazole & Placebo1 Tegaserod & Esomeprazole vs. Esomeprazole only
Risk of bias2 High High
High High
RCT= Randomized Controlled Trial; (U) = Unblinded Design; (B) = Blinded Design 1. Lifestyle modification recommended for both groups (intervention and control) 2. Risk of bias determined using the Cochrane risk of bias tool for RCTs
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Table 2: Summary of Outcomes Study
n
Mean Age
Treatment Duration
Chun and Lee, 2013
64
51.7
12 weeks
Hunchaisri, 2012
65
46.4
3 months
Ezzat et al., 2011P
87
33.5
8 weeks
Bafutto et al., 2009
32
Not Specified
30 days
Main Laryngopharyngeal Reflux Outcomes At 6 weeks: • Significant difference in mean reduction in RSI in treatment group (improvement of 12.51, SE 5.78) compared to control (8.8, SE 5.7), p0.05 At 12 weeks: • Significant difference in mean reduction in RSI in treatment group (improvement of 15.1, SE 6.4) compared to control (12.4, SE 5.7), p0.05 At 3 months: • No statistically significant difference in mean reduction in RSI in treatment group (improvement of 14.3, SE 1.3) compared to control (14.9, SE 1.1), p>0.05 At 8 weeks: • Significantly improved RSI score in treatment group (2.8, SE 0.5) compared to control group (3.7, SE 1), p
Department of Otolaryngology—Head and Neck Surgery, Western University, London,
Ontario, Canada; 2Division of Otolaryngology, University of British Columbia, Kelowna, British Columbia, Canada; 3Department of Otolaryngology, Tufts Medical Center, Boston, Massachusetts, USA Corresponding Author: Thomas L. Carroll, MD Director, The Center for Voice and Swallowing Tufts Medical Center, Department of Otolaryngology Assistant Professor Tufts University School of Medicine 800 Washington St. Box 850 Boston, MA 02111 Office: (617) 636-2887 Fax: (617) 636-1479 [email protected]
Key Words: Prokinetic agents, Laryngopharyngeal Reflux, Atypical Reflux, Gastroesophageal Reflux, Extraesophageal Reflux Word Count: 1545 Conflicts of Interests: None Financial Disclosures: None “This material has never been published and is not currently under evaluation in any other peer-reviewed publication” This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/lary.24738 The American Laryngological, Rhinological and Otological Society, Inc.
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Abstract Objectives: To systematically identify and evaluate prospective studies providing evidence for and against the use of prokinetic agents in the treatment of Laryngopharyngeal Reflux (LPR) disease. Data Sources: Pubmed, Embase, Biosis and Web of Science databases Review Methods: A systematic literature review was conducted to identify studies prospectively evaluating the effectiveness of prokinetic agents in the treatment of LPR. Data from eligible studies were independently extracted from each study by two authors. The primary outcome of interest was the improvement of LPR symptoms amongst study participants. Secondary outcomes included resolution of LPR physical signs and the development of side effects from therapy. Results: Amongst 724 unique articles identified four studies met inclusion criteria. These four investigations provided mixed evidence about the effectiveness of prokinetic agents in the treatment of LPR. The studies included in the review were deemed to be at high risk of bias. Three of the four investigations demonstrated a statistically significant difference in patient symptoms that favored the use of prokinetics in the management of LPR. The investigations were mixed in their report of improvement in physical examination findings amongst patients receiving and those not receiving prokinetic medical therapy. No significant adverse effects were described in any of these trials. Conclusions: Prokinetic agents may be a viable treatment option for LPR. The current body of literature is inadequate to make a recommendation for their use in this disease process. Further research should be conducted to assess the use of prokinetic medications in the management of LPR.
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Introduction: Laryngopharyngeal reflux (LPR) disease is a common condition with a negative impact on quality of life,1,2 affecting up to 10% of patients seen by otolaryngologists.3 It is defined as “the retrograde movement of gastric contents into the larynx, pharynx, and upper aerodigestive tract.”4 LPR is caused by retrograde flow of stomach contents via the esophagus into the larynx. Though it shares a similar pathophysiology to gastroesophageal reflux disease (GERD), LPR is a distinct entity, which can exist in patients with or without symptoms of GERD.5 Symptoms of LPR commonly include throat clearing, persistent cough, globus sensation and voice quality changes.6 Current treatment recommendations include lifestyle changes and antacid medications such as histamine-2 receptor antagonists (H2-antagonists) and proton pump inhibitors (PPI).7 In refractory cases surgical management with fundoplication procedures may be indicated.8,9 Promotility agents are a diverse group of drugs that promote anterograde movement through the gastrointestinal tract by a variety of mechanisms, including increasing lower esophageal sphincter pressure and enhancing peristalsis.10 They have been used with mixed results in patients with GERD.11 Given that GERD and LPR share similar underlying pathophysiology related to gastric motility it would be reasonable to expect that LPR patients could benefit from prokinetic agents. While used in the treatment of gastrointestinal motility disorders, prokinetic agents carry a risk of serious adverse events, such as extrapyramidal symptoms (e.g. metoclopramide)12 and potentially fatal cardiac arrhythmias (e.g. cisapride)13 as well as minor side effects, such as diarrhea.
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It is unclear if promotility agents provide benefit in the setting of LPR. Dosing, scheduling and patient selection protocols have not been established. A small number of randomized controlled studies (RCTs) had conflicting results. Uncontrolled retrospective studies demonstrated improved symptoms,14,15 but design limitations prevented drawing firm conclusions from the data. The purpose of this review is to systematically identify and evaluate prospective studies for evidence for and against the use of prokinetic agents in the treatment of LPR. Methods: A comprehensive systematic literature review was conducted using the Pubmed, Embase, Biosis and Web of Science databases. The search was limited to prospective studies of the treatment of LPR in human subjects. The search was comprehensive including the terms “Laryngopharyngeal Reflux,” “'Supraesophageal Gastric Reflux,” "Extraesophageal Reflux" or “Atypical Reflux” and “Treatment” or “Rand*.” Features such as MeSH terms (PubMed) and Explosion (EMBASE) were used to expand the articles available for inclusion. The searches included articles in the indices published between 1970 and the search date (February 25, 2013). No language restrictions were applied. Two authors (JTG and PTM) independently identified potentially relevant articles by reviewing the titles and abstracts of all retrieved studies. The full text of the selected studies were then analyzed to ensure that the following inclusion criteria were met: prospective study design; a patient population with a diagnosis of LPR; treatment arm including a prokinetic agent with or without the concomitant use of an antacid therapy (e.g. PPI or H2-Antagonist); presence of a comparison arm; and treatment outcomes
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available. References of the retained articles were reviewed to identify additional relevant articles that were not found with the initial search strategy. Data were independently extracted from each study by two authors and entered into a standardized database. Clinical data included treatment and control group demographic information, sample size, criteria for LPR diagnosis, intervention descriptions (e.g., doses and duration), and outcome parameters. Internal validity was assessed using the Cochrane risk of bias assessment tool for RCTs.16 The authors also assessed each study’s generalizability to other patient populations. The primary outcome of interest was metrics assessing the improvement of LPR symptoms. Secondary outcomes of interest included resolution of LPR physical signs and the development of side-effects from therapy. While we initially intended to perform a meta-analysis of the results, the low number of studies and heterogeneity in study design, patient selection criteria and study endpoints (type and timing) amongst them precluded meta-analysis. All discrepancies between authors were resolved by group discussion and consensus.
Results The initial searches yielded a total of 1277 titles (449 PubMed, 458 Embase, 90 Biosis and 280 Web of Science), among which, 724 were unique. 713 were excluded based on review of titles and abstracts, since they clearly did not meet inclusion criteria. 7 of the remaining 11 studies were excluded after full text review. The remaining 4 studies
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were included in the current systematic review (Figure 1).17-20 The characteristics of the 4 studies, including bias assessments, are described in Table 1. The included studies were comprised of 3 full-text articles and 1 conference abstract. There were 248 patients among the 4 studies. The investigations provided mixed evidence about the effectiveness of prokinetic agents in the treatment of LPR. Based on the Cochrane criteria all four studies demonstrated high-risk of bias. Since one study was published as a conference proceeding abstract, it lacked sufficient information for evaluation. The authors of this abstract were contacted to clarify methods used to address bias.17 Only one study used a placebo control to blind participants, and explained a clear method of blinding the study investigators.19 The generation of a randomization sequence and allocation concealment were concerns for all papers, as they were not clearly described. A summary of study findings is found in Table 2. All studies evaluated clinical symptoms in patients before and after treatment. Three studies used the Reflux Symptom Index (RSI)21 to characterize symptoms,18-20 whereas Bafutto et al. utilized a composite score from Likert scales.17 In addition to a patient-reported clinical symptom index, two authors also describe improvement in Reflux Finding Score (RFS) after treatment.4,18,19 Three investigations demonstrated a statistically significant difference in patient symptoms favoring the use of prokinetics,17,19,20 whereas one did not.18 Whereas Ezzat et al. demonstrated a significant difference in improvement in physical findings in favor of prokinetic use,19 Chun and Lee did not observe a significant difference in mean RFS improvement between groups.18 No significant adverse effects were described in any of the trials.
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Discussion Our systematic review identified four RCT’s that investigated the use of prokinetic agents in patients with LPR. Although three of the four studies suggested that prokinetics significantly reduced LPR symptoms, study limitations prevent drawing firm conclusions from the data. A common concern for potential bias among the investigations cited in this review was the lack of blinding in three of four papers.17,18,20 Additionally, the effectiveness of the randomization process was questionable in three of the investigations.17,19,20 Furthermore allocation concealment was not well-described in any of the papers.17-20 This raises concern for the possibility of residual confounding. In the case of one investigation,20 baseline characteristic differences and regression to the mean could account for the greater improvement in control patients when compared to the intervention group.22 Lifestyle modifications and medications such as H2-antagonists or PPI’s are the mainstay of treatment for patients with LPR. Fundoplication has been suggested, and is performed at some centers for patients with refractory LPR.8,23 This procedure is associated with significant morbidity in approximately 3% of cases.24,25 While prokinetic agents do have potential adverse effects, if effective at reducing symptoms of LPR, they may be an option for patients who do not achieve a satisfactory result with standard medical therapy. PPI’s act through irreversible blockade of H+/K+ ATPase transporters in the gastric mucosa, thereby reducing the acidity and volume of gastric secretions.26 By reducing the volume and acidity of secretions, there is less potential for esophageal and extra-
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esophageal reflux. While the larynx is vulnerable to damage from acidic refluxate, other components of refluxed material may contribute to LPR. Pepsin, a digestive enzyme secreted by chief cells in the stomach, has been isolated in the larynx of patients diagnosed with LPR.23 Animal studies suggest that the larynx is vulnerable to irritation and cell damage induced by this enzyme.27 While most active in acidic environments, pepsin activity is not completely attenuated at elevated pH levels.28 Therefore, reducing or eliminating laryngeal reflux of stomach contents is important, regardless of the pH of the refluxate. Activation or reactivation of refluxed pepsin (through subsequent acid reflux or an acidic diet) is likely the primary factor in the laryngeal and pharyngeal inflammation with acid playing a supporting role.29 Promotility agents may help accomplish this goal of reflux elimination in some patients. The prokinetic agents used in the trials we analyzed include itopride, tegaserod and domperidone. None of these medications are currently approved for sale in the United States. Although not marketable, Domperidone is approved for use for gastroesophageal reflux disease with upper GI symptoms, gastroparesis, and chronic constipation in patients who have failed conventional management through the FDA’s Expanded Access to Investigational Drugs program.30 It is available as a prescription medication in other countries, such as Canada. Metoclopramide is available in the United States. It can cause tardive dyskinesia in up to 20% of patients using it for greater than 12 weeks, and therefore prolonged use may be limited.31 Metoclopromide remains a management option for patients with GERD and underlying gastroparesis, and could be a consideration for LPR management in the United States.11
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Uniform diagnostic criteria were not described in the investigations included in our analysis. In order to adequately determine the effectiveness of an intervention on any disease process it is important to ensure the study population is actually affected by the condition of interest. The diagnosis and quantifying the severity of LPR can be a challenge, as the physical exam is subjective and reports on the significance of findings are conflicting.4 Furthermore, other disease conditions such as esophageal dysmotility present with similar symptoms (e.g. mucous, globus sensation and throat clearing). Future investigations should therefore contain clear inclusion criteria to allow for meaningful results. While the theoretical benefit of eliminating laryngeal reflux is clear, the benefit of using prokinetics to achieve this goal is less certain. Based on existing evidence from prospective RCTs, we cannot conclusively ascertain the effect of this group of medications on the clinical course of LPR. The literature examining the use of prokinetics for LPR management contains few studies, and those that exist have considerable limitations that may have introduced bias to their results. We feel that further research should focus on patients who fail treatment with antacid medications such as PPI’s as in the study designed by Baffuto et al. This methodology is clinically meaningful as the side effects of prokinetic drugs restrict their utility as a first-line treatment modality. Ultimately, the safety profile of currently available prokinetic agents may deem a study such as this useful only when comparing the prokinetic medication side effect risk profile to the risks of anti-reflux surgery. Conclusion
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Prokinetic agents may be a viable treatment option for LPR. The current body of literature is inadequate to make a conclusive recommendation for their use in this disease process. Further research should be conducted to assess the benefit and risk profile of prokinetic medication use in the management of LPR.
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Figure Legend Figure 1: Search Strategy Table 1: Study Characteristics and Assessment of Bias Table 2: Summary of Outcomes
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References 1. 2. 3. 4. 5. 6. 7.
8.
9. 10.
11.
12. 13.
14.
15.
Siupsinskiene N, Adamonis K, Toohill RJ. Quality of life in laryngopharyngeal reflux patients. The Laryngoscope. 2007;117:480-4. Cheung TK, Lam PK, Wei WI, et al. Quality of life in patients with laryngopharyngeal reflux. Digestion. 2009;79:52-7. Madani A, Sowerby L, Gregor JC, Wong E, Fung K. Detecting the other reflux disease. Journal of Family Practice. 2010;59:102-7. Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the reflux finding score (RFS). The Laryngoscope. 2001;111:1313-7. Koufman JA. Laryngopharyngeal reflux is different from classic gastroesophageal reflux disease. Ear, Nose and Throat Journal. 2002;81:7-9. Book DT, Rhee JS, Toohill RJ, Smith TL. Perspectives in laryngopharyngeal reflux: an international survey. The Laryngoscope. 2002;112:1399-406. Koufman JA, Aviv JE, Casiano RR, Shaw GY. Laryngopharyngeal reflux: position statement of the committee on speech, voice, and swallowing disorders of the American Academy of Otolaryngology-Head and Neck Surgery. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2002;127:32-5. Van Der Westhuizen L, Von SJ, Wilkerson BJ, et al. Impact of Nissen fundoplication on laryngopharyngeal reflux symptoms. American Surgeon. 2011;77:878-82. Ford CN. Evaluation and management of laryngopharyngeal reflux. JAMA : the journal of the American Medical Association. 2005;294:1534-40. Champion MC. Prokinetic therapy in gastroesophageal reflux disease. Canadian journal of gastroenterology = Journal canadien de gastroenterologie. 1997;11 Suppl B:55B-65B. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. American Journal of Gastroenterology. 2013;108:308-28. Kataria M, Traub M, Marsden C. Extrapyramidal side-effects of metoclopramide. The Lancet. 1978;2:1254-5. Wilhelms M, Rombach C, Scholz EP, Dossel O, Seemann G. Impact of amiodarone and cisapride on simulated human ventricular electrophysiology and electrocardiograms. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2012;14 Suppl 5:v90-v6. Oridate N, Takeda H, Mesuda Y, Nishizawa N, Asaka M, Fukuda S. New approach to the treatment of laryngopharyngeal reflux symptoms using rikkunshito (Japanese herbal medicine TJ-43) in patients who responded poorly to acid suppression therapy. Gastroenterology. 2008;134:A170. Ishoo E. Role of Tegaserod in treatment of laryngopharyngeal reflux. Otolaryngology - Head and Neck Surgery. 2007;137:P233-4.
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Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. 2011; www.cochrane-handbook.org. Accessed March 15, 2013. Bafutto M, Leite NV, Rezende Filho J. Effects of Combined Therapy with Esomeprazol and Tegaserod in Patients with Extra-Esophageal GERD Not Responsive to Esomeprazol. Gastroenterology. 2009;136:A434. Chun BJ, Lee DS. The effect of itopride combined with lansoprazole in patients with laryngopharyngeal reflux disease. European archives of otorhino-laryngology : official journal of the European Federation of Oto-RhinoLaryngological Societies (EUFOS) : affiliated with the German Society for OtoRhino-Laryngology - Head and Neck Surgery. 2013. Ezzat WF, Fawaz SA, Fathey H, El Demerdash A. Virtue of adding prokinetics to proton pump inhibitors in the treatment of laryngopharyngeal reflux disease: prospective study. Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale. 2011;40:350-6. Hunchaisri N. Treatment of laryngopharyngeal reflux: a comparison between domperidone plus omeprazole and omeprazole alone. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2012;95:73-80. Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the reflux symptom index (RSI). Journal of voice : official journal of the Voice Foundation. 2002;16:274-7. James KE. Regression toward the mean in uncontrolled clinical studies. Biometrics. 1973;29:121-30. Wassenaar E, Johnston N, Merati A, et al. Pepsin detection in patients with laryngopharyngeal reflux before and after fundoplication. Surgical endoscopy. 2011;25:3870-6. Wendling MR, Melvin WS, Perry KA. Impact of transoral incisionless fundoplication (TIF) on subjective and objective GERD indices: a systematic review of the published literature. Surgical endoscopy. 2013. Bergman S, Mikami DJ, Hazey JW, Roland JC, Dettorre R, Melvin WS. Endolumenal fundoplication with EsophyX: the initial North American experience. Surg Innov. 2008;15:166-70. Yang YX, Metz DC. Safety of proton pump inhibitor exposure. Gastroenterology. 2010;139:1115-27. Bulmer DM, Ali MS, Brownlee IA, Dettmar PW, Pearson JP. Laryngeal mucosa: its susceptibility to damage by acid and pepsin. The Laryngoscope. 2010;120:777-82. Ali MS, Parikh S, Chater P, Pearson JP. Bile acids in laryngopharyngeal refluxate: will they enhance or attenuate the action of pepsin? The Laryngoscope. 2013;123:434-9. Samuels TL, Johnston N. Pepsin as a marker of extraesophageal reflux. Annals Otology, Rhinology and Laryngology. 2010 Mar;119:203-8. Food and Drug Administration. Drugs: Domperidone- How to Obtain. 2014; http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDe
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31.
velopedandApproved/ApprovalApplications/InvestigationalNewDrugINDAp plication/ucm368736.htm. Accessed April 11, 2014. Food and Drug Administration. Safety: Reglan (metoclopramide) tablets, ODT (Orally Disintegrating Tablets), and injections. 2010; http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm170934.htm. Accessed April 11, 2014.
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Search Strategy 117x91mm (72 x 72 DPI)
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Table 1: Study Characteristics and Assessment of Bias Study
Design
Prior Treatment Status No treatment within past month
Chun and Lee, 2013
RCT (U)
Hunchaisri, 2012
RCT (U)
Unspecified
Ezzat et al., 2011
RCT (B)
Unspecified
Bafutto et al., 2009
RCT (U)
Patients had failed a trial with a PPI
Comparison Itopride & Lansoprazole vs. Lansoprazole only1 Domperidone & Omeprazole vs. Omeprazole only1 Itopride & Pantoprazole vs. Pantoprazole & Placebo1 Tegaserod & Esomeprazole vs. Esomeprazole only
Risk of bias2 High High
High High
RCT= Randomized Controlled Trial; (U) = Unblinded Design; (B) = Blinded Design 1. Lifestyle modification recommended for both groups (intervention and control) 2. Risk of bias determined using the Cochrane risk of bias tool for RCTs
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Table 2: Summary of Outcomes Study
n
Mean Age
Treatment Duration
Chun and Lee, 2013
64
51.7
12 weeks
Hunchaisri, 2012
65
46.4
3 months
Ezzat et al., 2011P
87
33.5
8 weeks
Bafutto et al., 2009
32
Not Specified
30 days
Main Laryngopharyngeal Reflux Outcomes At 6 weeks: • Significant difference in mean reduction in RSI in treatment group (improvement of 12.51, SE 5.78) compared to control (8.8, SE 5.7), p0.05 At 12 weeks: • Significant difference in mean reduction in RSI in treatment group (improvement of 15.1, SE 6.4) compared to control (12.4, SE 5.7), p0.05 At 3 months: • No statistically significant difference in mean reduction in RSI in treatment group (improvement of 14.3, SE 1.3) compared to control (14.9, SE 1.1), p>0.05 At 8 weeks: • Significantly improved RSI score in treatment group (2.8, SE 0.5) compared to control group (3.7, SE 1), p
