Objective : Globus pharyngeus (GP) is a common symptom of laryngopharyngeal reflux disease (LPRD), and proton pump inhibitor (PPI) and rikkunshito, a traditional Japanese medicine having prokinetic effect improve LPRD symptoms. In the present study, we examined the efficacy of high-dose PPI in combination with rikkunshito in patients complaining of GP. Methods : 106 patients complaining of GP without any organic endoscopic findings were enrolled. Results : Patients were first administrated with high-dose PPI alone for 4 to 8 weeks and the symptom was improved in 65 patients. Among 41 patients with PPI-refractory GP, 22 patients were administrated with high-dose PPI in combination with rikkunshito, and the symptom was improved in 14 of 22 patients 4 weeks later. The average value of a modified reflux symptom index of the responders was similar to that of non-responders. Only a few patients had positive values in reflux finding scores in both groups. Conclusion : The present findings suggest the existence of a high prevalence of LPRD in patients complaining of GP. The data also suggest that gastroesophageal dysmotility is involved in GP, in addition to excessive acid reflux. The pretherapeutic laryngopharyngeal symptoms and endoscopic findings could not predict the efficacy of the treatment for GP

Fukuda, Junya

Iwasaki, Hidetaka

Kamimura, Sei-ichiro

Kanamura, Ryo

Kondo, Eiji

Miyazaki, Katsushi

Nakano, Sei-ichi

Shizuku, Haruhiko

Takeda, Noriaki

Tokushima University Institutional Repository

INTRODUCTIONGlobus pharyngeus (GP), a constant or intermittent perceptionof a lump or a foreign body in the throat, is a common chief com-plaint in the otolaryngologist’s office and one of the symptoms oflaryngopharyngeal reflux disease (LPRD) (1). Since proton pumpinhibitors (PPIs) have been accepted as the standard treatment forLPRD (2), they are proved effective in controlling GP, and it is con-sidered that there is causal relationship between LPRD and GP. Onthe other hand, rikkunshito, a traditional Japanese medicine thatstimulates gastrointestinal movements is used as prokinetic totreat the symptoms of gastroesophageal reflux disease (GERD)(3). It was reported that adding prokinetic agents that accelerategastric emptying to PPIs improved symptoms of LPRD in the pa-tients refractory to the standard PPI therapy (4).In the present study, in order to clarify the prevalence of LPRDin patients complaining of GP, an attempt was made to examine theefficacy of the combination of rabeprazole, a PPI with rikkunshitoin controlling this sensation. We first examined the efficacy of ra-beprazole alone in patients with GP. In the patients who did notrespond to rabeprazole, the efficacy of rabeprazole in combinationwith rikkunshito was then examined. Finally we examined whetherthe initial symptoms and endoscopic findings evaluated with a modi-fied laryngopharyngeal reflux symptom index (RSI) (5, 6), and thepre-treatment laryngopharyngeal reflux finding scores (RFS) (7)could predict the efficacy of a PPI in combination with rikkunshito.PATIENTS AND METHODSPatientsThe present study includes 106 patients (41 males and 65 fe-males ; mean age : 62.514.1 years, range : 21-87 years old) com-plaining of GP. They did not have any findings as glottic/subglotticstenosis, carcinoma, leukoplakia or paradoxical vocal fold motionto examination with a video rhinolaryngoscope system equippedwith a flexible fiber optic endoscope of 3.1 -mm-diameter (VNL-100s, Pentax, Japan). This study was approved by the Committeefor Medical Ethics of Kochi National Hospital, Kochi Red CrossHospital and JA Kochi Hospital, and an informed consent was ob-tained from each patient prior to the study.Study designAll patients were first treated with rabeprazole alone at a doseof 20 mg/day for 4 weeks. Respondents continued to be treatedwith the same regimen for additional 4 weeks. Non-respondentsthen treated with a combination of rabeprazole at the same dose,and rikkunshito at a dose of 7.5 g/day for additional 4 weeks.EvaluationThe feeling of GP was evaluated by visual analogue scale (VAS)ranging from 0, no symptom to 100, presence of symptom at thefirst visit. VAS scores were then measured 2, 4 and 8 weeks afterthe treatment. The efficacy of the treatment on the symptom ofGP was determined in patients with more than 50% reduction inVAS (8).Before the treatment, the initial laryngopharyngeal symptomsand endoscopic findings were evaluated with a modified RSI andRFS. Belasfsky et al. developed RSI, a nine- item questionnaire forassessment of symptoms in patients with LPRD (5). It was modifiedto a four- item questionnaire by Oritate et al., which is usually usedclinically in Japan (6) (Table 1). RFS was also developed by BelasfskyORIGINALEfficacy of proton pump inhibitor in combination withrikkunshito in patients complaining of globus pharyngeusSei- ichi Nakano1, Hidetaka Iwasaki1, Eiji Kondo4, Katsushi Miyazaki2, Haruhiko Shizuku3, Sei- ichiro Kamimura3,Junya Fukuda2, Ryo Kanamura4 and Noriaki Takeda41Department of Otolaryngology, Kochi National Hospital, Kochi, Japan, 2Department of Otolaryngology, Kochi Red Cross Hospital, Kochi,Japan, 3Department of Otolaryngology, JA Kochi Hospital, Kochi, Japan and, 4Department of Otolaryngology, Institute of Medical Biosciences,Tokushima University Graduate School, Tokushima, JapanAbstract : Objective : Globus pharyngeus (GP) is a common symptom of laryngopharyngeal reflux disease (LPRD),and proton pump inhibitor (PPI) and rikkunshito, a traditional Japanese medicine having prokinetic effect im-prove LPRD symptoms. In the present study, we examined the efficacy of high-dose PPI in combination withrikkunshito in patients complaining of GP. Methods : 106 patients complaining of GP without any organic endo-scopic findings were enrolled. Results : Patients were first administrated with high-dose PPI alone for 4 to 8weeks and the symptomwas improved in 65 patients. Among 41 patients with PPI-refractory GP, 22 patients wereadministrated with high-dose PPI in combination with rikkunshito, and the symptom was improved in 14 of 22patients 4 weeks later. The average value of a modified reflux symptom index of the responders was similar tothat of non-responders. Only a few patients had positive values in reflux finding scores in both groups. Conclusion :The present findings suggest the existence of a high prevalence of LPRD in patients complaining of GP. The dataalso suggest that gastroesophageal dysmotility is involved in GP, in addition to excessive acid reflux. The pre-therapeutic laryngopharyngeal symptoms and endoscopic findings could not predict the efficacy of the treat-ment for GP. J. Med. Invest. 63 : 227-229, August, 2016Keywords : globus pharyngeus, laryngopharyngeal reflux disease, proton pump inhibitor, rikkunshitoReceived for publication February 19, 2016 ; accepted April 20, 2016.Address correspondence and reprint requests to Sei - ichi Nakano, M.D.,Department of Otolaryngology, Kochi National Hospital 1 -2 -25 Asakura-nishi, Kochi 780-8077, Japan and Fax : +81-88 -843-6385.The Journal of Medical Investigation Vol. 63 2016227et al. to evaluate eight endoscopic findings that are commonly ob-served in patients with LPRD (7) (Table 2). The video- images oflaryngopharynx were recorded by the video rhinolaryngoscopesystem with a flexible fiber optic endoscope of 3.1 -mm-diameter(VNL-100s, Pentax, Japan). They were then evaluated by anotherotolaryngologist blind to clinical data and independent from the ex-aminer. A total RFS score of 7 or more was considered positive.StatisticsWilcoxon signed-ranks test were used for statistical analysiswith Statcel 3 and p0.05 was considered significant.RESULTSA hundred and six patients complaining of GP were first admin-istrated with rabeprazole alone at a dose of 20 mg/day. The symp-tom of GP improved in 45 patients (42.5%) after treatment for twoweeks and in 65 patients (61.3%) for four weeks. All these patientsreceived an additional 4-week administration of rabeprazole witha lasting improvement of their symptom. The remaining 41 patientswere considered to have rabeprazole-refractory GP. Among them,22 patients were administrated rabeprazole at the same dose incombination with rikkunshito at a dose of 7.5 g/day and 19 whorefused further treatment dropped out. Four weeks after the com-bination therapy, the symptom of GP was improved in 14 of 22 pa-tients. Accordingly, a total of 79 patients (74.5%) responded to eitherPPI therapy alone or to the combination of PPI and rikkunshito(Fig.1).The initial value of the modified RSI was 5.574.07 in the 79patients who responded to either PPI therapy alone or to its combi-nation with rikkunshito. It was similar to the RSI value of 6.0010.84 in the 8 patients who were refractory to both therapies. Amongthe 79 patients who responded to either PPI therapy alone or to itscombination with rikkunshito, the initial endoscopic findings wereevaluated using RFS in 60 patients and 3 patients showed positiveRFS. Among the 8 patients who did not respond to both therapies,the initial endoscopic findings were evaluated using RFS in 6 pa-tients and a patient showed positive RFS.DISCUSSIONLPRD is caused by retrograde flow of acidic gastric contents viaesophagus into the larynx, and PPI is generally accepted as thestandard treatment for LPRD (1, 2). Moreover, it was reported thathigher dose PPI therapy for longer period was more effective inpatients with LPRD (9). Because GP is a common symptoms ofLPRD, in the present study, PPI therapy with rabeprazole at a highdose of 20 mg/day was administrated in patients complaining ofGP and 61% of them showed improvement of the symptom 4 to 8weeks later. The finding suggests that in more than half of patientscomplaining of GP, the underlying cause is LPRD. This observa-tion is indicative of a high prevalence of LPRD in patients com-plaining of GP.Prokinetic agents that stimulate anterograde movements throughthe gastrointestional tract is used to treat the symptoms of GERD(10). It was also reported that an addition of prokinetic agents toPPI therapy improved symptoms of LPRD in patients who wererefractory to the standard PPI therapy (4). Therefore, it is sug-gested that in addition to excessive acid reflux, dysmotility of theesophagogastrointestional tract is involved in the pathophysiologyof LPRD. Because rikkunshito enhances gastroesophageal clear-ance (11), it is used for the treatment of PPI-refractory patientswith both GERD and LPRD (3, 12). In the present study, 14 of 22PPI-refractory patients complaining of GP responded to the com-bination therapy of high dose rabeprazole with rikkunshito. Thisfinding suggests that gastroesophageal dysmotility is also involvedin the development of GP. But, in the remaining patients who wererefractory to both PPI alone and the combination therapy of PPIwith rikkunshito, their GP may be caused by psychiatric disease,allergies or postnasal drip.Several studies showed only a weak correlation between LPRD-like laryngopharyngeal symptoms, endoscopic findings, hypopha-ryngeal pH monitoring (13, 14). This is the reason why patientsinitially diagnosed as LPRD based on their symptoms and signs,often do not respond to PPI therapy. In fact, it was reported thatno pretherapeutic predictors of response to high dose PPI therapyTable 1 Laryngopharyngeal Reflux Symptom ScoresWithin the last month, how did the following problems affect you?0=no problem 5=severe problem1. Clearing your throat or an annoying cough 0 1 2 3 4 52. Hoarseness or a problem with your voice 0 1 2 3 4 53. Sensation of something sticking in your throat or a lump in your throatDifficulty swallowing food, liquids , or pills0 1 2 3 4 54. Heartburn, chest pain, indigestion, or stomach acid reflux 0 1 2 3 4 5Table 2 Reflux Finding Score (RFS)Reflux Finding Score (RFS)subglottic 0=absent2=presentVentricular 0=partial2=copmpleteErythema/hyperemia 2=arytenoids only4=diffuseVocal fold edema 1=mild2=moderate3=severe4=polypoidDiffuse laryngeal edema 1=mild2=moderate3=severe4=obstructingPosterior commissure hypertrophy 1=mild2=moderate3=severe4=obstructingGranuloma/granulation tissue 0=absent2=presentThick endolaryngeal mucus 0=absent2=present228 S. Nakano, et al. Medication for globus pharyngeussuch as symptoms, pH monitoring or esophageal manometry wasidentified in patients with LPRD (9). The present study shows thatin patients complaining of GP, the pretherapeutic value of a modi-fied RSI or positive RFS also did not predict the efficacy of PPI aloneor in combination with rikkunshito.In conclusion, the present study suggests a high prevalence ofLPRD in patients complaining of globus pharyngeus. Because theresponse to PPI therapy was unpredictable with neither laryngo-pharyngeal symptoms nor endoscopic findings, we propose thatpatients complaining of GP should be first treated with high dosePPI therapy for more than 4 weeks. We also propose that in caseof PPI-refractory GP, patients should be then treated with the com-bination therapy of high dose PPI with rikkunshito.CONFLICT OF INTERESTWe declare that we have no conflicts of interest.REFERENCES1. Campagnolo AM, Priston J, Thoen RH, Medeiros T, AssuncãoAR : Laryngopharyngeal reflux : diagnosis, treatment, and lat-est research. Int Arch Otorhinolaryngol 18 : 184-91, 20142. Ford CN : Evaluation and management of laryngopharyngealreflux. JAMA 294 : 1534-1540, 20053. Tominaga K, Iwakiri R, Fujimoto K, Fujiwara Y, Tanaka M,Shimoyama Y, Umegaki E, Higuchi K, Kusano M, Arakawa T ;GERD 4 Study Group : Rikkunshito improves symptoms inPPI-refractory GERD patients : a prospective, randomized,multicenter trial in Japan. J Gastroenterol 47 : 284-292, 20124. Glicksman JT, Mick PT, Fung K, Carroll TL : Prokineticagents and laryngopharyngeal reflux disease : a systematicreview. Laryngoscope 124 : 2375-2379, 20145. BelafskyPC,PostmaGN,Koufman JA : Validity and reliabilityof the reflux symptom index (RSI). J Voice 16 : 274-277, 20026. Oridate N, Takeda H, Yamamoto J, Asaka M, Mesuda Y,Nishizawa N, Mori M, Furuta Y, Fukuda S : Helicobacter py-lori Seropositive Predicts Outcomes of Acid Suppession Ther-apy for Laryngopharyngeal Reflux Symptoms. Laryngoscope116 : 547-553, 20067. Belafsky PC, Postma GN, Koufman JA : Laryngopharyngealreflux symptoms improve before changes in physical findings.Laryngoscope 111 : 979-981, 20018. Qadeer MA, Phillips CO, Lopez AR, Steward DL, Noordzij JP,Wo JM, Suurna M, Havas T, Howden CW, Vaezi MF : Protonpump inhibitor therapy for suspected GERD-related chroniclaryngitis : a meta-analysis of randomized controlled trials.Am J Gastroenterol 101 : 2646-2654, 20069. Park W, Hicks DM, Khandwala F, Richter JE, Abelson TI,Milstein C, Vaezi MF : Laryngopharyngeal reflux : prospectivecohort study evaluating optimal dose of proto-pump inhibitortherapy and pretherapy predictors of response. Laryngoscope115 : 1230-1238, 200510. Ren LH, Chen WX, Qian LJ, Li S, Gu M, Shi RH : Addition ofprokinetics to PPI therapy in gastroesophageal reflux disease :a meta-analysis. World J Gastroenterol 20 : 2412-2419, 201411. Kawahara H, Kubota A, Hasegawa T, Okuyama H, Ueno T,Ida S, Fukuzawa M : Effects of rikkunshito on the clinicalsymptoms and esophageal acid exposure in children withsymptomatic gastroesophageal reflux. Pediatr Surg Int 23 :1001-1005, 200712. Tokashiki R, Okamoto I, Funato N, Suzuki M : Rikkunshito im-proves globus sensation in patients with proton-pump inhibitor -refractory laryngopharyngeal reflux. World J Gastroenterol19 : 5118-5124, 201313. Noordzij JP, Khidr A, Desper E, Meek RB, Reibel JF, LevinePA : Correlation of pH probe-measured laryngopharyngeal re-flux with symptoms and signs of reflux laryngitis. Laryngoscope112 : 2192-2195, 200214. Merati AL, Lim HJ, Ulualp SO, Toohill RJ : Meta-analysis ofupper probe measurements in normal subjects and patientswith laryngopharyngeal reflux. Ann Otol Rhinol Laryngol 114 :177-182, 2005Fig. 1 : Disposition flow chart showing the number of responder or non-responder patients complaining of globus pharyngeus to PPI therapy withrabeprazole at a dose of 20 mg/day or to combination therapy of rabeprazole at a dose of 20 mg/day with rikkunshito at a dose of 7.5 g/day. PPI : protonpump inhibitor.The Journal of Medical Investigation Vol. 63 August 2016 229

Efficacy of proton pump inhibitor in combination with rikkunshito in patients complaining of globus pharyngeus

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Efficacy of proton pump inhibitor in combination with rikkunshito in patients complaining of globus pharyngeus

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