Research in Vestibular Science Vol. 15, No. 2, June 2016 Original Article pissn 2092-8882, eissn 2093-5501 메니에르병환자의치료에서 Isosorbide의유용성평가를위한다기관무작위연구 1 삼성서울병원이비인후과, 2 연세대학교의과대학세브란스병원이비인후과, 3 인하대병원이비인후과, 4 서울아산병원이비인후과, 5 고려대학교구로병원이비인후과, 6 분당서울대학교병원이비인후과, 7 순천향대학교부천병원이비인후과, 8 부산대학교병원이비인후과, 9 가천대길병원이비인후과 박현우 1, 정원호 1, 김성헌 2, 김규성 3, 정종우 4, 채성원 5, 구자원 6, 김보경 7, 고의경 8, 한규철 9 Multicenter Randomized Study on the Efficacy of Isosorbide in Patients with Mèniére s Disease Hyun-Woo Park 1, Won-Ho Chung 1, Sung-Huhn Kim 2, Kyu-Sung Kim 3, Jong-Woo Chung 4, Sung-Won Chae 5, Ja-Won Koo 6, Bo-Gyung Kim 7, Eui-Kyung Goh 8, Gyu-Cheol Han 9 1 Department of Otorhinolaryngology, Sungkyunkwan University, Samsung Seoul Hospital, Seoul; 2 Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul; 3 Department of Otorhinolaryngology, Inha University Hospital, Incheon; 4 Department of Otolaryngology, Asan Medical center, Seoul; 5 Department of Otorhinolaryngology, Korea University Guro Hospital, Seoul; 6 Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Bungdang; 7 Department of Otorhinolaryngology-Head and Neck Surgery, Soonchunhyang University College of Medicine, Bucheon; 8 Department of Otorhinolaryngology, Pusan National University Hospital, Busan; 9 Departments of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Gachon University of Medicine and Science, Incheon, Korea Received Mar 18, 2016 Revised May 21, 2016 Accepted May 26, 2016 Corresponding Author: Won-Ho Chung Department of Otorhinolaryngology-Head and Neck Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-3571 Fax: +82-2-3410-3879 E-mail: whchung@skku.edu Copyright c 2016 by The Korean Balance Society. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective: Mèniére s disease is one of the most common causes of episodic vestibular syndrome that shows symptom complexes of recurrent vertigo, hearing loss, tinnitus and ear fullness. Isosorbide (Isobide) is a osmotic diuretics which has been used for Meniere s disease to reduce the endolymphatic pressure. The purpose of this study was to evaluate the efficacy of isosorbide in the treatment of Mèniére s disease by comparing the combined therapy of isosorbide and betahistine (Meniace) to betahistine only. Methods: Among 220 patients enrolled with Mèniére s disease from 9 centers, 187 patients completed this clinical study. Patients were randomly subjected either to betahistine alone therapy at dose of 6 mg three times a day (n=97) or to combined therapy with isosorbide (dose of 30 ml three times a day) and betahistine (n=90) for 12 weeks. Two groups were compared at 4 and 12 weeks after treatment on frequency of vertigo, hearing level (pure tone audiometry, speech audiometry), electocochleography (ECoG), tinnitus (Tinnitus Handicap Inventory, THI) and quality of life (Korean functional level scale, Korean dizziness handicap inventory). Results: During first 4 weeks after treatment, the frequency of vertigo was not reduced in either betahistine alone therapy group or combined therapy group. However, between 8 and 12 weeks, the frequency of vertigo was significantly reduced in either group, and in the combined group frequency of vertigo was more significantly reduced than in the betahistine alone therapy group (p=0.041). The hearing level, ECoG, tinnitus and quality of life was not significantly different between two groups.
Conclusion: Isosorbide and betahistine combined therapy were more effective for vertigo control than betahistine alone therapy. Isosorbide is an effective diuretic in vertigo control in definite Mèniére's disease Res Vestib Sci 2016;15(2):44-50 Keywords: Meniere disease; Vertigo; Betahistine; Isosorbide 서론메니에르병은구역, 구토를동반한어지럼발작과난청, 이충만감의증상이반복되는질환이며원인은대부분알수없지만해부학적이상, 바이러스감염, 자가면역질환, 알레르기, 외상등이관여하고있을것으로추정하고있다. 1 메니에르병환자의내이의병리조직학적소견으로내림프수종이알려져있으나, 최근에는내림프수종이메니에르병의병인이라기보다는하나의부수적현상 (epiphenomenon) 으로보는견해가높다. 그러나메니에르병의치료에있어서는아직메니에르병의원인으로내림프수종을생각하고, 이에근거한치료방법이지속적으로사용되고있다. 2-5 메니에르병의치료목적은급성기에는어지럼발작시어지럼증상을완화시키는데있고, 만성기에는어지럼발작의재발을억제하고내이기능장애의진행을억제하여난청의악화를방지하는데있다. 메니에르병의만성기치료로는생활습관의변화, 약물치료와고실내약물주입술, 수술적치료로나눌수있다. 메니에르병에서저염식섭취와스트레스줄이기등과같은생활습관의변화와약물치료를통해서 70% 의어지럼발생을줄일수있다. 대표적인약물로는이뇨제와혈류개선제가있다. 6 이뇨제는메니에르병의치료에오래전부터사용되어왔으며, 메니에르병의병인이내림프수종이라는가정하에내이에서의내림프의압력을줄임으로써어지럼의발작을줄인다고하였다. 흔히사용되는이뇨제로는 hydrochlorothiazide 및 amiloride, furosemide 등이사용되고있다. 최근에는삼투성이뇨제로알려진 isosorbide가메니에르병에사용되고있는데 isosorbide 는신세뇨관의삼투압을높여수분의재흡수를억제해이뇨작용을하는약물로녹내장이나두개내압상승에사용되는약물이다. 메니에르병에서도이러한완만한삼투압 성이뇨작용을통하여내림프수종을경감시키며, 메니에르병의수반증상인어지럼, 이명, 난청에대해개선효과를나타낸다고한다. 7-9 또한혈류개선제로흔히사용되고있는약물인 betahistine은약한 H1 흥분작용및 H3 길항작용을가지고있어어지럼발작때과도하게분비되는히스타민을억제하고, 내이의모세혈관을이완시켜혈관조의혈류를증가시키거나혈관투과성을변동시켜메니에르병에서전정신경계의기능회복및어지럼발작치료에효과적인것으로알려져있다. 7,8 본연구에서는메니에르병의치료에있어서삼투성이뇨제인 isosorbide의효과를보고자하였다. 이를위하여메니에르병의치료에효과가있다는 betahistine의단독요법을시행한군과 betahistine과 isosorbide의병용요법을시행한군을무작위비교연구를통해서메니에르병의치료제로서 isosorbide의효용성과안정성을확인하고자하였다. 대상및방법본연구는 9개의기관이함께참여하여무작위배정의임상시험으로진행하였다. 대상자는미국이비인후-두경부외과학회 (American Academy of Otolaryngology-Head and Neck Surgery) 의진단기준 (1995) 에의해명확한 (definite) 메니에르병으로진단된환자로서최근 3개월간 2회이상의 20분이상지속되는회전성현훈의병력이있고, 청력검사로기록된난청이 1회이상존재하며, 이명이나이충만감이있는환자를대상으로하였다. 연령은 20세에서 80세미만으로과거력상메니에르병의치료로서최근 6개월이내에고실내주입술을시행받거나수술적치료를시행한대상이나최근 3개월내에동일의약품을투여한경험이있는대상은제외하였다. 총 9개의임상시험실시기관에서 231명의대상자 45
Res Vestib Sci Vol. 15, No. 2, Jun. 2016 가임상시험에참여할것을서면동의한후스크리닝검사를받았으며이중 11명의대상자가스크리닝탈락하였고, 최종적으로 betahistine ( 메네스정, Meniace, Dong Koo Pharmaceutical, Seoul, Korea) 을단독투여한군 110명과 betahistine과 isosorbide ( 이소바이드액, Isobide, Kowa Pharmaceutical, Nagoya, Japan) 를병용투여한군 110명등총 220명의환자가본연구에참여하였다. 이중 33명 (betahistine과 isosorbide를병용투여한군 20명, betahistine 단독군 13명 ) 이임상시험을중단하여 187명의대상자가계획된임상시험을완료하였다 (Figure 1). 특히어지럼의발작의빈도를확인하는데는어지럼의발작의빈도를지난 3개월간 4 24회의횟수를보이는군을이용하였다. 대상자의평균연령은 52.39±10.99세였고, 성별은남성이 91명 (45.0%), 여성이 111명 (55.0%) 이었다. 병용투여군의대상자는초기용량으로 isosorbide를 1일 90 ml를식사후 3회로나누어경구투여하고, betahistine은 1회 6 mg을 1일 3회투여하였다. 시험자의판단에따라이상반응등의사유로용량변경이필요한경우 isosorbide의용량은감량이가능하도록하였다. Betahistine 단독투여군의대상자는 betahistine을 1회 6 mg을 1일 3회투여하였다. 대상자는정기적으로방문하여정해진절차에따라해당검사를받았고, 유효성평가는어지럼발생빈도의변화와순음청력역치와여음명료도의변화, 전기와우도검사 (electocochleography, ECoG), 이명의변화및삶의질의변화를평가하였다. 어지럼발생빈도의변화는약물투여기간에따른차이를보기위하여약물투여시점이전 4주간의어지럼발작횟수대비약물투여직후 4주동안과 8주간약물투여후 4주간의어지럼발작횟수의차이를비교하였다. 청력의변화는순음청력역치 (0.5, 1, 2, 3 khz 4가지주파수의평균청력역치 ) 와어음명료도의변화를이용하였고, 전기와우도검사에서는 summating potential:action potential 비율의변화를, 이명은 Tinnitus Handicap Inventory (THI) 의변화를약물투여전과약물투여후 12주때의시점에서비교하였다. 삶의질은 Korean Functional Level Scale (KFLS) 과 Korean Dizziness Handicap Inventory (KDHI) 의점수를약물투여전대비투여후 2주, 4주, 12주때의시점에서비교하였다 (Figure 2). 두치료군간의차이를검정하기위해기저값과임상시험실시기관을공변량으로하고기저대비 12주시점에서 Figure 1. Distribution of subjects. Figure 2. Study design. PTA/SA, pure tone audiometry/speech audiometry; ECoG, electocochleography; THI, Tinnitus Handicap Inventory; KFLS, Korean functional level scale; KDHI, Korean Dizziness Handicap Inventory. 46
박현우외 9 인. 메니에르병환자의치료에서 Isosorbide 의유용성 의차이를반응변수로한공분산분석을실시하였다. 군내검정은 paired t-test 또는 Wilcoxon singed rank test를실시하였다. 결과메니에르병의환자에서 isosorbide와 betahistine 병용요법군과 betahistine 단독요법군과의치료효과를비교하였을때의결과는다음과같다 (Table 1). 약물을투여한후첫 4주 Table 1. Summary of effectiveness evaluation variable Betahistine+Isosorbide Betahistine p-value a) Change in number of vertigo during first 4 weeks of drug administration 1.38 (1.54) 0.79 (1.48) 0.7618 Change in number of vertigo between 8 to 12 weeks 3.84 (1.00) 1.40 (0.99) 0.0408 Change in pure tone audiometry 2.18 (0.89) 0.75 (0.88) 0.2148 Change in speech reception threshold 1.98 (1.04) 1.04 (1.05) 0.4906 Change in speed discrimination score 0.70 (1.63) 0.66 (1.59) 0.5218 Change in electrocochleography 0.00 (0.01) 0.02 (0.01) 0.1933 Change in Tinnitus Handicap Inventory 10.65 (2.47) 12.54 (2.47) 0.5614 Korean functional level scale 2 wk 0.46 (0.11) 0.77 (0.11) 0.0375 4 wk 0.49 (0.11) 0.81 (0.11) 0.0234 12 wk 0.63 (0.11) 0.763 (0.11) 0.5237 Korean dizziness headicap inventory 2 wk 6.34 (2.05) 10.81 (2.00) 0.0955 4 wk 10.06 (2.10) 14.23 (2.06) 0.1290 12 wk 11.58 (2.46) 14.52 (2.45) 0.3629 a) Difference between the treatment groups, significance at p<0.05. Figure 3. Change in number of vertigo during first 4 weeks of drug administration. Vertigo attack increased after drug administration for 4 weeks in both group (p-value=0.7618). Black, last 4 weeks at start; Grey, last 4 weeks at week 12 (full analysis set); LS, leastsquare; ANCOVA, analysis of covariance. 47
Res Vestib Sci Vol. 15, No. 2, Jun. 2016 동안의어지럼발작의빈도는두군모두에서증가되면서유의한치료효과를보이지않았다 (p-value=0.762) (Figure 3). 그러나 8주간약을복용한후에는병용요법군과단독요법군에서유의하게어지럼의발작횟수가줄어들었다. 특히병용요법군에서의어지럼의발작횟수가단독요법군보다유의하게줄어들어 isosorbide와 betahistine 병용요법시메니에르병의어지럼발작의예방에더욱유의한효과가있음을확인할수있었다 (p-value=0.041) (Figure 4). 순음청력검사와어음명료도를통한청력평가결과, betahistine 단독투여군의청력역치가변화를보이지못하였음에반해 betahistine과 isosorbide를병용투여군에서는순음청력검사의역치가 2.05 db 감소, 어음청력검사에서 1.92 db 감소하는등청력의개선효과를보였으나, 두군간에유의한차이를보이지는못하였다 (Table 1). 전기와우도검사에서도두군간의차이를보이지않았다. THI와 KDHI 을이용한평가에서는두군모두이명증상과삶의질이호전되는것을확인하였으나, 통계적인유의성은보이지않았으며 KFLS에서도두군모두삶의질이개선된것으로나타났지만 2주와 4주시점에는 betahistine단독군에서 betahistine과 isosorbide를병용투여군보다유의하게더큰감소를보였다 (Table 1). 임상시험중발생한이상약물반응은병용요법군에서는 8명 (7.4%), 단독요법군에서는 7명 (6.5%) 발생하였으며모두경증또는중등증이었고약물과관련된중증이상반응은발생하지않았다. 대부분두통이나소화불량, 설사, 오심, 발한, 불면증등이발생하였다. 고찰메니에르병의치료에서 isosorbide의효과는오래전부터보고되어왔는데 1993년 Kanda 등 10 의연구에서 isosorbide 를복용한메니에르병환자의약 80% 에서전정증상의호전을보고한바가있으며 1995년 Nozawa 등 11 은 isosorbide 를장기적으로복용했을때큰부작용없이메니에르병의증상이호전되었다고보고하였다. 본임상시험에서는메니에르병치료제로서사용되고있는 betahistine과 isosorbide 의서로다른작용기전에착안하여, 이두약물을병용하는경우 betahistine 단독요법에비해더욱의미있는증상의 Figure 4. Change in number of vertigo between the 4 weeks before start and the last 4 weeks. Vertigo attack decreased significantly during last 4 weeks in combined group (p-value=0.0408). Black, last 4 weeks at start; Grey, last 4 weeks at week 12 (full analysis set); LS, least square; ANCOVA, analysis of covariance. 48
박현우외 9 인. 메니에르병환자의치료에서 Isosorbide 의유용성 호전이있을것으로기대하고시험을시행하였다. 그리고그결과메니에르병의대표적증상인어지럼발작의발생횟수는모든군에서 12주시점에감소하여기대하였던것처럼현재시행되고있는약물치료법이유효한치료법임을확인할수있었다. 특히 isosorbide를 betahistine과병용투여한군에서 betahistine을단독투여한군에비해어지럼의발생의빈도가더욱유의하게감소하였음을보아 isosorbide가 betahistine과다른기전을통해서메니에르병의치료에있어서의미있는효과가있음을확인할수있었다. 또한청력개선에있어서도 betahistine과 isosorbide 병용군의순음청력검사와어음청력검사에서유의하지는않았지만기저치와비교하여청력역치가모두호전됨을확인할수있었다. 임상시험중발생한이상약물반응은주로어지럼, 비인두염, 구역, 구토, 두통, 식욕저하등모두경증또는중등증이었고약물과관련된중증이상반응은발생하지않았다. 따라서메니에르병환자에게 betahistine과 isosorbide의병용투여는 betahistine 단독투여에비해환자에게큰위험증가없이안전하게사용할수있는치료방법으로생각된다. 본임상시험에서치료시작직후 4주간의어지럼발작횟수는오히려증가하였으며 8주간약물투여후 4주간의어지럼발작횟수를확인했을때치료전 4주간과비교하여유의하게감소한것을확인할수있었다. 이는약물복용직후효과가충분히나타나지않으며최소 4주이상의약물을투여하여야효과가나타날수있음을시사한다. 약물투여후 8주에서 12주사이의어지럼빈도의차이를보기위하여치료전 3개월간의어지럼발작횟수를 4회이상 24회이하로제한하였다. 그이유는최소월 1회의어지럼발작과최대주 2회의어지럼발작을호소하였을때진성어지럼의가능성이높고데이터의신뢰도가높다고판단하였기때문이었다. 본임상실험에는몇가지한계점이있다. 첫째, isosorbide 와 betahistine의병용요법과 betahistine의단독요법을비교하였기때문에 isosorbide의단독효과를충분히입증할수가없었다. 윤리적인문제와위약제조에어려움이있어서위약을이용한이중맹검법을실시하지못하였다. 둘째, 약물투여후투여기간에따른약효를보기위하여단기간과장기간의약효를보지못하였고, 약물투여직후 4주와최대 12 주까지의효과만을관찰하였으므로, 약물투여기간에따른효과를입증할수가없었다. 본임상시험설계에한계가있었지만, betahistine과 isosorbide를병용했을때 betahistine을단독으로투여했을때보다더욱효과적으로어지럼발작을줄일수있었고, 청력의호전을보였다. 그리고, 약물에따른부작용도병용요법과단독요법을하였을때양군간의차이를보이지않으므로 isosorbide는심각한부작용없이안전하게메니에르병의치료제로서사용할수있을것으로생각된다. 결 메니에르병환자의치료에있어서 isosorbide와 betahistine 의병합요법은 betahistine의단독요법에비해어지럼의발생빈도를줄이는데있어서유의하게효과적이었다. Isosorbide 는심각한부작용없이안전하게사용할수있는약제이며, 메니에르병의어지럼발작을줄이는데효과적으로사용할수있을것으로생각한다. 론 중심단어 : 메니에르병, Betahistine, Isosorbide CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported. REFERENCES 1. Kiang NY. An auditory physiologist's view of Meniere s syndrome. In: Nadol JB Jr, editor. Second International Symposium on Ménière s disease. Amsterdam: Kugler & Ghedin; 1989. p.13-24. 2. Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Meniere s disease. American Academy of Otolaryngology-Head and Neck Foundation, Inc. Otolaryngol Head Neck Surg 1995;113:181-5. 3. Vasama JP, Linthicum FH Jr. Meniere s disease and endolymphatic hydrops without Meniere s symptoms: temporal bone histopathology. Acta Otolaryngol 1999;119:297-301. 4. Torok N. A review of neuro-otology: pathogenesis of neuro-otological diseases. Am J Med Sci 1963;246:496-513. 5. Paparella MM. Pathogenesis of Meniere s disease and Meniere s syndrome. Acta Otolaryngol Suppl 1984;406:10-25. 6. Kim K. Management of Meniere s disease. Res Vestibul Sci 2007;6:258-62. 7. Mira E, Guidetti G, Ghilardi L, Fattori B, Malannino N, Maiolino L, et al. Betahistine dihydrochloride in the treatment of peripheral vestibular vertigo. Eur Arch Otorhinolaryngol 2003;260:73-7. 49
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