方法：這是一項(xiàng)隨機(jī),、對照、交叉配對試驗(yàn)，本試驗(yàn)在巴西圣保羅大學(xué)的一家附屬醫(yī)院（the Hospital das Cl?′nicas da Faculdade de Medicina da Universidade de Sa?o Paulo）進(jìn)行,。74名患有重度持續(xù)性哮喘的病人隨機(jī)的分為兩組：A組先進(jìn)行10天的真針刺，經(jīng)過3周的洗脫期,，然后給予10天的假針刺,；B組先進(jìn)行10天的假針刺,，經(jīng)過3周的洗脫期，隨后進(jìn)行10天的真針刺,。當(dāng)病人有需要時(shí)可使用短效和長效的β2受體激動(dòng)劑,、吸入性糖皮質(zhì)激素。治療之前和每次治療之后測定病人的肺功能,，包括痰細(xì)胞計(jì)數(shù),、呼出氣一氧化氮、SF36和哮喘患者生活質(zhì)量問卷調(diào)查（QQLA）,。記錄患者每天的呼氣流速和每天的癥狀變化,。采用5%的顯著性標(biāo)準(zhǔn)（α＝0.05）。

結(jié)果：B組在真針刺之后痰液中的嗜酸性粒細(xì)胞和中性粒細(xì)胞增加了（P＝0.001）,，但是最大呼氣量有改善（P＝0.01）,。B組在假針刺之后病人反應(yīng)咳嗽（P＝0.037）、氣喘（P＝0.013）,、呼吸困難（P＝0.014）有減輕,。同樣地，病人在真針刺之后反應(yīng)咳嗽（P＝0.040）,、氣喘（P＝0.012）,、呼吸困難（P＜0.001）和夜間醒的次數(shù)（P＝0.009）有所減少。A組患者藥物使用次數(shù)有所減少,，假針刺之后病人反應(yīng)咳嗽（P＝0.007）、氣喘（P＝0.037）,、呼吸困難（P＜0.001）和藥物使用次數(shù)（P＜0.001）均有所減少,，真針刺之后病人感覺肺功能（P＝0.004）、身體方面（P＝0.002）,、健康狀態(tài)（P＜0.001）和生命力（P＝0.019）均有所改善,。假針刺可引起哮喘患者癥狀的顯著差異，但是真針刺和假針刺組之間并沒有差異,。真針刺和假針刺在肺功能和呼出氣一氧化氮沒有顯示差異,。治療期間生活質(zhì)量評估沒有顯著差異。

結(jié)論：真針刺和假針刺治療哮喘有不同的療效和結(jié)果,。本試驗(yàn)中交叉配對設(shè)計(jì)沒有作用,，因?yàn)閮煞N治療對緩解哮喘癥狀、改善患者生活質(zhì)量和減少炎癥細(xì)胞數(shù)都是有效的,。因此,，針灸作為主要干預(yù)措施治療哮喘時(shí)，假針刺不是一種安慰劑作用,。

關(guān)鍵詞：哮喘,、針灸,、假針刺、肺功能,、生活質(zhì)量,、癥狀

哮喘是一種慢性疾病，近幾十年其全球發(fā)病率呈增加趨勢,。據(jù)統(tǒng)計(jì),，目前大約有3億人患有哮喘。哮喘是一種呼吸道的慢性炎癥性疾病,，可出現(xiàn)氣道高反應(yīng)性和支氣管痙攣,，伴有痰液分泌增多和氣流受限。哮喘最常見的臨床癥狀是氣喘,、咳嗽,、胸悶和呼吸困難。藥物治療包括短效和長效的β2受體激動(dòng)劑,、糖皮質(zhì)激素（口服和吸入性的）,、白三烯和茶堿。雖然藥物和最新的治療方法可有效的控制哮喘癥狀,，但是已經(jīng)研究了大多數(shù)其他方法在控制哮喘癥狀,、提高患者生活質(zhì)量，特別是非傳統(tǒng)治療方法,。這些非傳統(tǒng)治療方法被稱為替代療法,，針灸已成為最受歡迎的控制哮喘癥狀的方法。

針灸是中國傳統(tǒng)治療方法,。近幾千年,，針灸被用來治療各種疾病，包括哮喘,。相比主流醫(yī)學(xué),，有人認(rèn)為針灸是一種替代療法，針灸治療一些疾病是有效的,，比如惡心,、嘔吐、牙痛,、頭痛和其他的疾病,。針灸治療沒有明顯的副作用，其不像糖皮質(zhì)激素一樣出現(xiàn)相應(yīng)的副作用,，針灸治療哮喘有效可能與促腎上腺皮質(zhì)激素和內(nèi)生的腎上腺皮質(zhì)的釋放相關(guān),，但是這是有爭議的。以前大多數(shù)關(guān)于針灸治療哮喘的文章都是發(fā)表在非英語類的雜志上,，并且他們?nèi)狈α己玫牧餍胁W(xué)設(shè)計(jì),。事實(shí)上,，關(guān)于針灸的研究在設(shè)計(jì)和建立安慰劑對照組時(shí)存在一些固有的困難。由于非公認(rèn)的方法診斷疾病的原因,，認(rèn)為某些疾病有不同的病因,、不同的病理生理機(jī)制和不同的治療方法。因此,，需要更多關(guān)于針灸治療哮喘的臨床療效的研究,。

為了更好的研究和理解針灸治療中度哮喘的療效，我們在巴西圣保羅大學(xué)的附屬醫(yī)院設(shè)計(jì)和實(shí)施了該研究,，我們主要使用下面的觀察指標(biāo),，包括癥狀、生活質(zhì)量的改善,、肺功能,、呼氣流速的改變和炎癥變化情況（測定細(xì)胞計(jì)數(shù)和NO）。

優(yōu)點(diǎn)和不足

本研究旨在使用對照,、隨機(jī),、雙盲、交叉配對設(shè)計(jì)的方法評估針灸治療哮喘的療效,。本試驗(yàn)主要顯示了針灸治療哮喘對以下觀察指標(biāo)的影響：癥狀,；痰液中的細(xì)胞計(jì)數(shù)、呼氣流速,、生活質(zhì)量,。

然而本研究的不足之處是：相當(dāng)多的患者未完成該實(shí)驗(yàn)提前退出；關(guān)于患者生活質(zhì)量的改善在真針刺和假針刺組之間沒有顯著差異,。

材料和方法

這是一個(gè)雙盲（受試者和操作者）,、隨機(jī)、交叉配對設(shè)計(jì)的試驗(yàn),，所有的受試者都接受真針刺和假針刺。樣本量沒有進(jìn)行特別的計(jì)算,，因?yàn)闃颖玖繉Χㄐ宰兞浚ㄉ钯|(zhì)量和癥狀等）沒有明確影響,。通過新聞?wù)心际茉囌撸缓笸ㄟ^電話評估患者的一般情況,，若情況滿足納入標(biāo)準(zhǔn),，則參加本試驗(yàn)。第一次面試后,，告訴受試者如何填寫每日癥狀評分量表,、如何測定呼氣流速、如何填寫生活質(zhì)量問卷調(diào)查（包括SF36,、哮喘患者生活質(zhì)量問卷調(diào)查-QQLA）,。然后,，第二次面試由志愿者完成。

治療之前和治療之后（真針刺和假針刺）首先完成生活質(zhì)量問卷調(diào)查,。因此,，每個(gè)受試者需要完成三次生活質(zhì)量問卷調(diào)查。這些調(diào)查表對評價(jià)呼吸功能受損病人的生活質(zhì)量是一個(gè)有用的工具,。有些問題特別有用,，比如體力受限程度、功能容量,、癥狀發(fā)作的次數(shù)和嚴(yán)重性,。

根據(jù)下面的標(biāo)準(zhǔn)總共有184名患者：非吸煙者、一秒用力呼氣容積（FEV1）≥70%,、呼氣流速變量≤20%,、哮喘發(fā)作次數(shù)最少一周兩次、最多一周五次,、每月夜間醒來次數(shù)小于四次,、使用吸入性β2短效或長效受體激動(dòng)劑和吸入性糖皮質(zhì)激素可緩解哮喘癥狀、無其他心臟疾病,、慢性阻塞性肺疾?。–OPD）。

排除標(biāo)準(zhǔn)：參加其他臨床試驗(yàn),、患有其他肺病或全身性疾病,、過去有出血或凝血障礙、最近由于上呼吸道感染哮喘癥狀加重,、使用抗抑郁藥,、懷孕、吸煙或戒煙年限小于1年,、吸毒者,。

使用簡單隨機(jī)抽樣把受試者分為2組，開始治療之前評估患者的肺功能,、痰液細(xì)胞計(jì)數(shù),、測定NO、體格檢查,。在此期間高速病人如何填寫每日癥狀評分量表,、如何測定呼氣流速、如何填寫生活質(zhì)量問卷調(diào)查,。隨后他們被隨機(jī)的分到兩個(gè)治療組：A組患者先接受10天的真針刺,，B組患者接受10天的假針刺，選擇與治療哮喘不相關(guān)的點(diǎn)。10天治療結(jié)束后評估患者的肺功能,、痰液細(xì)胞計(jì)數(shù),、NO。兩組經(jīng)過3周的洗脫期,，然后進(jìn)行交叉配對過程,，即A組和B組交換治療方式，A組接受假針刺,，B組接受真針刺,，10天治療結(jié)束之后，評估新的客觀指標(biāo),。治療期間,，若患者的哮喘癥狀加重可使用β激動(dòng)劑（長效或短效）和吸入性糖皮質(zhì)激素。在治療期間,，36名患者使用了短效β2激動(dòng)劑,6名使用了吸入性糖皮質(zhì)激素,，49名患者聯(lián)合使用了長效、短效β2激動(dòng)劑和吸入性糖皮質(zhì)激素,，3名使用了短效β2激動(dòng)劑、吸入性糖皮質(zhì)激素和白三烯,，2名使用了茶堿和短效β2激動(dòng)劑,。如圖1。

統(tǒng)計(jì)分析

定量連續(xù)變量使用t檢驗(yàn)或配對t檢驗(yàn)分析兩個(gè)獨(dú)立樣本,。

定性變量使用曼惠特尼檢驗(yàn)分析兩個(gè)獨(dú)立樣本或使用秩和檢驗(yàn)分析成對樣本,。

使用卡方檢驗(yàn)或確切概率法分析名義上的定性變量。

我們采用5%（α＝0.05）的統(tǒng)計(jì)顯著水平,。使用Minitab 15.0 and SPSS 16.0分析數(shù)據(jù),。

結(jié)果

本試驗(yàn)實(shí)施時(shí)間為2003年1月至2007年12月，總共有185名患者參加試驗(yàn),，最后只有72名患者完成了該試驗(yàn)。43名患者先進(jìn)行假針刺,，經(jīng)過三周的洗脫期,，隨后接受真針刺；31名患者先進(jìn)行真針刺,，經(jīng)過三周的洗脫期,，隨后接受假針刺。

本試驗(yàn)中男22名,，女52名；A組的平均年齡32.5,，B組的平均年齡37.4,。因?yàn)楸驹囼?yàn)持續(xù)時(shí)間較長,，因此試驗(yàn)中途有大量患者退出,，最后總共有111名患者因?yàn)楦鞣N原因退出了本試驗(yàn)，比如：工作繁忙,、搬家,、治療過程中哮喘癥狀加重、出現(xiàn)了其他的疾病,。除此之外,，我們的志愿者不能正確的填寫問卷調(diào)查，以至于不能使用這些問卷調(diào)查做評估,。

治療期沒有病人反應(yīng)不適或副反應(yīng),。

呼氣流速

B組患者在真針刺之后呼氣流速明顯增加，如表1,。

痰液細(xì)胞計(jì)數(shù)

B組患者在真針刺之后痰液中的嗜酸性粒細(xì)胞和中性粒細(xì)胞明顯減少，巨噬細(xì)胞明顯增加,，如表2,。

每日癥狀自評分

根據(jù)與哮喘相關(guān)的每日癥狀結(jié)果顯示：A組在真針刺之后患者對β2受體激動(dòng)劑的需要量相對于治療期間有明顯減少。除此之外,，A組在假針刺之后患者的咳嗽,、氣喘、呼吸困難和β2受體激動(dòng)劑噴霧使用相對于治療期間有明顯緩解,，如表3,。

B組患者在假針刺之后咳嗽、氣喘,、呼吸困難有明顯緩解,，真針刺之后患者的咳嗽、氣喘,、呼吸困難和夜間覺醒次數(shù)相比治療期間有明顯減少,，如表3。

生活質(zhì)量評價(jià)

哮喘生活質(zhì)量調(diào)查問卷（QQLA）

觀察發(fā)現(xiàn)真針刺和假針刺之后QQLA的一些癥狀有所改善,。然而,，在真針刺之后QQLA某些癥狀的緩解癥狀較假針刺之后明顯。但是，真針刺和假針刺治療過程中癥狀改善并沒有明顯差異,，如表4,。

SF-36醫(yī)學(xué)結(jié)果研究

正如上面描述的QQLA結(jié)果，SF36中我們也發(fā)現(xiàn)了相似的結(jié)果,。真針刺和假針刺之后相關(guān)的功能容量,、身體方面、一般健康狀況,、心理方面,、社交和生命力均有所改善，如表5,。然而,，真針刺和假針刺之間并沒有顯著差異。

我們發(fā)現(xiàn)在洗脫期患者的肺功能和NO呼出量并沒有差異,。

討論

數(shù)千年來,，針灸在亞洲已作為一種首選治療方法用來治療疾病，比如中國,、日本,、韓國、東南也,。雖然針灸療效是未知的,，但是大多數(shù)中醫(yī)治療師聲稱針灸治療哮喘是有效的。

本研究旨在證實(shí)針灸治療哮喘的一致性積極療效,。我們不僅研究對哮喘癥狀的控制,，而且確定針灸是否對小氣道炎癥有影響，因此我們收集的數(shù)據(jù)有肺功能,、痰液細(xì)胞計(jì)數(shù)和NO,。我們收集的數(shù)據(jù)也包括每日癥狀評分量表，兩個(gè)相關(guān)的調(diào)查問卷評估患者生活質(zhì)量的改善程度,。

本研究采用了交叉配對設(shè)計(jì)的方法,。招募期間的目的是，一旦收集了患者的肺功能,、癥狀評分,、生活質(zhì)量調(diào)查問卷、細(xì)胞計(jì)數(shù)和NO,，我們就認(rèn)為病人是對照組,。隨后，每個(gè)病人在不同治療期間,，他們可能是對照組或者是治療組,。這種設(shè)計(jì)是由風(fēng)險(xiǎn)的,，因?yàn)槲覀儧]有發(fā)現(xiàn)另一個(gè)有相似設(shè)計(jì)類型的試驗(yàn)，因此針灸的洗脫期不確定的,。經(jīng)過驗(yàn)證確定糖皮質(zhì)激素的洗脫期是兩周，因此我們決定延長針灸的洗脫期為3周,，但是我們?nèi)圆淮_定三周的洗脫期是否足夠長,。

由于本研究持續(xù)時(shí)間較長（大約4年），因此大多數(shù)患者因?yàn)楦鞣N原因（如表6）放棄了該試驗(yàn),。試驗(yàn)中患者的退出可能是我們試驗(yàn)額主要不足之處,，患者中途退出使我們不能得出針灸治療哮喘療效的強(qiáng)有力結(jié)論。

因?yàn)樵撛囼?yàn)持續(xù)時(shí)間較長,，我們沒有執(zhí)行良好的季節(jié)性控制,，鑒于治療期間哮喘的加重患者使用吸入性糖皮質(zhì)激素、長效或短效的β2受體激動(dòng)劑,。因?yàn)榇嬖谙疵撈谑褂盟幬锸潜厝坏?，因此我們不能明確區(qū)別藥物和針灸（真針刺和假針刺）對患者的影響，事實(shí)上這是我們研究的不足之處,。

因此,，肺功能和NO的結(jié)果表明沒有差異，這可能與我們沒有控制季節(jié),、藥物使用和無效的洗脫期有關(guān),。除此之外，由于藥物的使用,，包括吸入性糖皮質(zhì)激素,，我們預(yù)期炎癥過程（測量NO）在治療針灸前后有差異，然而并沒有觀察到,。

這個(gè)發(fā)現(xiàn)使我們認(rèn)為也許隨著哮喘癥狀的控制以至于大多數(shù)患者的慢性炎癥處于靜默期,。相反，B組在真針刺之后患者的嗜酸性粒細(xì)胞和中性粒細(xì)胞減少了,，這表明針灸治療可減輕炎癥,。此外，B組在真針刺之后患者的巨噬細(xì)胞增加了,，針灸增加巨噬細(xì)胞有正調(diào)節(jié)作用,，這是一個(gè)重要的特應(yīng)性變態(tài)反應(yīng)過程。

B組在真針刺之后呼氣流速有所改善,，這個(gè)事實(shí)再一次表明針灸緩解炎癥是有用的,。

確立假針刺點(diǎn)是困難的，傳統(tǒng)的來講,，假針刺點(diǎn)是距離治療部位較遠(yuǎn)的點(diǎn),，當(dāng)刺激時(shí),，可能有治療作用，也可能沒有治療作用,。然而,，關(guān)于假針刺點(diǎn)的確立存在爭議，某些研究表明假針刺點(diǎn)有小的治療作用,，因?yàn)槠つw上的任何痛點(diǎn)都可作為一個(gè)穴位,。因此，我們在真針刺和假針刺組之間不能區(qū)分出顯著效果,特別是哮喘癥狀和生活質(zhì)量評估,，我們推斷假針刺有治療作用,，但是療效較小。我們選擇遠(yuǎn)處經(jīng)絡(luò)上的穴位,，這些穴位對哮喘癥狀的控制可能有作用,，但是我們不能保證這些穴位對哮喘沒有作用。這個(gè)結(jié)論（哮喘癥狀和生活質(zhì)量）也有可能歸功于主觀測量的差異,。不足之處也解釋了真針刺和假針刺組之間在夜間覺醒次數(shù),、藥物使用減少和生活質(zhì)量調(diào)查問卷的療效差異。因此,，我們的結(jié)論支持假針刺沒有治療作用,，只有真針刺有較小的療效。

我們的結(jié)果似乎表明,，針灸治療氣道炎癥方面是有作用的,，因?yàn)槲覀儼l(fā)現(xiàn)患者呼氣流速有所改善，患者嗜酸性粒細(xì)胞和中性粒細(xì)胞減少,、巨噬細(xì)胞增加,。此發(fā)現(xiàn)表明針灸對免疫系統(tǒng)有正調(diào)節(jié)作用，雖然患者肺功能和呼出氣NO沒有差別,。相反,，根據(jù)患者癥狀，針灸（連同藥物）可能更好的控制癥狀和提高生活質(zhì)量,。

然而,，試驗(yàn)中退出的志愿者可能對針灸真正療效的評估是有影響，妨礙我們對針灸療效做更多積極的假設(shè),。真針刺和假針刺之間沒有顯著差異以至于我們對真針刺不能做出推斷,。然而，針灸可能不被認(rèn)為是一個(gè)有效的安慰劑,，因?yàn)樵诒驹囼?yàn)中顯示假針刺時(shí)有效的,。

根據(jù)上述討論的，我們認(rèn)為交叉配對設(shè)計(jì)并不適合用于針灸療效的評估,，因?yàn)槲覀兇_定可靠的洗脫期,，并且假針刺對哮喘癥狀控制也是有效的,。

進(jìn)一步的研究需要更好的理解針灸治療哮喘的療效，可能使用其他設(shè)備,，比如不透皮針,，但是有刺痛的感覺，為了更好的滿足假針刺的條件,。此外,，交叉配對設(shè)計(jì)不適合用于針灸療效評估。

針灸結(jié)合其他藥物（β2受體激動(dòng)劑,，不管長效或短效，白三烯,，吸入性糖皮質(zhì)激素）對控制哮喘癥狀和改善患者生活質(zhì)量是有效的,，此外，針灸在控制慢性氣道炎癥也可能是有效的,。然而,，由于各種原因，包括大多數(shù)志愿者的退出,，我們不能保證針灸對哮喘的作用,。

原文鏈接https://www.ncbi.nlm./pubmed/

英文原文

A randomized, controlled, crossover study in patients with mild and moderate asthma undergoing treatment with traditional Chinese acupuncture

Hong Jin Pai, Raymundo Soares Azevedo,Alfe′ sio Lu?′s Ferreira Braga

OBJECTIVES: This study sought to verify the effects of acupuncture as an adjuvant treatment for the control of asthma.

METHODS: This was a randomized, controlled, crossover trial conducted at the Hospital das Cl?′nicas da Faculdade de Medicina da Universidade de Sa?o Paulo. A total of 74 patients withmild/moderate, persistent asthma were randomized into two therapeutic groups: Group A – 31 patients underwent 10 real weekly acupuncture sessions, followed by a 3-week washout period and 10 sham weekly acupuncture sessions; and Group B - 43 patients underwent 10 sham weekly acupuncture sessions, followed by a 3-week washout period and 10 real weekly acupuncture sessions. Patients used short- and long-acting b-2 agonists and inhaled corticosteroids when necessary. Prior to treatment and after each period of 10 treatment sessions, the patients were evaluated for spirometry, induced sputum cell count, exhaled nitric

oxide (NO) and with the Short Form 36 (SF-36) and Questionnaire on Quality of Life-Asthma (QQLA) questionnaires.Daily peak flow and symptom diaries were registered. The level of significance adopted was 5% (a=0.05).

RESULTS: In Group B, after real acupuncture, there was a decrease in eosinophils (p=0.035) and neutrophils (p=0.047),an increase in macrophages (p=0.001) and an improvement in peak flow (p=0.01). After sham acupuncture treatment,patients experienced less coughing (p=0.037), wheezing (p=0.013) and dyspnea (p=0.014); similarly, after real acupuncture, patients reported less coughing (p=0.040), wheezing (p=0.012), dyspnea (po0.001) and nocturnal awakening episodes (p=0.009). In Group A, there was less use of rescue medication (p=0.043). After the sham procedure, patients in Group A experienced less coughing (p=0.007), wheezing (p=0.037), dyspnea (po0.001) and use of rescue medication (po0.001) and after real acupuncture, these patients showed improvements in functional capacity (p=0.004), physical aspects (p=0.002), general health status (po0.001) and vitality (p=0.019). Sham acupuncture also led to significant differences in symptoms, but these were not different from those seen with real acupuncture. Spirometry and exhaled NO levels did not show a difference between sham and real acupuncture treatment. In addition, no significant difference was demonstrated between treatments regarding the quality of life evaluation.

CONCLUSION: Real and sham acupuncture have different effects and outcomes on asthma control. The crossover approach was not effective in this study because both interventions led to improvement of asthma symptoms, quality of life and inflammatory cell counts. Thus, sham acupuncture cannot serve as a placebo in trials with acupuncture as the main intervention for asthma.

KEYWORDS: Asthma; Acupuncture; Sham; Spirometry; Quality of Life;Symptoms.

INTRODUCTION

Asthma is a chronic condition with a global incidence that has progressively increased in recent decades. It is estimated that approximately 300 million people are currently affected by asthma. Asthma is defined as a condition that causes chronic inflammation in the airways,leading to a state of hyper-responsiveness and resulting in bronchospasm, an increase in mucus production and limitation to air flow. The most common symptoms of asthma are wheezing, coughing, chest tightness and dyspnea.

Pharmacological treatment includes short-acting and some long-acting b-2 agonists, glucocorticoids (both oral and inhaled), a leukotriene modifier and theophylline, among others . Although medications and updated approaches have been effective tools for controlling asthma, many other approaches have been studied to help asthmatic patients reach both symptom control and improvement in their quality of life, particularly non-conventional healing techniques. Among these non-conventional approaches,termed alternative/complementary medicine, acupuncture has become one of the most popular techniques used to control asthma .

Acupuncture is one of several traditional Chinese medicine therapeutic methods. For thousands of years, acupuncture has been used to treat several conditions, including asthma . In comparison to mainstream medicine, acupuncture is considered a complementary/alternative healing technique and has been considered to be effective for conditions such as nausea and emesis post-chemotherapy,dental pain, osteoarthritis pain and headache, among others. The apparent lack of significant adverse effects, unlike those experienced with the use of glucocorticoids and the

possible effects linked to the release of adrenocorticotropic hormone (ACTH) and endogenous corticoids, supports the use of acupuncture for the treatment of asthma. Several studies have been conducted to investigate acupuncture in the treatment of asthma, with controversial results .Most previous studies favoring acupuncture for the treatment of asthma have been published in non-English language journals and they lack good epidemiological design . Indeed, there are some inherent difficulties in

designing and establishing placebo controls in studies involving acupuncture . Due to the nature of heterodox methods of diagnosis, some diseases or conditions can be understood as having different etiologic agents, diverse pathophysiologic mechanisms and different methods of treatment. Thus, more studies about the effect of acupuncture

in asthma are needed.

To better study and perhaps understand the possible effects of acupuncture in mild and moderate asthma, we designed and performed the present study in the Clinics Hospital of the University of S?o Paulo School of Medicine, one of the largest medical centers in Latin America, using the following primary end-points: symptomatic and quality of life improvement, spirometry and peak flow improvement

and inflammatory improvement (cell counting and nitric oxide (NO) measurements).

Strengths and limitations of this study

This study attempted to evaluate the effects of acupuncture on patients with asthma in a controlled, randomized, double-blind crossover trial and it may have shown the

positive effects of acupuncture for the following end-points:

1) Symptom control

2) Cell counts in induced sputum

3) Peak flow

4) Quality of life

However, there are several limitations of the study:

1) A significant number of patients quit the study prior to completion

2) No significant difference was demonstrated between the sham and real acupuncture treatments regarding the quality of life evaluation

MATERIAL AND METHODS

This was a double-blind (patient and clinicians), randomized, crossover clinical trial study where all enrolled patients underwent both sham and real acupuncture. A specific calculation for sample size was not performed because there was no defined effect to reach with the qualitative variables (quality of life evaluation, symptoms, etc.). We recruited patients through the written press and performed the first interview by phone to evaluate the general conditions needed for enrollment in the study. After the first interview, the patients were taught how to answer a daily symptom scale, perform peak flow measurements and answer quality of life questionnaires, including the Short Form 36 (SF-36) and Questionnaire on Quality of Life-Asthma (QQLA). Afterwards, a second interview was conducted and the volunteers were invited by research staff to participate in the project.

The quality of life questionnaires were completed initially, before beginning the treatment procedure and also after each treatment period (sham and real acupuncture). Hence, each patient answered both the questionnaires three times. These questionnaires are useful instruments for measuring quality of life in respiratory-impaired patients. Some of the questions were particularly useful, such as those regarding physical limitations,functional capacity and the frequency and severity of symptoms.A total 184 patients were included according to the following criteria: non-smokers; forced expiratory volume of first second (FEV1) ≥70% and peak flow variability ≤20%; asthma symptoms at least twice per week and a maximum 5 times per week; nocturnal awakening ＜ 4 times per month;use of relieving inhaled b-2 rapid-acting/long-acting or inhaled glucocorticoids; and lack of other cardiovascular disease or chronic obstructive pulmonary disease (COPD).

Patients interested in participating but not enrolled to this study were excluded according to the following criteria:participating in another clinical trial; co-morbidity with other lung or systemic disease; past bleeding or coagulopathy; recent asthma exacerbation by upper airway infection; use of antidepressant medication; pregnancy; smoker or ex-smoker who quit less than 1 year ago; or drug addict.

The enrolled patients were allocated randomly, using a simple random sampling method, to 2 groups and had their spirometry, sputum cell count, NO measurement and medical interview performed before they began the treatment. During this period of inclusion, the patients were taught how to perform daily peak flow measurements and how to complete daily symptom scales. Subsequently, they were randomly allocated into one of two treatment groups:1) Group A, in which patients first received real acupuncture for 10 weekly sessions and 2) Group B, in which patients first received sham acupuncture treatment with points not related to the treatment of asthma in traditional Chinese medicine (some are not described as acupoints) for 10 weekly sessions.

After 10 sessions, the patients in both groups underwent spirometry and induced sputum cells counts and NO measurements were again performed. Both groups underwent process, in which Group A and Group B exchanged the form of needling, with Group A receiving sham point needling and Group B receiving real acupoint needling. After 10 weekly sessions, new objective measurements were performed. During each study period, patients suffering an asthma exacerbation were rescued with b-agonists (both short-and long-acting) and inhaled glucocorticoids. During the period of treatment, 36 patients used short-acting b-2 agonists as rescue medications, 6 patients used inhaled corticosteroids, 49 patients used a

combination of short-acting b-2 and long-acting b-2 agonists with inhaled corticosteroids, 3 patients used b-2 short-acting agonists with inhaled corticosteroids and a leukotriene modifier and 2 used theophylline and a short-acting b-2 agonist. The

procedure is summarized in Figure 1.

The patients were randomly allocated; there was only one physician who performed acupuncture on the patients. Neither the patient, nor the interviewer, nor the technician who measured the induced sputum cell counts, NO measurements and spirometry had knowledge of the type of acupuncture (real or sham) the patients were undergoing.In the end, a total of 74 patients achieved a total of 20 sessions of treatment, comprising 10 with real acupuncture and 10 with sham acupuncture.

All of the patients underwent their laboratory exams in the Clinics Hospital of the University of S?o Paulo Faculty of Medicine and underwent the sessions of treatment in a location specifically prepared to perform this study.

The local Committee for Ethical Issues in Human Research approved this study.

Statistical analysis

The quantitative continuous variables were analyzed using the student’s t test for two independent samples or by paired t test, as appropriate.

The ordinal qualitative variables were analyzed using the Mann-Whitney test for two independent samples or by Wilcoxon test for two paired samples.

The nominal qualitative variables were analyzed using the Chi-Squared test or Fisher Exact test, as appropriate.

We adopted a statistical significance level of 5% (a=0.05). The analyses were performed using Minitab 15.0 and SPSS16.0 for Windows.

RESULTS

From January 2003 to December 2007, a total 185 volunteers were recruited. Of these, only 74 completed the study by passing through both the sham and real acupuncture treatment groups. Forty-three volunteers began with the sham technique (Group B), passed through the washout period and subsequently received real acupuncture treatment. Thirty-one subjects were allocated to the group that

first received real acupuncture (Group A) and after a washout period, the subjects passed to the sham acupuncture treatment.

The groups of volunteers comprised 52 females (70%) and 22 males (30%), with a mean age of 32.5 years for Group A (acupuncture as the first procedure) and 37.4 years for Group B (sham as the first procedure). Because this was a very long-term trial, we had a considerable loss of patients. A total 111 volunteers quit the trial for several reasons such as job overload, moving from former addresses, asthma symptoms brought under control during the trial and other concurrent diseases occurring while undergoing the trial. We also had problems with volunteers not filling out the proposed questionnaires, making it impossible to use these questionnaires for evaluation.

No patients reported any harm or adverse effects during the period of intervention.

Peak flow

There was a significant increase in peak flow measurements in Group B patients after the real acupuncture intervention (Table 1).

Cell counts in induced sputum analysis

There was a significant decrease in the eosinophil and neutrophil counts and a significant increase in the macrophage count in the induced sputum in Group B subjects after the real acupuncture procedure (Table 2).

Self-report of daily symptoms scale

In terms of daily symptoms related to asthma, there was a significant decrease among Group A subjects regarding theβ-2 agonists required, comparing the inclusion period to the period after the real acupuncture procedure. In addition, there was a significant decrease in coughing, wheezing,dyspnea and β-2 agonist spray use, comparing the inclusion period to that after the sham procedure (Table 3).

In Group B, there was also a significant decrease in coughing, wheezing, and dyspnea, comparing the inclusion period to that after the sham procedure. Comparing the inclusion period to that following real acupuncture treatment,there was also a significant decrease in coughing, wheezing,dyspnea and nocturnal awakening (Table 3).

Quality of life evaluation

A- Questionnaire on Quality of Life-Asthma, Universidade Federal de Sa?o Paulo, Escola de Medicina (QQLA). The results showed improvement in some domains of the QQLA and this improvement was observed after both the real acupuncture and after the sham procedure. However, after the real acupuncture, more domains showed improvement than after the sham procedure. In this questionnaire, patients experienced improvement in domains such as physical limitation, socio-economic aspects, symptom frequency and severity, adherence to treatment and social and psychological aspects (Table 4). However, there was no significant difference between the real acupuncture and the sham procedure treatments.

SF-36 medical outcome study

As described above for the QQLA, we found a very similar result for the SF-36. Both the sham and real acupuncture treatments seemed to improve domains related to functional capacity, physical aspects, general health status, mental health, social aspects and vitality (Table 5). However, there was no difference in this improvement when comparing sham and real acupuncture.

We also found no difference comparing the inclusion period to both the sham and real acupuncture periods for other measurements such as spirometry and NO exhaled measurements.

DISCUSSION

For thousands of years, acupuncture has been used as a first-choice treatment for several illnesses on the Asian continent, mostly in countries such as China, Japan and

Korea, as well as in Southeast Asia. Although the efficacy of acupuncture remains unknown (because of a lack of reliable case records from the distant past), most traditional Chinese medicine practitioners claim that acupuncture is effective in asthma symptom control.

This study was conducted to test the consistency of the positive effect of acupuncture in asthma control. We decided not only to study symptom control but also to determine whether acupuncture has some influence on small airway inflammation; thus, we collected data on spirometry, total cell counts in induced sputum and NO measurements. We also collected data on daily symptom scales and measured quality of life through two pertinent questionnaires.

The design of our study was a crossover type, to facilitate recruitment by not having to recruit separate control, sham (placebo) and real acupuncture groups (treatment group). The aim was that during the enrolling period, once we had collected the measurements for spirometry, the symptom scale, quality of life questionnaire, total cell counts in induced sputum and NO, the patients would be

considered a control group. Afterwards, while each one of the patients passed throughout the different stages of treatment, they would be delegated to a placebo (sham)group or a treatment (acupuncture) group. This type of design was quite risky because we could not find another similar study to establish an acceptable period of washout for the acupuncture effect.We decided to extend the well-validated washout period of two weeks for corticosteroids to a period of three weeks, without any certainty if the duration of this period would be long enough. The lack of difference between the sham and real acupuncture found at the end of this study may be accounted for by ineffectiveness of the washout period.

Due to the duration of the study period, which lasted longer than expected (more than 4 years), we experienced a considerable loss of volunteers who quit the study for several reasons, as listed in Table 6. Although alarming, this loss is expected in clinical trials lasting for long periods of time. This loss of subjects is possibly the main weakness of our study and prevented us from drawing convincing conclusions about the contribution of acupuncture to asthma treatment.

As this study took a long time to be completed (more than 4 years), we could not perform good seasonality control, given periods of asthma exacerbation, with use of inhaled glucocorticoids and both long- and short-acting b-agonists. Although a period of washout was established every time rescue medications were required, we could not be certain about distinguishing both the acupuncture (either real or sham) and rescue medication effects for the patients; this fact certainly impaired the strength of our study.

Thus, the results showing no difference in NO measurements and spirometry could be accounted for by poor seasonality control, rescue medication use and an ineffective washout period. Additionally, due to the heavy use of rescue medications,including inhaled glucocorticoids, we expected that the inflammatory process (expressed in NO measurements) would show differences between the pre-treatment group and both the

acupuncture and sham groups, although this was not observed. This finding led us to think that perhaps most asthma patients with controlled symptoms have silent, chronic airway inflammation.In contrast, we observed a decrease in eosinophils and neutrophils, especially in Group B, after the second intervention (real acupuncture), which may point to the inflammationreducing effects of acupuncture. Moreover, there was an increase in the macrophage count after real acupuncture in Group B, suggesting a positive modulatory effect of real acupuncture on increasing the macrophage count, which is important in the atopic allergy process.

Other results of note include the improvement of peak flow in Group B after the real acupuncture intervention; this fact again points to the possible inflammation-reducing effect of acupuncture.

We had difficulty establishing the sham points as a ‘‘true placebo’’. Classically, sham points are defined as distant points and may or may not technically have any therapeutic effects when stimulated. However, there remains no consensus about establishing sham points and there are studies suggesting that sham points could have some  minimal therapeutic effects because any aching point on the skin could serve as an acupuncture point .Therefore, we could not distinguish significant effects between treatment (acupuncture points) and placebo (sham points), particularly in the symptoms and quality of life evaluation,which led us to conclude that sham acupuncture may have therapeutic, yet minimal effects. We selected many acupoints

in distant meridians that could have an influence on asthma control, but we could not assure that these points really had no effect on asthma. This fact could have contributed to the lack of difference in the endpoints between the real and sham acupuncture in the subjective fields of measurements (symptoms and quality of life). This limitation could also explain the difference in effectiveness between the real acupuncture points and the sham points during nocturnal awakening, the decrease in use of rescue medication and the quality of life questionnaire. Thus, our results support the concept that sham acupuncture is not possible, only acupuncture delivering minimal effects.

The results of our study appear to suggest that acupuncture does play an effective role in airway inflammation because positive results were found in peak flow measurements and decreases in the eosinophil and neutrophil counts in the induced sputum and the increase in macrophages. These findings showed a positive modulating effect on the immune system, although no effects on spirometry or exhaled NO measurement were found. In contrast, in terms of symptoms, acupuncture (together with known medications) may offer better symptom control and a better quality of life.

However, the number of volunteers who quit this study may have compromised the measurement of the real effect of acupuncture, prohibiting us from making a more positive assumption about the effect of acupuncture. The lack of a significant difference between the sham and real acupuncture treatments also prevented us from deducing the effectiveness of real acupuncture. However, sham acupuncture

may not be considered an effective placebo as it showed an effect in this study.

Based on the points discussed above, we believe that the crossover study design does not appear to be appropriate for the evaluation of the effect of acupuncture, particularly because we did not establish a reliable washout period and sham acupuncture showed effects on asthma control.

Further studies are required to better understand the effects of acupuncture in asthma, perhaps using other type of devices such as a needle that does not penetrate the skin but gives the sensation of being pricked - to better fit the condition of sham

acupuncture points. In addition, the crossover design may not be appropriate for the evaluation of acupuncture effects.

Acupuncture, together with othermedications (like b-agonists,regardless of whether they are short- or long-acting, leuk