吳　萍　何曉麗　魏志浩　鄧秀楠　何嚴(yán)冬

1)重慶市公共衛(wèi)生醫(yī)療救治中心結(jié)核二科　重慶　400020　　2)解放軍第三軍醫(yī)大學(xué)西南醫(yī)院呼吸科　重慶　400038

加巴噴丁治療糖尿病神經(jīng)痛效果及對(duì)血清TNF-α和IL-6水平的影響

吳萍1)何曉麗2)魏志浩2)鄧秀楠2)何嚴(yán)冬2)

1)重慶市公共衛(wèi)生醫(yī)療救治中心結(jié)核二科重慶4000202)解放軍第三軍醫(yī)大學(xué)西南醫(yī)院呼吸科重慶400038

【摘要】目的探討加巴噴丁(GBP)應(yīng)用于糖尿病神經(jīng)痛(DPN)治療的效果，分析其對(duì)血清TNF-α和IL-6水平的影響。方法選取DPN患者48例，根據(jù)是否服用GBP分為分為GBP組與DPN對(duì)照組各24例，并選取同時(shí)期無神經(jīng)痛糖尿病患者24例為DM組，及同時(shí)期健康體檢者24例為正常對(duì)照組，對(duì)GBP組及DPN組治療前及治療1、2、4周后視覺模擬評(píng)分進(jìn)行對(duì)比，并對(duì)血清TNF-α和IL-6水平進(jìn)行測(cè)定。結(jié)果與NC組對(duì)比，DM組、GBP組及DPN對(duì)照組患者的空腹血糖水平顯著升高；治療后，與DPN對(duì)照組對(duì)比，GBP組各時(shí)期的VAS評(píng)分均低于DPN對(duì)照組，且GBP組各時(shí)期VAS評(píng)分對(duì)比差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)；與NC組對(duì)比，GBP組、DPN對(duì)照組及DM組血清TNF-α、IL-6 水平顯著升高，其中GBP組、DPN對(duì)照組血清TNF-α、IL-6 水平顯著高于DM組，GBP組治療后血清TNF-α、IL-6 水平明顯低于治療前及同期DPN對(duì)照組，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。結(jié)論加巴噴丁對(duì)糖尿病神經(jīng)痛的療效顯著，并能降低血清TNF-α、IL-6 水平，值得臨床推廣。

【關(guān)鍵詞】糖尿病神經(jīng)痛；加巴噴??；TNG-α；IL-6

神經(jīng)病理性疼痛是臨床慢性疼痛的類型之一，主要是因組織炎癥、損傷或神經(jīng)系統(tǒng)損傷而引發(fā)的，表現(xiàn)為異常性疼痛、痛覺過敏及神經(jīng)系統(tǒng)損傷[1-2]。糖尿病周圍神經(jīng)痛(DPN)是神經(jīng)病理性疼痛的一種主要類型，發(fā)病機(jī)制較為復(fù)雜，且臨床治療困難。研究顯示，白細(xì)胞介素-6(IL-6)、血漿腫瘤壞死因子(TNF-α)等促炎細(xì)胞因子在神經(jīng)病理性疼痛的維持及產(chǎn)生中具有重要作用[3-4]。加巴噴丁(GBP)作為一種神經(jīng)病理性疼痛治療的一線藥，作用機(jī)制尚不明確。本研究旨在對(duì)GBP應(yīng)用于糖尿病神經(jīng)痛治療的效果及其對(duì)IL-6、TNF-α的影響進(jìn)行探討，現(xiàn)報(bào)道如下。

1資料與方法

1.1一般資料選取2014-03—2015-02我院收治的DPN患者48例。納入標(biāo)準(zhǔn)：均符合糖尿病周圍神經(jīng)痛診斷標(biāo)準(zhǔn)。排除標(biāo)準(zhǔn)：伴嚴(yán)重心腦血管疾病、肝腎功能不全及與糖尿病周圍神經(jīng)痛無關(guān)的其他疼痛患者[5-6]。根據(jù)是否服用GBP分為GBP組與DPN對(duì)照組各24例，GBP組男10例，女14例，平均年齡(55.47±10.21)歲；DPN對(duì)照組男13例，女11例，平均年齡(56.32±11.42)歲。選取同時(shí)期無神經(jīng)痛糖尿病患者24例為DM組，男12例，女12例，平均年齡(55.32±9.22)歲；另選取同時(shí)期健康體檢者24例為正常對(duì)照組(NC組)，男9例，女15例，平均年齡(53.77±8.95)歲。各組平均年齡對(duì)比無顯著差異(P>0.05)。DM組、GBP組及DPN對(duì)照組病程對(duì)比差異無統(tǒng)計(jì)學(xué)意義(P>0.05)；與NC組對(duì)比，DM組、GBP組及DPN對(duì)照組空腹血糖(GLU)水平顯著升高，差異有統(tǒng)計(jì)學(xué)意義(P<0.01)。見表1。

表1　各組一般資料對(duì)比±s)

1.2方法對(duì)所有糖尿病患者進(jìn)行飲食控制、運(yùn)動(dòng)及控制血糖處理，血糖水平的控制目標(biāo)：空腹血糖<8.0 mmol/L，2 h餐后血糖<11.1 mmol/L。GBP組原有基礎(chǔ)治療上給予加巴噴丁治療(徐州恩華制藥有限公司產(chǎn)品，規(guī)格300 mg/粒)，服用方法：第1天口服300 mg/次，1次/d；第2天口服300 mg/次，2次/d；第3天口服300 mg/次，3次/d；如果在此劑量下仍未達(dá)到理想效果，在患者自身情況允許下，可進(jìn)一步增加劑量，最大劑量3600 mg/d；療程為4周。DPN對(duì)照組及DM組均由原有方法治療。

1.3療效判斷及觀察指標(biāo)疼痛程度根據(jù)視覺模擬評(píng)分(VAS)進(jìn)行判定，其中無痛為0分，劇痛為10分。觀察治療前與治療1、2、4周后的VAS評(píng)分變化以判定治療效果。血清TNF-α、IL-6 水平的測(cè)定應(yīng)用ELISA法(試劑盒購(gòu)自深圳晶美生物工程有限公司，按試劑盒說明操作)[7-8]。

2結(jié)果

2.1GBP組與DPN對(duì)照組VAS評(píng)分對(duì)比治療前GBP組與DPN對(duì)照組VAS評(píng)分差異無統(tǒng)計(jì)學(xué)意義(P>0.05)；治療后，與DPN對(duì)照組對(duì)比，GBP組1、2、4周VAS評(píng)分均顯著低于DPN對(duì)照組，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)，且GBP組各時(shí)期VAS評(píng)分對(duì)比差異均有統(tǒng)計(jì)學(xué)意義(F=57.768，P<0.01)。見表2。

表2　GBP組與DPN對(duì)照組VAS評(píng)分對(duì)比

2.2各組治療前后血清TNF-α、IL-6 水平對(duì)比與NC組對(duì)比，GBP組、DPN對(duì)照組及DM組血清TNF-α、IL-6 水平顯著升高，其中GBP組、DPN對(duì)照組血清TNF-α、IL-6 水平顯著高于DM組，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)；GBP組治療后血清TNF-α、IL-6 水平明顯低于治療前及同期DPN對(duì)照組，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。見表3。

表3各組治療前后血清TNF-α、IL-6 水平對(duì)比

組別n時(shí)間TNF-αIL-6GBP組24治療前9.24±1.168.17±4.06治療后6.13±1.255.93±3.56DPN對(duì)照組24治療前9.18±1.208.31±4.70治療后9.52±1.428.43±4.02DM組245.22±0.675.46±4.15NC組243.64±0.253.05±0.47

3討論

DPN是臨床常見的神經(jīng)病理性疼痛，其在2型糖尿病患者中的發(fā)生率為15%～20%，在1型糖尿病患者中的發(fā)生率為5%[9-10]。DPN具有較復(fù)雜的發(fā)病機(jī)制，一般認(rèn)為與高血糖引發(fā)的氧化應(yīng)激反應(yīng)、代謝紊亂、神經(jīng)遞質(zhì)及脊髓背根神經(jīng)節(jié)離子通道等有關(guān)，且各因素相互影響、相互作用，導(dǎo)致脊髓背根神經(jīng)節(jié)水平痛覺及外周神經(jīng)信號(hào)傳導(dǎo)、調(diào)制發(fā)生異常，膠質(zhì)細(xì)胞活化，背角神經(jīng)元敏化，并促進(jìn)各種疼痛遞質(zhì)、炎癥介質(zhì)的釋放，最終引發(fā)疼痛癥狀[11-12]。目前認(rèn)為小膠質(zhì)細(xì)胞、淋巴細(xì)胞、巨噬細(xì)胞等釋放的一系列的促炎性細(xì)胞因子，如血清TNF-α、IL-6，在神經(jīng)病理性疼痛的發(fā)生及維持中具有關(guān)鍵作用。實(shí)驗(yàn)發(fā)現(xiàn)，在糖尿病神經(jīng)痛大鼠的模型中顯示周圍神經(jīng)、脊髓的TNF-α和IL-6 水平顯著升高，而當(dāng)給予TNF-α拮抗劑可減輕、阻斷神經(jīng)損傷而引發(fā)的痛覺過敏，提示TNF-α在形成病理性疼痛的過程中起重要作用[13-16]。本研究顯示，糖尿病患者血清TNF-α、IL-6顯著高于正常體檢者，而糖尿病周圍神經(jīng)痛患者血清中TNF-α、IL-6水平顯著高于糖尿病患者。

加巴噴丁是γ-氨基丁酸衍生物，是應(yīng)用于神經(jīng)病理性疼痛治療的一線藥物，與傳統(tǒng)藥物對(duì)比，加巴噴丁具有不誘導(dǎo)肝藥酶、經(jīng)腎臟代謝、不與血漿蛋白結(jié)合。不良反應(yīng)較少及藥物間相互作用輕微等優(yōu)點(diǎn)[17-20]。目前對(duì)加巴噴丁治療神經(jīng)病理性疼痛的公認(rèn)機(jī)制：增強(qiáng)GABA介導(dǎo)通路的抑制性輸入以使中樞效應(yīng)發(fā)揮；對(duì)N-甲基-D-天冬氨酸受體進(jìn)行抑制，以減輕神經(jīng)元放電所致的神經(jīng)痛；對(duì)P/Q 電壓依賴性型Ca2+通道進(jìn)行抑制，以使去甲腎上腺素和興奮性氨基酸谷氨酸的釋放。本研究結(jié)果顯示，治療前GBP組與DPN對(duì)照組VAS評(píng)分差異無統(tǒng)計(jì)學(xué)意義(P>0.05)；治療后，與DPN對(duì)照組對(duì)比，GBP組1、2、4周的VAS評(píng)分均顯著低于DPN對(duì)照組(P<0.05)，且GBP組各時(shí)期VAS評(píng)分對(duì)比差異均有統(tǒng)計(jì)學(xué)意義(F=57.768，P<0.01)，GBP組在口服GBP 1周后VAS評(píng)分即顯著下降，此后口服2、4周VAS評(píng)分仍逐漸下降，提示GBP能顯著減輕DPN患者疼痛。在GBP組治療過程中，4例出現(xiàn)不良反應(yīng)，但均癥狀輕微，均可耐受，無肝、腎功能異常及血常規(guī)異常，具有較高的安全性。

綜上所述，加巴噴丁應(yīng)用于糖尿病神經(jīng)痛的治療療效顯著，并能降低患者血清TNF-α、IL-6 水平，值得臨床推廣。

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(收稿 2015-06-10)

Effect of gabapentin in the treatment of diabetic neuropathic pain and its effect on serum IL-6 and TNF-α

WuPing*,HeXiaoli,WeiZhihao,DengXiunan,HeYandong

*ChongqingPublicHealthMedicalCenter,Chongqing400020,China

【Abstract】Objective To investigate the effect of gabapentin in the treatment of diabetic neuropathic pain (DPN), and analyze the influence on TNF-α and IL-6 levels.Methods Forty-eight patients with DPN were divided into GBP group and DPN control group according to whether they were treated with GBP. Twenty-four DM patients without DPN were regarded as DM group while another twenty-three healthy patients were regarded as NC group. Visual analogue scales (VAS) of GBP and DPN groups were compared before treatment and 1, 2 weeks, 4 weeks after treatment. The TNF-α and IL-6 levels were also compared in the same period.Results Compared with NC group, the fasting blood-glucose levels of DM group, GBP group and DPN control group were significantly higher; VAS score of DPN group were significantly lower than those in GBP group in the same period. TNF-α and IL-6 levels of GBP group, DPN group and DM group were significantly higher than those in NC group. Furthermore, the TNF-α and IL-6 levels of GBP group and DPN group were also significantly higher than those in DM group and TNF-α and IL-6 levels of GBP group were increased after treatment (P<0.05).Conclusion Gabapentin applied to the treatment of diabetic neuropathic pain is effective, and can reduce the serum TNF-α and IL-6 levels, so it is worthy of clinical application.

【Key words】Diabetic neuropathic pain; Gabapentin; TNG-α; IL-6

基金項(xiàng)目：國(guó)家自然科學(xué)基金項(xiàng)目(30901575)

【中圖分類號(hào)】R587.2

【文獻(xiàn)標(biāo)識(shí)碼】A

【文章編號(hào)】1673-5110(2016)11-0025-03