膝宁方治疗膝关节骨关节炎肝肾亏虚证的临床研究
|
摘要
膝关节骨关节炎(膝OA)是一种因关节软骨退行性变所引起的以膝关节疼痛、肿胀、骨质增生为主要表现的关节病变。本病为中老年人临床常见病，随着社会的老龄化，其发病率呈上升趋势。由于膝关节疼痛、肿胀，使患者的生活质量受到极大影响，迄今尚无有效措施能够逆转骨质增生或抑制病变进展。中医药治疗本病具有一定优势，本研究在整理历代中医对本病认识的基础上，结合现代医学的治疗研究进展，对膝OA的诊断与治疗问题进行了总结，同时采用平行对照、区组随机的研究方法，客观评价了膝宁方对膝OA肝肾亏虚证平地行走疼痛治疗作用的临床疗效。
首先，通过对历代中医文献的系统整理，认为本病多以肝肾亏虚为基础，闪挫劳损及感受外邪为诱因，从而使气血瘀滞，痰湿内生，经脉痹阻，气血运行不畅，遂致关节肿胀、疼痛。治当益气养血、补益肝肾，扶正祛邪、标本兼顾。其次，通过对现代医学文献的调研，指出诊断膝OA应临床与影像学检查相结合，应重视病情轻重程度的评估，治疗宜中西医互参，取长补短，内外结合。采用药物改善血循环以降低骨内压、抑制活化的细胞因子及生长因子、清除氧自由基、提高组织局部透明质酸以保护受损的软骨细胞是膝OA的治疗研究方向。同时介绍了目前尚处于动物实验阶段的基因疗法，这是一种把治疗基因运用基因转导技术转移到患病关节内的治疗方法，具有较好的应用前景。
临床研究方面，以平地行走疼痛为主要效应指标，对膝宁方治疗膝OA肝肾亏虚证的临床疗效与扶他林治疗相对照进行了研究观察，共设治疗组20例、对照组20例。结果表明膝宁组治疗后患者平地行走疼痛、晨僵、僵直程度、下楼及上楼的关节活动情况均较治疗前明显改善，与扶他林组疗效相当，膝宁方对膝关节平地行走疼痛的缓解起效较慢，但至治疗后第4周对疼痛的缓解与扶他林治疗相似，且膝宁方在治疗后第4周对病情的整体改善有优于扶他林的趋势，总有效率为85％。安全性方面的观察结果表明，膝宁组胃肠道不适等不良反应明显少于扶他林治疗组，提示该方具有良好的安全性。
Osteoarthritis of knee is an arthropathy characterized by hyperosteogeny due to degenerative articular cartilage. It is a common disease of middle- and old-aged people, of which incidence is on a steady increase along with longer life span and increasing number of old people. Patients with osteoarthritis of knee suffer a lot in daily life for swelling and painful knee, however effective treatment to reverse hyperosteogeny or check the deterioration has not yet been available. Since TCM has certain advantages on it, this research summarized the diagnosis and treatment of osteoarthritis of knee on the basis of TCM understanding and study development of modern treatment. Meanwhile research methods of parallel control and randomized group were adopted and objective evaluation was made of XINING Formula's clinical effect on walking pain due to osteoarthritis of knee with deficiency of liver and kidney.
Firstly, after arranging systematically previous literature of TCM, it holds that osteoarthritis of knee is based mainly on the deficiency of liver and kidney and precipitated by sprain, strain and invasion by exogenous pathogens and that swelling and painful knee results from stagnation of Qi, blood and endogenous phlegm and damp as well as obstruction of meridians. Therefore, the treatment should highlight the following principles: invigorating Qi and replenishing blood, tonifying liver and kidney, supporting vital Qi and dispelling evil Qi as well as emphasizing root causes and branch symptoms.
Then through studying literature of western medicine, it believes that osteoarthritis of knee should be diagnosed with combination of clinic examination and radiology and that evaluation of degree of condition and integrative treatment of TCM and western medicine should be stressed to enhance therapeutic effect. The treatment of osteoarthritis of knee is targeted at improving blood circulation, reducing intraosseous pressure, inhibiting activated cell factors and growth factors, eliminating oxygen free radicals, increasing hyaloplasmic acid of local tissues to protect impaired cartilage cells. In addition, this thesis introduced gene therapy that is still under the stage of animal experiment, in which therapeutic gene is transplanted into affected joint. Therefore, it is promising in clinical application.
In clinical research, clinical effect of XINING Formula, taken walking pain as chief effect index, on treating osteoarthritis of knee with deficiency of liver and kidney was compared with Votalin. There were 20 cases in treatment group and 20 in control group. The results showed that XINING group improved significantly in terms of walking pain, morning stiffness, the severity of stiffness and knee activities during climbing upstairs and downstairs after treatment, which had no significance comparing with Votalin group. Walking pain was improved with XINING Formula in slow start which then showed similar effect with Votalin in the 4th week of treatment and had the tendency of better effect in improving general conditions in the 4th week with 85% totally effective rate. The result in safety showed that gastrointestinal discomfort in XINING group was less than that in Votalin group, which indicated this formula was better in safety.
首先，通过对历代中医文献的系统整理，认为本病多以肝肾亏虚为基础，闪挫劳损及感受外邪为诱因，从而使气血瘀滞，痰湿内生，经脉痹阻，气血运行不畅，遂致关节肿胀、疼痛。治当益气养血、补益肝肾，扶正祛邪、标本兼顾。其次，通过对现代医学文献的调研，指出诊断膝OA应临床与影像学检查相结合，应重视病情轻重程度的评估，治疗宜中西医互参，取长补短，内外结合。采用药物改善血循环以降低骨内压、抑制活化的细胞因子及生长因子、清除氧自由基、提高组织局部透明质酸以保护受损的软骨细胞是膝OA的治疗研究方向。同时介绍了目前尚处于动物实验阶段的基因疗法，这是一种把治疗基因运用基因转导技术转移到患病关节内的治疗方法，具有较好的应用前景。
临床研究方面，以平地行走疼痛为主要效应指标，对膝宁方治疗膝OA肝肾亏虚证的临床疗效与扶他林治疗相对照进行了研究观察，共设治疗组20例、对照组20例。结果表明膝宁组治疗后患者平地行走疼痛、晨僵、僵直程度、下楼及上楼的关节活动情况均较治疗前明显改善，与扶他林组疗效相当，膝宁方对膝关节平地行走疼痛的缓解起效较慢，但至治疗后第4周对疼痛的缓解与扶他林治疗相似，且膝宁方在治疗后第4周对病情的整体改善有优于扶他林的趋势，总有效率为85％。安全性方面的观察结果表明，膝宁组胃肠道不适等不良反应明显少于扶他林治疗组，提示该方具有良好的安全性。
Osteoarthritis of knee is an arthropathy characterized by hyperosteogeny due to degenerative articular cartilage. It is a common disease of middle- and old-aged people, of which incidence is on a steady increase along with longer life span and increasing number of old people. Patients with osteoarthritis of knee suffer a lot in daily life for swelling and painful knee, however effective treatment to reverse hyperosteogeny or check the deterioration has not yet been available. Since TCM has certain advantages on it, this research summarized the diagnosis and treatment of osteoarthritis of knee on the basis of TCM understanding and study development of modern treatment. Meanwhile research methods of parallel control and randomized group were adopted and objective evaluation was made of XINING Formula's clinical effect on walking pain due to osteoarthritis of knee with deficiency of liver and kidney.
Firstly, after arranging systematically previous literature of TCM, it holds that osteoarthritis of knee is based mainly on the deficiency of liver and kidney and precipitated by sprain, strain and invasion by exogenous pathogens and that swelling and painful knee results from stagnation of Qi, blood and endogenous phlegm and damp as well as obstruction of meridians. Therefore, the treatment should highlight the following principles: invigorating Qi and replenishing blood, tonifying liver and kidney, supporting vital Qi and dispelling evil Qi as well as emphasizing root causes and branch symptoms.
Then through studying literature of western medicine, it believes that osteoarthritis of knee should be diagnosed with combination of clinic examination and radiology and that evaluation of degree of condition and integrative treatment of TCM and western medicine should be stressed to enhance therapeutic effect. The treatment of osteoarthritis of knee is targeted at improving blood circulation, reducing intraosseous pressure, inhibiting activated cell factors and growth factors, eliminating oxygen free radicals, increasing hyaloplasmic acid of local tissues to protect impaired cartilage cells. In addition, this thesis introduced gene therapy that is still under the stage of animal experiment, in which therapeutic gene is transplanted into affected joint. Therefore, it is promising in clinical application.
In clinical research, clinical effect of XINING Formula, taken walking pain as chief effect index, on treating osteoarthritis of knee with deficiency of liver and kidney was compared with Votalin. There were 20 cases in treatment group and 20 in control group. The results showed that XINING group improved significantly in terms of walking pain, morning stiffness, the severity of stiffness and knee activities during climbing upstairs and downstairs after treatment, which had no significance comparing with Votalin group. Walking pain was improved with XINING Formula in slow start which then showed similar effect with Votalin in the 4th week of treatment and had the tendency of better effect in improving general conditions in the 4th week with 85% totally effective rate. The result in safety showed that gastrointestinal discomfort in XINING group was less than that in Votalin group, which indicated this formula was better in safety.
引文
1 Radin EL.Mechanical aspects ofosteoarthritis.Bull Rheum Dis, 1976, 26: 862.
2 Spector TD, Hart DJ, Nandra D.Low level increases in serum C-reactive protein are present in early osteoarthritis of the knee and pridict Progressive disease.Arthritis Rheum, 1997, 40: 723.
3 Goldring MB.Osteoarthritis and cartilage: the role of cytokines in this disorder.Curr Rheumatl 2000; 2:459
4 Price JS, Water JG, Darrah C, et al.therole of chondrocyte senescence in osteoarthritis.Aging Cell 2002; 1(1): 57
5 Martin JA, Buakwalter JA.The role of chondrocyte senescence in the pathogenesis of osteoarthritis an in limiting cartilage repair.J Bone Joint Surg Am 2003; 85 A2: 106
6 Shieh AC, Athanasiou KA.Biomechanies of single chondroeytes and osteoˉarthritis.Crit Rev Biomed Eng 2002; 30(4): 307
7 Teiehtahl A, Wluka A, Cicuttini FM.Abnormal biomechanies: a Precursor or result of knee osteoarthritis.Br J Sports Med 2003; 37(4): 289
8 Sinkov V, Cymet T.Osteoarthritis: understanding the pathophysiology, genetics, and treatments.J Natl Med Assoc 2003; 95(6): 475
9 Kim SJ, Kim YH.The modulation of integrin expression by the extracellular matrix in articular chondrocytes. Yonsei Med J 2003; 44(3): 493
10 Yoshihara Y, Nakamura H, Obata K, et al.Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis.Am Rhem Dis 2000; 59:455
11 Patwari P, Cook MN, Di Micco MA, et al.Proteoglycan degradation after injurious compression of bovine and human articular cartilage in vitro: interaction with exogenous cytokines.Arthritis Rheum 2003; 48(5): 1292
12 李景学，孙鼎元．骨关节X线诊断学．北京：人民卫生出版社，1992，376
13 林禾，许能銮．性关节炎2410张膝关节X线分析．福建医科大学学报，2000，34(2)：199
14 户松泰介．变形性膝关节关节造影像关节软骨变化临整外，1982，17：985
15 Tatsou Kobayashi.Osreophyteformation in the knee joint: Aradiological study.JJpn Orthop Assoc, 1994,68:139
16 林秋强，陈显恩，刘源．无症状膝关节炎．风湿病杂志，1997，2(4)：33
17 腰野富久，变形性膝关节症病因、诊断治疗．整形外科，1992，43(11)：1629
18 桥村正隆，黑板昌弘，水野耕作，变形性膝关节症 malalignment．整·灾外，1995，38：3
19 刘晓平，于秀淳．膝关节骨性关节炎胫骨上端骨内血管造影．临床放射学杂志，1994，13(2)：106
20 江浩主编．骨与关节MRI．上海科学技术出版社，1999年第1版：526-527
21 韩涛，王立德．放射性核素骨显像在老年性膝关节骨性关节炎诊治中的应用．中国矫形外科杂志，2001，8(3)：233
22 史念曹，董鲁霞．超声在膝关节骨性关节炎诊断中的应用．中国超声医学杂志，1996，12(10)
23 樊静，杨旭燕．超声诊断膝骨关节炎的价值探讨．中国超声医学杂志，1998，14(4)．
24 史念曾，薛庆法，史海红．膝关节骨性关节炎的超声诊断．临床医学，2002，22(7)：29
25 中华医学会风湿病学分会．骨关节炎诊治指南(草案)．中华风湿病学杂志，2003，7(11)：702
26 Lequesne MG, Samsons S.Indices of severity in OA weight bearing joints. J Rheum. 1991, 18(Suppl 27): 16
27 Insall J N, Ranawat C S, Aglietti P, et al. J Bone Joint Surg.1976; 6A: 244
28 腰野富久．OA膝治療成績判定基準．日整会誌，1988，62：901-902
29 王庆甫，黄沪．膝关节骨性关节炎的X线影像学分析．中国骨伤，2000，13(6)：348
30 季卫平，王小玲．吕国强膝关节退变的X线量化分析．中国中医骨伤科，1995，3(6)：9
31 杜宁，任峰，杨琦．膝关节骨关节病体征与功能的相互关系研究．中国中医骨伤科，1996，3(6)：9
32 吴海山主编．膝关节镜外科[M]．上海：上海科学技术文献出版社，1992，5814
33 David T.Feison.The Drevalence of Knee Osteoarthritis in the oldly.Arthritis Rhevmatism 1987,30:914
34 Ogilvie-Harris D J, Jackson RW.The arthroscopic treatment of chondromalaeia patella[J].J Bone Joint Surg(Br), 1984, 66:660-665
35 吴林生，金嫣莉．中药及手法治疗膝关节骨性关节炎121例疗效分析．中医杂志，1993， 34(12)：742
36 刘洪旺，刘志刚，孙宝金．退行性膝关节骨性关节病的中医辨证施治．中国骨伤，1997，10(4)：27．
37 张建福．骨质增生病的中西医诊疗．北京：中国中医药出版社，1995，59．
38 王勇，王天学，等．益肾宣痹汤治疗膝关节骨性关节炎．甘肃中医学院学报，2002，19(4)：35．
39 张雨时．虎潜丸加减治疗骨性关节炎18例．湖南中医杂志，1999，15(1)：31．
40 周成刚．复方软伤伸筋丸治疗膝关节骨性关节炎临床研究．中国中医骨伤科杂志2003，11(3)：5．
41 曹向阳，李无阴，等．壮筋活血汤治疗膝骨性关节炎152例．上海中医药杂志，2004，38(6)：30．
42 徐振奇，柴叶红，等．“膝痛消”熏洗治疗膝关节骨性关节炎的疗效．中国老年学杂志，2004，24(9)：791．
43 姜洪洋，薛剑冰，等．中药熏洗治疗膝关节骨性关节炎120例报告．中医正骨，2004，16(7)：50．
44 祁振良 中药熏洗治疗增生性膝关节炎[J]．中医外治杂志，1998，5(12)：59．
45 刘访文 中药熏洗治疗膝关节骨关节炎[J]．江苏中医，2000，21(11)：37．
46 邵晓，叶澍．中药熏蒸治疗膝关节骨性关节炎51例疗效观察．中医正骨，2004，16(7)：32．
47 何端仪，丛鹏．中药熏蒸治疗膝骨性关节炎95例．中医研究，2001，14(6)：59．
48 曹会民．蟾马逐痹浸液外用治疗骨性关节炎疗效观察．河北中医，2002，(24)8：576．
49 唐祯．通痹活血膏治疗四肢骨性关节炎96例．中医药信息，2001，18(3)：41．
50 崔育生．中药外敷治疗骨性关节炎．中医外治杂志，2004，13(5)：38．
51 高翔，吴韬，藤松茂，等．华伤膝Ⅰ号熨疗治疗膝关节病103例[J]．中医外治杂志，2001，10(5)：6～7．
52 余建设，杨新江，许映，等．中药热熨法治疗骨关节病45例[J]．安徽中医临床杂志，1997，9(4)：195-196．
53 尹兰山，蔡艳，等．中药蜡垫疗法治疗膝关节骨性关节炎126例．中国疗养医学，2002，11(1)：22．
54 李正祥．针刺并功能锻炼为主治疗膝关节骨性关节炎124例．现代康复，2000，4(12)1891．
55 任彬，杨敏．针刺为主治疗膝骨性关节炎152例．中国针灸，2002，22(12)：825．
56 李宁，吴滨，张永玲．艾灸配合运动疗法治疗膝关节骨性关节炎疗效观察．中国针灸，2002，22(11)：729．
57 黄静．瘢痕灸治疗膝骨关节炎50例疗效观察．针灸临床杂志，2002，18(3)：44．
58 李兰敏，张立夫，杨会道．电针治疗中老年骨性关节炎165例．针灸临床杂志，1997，13(10)：27．
59 李亚东．火针治疗膝关节骨性关节炎49例．山西中医，2002，18(3)：42．
60 陈玉玲，莫穗林．穴位注射在骨性关节炎治疗中的应用．中国医刊，2001，36(2)：44．
61 孙钢．膝关节骨性关节炎的手法治疗．中国骨伤，2002，15(5)：318．
62 张贺民．按摇膝眼法治疗膝关节骨性关节炎．中国临床医生，2002，30(4)：50．
63 汪利合．点穴加旋转屈伸手法治疗膝关节骨性关节炎．中国民间疗法，2002，10(11)：29
64 张凤山，孙铀．骨性关节炎的诊断及防治进展．新医学，2002，33(9)：526．
65 陈华庭，谭红爱．治疗骨性关节炎的特异性药物：硫酸氨基葡萄糖．医药导报，2001， 20 (12): 781.
66 Endes AF, Caramona MM, Carvalho AP, et al.Diacerhein and rhein prevent interleukinl beta induced nuclear factor kappa B activation by inhibiting the degradation of inhibitor kappa Balpha.Pharmacol Toxicol, 2002, 91: 22-28.
67 桂英．骨关节炎及其药物治疗的最佳选择．中华风湿病学杂志，2003，7(3)：129
68 袁欣，马飒飒．透明质酸钠治疗膝关节骨性关节炎关节疼痛活动障碍53例．现代康复，2001，5(10)：99．
69 黄象望，肖晟．高分子透明质酸钠囊内注射治疗膝关节骨性关节炎120例．湖南医学，2001，18(5)：355．
70 孙月娟，崔建伟，胡义明．得宝松局部封闭治疗膝关节骨性关节炎临床观察．青岛医药卫生，1997，29(5)：50．
71 侯金成，况兵．药物注射治疗类风湿与骨性关节炎概述．中国药业，2001，10(12)：64．
72 张国祥．蜂毒治疗膝关节炎75例．医学理论与实践，1999，9(12)：550．
73 史宝明，袁培义，郭钧，等．膝关节骨性关节炎的冲洗疗法．临床骨科杂志，2000，3(1)：46
74 侯凌枫，徐学明，黄儒收．关节冲洗液压扩张治疗膝骨性关节炎80例．中国厂矿医学，2001，14(1)：20．
75 何学艺，郑兵权，刘威．关节清理和钻孔减压治疗膝关节骨性关节炎．中医正骨，2002，14(1)：46．
76 孙新，王根兆．钻孔减压治疗膝骨性关节炎37例．前卫医药杂志，1995，12(6)：336．
77 朱建军，刘自建，宗兆凯．钻孔减压后冲洗治疗膝关节骨性关节炎62例报告．山东医药，2001，41(2)：49．
78 张鹏．胫骨高位截骨治疗膝关节骨性关节炎膝内翻33例报告．山西医药杂志，1999，28(6)：500．
79 黄小颂，张建军．胫骨高位截骨治疗膝关节骨性关节炎合并膝内翻畸形．中医正骨，2000，12(10)：42．
80 安挺秀，马长有，李进法，等．胫骨高位截骨合并骨膜移植治疗膝关节骨性关节炎．中国修复重建外科杂志，1998，12(4)：226．
81 刘宁，查振刚，姚平，等．全膝关节置换术治疗骨关节炎．生物学杂志，2004，21(3)：32．
82 何仲佳，刘先银，莫新发，等．保留后交叉韧带全膝关节置换术治疗骨性关节炎．中国矫形外科杂志，2004，12(17)：1293．
83 陆金荣，金才益，徐阿炳，等．人工全膝关节置换术治疗老年膝关节骨性关节炎18例．武警医学，2002，13(2)：88．
84 吴青，武国，蒋成，等．关节镜治疗膝关节骨性关节炎．四川医学，2004，25(4)：136．
85 张同仁，陈瑞光，陈鸿辉，等．关节镜下清理术治疗膝关节骨关节炎．中国内镜杂志，1999，5(2)：25．
86 敖邦华，姜衫，时广敬，等．OA液加膝关节镜清理治疗骨性关节炎78例．中国骨伤，1998，11(6)：45．
87 朱汉章．针刀学原理[M]．北京：人民卫生出版社，2002，685-686．
88 俞杰，明顺培，张秀芬．针刀疗法对兔膝骨关节炎关节液中IL-1β、IL-6、TNF-α水平的影响．中国中医骨伤科杂志，2002，10(4)：15-18．
89 周士枋，范振华．实用康复医学．南京：东南大学出版社，1998，134
90 陈景藻．现代物理治疗学．北京：人民军医出版社，2001，130-620
91 Kathleen B, Sweeney Mark A, Merrick CD, et al.Therapeutic magnets do not affect tissue temperatures.JAthl Train, 2001, 36(1): 27
92 Stelian J, Gil I, Habot B, et al.Improvement of pain and disability in elderly patients with degenerative osteoarthritis of the the knee treated with narrow-band light therapy.J Am Geriatr Soc, 1992, 40(1): 23
93 James NP, Elizabeth G, Gwenderlyn FJ, et al.A critical appraisal of clinical practice guidelines for the treatment of lower-limb osteoarthritis Arthritis Res, 2002, 4(1): 36
94 冯坤，郭建刚，王健智，等．补肾活血对骨关节炎软骨退变的拮抗作用研究．辽宁中医杂志，1999，26(11)：523．524
95 郭万首，马丽，吴东海，等．白介素1受体拮抗蛋白间接体内转基因对兔骨性关节炎的抑制作用．解放军医学杂志，2004，29(6)：475-478
96 邱贵兴．兔膝关节制动引起关节软骨退变的实验研究．中华外科杂志，1987，25(3)：175-177
97 王国文，潘海乐，曲波，等．参麦注射液对骨关节炎模型动物关节软骨胶原含量的影响．中国中医骨伤科杂志，2001，9(2)：14-16
98 Yasuhio, Tsuneok, HirokazuT, etal, EffactofSL-1010(sodiumhyaluronatewithhighmolecular weight)on experimental osteoarthritis induced by introarticularly, appalied in rabbits.Foia Pharmacol Japon. 1992, 100:67
99 江中潮，何洪阳，刘罡，等．骨生注射液对实验性骨性关节炎家兔血浆SOD和MDA的影响．中国骨伤，2004，17(10)：593-595
100 沈培芝．强筋方治疗实验性膝骨关节炎的组织病理学观察研究．中国中医骨伤科杂志，1995，3(1)：10-13
101 董建勇，赵晓薇，李立，等．实验性骨关节炎关节软骨P、K、Ca、S元素的变化．中国骨伤，1999，12(5)：25-26
102 汪青春，董蕙芳，沈培芝，等．中药对膝骨关节炎黑鼠血清SOD、HA、NO水平的影响．中医正骨，1999，11(5)：6-8
103 Olszewski J, Mc DormellJ, Stevens K, etal. Amatrixmetal lopro-teinase-generated aggre can neopitopeasa marker of skeletal matu-ration and aginginc artilage. Arthritis Rheum,1996, 39(7): 1234-1237.
104 高文香，刘元禄，李永生，等．补肾法防治兔膝关节骨性关节炎的病理形态学观察．中医正骨，1999，11(11)：13．16
105 黄涛，黄昌林．不同运动方式对骨性关节炎关节功能障碍的防治．中国康复，1999，14(1)：6-8
106 钟汉馨，黄涛．不同运动方式引起关节软骨改变的病理研究．现代康复，2001，5(1)：36-37
107 欧阳建江，黄有荣，熊仁英，等．川芎嗪对大白兔膝关节骨性关节炎血清SOD、MDA及NO的影响．广西中医药，2004，27(5)：40-42
108 王秀华，刘元禄，苏姿兵，等．丹参关节内注射对兔膝骨关节炎细胞因子IL-1及TNF的影响．中医正骨，2003，15(10)：1-3
109 赵丹慧，张艳，薛延，等．豚鼠原发性骨性关节炎超微结构与生化改变的动态观察．中华手外科杂志，1999，15(3)：180-183
110 蓝旭，刘雪梅，葛宝丰，等．豚鼠原发性骨性关节炎的血清IGF-I检测及义．中国 矫形外科杂志，2000，7(7)：667-668
111 俞杰，明顺培，张秀芬，等．针刀疗法对兔膝骨关节炎关节液中IL-1β、IL-6、TNF-α水平的影响．中国中医骨伤科杂志，2002，10(4)：15-18
112 马建兵，刘德玉，李堪印，等．中药对家兔实验性膝关节骨性关节炎氧自由基代谢的影响．中医正骨，2000，12(1)：8．10
113 王耶．丹参和透明质酸钠注射液对骨性关节炎治疗作用的实验研究．中国生化药物杂志，1998，19(5)：248-250
114 任峰．益气养血通络法(治血痹法)对小鼠骨关节病的实验研究．上海中医药杂志，1994，7：41-42
115 黄涛，徐传毅，邹季，等．活血止痛汤治疗早期骨性关节炎的实验研究．中医正骨，1999，11(5)：3-5
116 江伟达，郑效文，郑清波，等．中药关节Ⅲ号方治疗家兔膝骨关节炎的实验研究．中国中医骨伤科，1994，2(1)：1-3
117 曹月龙，冯伟，李宗举，等．软骨Ⅱ号对骨关节炎兔不同部位PGE2选择性抑制作用的实验研究．中国骨伤，2001，14(10)：597-598
118 郭建刚，冯坤，赵然，等．壮筋活血汤对骨性关节炎软骨退变作用的实验研究．中国骨伤，1999，12(5)：19-21
119 汪青春，石印玉，沈培芝，等．中药对膝骨关节炎小鼠关节软骨IL-1、iNOS基因表达的影响．山西医药杂志，1999，28(5)：381-383
120 郑召民，许振华，于晓牧．川芎对家兔膝关节骨性关节炎骨内压的影响．河南外科学杂志，1997，3(1)：30-31
121 邓廉夫，柴本甫．IL-1、TNF和IL-6与骨性关节炎．国外医学·创伤与外科基本问题分册，1996，17(2)：102-106
122 邵洪．氧自由基与蛋白质代谢．国外医学·分子生物学分册，1990，12：42
123 Panasiuk AF, Laroshuk GV, Mitrovich D. Effect of free and radical sonproliferation and metabolism of chondrocyres and onsensitivity of acellular monolayer to proteases Vopr.Med KHIM, 1995, 41: 19
124 Blanco FJ, Ochs RI, Schwarz H, et al.Chondrocyteapoptosis induced by nitricoxide.AmJPathol, 1995, 146:75
1 PelletierJP, Di Battista JA, RoughleyPJ, etal: Cytokines and Inflammation in Cartilage Degradation. In Moskowitz RW (ed). Osteoarthritis, Edition of Rheumatic Disease Clinics of North America. Philadelphia, WB Saunders Company 545-568, 1993
2 PelletierJP, Martel-Pelletier J, HowellDS: Etiopathogenesis of Osteoarthritis. In Koopman WJ (ed). Arthritis and Allied Conditions. A Textbook of Rheumatology. Ed 13. Baltimore, Williams & wilkins 1969-1984, 1997
3 Pelletier JP, McCollumR, CloutierJM, Martel-Pelletier J: Synthesis of metalloproteases and interleukin 6 (IL-6) in human osteoarthritic synovial membrane is an IL-1 mediated process. J Rheumatol 22: 109-114, 1995
4 Firestein GS, BergerAE, Tracey DE, et al: IL-1 receptor antagonist protein production and gene expression in rheumatoid arthritis and osteoarthritis synovium. J Immunol 149: 1054-1062, 1992.
5 Pelltier JP, Mineau F, Ranger P, et al: The increased synthesis of inducible intric oxide inhibits IL-1Ra synthesis by human articular chondrocytes : possible role in osteoarthritic cartilage degradation. Osteoarthritis cartilage4: 77364-366, 1999
6 Martel-Pelletier J, McCollum R, Di Battista JA, et al: The interleukin-1 receptor in normal and osteoarthritic human articular chondrocytes. Identification as the type I receptor and analysis of binding kinetics and biologic function .Arthritis Rheum 35: 530-540, 1992
7 Sadouk M, Pelletier JP, Tardif G, et al: Human synovial fibroblasts coexpress interleukin-1 receptor type I and type II mRNA: The increased level of the interleukin-1 receptor in osteoarthritic cells is related to an increased level of the type I receptor .Lab Invest 73: 347-355, 1995
8 ArendWP: Interleukin-lreceptor antagonist. Adv Immunol54: 167-227, 1993.
9 Arend WP, Dayer JM: Inhibition of the production and effects of interleukin-land tumor necrosis factor alpha in rheumatoid arthritis Rheum 38: 151-160, 1995.
10 Arner EC, Harris RR, DiMeo TM, et al : interleukin-1 receptor antagonist inhibits proteoglycan breakdown in antigen induced but not polycation induced arthritis in rabbit. J Rhumatol 22: 1338-1346, 1995.
11 Caron JP, Fernandes JC, Martel-Pelletier J, et al: Chondroprotective effect of intraarticular injections of interleukin-1 receptor antagonist in experimental osteoarthritis : Suppression of collagenase-1 expression. Arthritis Rheum39: 1535-1544, 1996
12 BandaraG, Mueller GM, Galea-Lauri J, etal: Intraarticular expression of biologically active interleukin 1-receptor-antagonist protein by ex vivo gene transfer. Proc Natl Acad Sci USA 90: 10764-10768, 1993.
13 Baragi VM, Renkiewicz RR, Jordan H, etal: Transplantation of transduced chondrocytes protects articular cartilage from interleukin 1-induced extracellular matrix degradation. J Clin Invest 96: 2454-2460, 1995
14 Bandara G, RobbinsPD, Georgescu HI, et al : Genetransfer to synoviovytes for gene treatmentforarthritis.DNA Cell Biol 11: 227-231, 1992
15 Evans C, Robbins PD: Prospects for treating arthritis by gene therapy.J Rheumatol 21: 779-782, 1994.
16 Evans CH, Robbins PD: Gene Therapy for Arthritis. In Wolff JA(ed). Gene Therapeutics: Methods and Applications of Direct Gene Transfer. Boston, Birkhauser 320-343, 1994.
17 Evans CH, Robbins PD: Pathways to gene therapy in rheumatoid arthritis.Curr Opin Rheumatol 8: 20-234, 1996.
18 HungGL, Galea-Lauri J, Mueller GM, et al: Suppression of intraarticular responses to interleukin-1 by transfer of the interleukin-1 receptor antagonist gene to synovium .Gene Therl: 64-69, 1994
19 MakarovSS, OlsenJC, Johnston WN, etal: Retrovirus mediated in vivo gene transfer to synovium in bacterial cell wall-induced arthritis in rats. Gene Ther2: 424-428, 1995
20 Otani K, NitalM. MacaulayW, etal: Suppression of antigen-induced arthritis in rabbits by ex vivo gene therapy. J Immunol 156: 3558-3562, 1996
21 Pelletier JP, Evans CH, et al: In vivo suppression of early experimental osteoarthritis by IL-Ra using gene therapy. Arthritis Rheum 40: 1012-1019, 1997
22 Roessler BJ, Allen ED, Wilson JM, et al: Adenoviral-mediated gene transfer to rabbit synovium in vivo. JClin Invesr92: 1085-1092, 1993
23 NitaLM, Ghivizzani SC, Galea-Lauri J, etal: Direct gene delivery to synovium. An evaluation of potential vectors in vitro and in vivo. Arthritis Rheum 39: 820-828, 1996
24 Tomita N, Morishita R, Higaki J, et al: In vivo gene transfer of insulin gene into neonatal rats by the HVJ-liposome method resulted in sustained transgene expression. Gene Ther 3: 477-482, 1996
25 Tomita T, Hashimoto H, Tomita N, et al: In vivo direct gene transfer into articular cartilage by intraarticular injection mediated by HVJ (sendaivirus) and liposomes. Arthritis Rheum 40: 901-906, 1997
26 Yovandich J, O'Malley B, Sikes M, Ledley FD: Gene transfer to synovial cells by intraarticular administration of plasmid DNA. Hum Gene Ther 6: 603-610, 1995
27 BudkerV, Zhang G. Danko I, et al: The efficient expression of intravascularly delivered DNA in rat muscle. Gene Ther5: 272-276, 1998
28 Hartikka j, Sawdey M, Cornefert-Jensen F, et al: An improved plasmid DNA expression vector for direct injection into skeletal muscle. Hum Gene Ther7: 1205-1217, 1996
29 Stephan DJ, Yang ZY, San H, et al: A new cationic liposome DNA complex enhances the efficiency of arterial gene transfer in vivo. Hum Gene Ther 7: 1803-1812, 1996
30 Prockop DJ: Heritable osteoarthritis. Diagnosis and possible modes of cell and gene therapy. Osteoarthritis Cartilage 7: 364-366, 1999
31 Evans CH, Robbins PD: Potential treatment of osteoarthritis by gene therapy.Rheum Dis Clin North Am 25: 333-344, 1999.
32 Khang R, Robbins PD, Evans CH: Methods for Gene Transfer to Synovium. In Robbins PD(ed). Gene Therapy Protocols. Totowa, Humana Press357-368, 1997
33 Naffakh N, Henri A, Villeval JL, et al: Sustained delivery of erythropoietin in mice by genetically modified skin fibroblasts.Proc Natl Acad Sci USA 92: 3194-3198, 1995
34 Scharfmann R, Axelrod JH, Verma IM: Long-term in vivo expression of retrovirus-mediated gene transfer in mouse fibroblast implants. Proc Natl Acad Sci USA 88: 4626-4630, 1991
35 Doughty LA, PatreneKD, Evans CH, etal: Consti-tutive systemic expression of IL-1Ra or soluble TNF receptor by genetically modified hematopoietic cells suppresses LPS induction of IL-6 and IL-10. Gene Ther 4: 252-257, 1997.
36 Ghivizzani SC, Lechman ER, Kang R, et al: Direct adenovirus-mediated gene transfer ofinterleukin 1 and tumor necrosis factor alpha soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects. Proc Natl Acad Sci USA 95: 4613-4618, 1998
37 Ghivizzani SC, Kang R, Georgescu HI, et al: Constitutive intraarticular expression of human IL-1 beta following gene transfer to rabbitsynovium produces all major pathologies of human rheumatoid arthritis. J Immunol 159: 3604-3612, 1997.
38 Morland LW, Baumgartner SW, SchiffMH, etal: Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein N Engl J Med 337: 141-147, 1997
39 MUller-Ladner U, Roberts CR, Franklin BN, etal: Human IL-IRa gene transfer into human synovial fibroblasts is chondroprotective. J Immunol 158: 3492-3498, 1997
40 Fernandes JC, Tardif G, Martel-pelletier J, et al: In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: Prevention of osteoarthritis progression. Am J Pathol154: 1159-1169, 1999.
41 MUller-Ladner U, Evans CH, Franklin BN, etal: Gene transfer of cytokine inhibitors into human synovial fibroblasts in the SCID mouse model. Arthritis Rheym 42: 490-497, 1999
42 Kang R, Marui T, Ghivizzani SC, et al: Ex vivo gene transfer to chondrocytes in full-thickness articular cartilage defects: A feasibility study. Osteoarthritis Cartilage 5: 139-143, 1997
43 Doherty PJ, Zhang H, Tremblay L, et al: Resurfacing of articular cartilage explants with genetically-modified human chonderocytes in vitro.Osteoarthri-tis Cartilage 6: 153-159, 1998.
44 AraiY, Kohbayashi K, etal: adenovirus vector-mediated gene transduction to chondrocytes : in vitro evaluation of therapeutic efficacy of transforming growth factor-beta 1 and heat shock protein 70 gene transduction J Rheumatol 24: 1787-1795, 1997
45 Evans CH, Ghivizzani SC, Kang R, et al: Gene therapy for rheumatic diseases.Arthritis Rheum 42: 1-16, 1999.
46 Brittberg M, Lindahl A, Nilsson A, et al: Treatment of deep cartilage defects in the knee with autologouschondrocyte transplantation. N Engl J Med 331: 889-895, 1994
47 Wakitani S, Goto T, Pineda SJ, etal: Mesenchymal cell-based repair of large, full-thickness defedcts of articular cartilage. J Bone Joint Surg76A: 579-592, 1994
48 Hilal G, Martel-Pelletier JP, et al: Osteoblast-like cells from human subchondral osteoarthritis bone demonstrate an altered phenotype in vivo: possible role in subchondral bone sclerosis. Arthritis Rheum41: 891-899, 1998
49 Glansbeek HL, Van Beuningen HM, Vitters EL, et al: Stimulation of articular cartilage repair in established artliritis by local administration of transforming growth factor-beta into knee joints. Lab Invest 78: 133-142, 1998
50 Sailor LZ, Hewick RM, Morris EA: Recombinant human bone morphogenetic protein-2 maintains the articular chondrocyte phenotype in long-term culture. J Orthop Res 14: 937-945, 1996
51 Gerich TG, Kang R, Fu FH, et al: Gene transfer to the rabbit patellar tendon: potential for genetic enhancement of tendon and ligament healing. Gene Ther 3: 1089-1093, 1996.
52 RazE, Watanabe A, Baird SM, etal: Systemic immunological effects of cytokine genes injected into skeletal muscle. Proc Natl Acad Sci USA90: 4523-4527, 1993
53 Song XY, Gu M, Jin WW, et al: Plasmid DNA encoding transforming growth factor-betal suppresses chronic disease in a streptococcal cell wall-induced arthritis model. J ClinInvest 101: 2615-2621, 1998
54 ShiozawaS, Shimizu K, TanakaK, Hino K: Studies on the contribution of c-fos/AP-1 to arthritic joint destruction. J ClinInvest99: 1210-1216, 1997
55 Chernajovsky Y, Adams G, Triantaphyllopoulos K; et al: Pathogenic lymphoid cells engineered to express TGF beta 1 ameliorate disease in a collagen-induced arthritis model. Gene Ther 4: 553-559, 1997.
56 Chernajovsky Y, Adams G, PodhajcerOL, et al: Inhibition of transfer of collagen-induced arthritis into SCID mice by ex vivo infection of spleen cells with retroviruses expressing soluble tumor necrosis factor receptor. Gene Ther 2: 731 -73 5, 1995.
57 BessisN, BoissierMC, FerraraP, etal: Attenuation of collagen-induced arthritis in mice by treatment with vector cells engineered to secrete interleukin-13.Eur J Immunol 26:2399-2403, 1996
58 Evans CH, Rediske JJ, Abramson SB, Robbins PD: Joint efforts: Tackling arthritis using gene therapy.Fist International Meeting on the Gene Therapy of Arthritis and Related Disorders.Bethesda, MD, December 2-3, 1998.Mol Med Today 5: 148-151, 1999.
59 Vacanti CA, Kim W, SchlooB, etal: Joint resurfacing with cartilage grown in situ from cell-polymer structures.Am J Sports Med 22: 485-488, 1994
60 Homminga GN, Bulstra SK, Bouwmeester PS, vander Linden AJ: Prichondral grafting for cartilage lesions of the knee. J Bone Joint Surg72B: 1003-1007, 1990
61 Kreder HJ, Moran M, Keeley FW, Salter RB: Biologic resurfacing of a major joint defect with cryopreserved allogeneic periosteum under the influence of continuous passive motion in a rabbit model. Clin Orthop300: 288-296, 1994
62 Mason JM, Grande DA, Barcia M, et al: Expression of human bone morphogenic protein 7 in primary rabbit periosteal cells: Potential utility in gene therapy for osteochondral repair. Gene Thwr5: 1098-1104, 1998
63 Evans CH, Robbins PD, GhivizzaniSC, etal: Clinical trial to assess the safety, feasibility znd eflBcacy transferring a potentially anti-arthritic cytokine gene to human joins with rheumatoid arthritis.Hum Gene Thei7: 1261-1280, 1996.
64 Palmer TD, Rosman GJ, Osborne WR, Miller AD: Genetically modified skin fibroblasts persist long after transplantation but gradually inactivate inactivate introduced genes. Proc Natl Acad Sci USA 88: 1330-1334, 1996
65 Vacanti CA, Kim W, Schloo B, et al: Joint resurfacing with cartilage grown in situ from cell-polymer structures.Am J Sports Med 22: 485-488, 1994
66 Fernandes JC, Martel-pelletier J, Pelletier JP: The use of gene therapy in osteoarthritis: Present and future.Curr Opin Orthop 10: 458-465, 1999.
1.Bellamy N, et al. Validation study ofWOMAC. J Rheumatol, 1988,Dec;15(12): 1833-40
2.Bonica JJ, et al. The management of pain. 2nd ed. Philadephia: Lea and Febiger, 1990. 581
3 Feldman M, McMahon AT. Ann Intern Med, 2000,132:134-143
2 Spector TD, Hart DJ, Nandra D.Low level increases in serum C-reactive protein are present in early osteoarthritis of the knee and pridict Progressive disease.Arthritis Rheum, 1997, 40: 723.
3 Goldring MB.Osteoarthritis and cartilage: the role of cytokines in this disorder.Curr Rheumatl 2000; 2:459
4 Price JS, Water JG, Darrah C, et al.therole of chondrocyte senescence in osteoarthritis.Aging Cell 2002; 1(1): 57
5 Martin JA, Buakwalter JA.The role of chondrocyte senescence in the pathogenesis of osteoarthritis an in limiting cartilage repair.J Bone Joint Surg Am 2003; 85 A2: 106
6 Shieh AC, Athanasiou KA.Biomechanies of single chondroeytes and osteoˉarthritis.Crit Rev Biomed Eng 2002; 30(4): 307
7 Teiehtahl A, Wluka A, Cicuttini FM.Abnormal biomechanies: a Precursor or result of knee osteoarthritis.Br J Sports Med 2003; 37(4): 289
8 Sinkov V, Cymet T.Osteoarthritis: understanding the pathophysiology, genetics, and treatments.J Natl Med Assoc 2003; 95(6): 475
9 Kim SJ, Kim YH.The modulation of integrin expression by the extracellular matrix in articular chondrocytes. Yonsei Med J 2003; 44(3): 493
10 Yoshihara Y, Nakamura H, Obata K, et al.Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis.Am Rhem Dis 2000; 59:455
11 Patwari P, Cook MN, Di Micco MA, et al.Proteoglycan degradation after injurious compression of bovine and human articular cartilage in vitro: interaction with exogenous cytokines.Arthritis Rheum 2003; 48(5): 1292
12 李景学，孙鼎元．骨关节X线诊断学．北京：人民卫生出版社，1992，376
13 林禾，许能銮．性关节炎2410张膝关节X线分析．福建医科大学学报，2000，34(2)：199
14 户松泰介．变形性膝关节关节造影像关节软骨变化临整外，1982，17：985
15 Tatsou Kobayashi.Osreophyteformation in the knee joint: Aradiological study.JJpn Orthop Assoc, 1994,68:139
16 林秋强，陈显恩，刘源．无症状膝关节炎．风湿病杂志，1997，2(4)：33
17 腰野富久，变形性膝关节症病因、诊断治疗．整形外科，1992，43(11)：1629
18 桥村正隆，黑板昌弘，水野耕作，变形性膝关节症 malalignment．整·灾外，1995，38：3
19 刘晓平，于秀淳．膝关节骨性关节炎胫骨上端骨内血管造影．临床放射学杂志，1994，13(2)：106
20 江浩主编．骨与关节MRI．上海科学技术出版社，1999年第1版：526-527
21 韩涛，王立德．放射性核素骨显像在老年性膝关节骨性关节炎诊治中的应用．中国矫形外科杂志，2001，8(3)：233
22 史念曹，董鲁霞．超声在膝关节骨性关节炎诊断中的应用．中国超声医学杂志，1996，12(10)
23 樊静，杨旭燕．超声诊断膝骨关节炎的价值探讨．中国超声医学杂志，1998，14(4)．
24 史念曾，薛庆法，史海红．膝关节骨性关节炎的超声诊断．临床医学，2002，22(7)：29
25 中华医学会风湿病学分会．骨关节炎诊治指南(草案)．中华风湿病学杂志，2003，7(11)：702
26 Lequesne MG, Samsons S.Indices of severity in OA weight bearing joints. J Rheum. 1991, 18(Suppl 27): 16
27 Insall J N, Ranawat C S, Aglietti P, et al. J Bone Joint Surg.1976; 6A: 244
28 腰野富久．OA膝治療成績判定基準．日整会誌，1988，62：901-902
29 王庆甫，黄沪．膝关节骨性关节炎的X线影像学分析．中国骨伤，2000，13(6)：348
30 季卫平，王小玲．吕国强膝关节退变的X线量化分析．中国中医骨伤科，1995，3(6)：9
31 杜宁，任峰，杨琦．膝关节骨关节病体征与功能的相互关系研究．中国中医骨伤科，1996，3(6)：9
32 吴海山主编．膝关节镜外科[M]．上海：上海科学技术文献出版社，1992，5814
33 David T.Feison.The Drevalence of Knee Osteoarthritis in the oldly.Arthritis Rhevmatism 1987,30:914
34 Ogilvie-Harris D J, Jackson RW.The arthroscopic treatment of chondromalaeia patella[J].J Bone Joint Surg(Br), 1984, 66:660-665
35 吴林生，金嫣莉．中药及手法治疗膝关节骨性关节炎121例疗效分析．中医杂志，1993， 34(12)：742
36 刘洪旺，刘志刚，孙宝金．退行性膝关节骨性关节病的中医辨证施治．中国骨伤，1997，10(4)：27．
37 张建福．骨质增生病的中西医诊疗．北京：中国中医药出版社，1995，59．
38 王勇，王天学，等．益肾宣痹汤治疗膝关节骨性关节炎．甘肃中医学院学报，2002，19(4)：35．
39 张雨时．虎潜丸加减治疗骨性关节炎18例．湖南中医杂志，1999，15(1)：31．
40 周成刚．复方软伤伸筋丸治疗膝关节骨性关节炎临床研究．中国中医骨伤科杂志2003，11(3)：5．
41 曹向阳，李无阴，等．壮筋活血汤治疗膝骨性关节炎152例．上海中医药杂志，2004，38(6)：30．
42 徐振奇，柴叶红，等．“膝痛消”熏洗治疗膝关节骨性关节炎的疗效．中国老年学杂志，2004，24(9)：791．
43 姜洪洋，薛剑冰，等．中药熏洗治疗膝关节骨性关节炎120例报告．中医正骨，2004，16(7)：50．
44 祁振良 中药熏洗治疗增生性膝关节炎[J]．中医外治杂志，1998，5(12)：59．
45 刘访文 中药熏洗治疗膝关节骨关节炎[J]．江苏中医，2000，21(11)：37．
46 邵晓，叶澍．中药熏蒸治疗膝关节骨性关节炎51例疗效观察．中医正骨，2004，16(7)：32．
47 何端仪，丛鹏．中药熏蒸治疗膝骨性关节炎95例．中医研究，2001，14(6)：59．
48 曹会民．蟾马逐痹浸液外用治疗骨性关节炎疗效观察．河北中医，2002，(24)8：576．
49 唐祯．通痹活血膏治疗四肢骨性关节炎96例．中医药信息，2001，18(3)：41．
50 崔育生．中药外敷治疗骨性关节炎．中医外治杂志，2004，13(5)：38．
51 高翔，吴韬，藤松茂，等．华伤膝Ⅰ号熨疗治疗膝关节病103例[J]．中医外治杂志，2001，10(5)：6～7．
52 余建设，杨新江，许映，等．中药热熨法治疗骨关节病45例[J]．安徽中医临床杂志，1997，9(4)：195-196．
53 尹兰山，蔡艳，等．中药蜡垫疗法治疗膝关节骨性关节炎126例．中国疗养医学，2002，11(1)：22．
54 李正祥．针刺并功能锻炼为主治疗膝关节骨性关节炎124例．现代康复，2000，4(12)1891．
55 任彬，杨敏．针刺为主治疗膝骨性关节炎152例．中国针灸，2002，22(12)：825．
56 李宁，吴滨，张永玲．艾灸配合运动疗法治疗膝关节骨性关节炎疗效观察．中国针灸，2002，22(11)：729．
57 黄静．瘢痕灸治疗膝骨关节炎50例疗效观察．针灸临床杂志，2002，18(3)：44．
58 李兰敏，张立夫，杨会道．电针治疗中老年骨性关节炎165例．针灸临床杂志，1997，13(10)：27．
59 李亚东．火针治疗膝关节骨性关节炎49例．山西中医，2002，18(3)：42．
60 陈玉玲，莫穗林．穴位注射在骨性关节炎治疗中的应用．中国医刊，2001，36(2)：44．
61 孙钢．膝关节骨性关节炎的手法治疗．中国骨伤，2002，15(5)：318．
62 张贺民．按摇膝眼法治疗膝关节骨性关节炎．中国临床医生，2002，30(4)：50．
63 汪利合．点穴加旋转屈伸手法治疗膝关节骨性关节炎．中国民间疗法，2002，10(11)：29
64 张凤山，孙铀．骨性关节炎的诊断及防治进展．新医学，2002，33(9)：526．
65 陈华庭，谭红爱．治疗骨性关节炎的特异性药物：硫酸氨基葡萄糖．医药导报，2001， 20 (12): 781.
66 Endes AF, Caramona MM, Carvalho AP, et al.Diacerhein and rhein prevent interleukinl beta induced nuclear factor kappa B activation by inhibiting the degradation of inhibitor kappa Balpha.Pharmacol Toxicol, 2002, 91: 22-28.
67 桂英．骨关节炎及其药物治疗的最佳选择．中华风湿病学杂志，2003，7(3)：129
68 袁欣，马飒飒．透明质酸钠治疗膝关节骨性关节炎关节疼痛活动障碍53例．现代康复，2001，5(10)：99．
69 黄象望，肖晟．高分子透明质酸钠囊内注射治疗膝关节骨性关节炎120例．湖南医学，2001，18(5)：355．
70 孙月娟，崔建伟，胡义明．得宝松局部封闭治疗膝关节骨性关节炎临床观察．青岛医药卫生，1997，29(5)：50．
71 侯金成，况兵．药物注射治疗类风湿与骨性关节炎概述．中国药业，2001，10(12)：64．
72 张国祥．蜂毒治疗膝关节炎75例．医学理论与实践，1999，9(12)：550．
73 史宝明，袁培义，郭钧，等．膝关节骨性关节炎的冲洗疗法．临床骨科杂志，2000，3(1)：46
74 侯凌枫，徐学明，黄儒收．关节冲洗液压扩张治疗膝骨性关节炎80例．中国厂矿医学，2001，14(1)：20．
75 何学艺，郑兵权，刘威．关节清理和钻孔减压治疗膝关节骨性关节炎．中医正骨，2002，14(1)：46．
76 孙新，王根兆．钻孔减压治疗膝骨性关节炎37例．前卫医药杂志，1995，12(6)：336．
77 朱建军，刘自建，宗兆凯．钻孔减压后冲洗治疗膝关节骨性关节炎62例报告．山东医药，2001，41(2)：49．
78 张鹏．胫骨高位截骨治疗膝关节骨性关节炎膝内翻33例报告．山西医药杂志，1999，28(6)：500．
79 黄小颂，张建军．胫骨高位截骨治疗膝关节骨性关节炎合并膝内翻畸形．中医正骨，2000，12(10)：42．
80 安挺秀，马长有，李进法，等．胫骨高位截骨合并骨膜移植治疗膝关节骨性关节炎．中国修复重建外科杂志，1998，12(4)：226．
81 刘宁，查振刚，姚平，等．全膝关节置换术治疗骨关节炎．生物学杂志，2004，21(3)：32．
82 何仲佳，刘先银，莫新发，等．保留后交叉韧带全膝关节置换术治疗骨性关节炎．中国矫形外科杂志，2004，12(17)：1293．
83 陆金荣，金才益，徐阿炳，等．人工全膝关节置换术治疗老年膝关节骨性关节炎18例．武警医学，2002，13(2)：88．
84 吴青，武国，蒋成，等．关节镜治疗膝关节骨性关节炎．四川医学，2004，25(4)：136．
85 张同仁，陈瑞光，陈鸿辉，等．关节镜下清理术治疗膝关节骨关节炎．中国内镜杂志，1999，5(2)：25．
86 敖邦华，姜衫，时广敬，等．OA液加膝关节镜清理治疗骨性关节炎78例．中国骨伤，1998，11(6)：45．
87 朱汉章．针刀学原理[M]．北京：人民卫生出版社，2002，685-686．
88 俞杰，明顺培，张秀芬．针刀疗法对兔膝骨关节炎关节液中IL-1β、IL-6、TNF-α水平的影响．中国中医骨伤科杂志，2002，10(4)：15-18．
89 周士枋，范振华．实用康复医学．南京：东南大学出版社，1998，134
90 陈景藻．现代物理治疗学．北京：人民军医出版社，2001，130-620
91 Kathleen B, Sweeney Mark A, Merrick CD, et al.Therapeutic magnets do not affect tissue temperatures.JAthl Train, 2001, 36(1): 27
92 Stelian J, Gil I, Habot B, et al.Improvement of pain and disability in elderly patients with degenerative osteoarthritis of the the knee treated with narrow-band light therapy.J Am Geriatr Soc, 1992, 40(1): 23
93 James NP, Elizabeth G, Gwenderlyn FJ, et al.A critical appraisal of clinical practice guidelines for the treatment of lower-limb osteoarthritis Arthritis Res, 2002, 4(1): 36
94 冯坤，郭建刚，王健智，等．补肾活血对骨关节炎软骨退变的拮抗作用研究．辽宁中医杂志，1999，26(11)：523．524
95 郭万首，马丽，吴东海，等．白介素1受体拮抗蛋白间接体内转基因对兔骨性关节炎的抑制作用．解放军医学杂志，2004，29(6)：475-478
96 邱贵兴．兔膝关节制动引起关节软骨退变的实验研究．中华外科杂志，1987，25(3)：175-177
97 王国文，潘海乐，曲波，等．参麦注射液对骨关节炎模型动物关节软骨胶原含量的影响．中国中医骨伤科杂志，2001，9(2)：14-16
98 Yasuhio, Tsuneok, HirokazuT, etal, EffactofSL-1010(sodiumhyaluronatewithhighmolecular weight)on experimental osteoarthritis induced by introarticularly, appalied in rabbits.Foia Pharmacol Japon. 1992, 100:67
99 江中潮，何洪阳，刘罡，等．骨生注射液对实验性骨性关节炎家兔血浆SOD和MDA的影响．中国骨伤，2004，17(10)：593-595
100 沈培芝．强筋方治疗实验性膝骨关节炎的组织病理学观察研究．中国中医骨伤科杂志，1995，3(1)：10-13
101 董建勇，赵晓薇，李立，等．实验性骨关节炎关节软骨P、K、Ca、S元素的变化．中国骨伤，1999，12(5)：25-26
102 汪青春，董蕙芳，沈培芝，等．中药对膝骨关节炎黑鼠血清SOD、HA、NO水平的影响．中医正骨，1999，11(5)：6-8
103 Olszewski J, Mc DormellJ, Stevens K, etal. Amatrixmetal lopro-teinase-generated aggre can neopitopeasa marker of skeletal matu-ration and aginginc artilage. Arthritis Rheum,1996, 39(7): 1234-1237.
104 高文香，刘元禄，李永生，等．补肾法防治兔膝关节骨性关节炎的病理形态学观察．中医正骨，1999，11(11)：13．16
105 黄涛，黄昌林．不同运动方式对骨性关节炎关节功能障碍的防治．中国康复，1999，14(1)：6-8
106 钟汉馨，黄涛．不同运动方式引起关节软骨改变的病理研究．现代康复，2001，5(1)：36-37
107 欧阳建江，黄有荣，熊仁英，等．川芎嗪对大白兔膝关节骨性关节炎血清SOD、MDA及NO的影响．广西中医药，2004，27(5)：40-42
108 王秀华，刘元禄，苏姿兵，等．丹参关节内注射对兔膝骨关节炎细胞因子IL-1及TNF的影响．中医正骨，2003，15(10)：1-3
109 赵丹慧，张艳，薛延，等．豚鼠原发性骨性关节炎超微结构与生化改变的动态观察．中华手外科杂志，1999，15(3)：180-183
110 蓝旭，刘雪梅，葛宝丰，等．豚鼠原发性骨性关节炎的血清IGF-I检测及义．中国 矫形外科杂志，2000，7(7)：667-668
111 俞杰，明顺培，张秀芬，等．针刀疗法对兔膝骨关节炎关节液中IL-1β、IL-6、TNF-α水平的影响．中国中医骨伤科杂志，2002，10(4)：15-18
112 马建兵，刘德玉，李堪印，等．中药对家兔实验性膝关节骨性关节炎氧自由基代谢的影响．中医正骨，2000，12(1)：8．10
113 王耶．丹参和透明质酸钠注射液对骨性关节炎治疗作用的实验研究．中国生化药物杂志，1998，19(5)：248-250
114 任峰．益气养血通络法(治血痹法)对小鼠骨关节病的实验研究．上海中医药杂志，1994，7：41-42
115 黄涛，徐传毅，邹季，等．活血止痛汤治疗早期骨性关节炎的实验研究．中医正骨，1999，11(5)：3-5
116 江伟达，郑效文，郑清波，等．中药关节Ⅲ号方治疗家兔膝骨关节炎的实验研究．中国中医骨伤科，1994，2(1)：1-3
117 曹月龙，冯伟，李宗举，等．软骨Ⅱ号对骨关节炎兔不同部位PGE2选择性抑制作用的实验研究．中国骨伤，2001，14(10)：597-598
118 郭建刚，冯坤，赵然，等．壮筋活血汤对骨性关节炎软骨退变作用的实验研究．中国骨伤，1999，12(5)：19-21
119 汪青春，石印玉，沈培芝，等．中药对膝骨关节炎小鼠关节软骨IL-1、iNOS基因表达的影响．山西医药杂志，1999，28(5)：381-383
120 郑召民，许振华，于晓牧．川芎对家兔膝关节骨性关节炎骨内压的影响．河南外科学杂志，1997，3(1)：30-31
121 邓廉夫，柴本甫．IL-1、TNF和IL-6与骨性关节炎．国外医学·创伤与外科基本问题分册，1996，17(2)：102-106
122 邵洪．氧自由基与蛋白质代谢．国外医学·分子生物学分册，1990，12：42
123 Panasiuk AF, Laroshuk GV, Mitrovich D. Effect of free and radical sonproliferation and metabolism of chondrocyres and onsensitivity of acellular monolayer to proteases Vopr.Med KHIM, 1995, 41: 19
124 Blanco FJ, Ochs RI, Schwarz H, et al.Chondrocyteapoptosis induced by nitricoxide.AmJPathol, 1995, 146:75
1 PelletierJP, Di Battista JA, RoughleyPJ, etal: Cytokines and Inflammation in Cartilage Degradation. In Moskowitz RW (ed). Osteoarthritis, Edition of Rheumatic Disease Clinics of North America. Philadelphia, WB Saunders Company 545-568, 1993
2 PelletierJP, Martel-Pelletier J, HowellDS: Etiopathogenesis of Osteoarthritis. In Koopman WJ (ed). Arthritis and Allied Conditions. A Textbook of Rheumatology. Ed 13. Baltimore, Williams & wilkins 1969-1984, 1997
3 Pelletier JP, McCollumR, CloutierJM, Martel-Pelletier J: Synthesis of metalloproteases and interleukin 6 (IL-6) in human osteoarthritic synovial membrane is an IL-1 mediated process. J Rheumatol 22: 109-114, 1995
4 Firestein GS, BergerAE, Tracey DE, et al: IL-1 receptor antagonist protein production and gene expression in rheumatoid arthritis and osteoarthritis synovium. J Immunol 149: 1054-1062, 1992.
5 Pelltier JP, Mineau F, Ranger P, et al: The increased synthesis of inducible intric oxide inhibits IL-1Ra synthesis by human articular chondrocytes : possible role in osteoarthritic cartilage degradation. Osteoarthritis cartilage4: 77364-366, 1999
6 Martel-Pelletier J, McCollum R, Di Battista JA, et al: The interleukin-1 receptor in normal and osteoarthritic human articular chondrocytes. Identification as the type I receptor and analysis of binding kinetics and biologic function .Arthritis Rheum 35: 530-540, 1992
7 Sadouk M, Pelletier JP, Tardif G, et al: Human synovial fibroblasts coexpress interleukin-1 receptor type I and type II mRNA: The increased level of the interleukin-1 receptor in osteoarthritic cells is related to an increased level of the type I receptor .Lab Invest 73: 347-355, 1995
8 ArendWP: Interleukin-lreceptor antagonist. Adv Immunol54: 167-227, 1993.
9 Arend WP, Dayer JM: Inhibition of the production and effects of interleukin-land tumor necrosis factor alpha in rheumatoid arthritis Rheum 38: 151-160, 1995.
10 Arner EC, Harris RR, DiMeo TM, et al : interleukin-1 receptor antagonist inhibits proteoglycan breakdown in antigen induced but not polycation induced arthritis in rabbit. J Rhumatol 22: 1338-1346, 1995.
11 Caron JP, Fernandes JC, Martel-Pelletier J, et al: Chondroprotective effect of intraarticular injections of interleukin-1 receptor antagonist in experimental osteoarthritis : Suppression of collagenase-1 expression. Arthritis Rheum39: 1535-1544, 1996
12 BandaraG, Mueller GM, Galea-Lauri J, etal: Intraarticular expression of biologically active interleukin 1-receptor-antagonist protein by ex vivo gene transfer. Proc Natl Acad Sci USA 90: 10764-10768, 1993.
13 Baragi VM, Renkiewicz RR, Jordan H, etal: Transplantation of transduced chondrocytes protects articular cartilage from interleukin 1-induced extracellular matrix degradation. J Clin Invest 96: 2454-2460, 1995
14 Bandara G, RobbinsPD, Georgescu HI, et al : Genetransfer to synoviovytes for gene treatmentforarthritis.DNA Cell Biol 11: 227-231, 1992
15 Evans C, Robbins PD: Prospects for treating arthritis by gene therapy.J Rheumatol 21: 779-782, 1994.
16 Evans CH, Robbins PD: Gene Therapy for Arthritis. In Wolff JA(ed). Gene Therapeutics: Methods and Applications of Direct Gene Transfer. Boston, Birkhauser 320-343, 1994.
17 Evans CH, Robbins PD: Pathways to gene therapy in rheumatoid arthritis.Curr Opin Rheumatol 8: 20-234, 1996.
18 HungGL, Galea-Lauri J, Mueller GM, et al: Suppression of intraarticular responses to interleukin-1 by transfer of the interleukin-1 receptor antagonist gene to synovium .Gene Therl: 64-69, 1994
19 MakarovSS, OlsenJC, Johnston WN, etal: Retrovirus mediated in vivo gene transfer to synovium in bacterial cell wall-induced arthritis in rats. Gene Ther2: 424-428, 1995
20 Otani K, NitalM. MacaulayW, etal: Suppression of antigen-induced arthritis in rabbits by ex vivo gene therapy. J Immunol 156: 3558-3562, 1996
21 Pelletier JP, Evans CH, et al: In vivo suppression of early experimental osteoarthritis by IL-Ra using gene therapy. Arthritis Rheum 40: 1012-1019, 1997
22 Roessler BJ, Allen ED, Wilson JM, et al: Adenoviral-mediated gene transfer to rabbit synovium in vivo. JClin Invesr92: 1085-1092, 1993
23 NitaLM, Ghivizzani SC, Galea-Lauri J, etal: Direct gene delivery to synovium. An evaluation of potential vectors in vitro and in vivo. Arthritis Rheum 39: 820-828, 1996
24 Tomita N, Morishita R, Higaki J, et al: In vivo gene transfer of insulin gene into neonatal rats by the HVJ-liposome method resulted in sustained transgene expression. Gene Ther 3: 477-482, 1996
25 Tomita T, Hashimoto H, Tomita N, et al: In vivo direct gene transfer into articular cartilage by intraarticular injection mediated by HVJ (sendaivirus) and liposomes. Arthritis Rheum 40: 901-906, 1997
26 Yovandich J, O'Malley B, Sikes M, Ledley FD: Gene transfer to synovial cells by intraarticular administration of plasmid DNA. Hum Gene Ther 6: 603-610, 1995
27 BudkerV, Zhang G. Danko I, et al: The efficient expression of intravascularly delivered DNA in rat muscle. Gene Ther5: 272-276, 1998
28 Hartikka j, Sawdey M, Cornefert-Jensen F, et al: An improved plasmid DNA expression vector for direct injection into skeletal muscle. Hum Gene Ther7: 1205-1217, 1996
29 Stephan DJ, Yang ZY, San H, et al: A new cationic liposome DNA complex enhances the efficiency of arterial gene transfer in vivo. Hum Gene Ther 7: 1803-1812, 1996
30 Prockop DJ: Heritable osteoarthritis. Diagnosis and possible modes of cell and gene therapy. Osteoarthritis Cartilage 7: 364-366, 1999
31 Evans CH, Robbins PD: Potential treatment of osteoarthritis by gene therapy.Rheum Dis Clin North Am 25: 333-344, 1999.
32 Khang R, Robbins PD, Evans CH: Methods for Gene Transfer to Synovium. In Robbins PD(ed). Gene Therapy Protocols. Totowa, Humana Press357-368, 1997
33 Naffakh N, Henri A, Villeval JL, et al: Sustained delivery of erythropoietin in mice by genetically modified skin fibroblasts.Proc Natl Acad Sci USA 92: 3194-3198, 1995
34 Scharfmann R, Axelrod JH, Verma IM: Long-term in vivo expression of retrovirus-mediated gene transfer in mouse fibroblast implants. Proc Natl Acad Sci USA 88: 4626-4630, 1991
35 Doughty LA, PatreneKD, Evans CH, etal: Consti-tutive systemic expression of IL-1Ra or soluble TNF receptor by genetically modified hematopoietic cells suppresses LPS induction of IL-6 and IL-10. Gene Ther 4: 252-257, 1997.
36 Ghivizzani SC, Lechman ER, Kang R, et al: Direct adenovirus-mediated gene transfer ofinterleukin 1 and tumor necrosis factor alpha soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects. Proc Natl Acad Sci USA 95: 4613-4618, 1998
37 Ghivizzani SC, Kang R, Georgescu HI, et al: Constitutive intraarticular expression of human IL-1 beta following gene transfer to rabbitsynovium produces all major pathologies of human rheumatoid arthritis. J Immunol 159: 3604-3612, 1997.
38 Morland LW, Baumgartner SW, SchiffMH, etal: Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein N Engl J Med 337: 141-147, 1997
39 MUller-Ladner U, Roberts CR, Franklin BN, etal: Human IL-IRa gene transfer into human synovial fibroblasts is chondroprotective. J Immunol 158: 3492-3498, 1997
40 Fernandes JC, Tardif G, Martel-pelletier J, et al: In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: Prevention of osteoarthritis progression. Am J Pathol154: 1159-1169, 1999.
41 MUller-Ladner U, Evans CH, Franklin BN, etal: Gene transfer of cytokine inhibitors into human synovial fibroblasts in the SCID mouse model. Arthritis Rheym 42: 490-497, 1999
42 Kang R, Marui T, Ghivizzani SC, et al: Ex vivo gene transfer to chondrocytes in full-thickness articular cartilage defects: A feasibility study. Osteoarthritis Cartilage 5: 139-143, 1997
43 Doherty PJ, Zhang H, Tremblay L, et al: Resurfacing of articular cartilage explants with genetically-modified human chonderocytes in vitro.Osteoarthri-tis Cartilage 6: 153-159, 1998.
44 AraiY, Kohbayashi K, etal: adenovirus vector-mediated gene transduction to chondrocytes : in vitro evaluation of therapeutic efficacy of transforming growth factor-beta 1 and heat shock protein 70 gene transduction J Rheumatol 24: 1787-1795, 1997
45 Evans CH, Ghivizzani SC, Kang R, et al: Gene therapy for rheumatic diseases.Arthritis Rheum 42: 1-16, 1999.
46 Brittberg M, Lindahl A, Nilsson A, et al: Treatment of deep cartilage defects in the knee with autologouschondrocyte transplantation. N Engl J Med 331: 889-895, 1994
47 Wakitani S, Goto T, Pineda SJ, etal: Mesenchymal cell-based repair of large, full-thickness defedcts of articular cartilage. J Bone Joint Surg76A: 579-592, 1994
48 Hilal G, Martel-Pelletier JP, et al: Osteoblast-like cells from human subchondral osteoarthritis bone demonstrate an altered phenotype in vivo: possible role in subchondral bone sclerosis. Arthritis Rheum41: 891-899, 1998
49 Glansbeek HL, Van Beuningen HM, Vitters EL, et al: Stimulation of articular cartilage repair in established artliritis by local administration of transforming growth factor-beta into knee joints. Lab Invest 78: 133-142, 1998
50 Sailor LZ, Hewick RM, Morris EA: Recombinant human bone morphogenetic protein-2 maintains the articular chondrocyte phenotype in long-term culture. J Orthop Res 14: 937-945, 1996
51 Gerich TG, Kang R, Fu FH, et al: Gene transfer to the rabbit patellar tendon: potential for genetic enhancement of tendon and ligament healing. Gene Ther 3: 1089-1093, 1996.
52 RazE, Watanabe A, Baird SM, etal: Systemic immunological effects of cytokine genes injected into skeletal muscle. Proc Natl Acad Sci USA90: 4523-4527, 1993
53 Song XY, Gu M, Jin WW, et al: Plasmid DNA encoding transforming growth factor-betal suppresses chronic disease in a streptococcal cell wall-induced arthritis model. J ClinInvest 101: 2615-2621, 1998
54 ShiozawaS, Shimizu K, TanakaK, Hino K: Studies on the contribution of c-fos/AP-1 to arthritic joint destruction. J ClinInvest99: 1210-1216, 1997
55 Chernajovsky Y, Adams G, Triantaphyllopoulos K; et al: Pathogenic lymphoid cells engineered to express TGF beta 1 ameliorate disease in a collagen-induced arthritis model. Gene Ther 4: 553-559, 1997.
56 Chernajovsky Y, Adams G, PodhajcerOL, et al: Inhibition of transfer of collagen-induced arthritis into SCID mice by ex vivo infection of spleen cells with retroviruses expressing soluble tumor necrosis factor receptor. Gene Ther 2: 731 -73 5, 1995.
57 BessisN, BoissierMC, FerraraP, etal: Attenuation of collagen-induced arthritis in mice by treatment with vector cells engineered to secrete interleukin-13.Eur J Immunol 26:2399-2403, 1996
58 Evans CH, Rediske JJ, Abramson SB, Robbins PD: Joint efforts: Tackling arthritis using gene therapy.Fist International Meeting on the Gene Therapy of Arthritis and Related Disorders.Bethesda, MD, December 2-3, 1998.Mol Med Today 5: 148-151, 1999.
59 Vacanti CA, Kim W, SchlooB, etal: Joint resurfacing with cartilage grown in situ from cell-polymer structures.Am J Sports Med 22: 485-488, 1994
60 Homminga GN, Bulstra SK, Bouwmeester PS, vander Linden AJ: Prichondral grafting for cartilage lesions of the knee. J Bone Joint Surg72B: 1003-1007, 1990
61 Kreder HJ, Moran M, Keeley FW, Salter RB: Biologic resurfacing of a major joint defect with cryopreserved allogeneic periosteum under the influence of continuous passive motion in a rabbit model. Clin Orthop300: 288-296, 1994
62 Mason JM, Grande DA, Barcia M, et al: Expression of human bone morphogenic protein 7 in primary rabbit periosteal cells: Potential utility in gene therapy for osteochondral repair. Gene Thwr5: 1098-1104, 1998
63 Evans CH, Robbins PD, GhivizzaniSC, etal: Clinical trial to assess the safety, feasibility znd eflBcacy transferring a potentially anti-arthritic cytokine gene to human joins with rheumatoid arthritis.Hum Gene Thei7: 1261-1280, 1996.
64 Palmer TD, Rosman GJ, Osborne WR, Miller AD: Genetically modified skin fibroblasts persist long after transplantation but gradually inactivate inactivate introduced genes. Proc Natl Acad Sci USA 88: 1330-1334, 1996
65 Vacanti CA, Kim W, Schloo B, et al: Joint resurfacing with cartilage grown in situ from cell-polymer structures.Am J Sports Med 22: 485-488, 1994
66 Fernandes JC, Martel-pelletier J, Pelletier JP: The use of gene therapy in osteoarthritis: Present and future.Curr Opin Orthop 10: 458-465, 1999.
1.Bellamy N, et al. Validation study ofWOMAC. J Rheumatol, 1988,Dec;15(12): 1833-40
2.Bonica JJ, et al. The management of pain. 2nd ed. Philadephia: Lea and Febiger, 1990. 581
3 Feldman M, McMahon AT. Ann Intern Med, 2000,132:134-143