Evaluation of the efficacy of a Chinese herbal medicine in the treatment of patients with osteoarthritis of the knee Degree title: Doctorate of Philosophy School: School of Biomedical and Health Sciences University: Victoria University, Australia Candidate: Bin Hua Supervisors: Dr. Kylie O’Brien and Dr. Alan Hayes Submission Date: 25 March 2011 Classification Date: 30 January 2012 Abstract Background Osteoarthritis (OA) is common but has no outright cure. Current therapeutic drugs mainly treat OA symptoms and often cause undesirable side effects. Chinese medicine (CM) is a popular alternative therapy for OA, however the majority of CM efficacy studies have been methodologically inadequate. CM has traditionally treated OA under the clinical descriptor of ‘Bi Syndrome’ (painful obstruction syndrome) which includes a range of musculoskeletal disorders. An emerging theory treats OA as a combination of two types of CM Syndromes: Bi Syndrome and Wei Syndrome (atrophy syndrome). There is a lack of objective evidence with respect to possible CM Syndromes of OA, the reliability of CM diagnosis and efficacy of CM treatment guided by this emerging theory. Objectives To investigate the efficacy and safety of a Chinese herbal medicine (CHM) formula developed on the basis of this emerging theory in the treatment of symptoms of knee OA; to investigate the reliability of CM diagnosis in OA patients. Methods A double blind, randomised, placebo controlled clinical trial was conducted in eligible Australian OA patients. Participants were randomised to receive either CHM or placebo over 12 weeks, with a one month follow-up. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) was the primary outcome variable. A CM examination conducted by two CM practitioners was incorporated. Data was analysed using SPSS software. Results There was no significant difference between the two groups in terms of change of the WOMAC indices of pain, stiffness and physical activity. However the stiffness index decreased significantly in the CHM group (only). Safety data indicated the CHM was safe and well tolerated. The new CM theory about treatment of OA as a combination of Syndromes was partially supported by the efficacy results. The reliability of CM diagnostic variables was generally low, and reliability was low for CM Syndrome 1 diagnosis according to Zang-fu Theory in patients with knee OA. Results support the notion that knee OA is an Interior, Deficiency and Yin disease. Conclusion There is some limited indication of a therapeutic effect for the CHM. Evidence in support of the emerging CM theory about OA is not conclusive. Larger scale studies over a longer time period are required. 2 Declaration of authenticity I, Bin Hua, declare that the Ph.D thesis entitled ‘Evaluation of the efficacy of a Chinese herbal medicine in the treatment of patients with osteoarthritis of the knee’ is no more than 100,000 words in length including quotes and exclusive of tables, figures, appendices, bibliography, references and footnotes. This thesis contains no material that has been submitted previously, in whole or in part, for the award of any other academic degree or diploma. Except where otherwise indicated, this thesis is my own work. Signature Date 3 Acknowledgements This thesis is a milestone in my life, an achievement due to four years of research that began when I first came to Australia in 2007. This thesis would not have been made possible without the guidance and the help of several individuals who contributed and extended their valuable assistance and time in the preparation and completion of this study. It is a pleasure to convey my gratitude to them all in this, my humble acknowledgment. First and foremost, I would like to express my deep and sincere gratitude to my supervisor, Dr. Kylie O’Brien, Associate Dean (Teaching and Learning) of the Faculty of Health, Engineering and Science, Victoria University, for her supervision, advice, and guidance from the very early stage of this research as well as giving me extraordinary help throughout all of my work. Above all and the most needed, she offered me an opportunity to study in Australia and provided me with encouragement and support in so many ways. Her true dedication to Chinese medicine has made her a true mentor with a constant oasis of ideas and passion for research, which have inspired and enriched my growth as a researcher. I gratefully acknowledge Dr. Alan Hayes, Assistant Dean for the Centre for Health, Research and Education, Victoria University, for his advice, supervision, and crucial contributions. His involvement in this Chinese medicine research with his originality has nourished my intellectual maturity, to my great benefit from now on. I wish to express my warm and sincere thanks to Associate Professor Peter Ryan, Monash University, who was the principal investigator of my study. This clinical trial could not be realised without his important guidance in the field of rheumatology research. Many thanks go in particular to Ms. Lisa Nelson, General Manager of Nucleus Network, Australia. My study could not have been conducted without her help, especially in offering usage of the Centre for Clinical Trials facility and organising professional staff to assist with the study. 4 It is a pleasure to pay tribute to Ms. Estelle Abbas. We worked together on the reliability study which is an important component of my thesis. I acknowledge the contribution of Dr. Regina Belski to my study in analysing the diet diaries of the study participants. I also thank my former supervisors, Dr. Damien Ryan and Professor Ian Rouse for their help on this study. During this research, I have collaborated with many colleagues for whom I have great regard, and I wish to extend my warmest thanks to all those who have helped me with my work within Victoria University, Nucleus Network, the Alfred Hospital, Melbourne, Australia, and in the Shuguang Hospital, Shanghai, China. To my colleagues at the School of Biomedical and Health Sciences, Victoria University I thank them for their benevolence which has provided the financial support that I have needed to produce and complete my study and thesis. For this I will always be grateful. In addition, I wish to thank my friends in Australia for helping me get through the difficult times, and for all the emotional support, entertainment and caring they provided. Finally, I thank my family for supporting me throughout all my studies at University and in daily life. In China, there is an influential proverb of Confucianism, ‘Don't stray far from home when your parents are there’ (父母在，不远游), but I have travelled thousands of kilometres from Middle Kingdom to Down Under and have been away from my parents for a long time. Without their encouragement and understanding it would have been impossible for me to finish this work. To them I dedicate this thesis. 5 Contents Abstract………………………………………………………………………………1 Declaration of authenticity……………………………………………………………3 Acknowledgements……………………………………………………………………4 Glossary………………………………………………………………………………12 Chapter 1 Introduction 1.1 Background of the research………………………………………………15 1.2 Study process……………………………………………………………19 1.3 Contribution of research to knowledge…………………………………20 1.4 Thesis structure…………………………………………………………21 Chapter 2 An Overview of Chinese Medicine 2.1 Introduction………………………………………………………………22 2.2 Chinese medicine concepts and theories…………………………………23 2.3 Aetiology and pathogenesis………………………………………………32 2.4 Diagnosis…………………………………………………………………37 2.5 Treatment…………………………………………………………………42 2.6 Conclusion………………………………………………………………45 Chapter 3 Pharmacologic and Non-Pharmacologic Treatment of Osteoarthritis 3.1 Introduction………………………………………………………………46 3.2 Pharmacologic agents……………………………………………………47 3.3 Non-pharmacologic therapies……………………………………………56 3.4 Conclusion………………………………………………………………58 Chapter 4 Complementary and Alternative Medicine Treatment of Osteoarthritis 6 4.1 Introduction………………………………………………………………59 4.2 Nutritional supplements…………………………………………………60 4.3 Vitamin and mineral supplements………………………………………67 4.4 Western herbal medicine…………………………………………………71 4.5 Conclusion………………………………………………………………76 Chapter 5 Chinese Medicine Understanding of Osteoarthritis 5.1 Introduction………………………………………………………………78 5.2 Aetiology and pathogenesis of osteoarthritis……………………………78 5.3 Arguments about identification of Syndromes of osteoarthritis…………80 5.4 Treatment principles for osteoarthritis in Chinese medicine……………82 5.5 Clinical treatment of osteoarthritis with Chinese medicine……………83 5.6 The scientific evidence base of Chinese medicine in OA treatment……84 5.7 Conclusion………………………………………………………………89 Chapter 6 Reliability of the Chinese Medicine Diagnostic System 6.1. Introduction……………………………………………………………124 6.2 Reliability of Chinese medicine diagnostic methods…………………125 6.3 Reliability of the Eight Guiding Principles……………………………131 6.4 Reliability of Syndrome Differentiation……………………………132 6.5 Reliability of Chinese medicine diagnosis in osteoarthritis…………135 6.6 Reliability of diagnosis in western medicine…………………………136 6.7 Conclusion………………………………………………………………137 Chapter 7 Methods 7.1 Introduction……………………………………………………………145 7 7.2 Anthropometric measurements…………………………………………147 7.3 Haemodynamic measurements…………………………………………148 7.4 Blood tests………………………………………………………………148 7.5 Radiography examination………………………………………………149 7.6 Functional measurements of osteoarthritis symptoms…………………150 7.6.1 WOMAC osteoarthritis index visual analogue scale (VAS) …150 7.6.2 Physician Global Assessment…………………………………153