Acupuncture for Fibromyalgia A big data-bench- bedside translational study in Taiwan

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1 Acupuncture for Fibromyalgia A big data-bench- bedside translational study in Taiwan The 11th ASA TCM Congress Dec 1, 2017 Hung-Rong Yen, M.D., Ph.D. Director, Research Center for Traditional Chinese Medicine (CMU) Division Head, Chinese Pediatrics, Department of Chinese Medicine (CMUH) Director/ Physician Scientist, Research Center for Traditional Chinese Medicine (CMUH) China Medical University & Hospital, Taichung, Taiwan 1

2 Chang Gung University Undergraduate TCM program (8-year program-tcm+wm licenses) (7-year program-tcm license) China Medical University Post-baccalaureate TCM program (5-year program-tcm license) Tzu-Chi University I-Shou University 2

3 3

4 China Medical University Ranks as 197 in the 2017 World Academic Ranking; Ranks in the top 400 in the 2016 UK Times Higher Education World Reputation Ranking School of Medicine (7-year M.D.) School of Pharmacy, Chinese Herbal Resource, Nursing, Rehabilitation, Public Health, Nutrition, Life Science, Health Management, Dentistry School of Chinese medicine (7 or 8-year M.D.) Post-Baccalaureate Chinese Medicine (5-year M.D. program) Graduate Institute of Chinese Medicine (2-year M.S., 5-year Ph.D.) Graduate Institute of Integration Chinese and Western Medicine Graduate Institute of Acupuncture Sciences (including international program for foreign M.D. and dentist) Lifu Museum of Chinese Medicine 4

The university where traditional Chinese

side Chinese Medicine: Top 1 Chinese Herb:

Medicine: Top 1 2000 1600 1200 800 400 0

首都醫科大學 560 515 482 462 119 201 134 98 119

5 The university where traditional Chinese medicine and Western medicine sit side by side Chinese Medicine: Top 1 Chinese Herb: Top 1 CMU CMU Integrative & Complementary Medicine: Top 哈佛大學 CMU 慶熙大學 746 南安普頓大學馬里蘭大學 Data source: In Cites, 2017/10/05 Acupuncture: Top 9 針灸首都醫科大學北京中醫藥大學香港科技大學成都中醫藥大學 Citation 數 SCI paper 數 CMU 中國醫藥大學柏林自由大學 47 5

Hospitals and Branches Taichung: Dept of Chinese Medicine: Outpatients: >25,000 per month 45 Attending physicians; 30 residents; 60 interns China Medical University Hospital China Medical University

6 Hospitals and Branches Taichung: Dept of Chinese Medicine: Outpatients: >25,000 per month 45 Attending physicians; 30 residents; 60 interns China Medical University Hospital China Medical University Dili Outpatient Department Fongyuan Branch Fongyuan Clinic Taipei Branch Caotun Branch Tainan Municipal An- Nan Hospital- China Medical University Taiwan Taichung Prison- Pei Teh Hospital The East District Branch of Taichung Central Taiwan Science Park Clinic China Medical University Beigang Hospital Huwei Clinic Top 4 hospital in Taiwan Outpatients: >160,000 per month ED patients: >12,000 per month Hospitalized patients: >6000 per month Surgical patients: >4000 per month 6

7 Post-graduate TCM Clinical Training Board Exam 2-yr general training to be a specialist in hospital Internal Medicine Gynecology Pediatrics Acupuncture TCM Specialist Attending Physician 1.Higher quality training to be hired in local clinic No limitation Traumatology to be a general practitioner in local clinic TCM practitioner TCM practitioner 2 years 2-5 years 2.Ability to deal with critical and emergent cases 3.Cross-talks with Western medical doctors Attending Physician 7

8 TCM USAGE IN TAIWAN 8 Yen, et al. RCHM J 2013

9 TCM Utilization in Taiwan 0.2% 41.3% 40.7% 59.3% 30.2% 1.8% 26.5% 9

Number of personal outpatient visits per year 80 70.

10 Number of personal outpatient visits per year % >20 10

11 TCM Treatment Approaches 28% 10% 4% 58% Herbal remedies Manipulative therapies Acupuncture Combined treatment 11

12 ACUPUNCTURE USAGE IN TAIWAN 12

13 Utilization of Acupuncture in Taiwan ranges from % in Table. Patients and visit counts of acupuncture users from in Taiwan Acupuncture users Year Valid Total Urbanization New subjects Female Male beneficiaries number (%) Level 1 Level 2 Level 3 Level 4 (%) Total visits ,752 54,106(7.98) 30,136 23,970 18,535 15,830 9,893 9,848 35,944(66.4) 132, ,220 55,967(8.19) 31,256 24,711 18,928 16,527 10,321 10,191 30,334(54.2) 142, ,815 58,120(8.44) 32,866 25,254 19,315 17,319 10,765 10,721 27,388(47.1) 139, ,144 55,768(8.00) 31,296 24,472 18,373 16,624 10,378 10,393 22,450(40.3) 131, ,958 55,069(7.82) 30,839 24,230 18,664 16,337 9,926 10,142 20,014(36.3) 121, ,048 57,253(8.06) 32,302 24,951 19,407 16,965 10,271 10,610 19,079(33.3) 124, ,391 60,529(8.45) 34,143 26,386 20,463 18,022 11,005 11,039 18,942(31.3) 133, ,504 71,416(9.90) 40,310 31,106 24,177 21,340 13,113 12,786 21,878(30.6) 159, ,666 78,735(10.8) 43,859 34,876 26,973 23,370 14,881 13,511 22,909(29.1) 171, ,446 79,536(10.9) 44,362 35,174 27,220 23,465 14,981 13,870 20,246(25.5) 176, , , , , , , , ,184 1,432,337 Wu MY and Yen HR, et al. (in revision) 13

14 Frequency distribution of acupuncture users by disease categories and age groups in Taiwan Table. Frequency distribution of acupuncture users by disease categories and age groups from in Taiwan Acupuncture, Age n (%) Diagnosis (ICD-9-CM range) All 20-39(%) 40-59(%) >60(%) Injury ( ) 8,160,624(50.6) 3,031,150(61.7) 3,630,624(51.8) 1,498,850(35.7) Diseases of the Musculoskeletal 6,744,878(41.8) 1,698,062(34.5) 2,894,757(41.3) 2,152,059(51.3) System/Connective Tissue ( ) Diseases of the Circulatory System ( ) 459,134(2.85) 26,925(0.55) 135,128(1.93) 297,081(7.08) Diseases of the Nervous System and Sense 385,228(2.39) 58,516(1.19) 170,672(2.44) 156,040(3.72) Organs ( ) Symptoms, Signs, and Ill-Defined Conditions 175,667(1.09) 40,811(0.83) 83,521(1.19) 51,335(1.22) ( ) Diseases of the Respiratory System ( ) 42,374(0.26) 14,323(0.29) 19,086(0.27) 8,965(0.21) Diseases of the Genitourinary System ( ) 363,74(0.23) 10,156(0.21) 22,272(0.32) 3,946(0.09) Mental Disorders ( ) 35,494(0.22) 16,454(0.33) 13,305(0.19) 5,735(0.14) Diseases of the Digestive System ( ) 34,866(0.22) 10,501(0.21) 15,581(0.22) 8,784(0.21) Neoplasms ( ) 20,130(0.12) 1,371(0.03) 11,565(0.17) 7,194(0.17) Endocrine, Nutritional, and Metabolic Diseases, 13,359(0.08) 2,218(0.05) 51,84(0.07) 5,957(0.14) and Immunity Disorders ( ) Diseases of the Skin and Subcutaneous Tissue 10,009(0.06) 6,003(0.12) 3,043(0.04) 963(0.02) ( ) Infectious and Parasitic Diseases ( ) 3,571(0.02) 301(0.01) 1,941(0.03) 1329(0.03) 14

15 Fibromyalgia Fibromyalgia is present in as much as 2% to 8% of the population, is characterized by widespread pain, and is often accompanied by fatigue, memory problems, and sleep disturbances. The prevalence of fibromyalgia is 5.84% in Taiwan. JAMA. 2014;311(15): PLoS ONE 2015; 10(9): e

16 16 Patient Self-report Survey

17 17

18 Pain Muscle Stiffness Muscle Tension Depression Fibromyalgia Cycle Daily Stress Fatigue Limited Activity 18

19 19

20 20 JAMA Apr 16;311(15):

21 29 usable raw data, including a total of patients (Archives of Internal Medicine 2012) 21 Science 2014; 346 (6216 Suppl)

22 22 Ann Rheum Dis 2017;76:

23 Acupuncture group n=25 Control group n=24 Mayo Clinic Proceedings

24 20 sessions of acupuncture Acupuncture group n = 34 Control group n = 24 Number of tender points below 4kg/cm 2 (TePsN) Journal of Rehabilitation Medicine

25 25 Nature Neuroscience 2010

26 Acupuncture controls systemic inflammation in sepsis Acupuncture rescues mice from established polymicrobial peritonitis 26 Nature Medicine 2014

27 Immunological Letters

28 Immunological Letters

29 29 Journal of Immunological Research 2014

30 Key Question: CAN ACUPUNCTURE REDUCED NEUROINFLAMMATION IN FIBROMYALGIA? 30

31 IMPLICATIONS FROM BIG DATA 31

32 Increased Risk of Coronary Heart Disease in Patients with Primary Fibromyalgia and Those with Concomitant Comorbidity PLoS ONE 2015; 10(9): e

33 Fibromyalgia (ICD-9-CM: ) patients at least 2 claim in LHID 2000, National Health Insurance Research Database (n=223,040) Newly diagnosed fibromyalgia patients during (n=189,512) Newly diagnosed fibromyalgia patients during (n=158,425) Excluded Missing information for age or sex and less than 18 years old. (n=11,221) Who withdraw the NHI data during the follow-up period (n=19,866). Ever received acupuncture treatment (n =81,843) Never received acupuncture treatment (N =76,582) 1:1 propensity score match Acupuncture cohort (n =58,899) No-acupuncture cohort (n = 58,899) 33

34 34

35 35

36 36

37 37 Wu MY, et al. Arthritis Research & Therapy 2017

38 EFFECTIVENESS AND MECHANISTIC STUDIES IN A PRECLINICAL FIBROMYALGIA ANIMAL MODEL 38

(Trio 300) ST-36 39 http://www.nricm.edu.

39 Electro- Acupuncture 2Hz, 1mA 100us, 15min Multifunction Electric Stimulator (Trio 300) ST

40 Electroacupuncture (EA) attenuated mechanical hyperalgesia induced by repeated intramuscular acid saline injection (fibromyalgia model, FM) as measured by von Frey filaments. 40

30pm Cold room 4±2 o C Transfer between cold temperature and room temperature every 30 minutes 120 110 100 90 80 0 Body weight 1 2

41 percentage Hotplate Withdral Latency (sec) Intermittent cold stress-induced experimental fibromyalgia model Day 0 Pre-stress Day 1 Day 2 Stress Day 3 Day ~ Post-stress 4.30pm Cold room 4±2 o C Transfer between cold temperature and room temperature every 30 minutes Body weight 1 2 Control 1 Control 2 Control 3 Control 4 FM 1 FM 2 FM 3 FM Thermal hyperalgesia 1 2 Control 1 Control 2 Control 3 Control 4 FM 1 FM 2 FM 3 FM 4 Male C57BL/6J mice 6-8 weeks old Day Day 4.30pm 4±2 o C 10am 4.30pm 4±2 o C 24±2 o C 41

42 Electroacupuncture reduced IFN-g and IL-17A in a murine cold stress-induced fibromyalgia model Electro- Acupuncture 2Hz, 1mA 100us, 15min 42

43 A RANDOMIZED CONTROLLED CLINICAL TRIAL Unpublished data 43

44 A randomized, assessor- and participantblinded, controlled, clinical trial 44

45 Verum (true acupuncture) v.s. Sham (sham control) ST-36 Streitberger device validated and published in Lancet 1998;352(9125):

46 LI4: 合谷 Hegu LI11: 曲池 Quchi

47 SP6: 三陰交 Sanyinjiao LR3: 太衝 Taichong

48 GB34: 陽陵泉 Yanglingquan ST36: 足三里 Zusanli

49 Characteristics of the patients with fibromyalgia enrolled in the clinical trial Table. Demographic characteristics of the participants enrolled in the study. Sham Control (n=21) Real Acupuncture (n=22) n(%) Mean (SD) Median (Q1~Q3) n(%) Mean (SD) Median (Q1~Q3) P-value SEX * Female 17(80.95) 20(90.91) Male 4(19.05) 2(9.09) Height (9.4) 158.1(153.2~166.7) (6.5) 159(155~163) Weight (14.1) 60(57~67) (9.7) 58(51.8~62.1) BMI (4.3) 24.4(20.5~26) 22 23(3.5) 22.6(20.8~24.8) 0.47 *: Fisher exact test : Wilcoxon's Rank-Sum Test 49

50 Verum (real) acupuncture decreased disease severity and improved insomnia and depression in fibromyalgia patients Table. Intra-group analysis of the participants receiving verum (real) acupuncture Real Acupuncture (n=22) *p-value Difference Week0 Week4 Variable (Week4-Week1) n Mean (SD) Median Median Median n Mean (SD) n Mean (SD) (Q1~Q3) (Q1~Q3) (Q1~Q3) Questionnaires WPI (Widespread Pain Index) (3.7) 12(10~14) (5.4) 7(4~12) (4.3) -4(-7~-1) Symptom Severity (1.9) 8.5(7~9) (2.8) 5(4~9) (2) -2(-3~-1) <.0001 SF (4.2) 80(77.2~83.3) (4.9) 79.6(75.5~82.2) (5.4) 0.3(-5.7~3.9) FIQR (12.8) 46.7(34.7~52.2) (18.5) 29.5(14.5~51.3) (13) -9.3(-14.2~-2.5) FIQR-1st domain (5) 4.3(1.7~9.7) (4.3) 3.5(2~8.3) (3.6) -0.5(-2.7~1) FIQR-2nd domain 22 8(4.4) 7.5(4~10) (5) 4.5(3~11) (4.3) -1.5(-3~0) FIQR-3 domain (7.3) 30.8(26~33) (11) 22.5(12.5~29.5) (7.3) -7(-12.5~-5) <.0001 FIQR-3-1 (pain) (2.2) 5.5(5~7) (2.2) 4(3~5) (2.6) -2(-3~0) FIQR-3-8 (tactile pain) (2) 6(5~7) (2.4) 4(2~5) (2.5) -1(-3~0) VAS (1.8) 5.6(5~7.5) (1.6) 3.4(3.1~5.1) (2) -1.6(-3.1~-0.8) <.0001 PSQI (3.5) 13.5(9~16) 22 10(3.7) 9.5(8~12) (3.5) -2(-5~0) BDII (10.6) 20(14~25) (9.9) 13(5~21) 22-6(6.5) -5(-10~-2) <.0001 Q1:1 st 25 th percentile Q3: 3 rd 25 th percentile 50

51 Sham (control) acupuncture improved quality of life, insomnia and depression in fibromyalgia patients Table. Intra-group analysis of the participants receiving sham (control) acupuncture Sham Control (n=21) *p-value Difference Week0 Week4 Variable (Week4-Week1) n Mean (SD) Median Median Median n Mean (SD) n Mean (SD) (Q1~Q3) (Q1~Q3) (Q1~Q3) Questionnaires WPI (Widespread Pain Index) 21 12(4.6) 11(8~16) 21 11(4.7) 10(8~16) 21-1(2.7) 0(-2~0) Symptom Severity (2.1) 8(7~10) (2.7) 6(5~9) (1.8) -1(-2~0) SF (5.8) 83.3(78.8~86) (6.8) 79.3(73.3~83.4) (6.4) -5.1(-7.9~1.6) FIQR (21.3) 52.7(40~65.2) (20.5) 40.8(24.8~54.3) (12.1) -6.3(-19.8~-5) FIQR-1st domain (8.6) 5(3.7~13) (6.9) 6.7(4.3~10) (5) 0(-2.3~2) FIQR-2nd domain (6.2) 14(9~17) (5.7) 9(4~12) (4.8) -2(-7~0) FIQR-3 domain (8.9) 33.5(25~40.5) (9.3) 22.5(18~31.5) (5.9) -6(-9.5~-3.5) <.0001 FIQR-3-1 (pain) (2.4) 7(5~8) (2.8) 5(3~8) (2) -2(-3~0) FIQR-3-8 (tactile pain) (2.5) 7(5~9) (2.9) 5(3~7) 21-2(2.3) -2(-3~-1) VAS (2.2) 7.1(5.4~7.9) (2.3) 5.3(3.8~7.7) (2.2) -0.5(-2.9~0.4) PSQI (3.4) 14(12~16) (4.4) 12(8~14) (2.7) -2(-4~0) BDII (12.2) 22(11~30) (12.3) 15(8~27) 21-5(8.7) -4(-9~2) Q1:1 st 25 th percentile Q3: 3 rd 25 th percentile 51

52 Compared to sham control, verum (true) acupuncture improved widespread pain index in fibromyalgia Table. Inter-group analysis of the participants receiving sham (control) versus verum (real) acupuncture treatment Sham Control (n=21) Real Acupuncture (n=22) Variable Difference between week4 and week0 Difference between week4 and week0 *p-value n Mean (SD) Median (Q1~Q3) n Mean (SD) Median (Q1~Q3) Questionnaires WPI (Widespread Pain Index) 21-1(2.7) 0(-2~0) (4.3) -4(-7~-1) Symptom Severity (1.8) -1(-2~0) (2) -2(-3~-1) SF (6.4) -5.1(-7.9~1.6) (5.4) 0.3(-5.7~3.9) FIQR (12.1) -6.3(-19.8~-5) (13) -9.3(-14.2~-2.5) FIQR-1st domain (5) 0(-2.3~2) (3.6) -0.5(-2.7~1) FIQR-2nd domain (4.8) -2(-7~0) (4.3) -1.5(-3~0) FIQR-3 domain (5.9) -6(-9.5~-3.5) (7.3) -7(-12.5~-5) FIQR-3-1 (pain) (2) -2(-3~0) (2.6) -2(-3~0) 0.99 FIQR-3-8 (tactile pain) 21-2(2.3) -2(-3~-1) (2.5) -1(-3~0) VAS (2.2) -0.5(-2.9~0.4) (2) -1.6(-3.1~-0.8) PSQI (2.7) -2(-4~0) (3.5) -2(-5~0) BDII 21-5(8.7) -4(-9~2) 22-6(6.5) -5(-10~-2) Q1:1 st 25 th percentile Q3: 3 rd 25 th percentile *: Wilcoxon's Rank-Sum Test 52

volume-rendered brain template and the 3-orthogonal maximum

53 FDG PET/CT Scan: Significant clusters representing increased metabolism after real-acupuncture treatment overlaying on a volume-rendered brain template and the 3-orthogonal maximum intensity projection glass brain graphic displays of SPM2 (statistical parametric mapping) 53

54 Significant clusters representing increased metabolism after real-acupuncture treatment overlaying on the transaxial slices of MRIcro T1 weighted image template. 54

metabolism of FDG after realacupuncture treatment could be in

55 FDG PET/CT Scan When the voxel height threshold p < 0.005, uncorrected for multiple comparison, relatively increased metabolism of FDG after realacupuncture treatment could be in bilateral frontal lobes (right BA8, right BA9 and left BA 11) and left temporal lobe (BA 20 and 21). 55

56 p g /m l p g /m l p g /m l p g /m l p g /m l p g /m l p g /m l p g /m l Serum Immunological Profiles IF N -r C IFN-g IF N -r T P= * IL -6 C IL-6 IL -6 T 1 0 P= ** C o n tr o l-b e fo r e C o n tr o l-a fte r 0 T r e a tm e n t-b e fo r e T r e a tm e n t-a fte r 0 C o n tr o l-b e fo r e C o n tr o l-a fte r 0 T re a tm e n t-b e fo re T re a tm e n t-a fte r M IP -1 a C MIP-1a M IP -1 a T 5 0 P= ** IL -8 C IL IL -8 T P= ** C o n tr o l-b e fo r e C o n tr o l-a fte r 0 T r e a tm e n t-b e fo r e T r e a tm e n t-a fte r 0 C o n tr o l-b e fo r e C o n tr o l-a fte r 0 T re a tm e n t-b e fo re T re a tm e n t-a fte r 56

57 Big Data: Acupuncture for FM patients Fibromyalgia (FM) Bench: Acupuncture in FM mice Bedside: Acupuncture RCT trial 57

58 Summary Big data: Acupuncture decreased the risk of coronary heart disease in fibromyalgia patients Bench: Acupuncture ameliorated thermal and mechanical hyperalgesia as well as reduced IFN-g and IL-17 in a murine fibromyalgia model Bedside: Acupuncture reduced widespread pain index, reduced inflammatory cytokines, and altered glucose metabolism in the brain. 58

59 Acknowledgement Research Center for Traditional Chinese Medicine, CMUH (The Yen Lab) Ming-Cheng Huang N-Ting Wu Mei-Yao Wu Ni Truong Dept of Chinese Medicine, CMUH Yu-Chen Lee Mao-Feng Sun Dept of Rheumatology, CMUH Jiunn-Horng Chen Joung-Liang Lan Dept of Nuclear Medicine, CMUH Te-Chun Hsieh Chia-Hung Kao Funding supports from the Aim for Top University Plan, Ministry of Education 59

60 Q&A 60

61 Chinese Medicine Health Promotion In Daily Life

http://www.ewant.org/ Hung-Rong Yen, M.D.

62 Hung-Rong Yen, M.D., Ph.D. Director, Research Center for Traditional Chinese Medicine China Medical University & Hospital Taichung, Taiwan 62

Journal of Chinese Medicine. Vol.20, No.1, Vol.20, No.3,

Journal of Chinese Medicine. Vol.20, No.1, Vol.20, No.3, 163 Journal of Chinese Medicine Vol.20, No.1,2 1-96 Vol.20, No.3,4 97-162 ~ - 145 45-135 21 117 79-19 137-135 ~ - 137 65 87-65 - 145-65 - 153-79 - 153-87 47-137 - 65-87 - 47-145 - 145-47 - 19 164 153 HT7