1. Paradoxes in Acupuncture Research: Strategies for Moving Forward SAR White Paper Identifying Acupuncture Research Confounding Factors

2. Two Types of Acu Research Clinical Trials where a modality is tested in a real world setting Clinical Trials where a modality is tested in a real world setting How does it perform? How does it perform? How does it perform compared to usual care? How does it perform compared to usual care? How does it perform compared to sham? How does it perform compared to sham? Basic science research: Basic science research: what happens in the body when a needle is inserted? What is the mechanism with which acu works?

3. There is mounting evidence that acupuncture treatments are superior to usual care for some chronic pain conditions. There is mounting evidence that acupuncture treatments are superior to usual care for some chronic pain conditions.

4. How does acu compare to usual mainstream care? German Low Back Pain study with 1162 patients: acu almost twice as effective as mainstream care German Low Back Pain study with 1162 patients: acu almost twice as effective as mainstream care Seattle Low Back Pain study with 640 patients: 60% of acu patents had clinical improvements compared to 39% mainstream care. Seattle Low Back Pain study with 640 patients: 60% of acu patents had clinical improvements compared to 39% mainstream care. University of MD study showed acu significantly reduced pain and improved function for OA of knee. University of MD study showed acu significantly reduced pain and improved function for OA of knee.

5. Acu compared to usual care: Chronic headache patients used 15% less meds, made 25% fewer visits to gp’s, took 15% fewer sick days than control group (Vickers, et al, 2004); Chronic headache patients used 15% less meds, made 25% fewer visits to gp’s, took 15% fewer sick days than control group (Vickers, et al, 2004); Chronic neck pain: acu was superior to no acu at the end of 3 months (avg. 15 sessions) (Witt et al 2006a) Chronic neck pain: acu was superior to no acu at the end of 3 months (avg. 15 sessions) (Witt et al 2006a)

6. Is Acu cost effective? When added to usual care, is the benefit worth the additional cost? When added to usual care, is the benefit worth the additional cost? How do the outcomes and costs of “stand alone” acu compare to usual care? How do the outcomes and costs of “stand alone” acu compare to usual care? What is the cost incurred in improving the quality of life (Quality Adjusted Life Year)/ What is the cost incurred in improving the quality of life (Quality Adjusted Life Year)/ Very few studies look at this, but it is a calculation that our patients make Very few studies look at this, but it is a calculation that our patients make

7. Basic Science Research: Acu-induced clinical improvements in chronic pain and carpal tunnel syndrome correlate with changes in brain activity. Harris, et al 2006, newberg et al 2005 Acu-induced clinical improvements in chronic pain and carpal tunnel syndrome correlate with changes in brain activity. Harris, et al 2006, newberg et al 2005 Ultrasonic stim of points activated the brain in the same way as needles, with no pain. Jones, 1998 Ultrasonic stim of points activated the brain in the same way as needles, with no pain. Jones, 1998 The diffusion of a radioisotope injected at acupoints showed the meridian pathway. Vernegeol et al 1985 The diffusion of a radioisotope injected at acupoints showed the meridian pathway. Vernegeol et al 1985

8. Science, cont’d Undetermined whether traditional sensory indications of acu points correlate with specific brain regions both positive and negative findings Undetermined whether traditional sensory indications of acu points correlate with specific brain regions both positive and negative findings Evidence of hormonal involvement: Evidence of hormonal involvement: Time course of acu analgesia is consistent with humoral rather than neural mediation Time course of acu analgesia is consistent with humoral rather than neural mediation Electro-acu releases endogenous opioids (difference between high and low frequencies) Electro-acu releases endogenous opioids (difference between high and low frequencies)

9. Science, cont’d Just released research shows acupuncture significantly reduces levels of a protein in rats linked to chronic stress Just released research shows acupuncture significantly reduces levels of a protein in rats linked to chronic stress

10. * Gaps in current knowledge that affect affect acu research * Strategies to resolve the paradoxes that the research has highlighted

11. Research results: Overall acupuncture treatments are, at most, marginally more effective than sham Overall acupuncture treatments are, at most, marginally more effective than sham Sham acu treatments are more effective than conventional placebos when compared to no treatment Sham acu treatments are more effective than conventional placebos when compared to no treatment No evidence which part of acu treatments are therapeutic (new meta analysis sheds more light - see discussion below) No evidence which part of acu treatments are therapeutic (new meta analysis sheds more light - see discussion below)

12. Two Paradoxes 1) A large number of clinical trials show that true acu is superior to usual care, but does not outperform sham acu 2) Research has shown physiologic effects vary as a function of needling (insertion depth, stimulation) but not how that influences therapeutic outcomes

13. What Constitutes an Acu Treatment? Needling components Needling components Diagnosis Diagnosis Palpation Palpation Belief and Expectancy of practitioner and patient Belief and Expectancy of practitioner and patient Therapeutic setting Therapeutic setting Time Time Attention of the Practitioner Attention of the Practitioner Rapport between Practitioner and Patient Rapport between Practitioner and Patient

14. Sham Acupuncture Aim is to perform a mock treatment that the subject believes is an acupuncture treatment, but which is missing all relevant needling and non-needling “active” components. Aim is to perform a mock treatment that the subject believes is an acupuncture treatment, but which is missing all relevant needling and non-needling “active” components.

15. Components that have been controlled for: needle/point location needle/point location degree of needle insertion degree of needle insertion needle stimulation needle stimulation interaction with practitioner interaction with practitioner

16. Acupuncture Points Research has shown considerable variability in the precise location of points across practitioners Research has shown considerable variability in the precise location of points across practitioners Little scientific evidence to support the distinction between acu and non-acu points* Little scientific evidence to support the distinction between acu and non-acu points* Limited research on their bio-electric properties and anatomical correlations Limited research on their bio-electric properties and anatomical correlations

17. This lack of understanding of what is and what is not an acu point impacts our ability to interpret the results of clinical trials that compare needling at acu and nonacu (sham) points.

18. Acu related terms are not well defined, and have created confusion and impeded progress in research.

19. Clarification of Terms Clarity is needed in describing the treatment: just needling, or a multi-component treatment that involves history taking, physical exams, diagnosis, and education and non-needling procedures such as laser, TENS, heat lamps, etc. Clarity is needed in describing the treatment: just needling, or a multi-component treatment that involves history taking, physical exams, diagnosis, and education and non-needling procedures such as laser, TENS, heat lamps, etc.

20. 4 components of Acu treatment Needling components (needle size, depth, stimulation, location) Needling components (needle size, depth, stimulation, location) Specific theory-related, nonneedling components such as palpation and moxa Specific theory-related, nonneedling components such as palpation and moxa Specific “psychological” components such as history taking, diagnosis, education Specific “psychological” components such as history taking, diagnosis, education Generic non-needling components that are not unique to acu, such as belief and expectation, attention, time Generic non-needling components that are not unique to acu, such as belief and expectation, attention, time

21. Paradox 1:(true acu performs only slightly better than sham acu) Verum and sham treatments are equivalent, because the therapeutic effects of both are due to nonspecific effects Verum and sham treatments are equivalent, because the therapeutic effects of both are due to nonspecific effects Specific therapeutic effects do exist, but are not detected in sham-controlled trials because Specific therapeutic effects do exist, but are not detected in sham-controlled trials because Sham acu is not inert Sham acu is not inert Verum acu is less than optimal Verum acu is less than optimal

22. Paradox 2: it is unclear to what extent needling procedures influence clinical outcomes Laboratory research may not be applicable to clinical research Laboratory research may not be applicable to clinical research Some of the physiological effects are not related to therapy Some of the physiological effects are not related to therapy Needling effects could be small compared to effects of other components Needling effects could be small compared to effects of other components

23. Paradox 2, cont’d. Sham controlled trials are problematic because Sham controlled trials are problematic because The influence of needling techniques is poorly understood, and The influence of needling techniques is poorly understood, and Objective bio-markers relative to commonly treated conditions are lacking. Objective bio-markers relative to commonly treated conditions are lacking.

24. Future Research Clarify terms and maintain clarity when describing methods Clarify terms and maintain clarity when describing methods Clinical approaches need to understand acu treatments as complex interventions Clinical approaches need to understand acu treatments as complex interventions

25. Recommendations for Future Research Use clinical experience to identify key components specific to acu and to systematically study their therapeutic effects as well as their effects on physiology. Use clearly defined controls designed to test the specific component being evaluated (needle location, depth, etc.) This will lead to a clearer understanding of how to create sham protocol.

26. Possible Clinical Studies What components of acu treatment, other than needling, are of most importance? What components of acu treatment, other than needling, are of most importance? Use medical imaging and biomarkers to evaluate the physiological effects Use medical imaging and biomarkers to evaluate the physiological effects

27. Possible Studies cont’d Use qualitative methods to explore the acupuncture process Use qualitative methods to explore the acupuncture process Compare whole systems of CAM and biomedical interventions that reflect real-world practice Compare whole systems of CAM and biomedical interventions that reflect real-world practice Once effectiveness is demonstrated, future trials can explore the components. Once effectiveness is demonstrated, future trials can explore the components.

28. Possible studies, cont’d Through studies, improve the consensus regarding diagnosis and treatment of particular conditions. This systemic study could identify an optimal protocol for a specific condition, based on both biomedical and traditional diagnostic techniques. Through studies, improve the consensus regarding diagnosis and treatment of particular conditions. This systemic study could identify an optimal protocol for a specific condition, based on both biomedical and traditional diagnostic techniques.

29. Possible “science” studies Improve understanding of “point specificity”, by including non-acu point controls along similar nerves. Improve understanding of “point specificity”, by including non-acu point controls along similar nerves. What are the physiological responses to acupuncture points and non-acu points. Do acu points have distinct histological and/or biochemical characteristics? What are the physiological responses to acupuncture points and non-acu points. Do acu points have distinct histological and/or biochemical characteristics?

30. Possible “science” research, cont’d Studies to identify the physiological effects associated with individual components of acu, both needling and non-needling. Studies to identify the physiological effects associated with individual components of acu, both needling and non-needling. Studies to assess the physiological effects of nonspecific needling and treatment components. Studies to assess the physiological effects of nonspecific needling and treatment components.

31. Possible ‘science” research, cont’d Studies to examine the effects of verum and sham needling on local tissues and the nervous system Studies to examine the effects of verum and sham needling on local tissues and the nervous system Determine the biomarkers that relate to a given pathology and how they improve with treatment. Determine the biomarkers that relate to a given pathology and how they improve with treatment.

32. Recommended research, cont’d In order to assess effective needling, determine the biomarkers and clinical outcome measures of both immediate and delayed physiologic responses (e.g., pulses and brain activation patterns) In order to assess effective needling, determine the biomarkers and clinical outcome measures of both immediate and delayed physiologic responses (e.g., pulses and brain activation patterns)

33. Designing Appropriate Controls What to mimic What to mimic For example, retractable needles For example, retractable needles What to avoid What to avoid For example, “active” needling, once it is known

34. In conclusion: Acupuncture research must include both “top down” and “bottom up” approaches

35. Top Down: acu treatments as multicomponent “whole system” interventions, compared to “usual care” Top Down: acu treatments as multicomponent “whole system” interventions, compared to “usual care” Bottom Up: mechanistic studies that focus on understanding individual treatment components and how they translate into clinical outcomes. Bottom Up: mechanistic studies that focus on understanding individual treatment components and how they translate into clinical outcomes.

36. Translational Acu Research Strategy Translational process (T1)Translational process (T2) Bench Patient Community Animal Experiments Human Subject experiments Controlled clinical trials Survey research Cost effectiveness research  Basic science Informed approaches Clinical practice- Informed approaches

37. These approaches will deepen our understanding of complex systems of care.

38. We must remember to build clinical relevance into the design of clinical as well as basic science research.

39. Unique Considerations in Fertility Treatment To help inform future research on fertility acupuncture, Cochrane et al analyzed responses from ten fertility acupuncturists to define how best to treat fertility. The researchers used a complex consensus-building technique in this qualitative study that spanned two phases. Three acupuncturists were intensely interviewed in phase one to generate enough material to guide a forum in the second phase. Seven more acupuncturists were recruited, and during second phase, all ten participants discussed the themes and responses from the first phase and then a questionnaire was developed and distributed. Participants were asked to rank statements according to relevance. The participants felt the following to be highly relevant: acupuncture should not be limited to needling but include more aspects of TCM like diet, therapeutic relationship, etc. (7 of 10). When asked "Fertility acupuncture should be a specialist endeavor requiring...," the participants felt it highly relevant that fertility acupuncturists should have knowledge of traditional Chinese medicine (TCM) gynecology (9 of 10), and knowledge of ART procedures (8 of 10) and reproductive endocrinology and physiology (7 of 10), as well as capable of engaging the patient-practitioner relationship (7 of 10). Additionally, participants felt the TCM pattern (6 of 10), state of the Shen (5 of 10) and the timing of treatment (4 of 10) as highly relevant in guiding treatment. Biomedical diagnosis (6 of 10) and menstrual cycle phases (6 of 10) were rated as relevant in guiding treatment. [Source: Cochrane S, Smith CA, Possamai-Inessedy A. Development of a fertility acupuncture protocol: defining acupuncture treatment protocol to support and treat women experiencing conception delays. J Altern Complement Med. 2011. 17(4):329-337. http://www.ncbi.nlm.nih.gov/pubmed/21495903 ]

40. This strategy will result in a broader and stronger basis of support for the study of acupuncture and other complex treatments.

41. New Meta-Analysis of Acu for Chronic Pain Sheds light on some of these outstanding questions Sheds light on some of these outstanding questions See next Power Point for details! See next Power Point for details!