Percutaneous direct current stimulation - a new electroceutical solution for severe neurological pain and soft tissue injuries.

There is a high medical need to improve the effectiveness of the treatment of pain and traumatic soft tissue injuries. In this context, electrostimulating devices have been used with only sporadic success. There is also much evidence of endogenous electrical signals that play key roles in regulating the development and regeneration of many tissues. Transepithelial potential gradients are one source of the direct current (DC) electrical signals that stimulate and guide the migration of inflammatory cells, epithelial cells, fibroblasts and mesenchymal stem cells to achieve effective wound healing. Up to now, this electrophysiological knowledge has not been adequately translated into a clinical treatment. Here, we present a mobile, handheld electroceutical smart device based on a microcontroller, an analog front end and a battery, which generates DC electric fields (EFs), mimicking and modulating the patient's own physiological electrical signals. The electrical stimulation is applied to percutaneous metal probes, which are located close to the inflamed or injured tissue of the patient. The treatment can be used in an ambulatory or stationary environment. It shows unexpectedly, highly effective treatment for certain severe neurological pain conditions, as well as traumatic soft tissue injuries (muscle/ligament ruptures, joint sprains). Without EF intervention, these conditions, respectively, are either virtually incurable or take several months to heal. We present three cases - severe chronic cluster headache, acute massive muscle rupture of the rectus femoris and an acute ankle sprain with a ruptured anterior talofibular ligament - to demonstrate clinical effectiveness and discuss the fundamental differences between mimicking DC simulation and conventional transcutaneous electric nerve stimulation (TENS) or TENS-like implanted devices as used for peripheral nerve cord, spinal cord or dorsal root stimulation.

Acupuncture in treatment of musculoskeletal disorders of orchestra musicians.

OBJECTIVE: Playing-related musculoskeletal disorders (PRMD) are common among musicians. Acupuncture is well established in Germany as a treatment for orthopedic conditions, but it is not commonly used in the treatment of PRMD yet. The authors examined the musicians' health literature and provide a brief overview about the background of acupuncture. Three case studies are presented to show possible benefits for the treatment of PRMD. PARTICIPANTS: 2456 medical doctors, members of the German research group for acupuncture. METHODS: We searched literature and Medline Database for publications about acupuncture, musicians' medicine and musculoskeletal disorders. Additionally we asked medical doctors, via a questionnaire, about the treatment of professional musicians as patients. Case studies are presented. RESULTS: No research was found to support the use oft acupuncture in PRMD. The survey study found that medical doctors are not satisfied with the quality of medical health care provided to musicians and regard specialist knowledge as being important. CONCLUSION: Evidence on the benefits of acupuncture for musculoskeletal disorders suggests that it could be of benefit as a complementary treatment of PRMD. We suggest performing clinical trials to demonstrate the value of standard treatment, acupuncture and complementary medicine for PRMD.

An international expert survey on acupuncture in randomized controlled trials for low back pain and a validation of the low back pain acupuncture score.

BACKGROUND: Acupuncture is a promising treatment approach in patients with chronic low back pain (cLBP) but little is known about the quality of acupuncture in randomized controlled trials (RCT) of acupuncture cLBP. - OBJECTIVE: To determine how international experts (IES) rate the quality of acupuncture in RCTs of cLBP; independent international validation of the Low Back Pain Acupuncture Score (LBPAS). METHODOLOGY: Fifteen experts from 9 different countries outside China were surveyed (IES). They were asked to read anonymized excerpts of 24 RCTs of cLBP and answer a three-item questionnaire on how the method of acupuncture conformed to 1) Chinese textbook standards, 2) the expert?s personally preferred style, and 3) how acupuncture is performed in the expert?s country. Likert scale rating, calculation of the mode for each answer, and Spearman?s rank correlation coefficient between all three answers and the LBPAS were calculated. RESULTS: On comparison with Chinese textbook standards (question 1), 6 RCTs received a good rating, 8 trials a fair and 10 trials a poor or very poor rating. 5 of the 6 trials rated good, received at least a good rating also in question 2 or 3. We found a high correlation of 0.85 (p<0.0001) between the IES and LBPAS ratings for question 1 and question 2, and a correlation of 0.66 (p<0.0001) for question 3. CONCLUSION: The international expert survey (IES) revealed that only 6 out of 24 (25%) RCTs of acupuncture for cLBP were rated "good" in respect to Chinese textbook acupuncture standards. There were only small differences in how the acupuncture quality was rated in comparison to Chinese textbook acupuncture, personally preferred and local styles of acupuncture. The rating showed a high correlation with the Low Back Pain Acupuncture Score LBPAS.

[Anaesthetic effect of acupuncture during an inguinal hernia repair ­ a self-experiment]. / Akupunkturanästhesie bei Leistenbruchoperation - ein Selbstversuch.

There are references in the media and in the literature to the use of acupuncture as an anaesthetic in surgical operations. The author, an experienced acupuncturist, tested the anaesthetic effect of acupuncture during an inguinal hernia repair in a self-experiment. Acupuncture combined with electrostimulation was administered for the 6-cm skin cut and preparation to 15 mm in depth. However, acupuncture alone provided an inadequate anaesthetic effect for the entire operation and an additional local anaesthetic had to be administered.

German Randomized Acupuncture Trial for chronic shoulder pain (GRASP) - a pragmatic, controlled, patient-blinded, multi-centre trial in an outpatient care environment.

UNLABELLED: The German Randomized Acupuncture Trial for chronic shoulder pain (GRASP) comprised 424 outpatients with chronic shoulder pain (CSP) > or =6 weeks and an average pain score of VAS > or =50 mm, who were randomly assigned to receive Chinese acupuncture (verum), sham acupuncture (sham) or conventional conservative orthopaedic treatment (COT). The patients were blinded to the type of acupuncture and treated by 31 office-based orthopaedists trained in acupuncture; all received 15 treatments over 6 weeks. The 50% responder rate for pain was measured on a VAS 3 months after the end of treatment (primary endpoint) and directly after the end of the treatment (secondary endpoint). RESULTS: In the ITT (n=424) analysis, percentages of responders for the primary endpoint were verum 65% (95% CI 56-74%) (n=100), sham 24% (95% CI 9-39%) (n=32), and COT 37% (95% CI 24-50%) (n=50); secondary endpoint: verum 68% (95% CI 58-77%) (n=92), sham 40% (95% CI 27-53%) (n=53), and COT 28% (95% CI 14-42%) (n=38). The results are significant for verum over sham and verum over COT (p<0.01) for both the primary and secondary endpoints. The PPP analysis of the primary (n=308) and secondary endpoints (n=360) yields similar responder results for verum over sham and verum over COT (p<0.01). Descriptive statistics showed greater improvement of shoulder mobility (abduction and arm-above-head test) for the verum group versus the control group immediately after treatment and after 3 months. The trial indicates that Chinese acupuncture is an effective alternative to conventional orthopaedic treatment for CSP.

Acupuncture induces a pro-inflammatory immune response intensified by a conditioning-expectation effect.

BACKGROUND: In a previous study it has been shown that acupuncture activates the respiratory burst (RB) of neutrophils as measured by the differences to baseline of the mean channel number of fluorescence intensity (mfi) in volunteers. Since this result could have been affected by a placebo effect, a study has been designed that controls for the different facets of placebo mechanisms such as expectancy, suggestibility, and conditioning. PARTICIPANTS AND METHODS: 60 healthy volunteers were randomized either to acupuncture of the acupoint Large Intestine 11 (LI 11) (groups 1 and 2) or relaxation (group 3) twice a week for 4 weeks. Only acupuncture group 1 and the relaxation group were provided with the additional suggestion that the treatment may strengthen the immune system. RESULTS: The repeated measurement analysis for differences of follow-ups to baseline showed significantly different treatment effects for neutrophils but not for monocytes (unprimed neutrophils: p = 0.004; neutrophils primed with TNF-alpha/FMLP or with FMLP only: p = 0.026 and p = 0.019, respectively) between groups. For both cell types post-hoc Dunnett's t-tests using the relaxation group as control showed significantly stronger treatment effects for acupuncture group 1. Combining all priming procedures, the average increase in mfi for both cell types was about 30% greater in acupuncture group 1 than in the relaxation group. Plasma concentrations of pro-inflammatory cytokines only increased significantly in the acupuncture groups. CONCLUSION: Repetitive acupuncture increases the cytotoxicity of leukocytes in healthy volunteers, which might be intensified by a conditioning-expectation effect.

Chinese acupuncture for chronic low back pain: an international expert survey.

BACKGROUND: Chinese acupuncture is widely accepted in western countries, and a number of clinical trials are testing Chinese acupuncture, especially for chronic low back pain (cLBP). However, little is known about how practitioners perform acupuncture treatment in daily clinical work and whether treatment styles differ among practitioners and countries. OBJECTIVE: To investigate whether styles of Chinese acupuncture treatment for cLBP are heterogeneous among different practitioners and countries. METHODOLOGY: Literature review, a prospective survey of international experts using a questionnaire with open and closed questions, and personal interviews. RESULTS: Data were collected from 18 experts in 10 different countries. The typical treatment regimen for cLBP, based on a composite of experts' responses, consisted of 11 sessions lasting 25 minutes each, held twice weekly. The typical practitioner inserted 12 needles, would select individual points according to channels and syndromes, and would identify syndromes such as kidney deficiency (yin and yang), cold dampness, and qi and blood stagnation. Preferred points were BL 23, BL 40, GB 34, BL 54, BL 60, BL 54, and Huatuo, although there was a high variation in additional local and distal points. Generally speaking, no expert would administer fewer than 6 treatments, omit Ahshi points, restrict needle insertion to 1 cm or less, or adhere solely to fixed points for all patients. CONCLUSIONS: For the first time it has been shown that there is a broad consistency in fundamental aspects of Chinese acupuncture for cLBP across different kinds of practitioners and different countries. These data can be used as minimal standards for the design and funding of future clinical trials.

The status and future of acupuncture clinical research.

On November 8-9, 2007, the Society for Acupuncture Research (SAR) hosted an international conference to mark the tenth anniversary of the landmark National Institutes of Health Consensus Development Conference on Acupuncture. More than 300 acupuncture researchers, practitioners, students, funding agency personnel, and health policy analysts from 20 countries attended the SAR meeting held at the University of Maryland School of Medicine, Baltimore, MD. This paper summarizes important invited lectures in the area of clinical research. Specifically, included are: a review of the recently conducted German trials and observational studies on low-back pain (LBP), gonarthrosis, migraine, and tension-type headache (the Acupuncture Research Trials and the German Acupuncture Trials, plus observational studies); a systematic review of acupuncture treatment for knee osteoarthritis (OA); and an overview of acupuncture trials in neurologic conditions, LBP, women's health, psychiatric disorders, and functional bowel disorders. A summary of the use of acupuncture in cancer care is also provided. Researchers involved in the German trials concluded that acupuncture is effective for treating chronic pain, but the correct selection of acupuncture points seems to play a limited role; no conclusions could be drawn about the placebo aspect of acupuncture, due to the design of the studies. Overall, when compared to sham, acupuncture did not show a benefit in treating knee OA or LBP, but acupuncture was better than a wait-list control and standard of care, respectively. In women's health, acupuncture has been found to be beneficial for patients with premenstrual syndrome, dysmenorrhea, several pregnancy-related conditions, and nausea in females who have cancers. Evidence on moxibustion for breech presentation, induction of labor, and reduction of menopausal symptoms is still inconclusive. In mental health, evidence for acupuncture's efficacy in treating neurologic and functional bowel disorder is still inconclusive. For chronic cancer-related problems such as pain, acupuncture may work well in stand-alone clinics; however, for acute or treatment-related symptoms, integration of acupuncture care into a busy and complex clinical environment is unlikely, unless compelling evidence of a considerable patient benefit can be established.

Acupuncture for tension-type headache: a multicentre, sham-controlled, patient-and observer-blinded, randomised trial.

Acupuncture treatment is frequently sought for tension-type headache (TTH), but there is conflicting evidence as to its effectiveness. This randomised, controlled, multicentre, patient-and observer-blinded trial was carried out in 122 outpatient practices in Germany on 409 patients with TTH, defined as > or =10 headache days per month of which < or =1 included migraine symptoms. Interventions were verum acupuncture according to the practice of traditional Chinese medicine or sham acupuncture consisting of superficial needling at nonacupuncture points. Acupuncture was administered by physicians with specialist acupuncture training. Ten 30-min sessions were given over a six-week period, with additional sessions available for partial response. Response was defined as >50% reduction in headache days/month at six months and no use of excluded concomitant medication or other therapies. In the intent-to-treat analysis (all 409 patients), 33% of verum patients and 27% of sham controls (p=0.18) were classed as responders. Verum was superior to sham for most secondary endpoints, including headache days (1.8 fewer; 95% CI 0.6, 3.0; p=0.004) and the International Headache Society response criterion (66% vs. 55% response, risk difference 12%, 95% CI: 2%-21%; p=0.024).). The relative risk on the primary and secondary response criterion was very similar ( approximately 0.8); the difference in statistical significance may be due to differences in event rate. TTH improves after acupuncture treatment. However, the degree to which treatment benefits depend on psychological compared to physiological effects and the degree to which any physiological effects depend on needle placement and insertion depth are unclear.

Role of acupuncture in the treatment of migraine.

Since the last Cochrane review of acupuncture and headache in 2001, which found methodological and/or reporting shortcomings in the majority of the studies, several large, randomized trials on the effectiveness of acupuncture as a treatment for headache have been published. Following a brief overview of the pathophysiology of migraine and possible action mechanisms of acupuncture, we look at current studies on acupuncture and migraine and discuss the results. From these results and our own studies on acupuncture and migraine, we conclude that a 6-week course of acupuncture is not inferior to a 6-month prophylactic drug treatment, but that specific Chinese point selection, point stimulation and needling depth are not as important as had been thought. The review suggests that acupuncture should be integrated into existing migraine therapy protocols.

German Acupuncture Trials (GERAC) for chronic low back pain: randomized, multicenter, blinded, parallel-group trial with 3 groups.

BACKGROUND: To our knowledge, verum acupuncture has never been directly compared with sham acupuncture and guideline-based conventional therapy in patients with chronic low back pain. METHODS: A patient- and observer-blinded randomized controlled trial conducted in Germany involving 340 outpatient practices, including 1162 patients aged 18 to 86 years (mean +/- SD age, 50 +/- 15 years) with a history of chronic low back pain for a mean of 8 years. Patients underwent ten 30-minute sessions, generally 2 sessions per week, of verum acupuncture (n = 387) according to principles of traditional Chinese medicine; sham acupuncture (n = 387) consisting of superficial needling at nonacupuncture points; or conventional therapy, a combination of drugs, physical therapy, and exercise (n = 388). Five additional sessions were offered to patients who had a partial response to treatment (10%-50% reduction in pain intensity). Primary outcome was response after 6 months, defined as 33% improvement or better on 3 pain-related items on the Von Korff Chronic Pain Grade Scale questionnaire or 12% improvement or better on the back-specific Hanover Functional Ability Questionnaire. Patients who were unblinded or had recourse to other than permitted concomitant therapies during follow-up were classified as nonresponders regardless of symptom improvement. RESULTS: At 6 months, response rate was 47.6% in the verum acupuncture group, 44.2% in the sham acupuncture group, and 27.4% in the conventional therapy group. Differences among groups were as follows: verum vs sham, 3.4% (95% confidence interval, -3.7% to 10.3%; P = .39); verum vs conventional therapy, 20.2% (95% confidence interval, 13.4% to 26.7%; P < .001); and sham vs conventional therapy, 16.8% (95% confidence interval, 10.1% to 23.4%; P < .001. CONCLUSIONS: Low back pain improved after acupuncture treatment for at least 6 months. Effectiveness of acupuncture, either verum or sham, was almost twice that of conventional therapy.

Designing an acupuncture study: II. The nationwide, randomized, controlled German acupuncture trials on low-back pain and gonarthrosis.

BACKGROUND: In the nationwide German Acupuncture Trials (GERAC), verum acupuncture, mirroring the Traditional Chinese Medicine (TCM) acupuncture style, was tested against sham acupuncture and guideline standard therapy for the entities classified in the West as chronic low back pain (LBP) and gonarthrosis (GON). OBJECTIVE: The objective was to develop broadly consensual acupuncture and control protocols for the treatment of LBP and GON in the GERAC trials. METHODOLOGY: Extensive literature study and consultation with acupuncture experts were consulted. Personal interviews, both free and structured, e-mail discussions, and phone conferences were used as well. RESULTS: Broadly consensual acupuncture protocols for LBP and GON for verum and invasive sham acupuncture were developed. They included semistandardized point combinations with clearly described point selection rules based on TCM acupuncture diagnosis. A procedure was developed to help ensure homogenous treatment quality in a large multicenter trial. CONCLUSIONS: With 1162 randomized patients for LBP and 1039 patients for GON, the GERAC study design allowed acupuncture to be tested in a naturalistic environment. The rigorous study design and large number of physician investigators guaranteed a high external validity for the results. The results will help determine the significance of Chinese acupuncture in the context of Western medicine for the treatment of LBP and GON.

Designing an acupuncture study: the nationwide, randomized, controlled, German acupuncture trials on migraine and tension-type headache.

BACKGROUND: In the nationwide German Acupuncture Trials (GERAC) verum acupuncture, based on Traditional Chinese Medicine (TCM), was to be tested against sham acupuncture for the entities classified in the West as "migraine" (MIG) and "tension-type headache" (TTH). However, there were no generally accepted guidelines on how to perform a consistent verum or sham treatment. OBJECTIVE: To design broadly consensual verum and sham acupuncture treatment protocols for MIG and TTH for the GERAC. METHODOLOGY: Extensive literature study and consultation with acupuncture experts. Personal interviews, both free and structured, e-mail discussions, and phone conferences were used. RESULTS: Broadly consensual acupuncture protocols for MIG and TTH for verum and sham acupuncture were developed. They included semi-standardized point combinations with clearly described point selection rules based on TCM acupuncture diagnoses. A procedure was developed to help ensure homogenous treatment quality in a large multicenter trial. CONCLUSIONS: The GERAC study design allowed acupuncture to be tested in a naturalistic environment. The rigorous study design and the large number of physician investigators guaranteed a high external validity for the results. The results will help determine the significance of Chinese acupuncture in the context of Western medicine for the treatment of MIG and TTH.

Efficacy of acupuncture for the prophylaxis of migraine: a multicentre randomised controlled clinical trial.

BACKGROUND: Our aim was to assess the efficacy of a part-standardised verum acupuncture procedure, in accordance with the rules of traditional Chinese medicine, compared with that of part-standardised sham acupuncture and standard migraine prophylaxis with beta blockers, calcium-channel blockers, or antiepileptic drugs in the reduction of migraine days 26 weeks after the start of treatment. METHODS: This study was a prospective, randomised, multicentre, double-blind, parallel-group, controlled, clinical trial, undertaken between April 2002 and July 2005. Patients who had two to six migraine attacks per month were randomly assigned verum acupuncture (n=313), sham acupuncture (n=339), or standard therapy (n=308). Patients received ten sessions of acupuncture treatment in 6 weeks or continuous prophylaxis with drugs. Primary outcome was the difference in migraine days between 4 weeks before randomisation and weeks 23-26 after randomisation. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN52683557. FINDINGS: Of 1295 patients screened, 960 were randomly assigned to a treatment group. Immediately after randomisation, 125 patients (106 from the standard group) withdrew their consent to study participation. 794 patients were analysed in the intention-to-treat popoulation and 443 in the per-protocol population. The primary outcome showed a mean reduction of 2 .3 days (95% CI 1.9-2.7) in the verum acupuncture group, 1.5 days (1.1-2.0) in the sham acupuncture group, and 2.1 days (1.5-2.7) in the standard therapy group. These differences were statistically significant compared with baseline (p<0.0001), but not across the treatment groups (p=0.09). The proportion of responders, defined as patients with a reduction of migraine days by at least 50%, 26 weeks after randomisation, was 47% in the verum group, 39% in the sham acupuncture group, and 40% in the standard group (p=0.133). INTERPRETATION: Treatment outcomes for migraine do not differ between patients treated with sham acupuncture, verum acupuncture, or standard therapy.

Designing an acupuncture study to meet evidence-based medical criteria: methodological considerations for logistic design and development of treatment interventions arising from the German randomized controlled acupuncture trial on chronic shoulder pain (GRASP).

The results from studies on potential treatment effects of acupuncture are often limited due to serious difficulties in methodology. Randomized controlled trials on acupuncture should test a widely accepted treatment strategy of verum and sham acupuncture. However, in clinical practice various patterns of acupuncture techniques are employed, and up to now no generally accepted guidelines on how to perform a reliable verum or sham treatment have been established. Another limitation is that in most studies the study populations are too small to obtain reliable data and to detect subtle differences between the unspecific needling of sham acupuncture and specific needling of verum acupuncture with sufficient statistical power. Moreover, only a multicenter trial in an outpatient setting would guarantee a naturalistic environment in which acupuncture is used in clinical practice. In the present report we discuss such methodological aspects in detail and summarize some practical considerations for planning an acupuncture trial that fulfills evidence-based medical criteria. The largest German study on the treatment effects of acupuncture in patients with chronic shoulder pain (recruited patients n = 452), might serve as an example for such a well-designed study. Before we could conduct our study, clear definitions and protocols for the verum and sham acupuncture treatments as well as adequate endpoints had to be developed. For this we used a combination of a comprehensive study of the literature and structured interviews with experienced physicians followed by an expert panel. A total of 41 physicians had to be trained to achieve a homogeneously high quality of acupuncture treatment. The latter represents a prerequisite for reproducibility, constituting a critical component of rigorous efficacy trials in scientific acupuncture research.

The German multicenter, randomized, partially blinded, prospective trial of acupuncture for chronic low-back pain: a preliminary report on the rationale and design of the trial.

BACKGROUND: The efficacy of acupuncture treatment for chronic low-back pain has not been reliably proven because of a lack of good quality studies, leading to the necessity of developing the German Acupuncture Trial for Chronic Low-Back Pain (GERAC-cLBP) study. OBJECTIVE: The aim is to assess the effectiveness of traditional Chinese acupuncture for chronic low-back pain compared to sham acupuncture and with a conventional standard therapy. METHODS: This trial is a nationwide, multicenter, randomized, prospective, partially blinded study. The primary endpoint is the success rate after 6 months. Success is defined as an improvement of 33% or more of three pain-related items on the Van-Korff Pain Score or an improvement of 12% or more in the disability measured by the Hanover Functional Ability Questionnaire. Assessment of the effectiveness of the blinding of patients to the form of acupuncture they received will be conducted. All clinical endpoints are assessed centrally by blinded independent observers. The sample size, with a total of 1062 patients to be enrolled, is based on power calculations. Independent central randomization, data collection, data processing, and statistical analysis are provided. Success rates will be tested for differences using two-sided Fisher exact tests. In the primary analysis, all tests will be carried out on the basis of the intention-to-treat principle. Secondary analyses will be conducted according to protocol approaches. TRIAL STATUS: The pilot phase of the trial started in February 2002, the estimated duration of the study is 2.5 years. Enrollment is anticipated to be completed in the winter of 2003. CONCLUSION: The GERAC-cLBP study is currently the world's largest controlled trial of the effectiveness of acupuncture treatment for low-back pain. It will contribute to the evaluation of efficacy by means of evidence based medicine.

Does acupuncture improve the orthopedic management of chronic low back pain--a randomized, blinded, controlled trial with 3 months follow up.

This prospective, randomised controlled trial, with three parallel groups, patient and observer blinded for verum and sham acupuncture and a follow up of 3 months raises the question: "Does a combination of acupuncture and conservative orthopedic treatment improve conservative orthopedic treatment in chronic low back pain (LBP). 186 in-patients of a LBP rehabilitation center with a history of LBP >or=6 weeks, VAS >or=50mm, and no pending compensation claims, were selected; for the three random group 4 weeks of treatment was applied. 174 patients met the protocol criteria and reported after treatment, 124 reported after 3 months follow up. Patients were assorted 4 strata: chronic LBP, or=5 years. Analysis was by intention to treat. Group 1 (Verum+COT) received 12 treatments of verum acupuncture and conservative orthopedic treatment (COT). Group 2 (Sham+COT) received 12 treatments of non-specific needling and COT. Group 3 (nil+COT) received COT alone. Verum- and Sham acupuncture were blinded against patient and examiner. The primary endpoints were pain reduction >or=50% on VAS 3 months after the end of the treatment protocol. Secondary endpoints were pain reduction >or=50% on VAS and treatment efficacy on a four-point box scale directly after the end of the treatment protocol and treatment efficacy after 3 months. In the whole sample a pain relief of >or=50% on VAS was reported directly after the end of treatment protocol: Verum+COT 65% (95%CI 51-77%), Sham+COT 34% (95%ci 22-49%), nil+COT 43% (95%ci 29-58%) - results are significant for Verum+COT over Sham+COT (P