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1.  DAMGO in the central amygdala alleviates the affective dimension of pain in a rat model of inflammatory hyperalgesia 
Neuroscience  2013;252:10.1016/j.neuroscience.2013.08.030.
Pain has sensory-discriminative and emotional-affective dimensions. Recent studies show that the affective component can be assessed with a conditioned place avoidance (CPA) test. We hypothesized that systemic morphine before a post-conditioning test would more potently attenuate the affective aspect compared to the sensory component and that DAMGO, a μ-selective opioid receptor agonist, injected into the central nucleus of the amygdala (CeA) would reduce established CPA. A rat model of inflammatory pain, produced by a complete Freund adjuvant (CFA) injection into the hind paw, was combined with a CPA test. Three experiments were performed on adult male Sprague-Dawley rats. Systemic morphine (0.5 or 1.0 mg/kg) in Experiment 1, intrathecal (i.t.) morphine (2.5 μg/rat) in Experiment 2, and intra-CeA DAMGO (7.7-15.4 ng/0.4μl) in Experiment 3 were given to CFA-injected rats (n=6-8/group) prior to a post-conditioning test. Saline-injected rats were used as control. Time spent in a pain-paired compartment was recorded twice, before conditioning and after a post-conditioning test. Paw withdrawal latency (PWL) to a noxious thermal stimulus was measured before experiment at day −1 and after the post-conditioning test; hyperalgesia was defined as a decrease in PWL. The data showed that CFA-injected rats had significantly negative CPA compared to those of saline-injected rats (P<0.05). Low dosage systemic morphine significantly (P<0.05) reduced CFA-induced CPA but had no effect on PWL. I.t. morphine did not inhibit the display of CPA but significantly increased PWL, suppressing hyperalgesia (P<0.05). Intra-CeA DAMGO significantly inhibited the display of CPA compared to saline (P<0.05) but had no effect on PWL. The data demonstrates that morphine attenuates the affective component more powerfully than it does the sensory and suggests that the sensory and the emotional-affective dimensions are underpinned by different mechanisms.
doi:10.1016/j.neuroscience.2013.08.030
PMCID: PMC3864641  PMID: 23994597
Conditioned place avoidance; pain; opioid; amygdala; spinal cord; hyperalgesia
2.  The effects of acupuncture on rates of clinical pregnancy among women undergoing in vitro fertilization: a systematic review and meta-analysis 
Human Reproduction Update  2013;19(6):696-713.
BACKGROUND
Recent systematic reviews of adjuvant acupuncture for IVF have pooled heterogeneous trials, without examining variables that might explain the heterogeneity. The aims of our meta-analysis were to quantify the overall pooled effects of adjuvant acupuncture on IVF clinical pregnancy success rates, and evaluate whether study design-, treatment- and population-related factors influence effect estimates.
METHODS
We included randomized controlled trials that compared needle acupuncture administered within 1 day of embryo transfer, versus sham acupuncture or no adjuvant treatment. Our primary outcome was clinical pregnancy rates. We obtained from all investigators additional methodological details and outcome data not included in their original publications. We analysed sham-controlled and no adjuvant treatment-controlled trials separately, but since there were no large or significant differences between these two subsets, we pooled all trials for subgroup analyses. We prespecified 11 subgroup variables (5 clinical and 6 methodological) to investigate sources of heterogeneity, using single covariate meta-regressions.
RESULTS
Sixteen trials (4021 participants) were included in the meta-analyses. There was no statistically significant difference between acupuncture and controls when combining all trials [risk ratio (RR) 1.12, 95% confidence interval (CI), 0.96–1.31; I2 = 68%; 16 trials; 4021 participants], or when restricting to sham-controlled (RR 1.02, 0.83–1.26; I2 = 66%; 7 trials; 2044 participants) or no adjuvant treatment-controlled trials (RR 1.22, 0.97–1.52; I2 = 67%; 9 trials; 1977 participants). The type of control used did not significantly explain the statistical heterogeneity (interaction P = 0.27). Baseline pregnancy rate, measured as the observed rate of clinical pregnancy in the control group of each trial, was a statistically significant effect modifier (interaction P < 0.001), and this covariate explained most of the heterogeneity of the effects of adjuvant acupuncture across all trials (adjusted R2 = 93%; I2 residual = 9%). Trials with lower control group rates of clinical pregnancy showed larger effects of adjuvant acupuncture (RR 1.53, 1.28–1.84; 7 trials; 1732 participants) than trials with higher control group rates of clinical pregnancy (RR 0.90, 0.80–1.01; 9 trials; 2289 participants). The asymmetric funnel plot showed a tendency for the intervention effects to be more beneficial in smaller trials.
CONCLUSIONS
We found no pooled benefit of adjuvant acupuncture for IVF. The subgroup finding of a benefit in trials with lower, but not higher, baseline pregnancy rates (the only statistically significant subgroup finding in our earlier review) has been confirmed in this update, and was not explained by any confounding variables evaluated. However, this baseline pregnancy rate subgroup finding among published trials requires further confirmation and exploration in additional studies because of the multiple subgroup tests conducted, the risk of unidentified confounders, the multiple different factors that determine baseline rates, and the possibility of publication bias.
doi:10.1093/humupd/dmt026
PMCID: PMC3796945  PMID: 23814102
acupuncture; assisted conception; complementary medicine; in vitro fertilization; systematic review
3.  Physician Perspectives on Comparative Effectiveness Research: Implications for Practice-based Evidence 
Comparative effectiveness research (CER) is defined by the Institute of Medicine as “the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care.” The goal of CER is to provide timely, useful evidence to healthcare decision makers including physicians, patients, policymakers, and payers. A prime focus for the use of CER evidence is the interaction between physician and patient. Physicians in primary practice are critical to the success of the CER enterprise. A 2009 survey suggests, however, that physician attitudes toward CER may be mixed—somewhat positive toward the potential for patient care improvement, yet negative toward potential restriction on physician freedom of practice. CER methods and goals closely parallel those of practice-based research, an important movement in family medicine in the United States since the 1970s. This article addresses apparent physician ambivalence toward CER and makes a case for family medicine engagement in CER to produce useful practice-based evidence. Such an effort has potential to expand care options through personalized medicine, individualized guidelines, focus on patient preferences and patient-reported outcomes, and study of complex therapeutic interventions, such as integrative care. Academic medical researchers will need to collaborate with experienced family physicians to identify significant practice-based research questions and design meaningful studies. Such collaborations would shape CER to produce high-quality practice-based evidence to inform family and community medicine.
doi:10.7453/gahmj.2012.1.4.004
PMCID: PMC3833509  PMID: 24278829
Comparative effectiveness research; practice-based evidence; complementary and alternative medicine; patient-reported outcomes
4.  Effectiveness guidance document (EGD) for Chinese medicine trials: a consensus document 
Trials  2014;15:169.
Background
There is a need for more Comparative Effectiveness Research (CER) on Chinese medicine (CM) to inform clinical and policy decision-making. This document aims to provide consensus advice for the design of CER trials on CM for researchers. It broadly aims to ensure more adequate design and optimal use of resources in generating evidence for CM to inform stakeholder decision-making.
Methods
The Effectiveness Guidance Document (EGD) development was based on multiple consensus procedures (survey, written Delphi rounds, interactive consensus workshop, international expert review). To balance aspects of internal and external validity, multiple stakeholders, including patients, clinicians, researchers and payers were involved in creating this document.
Results
Recommendations were developed for “using available data” and “future clinical studies”. The recommendations for future trials focus on randomized trials and cover the following areas: designing CER studies, treatments, expertise and setting, outcomes, study design and statistical analyses, economic evaluation, and publication.
Conclusion
The present EGD provides the first systematic methodological guidance for future CER trials on CM and can be applied to single or multi-component treatments. While CONSORT statements provide guidelines for reporting studies, EGDs provide recommendations for the design of future studies and can contribute to a more strategic use of limited research resources, as well as greater consistency in trial design.
doi:10.1186/1745-6215-15-169
PMCID: PMC4045891  PMID: 24885146
Comparative effectiveness research; Effectiveness guidance document; Chinese medicine research
5.  Key factors in developing the trinitrobenzene sulfonic acid-induced post-inflammatory irritable bowel syndrome model in rats 
AIM: To investigate the key factors in developing the trinitrobenzene sulfonic acid (TNBS)-induced post-inflammatory irritable bowel syndrome (PI-IBS) model in rats.
METHODS: TNBS was administered to rats at the following conditions: (1) with different doses (20, 10, 5 mg/0.8 mL per rat); (2) with same dose in different concentrations (20 mg/rat, 25, 50 mg/mL); (3) in different ethanol percentage (25%, 50%); and (4) at depth either 4 cm or 8 cm from anus. At 5 d and 4 wk after TNBS administration, inflammation severity and inflammation resolution were evaluated. At 4 and 8 wk after TNBS application, visceral hyperalgesia and enterochromaffin (EC) cell hyperplasia were assayed by abdominal withdrawal reflex test, silver staining and capillary electrophoresis.
RESULTS: Our results showed that: (1) TNBS induced dose-dependent acute inflammation and inflammation resolution. At 5 d post TNBS, the pathological score and myeloperoxidase (MPO) activity in all TNBS treated rats were significantly elevated compared to that of the control (9.48 ± 1.86, 8.18 ± 0.67, 5.78 ± 0.77 vs 0, and 3.55 ± 1.11, 1.80 ± 0.82, 0.97 ± 0.08 unit/mg vs 0.14 ± 0.01 unit/mg, P < 0.05). At 4 wk post TNBS, the pathological score in high and median dose TNBS-treated rats were still significantly higher than that of the control (1.52 ± 0.38 and 0.80 ± 0.35 vs 0, P < 0.05); (2) Intracolonic TNBS administration position affected the persistence of visceral hyperalgesia. At 4 wk post TNBS, abdominal withdrawal reflex (AWR) threshold pressure in all TNBS-treated groups were decreased compared to that of the control (21.52 ± 1.73 and 27.10 ± 1.94 mmHg vs 34.44 ± 1.89 mmHg, P < 0.05). At 8 wk post TNBS, AWR threshold pressure in 8 cm administration group was still significantly decreased (23.33 ± 1.33 mmHg vs 36.79 ± 2.29 mmHg, P < 0.05); (3) Ethanol percentage affected the TNBS-induced inflammation severity and visceral hyperalgesia. In TNBS-25% ethanol-treated group, the pathological score and MPO activity were significantly lowered compared to that of the TNBS-50% ethanol-treated group, while AWR threshold pressure were significantly elevated (36.33 ± 0.61 mmHg vs 23.33 ± 1.33 mmHg, P < 0.05); and (4) TNBS (5 mg/0.8 mL per rat, in 50% ethanol, 8 cm from anus)-treated rats recovered completely from the inflammation with acquired visceral hyperalgesia and EC cell hyperplasia at 4 wk after TNBS administration.
CONCLUSION: TNBS dosage, concentration, intracolonic administration position, and ethanol percentage play important roles in developing visceral hyperalgesia and EC cell hyperplasia of TNBS-induced PI-IBS rats.
doi:10.3748/wjg.v18.i20.2481
PMCID: PMC3360446  PMID: 22654445
Post-inflammatory; Irritable bowel syndrome; Rat model; Trinitrobenzene sulfonic acid; Key factors
6.  Spinal interleukin-17 promotes thermal hyperalgesia and NMDA NR1 phosphorylation in an inflammatory pain rat model 
Pain  2012;154(2):294-305.
It is known that interleukin-17 (IL-17) is associated with autoimmune disorders and that peripheral IL-17 plays a role in arthritis and neuropathic pain. The present study investigated the possibility of spinal cell expression of IL-17 during inflammatory pain and possible IL-17 involvement in such pain. Hyperalgesia was induced by injecting complete Freund’s adjuvant (CFA, 0.08 ml, 40 μg Mycobacterium tuberculosis) into one hind paw of the rat. Paw withdrawal latency (PWL) was tested before (−48 h) and 2 and 24 h after CFA to assess hyperalgesia. IL-17 antibody (0.2–2 μg/rat) was given intrathecally (i.t.) 24 h before CFA to block the action of basal IL-17 and 2 h prior to each of two PWL tests to block CFA-induced IL-17. I.t. recombinant IL-17 (10–400 ng/rat) was administered to naive rats to determine its effects on PWL and phosphorylated-NR1 (p-NR1). P-NR1 modulates N-methyl-D-aspartate receptor (NMDAR) activity to facilitate pain. Spinal cords were removed for IL-17 immunostaining, double immunostaining of IL-17/cell markers and IL-17 receptor A (IL-17RA)/NR1, for western blot of IL-17, p-NR1, IL-17RA, and GFAP, for in situ IL-17RA hybridization, and for real time PCR of IL-17RA. The data shows that 1) IL-17 is up-regulated in activated and non-activated astrocytes, 2) IL-17RA is localized in NR1-immunoreactive neurons and up-regulated, and 3) IL-17 antibody at 2 μg/rat significantly increased PWL (P<0.05) and decreased p-NR1 and IL-17RA compared to control in CFA- and IL-17-injected rats. The results suggest that spinal IL-17 is produced by astrocytes and enhances p-NR1 to facilitate pain.
doi:10.1016/j.pain.2012.10.022
PMCID: PMC3563420  PMID: 23246025
Interleukin-17; spinal cord; glial cells; hyperalgesia; inflammation; pain
7.  Preclinical safety evaluation of the aqueous acetone extract of Chinese herbal formula Modified Huo Luo Xiao Ling Dan 
Objective
To investigate the safety of oral administration of Modified Huo Luo Xiao Ling Dan (HLXLD), a compound traditional Chinese herbal medicine.
Methods
The toxicological information of HLXLD and its individual constituent herbs was searched in cintcm or TCMlars (www.cintcm.com), PubMed (MEDLINE), Chinese Herbal Medicine (1999) and WHO Monographs on Selected Medicinal Plants (Vol. I—III). Single-dose acute toxicity was assessed by using the highest possible dosage. Motor function test was used to determine whether the herbal formula might cause motor impairment. Nine-day HLXLD repeat-dose sub-chronic toxicity/adverse effects, and 42-day chronic toxicity/adverse effects in rats were also assessed.
Results
The literature searches showed that HLXLD and its eleven ingredient herbs had no side/adverse effects listed in the traditional Chinese medicine literature. Under the dosages proposed in the formula, the HLXLD formula had no side/adverse effects according to MEDLINE, Chinese Herbal Medicine and WHO Monographs on Selected Medicinal Plants. The studies in rats showed: (1) in single-dose acute toxicity assessment, the maximal feasible single oral dose, 9.20 g/kg HLXLD, showed no significant effect on clinical signs, or body weight and mortality over a 14-day period in rats; (2) during motor function test, nine-day repeat-dose of daily HLXLD treatment at 4.60 g/kg did not cause motor impairment; (3) in nine-day HLXLD repeat-dose sub-chronic toxicity/adverse effects assessment, there were no noticeable abnormal behavioral changes or obvious adverse reactions and signs in complete Freund's adjuvant inflamed rats (highest observed dosage: 4.60 g/kg), and no noticeable adverse effects were observed during, or 14 days after nine-day treatment at 4.60 g/kg in non-inflamed rats; (4) during 42-day chronic toxicity/adverse effects assessments, no noticeable abnormal behavioral changes, no obvious adverse reactions and signs were observed in normal rats administered with HLXLD at a dose of 2.30 g/kg and the values of serum biochemistry and histopathology were in normal range.
Conclusion
Both existing information and animal data support that Modified HLXLD is a safe herbal product for clinical application.
PMCID: PMC3739922  PMID: 20456842
Chinese herb formula; Modified Huo Luo Xiao Ling Dan; Safety; Literature investigation; Acute toxicity tests; Motor function; Sub-acute toxicity; Chronic toxicity tests; Rats
8.  Microarray Analysis Reveals the Molecular Basis of Antiarthritic Activity of Huo-Luo-Xiao-Ling Dan 
Rheumatoid arthritis (RA) is a chronic inflammatory disease of autoimmune origin. Huo-luo-xiao-ling dan (HLXL) is an herbal mixture that has been used in traditional Chinese medicine over several decades to treat chronic inflammatory diseases including RA. However, the mechanism of the anti-arthritic action of this herbal remedy is poorly understood at the molecular level. In this study, we determined by microarray analysis the effects of HLXL on the global gene expression profile of the draining lymph node cells (LNC) in the rat adjuvant arthritis (AA) model of human RA. In LNC restimulated in vitro with the disease-related antigen mycobacterial heat-shock protein 65 (Bhsp65), 84 differentially expressed genes (DEG) (64 upregulated and 20 downregulated) versus 120 DEG (94 upregulated and 26 downregulated) were identified in HLXL-treated versus vehicle (Water)-treated rats, respectively, and 62 DEG (45 upregulated and 17 downregulated) were shared between the two groups. The most affected pathways in response to HLXL treatment included immune response, inflammation, cellular proliferation and apoptosis, and metabolic processes, many of which are directly relevant to arthritis pathogenesis. These results would advance our understanding of the mechanisms underlying the anti-arthritic activity of HLXL.
doi:10.1155/2013/524746
PMCID: PMC3745855  PMID: 23983789
9.  Acupuncture for treatment of irritable bowel syndrome 
Background
Irritable bowel syndrome (IBS) is a common, costly, and difficult to treat disorder that impairs health-related quality of life and work productivity. Evidence-based treatment guidelines have been unable to provide guidance on the effects of acupuncture for IBS because the only previous systematic review included only small, heterogeneous and methodologically unsound trials.
Objectives
The primary objectives were to assess the efficacy and safety of acupuncture for treating IBS.
Search methods
MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, the Cumulative Index to Nursing and Allied Health, and the Chinese databases Sino-Med, CNKI, and VIP were searched through November 2011.
Selection criteria
Randomized controlled trials (RCTs) that compared acupuncture with sham acupuncture, other active treatments, or no (specific) treatment, and RCTs that evaluated acupuncture as an adjuvant to another treatment, in adults with IBS were included.
Data collection and analysis
Two authors independently assessed the risk of bias and extracted data. We extracted data for the outcomes overall IBS symptom severity and health-related quality of life. For dichotomous data (e.g. the IBS Adequate Relief Question), we calculated a pooled relative risk (RR) and 95% confidence interval (CI) for substantial improvement in symptom severity after treatment. For continuous data (e.g. the IBS Severity Scoring System), we calculated the standardized mean difference (SMD) and 95% CI in post-treatment scores between groups.
Main results
Seventeen RCTs (1806 participants) were included. Five RCTs compared acupuncture versus sham acupuncture. The risk of bias in these studies was low.We found no evidence of an improvement with acupuncture relative to sham (placebo) acupuncture for symptom severity (SMD-0.11, 95%CI −0.35 to 0.13; 4 RCTs; 281 patients) or quality of life (SMD = −0.03, 95%CI −0.27 to 0.22; 3 RCTs; 253 patients). Sensitivity analyses based on study quality did not change the results. A GRADE analysis indicated that the overall quality of the evidence for the primary outcomes in the sham controlled trials was moderate due to sparse data. The risk of bias in the four Chinese language comparative effectiveness trials that compared acupuncture with drug treatment was high due to lack of blinding. The risk of bias in the other studies that did not use a sham control was high due to lack of blinding or inadequate methods used for randomization and allocation concealment or both. Acupuncture was significantly more effective than pharmacological therapy and no specific treatment. Eighty-four per cent of patients in the acupuncture group had improvement in symptom severity compared to 63% of patients in the pharmacological treatment group (RR 1.28, 95% CI 1.12 to 1.45; 5 studies, 449 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to a high risk of bias (no blinding) and sparse data. Sixty-three per cent of patients in the acupuncture group had improvement in symptom severity compared to 34% of patients in the no specific therapy group (RR 2.11, 95% CI 1.18 to 3.79; 2 studies, 181 patients). There was no statistically significant difference between acupuncture and Bifidobacterium (RR 1.07, 95% CI 0.90 to 1.27; 2 studies; 181 patients) or between acupuncture and psychotherapy (RR 1.05, 95% CI 0.87 to 1.26; 1 study; 100 patients). Acupuncture as an adjuvant to another Chinese medicine treatment was significantly better than the other treatment alone. Ninety-three per cent of patients in the adjuvant acupuncture group improved compared to 79% of patients who received Chinese medicine alone (RR 1.17, 95% CI 1.02 to 1.33; 4 studies; 466 patients). There was one adverse event (i.e. acupuncture syncope) associated with acupuncture in the 9 trials that reported this outcome, although relatively small sample sizes limit the usefulness of these safety data.
Authors’ conclusions
Sham-controlled RCTs have found no benefits of acupuncture relative to a credible sham acupuncture control for IBS symptom severity or IBS-related quality of life. In comparative effectiveness Chinese trials, patients reported greater benefits from acupuncture than from two antispasmodic drugs (pinaverium bromide and trimebutine maleate), both of which have been shown to provide a modest benefit for IBS. Future trials may help clarify whether or not these reportedly greater benefits of acupuncture relative to pharmacological therapies are due entirely to patients’ preferences for acupuncture or greater expectations of improvement on acupuncture relative to drug therapy.
doi:10.1002/14651858.CD005111.pub3
PMCID: PMC3718572  PMID: 22592702
*Acupuncture Therapy; Irritable Bowel Syndrome [*therapy]; Randomized Controlled Trials as Topic; Humans
10.  Bibliometric and content analysis of the Cochrane Complementary Medicine Field specialized register of controlled trials 
Systematic Reviews  2013;2:51.
Background
The identification of eligible controlled trials for systematic reviews of complementary and alternative medicine (CAM) interventions can be difficult. To increase access to these difficult to locate trials, the Cochrane Collaboration Complementary Medicine Field (CAM Field) has established a specialized register of citations of CAM controlled trials. The objective of this study is to describe the sources and characteristics of citations included in the CAM Field specialized register.
Methods
Between 2006 and 2011, regular searches for citations of CAM trials in MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL) were supplemented with contributions of controlled trial citations from international collaborators. The specialized register was ‘frozen’ for analysis in 2011, and frequencies were calculated for publication date, language, journal, presence in MEDLINE, type of intervention, and type of medical condition.
Results
The CAM Field specialized register increased in size from under 5,000 controlled trial citations in 2006 to 44,840 citations in 2011. Most citations (60%) were from 2000 or later, and the majority (71%) were reported in English; the next most common language was Chinese (23%). The journals with the greatest number of citations were CAM journals published in Chinese and non-CAM nutrition journals published in English. More than one-third of register citations (36%) were not indexed in MEDLINE. The most common CAM intervention type in the register was non-vitamin, non-mineral dietary supplements (e.g., glucosamine, fish oil) (34%), followed by Chinese herbal medicines (e.g., Astragalus membranaceus, Schisandra chinensis) (27%).
Conclusions
The availability of the CAM Field specialized register presents both opportunities and challenges for CAM systematic reviewers. While the register provides access to thousands of difficult to locate trial citations, many of these trials are of low quality and may overestimate treatment effects. When including these trials in systematic reviews, adequate analysis of their risk of bias is of utmost importance.
doi:10.1186/2046-4053-2-51
PMCID: PMC3704678  PMID: 23826877
Complementary medicine; Randomized controlled trials; Data collection; Registries
11.  Acupuncture for irritable bowel syndrome: systematic review and meta-analysis 
Objective
Evidence-based treatment guidelines have been unable to provide evidence-based guidance on the effects of acupuncture for irritable bowel syndrome (IBS) because the only previous systematic review included only small, heterogeneous and methodologically unsound trials. We conducted a new systematic review and meta-analysis of randomized controlled trials (RCTs) to estimate the effects of acupuncture for treating IBS.
Methods
MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, Cumulative Index to Nursing and Allied Health, and the Chinese databases Sino-Med, CNKI, and VIP were searched through November 2011. Eligible RCTs compared acupuncture with sham acupuncture, other active treatments, or no (specific) treatment, and evaluated acupuncture as an adjuvant to another treatment. Our outcomes were overall IBS symptom severity and health-related quality of life. Dichotomous data were pooled to provide a relative risk (RR) of substantial improvement after treatment, and continuous data were pooled to provide a standardized mean difference (SMD) in post-treatment scores between groups.
Results
Seventeen RCTs (N=1806) were included. We found no evidence of an improvement with acupuncture relative to sham acupuncture on symptom severity (SMD = −0.11, 95% confidence interval: −0.35 to 0.13; 4 RCTs) or quality of life (SMD = −0.03, −0.27 to 0.22; 3 RCTs). Because of the homogeneity of the results of the sham-controlled trials, results were unaffected by restriction to the 4 sham-controlled RCTs that used adequate randomization, blinding, and had few withdrawals/drop-outs. Among RCTs that did not use a placebo control, acupuncture was more effective than pharmacological therapy (RR of symptom improvement=1.28, 1.12 to 1.45; 5 RCTs) and no (specific) treatment (RR = 2.11, 1.18 to 3.79; 2 RCTs). There was no difference between acupuncture and Bifidobacterium (RR = 1.07, 0.90 to 1.27; 2 RCTs) or between acupuncture and psychotherapy (RR=1.05, 0.87 to 1.26; 1 RCT). Acupuncture as an adjuvant to another Chinese medicine treatment was statistically significantly better than the other treatment alone, in trials with a high risk of bias (RR = 1.17, 1.02 to 1.33; 4 RCTs).
Conclusions
Sham-controlled RCTs have found no benefits of acupuncture relative to a credible sham acupuncture control on IBS symptom severity or IBS-related quality of life. In comparative effectiveness Chinese trials, patients reported greater benefits from acupuncture than from pharmacological therapies. Future trials may help clarify whether or not these reportedly greater benefits of acupuncture relative to pharmacological therapies are due entirely to patients’ preferences for acupuncture or patients’ greater expectations of improvement on acupuncture relative to drugs.
doi:10.1038/ajg.2012.66
PMCID: PMC3671917  PMID: 22488079
12.  Chinese Herbal Formula Huo-Luo-Xiao-Ling Dan Protects against Bone Damage in Adjuvant Arthritis by Modulating the Mediators of Bone Remodeling 
Huo-luo-xiao-ling dan (HLXL) is an herbal mixture that has long been used in traditional Chinese medicine for the treatment of rheumatoid arthritis (RA) and other inflammatory disorders. Despite the availability of potent conventionally used drugs for RA, their limited efficacy in a proportion of patients coupled with their high cost and severe adverse effects has necessitated the search for novel therapeutics for this debilitating disease. Further, the control of both inflammation and bone damage is essential for effective management of arthritis. The aim of our study was to evaluate the efficacy of HLXL against arthritic bone damage in adjuvant arthritis (AA) model of RA. Our results show that HLXL treatment suppressed inflammatory arthritis and reduced bone and cartilage damage in the joints of arthritic Lewis rats. HLXL-induced protection against bone damage was mediated primarily via inhibition of mediators of osteoclastic bone remodeling (e.g., receptor activator of nuclear factor kappa-B ligand; RANKL), skewing of RANKL/osteoprotegerin (OPG) ratio in favor of antiosteoclastic activity, reduction in the number of osteoclasts in the arthrodial joint's bone, and inhibition of cytokine production and MMP activity. Our results suggest that HLXL might offer a promising alternative/adjunct treatment for both inflammation and bone damage in RA.
doi:10.1155/2013/429606
PMCID: PMC3670518  PMID: 23762133
13.  Evaluating Traditional Chinese Medicine Using Modern Clinical Trial Design and Statistical Methodology: Application to a Randomized Controlled Acupuncture Trial 
Statistics in Medicine  2011;31(7):619-627.
Traditional Chinese medicine (TCM), used in China and other Asian counties for thousands of years, is increasingly utilized in Western countries. However, due to inherent differences in how Western medicine and this ancient modality are practiced, employing so-called Western medicine-based gold standard research methods to evaluate TCM is challenging. This article is a discussion of the obstacles inherent in the design and statistical analysis of clinical trials of TCM. It is based on our experience in designing and conducting a randomized controlled clinical trial of acupuncture for post-operative dental pain control in which acupuncture was shown to be statistically and significantly better than placebo in lengthening the median survival time to rescue drug. We demonstrate here that PH assumptions in the common Cox model did not hold in that trial and that TCM trials warrant more thoughtful modeling and more sophisticated models of statistical analysis. TCM study design entails all the challenges encountered in trials of drugs, devices, and surgical procedures in Western medicine. We present possible solutions to some but leave many issues unresolved.
doi:10.1002/sim.4003
PMCID: PMC3116954  PMID: 21344469
traditional Chinese medicine (TCM); acupuncture; postoperative dental pain; accelerated failure time model; blinding in randomized clinical trials
14.  Involvement of spinal serotonin receptors in electroacupuncture anti-hyperalgesia in an inflammatory pain rat model 
Neurochemical research  2011;36(10):1785-1792.
We previously showed that electroacupuncture (EA) activates medulla-spinal serotonin-containing neurons. The present study investigated the effects of intrathecal 5,7-dihydroxytryptamine creatinine sulfate (5,7-DHT), a selective neurotoxin for serotonergic terminals, the 5-hydroxytryptamine 1A receptor (5-HT1AR) antagonist NAN-190 hydrobromide and the 5-HT2C receptor (5-HT2CR) antagonist SB-242,084 on EA anti-hyperalgesia. EA was given twice at acupoint GB30 after complete Freund’s adjuvant (CFA) injection into hind paw. CFA-induced hyperalgesia was measured by assessing hind paw withdrawal latency (PWL) to a noxious thermal stimulus 30 min post-EA. Serotonin depletion and the 5-HT1AR antagonist blocked EA anti-hyperalgesia; the 5-HT2CR antagonist did not. Immunohistochemical staining showed that spinal 5-HT1AR was expressed and that 5-HT2CR was absent in naive and CFA-injected animals 2.5 hr post-CFA. These results show a correlation between EA anti-hyperalgesia and receptor expression. Collectively, the data show that EA activates supraspinal serotonin neurons to release 5-HT, which acts on spinal 5-HT1AR to inhibit hyperalgesia.
doi:10.1007/s11064-011-0495-1
PMCID: PMC3581079  PMID: 21556842
acupuncture; serotonin; spinal cord; hyperalgesia; complete Freund’s adjuvant
15.  Acupuncture alleviates the affective dimension of pain in a rat model of inflammatory hyperalgesia 
Neurochemical research  2011;36(11):2104-2110.
Although studies demonstrate that electroacupuncture (EA) alleviates the sensory dimension of pain, they have not addressed EA’s effect on the affective dimension. An inflammatory pain rat model, produced by a complete Freund adjuvant (CFA) injection into the hind paw, was combined with a conditioned place avoidance (CPA) test to determine EA’s effects and its underpinning mechanism on the affective dimension of pain. CFA-injected rats showed place aversion, i.e. the affective dimension of pain, by spending less time in a pain-paired compartment after conditioning than before, while saline-injected rats did not. CFA rats given EA treatment at GB30 before a postconditioning test showed no aversion to the pain-paired compartment, indicating that EA inhibited the affective response. Intra-rostral anterior cingulate cortex (rACC) administration of a κ-, but not μ-opioid receptor antagonist, blocked EA action. These data demonstrate that EA activates opioid receptors in the rACC to inhibit the affective dimension of pain.
doi:10.1007/s11064-011-0534-y
PMCID: PMC3581325  PMID: 21695393
acupuncture; opioid; anterior cingulate cortex; pain; complete Freund’s adjuvant
16.  Electroacupuncture alleviates affective pain in an inflammatory pain rat model 
Pain has both sensory-discriminative and emotional-affective dimensions. Previous studies demonstrate that electroacupuncture (EA) alleviates the sensory dimension but do not address the affective. An inflammatory pain rat model, produced by a complete Freund adjuvant (CFA) injection into the hind paw, was combined with a conditioned place avoidance (CPA) test to determine whether EA inhibits spontaneous pain-induced affective response and, if so, to study the possibility that rostral anterior cingulate cortex (rACC) opioids underlie this effect. Male Sprague-Dawley rats (250–275g, Harlan) were used. The rats showed place aversion (i.e. affective pain) by spending less time in a pain-paired compartment after conditioning than during a preconditioning test. Systemic non-analgesic morphine (0.5 and 1.0 mg/ kg, i.p.) inhibited the affective reaction, suggesting that the affective dimension is underpinned by mechanisms different from those of the sensory dimension of pain. Morphine at 0.5 and at 1 mg/kg did not induce reward. Rats given EA treatment before pain-paired conditioning at GB 30 showed no aversion to the pain-paired compartment, indicating that EA inhibited the affective dimension. EA treatment did not produce reward or aversive effect. Intra-rACC administration of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP), a selective mu opioid receptor antagonist, but not norbinaltorphimine (nor-BNI), a selective kappa opioid receptor antagonist, blocked EA inhibition of the affective dimension. These data demonstrate that EA activates opioid receptors in the rACC to inhibit pain-induced affective responses and that EA may be an effective therapy for both the sensory-discriminative and the affective dimensions of pain.
doi:10.1016/j.ejpain.2011.07.002
PMCID: PMC3266461  PMID: 22323370
Acupuncture; Anterior cingulate cortex; Opioid; Affective pain; CTOP
17.  Building a Strategic Framework for Comparative Effectiveness Research in Complementary and Integrative Medicine 
The increasing burden of chronic diseases presents not only challenges to the knowledge and expertise of the professional medical community, but also highlights the need to improve the quality and relevance of clinical research in this domain. Many patients now turn to complementary and integrative medicine (CIM) to treat their chronic illnesses; however, there is very little evidence to guide their decision-making in usual care. The following research recommendations were derived from a CIM Stakeholder Symposium on Comparative Effectiveness Research (CER): (1) CER studies should be made a priority in this field; (2) stakeholders should be engaged at every stage of the research; (3) CER study designs should highlight effectiveness over efficacy; (4) research questions should be well defined to enable the selection of an appropriate CER study design; (5) the CIM community should cultivate widely shared understandings, discourse, tools, and technologies to support the use and validity of CER methods; (6) Effectiveness Guidance Documents on methodological standards should be developed to shape future CER studies. CER is an emerging field and its development and impact must be reflected in future research strategies within CIM. This stakeholder symposium was a first step in providing systematic guidance for future CER in this field.
doi:10.1155/2012/531096
PMCID: PMC3544532  PMID: 23346206
18.  Evidence from the Cochrane Collaboration for Traditional Chinese Medicine Therapies 
Background
The Cochrane Collaboration, an international not-for-profit organization that prepares and maintains systematic reviews of randomized trials of health care therapies, has produced reviews summarizing much of the evidence on Traditional Chinese Medicine (TCM). Our objective was to review the evidence base according to Cochrane systematic reviews.
Methods
In order to detect reviews focusing on TCM, we searched the titles and abstracts of all reviews in Issue 4, 2008 of the Cochrane Database of Systematic Reviews. For each review, we extracted data on the number of trials included and the total number of participants. We provided an indication of the strength of the review findings by assessing the reviewers’ abstract conclusions statement. We supplemented our assessment of the abstract conclusions statements with a listing of the comparisons and outcomes showing statistically significant meta-analyses results.
Results
We identified 70 Cochrane systematic reviews of TCM, primarily acupuncture (n = 26) and Chinese herbal medicine (n = 42), and 1 each of moxibustion and t’ai chi. Nineteen (19) of 26 acupuncture reviews and 22/42 herbal medicine reviews concluded that there was not enough good quality trial evidence to make any conclusion about the efficacy of the evaluated treatment, while the remaining 7 acupuncture and 20 herbal medicine reviews and each of the moxibustion and t’ai chi reviews indicated a suggestion of benefit, which was qualified by a caveat about the poor quality and quantity of studies. Most reviews included many distinct interventions, controls, outcomes, and populations, and a large number of different comparisons were made, each with a distinct forest plot.
Conclusions
Most Cochrane systematic reviews of TCM are inconclusive, due specifically to the poor methodology and heterogeneity of the studies reviewed. Some systematic reviews provide preliminary evidence of Chinese medicine’s benefits to certain patient populations, underscoring the importance and appropriateness of further research. These preliminary findings should be considered tentative and need to be confirmed with rigorous randomized controlled trials.
doi:10.1089/acm.2008.0414
PMCID: PMC2856612  PMID: 19757977
19.  Evidence from the Cochrane Collaboration for Traditional Chinese Medicine Therapies 
Abstract
Background
The Cochrane Collaboration, an international not-for-profit organization that prepares and maintains systematic reviews of randomized trials of health care therapies, has produced reviews summarizing much of the evidence on Traditional Chinese Medicine (TCM). Our objective was to review the evidence base according to Cochrane systematic reviews.
Methods
In order to detect reviews focusing on TCM, we searched the titles and abstracts of all reviews in Issue 4, 2008 of the Cochrane Database of Systematic Reviews. For each review, we extracted data on the number of trials included and the total number of participants. We provided an indication of the strength of the review findings by assessing the reviewers' abstract conclusions statement. We supplemented our assessment of the abstract conclusions statements with a listing of the comparisons and outcomes showing statistically significant meta-analyses results.
Results
We identified 70 Cochrane systematic reviews of TCM, primarily acupuncture (n = 26) and Chinese herbal medicine (n = 42), and 1 each of moxibustion and t'ai chi. Nineteen (19) of 26 acupuncture reviews and 22/42 herbal medicine reviews concluded that there was not enough good quality trial evidence to make any conclusion about the efficacy of the evaluated treatment, while the remaining 7 acupuncture and 20 herbal medicine reviews and each of the moxibustion and t'ai chi reviews indicated a suggestion of benefit, which was qualified by a caveat about the poor quality and quantity of studies. Most reviews included many distinct interventions, controls, outcomes, and populations, and a large number of different comparisons were made, each with a distinct forest plot.
Conclusions
Most Cochrane systematic reviews of TCM are inconclusive, due specifically to the poor methodology and heterogeneity of the studies reviewed. Some systematic reviews provide preliminary evidence of Chinese medicine's benefits to certain patient populations, underscoring the importance and appropriateness of further research. These preliminary findings should be considered tentative and need to be confirmed with rigorous randomized controlled trials.
doi:10.1089/acm.2008.0414
PMCID: PMC2856612  PMID: 19757977
20.  The effects of opioid receptor antagonists on electroacupuncture-produced anti-allodynia/hyperalgesia in rats with paclitaxel-evoked peripheral neuropathy 
Brain research  2011;1414:58-65.
Research supports the effectiveness of acupuncture for conditions such as chronic low back and knee pain. In a five-patient pilot study the modality also improved the symptoms of chemotherapy-induced neuropathic pain. Using an established rat model of paclitaxel-induced peripheral neuropathy, we evaluated the effect of electroacupuncture (EA) on paclitaxel-induced hyperalgesia and allodynia that has not been studied in an animal model. We hypothesize that EA would relieve the paclitaxel-induced mechanical allodynia and hyperalgesia, which was assessed 30 minutes after EA using von Frey filaments. Beginning on day 13, the response frequency to von Frey filaments (4-15 g) was significantly increased in paclitaxel-injected rats compared to those injected with vehicle. EA at 10Hz significantly (p<0.05) decreased response frequency at 4-15 g compared to sham EA; EA at 100Hz only decreased response frequency at 15 g stimulation. Compared to sham EA plus vehicle, EA at 10Hz plus either a μ, δ, or κ opioid receptor antagonist did not significantly decrease mechanical response frequency, indicating that all three antagonists blocked EA inhibition of allodynia and hyperalgesia. Since we previously demonstrated that μ and δ but not κ opioid receptors affect EA anti-hyperalgesia in an inflammatory pain model, these data show that EA inhibits pain through different opioid receptors under varying conditions. Our data indicate that EA at 10Hz inhibits mechanical allodynia/hyperalgesia more potently than does EA at 100Hz. Thus, EA significantly inhibits paclitaxel-induced allodynia/hyperalgesia through spinal opioid receptors, and EA may be a useful complementary treatment for neuropathic pain patients.
doi:10.1016/j.brainres.2011.08.004
PMCID: PMC3176966  PMID: 21872220
Chemotherapy pain; Acupuncture; Hyperalgesia; Spinal cord; Opioid
21.  Effectiveness guidance document (EGD) for acupuncture research - a consensus document for conducting trials 
Background
There is a need for more Comparative Effectiveness Research (CER) to strengthen the evidence base for clinical and policy decision-making. Effectiveness Guidance Documents (EGD) are targeted to clinical researchers. The aim of this EGD is to provide specific recommendations for the design of prospective acupuncture studies to support optimal use of resources for generating evidence that will inform stakeholder decision-making.
Methods
Document development based on multiple systematic consensus procedures (written Delphi rounds, interactive consensus workshop, international expert review). To balance aspects of internal and external validity, multiple stakeholders including patients, clinicians and payers were involved.
Results
Recommendations focused mainly on randomized studies and were developed for the following areas: overall research strategy, treatment protocol, expertise and setting, outcomes, study design and statistical analyses, economic evaluation, and publication.
Conclusion
The present EGD, based on an international consensus developed with multiple stakeholder involvement, provides the first systematic methodological guidance for future CER on acupuncture.
doi:10.1186/1472-6882-12-148
PMCID: PMC3495216  PMID: 22953730
Comparative effectiveness research; Effectiveness guidance document; Acupuncture
22.  Rostral ventromedial medulla μ, but not κ, opioid receptors are involved in electroacupuncture anti-hyperalgesia in an inflammatory pain rat model 
Brain research  2011;1395:38-45.
It has been reported that intracerebroventricular injection of a μ receptor antagonist blocked 2 but not 100 Hz electroacupuncture (EA)-produced analgesia in an uninjured animal model. Because persistent pain changes neural response to external stimulation, we hypothesized that the mechanisms of EA anti-hyperalgesia may be different in persistent pain than in health. Hyperalgesia, decreased paw withdrawal latency (PWL) to a noxious thermal stimulus, was induced by subcutaneously injecting complete Freund’s adjuvant (CFA) into the hind paws of rats. Selective antagonists against μ (CTOP: D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2, 6.25 nmol) and κ (Nor-BIN: nor-binaltorphimine, 10 nmol) opioid receptors were infused into the rostral ventromedial medulla (RVM) 10 min before 30-min EA treatment at acupoint Huanti (GB30) 1 hr 30 min post-CFA. PWL was measured before and 2.5 post-CFA. Both 10 Hz and 100 Hz EA-produced anti-hyperalgesia were blocked by intra-RVM μ, but not κ, receptor antagonists. Double immunofluorescence staining demonstrated that μ receptor-containing neurons were GABAnergic and that GABAa receptor-containing neurons were serotonergic in the RVM. The results demonstrated an involvement of RVM μ, but not κ, receptors in EA-produced anti-hyperalgesia. In summary, EA may induce release of endogenous endomorphins that activate μ opioid receptors in GABAnergic neurons to suppress the release of GABA. This removes the tonic inhibition of GABA on serotonergic neurons in the RVM, and activation of these serotonergic neurons inhibits pain. EA may be used as complementary treatment for inflammatory pain.
doi:10.1016/j.brainres.2011.04.037
PMCID: PMC3105222  PMID: 21565329
acupuncture; hyperalgesia; pain; opioid receptor; RVM
23.  Modified Huo-Luo-Xiao-Ling Dan Suppresses Adjuvant Arthritis by Inhibiting Chemokines and Matrix-Degrading Enzymes 
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the joints that can lead to deformities and disability. The prolonged use of conventionally used drugs is associated with severe adverse reactions. Therefore, safer and less expensive therapeutic products are continually being sought. Huo-Luo-Xiao-Ling dan (HLXL), a traditional Chinese herbal mixture, and its modified versions possess anti-arthritic activity. In this paper, we examined the influence of modified HLXL on two of the key mediators of arthritic inflammation and tissue damage, namely, chemokines and matrix-metalloproteinases (MMPs) in the rat adjuvant-induced arthritis (AA) model of RA. We treated arthritic Lewis rats with HLXL (2.3 g/kg) by daily gavage beginning at the onset of AA. The control rats received the vehicle. At the peak phase of AA, rats were sacrificed and their draining lymph node cells (LNC) and spleen adherent cells (SAC) were tested. The HLXL-treated rats showed a significant reduction in the levels of chemokines (RANTES, MCP-1, MIP-1α, and GRO/KC), MMPs (MMP 2 and 9), as well as cytokines (IL-6 and IL-17) that induce them, compared to the control vehicle-treated rats. Thus, HLXL controls arthritis in part by suppressing the mediators of immune pathology, and it might offer a promising alternative/adjunct treatment for RA.
doi:10.1155/2012/589256
PMCID: PMC3310235  PMID: 22474510
24.  How Well Do Randomized Trials Inform Decision Making: Systematic Review Using Comparative Effectiveness Research Measures on Acupuncture for Back Pain 
PLoS ONE  2012;7(2):e32399.
Background
For Comparative Effectiveness Research (CER) there is a need to develop scales for appraisal of available clinical research. Aims were to 1) test the feasibility of applying the pragmatic-explanatory continuum indicator summary tool and the six CER defining characteristics of the Institute of Medicine to RCTs of acupuncture for treatment of low back pain, and 2) evaluate the extent to which the evidence from these RCTs is relevant to clinical and health policy decision making.
Methods
We searched Medline, the AcuTrials™ Database to February 2011 and reference lists and included full-report randomized trials in English that compared needle acupuncture with a conventional treatment in adults with non-specific acute and/or chronic low back pain and restricted to those with ≥30 patients in the acupuncture group. Papers were evaluated by 5 raters.
Principal Findings
From 119 abstracts, 44 full-text publications were screened and 10 trials (4,901 patients) were evaluated. Due to missing information and initial difficulties in operationalizing the scoring items, the first scoring revealed inter-rater and inter-item variance (intraclass correlations 0.02–0.60), which improved after consensus discussions to 0.20–1.00. The 10 trials were found to cover the efficacy-effectiveness continuum; those with more flexible acupuncture and no placebo control scored closer to effectiveness.
Conclusion
Both instruments proved useful, but need further development. In addition, CONSORT guidelines for reporting pragmatic trials should be expanded. Most studies in this review already reflect the movement towards CER and similar approaches can be taken to evaluate comparative effectiveness relevance of RCTs for other treatments.
doi:10.1371/journal.pone.0032399
PMCID: PMC3289651  PMID: 22389699
25.  Herbal medicinal products target defined biochemical and molecular mediators of inflammatory autoimmune arthritis 
Rheumatoid arthritis (RA) is a chronic debilitating disease characterized by synovial inflammation, damage to cartilage and bone, and deformities of the joints. Several drugs possessing anti-inflammatory and immunomodulatory properties are being used in the conventional (allopathic) system of medicine to treat RA. However, the long-term use of these drugs is associated with harmful side effects. Therefore, newer drugs with low or no toxicity for the treatment of RA are actively being sought. Interestingly, several herbs demonstrate anti-inflammatory and anti-arthritic activity. In this review, we describe the role of the major biochemical and molecular mediators in the pathogenesis of RA, and highlight the sites of action of herbal medicinal products that have anti-arthritic activity. With the rapidly increasing use of CAM products by patients with RA and other inflammation-related disorders, our review presents timely information validating the scientific rationale for the use of natural therapeutic products.
doi:10.1016/j.bmc.2010.10.053
PMCID: PMC3020797  PMID: 21115252
Complementary and alternative medicine (CAM); Herbal products; Inflammatory mediators; Rheumatoid arthritis (RA)

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