Brian M. Berman

Effectiveness of Acupuncture as Adjunctive Therapy in Osteoarthritis of the Knee: A Randomized, Controlled Trial

Context Previous studies of acupuncture for osteoarthritis have had conflicting results. This may have occurred because most studies have included small samples, a limited number of treatment sessions, or other limitations. Contribution This randomized, controlled trial compared 24 acupuncture sessions over 26 weeks with sham acupuncture or arthritis education in 570 patients with osteoarthritis of the knee. Acupuncture led to greater improvements in function but not pain after 8 weeks and in both pain and function after 26 weeks. No adverse effects were associated with acupuncture. Cautions Many participants dropped out of the study, so readers should interpret the findings at 26 weeks with caution. The Editors Osteoarthritis is the most common form of arthritis and is a major cause of morbidity, limitation of activity, and health care utilization, especially in elderly patients (1, 2). Pain and functional limitation are the primary clinical manifestations of osteoarthritis of the knee. Current recommendations for managing osteoarthritis, including guidelines published by the American College of Rheumatology (3) and European League of Associations of Rheumatology (4), focus on relieving pain and stiffness and maintaining or improving physical function as important goals of therapy. No curative therapies exist for osteoarthritis; thus, both pharmacologic and nonpharmacologic management focus on controlling pain and reducing functional limitation (5). Nonpharmacologic therapy, which includes patient education, social support, physical and occupational therapy, aerobic and resistive exercises, and weight loss, is the cornerstone of a multidisciplinary approach to osteoarthritis patient management (3). Pharmacologic therapies include nonopioid analgesics (such as acetaminophen), nonsteroidal anti-inflammatory drugs (NSAIDs) (including cyclooxygenase-2 [COX-2] enzyme selective inhibitors), topical analgesics (capsaicin cream), opioid analgesics, and intra-articular steroid and hyaluronate injections. Often, these agents are used in combination for additive analgesic efficacy (6). Pharmacologic management of osteoarthritis is often ineffective, and agents such as NSAIDs may cause unwanted and dangerous side effects (7, 8). Complementary and alternative medicine is another approach to treating osteoarthritis (9-12), particularly in Asian societies (13). Many U.S. patients with osteoarthritis also use complementary and alternative medical therapies (14). A systematic review of acupuncture and knee osteoarthritis (15) identified 7 small randomized, controlled trials published in English. Within the methodologic limitations of the studies, the evidence suggested that acupuncture seemed to alleviate knee pain and function compared with sham acupuncture controls, although 2 trials comparing acupuncture with an active, nonpharmacologic treatment (physical therapy) did not indicate such an effect (16, 17). Before conducting our large-scale trial, we completed both a pilot study (18) and a randomized, single-blind trial (19) of the effect of acupuncture on osteoarthritis of the knee. Participants in the uncontrolled pilot study (n= 12) showed statistically significant improvement in both self-reported pain and physical function, as well as performance measures of physical function after 8 weeks of acupuncture treatment and at 12-week follow-up as compared with their baseline (18). In our larger randomized, single-blind trial (n= 73), which examined the benefit of acupuncture added to standard management with NSAIDs, the acupuncture treatment group experienced statistically significant improvements in self-reported pain and disability scores compared with a standard-care control group as late as 4 weeks after the end of treatment (19). However, this effect diminished within 18 weeks (26 weeks after the beginning of the trial) after the final acupuncture treatment. Together, however, the previously conducted trials (both our preliminary studies [18, 19] and those referenced in the systematic review [15]) have 3 methodologic limitations: lack of credible controls for the placebo effect, inadequate assessment of long-term treatment benefits, and insufficient sample sizes. We tested the hypothesis that an 8-week intensive acupuncture treatment regimen, followed by an 18-week tapering regimen, reduces pain and improves function among patients with knee osteoarthritis as compared with both sham acupuncture and education control groups. Methods Patient Recruitment We recruited patients for this multisite, placebo-controlled trial from March 2000 through December 2003, primarily through print and radio advertisements. The 3 sites were the Integrative Medicine Clinic of the University of Maryland School of Medicine, Baltimore, Maryland; the Innovative Medical Research Center (a private research firm), Towson, Maryland; and the Hospital for Special Surgery, New York City, New York. The institutional review boards of the 3 sites approved the study. We determined the sample size (n= 570) by a power analysis based on our randomized pilot study (19), adjusted by the estimated decrease in effect size resulting from the inclusion of a sham acupuncture group designed to control for placebo effects. Patients met the following inclusion criteria: age 50 years or older, a diagnosis of osteoarthritis of the knee, radiographic evidence of at least 1 osteophyte at the tibiofemoral joint (KellgrenLawrence grade 2), moderate or greater clinically significant knee pain on most days during the past month, and willingness to be randomly assigned. Exclusion criteria were the presence of serious medical conditions that precluded participation in study, bleeding disorders that might contraindicate acupuncture, intra-articular corticosteroid or hyaluronate injections (as well as any knee surgeries or concomitant use of topical capsaicin cream) during the past 6 months, previous experience with acupuncture, or any planned events (including total knee replacement) that would interfere with participation in the study during the following 26 weeks. After a brief telephone screening, patients were scheduled to visit 1 of the 3 participating sites to sign an informed consent statement and undergo a brief rheumatologic examination (including radiographic examination of affected knees) by a physician or a nurse practitioner. Because the education course was a group activity, patients were recruited until a cohort of 12 to 21 patients was formed, at which point each cohort at each site was randomly assigned to 1 of 3 groups by a computer-generated process using randomly selected blocks of 3, 6, and 9. We assured allocation concealment by using disguised letter codes that were generated and sent to the site coordinators by a central statistical core. We used this procedure to ensure that approximately equal numbers of participants were in each treatment group across the course of the study, to ensure that each cohort would have participants assigned to all 3 treatment groups, and to make the breaking of the group assignment process more difficult. The research assistants who collected assessments from participants, the participants themselves (in the true acupuncture and sham acupuncture groups), and the statistician were blinded to group assignment. Assessments were conducted at baseline and 4, 8, 14, and 26 weeks after randomization. Study Interventions We developed and modified the acupuncture treatment and sham control protocols from previously reported and validated procedures (18-21). During the trial, 7 acupuncturists were used: 3 at the Integrative Medicine Clinic, 3 at the Innovative Medical Research Center, and 1 at the Hospital for Special Surgery. In general, acupuncturists were assigned to the same participants throughout the 26-week treatment schedule, except for vacation conflicts and staff turnover, and provided approximately the same proportions of true versus sham procedures. All acupuncturists were state-licensed and had at least 2 years of clinical experience. The studys principal acupuncturist trained and supervised the acupuncturists in performing true or sham procedures and avoiding interactions that could inadvertently communicate group assignment. True Acupuncture The true acupuncture (experimental) group underwent 26 weeks of gradually tapering treatment according to the following schedule: 8 weeks of 2 treatments per week followed by 2 weeks of 1 treatment per week, 4 weeks of 1 treatment every other week, and 12 weeks of 1 treatment per month. We based the acupuncture point selections on Traditional Chinese Medicine meridian theory to treat knee joint pain, known as the Bi syndrome. These points consisted of 5 local points (Yanglinquan [gall bladder meridian point 34], Yinlinquan [spleen meridian point 9], Zhusanli [stomach meridian point 36], Dubi [stomach meridian point 35], and extra point Xiyan) and 4 distal points (Kunlun [urinarybladder, meridian point 60], Xuanzhong [gall bladder meridian point 39], Sanyinjiao [spleen meridian point 6], and Taixi [kidney meridian point 3]) on meridians that traverse the area of pain (22, 23). The same points were treated for each affected leg. If both knees were affected, 9 needles were inserted in each leg. (The outcome measures were not specifically targeted to whether the patient had osteoarthritis in 1 or both knees, and we observed no differential effects on the basis of the number of knees treated.) The acupuncturists inserted 1.5-inch (for local points) and 1-inch (for distal points) 32-gauge (0.25-mm diameter) acupuncture needles to a conventional depth of approximately 0.3 to 1.0 inch, depending on point location. All participants in the treatment group achieved the De-Qi sensation, a local sensation of heaviness, numbness, soreness, or paresthesia that accompanies the insertion and manipulation of needles during acupuncture, at these 9 points. Acupuncturists applied electrical stimulati

Is acupuncture effective for the treatment of chronic pain? A systematic review

&NA; Pain is the major complaint of the estimated one million U.S. consumers who use acupuncture each year. Although acupuncture is widely available in chronic pain clinics, the effectiveness of acupuncture for chronic pain remains in question. Our aim was to assess the effectiveness of acupuncture as a treatment for chronic pain within the context of the methodological quality of the studies. MEDLINE (1966–99), two complementary medicine databases, 69 conference proceedings, and the bibliographies of other articles and reviews were searched. Trials were included if they were randomized, had populations with pain longer than three months, used needles rather than surface electrodes, and were in English. Data were extracted by two independent reviewers using a validated instrument. Inter‐rater disagreements were resolved by discussion. Fifty one studies met inclusion criteria. Clinical heterogeneity precluded statistical pooling. Results were positive in 21 studies, negative in 3 and neutral in 27. Three fourths of the studies received a low‐quality score and low‐quality trials were significantly associated with positive results (P=0.05). High‐quality studies clustered in designs using sham acupuncture as the control group, where the risk of false negative (type II) errors is high due to large sample size requirements. Six or more acupuncture treatments were significantly associated with positive outcomes (P=0.03) even after adjusting for study quality. We conclude there is limited evidence that acupuncture is more effective than no treatment for chronic pain; and inconclusive evidence that acupuncture is more effective than placebo, sham acupuncture or standard care. However, we have found an important relationship between the methodology of the studies and their results that should guide future research.

Meta-Analysis: Acupuncture for Low Back Pain

Context Many people with back pain seek treatment with acupuncture, but the effectiveness of acupuncture for low back pain is controversial. Contribution This meta-analysis of 33 randomized, controlled trials that compared acupuncture with sham, other active, or no treatment found evidence that acupuncture is more effective than sham or no treatment for patients with chronic low back pain. Evidence about acupunctures effectiveness compared with other active treatments or for patients with acute back pain is inconclusive. Cautions Quality of included trials varied. The Editors Low back pain is the most common cause of activity limitation in people younger than 45 years of age in the United States and is the second most frequent reason for visits to the physician (1). A 1997 U.S. survey showed that 54% of patients reporting back or neck pain had used a complementary therapy within the past year (2), while a 2002 study showed back pain to be the most common reason for visits to acupuncturists in the United States (3). Given this high degree of public interest, the question of whether acupuncture alleviates low back pain is relevant. Before our study, at least 3 publications systematically reviewed the primary research up to 1996 (4-6). Their conclusions, limited by the paucity, heterogeneity, and poor quality of the studies, were somewhat discordant. Several new studies have since been published. Some of these studies have been reviewed (7), but the review did not take full account of study quality and did not attempt a meta-analysis of the data. We decided to undertake a new systematic review and meta-analysis to test the hypotheses that, for treating low back pain, acupuncture is more effective than penetrating and nonpenetrating sham acupuncture, other sham treatments, active treatments, and no treatment. In addition, we address the hypothesis that treatment effect size is correlated with study quality, treatment factors, and patient factors. Methods Search We searched the following computerized databases from their inception until August 2004: MEDLINE; Cochrane Central; EMBASE; AMED; CINAHL; and 2 specialized European databases (CISCOM in London, United Kingdom [to February 2003], and GERA in La Garde, France) that include gray literature, such as unpublished studies and conference reports. We performed text word searches of titles and abstracts for acupuncture, electroacupuncture, percutaneous electrical nerve stimulation, and backache, back pain, low back pain, dorsalgia, and lumbago. We contacted experts in Japan who updated their earlier search of Igaku Chuo Zasshi (19872003) (8) and also hand-searched the Journal of the Japan Society of Acupuncture and Moxibustion (20002004). We reconsidered all studies that were included in previous reviews (4-7) for inclusion in our review. In addition, we screened our own files, and we contacted experts in the United Kingdom, United States, Germany, Italy, Sweden, and Norway and asked them to contribute any studies of which they were aware (see Acknowledgments). We obtained copies of all papers that could be reports of randomized, controlled trials (RCTs) or reviews of RCTs (9). We scanned the bibliographies of all papers retrieved for further references. We excluded unpublished reports. Study Selection Two authors independently considered articles reporting random assignment of human participants to acupuncture or a control group for the treatment of any type of low back pain for inclusion. We excluded studies that included both patients with neck and low back pain, unless the data for patients with low back pain were available separately. We defined acupuncture in an inclusive manner to reflect its use in various traditions and theoretical approaches: The intervention had to involve the insertion of needles into the skin, but not for the purpose of injection. This definition includes any intervention that the study author or authors described as acupuncture or that the reviewers clearly identified as acupuncture. We excluded therapies that are similar to acupuncture but do not involve needle insertion (for example, laser acupuncture and electroacupuncture without needles) because most authorities believe acupuncture entails needle insertion (10). We excluded trials that compared 1 form of acupuncture only with another form. We included studies that provided usable data for any of the following outcome measures: pain, measures of functional status (for example, Oswestry and Roland Disability Questionnaire), overall improvement, return to work, and analgesic consumption. We excluded studies that reported only relief of pain immediately after a single treatment with acupuncture. We included reports written in English, Japanese, Korean, and Chinese, as well as in Germanic (including Scandinavian) and Romance languages. Where necessary, we obtained translations of essential details. When more than 1 publication described a single trial, we included only 1 report. Data Abstraction Two authors abstracted data independently onto a piloted spreadsheet, except in the case of nonEnglish-language articles, from which an expert extracted data and checked them in-house (see Acknowledgments). Differences were settled by discussion with reference to the original article. In the few instances where disagreements persisted, we consulted an additional independent researcher who is an expert in review methods. For our purposes, we defined 3 styles of acupuncture and 3 methods (Table 1). Table 1. Acupuncture-Related Terms and Their Relevance We extracted data for 5 outcome categories (pain, functional status, overall improvement, return to full work, and analgesic consumption) where available. We extracted outcomes for all time intervals reported. We considered outcomes less than 6 weeks to be short-term, and we used the measurement closest to 3 weeks for the meta-analysis. We considered outcomes more than 6 weeks to be long-term, and we included the measurement closest to 6 months in the meta-analysis. For crossover studies, we considered the risk for carryover effects to be prohibitive, so we considered only the first group of the study. Quality Assessment We assessed the quality of the studies in 2 ways. First, by using a modification of a validated method (11), we awarded a maximum of 5 points in 3 categories: randomization (2 points for an appropriate method, 1 point if method not described, or 0 points for an inappropriate method); blinding (1 point for patient blinding and 1 point if blinding was tested after treatment); and withdrawals and dropouts (1 point if a statement gave full details of withdrawals and dropouts or confirmed that no patient withdrew or dropped out). As recommended (11), a score of 2 points or less indicates poor quality. Second, we assessed quality by using 10 criteria taken from the Cochrane Back Review Group (Table 2) (12), used in a recent review (13), extracted by 1 author with random confirmation by another author. A score of 4 points or less indicates poor quality. Table 2. Cochrane Back Review Group Criteria List for Methodologic Quality Assessment of Randomized, Controlled Trials Quantitative Data Synthesis We placed the studies into predefined subgroups defined according to the following criteria: 1) acute (3 months) or chronic (>3 months) low back pain (where not described, a decision was made from the trial setting and recruitment information [for example, we considered primary care to include acute pain and secondary care to cover chronic pain]); 2) style of acupuncture (Table 1); and 3) control group (sham acupuncture involving needle penetration, nonpenetrating sham acupuncture, sham transcutaneous electrical nerve stimulation [TENS] [Table 1], no additional treatment, and other active treatments). The no-additional-treatment control grouping includes studies that administered adjunctive treatment, such as physical therapy, to both the acupuncture and the control group and also includes those studies in which the control intervention consisted of providing patients with educational materials on low back pain. The primary outcome of the review was quantitative synthesis of the short-term effectiveness of acupuncture on pain in each category. To test whether sham acupuncture and controlled trials of sham TENS were sufficiently homogeneous to combine for the secondary analyses, we used the I2 method (14). We used Comprehensive Meta-Analysis software (Biostat, Inc., Englewood, New Jersey) for data analysis. We used the inverse-variance computational model, and we used the more conservative random-effects model to account for the expected heterogeneity. We performed separate analyses for each main outcome measure by using standardized mean difference (the Hedge g effect size) or odds ratio, depending on the nature of the measure. For the standardized mean difference, 1 unit of effect size for pain and functioning corresponds with a 25-point difference on the visual analogue scale (VAS) and a 6-point difference on the Roland Disability score. Using standards established by the Cochrane Back Group Editorial Board, we considered a minimum 10-mm difference on the VAS and a 2-point difference on the Roland Disability score to be clinically important (13). We analyzed short-term end points and long-term end points, as defined earlier. When the studies in any predefined subgroup were clinically very heterogeneous or insufficient data were reported for pooling, we planned to use a narrative synthesis rather than a meta-analysis. We assessed for the likelihood of small study bias by using a funnel plot. In reports that did not provide these values, we used the method previously described (13), in which the median is the mean and the SD is 25% of the measures range. To test the effect of these assumptions, we performed a sensitivity analysis on the short-term pain primary outcome measure, substituting imputed mean values both 1 SD higher and 1 SD lower th

Acupuncture for osteoarthritis of the knee: A systematic review

OBJECTIVE To evaluate trials of acupuncture for osteoarthritis (OA) of the knee, to assess the methodologic quality of the trials and determine whether low-quality trials are associated with positive outcomes, to document adverse effects, to identify patient or treatment characteristics associated with positive response, and to identify areas of future research. METHODS Eight databases and 62 conference abstract series were searched. Randomized or quasi-randomized trials of all languages were included and evaluated for methodologic quality using the Jadad scale. Outcomes were pain, function, global improvement, and imaging. Data could not be pooled; therefore, a best-evidence synthesis was performed to determine the strength of evidence by control group. The adequacy of the acupuncture procedure was assessed by 2 acupuncturists trained in treating OA and blinded to study results. RESULTS Seven trials representing 393 patients with knee OA were identified. For pain and function, there was limited evidence that acupuncture is more effective than being on a waiting list for treatment or having treatment as usual. For pain, there was strong evidence that real acupuncture is more effective than sham acupuncture; however, for function, there was inconclusive evidence that real acupuncture is more effective than sham acupuncture. There was insufficient evidence to determine whether the efficacy of acupuncture is similar to that of other treatments. CONCLUSION The existing evidence suggests that acupuncture may play a role in the treatment of knee OA. Future research should define an optimal acupuncture treatment, measure quality of life, and assess acupuncture combined with other modalities.

Meta-analysis: Acupuncture for osteoarthritis of the knee

Context Previous studies have come to inconsistent conclusions about the effectiveness of acupuncture for treating knee osteoarthritis. Contribution This meta-analysis of 9 trials showed that sham-controlled trials identified no clinically meaningful short-term benefits in pain or function with acupuncture for knee osteo-arthritis, although trials that did not use a sham control identified some benefits. Implications The use of different types of comparisons (sham acupuncture vs. interventions in which the participant knew whether they were receiving acupuncture) explains the variability in the conclusions of published trials about the effectiveness of acupuncture for treating knee osteo-arthritis. Placebo or expectation effects probably account for the observed benefits. The Editors Osteoarthritis is the leading cause of disability among older adults (1, 2). The joint most commonly affected by osteoarthritis is the knee (3, 4). The prevalence, disability, and associated costs of knee osteoarthritis are expected to steadily increase over the next 25 years because of aging in the population (5). Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are the most commonly used pharmacologic agents for treating knee osteoarthritis (6, 7). However, according to a recent systematic review (8), NSAIDs are only slightly better than placebo in providing short-term pain relief and their effects are probably too small to be meaningful to patients (8). Furthermore, many NSAIDs are associated with considerable side effects (9). Gastrointestinal bleeding, the most clinically substantial effect (10), causes approximately 2200 deaths and 12000 emergency hospital admissions each year in the United Kingdom alone (11) and is of particular concern to older patients (10). Acetaminophen may have a better toxicity profile than that of NSAIDs (6). However, a recent systematic review (12) suggests that acetaminophen is modestly less effective than NSAIDs and that the clinical significance of acetaminophen is questionable because it results in only a 5% greater improvement from baseline in pain than does placebo in the short term. The evidence for nonpharmacologic treatments for knee osteoarthritis is generally sparse and inconclusive (13). However, 2 effective nonpharmacologic treatments are exercise (14) and weight loss (15). Some patients with osteoarthritis, however, may have difficulty exercising or losing weight. The need for additional safe and effective treatments for osteoarthritis is clear. Acupuncture is a safe treatment that has a low risk for serious side effects (1619). Given its safety, whether acupuncture is effective for treating osteoarthritis of the knee is a highly relevant question. Our objective was to conduct a systematic review and meta-analysis of the effects of acupuncture for treating knee osteoarthritis. Methods Data Sources and Study Selection We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases to January 2007 to identify randomized, controlled trials (RCTs). We combined acupuncture-related terms with osteoarthritis-related terms and limited the search to RCTs (20). We considered older RCTs that were included in previous reviews of acupuncture for osteoarthritis (2124) for inclusion. Two authors independently selected articles and resolved disagreements by discussion. Our selection criteria were published RCTs of acupuncture in patients who had received a diagnosis of knee osteoarthritis. We considered the 2 outcomes of pain and function. We applied no language restrictions. We included only RCTs in which the acupuncture treatment involved the insertion of needles into traditional meridian points. The needles could be inserted into tender points in addition to the traditional meridian points and could be electrically stimulated. We excluded RCTs of dry needling or trigger-point therapy. We also excluded RCTs that compared only 2 different forms of active acupuncture. We prespecified that trials have at least 6 weeks of observation. This criterion has not been validated as a threshold for study inclusion. However, we thought that RCTs with observation periods less than 6 weeks may also have methodological shortcomings (25, 26) that may exaggerate their results of benefits (27, 28). Data Extraction and Quality Assessment Two authors independently extracted data and resolved disagreements by discussion. They extracted information pertaining to the quality of the methods, participants, interventions, and outcomes (including adverse effects). When a study reported more than 1 pain or function outcome measure, we gave preference to the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function measures because the WOMAC is the most widely used and thoroughly validated instrument for assessing patients with knee osteoarthritis (2931). We contacted corresponding authors via e-mail and requested that they review the information we extracted from their studies, clarify any ambiguities, and supply missing information. We evaluated internal validity of the RCTs by using an 11-item scale developed by the Cochrane Back Review Group (32). We considered a score of 6 or more points to indicate high internal validity on the basis of data from ongoing research, in which 1 of the authors is involved. For the patient and outcomes assessor blinding items on the scale, we assigned sham-controlled trials 0.5 point rather than 1 point because we could not be certain that all shams were sufficiently credible in fully blinding patients to the treatment being evaluated. However, we assigned 1 point to sham-controlled trials that evaluated the credibility of the sham and found it to be indistinguishable from true acupuncture. Acupuncture Assessment No consensus exists on how best to assess treatment adequacy in acupuncture RCTs, and no methods have been validated (26). We used a method that involved assessing the adequacy of the following 4 aspects of the acupuncture treatment: choice of acupuncture points, number of sessions, needling technique, and experience of the acupuncturist. The adequacy of the sham intervention was also assessed by using an open-ended question. Two acupuncturists, who had previously used this adequacy assessment instrument for an earlier systematic review (33) on acupuncture, made these assessments. The acupuncturists assessed adequacy independently and achieved consensus by discussion. Assessments were based on only the description of the study population and the acupuncture procedure. The assessors were blinded to the results of the study and the publication. We asked the assessors to guess the identity of each study being assessed to test the success of the blinding. Data Synthesis and Analysis We placed RCTs into categories according to control groups, which were sham, usual care, and waiting list. We defined sham control as a sham intervention that was designed to be credible as the active treatment. We defined the usual care control as groups that received some additional standard care therapy that was not provided to the acupuncture group and waiting list control as groups that received no care while waiting for acupuncture. For our meta-analyses, we defined the short-term follow-up point as the measurement point closest to 8 weeks but no longer than 3 months after randomization. We defined the long-term outcome as the measurement point closest to 6 months but longer than 3 months after randomization. Because some RCTs used the visual analogue scale version of the WOMAC instrument and others used the Likert version, we used standardized mean differences as the principal measure of effect size so that the results of the RCTs could be combined. We calculated standardized mean differences (Hedge adjusted g) for all RCTs by using differences in improvements between groups divided by the SDs of improvements pooled from the 2 groups (34). For 3 RCTs (3537), we made some conservative assumptions to compute the standardized mean differences (Appendix Table 1). Appendix Table 1. Original Data from Included Studies and Assumptions Used to Derive the Meta-analysis Study Data* We used the DerSimonian and Laird (38) model, which is the random-effects model used in RevMan software, version 4.2 (Nordic Cochrane Centre, Copenhagen, Denmark) (39). This model estimates the average treatment effect by incorporating heterogeneity among clinically diverse trials with different, but related, treatment effects (40). When heterogeneity exists, the model (38) assigns smaller studies more weight than they would receive in a fixed-effects model (40). To evaluate statistical heterogeneity within our trial categories, we used I 2 tests on all outcomes included in our meta-analysis. We conducted sensitivity analyses for the short-term outcome of sham-controlled RCTs, restricting the analyses to RCTs assessed as adequate based on each item of the 11-item Cochrane scale (32) and the 4 aspects of the acupuncture treatment adequacy. We performed additional sensitivity analyses for funding source (industry vs. nonindustry) and follow-up length (3 months). We also evaluated whether the pooled effects of acupuncture met the threshold for minimal clinically important differences, defined as the smallest differences in scores that patients would perceive to be beneficial (29). The clinically relevant effects for knee osteoarthritis have been estimated to be standardized mean differences of 0.39 for WOMAC pain and 0.37 for WOMAC function (29). Role of the Funding Source The study was funded by the National Institutes of Health, National Center for Complementary and Alternative Medicine. The funding source had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Results Study Characteristics We included 11 RCTs (3537, 4148) of 2821 patients with osteoarthritis (Figure 1). All studies but 1 (42) we

Effects of acupuncture on rates of pregnancy and live birth among women undergoing in vitro fertilisation: systematic review and meta-analysis.

Objective To evaluate whether acupuncture improves rates of pregnancy and live birth when used as an adjuvant treatment to embryo transfer in women undergoing in vitro fertilisation. Design Systematic review and meta-analysis. Data sources Medline, Cochrane Central, Embase, Chinese Biomedical Database, hand searched abstracts, and reference lists. Review methods Eligible studies were randomised controlled trials that compared needle acupuncture administered within one day of embryo transfer with sham acupuncture or no adjuvant treatment, with reported outcomes of at least one of clinical pregnancy, ongoing pregnancy, or live birth. Two reviewers independently agreed on eligibility; assessed methodological quality; and extracted outcome data. For all trials, investigators contributed additional data not included in the original publication (such as live births). Meta-analyses included all randomised patients. Data synthesis Seven trials with 1366 women undergoing in vitro fertilisation were included in the meta-analyses. There was little clinical heterogeneity. Trials with sham acupuncture and no adjuvant treatment as controls were pooled for the primary analysis. Complementing the embryo transfer process with acupuncture was associated with significant and clinically relevant improvements in clinical pregnancy (odds ratio 1.65, 95% confidence interval 1.27 to 2.14; number needed to treat (NNT) 10 (7 to 17); seven trials), ongoing pregnancy (1.87, 1.40 to 2.49; NNT 9 (6 to 15); five trials), and live birth (1.91, 1.39 to 2.64; NNT 9 (6 to 17); four trials). Because we were unable to obtain outcome data on live births for three of the included trials, the pooled odds ratio for clinical pregnancy more accurately represents the true combined effect from these trials rather than the odds ratio for live birth. The results were robust to sensitivity analyses on study validity variables. A prespecified subgroup analysis restricted to the three trials with the higher rates of clinical pregnancy in the control group, however, suggested a smaller non-significant benefit of acupuncture (odds ratio 1.24, 0.86 to 1.77). Conclusions Current preliminary evidence suggests that acupuncture given with embryo transfer improves rates of pregnancy and live birth among women undergoing in vitro fertilisation.

Spinal glial activation in a new rat model of bone cancer pain produced by prostate cancer cell inoculation of the tibia.

&NA; Studies suggest that astrocytes and microglia in the spinal cord are involved in the development of persistent pain induced by tissue inflammation and nerve injury. However, the role of glial cells in bone cancer pain is not well understood. The present study evaluated the spinal glial activation in a novel rat model of bone cancer pain produced by injecting AT‐3.1 prostate cancer cells into the unilateral tibia of male Copenhagen rats. The structural damage to the tibia was monitored by radiological analysis. The thermal hyperalgesia, mechanical hyperalgesia and allodynia, and spontaneous flinch were measured. The results showed that: (1) inoculation of prostate cancer cells, but not the vehicle Hanks solution, induced progressive bone destruction at the proximal epiphysis of the tibia from day 7–20 post inoculation; (2) the inoculation also induced progressive thermal hyperalgesia, mechanical hyperalgesia, mechanical allodynia, and spontaneous flinches; (3) astrocytes and microglia were significantly activated in the spinal cord ipsilateral to the cancer leg, characterized by enhanced immunostaining of both glial fibrillary acidic protein (GFAP, astrocyte marker) and OX‐42 (microglial marker); (4) IL‐1β was up‐regulated in the ipsilateral spinal cord, evidenced by an increase of IL‐1β immunostained astrocytes. These results demonstrate that injection of AT‐3.1 prostate cancer cells into the tibia produces progressive hyperalgesia and allodynia associated with the progression of tibia destruction, indicating the successful establishment of a novel male rat model of bone cancer pain. Further, bone cancer activates spinal glial cells, which may release IL‐1β and other cytokines and contribute to hyperalgesia.

Is Acupuncture Analgesia an Expectancy Effect? Preliminary Evidence Based on Participants’ Perceived Assignments in Two Placebo-Controlled Trials

This purpose of this article is to contrast the analgesic efficacy of acupuncture following dental surgery with the analgesic effects based on the expectation of benefit in two independently conducted placebo-controlled trials evaluating acupuncture as an adjunctive therapy for dental surgery. Both trials used pain following dental surgery as the outcome variable, and both included a blinding check to ascertain patients’ beliefs regarding which treatment they were receiving. Although no statistically significant analgesic effect was observed between the acupuncture and placebo groups, participants in both experiments who believed they received real acupuncture reported significantly less pain than patients who believed that they received a placebo. Patients’ beliefs regarding the receipt of acupuncture bore a stronger relationship to pain than any specific action possessed by acupuncture. These results also support the importance of both employing credible controls for the placebo effect in clinical trials and evaluating the credibility of those controls.

Mindfulness intervention for child abuse survivors

Twenty-seven adult survivors of childhood sexual abuse participated in a pilot study comprising an 8-week mindfulness meditation-based stress reduction (MBSR) program and daily home practice of mindfulness skills. Three refresher classes were provided through final follow-up at 24 weeks. Assessments of depressive symptoms, post-traumatic stress disorder (PTSD), anxiety, and mindfulness, were conducted at baseline, 4, 8, and 24 weeks. At 8 weeks, depressive symptoms were reduced by 65%. Statistically significant improvements were observed in all outcomes post-MBSR, with effect sizes above 1.0. Improvements were largely sustained until 24 weeks. Of three PTSD symptom criteria, symptoms of avoidance/numbing were most greatly reduced. Compliance to class attendance and home practice was high, with the intervention proving safe and acceptable to participants. These results warrant further investigation of the MBSR approach in a randomized, controlled trial in this patient population.

IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats

&NA; Although it has been shown that pro‐inflammatory cytokines such as interleukin‐1β (IL‐1β) facilitate perception of noxious inputs at the spinal level, the mechanisms have not been understood. This study determined the cell type that produces IL‐1β, the co‐localization of IL‐1 receptor type I (IL‐1RI) and Fos and NR1 in the spinal cord, and the effects of IL‐1 receptor antagonist (IL‐1ra) on NR1 phosphorylation and hyperalgesia in a rat model of inflammatory pain. Phosphorylation of NR1, an essential subunit of the NMDA receptor (NMDAR), is known to modulate NMDAR activity and facilitate pain. Hyperalgesia was induced by injecting complete Freund’s adjuvant (CFA, 0.08 ml, 40 μg Mycobacterium tuberculosis) into one hind paw of each rat. Paw withdrawal latency (PWL) was tested before CFA (−48 h) for baseline and 2 and 24 h after CFA to assess hyperalgesia. IL‐1ra was given (i.t.) 24 h before CFA to block the action of basal IL‐1β and 2 h prior to each of two PWL tests to block CFA‐induced IL‐1β. Spinal cords were removed for double immunostaining of IL‐1β/neuronal marker and IL‐1β/glial cell markers, IL‐1RI/Fos and IL‐1RI/NR1, and for Western blot to measure NR1 phosphorylation. The data showed that: (1) astrocytes produce IL‐1β, (2) IL‐1RI is localized in Fos‐ and NR1‐immunoreactive neurons within the spinal dorsal horn, and (3) IL‐1ra at 0.01 mg/rat significantly increased PWL (P < 0.05) and inhibited NR1 phosphorylation compared to saline control. The results suggest that spinal IL‐1β is produced by astrocytes and enhances NR1 phosphorylation to facilitate inflammatory pain.