Effect of placebo acupuncture over no-treatment: A simple model incorporating the placebo and nocebo effects.

Conventionally in controlled trials of drugs or modalities, the placebo and nocebo effects have been determined separately and understood to be the difference between the placebo and no-treatment groups. Recently, the effect of placebo acupuncture over no-treatment was found to be associated with the placebo and nocebo effects together. If these two effects are inseparable in acupuncture treatment, the conventional method of determining placebo and nocebo effects at the trial level will not reflect pure placebo or nocebo effects. Furthermore, if these effects are inseparable, observations about the efficacy of acupuncture will be biased when considering only the placebo effect. A simple mathematical model incorporating both the placebo and nocebo effects will be provided to see how the efficacy of acupuncture is affected.

Nonspecific adverse events in knee osteoarthritis clinical trials: a systematic review.

BACKGROUND: Adverse events (AEs) derived from nonspecific activity of treatments can impair the validity of trials, and even make it difficult to identify specific AEs associated with treatments. To better understand these nonspecific AEs, we investigated the AEs in placebo groups by using knee osteoarthritis clinical trials. METHODS: Randomized, placebo-controlled, knee osteoarthritis trials were identified by searching electronic databases. We determined the rate of patients with AEs and the rate of dropouts caused by AEs in the active and placebo groups. Furthermore, we calculated the rate of patients for individual AEs in the placebo groups. Finally, we performed secondary analyses to identify the factors associated with these rates. RESULTS: Overall, 272 papers reporting 281 trials were included in the analysis. The rates of patients with AEs were 31.8% in the active groups and 27.4% in the placebo groups. The rate of the placebo groups accounted for 86.2% of the rate of the active groups. The rates of dropouts caused by AEs were 5.2% in the active groups and 4.8% in the placebo groups. The rate of the placebo groups accounted for 92.3% of the rate of the active groups. AEs in the placebo groups included a number of clinical conditions, with elevated alanine aminotransferase (0.59%; 95% CI: 0.46 to 0.77) being the most common objective outcome and headache (4.48%; 95% CI: 4.20 to 4.79) being the most frequent subjective outcome. The rate of patients with AEs and the rate of dropouts caused by AEs were associated with the treatment type, delivery route, and study design. CONCLUSIONS: The nonspecific AEs substantially accounted for the development of AEs in the active groups and included conditions involving the entire body.

Effectiveness of sling exercise for chronic low back pain: a systematic review.

[Purpose] This study investigated effects of sling exercise for patients with chronic low back pain. [Methods] We reviewed all relevant papers indexed in PubMed, SCOPUS, and the Cochrane Registered Trials. Eligible trials were randomized controlled trials that compared sling exercise with any type of treatment. We extracted data on muscle thickness, muscle activation, pain, and disability, and assessed the methodological quality of the data. Seven studies met our inclusion criteria. [Results] When sling exercise had an impact on activation of the trunk muscles, increasing the trunk muscle thickness, and the reduction in pain and disability had been assessed shortly after the final exercise session, it was more effective than general exercise at activating trunk muscles, but not more effective at increasing trunk muscle thickness and improving pain and disability than general exercise. [Conclusion] As sling therapy studies are based on a small number of trials, we cannot draw conclusions about the therapeutic effects of sling exercise. When segmental stabilizing exercise and individually designed programs are added to sling exercise, it increases the effectiveness of sling exercise at improving low back pain. This should be the focus of future studies.

Clinically meaningful nocebo effect occurs in acupuncture treatment: a systematic review.

OBJECTIVE: To investigate the nocebo effect using randomized acupuncture trials that include sham and no-treatment groups. STUDY DESIGN AND SETTING: Electronic databases were searched to retrieve eligible trials from their inception until June 2013. Risk differences were then calculated using the acupuncture and sham groups to determine the treatment effect and the sham and no-treatment groups to determine the nocebo effect. RESULTS: In total, 58 eligible trials were analyzed. On the basis of the rate of patients with any adverse event in 31 trials reporting available data, the treatment effect was 0.012 (95% confidence interval [CI]: 0.003, 0.021), with a number needed to harm (NNH) of 83 (95% CI: 48, 333). The nocebo effect was 0.049 (95% CI: 0.012, 0.086), with an NNH of 20 (95% CI: 12, 83). By contrast, the rate of dropouts due to adverse events in 39 trials reporting available data showed no differences for both effects. In addition, nearly 70% of the trials reported zero dropouts in the sham and no-treatment groups. CONCLUSION: Our findings suggest that (1) the nocebo effect of acupuncture is clinically meaningful and (2) the rate of patients with any adverse event may be a more appropriate indicator of the nocebo effect.

A re-analysis of studies regarding the use of Glycyrrhiza spp. in women during pregnancy.

The use of herbal medicines as a form of primary and adjunctive healthcare continues to grow internationally. It is therefore important that healthcare practitioners stay abreast of potential contraindications that may arise when these medicines are taken together with orthodox treatment or are prescribed during pregnancy. This article analyses the most popularly cited clinical research concerning the use of Glycyrrhiza spp. during pregnancy. It also aims to serve as guidance for healthcare professionals who either prescribe herbal medicines or have cause to advise patients in relation to the use of glycyrrhiza by women during pregnancy.

Eligibility criteria in knee osteoarthritis clinical trials: systematic review.

There is an increasing concern over generalizability of trial results. We investigated eligibility criteria of knee osteoarthritis clinical trials. Eligible trials were randomized, placebo-controlled trials that were identified by searches in MEDLINE, SCOPUS, and the Cochrane Central Register of Controlled Trials. We then attempted to extract data on the eligibility criteria by employing predetermined criteria. From 355 randomized knee osteoarthritis trials, we reviewed data categorized by non-osteoarthritis-related and osteoarthritis-related factors. A variety of items were used in the eligibility criteria. Regarding the non-osteoarthritis-related factors, ethical considerations, such as inability to give an informed consent (79.4 %) or medical conditions potential for risks by test treatments (56.0 %) or by participation in a trial (57.2 %), were the common reasons for excluding patients from a trial. Concerning the osteoarthritis-related factors, most of the trials did not specify age and symptom severity. When trials specifying these items were investigated, patients with 40 to 80 years in age and grade 2 in the Kellgren-Lawrence scale were mostly included into a trial. For the pain intensity, patients with ≥20-40 in the 100-mm visual analog scale and ≥6-8 in the WOMAC pain subscale were commonly enrolled into a trial. These findings warrant further investigation on the generalizability of trial results.

Barriers to participant retention in knee osteoarthritis clinical trials: a systematic review.

OBJECTIVE: We investigated the reasons and rates of attrition in knee osteoarthritis trials through a systematic review of randomized, placebo-controlled, clinical trials. METHODS: Randomized trials were identified by searches conducted in MEDLINE, SCOPUS, and the Cochrane Central Register of Controlled Trials. We then attempted to identify and describe the reasons for attrition and their associated themes. For each theme, we calculated the rate of patients who discontinued a trial from the total number of dropouts in each trial. The rates obtained with different trials were combined using a random effects model. We also performed a random effects meta-regression analysis to identify sources associated with the rates. RESULTS: Overall, 259 studies consisting of 266 trials and 13,593 patients were included in the analysis. From these, we short-listed 54 attrition reasons and identified 21 key themes. "Ineffectiveness" and "adverse event" were the reasons frequently reported by >5% of the dropouts. On further investigation of the theme ineffectiveness, the attrition rate was associated with delivery routes of treatment, trial duration, flare design, prohibition of usual analgesics, and allowing the use of escape medication. In cases of adverse events, we found that the treatment type and delivery route affected the attrition rate. CONCLUSIONS: Our findings not only support the importance of the intention-to-treat analysis, but also suggest the possibility of controlling the attrition at the study level.

Effects of pulsed electromagnetic field on knee osteoarthritis: a systematic review.

OBJECTIVE: Many reviews have been previously published on the efficacy of pulsed electromagnetic field (PEMF) in the management of knee OA. However, their results regarding pain and function yielded conflicting conclusions. Therefore this study was conducted to determine the efficacy of PEMF as compared with a placebo. METHODS: We reviewed randomized, placebo-controlled trials using electronic databases. We also manually reviewed sources to identify additional relevant studies. RESULTS: Fourteen trials were analysed, comprising 482 patients in the treatment group and 448 patients in the placebo group. When the efficacy of PEMF in treating pain was investigated, no significant effects were observed at any of the time points considered. However, when trials employing high-quality methodology were analysed, PEMF was significantly more effective at 4 and 8 weeks than the placebo. When the efficacy of PEMF was evaluated for function, a significant improvement was observed 8 weeks after the treatment initiation, with a standardized mean difference of 0.30 (95% CI 0.07, 0.53). No significant association was found between the use of PEMF and the occurrence of adverse events, as indicated by a relative risk of 1.47 (95% CI 0.67, 3.20). However, three (21.4%) trials applied electromagnetic field intensity over the levels recommended by the International Commission on Non-Ionizing Radiation Protection. CONCLUSION: The present study provided suggestive evidence supporting PEMF efficacy in the management of knee OA. Our results further raise the need for more well-controlled trials, employing adequate methodology, to conclusively evaluate the efficacy of PEMF.

Time Course of Placebo Effect of Acupuncture on Pain: A Systematic Review.

Objectives. Our objective was to investigate the time course of the placebo effect of acupuncture on pain and the factors affecting the placebo effect. Methods. Previously we retrieved three-armed randomized acupuncture trials including sham and no-treatment groups which were published until October 2009. We searched electronic databases again to identify additional trials from October 2009 to December 2011. After a screening of trials, fifteen three-armed acupuncture trials for pain were included in the analysis. Standardized mean differences between the sham and no-treatment groups were calculated for placebo effect. We then plotted the magnitude of the placebo effect over time. Results. The placebo effect gradually has increased for 12 weeks with a standardized mean difference of 0.74 (95% CI: 0.54 to 0.94). Then it decreased after 12 weeks as time passed. When the placebo effects were compared for factors including methodological qualities, they were not affected by all factors, except patient blinding. Trials with sufficient patient blinding showed a larger placebo effect at 8 weeks than those with insufficient patient blinding (P = 0.0009). Conclusion. The placebo effect of acupuncture showed a unique pattern, which was affected by insufficient patient blinding.

Placebo effect was influenced by publication year in three-armed acupuncture trials.

OBJECTIVES: We investigated the relationship between the placebo effect and the trial or patient characteristics. DATA SOURCES: We identified randomized clinical trials with acupuncture, sham and no-treatment groups in which no-treatment or conventional therapy was applied to the no-treatment group. Thirty-one trials in which no treatment was applied in the no-treatment group were categorised as 'strict' trials. Thirty-nine trials in which no-treatment or conventional therapy was applied to the no-treatment group were categorised as 'less strict' trials. We calculated the treatment effect, defined as the difference in the effect size between the acupuncture and no-treatment groups, and the placebo effect, defined as the difference in the effect size between the sham and no-treatment groups. Then, a random effect meta-regression analysis was performed on the two effects with respect to trial or patient characteristics. RESULTS: The treatment effect was not found to be associated with any factors in both the strict and less strict trials. However, the placebo effect was found to be associated with the publication year in both the strict and less strict trials (P=0.009 and 0.005, respectively). The placebo effect increased by 0.05 in effect size per year in trials that were published more recently. CONCLUSION: While the treatment effect was not influenced by any trial or patient characteristics, the placebo effect was associated with the publication year.

Three-armed trials including placebo and no-treatment groups may be subject to publication bias: systematic review.

BACKGROUND: It has been argued that placebos may not have important clinical impacts in general. However, there is increasing evidence of a publication bias among trials published in journals. Therefore, we explored the potential for publication bias in randomized trials with active treatment, placebo, and no-treatment groups. METHODS: Three-armed randomized trials of acupuncture, acupoint stimulation, and transcutaneous electrical stimulation were obtained from electronic databases. Effect sizes between treatment and placebo groups were calculated for treatment effect, and effect sizes between placebo and no-treatment groups were calculated for placebo effect. All data were then analyzed for publication bias. RESULTS: For the treatment effect, small trials with fewer than 100 patients per arm showed more benefits than large trials with at least 100 patients per arm in acupuncture and acupoint stimulation. For the placebo effect, no differences were found between large and small trials. Further analyses showed that the treatment effect in acupuncture and acupoint stimulation may be subject to publication bias because study design and any known factors of heterogeneity were not associated with the small study effects. In the simulation, the magnitude of the placebo effect was smaller than that calculated after considering publication bias. CONCLUSIONS: Randomized three-armed trials, which are necessary for estimating the placebo effect, may be subject to publication bias. If the magnitude of the placebo effect is assessed in an intervention, the potential for publication bias should be investigated using data related to the treatment effect.

Effects of botulinum toxin A on calf muscles in children with cerebral palsy: a systematic review.

OBJECTIVE: To assess the efficacy of botulinum toxin A injection for the management of spastic calf muscles in children with cerebral palsy. DATA SOURCES: We reviewed all relevant literature indexed in MEDLINE, CINAHL, EMBASE, PEDro and the Cochrane Registered Trials, and also hand reviewed abstracts. METHODS: Eligible studies were randomized controlled trials that compared botulinum toxin A injection with any type of treatment or no treatment with identical conditions. We extracted data on calf muscle tone, passive ankle range of motion, gait speed, ankle kinematics and Gross Motor Function Measure, and assessed methodological qualities. RESULTS: Fifteen studies met our inclusion criteria. When botulinum injection was compared with a non-sham control, it was found to be effective at improving calf muscle tone (one month: -2.73 (confidence interval (CI) -3.42 to -2.04), three months: -1.72 (-2.68 to -0.76)), passive ankle range of motion (one month: 3.29 (CI 2.52 to 4.05), three months: 1.00 (CI 0.44 to 1.56)) and gait speed (one month: 0.91 (CI 0.29 to 1.53), three months: 0.61 (CI 0.01 to 1.21)) for four months, as well as Gross Motor Function Measure (2.02 (CI 1.30 to 2.75)) for two months. When compared with sham injection, botulinum injection was only effective on Gross Motor Function Measure (0.98 (CI 0.28 to 1.69)) after four months. CONCLUSIONS: Although we found evidence supporting the efficacy of botulinum toxin A in studies comparing botulinum injection with non-sham controls, we did not find clear evidence of support in studies comparing botulinum injection with sham injection.

Interventions for hemiplegic shoulder pain: systematic review of randomised controlled trials.

PURPOSE: The primary aim of this study was to assess the effectiveness of possible interventions for hemiplegic shoulder pain. The secondary aim was to investigate whether reduction of subluxation or spasticity can decrease shoulder pain and whether a change in shoulder pain is related to change in passive shoulder external rotation. METHOD: MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials databases were searched to obtain the randomised, controlled trials. Two authors independently extracted data and assessed the methodological quality of studies. RESULTS: Eight randomised trials were found in electronic databases. Aromatherapy plus acupressure, slow-stroke back massage and intramuscular neuromuscular electric stimulation were more effective than the controls at the end of treatment sessions. Intramuscular botulinum neurotoxin A injection and intraarticular triamcinolone acetonide injection were not helpful at one or three months after the end of treatment. Only intramuscular electric stimulation was effective at three months. These analyses found that shoulder pain improved independently of spasticity and subluxation. It was confirmed that the change in shoulder pain was associated with change in passive shoulder external rotation. CONCLUSIONS: Although five interventions were used for managing hemiplegic shoulder pain, their effects were limited in the context of trials.

Does random participant assignment cause fewer benefits in research participants? Systematic review of partially randomized acupuncture trials.

OBJECTIVES: It has been suggested that the random assignment of participants does not cause harm to patients in clinical trials. However, in a recent study, patient preference affected the health outcome of the patients. It can therefore be assumed that patients who are allocated at random may be affected by placebo effects that are associated with the treatment of their choice. The aim of this study was to determine whether random participant assignment in acupuncture trials causes fewer benefits to the participants. DATA SOURCES: The following computerized databases were searched from their inception to December 2008: MEDLINE, SCOPUS, CINAHL, Cochrane Registered Trial, British Library Direct, and Google Scholar. REVIEW METHODS: This was a systematic review of partially randomized acupuncture trials with adequate randomization generation and concealment of participant group allocation as well as large enough sample sizes to satisfy a power calculation. RESULTS: Six (6) trials that met the selection criteria were included. The randomized acupuncture group comprised patients with different demographics and health outcomes than the observational group. Substantial numbers of eligible patients refused to participate in the randomization. The baseline patient characteristics were different between the randomized acupuncture group and the observational group. The proportion of patients who dropped out of or withdrew from the study was also different between the groups, with significantly more dropping out from the observational group than the randomized group. Patients in the observational group had significantly better health outcomes than patients in the randomized group, with a standardized mean difference of 0.06 (95% confidence interval 0.03-0.09). CONCLUSIONS: We found that patients who were randomly assigned to treatment groups in acupuncture trials had fewer health benefits than those who were nonrandomly assigned.