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      Examination of overall treatment effect and the proportion attributable to contextual effect in osteoarthritis: meta-analysis of randomised controlled trials

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          Abstract

          Objective

          To examine the overall treatment effect and the proportion attributable to contextual effect (PCE) in randomised controlled trials (RCTs) of diverse treatments for osteoarthritis (OA).

          Methods

          We searched Medline, Embase, Central, Science Citation Index, AMED and CINAHL through October 2014, supplemented with manual search of reference lists, published meta-analyses and systematic reviews. Included were RCTs in OA comparing placebo with representative complementary, pharmacological, non-pharmacological and surgical treatments. The primary outcome was pain. Secondary outcomes were function and stiffness. The effect size (ES) of overall treatment effect and the PCE were pooled using random-effects model. Subgroup analyses and meta-regression were conducted to examine determinants of the PCE.

          Results

          In total, 215 trials (41 392 participants) were included. The overall treatment effect for pain ranged from the smallest with lavage (ES=0.46, 95% CI 0.24 to 0.68) to the largest with topical non-steroidal anti-inflammatory drugs (ES=1.37, 95% CI 1.19 to 1.55). On average, 75% (PCE=0.75, 95% CI 0.72 to 0.79) of pain reduction was attributable to contextual effect. It varied by treatment from 47% (PCE=0.47, 95% CI 0.32 to 0.70) for intra-articular corticosteroid to 91% (PCE=0.91, 95% CI 0.60 to 1.37) for joint lavage. Similar results were observed for function and stiffness. Treatment delivered by needle/injection and other means than oral medication, longer duration of treatment, large sample size (≥100 per arm) and public funding source were associated with increased PCE for pain reduction.

          Conclusions

          The majority (75%) of the overall treatment effect in OA RCTs is attributable to contextual effects rather than the specific effect of treatments. Reporting overall treatment effect and PCE, in addition to traditional ES, permits a more balanced, clinically meaningful interpretation of RCT results. This would help dispel the frequent discordance between conclusions from RCT evidence and clinical experience—the ‘efficacy paradox’.

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          Small study effects in meta-analyses of osteoarthritis trials: meta-epidemiological study

          Eveline Nüesch, Sven Trelle, Stephan Reichenbach … (2010)
          Objective To examine the presence and extent of small study effects in clinical osteoarthritis research. Design Meta-epidemiological study. Data sources 13 meta-analyses including 153 randomised trials (41 605 patients) that compared therapeutic interventions with placebo or non-intervention control in patients with osteoarthritis of the hip or knee and used patients’ reported pain as an outcome. Methods We compared estimated benefits of treatment between large trials (at least 100 patients per arm) and small trials, explored funnel plots supplemented with lines of predicted effects and contours of significance, and used three approaches to estimate treatment effects: meta-analyses including all trials irrespective of sample size, meta-analyses restricted to large trials, and treatment effects predicted for large trials. Results On average, treatment effects were more beneficial in small than in large trials (difference in effect sizes −0.21, 95% confidence interval −0.34 to −0.08, P=0.001). Depending on criteria used, six to eight funnel plots indicated small study effects. In six of 13 meta-analyses, the overall pooled estimate suggested a clinically relevant, significant benefit of treatment, whereas analyses restricted to large trials and predicted effects in large trials yielded smaller non-significant estimates. Conclusions Small study effects can often distort results of meta-analyses. The influence of small trials on estimated treatment effects should be routinely assessed.
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            Placebo response in studies of major depression: variable, substantial, and growing.

            Cathryn M. Gould, Robyn Sysko, Stuart N Seidman … (2002)
            Intense debate persists about the need for placebo-controlled groups in clinical trials of medications for major depressive disorder (MDD). There is continuing interest in the development of new medications, but because effective antidepressants are already available, ethical concerns have been raised about the need for placebo groups in new trials. To determine whether the characteristics of placebo control groups in antidepressant trials have changed over time. We searched MEDLINE and PsychLit for all controlled trials published in English between January 1981 and December 2000 in which adult outpatients with MDD were randomly assigned to receive medication or placebo. Seventy-five trials met our criteria for inclusion. Data were extracted from the articles by 2 of the authors and discrepancies were resolved via discussion and additional review by a third author. The mean (SD) proportion of patients in the placebo group who responded was 29.7% (8.3%) (range, 12.5%-51.8%). Most studies examined more than a single active medication, and, in the active medication group with the greatest response, the mean (SD) proportion of patients responding was 50.1% (9.0%) (range, 31.6%-70.4%). Both the proportion of patients responding to placebo and the proportion responding to medication were significantly positively correlated with the year of publication (for placebo: n = 75; r = 0.45; 95% confidence interval [CI], 0.25-0.61; P<.001; for medication: n = 75; r = 0.26; 95% CI, 0.03-0.46; P =.02). The association between year of publication and response rate was more statistically robust for placebo than medication. The response to placebo in published trials of antidepressant medication for MDD is highly variable and often substantial and has increased significantly in recent years, as has the response to medication. These observations support the view that the inclusion of a placebo group has major scientific importance in trials of new antidepressant medications and indicate that efforts should continue to minimize the risks of such studies so that they may be conducted in an ethically acceptable manner.
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              The placebo is powerful: estimating placebo effects in medicine and psychotherapy from randomized clinical trials.

              Thomas Baskin, Bruce E Wampold, William Tierney … (2005)
              The logic of the randomized double-blind placebo control group design is presented, and problems with using the design in psychotherapy are discussed. Placebo effects are estimated by examining clinical trials in medicine and psychotherapy. In medicine, a recent meta-analysis of clinical trials with treatment, placebo, and no treatment arms was conducted (Hróbjartsson & Gøtzsche, 2001), and it was concluded that placebos have small or no effects. A re-analysis of those studies, presented here, shows that when disorders are amenable to placebos and the design is adequate to detect the effects, the placebo effect is robust and approaches the treatment effect. For psychological disorders, particularly depression, it has been shown that pill placebos are nearly as effective as active medications whereas psychotherapies are more effective than psychological placebos. However, it is shown that when properly designed, psychological placebos are as effective as accepted psychotherapies.
              Article 0 comments Cited 63 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Ann Rheum Dis
                Journal ID (iso-abbrev): Ann. Rheum. Dis
                Journal ID (hwp): annrheumdis
                Journal ID (publisher-id): ard
                Title: Annals of the Rheumatic Diseases
                Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                ISSN (Print): 0003-4967
                ISSN (Electronic): 1468-2060
                Publication date (Print): November 2016
                Publication date (Electronic): 16 February 2016
                Volume: 75
                Issue: 11
                Pages: 1964-1970
                Affiliations
                [1 ]Division of Rheumatology, Orthopaedics and Dermatology, University of Nottingham , Nottingham, UK
                [2 ]Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology , Chengdu, China
                [3 ]Pinfold Medical Practice , Loughborough, UK
                [4 ]School of Health Sciences, University of East Anglia , Norwich, UK
                Author notes

                Handling editor Tore K Kvien

                [Correspondence to ] Dr Weiya Zhang, Academic Rheumatology, Division of Rheumatology, Orthopaedics and Dermatology, Clinical Sciences Building, University of Nottingham, Nottingham NG5 1PB, UK; weiya.zhang@ 123456nottingham.ac.uk
                Article
                Publisher ID: annrheumdis-2015-208387
                DOI: 10.1136/annrheumdis-2015-208387
                PMC ID: 5099197
                PubMed ID: 26882927
                SO-VID: b18a79df-83ad-4009-bef7-cbeb679d420f
                Copyright © Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
                License:

                This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

                History
                Date received : 7 August 2015
                Date revision received : 10 January 2016
                Date accepted : 16 January 2016
                Categories
                Subject: 1506
                Subject: Clinical and Epidemiological Research
                Series title: Extended report
                Custom metadata
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                ScienceOpen disciplines: Immunology
                Keywords: osteoarthritis,treatment,epidemiology
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: osteoarthritis, treatment, epidemiology

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