Critical Review| Volume 20, ISSUE 5, P489-500, May 2019

The Blind Leading the Not-So-Blind: A Meta-Analysis of Blinding in Pharmacological Trials for Chronic Pain

Published:September 21, 2018DOI:


      Patient blinding is a critical feature of double-blind placebo-controlled randomized controlled trials (RCTs). Yet, very little is known about practices for assessing and reporting blinding in chronic pain trials. We examined the rates and predictors of assessing blinding and its success in pharmacological RCTs for chronic pain. Four-hundred eight trials (n = 103,983 participant) were identified via a systematic search between 2006 and 2016. Only 23 RCTs (5.6%) reported assessing patient blinding. Larger sample size, reference to a CONSORT statement, and pharmaceutical sponsorship were associated with lower rates of assessing blinding. A meta-analysis of the available data using Bang's Blinding Index indicated that blinding was not successful when combined across studies (g = 1.12, 95% confidence interval .92–2.01). Moderator analysis revealed that higher rates of adverse events and larger treatment effect sizes were associated with worse blinding outcomes, whereas including “don't know” responses seemed to improve blinding. Overall then, blinding is rarely reported and often fails in RCTs of pharmacological interventions for chronic pain. To address this finding, we recommend that all researchers conducting RCTs for chronic pain assess and report on the status of patient blinding when reporting the trial outcome.


      This meta-analysis examined patient blinding in pharmacological RCTs of chronic pain. The results indicated that blinding is rarely assessed and often fails. Some study characteristics were associated with lower rates of assessing blinding and its success, for example, pharmaceutical sponsorship and side effects. Implications and recommendations for chronic pain RCTs are discussed.


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        • Altman DGD
        • Schulz KFP
        • Moher DM
        • Egger MMD
        • Davidoff FMD
        • Elbourne DP
        • Gotzsche PCMD
        • Lang TMA
        • for the CONSORT Group
        The revised CONSORT statement for reporting randomized trials: Explanation and elaboration.
        Ann Intern Med. 2001; 134: 663-694
        • Alves CR
        • Santiago BM
        • Lima FR
        • Otaduy MC
        • Calich AL
        • Tritto AC
        • de Sa Pinto AL
        • Roschel H
        • Leite CC
        • Benatti FB
        • Bonfa E
        • Gualano B
        Creatine supplementation in fibromyalgia: A randomized, double-blind, placebo-controlled trial.
        Arthritis Care Res. 2013; 65: 1449-1459
        • Atkinson JH
        • Slater MA
        • Capparelli EV
        • Patel SM
        • Wolfson T
        • Gamst A
        • Abramson IS
        • Wallace MS
        • Funk SD
        • Rutledge TR
        • Wetherell JL
        • Matthews SC
        • Zisook S
        • Garfin SR
        A randomized controlled trial of gabapentin for chronic low back pain with and without a radiating component.
        Pain. 2016; 157: 1499-1507
        • Attal N
        • de Andrade DC
        • Adam F
        • Ranoux D
        • Teixeira MJ
        • Galhardoni R
        • Raicher I
        • Uceyler N
        • Sommer C
        • Bouhassira D
        Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): A randomised, double-blind, placebo-controlled trial.
        Lancet Neurol. 2016; 15: 555-565
        • Baethge C
        • Assall OP
        • Baldessarini RJ
        Systematic review of blinding assessment in randomized controlled trials in schizophrenia and affective disorders 2000-2010.
        Psychother Psychosom. 2013; 82: 152-160
        • Bang H
        • Ni L
        • Davis CE
        Assessment of blinding in clinical trials.
        Control Clin Trials. 2004; 25: 143-156
        • Bausell R
        • Lao L
        • Bergman S
        • Lee W-L
        • Berman BM
        Is acupuncture analgesia an expectancy effect? Preliminary evidence based on participants' perceived assignments in two placebo-controlled trials.
        Eval Health Prof. 2005; 28: 9-26
        • Bischoff JM
        • Ringsted TK
        • Petersen M
        • Sommer C
        • Uceyler N
        • Werner MU
        A capsaicin (8%) patch in the treatment of severe persistent inguinal postherniorrhaphy pain: A randomized, double-blind, placebo-controlled trial.
        PLoS ONE [Electronic Resource]. 2014; 9: e109144
        • Boutron I
        • Estellat C
        • Ravaud P
        A review of blinding in randomized controlled trials found results inconsistent and questionable.
        J Clin Epidemiol. 2005; 58: 1220-1226
        • Colagiuri B
        Participant expectancies in double-blind randomized placebo-controlled trials: Potential limitations to trial validity.
        Clin Trials. 2010; 7: 246-255
        • Colagiuri B
        • Boakes RA
        Perceived treatment, feedback, and placebo effects in double-blind RCTs: An experimental analysis.
        Psychopharmacology (Berl). 2010; 208: 433-441
        • Colagiuri B
        • Morley KC
        • Boakes RA
        • Haber PS
        Expectancy in double-blind placebo-controlled trials: An example from alcohol dependence.
        Psychother Psychosom. 2009; 78: 167-171
        • Crisp A
        Blinding in pharmaceutical clinical trials: An overview of points to consider.
        Contemp Clin Trials. 2015; 43: 155-163
        • Dar R
        • Stronguin F
        • Etter J-F
        Assigned versus perceived placebo effects in nicotine replacement therapy for smoking reduction in swiss smokers.
        J Consult Clin Psychol. 2005; 73: 350-353
        • Duval S
        • Tweedie R
        Trim and fill: A simple funnel-plot–based method of testing and adjusting for publication bias in meta-analysis.
        Biometrics. 2000; 56: 455-463
        • Dworkin RH
        • Turk DC
        • Peirce-Sandner S
        • Baron R
        • Bellamy N
        • Burke LB
        • Chappell A
        • Chartier K
        • Cleeland CS
        • Costello A
        Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations.
        Pain. 2010; 149: 177-193
        • Egger M
        • Smith GD
        • Schneider M
        • Minder C
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • Fergusson D
        • Glass KC
        • Waring D
        • Shapiro S
        Turning a blind eye: The success of blinding reported in a random sample of randomised, placebo controlled trials.
        BMJ. 2004; 328: 432-436
        • Feys F
        • Bekkering GE
        • Singh K
        • Devroey D
        Do randomized clinical trials with inadequate blinding report enhanced placebo effects for intervention groups and nocebo effects for placebo groups?.
        Syst Rev. 2014; 3: 14
        • Fisher S
        • Greenberg RP
        How sound is the double-blind design for evaluating psychotropic drugs?.
        J Nerv Ment Dis. 1993; 181: 345-350
        • Hedges LV
        Distribution theory for Glass's estimator of effect size and related estimators.
        J Educ Stat. 1981; 6: 107-128
        • Higgins J
        • Thompson SG
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558
        • Higgins JP
        • Altman DG
        Assessing risk of bias in included studies.
        Cochrane Handbook Syst Rev Interv. 2008; : 187-241
        • Higgins JP
        • Thompson SG
        • Deeks JJ
        • Altman DG
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557
        • Hrobjartsson A
        • Boutron I
        Blinding in randomized clinical trials: Imposed impartiality.
        Clin Pharmacol Ther. 2011; 90: 732-736
        • Hrobjartsson A
        • Emanuelsson F
        • Skou Thomsen AS
        • Hilden J
        • Brorson S
        Bias due to lack of patient blinding in clinical trials. A systematic review of trials randomizing patients to blind and nonblind sub-studies.
        Int J Epidemiol. 2014; 43: 1272-1283
        • Hróbjartsson A
        • Forfang E
        • Haahr MT
        • Als-Nielsen B
        • Brorson S
        Blinded trials taken to the test: An analysis of randomized clinical trials that report tests for the success of blinding.
        Int J Epidemiol. 2007; 36: 654-663
        • James KE
        • Bloch DA
        • Lee KK
        • Kraemer HC
        • Fuller RK
        An index for assessing blindness in a multi-centre clinical trial: Disulfiram for alcohol cessation: A VA cooperative study.
        Stat Med. 1996; 15: 1421-1434
        • Jensen JS
        • Bielefeldt AØ
        • Hróbjartsson A
        Active placebo control groups of pharmacologicalal interventions were rarely used but merited serious consideration: A methodological overview.
        J Clin Epidemiol. 2017; 87: 35-46
        • Karanicolas PJ
        • Bhandari M
        • Taromi B
        • Akl EA
        • Bassler D
        • Alonso-Coello P
        • Rigau D
        • Bryant D
        • Smith SE
        • Walter SD
        • Guyatt GH
        Blinding of outcomes in trials of orthopaedic trauma: An opportunity to enhance the validity of clinical trials.
        J Bone Joint Surg Am. 2008; 90: 1026-1033
        • Kolahi J
        • Bang H
        • Park J
        • Desbiens N
        CONSORT 2010 and controversies regarding assessment of blindness in RCTs.
        Dent Hypotheses. 2010; 1: 99-105
        • Kwoh CK
        • Roemer FW
        • Hannon MJ
        • Moore CE
        • Jakicic JM
        • Guermazi A
        • Green SM
        • Evans RW
        • Boudreau R
        Effect of oral glucosamine on joint structure in individuals with chronic knee pain: a randomized, placebo-controlled clinical trial.
        Arthritis Rheumatol. 2014; 66: 930-939
        • Lewis SC
        • Bhattacharya S
        • Wu O
        • Vincent K
        • Jack SA
        • Critchley HO
        • Porter MA
        • Cranley D
        • Wilson JA
        • Horne AW
        Gabapentin for the Management of Chronic Pelvic Pain in Women (GaPP1): A pilot randomised controlled trial.
        PloS One. 2016; 11: e0153037
        • Margraf J
        • Ehlers A
        • Roth WT
        • Clark DB
        • Sheikh J
        • Agras WS
        • Taylor CB
        How "blind" are double-blind studies?.
        J Consult Clin Psychol. 1991; 59: 184-187
        • McRae C
        • Cherin E
        • Yamazaki TG
        • Diem G
        • Vo AH
        • Russell D
        • Ellgring JH
        • Fahn S
        • Greene P
        • Dillon S
        • Winfield H
        • Bjugstad KB
        • Freed CR
        Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial.
        Arch Gen Psychiatr. 2004; 61: 412-420
        • Moher D
        • Liberati A
        • Tetzlaff J
        • Altman DG
        • Group P
        Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement.
        PLoS Med. 2009; 6e1000097
        • Munts AG
        • van der Plas AA
        • Ferrari MD
        • Teepe-Twiss IM
        • Marinus J
        • van Hilten JJ
        Efficacy and safety of a single intrathecal methylprednisolone bolus in chronic complex regional pain syndrome.
        Eur J Pain. 2010; 14: 523-528
        • Pach D
        • Brinkhaus B
        • Roll S
        • Wegscheider K
        • Icke K
        • Willich SN
        • Witt CM
        Efficacy of injections with Disci/Rhus toxicodendron compositum for chronic low back pain–a randomized placebo-controlled trial.
        PLoS ONE [Electronic Resource]. 2011; 6: e26166
        • Park J
        • Bang H
        • Canette I
        • Park J
        • Bang H
        • Canette I
        Blinding in clinical trials, time to do it better.
        Complement Ther Med. 2008; 16: 121-123
        • Poe GS
        • Seeman I
        • McLaughlin J
        • Mehl E
        • Dietz M
        “Don't Know” boxes in factual questions in a mail questionnaire: Effects on level and quality of response.
        Public Opinion Q. 1988; 52: 212-222
        • Schulz KF
        • Altman DG
        • Moher D
        CONSORT 2010 Statement: Updated guidelines for reporting parallel group randomised trials.
        BMJ. 2010; 340
        • Sharpe L
        • Ryan B
        • Allard S
        • Sensky T
        Testing for the integrity of blinding in clinical trials: How valid are forced choice paradigms?.
        Psychother Psychosom. 2003; 72: 128-131
        • Snijders GF
        • van den Ende CH
        • van Riel PL
        • van den Hoogen FH
        • den Broeder AA
        • group Ns
        The effects of doxycycline on reducing symptoms in knee osteoarthritis: results from a triple-blinded randomised controlled trial.
        Ann Rheum Dis. 2011; 70: 1191-1196
        • Swartzman LC
        • Burkell J
        Expectations and the placebo effect in clinical drug trials: Why we should not turn a blind eye to unblinding, and other cautionary notes.
        Clin Pharmacol Ther. 1998; 64: 1-7
        • Thomas JL
        • Guo H
        • Lynam IM
        • Powell JN
        • Okuyemi KS
        • Bronars CA
        • Ahluwalia JS
        The impact of perceived treatment assignment on smoking cessation outcomes among African-American smokers.
        J Gen Intern Med. 2008; 23: 1361-1366
        • Yusoff R
        • Janor RM
        Should we provide non-attitude options in rating scales?.
        in: International Symposium on Mathematical Sciences & Computing Research (iSMC), 19th and 20th May Malaysia. 2015