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Review of Randomized Placebo-Controlled Trials

      We read the recent review by Sochacki et al.
      • Sochacki K.R.
      • Mather R.C.
      • Nwachukwu B.U.
      • et al.
      Sham surgery studies in orthopedic surgery may just be a sham: A systematic review of randomized placebo-controlled trials.
      with great interest. The authors’ main conclusion is that major orthopaedic trials involving sham surgery have methodologic deficiencies that may invalidate their conclusions. Considering that no rigorous evidence supports the use of interventions included in these trials, we find the authors’ conclusions incongruous.
      Evidently, no study is perfect. But do the suggested limitations invalidate the results of sham-controlled trials? The assumption that the included interventions provide benefits is based on data from observational studies that lack even the simplest concept in efficacy analysis, a control group. The authors seem to be implying that we are supposed to rely on observational data or expert opinions rather than data from placebo-controlled studies.
      One of the criticisms concerns the lack of analysis of genetic markers for placebo effect. This critique is not valid for 2 reasons. First, there is no reason to presume that knowing the “placebo genes” of the trial population is needed to reduce bias. On the contrary, randomization is the best tool we have to avoid such bias since randomization will distribute hidden covariates efficiently. Second, the study of the genetics of the placebo response is in its infancy and should so far be considered basic research.
      • Hall K.T.
      • Loscalzo J.
      • Kaptchuk T.J.
      Genetics and the placebo effect: The placebome.
      The results have not yet been applied in clinical studies in any field of medicine. Considering the current status of the “placebome” research, it is a gross overstatement to demand the analysis of genetic markers for placebo response in orthopaedic or any other clinical trial.
      Another criticism concerns 2 studies performed in Finland. According to the authors, sisu, a mystic cultural characteristic defining the resilience of Finns, invalidates the generalizability of the study results. Here the authors refer to 2 articles. The first one is a review describing the potential advantages the Nordic countries have for pioneering in genome-wide association studies.
      • Palotie A.
      • Widén E.
      • Ripatti S.
      From genetic discovery to future personalized health research.
      It describes the collaborative initiative called SISu (Sequencing Initiative Suomi [=Finland in Finnish]). Here, SISu is simply an acronym that has nothing to do with sisu, the “form of courage, grit, and determination” in Finland. Nowhere in this paper do the authors claim that studies including patients “born and raised in Finland” could not be extrapolated to the rest of the world. The second reference is to a short story of an elderly man with metastatic melanoma written by his treating doctor after the patient’s death.
      • Cohen J.V.
      Sisu—the ability to keep fighting after most would quit.
      The man certainly displayed sisu during his life, but again, the story provides no justification for the claims made by the authors.
      Finally, authors state that “no patients underwent psychiatric or psychologic evaluation to test their competence to participate in a randomized sham surgery trial.” They seem to imply that consenting to a potentially harmful surgical procedure that has not been rigorously evaluated does not require psychiatric evaluation but consenting a study evaluating such a procedure does.
      Regardless of the presented shortcomings, sham-controlled studies provide the greatest level of evidence we can currently deliver to our patients. While any improvement in methodology should be embraced, the claims made by authors are not supported by their analysis.

      Supplementary Data

      References

        • Sochacki K.R.
        • Mather R.C.
        • Nwachukwu B.U.
        • et al.
        Sham surgery studies in orthopedic surgery may just be a sham: A systematic review of randomized placebo-controlled trials.
        Arthroscopy. 2020; 36: 2750-2762
        • Hall K.T.
        • Loscalzo J.
        • Kaptchuk T.J.
        Genetics and the placebo effect: The placebome.
        Trends Mol Med. 2015; 21: 285-294
        • Palotie A.
        • Widén E.
        • Ripatti S.
        From genetic discovery to future personalized health research.
        N Biotechnol. 2013; 30: 291-295
        • Cohen J.V.
        Sisu—the ability to keep fighting after most would quit.
        JAMA Oncol. 2018; 4: 1329