Placebo response and effect in randomized clinical trials: meta-research with focus on contextual effects

Abstract

Background Contextual effects (i.e., placebo response) refer to all health changes resulting from administering an apparently inactive treatment. In a randomized clinical trial (RCT), the overall treatment effect (i.e., the post-treatment effect in the intervention group) can be regarded as the true effect of the intervention plus the impact of contextual effects. This meta-research was conducted to examine the average proportion of the overall treatment effect attributable to contextual effects in RCTs across clinical conditions and treatments and explore whether it varies with trial contextual factors. Methods Data was extracted from trials included in the main meta-analysis from the latest update of the Cochrane review on “Placebo interventions for all clinical conditions” (searched from 1966 to March 2008). Only RCTs reported in English having an experimental intervention group, a placebo comparator group, and a no-treatment control group were eligible. Results In total, 186 trials (16,655 patients) were included. On average, 54% (0.54, 95%CI 0.46 to 0.64) of the overall treatment effect was attributable to contextual effects. The contextual effects were higher for trials with blinded outcome assessor and concealed allocation. The contextual effects appeared to increase proportional to the placebo effect, lower mean age, and proportion of females. Conclusion Approximately half of the overall treatment effect in RCTs seems attributable to contextual effects rather than to the specific effect of treatments. As the study did not include all important contextual factors (e.g., patient-provider interaction), the true proportion of contextual effects could differ from the study’s results. However, contextual effects should be considered when assessing treatment effects in clinical practice. Trial registration PROSPERO CRD42019130257. Registered on April 19, 2019.

The importance of selecting the correct site to apply spinal manipulation when treating spinal pain: Myth or reality? A systematic review

“…These systemic and non-specific factors could contribute to an increased improvement following SMT. The same has been observed in acupuncture 55 and exercise 56 , and it is a general finding across multiple interventions 57 . The same argument can be made for SMT in general, as it is non-superior to non-thrust mobilization or even sham SMT 58 .…”

Does wearing arthritis gloves help with hand pain and function? A qualitative study into patients’ views and experiences

“…a situation where a negative outcome occurs owing to a belief that the intervention will cause harm) represent complex and distinct psychoneurobiological phenomena, in which behavioural and neurophysiological changes follow the application of a treatment [ 32 ]. The therapist and the patient’s characteristics, the patient–therapist relationship and the characteristics of the treatment are all contextual factors influencing clinical outcomes [ 32 , 33 ]. Thus, when evaluating the effectiveness of treatments, the importance of patients’ expectations, feelings and clinical context should not be ignored [ 33 ].…”

“…The therapist and the patient’s characteristics, the patient–therapist relationship and the characteristics of the treatment are all contextual factors influencing clinical outcomes [ 32 , 33 ]. Thus, when evaluating the effectiveness of treatments, the importance of patients’ expectations, feelings and clinical context should not be ignored [ 33 ]. The placebo effect might have played a role in participants’ appraisal of arthritis glove wearing, because both gloves were prescribed and fitted by rheumatology occupational therapists in a hospital setting, and the placebo/control gloves had the credible appearance of arthritis gloves.…”

Knee-extensor strength, symptoms, and need for surgery after two, four, or six exercise sessions/week using a home-based one-exercise program: A randomized dose-response trial of knee-extensor resistance exercise in patients eligible for knee replacement (the QUADX-1 trial)

“…50 The effects observed in the present trial across different outcomes may be a small specific effect of exercise and/or of other contextual factors. It could be caused by contact with healthcare professionals [58][59][60] , regression to the mean, natural cause of the disease, 61 or simply by placebo effect 50 -making it difficult to ascribe too much specific cause-of-effect to exercise therapy. In line with this, the recent DISCO trial found equivalent improvements after a supervised exercise and education program, and saline injections in patients with knee OA.…”

“…This re-evaluation based on symptom changes, combined with additional attention from an orthopedic surgeon, could have facilitated the patients' decision to postpone surgery. [58][59][60][65][66][67][68] This is exemplified in table 4 showing that patients who believe they need surgery, undergo surgery, while those who "don't know" or do not believe they need surgery postpone it.…”