The research progress of open-label placebo (OLP) and implications for future studies: a systematic survey

Article type
Authors
Ma T1, Zhang Y2, Zi M3, Fang H4, Jin Q5, Lu C2, Yang M2, Liu J6
1 Beijing University of Chinese Medicine, Xiyuan Hospital, Beijing
2Center for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine; Beijing GRADE Center, Institute for Excellence in Evidence-Based Chinese Medicine, Beijing
3Xiyuan Hospital, First Clinical Medical College of China Academy of Chinese Medical Sciences
4Department of Traditional Chinese Medicine Pulmonary Diseases, China-Japan Friendship Hospital
5 Beijing University of Chinese Medicine, Dongzhimen Hospital, Beijing
6Center for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine; Beijing GRADE Center, Institute for Excellence in Evidence-Based Chinese Medicine, Beijing
Abstract
Background: Single or double blinding techniques were often used in randomized controlled trials (RCTs). However, post-1960s transparency and honesty in researches were getting more concerns from the ethical perspectives. Several trials introduced open-label placebo (OLP) in trial design. The participants who were allocated to placebo group had been clearly informed and definitely knew what they were taking, ie. OLP design. It was found that there were certain therapeutic effects in OLP group. A growing number of trials covered a quite different disease types revealed the similar results.

Objectives: This study aims to systematically review OLP trials, and explore the P(patients), I(interventions), C(comparisons), O(outcomes), and Setting etc., meanwhile summarize methodological aspects for OLP design. Afterwards, we will discuss the potential use of OLP for future researches, esp. traditional Chinese medicine (TCM).

Methods: Systematic searching has been done in CNKI and PUBMED (from its inception till Dec 31, 2019). Only original articles will be included. The characteristics and the methodological elements were summarized.

Results: Totally, 34 RCT trials were retrieved, including 6 cross-over RCTs and 8 paralleled -ones. Among them, 23 explicitly mentioned the process of informed consent. The sample size ranged from 9 to 539, and there were 32 experiments with a sample size of less than 160 people. Thirty-three trials were observed for at most three months, and only one study lasted for a year. Thirteen trials found the positive effects of OLP, while two failed to show the effectiveness. Still nineteen trials didn’t give any conclusive results about the effects as OLP is just one of the comparison groups. A total of 21 trials were conducted on diseases with symptoms,such as depression, pain, itching, test anxiety, rhinitis subjective symptoms etc.

Conclusions: So far, most of the OLP design still mainly focus the short-term and subjective outcomes with relatively small sample size OLP might be effective for a variety of diseases with temporarily no specific drugs and no side effects, which can avoid the nocebo phenomenon in controlled trials and ethically guarantee the right of subjects to know. It could be a new advance in the field of placebos. The mechanism of OLP positive reaction may be related to positive hints, doctor-patient relationship, prediction and error processing(PEP), neurobiological factors, spontaneous remission, regression mean effect, Hawthorne effect, etc.
For RCTs of TCM, doubling blinding is always challenged by preparing perfect stimulator for placebo. Besides, some argues TCM is lack of specific effects beyond of placebo effects. In these circumstances, OLP could be one solution.

Patient or healthcare consumer involvement: There was no patients participated in this study. The OLP conceptions relates to patients' welfare.