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Different Placebos, Different Mechanisms, Different Outcomes: Lessons for Clinical Trials.

ABSTRACT: Clinical trials use placebos with the assumption that they are inert, thus all placebos are considered to be equal. Here we show that this assumption is wrong and that different placebo procedures are associated to different therapeutic rituals which, in turn, trigger different mechanisms and produce different therapeutic outcomes. We studied high altitude, or hypobaric hypoxia, headache, in which two different placebos were administered. The first was placebo oxygen inhaled through a mask, whereas the second was placebo aspirin swallowed with a pill. Both placebos were given after a conditioning procedure, whereby either real oxygen or real aspirin was administered for three consecutive sessions to reduce headache pain. We found that after real oxygen conditioning, placebo oxygen induced pain relief along with a reduction in ventilation, blood alkalosis and salivary prostaglandin (PG)E2, yet without any increase in blood oxygen saturation (SO2). By contrast, after real aspirin conditioning, placebo aspirin induced pain relief through the inhibition of all the products of cyclooxygenase, that is, PGD2, PGE2, PGF2, PGI2, thromboxane (TX)A2, without affecting ventilation and blood alkalosis. Therefore, two different placebos, associated to two different therapeutic rituals, used two different pathways to reduce headache pain. The analgesic effect following placebo oxygen was superior to placebo aspirin. These findings show that different placebos may use different mechanisms to reduce high altitude headache, depending on the therapeutic ritual and the route of administration. In clinical trials, placebos and outcome measures should be selected very carefully in order not to incur in wrong interpretations.

SUBMITTER: Benedetti F

PROVIDER: S-EPMC4633056 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Different Placebos, Different Mechanisms, Different Outcomes: Lessons for Clinical Trials.

Benedetti Fabrizio F Dogue Sara S

PloS one 20151104 11

Clinical trials use placebos with the assumption that they are inert, thus all placebos are considered to be equal. Here we show that this assumption is wrong and that different placebo procedures are associated to different therapeutic rituals which, in turn, trigger different mechanisms and produce different therapeutic outcomes. We studied high altitude, or hypobaric hypoxia, headache, in which two different placebos were administered. The first was placebo oxygen inhaled through a mask, wher ...[more]

PMID: 26536471

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Project description:BackgroundTrial participants in placebo groups report experiencing adverse events (AEs). Existing systematic reviews have not been synthesized, leaving questions about why these events occur as well as their prevalence across different conditions unanswered.Objectives(1) To synthesize the evidence of prevalence of AEs in trial placebo groups across different conditions. (2) To compare AEs in trial placebo groups with AEs reported in untreated groups within a subset of randomized trials.Search methodsWe searched PubMed for records with the word "nocebo" in the title and "systematic" in any field. We also contacted experts and hand-searched references of included studies.Study eligibilityWe included any systematic review of randomized trials where nocebo effects were reported. We excluded systematic reviews of non-randomized studies.Participants and interventionsWe included studies in any disease area.Study appraisal and synthesis methodsWe appraised the quality of the studies using a shortened version of the Assessment of Multiple Systematic Reviews tool (AMSTAR) tool. We reported medians and interquartile ranges (IQRs) of AEs. Among the trials within the review that included untreated groups, we compared the prevalence of AEs in untreated groups with the prevalence of AEs in placebo groups.ResultsWe identified 20 systematic reviews. These included 1271 randomized trials and 250,726 placebo-treated patients. The median prevalence of AEs in trial placebo groups was 49.1% (IQR 25.7-64.4%). The median rate of dropouts due to AEs was 5% (IQR 2.28-8.4%). Within the 15 of trials that reported AEs in untreated groups, we found that the AE rate in placebo groups (6.51%) was higher than that reported in untreated groups (4.25%).LimitationsThis study was limited by the quality of included reviews and the small number of trials that included untreated groups.Conclusions and implications of key findingsAEs in trial placebo groups are common and cannot be attributed entirely to natural history. Trial methodologies that reduce AEs in placebo groups while satisfying the requirement of informed consent should be developed and implemented.

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Different Placebos, Different Mechanisms, Different Outcomes: Lessons for Clinical Trials.

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Different Placebos, Different Mechanisms, Different Outcomes: Lessons for Clinical Trials.

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