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.
Highlights
The use of placebo control groups is crucial in the current methodology of clinical trials
We found no significant changes across the 4 sessions at high altitude (Fig 3), showing that all these parameters were stable over time
The ritual of the oxygen mask, acting as a conditioned stimulus (CS), associated several times with oxygen delivery, acting as the unconditioned stimulus (US), leads to a conditioned response (CR), whereby the mask ritual alone is capable of inducing the same unconditioned response (UR) of the oxygen, yet without any increase in SO2
Summary
The use of placebo control groups is crucial in the current methodology of clinical trials. High altitude, or hypobaric hypoxia, headache has emerged as an interesting model to better understand the biological underpinnings of placebo analgesia [6,7]. This kind of headache is part of a clinical condition known as acute mountain sickness (AMS), which is usually diagnosed by means of the Lake Louise Score (LLS) questionnaire [8]. This is aimed at detecting several symptoms, such as headache, nausea/vomiting, dizziness, insomnia, as well as neurological symptoms, which emphasize the complex nature of this hypoxia-related clinical syndrome. AMS is triggered by the drop in atmospheric oxygen pressure at high altitude [9,10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
