High-altitude, or hypobaric hypoxia, headache has recently emerged as an interesting model to study placebo and nocebo responses, and particularly their peripheral mechanisms. In this study, we analyze the response of this type of headache to either real or sham (placebo) oxygen (O2) administration at an altitude of 3500 m, where blood oxygen saturation (SO2) drops from the normal value of about 98% to about 85%. In a trial in which a double-blind administration of either 100% O2 or sham O2 was administered, we tested pre- and post-exercise headache, along with fatigue, heart rate (HR) responses, and prostaglandin E2 (PGE2) salivary concentration. Although real O2 breathing increased SO2 along with a decrease in pre- and post-exercise headache, fatigue, HR, and PGE2, placebo O2 changed neither pre-/post-exercise headache nor SO2/HR/PGE2, but it decreased fatigue. However, in another group of subjects, when sham O2 was delivered after 2 previous exposures to O2 (O2 preconditioning), it decreased fatigue, post-exercise headache, HR, and PGE2, yet without any increase in SO2. Three main findings emerge from these data. First, placebo O2 is effective in reducing post-exercise headache, along with HR and PGE2 decrease, only after O2 preconditioning. Second, pre-exercise (at rest) headache is not affected by placebo O2, which emphasizes the limits of a placebo treatment at high altitude. Third, fatigue is affected by placebo O2 even without prior O2 conditioning, which suggests the higher placebo sensitivity of fatigue compared with headache pain at high altitude.
Sham (placebo) oxygen reduces high-altitude headache and prostaglandin E2 only after oxygen preconditioning, highlighting the important role of learning in placebo analgesia.
aDepartment of Neuroscience, University of Turin Medical School, Turin, Italy
bINN-CNR Plateau Rosa Laboratories, Breuil-Cervinia/Zermatt, Italy/Switzerland
cGiancarlo Quarta Foundation, Milan, Italy
Corresponding author. Address: Department of Neuroscience, University of Turin Medical School, Corso Raffaello 30, 10125 Turin, Italy. Tel.: +39 011 6708492; fax: +39 011 6708174. E-mail address: fabrizio.benedetti@unito.it (F. Benedetti).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received April 17, 2015
Received in revised form June 13, 2015
Accepted June 26, 2015
