The Special Case of High-Altitude Headache

Placebo responses have been widely studied in the clinical context and across a variety of different systems. Recent research has shown that placebos and nocebos induce powerful psychological effects that can change the physiology of different body functions and that these changes follow very similar pathways as those induced by drugs. For example, placebo and nocebo effects have been shown to affect both the clinical symptoms and the related biochemical and physiological changes of high-altitude hypoxia headache, where positive or negative expectations lead to the suppression or enhancement of the cyclooxygenase (COX)-prostaglandin (PG) pathway which, in turn, induces pain amelioration or worsening, respectively. High-altitude headache is one of the core neurological hallmarks of the acute mountain sickness (AMS) syndrome and is associated with the ascent to high altitudes and the concomitant drop in atmospheric oxygen pressure. Cellular hypoxia due to reduced barometric pressure seems to be the common final pathway for headache as altitude increases. Within this context, the high-altitude or hypobaric hypoxia headache model represents an extremely valuable opportunity to investigate placebo effects at high altitude, as it represents a borderline condition between the clinical and the experimental setting and allows to induce a clinical condition by bringing healthy subjects from a region of high oxygen pressure (sea level, 159 mmHg) to a region of lower oxygen pressure (high altitude, e.g., 3500 m, 102 mmHg), ruling out ethical constraints. Interestingly, placebo and nocebo research relying on the hypoxia headache model has shown how positive or negative psychosocial cues represent crucial triggers for the decrease and increase in perceived headache and salivary COX products, respectively, suggesting how placebo and nocebo responses are in all respects both psychological and biological phenomena.