Systemic inflammation decreases pain threshold in humans in vivo

Abstract

Background: Hyperalgesia is a well recognized hallmark of disease. Pro-inflammatory cytokines have been suggested to be mainly responsible, but human data are scarce. Changes in pain threshold during systemic inflammation evoked by human endotoxemia, were evaluated with three quantitative sensory testing methods.

Methods and results: Pressure pain thresholds, electrical pain thresholds and tolerance to the cold pressor test were measured before and 2 hours after the intravenous administration of 2 ng/kg purified E. coli endotoxin in 27 healthy volunteers. Another 20 subjects not exposed to endotoxemia served as controls. Endotoxemia led to a rise in body temperature and inflammatory symptom scores and a rise in plasma TNF-α, IL-6, IL-10 and IL-1RA. During endotoxemia, pressure pain thresholds and electrical pain thresholds were reduced with 20 ± 4 % and 13 ± 3 %, respectively. In controls only a minor decrease in pressure pain thresholds (7 ± 3 %) and no change in electrical pain thresholds occurred. Endotoxin-treated subjects experienced more pain during the cold pressor test, and fewer subjects were able to complete the cold pressor test measurement, while in controls the cold pressor test results were not altered. Peak levels and area under curves of each individual cytokine did not correlate to a change in pain threshold measured by one of the applied quantitative sensory testing techniques.

Conclusions and significance: In conclusion, this study shows that systemic inflammation elicited by the administration of endotoxin to humans, results in lowering of the pain threshold measured by 3 quantitative sensory testing techniques. The current work provides additional evidence that systemic inflammation is accompanied by changes in pain perception.

Figure 1. Plasma cytokine levels during human endotoxemia.

Data expressed as mean±SEM. At T=0 h endotoxin was administered. A: TNF-α, B: IL-10, C: IL-6, D: IL-1RA. h: hours.

Figure 2. Relative change in pain thresholds during human endotoxemia.

A: combined pain pressure threshold (PPT) and B: combined electrical pain threshold (EPT) measured 2 hours after endotoxin administration. Values are depicted as percentage change from baseline (-1 h), where baseline was set at 100%. White bars: control subjects, black bars: endotoxin treated subjects. Data expressed as mean±SEM. h: hours.

Figure 3. Change in tolerance to the cold pressor test during human endotoxemia.

A and B: Amount of discomfort in response to immersion of one hand in ice water, rated on a 0-10 numeric rating scale (NRS). C and D: Percentage of subjects with hand in ice water. Open circles: . T=-1 hour (before endotoxin treatment), black dots: T=2 hours, (after endotoxin treatment). A and C: results in endotoxin treated group, B and D: results in control group.