H J Hijma1, L M Moss2, P Gal3, D Ziagkos4, M L de Kam5, M Moerland6, G J Groeneveld7. 1. Centre for Human Drug Research, 2333 CL Leiden, The Netherlands; Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands. Electronic address: hhijma@chdr.nl. 2. Centre for Human Drug Research, 2333 CL Leiden, The Netherlands; Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands. Electronic address: lmoss@chdr.nl. 3. Centre for Human Drug Research, 2333 CL Leiden, The Netherlands; Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands. Electronic address: pgal@chdr.nl. 4. Centre for Human Drug Research, 2333 CL Leiden, The Netherlands. Electronic address: dziagkos@chdr.nl. 5. Centre for Human Drug Research, 2333 CL Leiden, The Netherlands. Electronic address: mdekam@chdr.nl. 6. Centre for Human Drug Research, 2333 CL Leiden, The Netherlands; Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands. Electronic address: mmoerland@chdr.nl. 7. Centre for Human Drug Research, 2333 CL Leiden, The Netherlands; Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands. Electronic address: GGroeneveld@chdr.nl.
Abstract
BACKGROUND AND AIMS: Following an infection, cytokines not only regulate the acute immune response, but also contribute to symptoms such as inflammatory hyperalgesia. We aimed to characterize the acute inflammatory response induced by a human endotoxemia model, and its effect on pain perception using evoked pain tests in two different dose levels. We also attempted to determine whether combining a human endotoxemia challenge with measurement of pain thresholds in healthy subjects could serve as a model to study drug effects on inflammatory pain. METHODS AND RESULTS: This was a placebo-controlled, randomized, cross-over study in 24 healthy males. Twelve subjects were administered a bolus of 1 ng/kg LPS intravenously, and twelve 2 ng/kg LPS. Before days of placebo/LPS administration, subjects completed a full study day without study drug administration, but with identical pain threshold testing. Blood sampling and evoked pain tests (electrical burst and -stair, heat, pressure, and cold pressor test) were performed pre-dose and at frequent intervals up to 10hr post-dose. Data were analysed with a repeated-measures ANCOVA. For both dose levels, LPS induced an evident acute inflammatory response, but did not significantly affect any of the pain modalities. In a post-hoc analysis, lowering of pain thresholds was observed in the first 3 h after dosing, corresponding with the peak of the acute inflammatory response around 1-3 h post-dose. CONCLUSION:Mild acute systemic inflammation, as induced by 1 ng/kg and 2 ng/kg LPS intravenous administration, did not significantly change pain thresholds in this study. The endotoxemia model in combination with evoked pain tests is not suitable to study acute inflammatory hyperalgesia in healthy males.
RCT Entities:
BACKGROUND AND AIMS: Following an infection, cytokines not only regulate the acute immune response, but also contribute to symptoms such as inflammatory hyperalgesia. We aimed to characterize the acute inflammatory response induced by a human endotoxemia model, and its effect on pain perception using evoked pain tests in two different dose levels. We also attempted to determine whether combining a human endotoxemia challenge with measurement of pain thresholds in healthy subjects could serve as a model to study drug effects on inflammatory pain. METHODS AND RESULTS: This was a placebo-controlled, randomized, cross-over study in 24 healthy males. Twelve subjects were administered a bolus of 1 ng/kg LPS intravenously, and twelve 2 ng/kg LPS. Before days of placebo/LPS administration, subjects completed a full study day without study drug administration, but with identical pain threshold testing. Blood sampling and evoked pain tests (electrical burst and -stair, heat, pressure, and cold pressor test) were performed pre-dose and at frequent intervals up to 10hr post-dose. Data were analysed with a repeated-measures ANCOVA. For both dose levels, LPS induced an evident acute inflammatory response, but did not significantly affect any of the pain modalities. In a post-hoc analysis, lowering of pain thresholds was observed in the first 3 h after dosing, corresponding with the peak of the acute inflammatory response around 1-3 h post-dose. CONCLUSION: Mild acute systemic inflammation, as induced by 1 ng/kg and 2 ng/kg LPS intravenous administration, did not significantly change pain thresholds in this study. The endotoxemia model in combination with evoked pain tests is not suitable to study acute inflammatory hyperalgesia in healthy males.
Authors: Igor Radanovic; Naomi Klarenbeek; Robert Rissmann; Geert Jan Groeneveld; Emilie M J van Brummelen; Matthijs Moerland; Jacobus J Bosch Journal: Front Oncol Date: 2022-08-29 Impact factor: 5.738