Background & Aims

Inflammation plays a crucial role in the pathophysiology of many highly prevalent clinical conditions, including chronic pain [1, 2]. While beneficial effects of positive treatment expectations are well-proven for pain and related symptoms outside the context of inflammation [3-5], expectation effects on inflammatory pain and the efficacy of anti-inflammatory drug treatments remain less well studied. We herein employed human experimental endotoxemia as an established model to study the psychobiological and immune mechanisms underlying pain and hyperalgesia during systemic inflammation that allows to test pharmaceutical treatments and psychological interventions targeting sickness symptoms [6, 7]. In a fully-balanced placebo design, we tested the hypothesis that positive expectations regarding treatment with the anti-inflammatory drug ibuprofen improve inflammation-induced hyperalgesia, and increase the efficacy of ibuprofen treatment during experimental endotoxemia.

Methods

All N=124 healthy volunteers received 0.8ng/kg endotoxin (LPS) i.v. to induce acute systemic inflammation and increased pain sensitivity. In a fully-balanced placebo design, volunteers were randomized to receive either 600mg ibuprofen or a placebo pill prior to LPS-injection (factor 1: medication). Pill administration was randomly combined with either positive or neutral verbal information to modulate treatment expectation (factor 2: expectation), resulting in a total of four experimental groups. To characterize LPS-induced immune activation, pro-inflammatory cytokines were repeatedly analyzed up to six hours after LPS-injection. Pressure pain thresholds (PPTs) were assessed as an established measure of LPS-induced hyperalgesia, and expected and perceived pain intensity was rated on visual analogue scales (VAS). As previously accomplished, PPTs were tested bilaterally for different muscle groups before and 3 hours post LPS injection, when pain sensitivity is reportedly increased [8].

Results

LPS administration led to an acute transient systemic inflammatory response with significant increases in pro-inflammatory cytokines (all p<.001, time effects). We observed the expected increase in pain sensitivity in response to LPS in all experimental groups, as reflected by decreased mean PPTs, and increased VAS pain intensity ratings for all muscle groups (all p<.001, time effects). LPS-induced hyperalgesia was significantly attenuated by ibuprofen (p<.001, time x medication interaction), while verbally induced treatment expectations did not affect pressure pain sensitivity. Remarkably, exploratory analysis of expected pain intensity revealed an effect of ibuprofen treatment: ibuprofen-treated volunteers expected PPT assessment to be less painful compared to placebo-treated volunteers (p<.01), suggesting an effect of treatment experience on symptom expectation.

Conclusions

We herein implemented a fully-balanced placebo study, allowing to test the effects of an active anti-inflammatory drug, treatment expectations, and their interaction on inflammation-induced pain. In line with previous experimental endotoxemia studies, we successfully induced hyperalgesia, reflected by decreased PPTs in all volunteers. We found that anti-inflammatory treatment with ibuprofen effectively ameliorated inflammation-induced hyperalgesia. Against our hypotheses, verbal induction of treatment expectations did not improve pain sensitivity or drug efficacy. This may indicate that in the complex context of experimental inflammation, characterized by various inflammation-induced physical and psychological symptoms, verbal suggestions are not sufficient to improve pain. Interestingly, ibuprofen treatment affected volunteers’ expectations of pain intensity during PPT testing, supporting the importance of treatment experience in shaping symptom expectations.

References

1.Grace, P.M., et al., Pathological pain and the neuroimmune interface. Nature Reviews Immunology, 2014. 14(4): p. 217-231.
2.Walker, A.K., et al., Neuroinflammation and comorbidity of pain and depression. Pharmacol Rev, 2014. 66(1): p. 80-101.
3.Peerdeman, K.J., et al., Relieving patients’ pain with expectation interventions: a meta-analysis. Pain, 2016. 157(6): p. 1179-1191.
4.Enck, P., et al., The placebo response in medicine: minimize, maximize or personalize? Nat Rev Drug Discov, 2013. 12(3): p. 191-204.
5.Atlas, L.Y. and T.D. Wager, How expectations shape pain. Neurosci Lett, 2012. 520(2): p. 140-8.
6.Lasselin, J., et al., Sick for science: experimental endotoxemia as a translational tool to develop and test new therapies for inflammation-associated depression. Molecular Psychiatry, 2021. 26(8): p. 3672-3683.
7.Schmidt, J., et al., Systemische Entzündung, „Sickness Behavior“ und Erwartungsprozesse. Der Schmerz, 2022. 36(3): p. 166-171.
8.Benson, S. and B. Karshikoff, How Can Experimental Endotoxemia Contribute to Our Understanding of Pain? A Narrative Review. Neuroimmunomodulation, 2023. 30(1): p. 250-267.

Presenting Author

Justine Schmidt

Poster Authors

Justine Schmidt

M.Sc. Psychology

Institute of Medical Education, University Hospital Essen

Lead Author

E-mail

Johanna Reinold

Dr.

Lead Author

E-mail

Sigrid Elsenbruch

Prof. Dr.

Ruhr University Bochum

Lead Author

E-mail

Oliver Witzke

Prof. Dr.

Lead Author

E-mail

Manfred Schedlowski

Prof. Dr.

Lead Author

E-mail

Harald Engler

Prof. Dr.

University Hospital Essen, Germany

Lead Author

E-mail

Sven Benson

Prof. Dr.

Lead Author

E-mail

Topics

  • Models: Acute Pain