The brain signature of paracetamol in healthy volunteers: a double-blind randomized trial

Gisèle Pickering, Adrian Kastler, Nicolas Macian, Bruno Pereira, Romain Valabrègue, Stéphane Lehericy, Louis Boyer, Claude Dubray, Betty Jean, Gisèle Pickering, Adrian Kastler, Nicolas Macian, Bruno Pereira, Romain Valabrègue, Stéphane Lehericy, Louis Boyer, Claude Dubray, Betty Jean

Abstract

Background: Paracetamol's (APAP) mechanism of action suggests the implication of supraspinal structures but no neuroimaging study has been performed in humans.

Methods and results: This randomized, double-blind, crossover, placebo-controlled trial in 17 healthy volunteers (NCT01562704) aimed to evaluate how APAP modulates pain-evoked functional magnetic resonance imaging signals. We used behavioral measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli with APAP or placebo administration. Region-of-interest analysis revealed that activity in response to noxious stimulation diminished with APAP compared to placebo in prefrontal cortices, insula, thalami, anterior cingulate cortex, and periaqueductal gray matter.

Conclusion: These findings suggest an inhibitory effect of APAP on spinothalamic tracts leading to a decreased activation of higher structures, and a top-down influence on descending inhibition. Further binding and connectivity studies are needed to evaluate how APAP modulates pain, especially in the context of repeated administration to patients with pain.

Keywords: fMRI; nociception; pain; paracetamol; pharmacology.

Figures

Figure 1
Figure 1
Chronology of the study. Notes: PT: determination of pain threshold with Thermotest pathway (Medoc Ltd, Ramat Yishai, Israel). *Pain stimulation following the pain paradigm with Thermotest pathway (Medoc) and acquisition of data with fMRI 3 Tesla (recording session duration: 40 minutes). Waiting period** outside from the MRI. Abbreviations: APAP, paracetamol; min, minute(s); fMRI, functional magnetic resonance imaging; MRI, magnetic resonance imaging.
Figure 2
Figure 2
Thermal pain paradigm used in the fMRI trial. Abbreviation: fMRI, functional magnetic resonance imaging.
Figure 3
Figure 3
Flowchart of the study.
Figure 4
Figure 4
Pain matrix at baseline showing activation of left and right prefrontal cortices, dorsal anterior cingulate cortex, left and right insula, thalamus, and periaqueductal gray matter.
Figure 5
Figure 5
ROI analysis performed on physical pain regions revealed anti-nociceptive effect of APAP compared to placebo. Notes: Bar graphs demonstrate the β-values of APAP deactivation (T+100 minutes > baseline) and placebo deactivation (T+100 minutes > baseline) extracted from each cluster. β-values associated with APAP differed significantly from the β-values associated with placebo in all regions (prefrontal cortices left and right [lPRC, rPFC], anterior cingulate cortex [ACC], anterior [a], medium [m], dorsal [d]), insula left and right (lIn, rIn), and thalamus left and right (lTh, rTh) but in the periaqueductal gray matter (PAG). Abbreviations: ROI, regions-of-interest; APAP, paracetamol.

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