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

Pickering, Gisèle; Kastler, Adrian; Macian, Nicolas; Pereira, Bruno; Valabrègue, Romain; Lehericy, Stéphane; Boyer, L.; Dubray, Claude

doi:10.2147/dddt.s81004

Cited by 19 publications

(28 citation statements)

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“…Our study found that at rest, paracetamol FAAH-dependently decreased many spontaneous functional connections between critical structures involved in pain in subcortical regions such as the striatum, thalamus, PAG, the BNST, hippocampus, and basal forebrain region together with somatosensory, retrosplenial, cingulate, and insular cortices. In addition, the pain-evoked connectome observed during a noxious stimulation was drastically decreased in paracetamol-treated animals, again by an FAAH-dependent mechanism, suggesting that AM404 production by FAAH (Högestätt et al, 2005) (Pickering et al, 2015). Nevertheless, although these studies show that paracetamol can reduce pain-related activity of brain structures, they do not discriminate between peripheral and central location of its effect.…”

Section: Brain Connectome Modification During Paracetamol Challengementioning

confidence: 74%

“…Concerning paracetamol, a clinical Tc 99m SPECT imaging study reported a decrease in pain rating associated with a reduction of the cerebral blood flow in thalamus prefrontal cortex, sensorimotor area, anterior cingulate, and caudate nucleus after postoperative dental surgery in patients treated with paracetamol (Newberg et al, ). In addition, a clinical rs‐fMRI study performed in healthy volunteers demonstrated that paracetamol, compared with placebo, significantly reduced the pain‐related BOLD signal responses arising from noxious thermal stimulation, in insula, anterior cingulate cortices, prefrontal cortex, and thalamus (Pickering et al, ). Nevertheless, although these studies show that paracetamol can reduce pain‐related activity of brain structures, they do not discriminate between peripheral and central location of its effect.…”

Section: Discussionmentioning

confidence: 99%

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Paracetamol is a centrally acting analgesic using mechanisms located in the periaqueductal grey

Barrière

Boumezbeur

Dalmann

et al. 2020

British J Pharmacology

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Background and Purpose We previously demonstrated that paracetamol has to be metabolised in the brain by fatty acid amide hydrolase enzyme into AM404 (N‐(4‐hydroxyphenyl)‐5Z,8Z,11Z,14Z‐eicosatetraenamide) to activate CB1 receptors and TRPV1 channels, which mediate its analgesic effect. However, the brain mechanisms supporting paracetamol‐induced analgesia remain unknown. Experimental Approach The effects of paracetamol on brain function in Sprague‐Dawley rats were determined by functional MRI. Levels of neurotransmitters in the periaqueductal grey (PAG) were measured using in vivo 1H‐NMR and microdialysis. Analgesic effects of paracetamol were assessed by behavioural tests and challenged with different inhibitors, administered systemically or microinjected in the PAG. Key Results Paracetamol decreased the connectivity of major brain structures involved in pain processing (insula, somatosensory cortex, amygdala, hypothalamus, and the PAG). This effect was particularly prominent in the PAG, where paracetamol, after conversion to AM404, (a) modulated neuronal activity and functional connectivity, (b) promoted GABA and glutamate release, and (c) activated a TRPV1 channel‐mGlu5 receptor‐PLC‐DAGL‐CB1 receptor signalling cascade to exert its analgesic effects. Conclusions and Implications The elucidation of the mechanism of action of paracetamol as an analgesic paves the way for pharmacological innovations to improve the pharmacopoeia of analgesic agents.

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Section: Brain Connectome Modification During Paracetamol Challengementioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Paracetamol is a centrally acting analgesic using mechanisms located in the periaqueductal grey

Barrière

Boumezbeur

Dalmann

et al. 2020

British J Pharmacology

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“…A number of brain regions and cerebral interconnections have been described to be involved in predecisional processing and planning actions: parietal-frontal circuits, anterior cingulate and orbitofrontal cortices, and hippocampus 19,20. These cerebral areas and others are also activated during the pain experience; they belong to the pain matrix and have been shown to be deactivated by APAP as described by a recent functional magnetic resonance imaging study 18,21. Evidence from pharmacological experiments in humans has underlined the complex roles of dopamine and serotonin in decision making 22.…”

Section: Discussionmentioning

confidence: 99%

“…This test was chosen in the context of APAP effect on central structures looking for potential improvement of matching 18. The chosen outcome was the total number of trials for which the subject selected the correct stimulus on his or her first response when the target stimulus and the three distractors were presented after the stimulus had been hidden with delays of 0, 4,000, and 12,000 ms. A higher score is better.…”

Section: Methodsmentioning

confidence: 99%

Paracetamol sharpens reflection and spatial memory: a double-blind randomized controlled study in healthy volunteers

Pickering¹,

Macian²,

Dubray³

et al. 2016

DDDT

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BackgroundAcetaminophen (APAP, paracetamol) mechanism for analgesic and antipyretic outcomes has been largely addressed, but APAP action on cognitive function has not been studied in humans. Animal studies have suggested an improved cognitive performance but the link with analgesic and antipyretic modes of action is incomplete. This study aims at exploring cognitive tests in healthy volunteers in the context of antinociception and temperature regulation. A double-blind randomized controlled study (NCT01390467) was carried out from May 30, 2011 to July 12, 2011.MethodsForty healthy volunteers were included and analyzed. Nociceptive thresholds, core temperature (body temperature), and a battery of cognitive tests were recorded before and after oral APAP (2 g) or placebo: Information sampling task for predecisional processing, Stockings of Cambridge for spatial memory, reaction time, delayed matching of sample, and pattern recognition memory tests. Analysis of variance for repeated measures adapted to crossover design was performed and a two-tailed type I error was fixed at 5%.ResultsAPAP improved information sampling task (diminution of the number of errors, latency to open boxes, and increased number of opened boxes; all P<0.05). Spatial planning and working memory initial thinking time were decreased (P=0.04). All other tests were not modified by APAP. APAP had an antinociceptive effect (P<0.01) and body temperature did not change.ConclusionThis study shows for the first time that APAP sharpens decision making and planning strategy in healthy volunteers and that cognitive performance and antinociception are independent of APAP effect on thermogenesis. We suggest that cognitive performance mirrors the analgesic rather than thermic cascade of events, with possibly a central role for serotonergic and cannabinoid systems that need to be explored further in the context of pain and cognition.

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“…Ottani et al [17] suggested that paracetamol could also have an effect on the endogenous cannabinoid system involving CB 1 receptors in the brain or spinal cord. Paracetamol also might inhibit pain sensation by decreasing the activation of higher brain structures (eg, anterior cingulate cortex or prefrontal cortices) involved in pain and cognitive/ affective processing [18].…”

Section: Summary Of the Evidence On Performancementioning

confidence: 99%

Analgesics and Sport Performance: Beyond the Pain‐Modulating Effects

Holgado

Hopker

Sanabria

et al. 2017

PM&R

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1Analgesics are widely used in sport to treat pain and inflammation associated with injury. However, there 2 is growing evidence that some athletes might be taking these substances in an attempt to enhance Introduction 18There is little doubt that when exercise is performed above certain intensities, or over a prolonged period 19 of time, it causes feeling of pain and discomfort. Sayings such as 'no pain, no gain' are often heard in 20 relation to both training and competition settings across a variety of different sports. Indeed, these 21 feelings of exercise-induced pain have been shown to have a negative effect on training and performance 22 [1]. As a consequence, there has been a trend for athletes from all levels and ages to use pharmacological 23 analgesics substances prior to training and competition up to 4-fold more than their age-matched general 24 population [2]. The general term analgesic covers a variety of different pharmacological substances, 25 including non-steroidal anti-inflammatory drugs (NSAIDs), non-opioid analgesic (such as paracetamol 26 2 and others), weak opioids (for example tramadol, codeine or morphine [3]) and orally administered or 27 injected glucorticosteroids [4,5]. Indeed, paracetamol and NSAIDs are one of the most recurrent groups 28 of pharmacological substances used by athletes ranging from 11 up to 92% [6,7]. For instance, it is 29 common for athletes with minor injuries to continue training and even competing, by treating their minor 30 health issues with analgesic [8]. 31The aforementioned negative association between pain and exercise capacity increases the likelihood of 32 analgesic use as a method to increase the level of performance during competition [5,9]. Furthermore, the 33 trends for more frequent use of analgesics in-competition vs. out-competition, use of more than one drug 34 at the same time, and administration of these medications at supratherapeutic dosages, all suggest athletes 35 may be using these analgesics as ergogenic aids [4,5]. Therefore, in contrast to the post-exercise use of 36 analgesics to accelerate recovery, there is potential for their prophylactic use as a potential performance 37 enhancing intervention. In comparison to what is known about the use of analgesics for treating sporting 38 injury [10,11], much less is known about their effects on exercise related physiology and performance 39 [12][13][14]. However, as analgesics exert a pharmacological action on key physiological systems related to 40 exercise performance, a theoretical rationale exists whereby these drugs could provide a significant 41 ergogenic effect. 42 Material and methods 43The aim of this manuscript was to review the literature and evaluate the evidence for the ergogenic effect 44 of analgesics, expected dosages, and potential side effects. A computer search of scientific databases 45 (PubMed, Web of Science, ScienceDirect and Scopus) was made for English language articles 46 investigating the use of analgesics in sport for all period of time up to September 2...

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

Cited by 19 publications

References 50 publications

Paracetamol is a centrally acting analgesic using mechanisms located in the periaqueductal grey

Paracetamol is a centrally acting analgesic using mechanisms located in the periaqueductal grey

Paracetamol sharpens reflection and spatial memory: a double-blind randomized controlled study in healthy volunteers

Analgesics and Sport Performance: Beyond the Pain‐Modulating Effects

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