Clinical trial NCT01821872: Paracetamol CSF Pharmacokinetics Study
Official title: A Single Centre Prospective Randomised Study to Investigate the Cerebrospinal Fluid (CSF) Pharmacokinetics of Intravenous Paracetamol in Humans
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Paracetamol
Keywords: paracetamol
acetaminophen
AM404
CSF
pharmacokinetics
Lead sponsor: Barts & The London NHS Trust
Sponsor class: OTHER
First posted: 2013-04-01
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: Despite its use for decades all over the world, the exact mechanism of action of paracetamol is not fully understood and essentially involves a combination of hypotheses. It is known to have an effect via the central nervous system, and of the many mechanisms proposed, one hypothesis is that it may have indirectly activate CB1 (cannabinoid) receptors, through its novel metabolite AM404.

This study aims to elucidate cerebrospinal levels of paracetamol and to measure the concentration of its metabolites, including AM404 in CSF. This may, in turn, give us useful information on the mechanism of action of paracetamol.

Detailed description: Patients undergoing spinal blockade for urological surgery were administered 1g paracetamol intravenously at varying intervals prior to spinal anaesthesia, at which time 5mls of cerebrospinal fluid and 10mls of blood were sampled, and analysed for concentrations of paracetamol, paracetamol glucuronide, paracetamol sulphate, and AM404, a known endocannabinoid reuptake inhibitor, and metabolite of paracetamol.

Paracetamol readily penetrates into the cerebrospinal fluid in animal studies and in children. This could account for the rapid central analgesic and antipyretic action of intravenous paracetamol however this remains to be studied in adults. AM404 has never before been identified in humans, and its presence in CSF following paracetamol supports the hypothesis of a central mechanism of action of paracetamol via AM404.

Eligibility criteria: Inclusion Criteria:

* Adult subjects aged 18 to 80 years
* Subjects undergoing surgery who require a spinal anaesthetic and paracetamol as part of their routine anaesthetic plan
* Subjects with an American Society of Anesthesiology score of I-III

Exclusion Criteria:

* Subjects with any contraindication to spinal anaesthesia
* Subjects with known clotting abnormalities
* Pregnant or lactating women
* Subjects with known hypersensitivity to paracetamol
* Patients with severe hepatocellular insufficiency
* Patients already taking regular doses of paracetamol
* Any subjects deemed medically unsuitable by the investigator

Primary outcomes:
measure: Measurement of AM404 in CSF
timeFrame: 5-211 minutes post-administration of paracetamol
Secondary outcomes:
measure: Measurement of paracetamol in plasma and CSF
timeFrame: 5-211 minutes post administration of paracetamol
measure: Measurement of paracetamol glucuronide and sulphate conjugates in plasma and CSF.
timeFrame: 5-211 minutes post administration of paracetamol
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
Study officials:
affiliation: Pain and Anaesthesia Research Centre, Barts Health NHS Trust
name: Vivek Mehta, MD
role: STUDY_DIRECTOR
References: