Paracetamol CSF Pharmacokinetics Study

A Single Centre Prospective Randomised Study to Investigate the Cerebrospinal Fluid (CSF) Pharmacokinetics of Intravenous Paracetamol in Humans

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.

Study Overview

• Status: Completed
• Conditions: Paracetamol
• Intervention / Treatment: Drug: Administration 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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, EC1A
    • St Bartholomew's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Sampling at approx 15 minutes; Plasma and CSF samples to be taken at 15 minutes post administration of intravenous paracetamol	Drug: Administration of paracetamol; Administration of 1g intravenous paracetamol; Other Names: Perfalgan
ACTIVE_COMPARATOR: Sampling at approx 30 minutes; Plasma and CSF samples to be taken at 30 minutes post administration of intravenous paracetamol	Drug: Administration of paracetamol; Administration of 1g intravenous paracetamol; Other Names: Perfalgan
ACTIVE_COMPARATOR: Sampling at approx 120minutes; Plasma and CSF samples to be taken at 120 minutes post administration of intravenous paracetamol	Drug: Administration of paracetamol; Administration of 1g intravenous paracetamol; Other Names: Perfalgan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of AM404 in CSF	AM404 is a metabolite of paracetamol thought to be formed in the brain.	5-211 minutes post-administration of paracetamol

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of paracetamol in plasma and CSF	Concentrations of paracetamol measured in plasma and CSF following intravenous paracetamol administration.	5-211 minutes post administration of paracetamol
Measurement of paracetamol glucuronide and sulphate conjugates in plasma and CSF.	Concentrations of glucuronide and sulphate conjugates of paracetamol measured in plasma and CSF following intravenous paracetamol administration.	5-211 minutes post administration of paracetamol

Collaborators and Investigators

• Sponsor: Barts & The London NHS Trust
• Investigators: Study Director: Vivek Mehta, MD, Pain and Anaesthesia Research Centre, Barts Health NHS Trust

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (ACTUAL): August 1, 2011
• Study Completion (ACTUAL): November 1, 2011

Study Registration Dates

• First Submitted: March 27, 2013
• First Submitted That Met QC Criteria: March 27, 2013
• First Posted (ESTIMATE): April 1, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): April 4, 2013
• Last Update Submitted That Met QC Criteria: April 2, 2013
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Keywords: pharmacokinetics; acetaminophen; paracetamol; CSF; AM404
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: 7258 (Other Grant/Funding Number: DHHS)