Clinical trial NCT01520792: Paracetamol and Pharmacogenetic
Official title: Paracétamol and Pharmacogenetic in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: pharmacogenetic of paracetamol
Pain threshold
Lead sponsor: University Hospital, Clermont-Ferrand
Sponsor class: OTHER
First posted: 2012-01-30
Enrollment: 100
Sex: MALE
Minimum age (years): 18
Maximum age (years): 30
Standard ages: ADULT
Accepts healthy volunteers: yes
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Recent works has emphasized that the mechanism of action of paracetamol analgesic depend on its metabolism in the body, since a breakdown product of paracetamol, the AM404 is now considered the analgesic metabolite of paracetamol suggesting as paracetamol may be a pro-drug.

Indeed, it has been shown that paracetamol may have a deleterious effect, especially in vulnerable populations (hepatic insufficiency, elderly). First results showed a very significant decrease in sulfatation and gluthatione and increased phase 1 metabolism of acetaminophen, which involves enzymes such as cytochrome P450.

Multifactorial causes, combining nutrition (depletion of sulfur amino acids), increased detoxification of toxic metabolites of paracetamol, stress or trauma are discussed to explain the results.

Clinical studies showed a great variability of pain assessment by patients and variability in the metabolic response of paracetamol. Genetic factors probably play a role remains largely unknown.

The review of the literature on genetic polymorphism shows the involvement of a number of enzymes that are well known, predominantly on the metabolism of acetaminophen liver, but without connection with its analgesic effect. This is a critical missing link in the understanding of the analgesic effect of paracetamol.

Detailed description: Randomized, single-center, placebo-controlled, double-blind, cross-over in 100 healthy volunteers meeting the inclusion criteria and receiving 2g of paracetamol orally or placebo on two study periods separated by one week.

The evaluation criterion is the difference in areas under the curve of pain thresholds to thermal and mechanical stimulations test

Eligibility criteria: Inclusion Criteria:

* Healthy volunteers
* Males
* Aged between 18 and 30 years

Exclusion Criteria:

* Subject without cons-indications of paracetamol

Primary outcomes:
measure: Correlation between Pharmacogenetic profile and pain threshold
timeFrame: until 14 days before the administration
Secondary outcomes:
measure: Measures of thermal and mechanical pain thresholds
timeFrame: until 1 hour before the administration
measure: Determination of blood concentration of gluthatione
timeFrame: until 1 hour before administration
Other outcomes:
Locations:
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand
Study officials:
affiliation: University Hospital, Clermont-Ferrand
name: Gisèle PICKERING
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pickering G, Creveaux I, Macian N, Pereira B. Paracetamol and Pain Modulation by TRPV1, UGT2B15, SULT1A1 Genotypes: A Randomized Clinical Trial in Healthy Volunteers. Pain Med. 2020 Apr 1;21(4):661-669. doi: 10.1093/pm/pnz037.