N‐acetylcysteine prevents glutathione decrease and does not interfere with paracetamol antinociceptive effect at therapeutic dosage: a randomized double‐blind controlled trial in healthy subjects

Paracetamol ( APAP ) may lead to hepatic changes even at therapeutic dosages. Glutathione ( GSH ) plays a pivotal role in APAP metabolism as it allows the detoxification of a toxic metabolite. N‐Acetylcysteine ( NAC ) is APAP antidote, is also largely used as a mucoactive drug and is often associated with APAP . This study aims at evaluating if 1‐ NAC modifies APAP pain efficacy and 2‐ NAC prevents glutathione depletion with APAP at therapeutic doses. This double‐blind randomized controlled study ( NCT 02206178) was carried out in 24 healthy volunteers. APAP was given for 4 days (1 g ×4 daily) with NAC or with placebo. Thermal pain tests, whole blood GSH , and hepatic enzymes ( ASAT , ALAT ) were measured before (D0) and after (D4) oral APAP ‐ NAC or APAP ‐placebo intake. anova for repeated measures adapted to cross‐overdesign was performed and a two‐tailed type I error was fixed at 5%. The primary endpoint was the area under the curve (0–240 min) of pain intensity (Numerical Scale) after thermal pain stimulation using Pathway‐Medoc ® . APAP antinociceptive effect was similar in both groups. GSH was maintained to its baseline value in the APAP / NAC group but diminished in the APAP /placebo group ( P = 0.033). This study shows for the first time that APAP antinociceptive effectiveness is not influenced by NAC . It also shows that the effect of APAP at therapeutic dosage on GSH may be counteracted by NAC . These issues are particularly important for patients as APAP is often prescribed for years as a first‐line pain treatment and further trials in patients are now warranted.