A Risk-Benefit Assessment of Paracetamol (Acetaminophen) Combined with Caffeine

Abstract

Paracetamol/caffeine (1,000 mg/130 mg) is effective and safe for use in acute management of pain. The hepatotoxicity of overdoses of paracetamol results from its oxidative metabolism, caffeine does not produce any increase in oxidative metabolism of therapeutic concentrations of paracetamol.

Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

“…It was found that CAF slightly enhances the inhibitory effects of APAP on genes involved in pain perception and modulation ( Figure 7). These results may explain the observed increase in the clinical efficacy of APAP at the cellular scale induced by co‐administration of CAF 8, 9, 10…”

“…A mean toxic dose of APAP (34 g) was identified in literature at a sublethal level,32, 33 whereas the dose level of CAF (4.4 g) was derived from a relative dose ratio of 1000:130, according to therapeutic indications used in drug combination therapy 8, 9, 10. Note that APAP and CAF are frequently co‐administered because CAF is supposed to enhance the analgesic effect of APAP 8, 9, 10…”

“…Note that APAP and CAF are frequently co‐administered because CAF is supposed to enhance the analgesic effect of APAP 8, 9, 10…”

“…From a therapeutic perspective, CAF is expected to increase the analgesic effect of APAP in humans 8, 9, 10. To explore this effect in our model, PD responses on pain‐related genes35 were predicted for single‐administration and co‐administration of APAP and CAF, respectively, by applying dose levels up to a maximum daily dose (APAP: 4,000 mg, Drugs.com; APAP/CAF: 4,000 mg/520 mg)8 ( Figure 7).…”

“…PICD was applied for a co‐administration of APAP and CAF with a relative dose ratio of 1000:130, according to therapeutic indications 8, 9. When both drugs were given concomitantly, the PICD‐based PD response of APAP ( ${\mathrm{P}\mathrm{D} \mathrm{r}\mathrm{e}\mathrm{s}\mathrm{p}\mathrm{o}\mathrm{n}\mathrm{s}\mathrm{e}}_{\mathrm{D}\mathrm{D}\mathrm{I}}\left(\mathrm{normalA}\mathrm{normalP}\mathrm{normalA}\mathrm{normalP}\right)$) were adjusted according to its changed concentration‐time profile caused by the competitive inhibition of CAF on ABCB1‐mediated and CYP2E1‐mediated transport and metabolization of APAP, respectively 5, 7, 16, 19.…”