Effect of metamizol on morphine pharmacokinetics and pharmacodynamics after acute and subchronic administration in arthritic rats

The aim of the present study was to investigate whether metamizol alters the pharmacokinetics of morphine and to determine the relationship between morphine plasma levels and antinociceptive effect produced after co-administration of drugs under acute and subchronic treatments using the pain-induced functional impairment model in rat (PIFIR model). Administration of morphine + metamizol under acute treatment produced a significantly higher antinociceptive effect than that obtained with morphine alone (P < 0.05). This effect remained unaltered after subchronic treatments for 6 and 12 days. In addition, after the simultaneous administration of the drugs in a single dose, a pharmacokinetic interaction was found, which significantly (P < 0.001) increased maximum plasma concentration (Cmax), concentration at 4 h (C4h), partial areas under the plasma concentration–time curve from zero to 4 h (AUC0–4) and from zero to 24 h (AUC0–24). Moreover, whereas plasma concentration of morphine markedly decreased up to 4 h (C4h) after subchronic administration of the opioid, multiple dosing of the morphine + metamizol combination produced an accumulation of the drug in plasma (P < 0.001). The increase observed in morphine plasma levels after co-administration of metamizol may be explained by a possible enzymatic inhibition of the glucuronosyl–transferase system involved in the metabolism of morphine. This study reveals both a pharmacodynamic and a pharmacokinetic interaction between morphine and metamizol, leading to an increased antinociceptive effect and a delay in tolerance development.