THE INFLUENCE OF HEMORRHAGIC-SHOCK ON THE PHARMACOKINETICS AND THE ANALGESIC EFFECT OF MORPHINE IN THE RAT

The influence of hemorrhagic shock (removal of 30% of the blood volume ) on the pharmacokinetics and the analgesic effect of morphine was inv estigated in conscious rats. Plasma concentrations of morphine after a bolus injection (5 mg/kg) are higher in the shock animals, which is a ttributed to a small decrease in clearance (-22%; P > 0.05) and a sign ificant decrease in distribution volume (-33%; P < 0.05) of the drug. The areas under the plasma concentration-time curve of the metabolite morphine-3-glucuronide (M3G) are significantly higher (+237%; P < 0.01 ) in the shock rats, which is probably explained by a decreased distri bution and renal excretion. The analgesic effect of morphine was evalu ated using the tail-flick test during a continuous infusion (10 mg/kg/ h) with measurement of the plasma concentrations of morphine and M3G. Data from these experiments show higher plasma concentrations of morph ine (+33%; P < 0.05) and M3G (+66%; P > 0.05) during shock, and a sign ificantly increased analgesic effect (+43%; P < 0.05). Our data sugges t that the increased analgesic effect of morphine during hemorrhagic s hock can most likely be explained by pharmacokinetic changes resulting in higher morphine concentrations. (C) Elsevier, Paris.