A novel acute toxicity resulting from the administration of morphine and Adriamycin to mice

The toxic potential of the combination of morphine and Adriamycin (doxorubicin) has been evaluated in mice. Intravenous administration of 20 or 40 mg Adriamycin/kg resulted in a dose-related mortality beginning 4 days postdose. Increasing the dose of Adriamycin to 75 mg/kg caused a biphasic mortality pattern, with 30% of the animals dying within 30 min of drug treatment. Pretreatment with morphine (20 mg/kg) reduced by 80% the dose of Adriamycin required to induce a 30% mortality at 30 min post-Adriamycin administration. Morphine pretreatment also caused a dose-dependent increase in plasma Adriamycin, as measured by total plasma fluorescence. Morphine or Adriamycin administered alone resulted in a slight hematocrit increase. The combination of morphine and Adriamycin caused an increase in hematocrit to maximal levels of approximately 75% from basal levels of about 48%. The increase in hematocrit after morphine plus Adriamycin exceeded the rise caused by higher doses of Adriamycin which, without morphine, resulted in similar plasma Adriamycin levels. The temporal relationship between the elevated hematocrit and early (30 min) mortality suggest a cause/effect relationship between these two events following combined morphine plus Adriamycin treatment.