Evaluation of histamine release during constant rate infusion of morphine in dogs

Objective: To evaluate histamine release and selected physiologic variables during constant rate infusion (CRI) of morphine in dogs. Animals: Five healthy, conscious, intact female dogs. Material and methods: Using a Latin square, repeated-measures design, dogs were randomly assigned to three treatment groups to receive a 4-hour CRI of saline (SAL), or a loading dose of morphine at 0.3 mg kg^-1 (LM), or 0.6 mg kg^-1 (HM), followed by an infusion of 0.17 mg kg^-1 hour^-1 (LM) and 0.34 mg kg^-1 hour^-1 (HM) respectively. Dogs received each of the three treatments at intervals of at least 7 days. Plasma histamine concentration, skin flushing, edema and wheals, heart rate and rhythm and non-invasive arterial blood pressure were measured before the loading dose and at 1, 2, 5, 15, 30, 60, 120, 180 and 240 minutes during the CRI, or at the time of occurrence. Results: The loading dose induced the highest histamine release in the HM group being statistically higher than the SAL group. The histamine release obtained in the LM group after the loading dose did not differ from SAL. During the infusion, plasma histamine levels were numerically higher in the LM group. Besides one dog that developed hypotension for 2 minutes after the loading dose in the HM group and one dog that showed occasional ventricular premature contractions during both morphine infusions, cardiovascular variables were similar among the three treatment groups. Conclusions and clinical relevance: Both doses of morphine induced variable histamine release with minimal adverse cardiovascular effects in these concious, healthy dogs. The plasma histamine levels obtained may be associated with significant hemodynamic changes in patients with limited cardiovascular reserve and sympathetic nervous tone.