Hormonal Mechanisms

Morphine (1–3 mg/kg) causes histamine release and sympathoadrenal activation. The release of catecholamines

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Increases in plasma histamine after morphine cause dilatation of terminal arterioles and direct positive cardiac chronotropic and inotropic actions. Hormonal alterations contribute to the cardiovascular changes seen after morphine and include an increase in cardiac index and a decrease in arterial blood pressure and systemic vascular resistance.^[214] Cardiovascular changes after morphine are similar when patients are pretreated with diphenhydramine (a histamine H₁ -antagonist) or cimetidine (a histamine H₂ -antagonist). However, in patients pretreated with both H₁ - and H₂ -antagonists, the cardiovascular responses are significantly attenuated despite comparable increases in plasma histamine concentrations. Meperidine also causes histamine release more frequently than most other opioids. Unlike morphine or meperidine, fentanyl, alfentanil, and remifentanil do not produce increases in plasma histamine, and hypotension is less frequent with these opioids. Although large doses of fentanyl produce significant increases in plasma catecholamines in dogs, large doses of fentanyl (24–75 µg/kg) decrease rather than increase plasma catecholamine and cortisol concentrations in humans.

Opioids also may have direct effects on adrenal secretory mechanisms. Gaumann and coworkers have reported that sufentanil produced 6- to 20-fold increases in adrenal vein concentrations of catecholamines and parallel increases in arterial blood pressures in cats.^[215] Although μ-opioid agonists do modulate the adrenal secretory response to pain, the adrenal secretory response to hemorrhage is preserved after sufentanil administration.