Dexmedetomidine as a Novel Countermeasure for Cocaine-Induced Central Sympathoexcitation in Cocaine-Addicted Humans

Abstract

Cocaine-induced acute hypertension is mediated largely by increased central sympathetic nerve activity. We hypothesized that dexmedetomidine, a central sympatholytic, reverses cocaine-induced increases in sympathetic nerve activity, mean arterial pressure (MAP), and heart rate (HR) in cocaine-addicted subjects. First, we conducted a dose-finding study in 15 nontreatment-seeking cocaine-addicted subjects and 12 cocaine-naive healthy controls to find doses of intravenous dexmedetomidine that lower MAP and HR in the absence of acute-cocaine challenge. We then conducted a placebo-controlled treatment trial in 26 cocaine-addicted subjects to determine whether dexmedetomidine reverses MAP and HR increases after intranasal cocaine (3 mg/kg). Skin sympathetic nerve activity (measured in the second protocol) and skin vascular resistance (measured in both protocols) served as indices of cocaine-sensitive central sympathoexcitation. In doses up to 0.6 µg/kg IV, dexmedetomidine alone caused comparable dose-dependent decreases in blood pressure in cases and controls but a 1.0 µg/kg dose was required to lower HR. In cocaine-addicted subjects, low-dose dexmedetomidine (0.4 µg/kg; n=14) abolished cocaine-induced increases in skin sympathetic nerve activity (156 ± 26 versus -15 ± 22%, cocaine/placebo versus cocaine/dexmedetomidine; P<0.05), skin vascular resistance (+10 ± 2 versus -2 ± 3 U; P<0.05), and MAP (+6 ± 1 versus -5 ± 2 mm Hg; P<0.01) without affecting HR (+13 ± 2 versus +9 ± 2 bpm; P=ns). When dexmedetomidine was increased to 1 µg/kg (high dose; n=12) to reverse cocaine-induced increases in HR, MAP did not fall further and increased paradoxically in 4 of 12 subjects. Thus, in a low nonsedating dose, dexmedetomidine constitutes a putative new treatment for cocaine-induced acute hypertension but higher sedating doses can increase blood pressure unpredictably during acute-cocaine challenge and should be avoided.