Tolerance and physical dependence to a short-acting benzodiazepine, midazolam

Midazolam is a new ultra short-acting benzodiazepine whose physical dependence properties have not been well characterized. Our laboratory has demonstrated previously that physical dependence to the long-acting chlordiazepoxide in the rat is inducible by a single intoxicating dose, whereas maximal dependence required chronically equivalent maximally tolerable dosing b.i.d. for 5 weeks. Based on the methods developed in our laboratory to quantify benzodiazepine intoxication and withdrawal, Trs were designed to evaluate midazolam's capacity to induce dependence in the rat after definable acute (120 mg/kg p.o.), sub-acute (120 mg/kg q.i.d. x 3 days) and chronic (120-180 mg/kg bid. x 5 weeks) dosing that was near maximally tolerable. A single dose of midazolam failed to produce withdrawal signs. Tolerance and dependence increased as a function of midazolam dose and duration of Tr.