Anticonvulsant effect of clonazepam in the dog: development of tolerance and physical dependence

Dogs were treated with clonazepam, 0.5 mg/kg orally, b.i.d., for 3-6 weeks. The development of tolerance to the anticonvulsant effect was followed by weekly determinations of the convulsive threshold by infusion of pentetrazole, 10 min after i.v. injection of 0.1 mg/kg clonazepam. In all 6 dogs tolerance was apparent after 1-2 weeks of treatment; in 1 dog the anticonvulsant effect had been totally lost after 3 weeks of treatment. Tolerance is regarded to be "functional" since the elimination half-life of clonazepam increased considerably with the duration of the treatment. One day after withdrawal of clonazepam the convulsive threshold had fallen below the control value in all dogs, but 1 week later it had recovered to the control level. Other signs of physical dependence after withdrawal were hyperthermia in 2 dogs as well as anorexia with weight loss in 5 out of the 6 dogs. In anesthetized dogs, relaxed by suxamethonium and ventilated, the effect of repeated injections of clonazepam on the EEG spiking activity maintained by an infusion of pentetrazole was studied; there was no indication for the development of acute tolerance.