The effect of benzodiazepines on the analgesic effect of morphine and sodium salicylate

Using the phenylquinone writhing method as a criterion for analgesia in mice, oral administration of chlordiazepoxide, clonazepam and flurazepam produced large analgesic ED₅₀ values. No analgesic activity could be detected for diazepam, nitrazepam or medazepam up to 500 mg/kg. Chlordiazepoxide enhanced morphine analgesia while the other benzodiazepines produced a significant reduction. Both chlordiazepoxide and clonazepam increased the analgesic activity of sodium salicylate, while nitrazepam reduced its activity. Diazepam, medazepam and flurazepam did not alter the analgesic activity of sodium salicylate. From the time course of action studies, all benzodiazepines increased the activity of morphine during the first 15 min after administration but reduced its activity from 45 min onwards. In this respect the benzodiazepines produced a biphasic effect on morphine analgesia. A complex picture was seen when the benzodiazepines were combined with sodium salicylate. Nitrazepam was the only compound not to prolong the analgesic activity of sodium salicylate. It is concluded that the benzodiazepines, although structurally similar, produce differing pharmacological effects when used in conjunction with analgesic agents.