Antinociceptive interaction between alprazolam and opioids

Alprazolam is a triazolobenzodiasapine, with a potent anxiolytic action and a short half-life. Alprazolam analgesia was measured, using the radiant heat tailflick assay in mice, which was administered alone or in combination with opioids. Intrathecally administered alprazolam produced a dose-response increase in the tailflick latency with an ED₅₀ of 34 μg (19.4-72.5, 95% CL). There were almost no effects after intracerebroventricular injections. Naloxone almost completely abolished the analgesia response mediated by alprazolam. This sensitivity to naloxone indicates that at least some of the analgesic effects of alprazolam are mediated by an opioid mechanism of action. When administered together with various antagonists of opioid receptor subtypes, we found that the μ antagonists, but not the δ and κ₁ subtypes inhibited alprazolam analgesia significantly. No effect was found when alprazolam was coadministrated with κ₃ opioid agonists. In addition, we found a supra-additivity (synergistic) increase in analgesia when alprazolam was given with morphine. Competition binding assays show the highest affinity of alprazolam to the μ₁ subtype. In summary, we conclude that alprazolam mediates its analgesic effect, most probably via an μ opiate mechanism of action.