Analgesic effects of systemic midazolam: comparison with intrathecal administration

Midazolam has antinociceptive effects when administered intrathecally, while its effects associated with systemic administration remain controversial. In the present study, the antinociceptive properties of systemically vs intrathecally administered midazolam were investigated in a rat model of thermal and inflammatory pain.

One hundred seventy-six (n = 8 animals per dose escalation) male Sprague-Dawley rats were instrumented with lumbar intrathecal catheters. Tail withdrawal in response to thermal stimulation, or paw flinching and shaking in response to sc hind paw formalin injection were compared following intrathecal injection of midazolam (1, 3, 10, 30, or 100 microg in 10 microL) or ip administration (3, 30, 300, or 3,000 microg in 300 microL). Saline 10 microL or 300 microL was used as a control. Behavioural side effects and motor disturbance were also examined.

Intrathecal administration of midazolam increased tail flick latency dose dependently (P < 0.05) with a 50% effective dose (ED50) of 1.60 microg, whereas ip administration did not increase latency. Both intrathecal and ip routes of administration decreased the number of paw flinches in both phases 1 and 2 of the formalin test (P < 0.05). The ED50s were 1.26 microg [confidence interval (CI), 0.35-3.18 microg], (phase 1) and 1.20 microg (CI, 0.29-3.71 microg), (phase 2) with intrathecal administration, and 11.6 microg (CI, 2.5-19.3 microg), (phase 1) and 52.2 microg (CI, 18.3-102.7 microg), (phase 2) with ip administration.

Systemically administered midazolam induced antinociception for inflammatory pain only, while intrathecal administration elicited antinociceptive effects on both acute thermal and inflammatory-induced pain.