CHRONIC SUBARACHNOID MIDAZOLAM (DORMICUM) IN THE RAT - MORPHOLOGIC EVIDENCE OF SPINAL-CORD NEUROTOXICITY

Background and Objectives. In humans, the benzodiazepine midazolam has been reported to exert an antinociceptive action after subarachnoid i njections. It has been shown that subarachnoid midazolam given to rabb its produces significant pathology in spinal cord morphology, as detec ted with light microscopy. In order to further characterize these chan ges, this study was performed, using a more sensitive histologic techn ique, including electron microscopy as well as unbiased morphometry. M ethods. The histopathology of the rat lumbar spinal cord was investiga ted after chronic subarachnoid administration of a commercially availa ble preparation of midazolam. After daily injections of 100 mu g of mi dazolam, the animals were transcardially perfused on the twentieth day with a mixture of formaldehyde and glutaraldehyde. Results. Morphomet ric evaluation of cell number and mean cell volume (MCV) by the disect or method revealed a significantly lower (P < .05) cell number and a t endency toward higher MCV in the midazolam-injected group (n = 6), com pared to the rats injected with saline (n = 6). The higher MCV, in com bination with a reduced number of nerve cells, indicated a loss of sma ll neurons. The electron microscopic findings confirmed that midazolam caused neuronal death, since degenerated cell somata, fibers, and ter minals were observed in most of the rats. Furthermore, an increased nu mber of microglial cells phagocytosing nerve structures were also seen mainly in the dorsal horn. Conclusions. The authors found that chroni c subarachnoid administration of midazolam gives objective signs of ne urotoxicity in the rat spinal cord. The authors' findings are in contr ast to these of an earlier light microscopic study in the rat. The pre sent results emphasize both the necessity of morphometric and ultrastr uctural studies before spinal administration of novel drugs to humans and the neurotoxic potential of midazolam. Since neurotoxicity of mida zolam now has been demonstrated in both rats and rabbits, there may be reason to be sceptical of the use of subarachnoid midazolam in humans .