European Journal of Anaesthesiology 2005; 22: 907–912 © 2005 European Society of Anaesthesiology ISSN 0265-0215 Original Article Neurotoxicity with single dose intrathecal midazolam administration B. Ugur * , K. Basaloglu † , T. Yurtseven ¶ , U. Ates ‡ , O. N. Aydin * , D. Özenç ¶ , M. Yurtseven ‡ , A. Gürel * Adnan Menderes University Medical Faculty, Departments of * Anaesthesiology and Reanimation, † Histology and Embryology, Aydin; Ege University Medical Faculty, Departments of ¶ Neurosurgery, ‡ Histology and Embryology, Izmir, Turkey Summary Background and objective: The aim of study was to investigate the electron microscopic changes in the medulla of the spinal cord that occur with intrathecal midazolam administration. Methods: Twenty-eight albino rabbits of New Zealand type were randomized into two groups. Following anaesthesia, 16 rabbits were given 300 μg of mida- zolam (Group M) and 12 rabbits were given 0.3mL of normal saline solution (Group C) intrathecally. Eight rabbits from Group M (Group M1) and 6 rabbits from Group C (Group C1) were sacrificed 24 h after the anaes- thesia and 8 rabbits from Group M (Group M2) and 6 rabbits from Group C (Group C2) were sacrificed 6 days after the anaesthesia. The lumbosacral portion was removed by laminectomy and thin sections were examined microscopically. Results: Severe separation in myelin lamella of the large axons, honeycomb appearance, slight separation in myelin lamella of small to moderately large axons, degenerate vacuoles in the cytoplasm and nuclear membrane irregularity were observed in neurons of Groups M1 and M2. Myelin lamella and nuclear membranes were found to be regular, vacuoles and oedema were observed in the neurons in the Groups C1 and C2. Conclusion: Midazolam administered at single dose by the intrathecal route may have neurotoxic effects on the neurons and myelinated axons at 24 h and 6 days following administration. Keywords: MICROSCOPY ELECTRON; MIDAZOLAM; INJECTIONS SPINAL, intrathecal; NEUROTOXICITY; RABBITS. Introduction Intrathecal and epidural drug administration for post- operative analgesia and relief of cancer pain is widely used. Various drugs have been administered and eval- uated for intrathecal or epidural routes in animals and human beings [1–3]. The first drugs were opioids which were followed by -2 agonists such as cloni- dine, local anaesthetics and several peptides [4–6]. The development of spinal drugs such as midazolam that optimize antinociceptive effects and minimize adverse effects therefore seems desirable as an alter- native to opioids or local anaesthetics in morphine- tolerant patients [7]. Midazolam is a widely used systemic adjuvant delivered for its sedative, anxiolytic and amnesic effects [8,9]. Benzodiazepines may modulate the affinity of -aminobutyric acid (GABA) at its receptors while enhancing its control of chloride channel activity [10]. When intrathecally administered, they have relieved pain of somatic origin, produced selective sensory blockade and blocked somatosympathetic reflexes [7]. It is important to perform neurotoxicity screening in animals of compounds intended for spinal adminis- tration before performing clinical experiments in Correspondence to: Bakiye Ugur, Adnan Menderes Universitesi, Tip Fakültesi, Anesteziyoloji ve Reanimasyon Departmani 09100, Aydin, Turkey. E-mail: bakiyeugur@hotmail.com; Tel: +90 256 444 1256; Fax: +90 256 214 6495 Accepted for publication September 2005 EJA 3058