Midazolam, despite of being the commonest benzodiazepine used in anaesthesia and perioperative care, is a relatively newer addition to the list of adjuvant used in subarachnoid block. Midazolam causes spinally mediated analgesia and the segmental analgesia produced by intrathecal midazolam is mediated by the benzodiazepine-GABA receptor complex. Initial animal studies questioned the safety of intrathecal midazolam in terms of possible neurotoxicity. However subsequent clinical studies also failed to show any neurotoxicity of high dose midazolam even on long-term use. Addition of intrathecal midazolam to bupivacaine significantly improves the duration and quality of spinal anaesthesia and provides prolonged perioperative analgesia without any significant side effects. Clinical studies also reported its safety and efficacy in pregnant women, but some studies also reported mild sedation with intrathecal midazolam. It is also reported to decrease the incidence of PONV. Intrathecal midazolam does not have any clinically significant effect on perioperative hemodynamics. 1. Introduction Midazolam, synthesized by Walsar and colleagues in 1976, is the first clinically used water soluble benzodiazepine [1]. It is also the first benzodiazepine that was produced primarily for use in anaesthesia [2]. 2. Commercial Preparation Midazolam is supplied as hydrochloride salt with a pH less than 4.0 (buffered to an acidic pH of 3.5). This is important because midazolam is characterized by a pH-dependent ring-opening phenomenon in which the ring remains open at pH value of <4, thus maintaining water solubility of the drug. The ring closes at pH value of >4, as when the drug is exposed to physiologic pH, thus converting midazolam to a highly lipid-soluble drug [3] and this lipophilicity is responsible for its rapid CNS effect and large volume of distribution [4]. The hydrochloride salt of midazolam, which is formed, is soluble in aqueous solutions. The imidazole ring of midazolam is responsible for its stability in solution and rapid metabolism. 3. Mechanism of Action Midazolam exerts its effect by occupying benzodiazepine receptor that modulates γ-amino butyric acid (GABA), the major inhibitory neurotransmitter in the brain. Benzodiazepine receptors are found in the olfactory bulb, cerebral cortex, cerebellum, hippocampus, substantia nigra, inferior colliculus, brain stem, and spinal cord. There are two types of GABA receptors; benzodiazepine receptors are part of the benzodiazepine -GABAA-chloride channel receptor complex. Benzodiazepine binding site is located on the γ2
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