Generic Name: neostigmine, neostigmine methylsulfate Trade Name: Neostigmine™ Drug Class: acetylcholinesterase inhibitor Manufacturer: Baxter Healthcare Corporation, Deerfield, IL 60015 Chemical Structure: see Figure 120.1 Chemical Name: dimethylcarbamate (m-hydroxyphenyl)trimethylammonium methylsulfate Chemical Formula: C12H19N2O2; molecular wt 223.294 g/mol Introduction Neostigmine methylsulfate is a cholinesterase inhibitor commonly used for reversal of non-depolarizing neuromuscular blockade. Neuraxial administration of neostigmine as an analgesic agent is still in an experimental stage. A severe nausea side effect limits its intrathecal application. Recent studies employing epidural neostigmine have reported effective analgesia, opioid, and local anesthetic sparing effects, and reduction in opioid-related side effects. Major and minor sites of action Neostigmine is approved for the reversal of non-depolarizing neuromuscular blockade. It directly inhibits acetylcholinesterase, the key enzyme responsible for deactivation of acetylcholine (Ach) in central and peripheral cholinergic synapses. Increased concentration of Ach and activation of spinal cho- linergic receptors suppress pain transmission. Following administration of neostigmine, the concentration of Ach expressed at spinal cholinergic neuronal endings is increased, resulting in measurable analgesic effects. Also, perfusion of rat spinal cord with Ach increases nitric oxide (NO) synthesis, which may also provide analgesic effects. Following epidural administration, neostigmine concentration in CSF is about 1/10 of that observed with intrathecal dosing, which may explain the reduced incidence of nausea and vomiting observed in multiple studies when using it epidurally. Receptor interaction Neostigmine offers additive analgesic effects when combined with opioids and alpha-2-adrenoceptor agonists such as clonidine. Opioids and NE receptors modulate pain via descending inhibitory fibers, whereas Ach receptors are suppressive at local interneurons. This addition of local modulation of noxious transmission may explain the opioid and local anesthetic sparing potential of neostigmine.