PHASE-I SAFETY ASSESSMENT OF INTRATHECAL NEOSTIGMINE METHYLSULFATE INHUMANS

Background: In dogs, sheep, and rats, spinal neostigmine produces anal gesia alone and enhances analgesia from alpha(2)-adrenergic agonists. This study assesses side effects and analgesia from intrathecal neosti gmine in healthy volunteers. Methods: After institutional review board approval and informed consent, 28 healthy volunteers were studied. Th e first 14 volunteers received neostigmine (50-750 mu g) through a #19 .5 spinal needle followed by insertion of a spinal catheter. The remai ning 14 volunteers received neostigmine through a #25 or #27 spinal ne edle without a catheter. Safety measurements included blood pressure, heart rate, oxyhemoglobin saturation, end-tidal carbon dioxide, neurol ogic evaluation, and computer tests of vigilance and memory. Analgesia in response to ice water immersion was measured. Results: Neostigmine (50 mu g) through the #19.5 needle did not affect any measured variab le. Neostigmine (150 mu g) caused mild nausea, and 500-750 mu g caused severe nausea and vomiting. Neostigmine (150-750 mu g) produced subje ctive leg weakness, decreased deep tendon reflexes, and sedation. The 750-mu g dose was associated with anxiety, increased blood pressure an d heart rate, and decreased end-tidal carbon dioxide. Neostigmine (100 -200 mu g) in saline, injected through a #25 or #27 needle, caused pro tracted, severe nausea, and vomiting. This did not occur when dextrose was added to neostigmine. Neostigmine by either method of administrat ion reduced visual analog pain scores to immersion of the foot in ice water. Conclusions: The incidence and severity of these adverse events from intrathecal neostigmine appears to be affected by dose, method o f administration, and baricity of solution. These effects in humans ar e consistent with studies in animals. Because no unexpected or dangero us side effects occurred, cautious examination of intrathecal neostigm ine alone and in combination with other agents for analgesia is warran ted.