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Enhancement of analgesia from systemic opioid in humans by spinal cholinesterase inhibition.

Intravenous opioids cause analgesia and increase release of ACh in spinal cord dorsal horn in animals, and these effects are enhanced by intrathecal neostigmine injection. The purpose of the current study was to test whether intrathecal neostigmine enhanced analgesia and increased cerebrospinal fluid concentrations of ACh over those induced by i.v. alfentanil in volunteers, and also to test whether neostigmine enhanced alfentanil-induced side effects. After human studies committee approval, 40 healthy volunteers received an intrathecal injection of saline or neostigmine (50, 100 or 200 microg) followed in 60 min by a computer-controlled, stepped i.v. infusion of alfentanil to escalating targeted plasma concentrations. Pain report to hand and foot immersion in ice water, sedation, nausea, weakness, vital signs, end-tidal CO2 and oxyhemoglobin saturation were measured 60 min after spinal injection and at the end of each 20-min alfentanil infusion. Cerebrospinal fluid was sampled once after drug administration. Intrathecal neostigmine alone caused analgesia in the foot but not in the hand, and was accompanied by leg weakness, whereas IV alfentanil alone caused equivalent analgesia in both the hand and the foot and was accompanied by nausea, sedation, increased end-tidal CO2 and decreased oxyhemoglobin saturation. Neostigmine enhanced analgesia but not respiratory effects induced by i.v. alfentanil; it also enhanced nausea and sedation. Intravenous alfentanil increased cerebrospinal fluid ACh concentration, and neostigmine enhanced this change. These data in humans are consistent with a spinal cholinergic mechanism of i.v. opioid analgesia. Because neostigmine enhances both analgesia and side effects induced by i.v. alfentanil, the clinical utility of their use in combination will depend on the relative strength of these interactions.