Interaction between intrathecal neostigmine and epidural clonidine in human volunteers.
BACKGROUND
alpha 2-Adrenergic agonists are thought to produce analgesia, in part, by activating spinal acetylcholine release. The purpose of the current study was to examine the interaction between intrathecal neostigmine and epidural clonidine for analgesia and side effects in humans.


METHODS
A total of 58 volunteers received an intrathecal injection of 5% dextrose in normal saline (D5NS) or neostigmine (50, 100, or 200 micrograms in D5NS), followed in 1 h by epidural saline or clonidine (computer-controlled infusion targeted to 50, 100, 200, or 400 ng/ml in cerebrospinal fluid) using an isobolographic design. Visual analog scale pain to a noxious cold stimulus, nausea, weakness, sedation, and other safety variables was measured before and at specified intervals after drug administration.


RESULTS
The first 21 volunteers randomized to receive intrathecal hyperbaric neostigmine rather than D5NS received the drug while in the sitting position, and had none-to-minimal analgesia 1 h later. The remaining volunteers received the drug while in the lateral position, and demonstrated dose-dependent analgesia in the foot 1 h later. Epidural clonidine also caused dose-dependent analgesia. The combination of neostigmine and clonidine resulted in an additive enhancement for analgesia, but no enhancement of each drug's side effects, and a reduction in clonidine-induced hypotension. Neostigmine injected into subjects in the lateral position diminished clonidine-induced reductions in blood pressure and plasma norepinephrine.


CONCLUSIONS
These results support enhancement of alpha 2-adrenergic analgesia by intrathecal neostigmine, but do not demonstrate synergy, as observed in animals. Lack of enhancement of side effects suggests this combination may be clinically useful.
Hood
D D
DD
Department of Anesthesia, Wake Forest University Medical Center, Winston-Salem, North Carolina 27157-1009, USA. dhood@bgsm.edu
Mallak
K A
KA
Eisenach
J C
JC
Tong
C
C
D000109:Acetylcholine / Q000134:cerebrospinal fluid / Q000378:metabolism; D000316:Adrenergic alpha-Agonists / Q000009:adverse effects / Q000494:pharmacology*; D000328:Adult; D015360:Analgesia, Epidural; D001794:Blood Pressure / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D003000:Clonidine / Q000009:adverse effects / Q000494:pharmacology*; D006152:Cyclic GMP / Q000134:cerebrospinal fluid; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007268:Injections, Epidural; D007278:Injections, Spinal; D009325:Nausea / Q000139:chemically induced; D009388:Neostigmine / Q000009:adverse effects / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood / Q000134:cerebrospinal fluid; D010147:Pain Measurement / Q000187:drug effects; D013268:Stimulation, Chemical
D000316:Adrenergic alpha-Agonists; D002800:Cholinesterase Inhibitors; D009388:Neostigmine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D003000:Clonidine; D000109:Acetylcholine; D009638:Norepinephrine