Intrathecal administration of liposomal neostigmine prolongs analgesia in mice.
BACKGROUND
There is substantial evidence that cholinomimetic drugs increase pain threshold. However, the profound side effects of these agents have limited their clinical use either as analgesics or as analgesic adjuncts. A delivery system that would assure a slow and sustained drug release may be of value in ameliorating the problem of untoward effects.


METHODS
The acetylcholinesterase inhibitor neostigmine was encapsulated into multilamellar lipid vesicles composed of phosphocholine and cholesterol. Three doses of plain or liposomal neostigmine were administered by the intrathecal route to mice (n=8-10/group), and analgesic duration was quantified by tail flick test. The doses were chosen based on preliminary experiments, which showed the maximum tolerated intrathecal doses of plain and liposomal neostigmine formulation were 0.625 microg and 80 microg, respectively. Two other doses for each formulation were then derived by 1:1 serial dilutions. Results were compared using survival analysis.


RESULTS
The median antinociceptive duration for plain neostigmine was 0.33, 0.99 and 1.0 h for the 0.115, 0.312 and 0.625 microg doses, respectively. For the liposomal formulation, the median antinociceptive duration was 1.0, 1.5 and 6.0 h for the 20, 40 and 80 microg doses, respectively.


CONCLUSIONS
Liposomal neostigmine provides prolonged spinal antinociception, and permits the safe administration of a relatively large dose, because drug is gradually released from the liposomal depot. This technology holds promise for the development of a clinically useful neostigmine formulation to provide spinal analgesia.
Grant
G J
GJ
Department of Anesthesiology, New York University School of Medicine, New York 10016, USA. gilbert.grant@med.nyu.edu
Piskoun
B
B
Bansinath
M
M
D015360:Analgesia, Epidural; D000818:Animals; D018678:Cholinergic Agents / Q000008:administration & dosage; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D007278:Injections, Spinal; D008081:Liposomes; D008297:Male; D051379:Mice; D009388:Neostigmine / Q000008:administration & dosage*; D017288:Pain Threshold / Q000187:drug effects
D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D008081:Liposomes; D009388:Neostigmine