Correspondence  |   April 2000
Analgesic Effects of Neostigmine in the Periphery
Author Notes
  • Department of Anesthesiology and Intensive
  • Department of Anesthesiology and Intensive Care Medicine
  • Freie University Berlin
  • Benjamin-Franklin-University Clinic
  • Berlin, Germany
Article Information
Correspondence   |   April 2000
Analgesic Effects of Neostigmine in the Periphery
Anesthesiology 4 2000, Vol.92, 1207. doi:
Anesthesiology 4 2000, Vol.92, 1207. doi:
To the Editor:
—In recent years, the journal ANESTHESIOLOGY has published several reports on the analgesic effectiveness of the cholinesterase inhibitor neostigmine. Although there is good evidence for a spinal action of neostigmine, 1,2 a rationale for a peripheral mechanism of action is lacking. Intrathecal injection of neostigmine produces analgesic effects in animals, 3 including humans, 4 accompanied by a high incidence of side effects. The inhibition of spinal cholinesterase results in an increase of endogenous acetylcholine, which is most likely released from intrinsic cholinergic neurons within the dorsal horn of the spinal cord. 5 These cholinergic neurons terminate in the vicinity of primary afferents, 5 which express muscarinic receptors. 6,7 Consistently, analgesic effects of intrathecal neostigmine could be reversed by muscarinic receptor antagonists. 8 The analgesic effect may be explained by a muscarinic presynaptic inhibition of glutamatergic afferents, similar to how it has been described in the neostriatum. 9 An important prerequisite for the effectiveness of neostigmine is a tonic cholinergic activity. 10,11 
Although these mechanisms are clearly described for the spinal cord, evidence is lacking for the periphery. Therefore, the negative result of adding neostigmine to a mepivacaine axillary plexus block in the study by Bouaziz et al.  12 is not surprising. How would neostigmine exert an effect within the nerve sheath of the axillary plexus? An endogenous release of acetylcholine does not exist. Interestingly, the authors hypothesized a peripheral action of neostigmine based on the demonstration of peripheral muscarinic receptors only 6; however, this is not enough. In their discussion, they refer to studies that investigated the effects of muscarinic agonists in spinal cord slice preparations i  n vitro  13 or intrathecally in vivo  . 14 However, these effects are not described for peripheral nerve endings, and neostigmine should not be confused with muscarinic agonists. Therefore, a lack of neostigmine effectiveness within the nerve sheath of the axillary plexus should have been anticipated. For the same reasons, the results of experimental 15 and clinical 16 studies that showed analgesic effectiveness of intraarticular neostigmine are surprising. In rats, the intraarticular injection of neostigmine produces moderate analgesia to thermal stimuli, 15 which is allegedly reversible by intraarticular atropine, although data were not shown in that study. In patients undergoing arthroscopic meniscus repair, intraarticular injection of 500 mg neostigmine resulted in a significant difference in pain intensity at 1 h postoperatively, in total consumption of intravenous rescue analgesics, and in time to first analgesic use. 16 To support their hypothesis of a peripheral site of action, the authors refer to “preclinical data suggesting peripheral antinociceptive effects of acetylcholine.”17 However, acetylcholine is an agonist at muscarinic receptors. Again, the cholinesterase inhibitor neostigmine should not be confused with muscarinic agonists. In both cases, the question arises: Which cells in the periphery are responsible for a tonic cholinergic activity? This question has not been addressed in either of these studies; therefore, the mechanism of action of peripherally applied neostigmine is still lacking, and the identification of the presumed source of peripheral acetylcholine is urgently needed.
Hwang J-H, Hwang K-S, Leem J-K, Park P-H, Han S-M, Lee D-M: The antiallodynic effects of intrathecal cholinesterase inhibitors in a rat model of neuropathic pain. A NESTHESIOLOGY 1999; 90:492–9Hwang, J-H Hwang, K-S Leem, J-K Park, P-H Han, S-M Lee, D-M
Lauretti GR, de Oliveira R, Reis MP, Juliao MC, Pereira NL: Study of three different doses of epidural neostigmine coadministered with lidocaine for postoperative analgesia. A NESTHESIOLOGY 1999; 90:1534–8Lauretti, GR de Oliveira, R Reis, MP Juliao, MC Pereira, NL
Yaksh TL, Grafe MR, Malkmus S, Rathbun ML, Eisenach JC: Studies on the safety of chronically administered intrathecal neostigmine methylsulfate in rats and dogs. A NESTHESIOLOGY 1995; 82:412–27Yaksh, TL Grafe, MR Malkmus, S Rathbun, ML Eisenach, JC
Klamt JG, Garcia LV, Prado WA: Analgesic and adverse effects of a low dose of intrathecally administered hyperbaric neostigmine alone or combined with morphine in patients submitted to spinal anaesthesia: Pilot studies. Anaesthesia 1999; 54:27–31Klamt, JG Garcia, LV Prado, WA
Ribeiro-da-Silva A, Cuello AC: Choline acetyltransferase-immunoreactive profiles are presynaptic to primary sensory fibers in the rat superficial dorsal horn. J Comp Neurol 1990; 295:370–84Ribeiro-da-Silva, A Cuello, AC
Day NS, Berti-Mattera LN, Eichberg J: Muscarinic cholinergic receptor-mediated phosphoinositide metabolism in peripheral nerve. J Neurochem 1991; 56:1905–13Day, NS Berti-Mattera, LN Eichberg, J
Wanke E, Bianchi L, Mantegazza M, Guatteo E, Mancinelli E, Ferroni A: Muscarinic regulation of Ca2+ currents in rat sensory neurons: Channel and receptor types, dose-response relationships and cross-talk pathways. Eur J Neurosci 1994; 6:381–91Wanke, E Bianchi, L Mantegazza, M Guatteo, E Mancinelli, E Ferroni, A
Naguib M, Yaksh TL: Characterization of muscarinic receptor subtypes that mediate antinociception in the rat spinal cord. Anesth Analg 1997; 85:847–53Naguib, M Yaksh, TL
Barral J, Galarraga E, Bargas J: Muscarinic presynaptic inhibition of neostriatal glutamatergic afferents is mediated by Q-type Ca2+ channels. Brain Res Bull 1999; 49:285–9Barral, J Galarraga, E Bargas, J
Bouaziz H, Tong C, Eisenach JC: Postoperative analgesia from intrathecal neostigmine in sheep. Anesth Analg 1995; 80:1140–4Bouaziz, H Tong, C Eisenach, JC
Zhuo M, Gebhart GF: Tonic cholinergic inhibition of spinal mechanical transmission. Pain 1991; 46:211–22Zhuo, M Gebhart, GF
Bouaziz H, Paqueron X, Bur ML, Merle M, Laxenaire MC, Benhamou D: No enhancement of sensory and motor blockade by neostigmine added to mepivacaine axillary plexus block. A NESTHESIOLOGY 1999; 91:78–83Bouaziz, H Paqueron, X Bur, ML Merle, M Laxenaire, MC Benhamou, D
Urban L, Willets J, Murase K, Randic M: Cholinergic effects on spinal dorsal horn neurons in vitro: An intracellular study. Brain Res 1989; 500:12–20Urban, L Willets, J Murase, K Randic, M
Iwamoto ET, Marion L: Pharmacologic evidence that spinal muscarinic analgesia is mediated by an L-arginin/nitric oxide/cyclic GMP cascade in rats. J Pharmacol Exp Ther 1994; 271:601–8Iwamoto, ET Marion, L
Buerkle H, Boschin M, Marcus MAE, Brodner G, Wüsten R, Van Aken H: Central and peripheral analgesia mediated by the acetylcholinesterase-inhibitor neostigmine in the rat inflamed knee joint model. Anesth Analg 1998; 86:1027–32Buerkle, H Boschin, M Marcus, MAE Brodner, G Wüsten, R Van Aken, H
Yang LC, Chen LM, Wang CJ, Buerkle Postoperative analgesia by intra-articular neostigmine in patients undergoing knee arthroscopy. A NESTHESIOLOGY 1998; 88:334–9Yang, LC Chen, LM Wang, CJ Buerkle,
Ferreira SH, Duarte ID, Lorenzetti BB: Molecular base of acetylcholine and morphine analgesia. Agents Actions Suppl 1991; 32:101–6Ferreira, SH Duarte, ID Lorenzetti, BB