Editorial Views  |   February 1995
Spinally Administered Neostigmine—Something to Celebrate 
Author Notes
  • Department of Anesthesiology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510.
  • Submitted for publication, November 10, 1994. Accepted for publication November 10, 1994.
Article Information
Editorial Views
Editorial Views   |   February 1995
Spinally Administered Neostigmine—Something to Celebrate 
Anesthesiology 2 1995, Vol.82, 327-328. doi:
Anesthesiology 2 1995, Vol.82, 327-328. doi:
Key words: Anesthesia, spinal, Cholinesterase, inhibitors: neostigmine, Pain control.
Three related papers in this issue of ANESTHESIOLOGY are a special cause for celebration. Studies by Hood et al. and Yaksh et al. [1–3 ] help us to (1) explore the expanding potential of spinal pharmacology for pain control;(2) acknowledge the proper way to examine the toxicology of spinal drug application; and (3) recognize the continuing contributions that academic anesthesiology programs make to both the specialty of anesthesiology and improvements in clinical care.
At the most recent annual meeting of the American Society of Anesthesiologists, Pierce, at the start of her abstract presentation, [4 ] exhorted the audience to look beyond opioids and alpha2-adrenergic receptors when thinking of pain modulation. That exhortation is especially appropriate to those of use engaged in studies of spinal modulation of pain processing. Before Melzack and Wall's suggestion of a spinal gate, [5 ] there was a general impression that the sensory role of the spinal cord was not unlike that of a telephone wire that simply connected two sites, the peripheral nervous system with the brain. With the suggestion that opioids could modulate pain processing within the spinal cord [6–8 ] and proof of the effectiveness of spinal analgesia, [9–10 ] laboratories began to examine more closely the spinal physiology and pharmacology of pain modulation. The readership of ANESTHESIOLOGY is now quite comfortable with the idea that spinal opioid and alpha2-adrenergic receptors are positioned so that their activation will decrease behavioral responses to pain in experimental animals and pain sensations in humans. However, the richness of both the physiology and pharmacology of spinal sensory processing extends well beyond those two neurotransmitter systems.
In 1991, Willis and Coggeshall [11 ] reviewed the then current state of spinal chemical neuroanatomy, i.e., those chemical systems that have been shown to exist within the spinal cord. Their list of systems included the following: acetylcholine, adenosine, bombesingastrin, brain natriuretic peptide, calcitonin gene-related peptide, cholecystokinin, corticotropin-releasing factor, cytochrome oxidase, dopamine, dynorphin, enkephalin, fluoride-resistant acid phosphatase, galanin, gamma aminobutyric acid, glutamate, glycine, histamine, neurotensin, neuropeptide Y, noradrenalin, serotonin, somatostatin, substance P, thyrotropin-releasing hormone, and vasoactive intestinal polypeptide. That list has grown since 1991. In 1993, Dickenson [12 ] summarized the role of neurotransmitter systems in modulating spinal pain processing and included in that summary more than 25 neurotransmitter systems, many of them listed by Willis and Coggeshall in 1991. If we multiply this formidable but incomplete list by potential sites of action within the spinal cord, for example, presynaptic control of transmitter release, postsynaptic control of second-order neuronal responses to primary afferents, excitatory or inhibitory interneuronal influences on both presynaptic and postsynaptic effects, and descending systems modulating all of the above, an optimist will see a wealth of potential ways to enhance spinal analgesia.
Efforts to include cholinergic systems in spinal analgesia is an important step toward bringing our ever-expanding understanding of spinal sensory processing into the clinic. Although, as the authors point out, side effects, such as nausea and motor weakness, may limit the clinical utility of spinal neostigmine, we celebrate their progress toward better definition of systems that can be called on to produce spinal analgesia. Although some may argue that current techniques are adequate, for the patient with chronic pain unresponsive to current treatment modalities hope for the future lies in our ability to further explore spinal sensory processing.
Our second cause for celebration is acknowledgment of a proper way to examine the toxicology of spinal agents. Despite an in-depth understanding of the effects of systemically administered neostigmine, the authors recognize the absolute necessity of exploring the possibility of spinal toxicity when neostigmine is administered by that route. Several editorials and comments addressing this issue have appeared in recent years in ANESTHESIOLOGY. [13–15 ] Suffice it to say that we celebrate the fact that the authors have provided model systems and a rationale that will serve us well as we explore the toxicity of spinally administered agents before initial clinical studies. Although the experimental models and endpoints may need to be modified, the rationale of identifying dose-dependent behavioral endpoints indicating toxicity that could limit clinical use of agents is a model that should be followed by others. As the authors point out, animal toxicology studies do not guarantee safety. However, they provide essential knowledge about the wisdom of initiating phase I clinical trials.
Our final reason for celebration is the joining of basic and clinical research in an environment that reflects the best of academic anesthesiology. If we fail to acknowledge the value of an academic environment to the specialty of anesthesiology. If we allow “market forces” to turn anesthesiology departments into private practice clinics, where will the work of this type be done and by whom? The anesthesiology departments from which these studies originate and the principal investigators responsible for their conduct are examples of the value of an enriching academic environment to the specialty of anesthesiology. We celebrate the bright future that studies of this type portend.
J.G. Collins, Ph.D.; Department of Anesthesiology; Yale University School of Medicine; 333 Cedar Street; New Haven, Connecticut 06510.
Yaksh TL, Grafe MR, Malkmus S, Rathbun ML, Eisenach JC: Studies on the safety of chronically administered intrathecal neostigmine methylsulfate in rats and dogs. ANESTHESIOLOGY 82:412-427, 1995.
Hood DD, Eisenach JC, Tong C, Tommasi E, Yaksh TL: Cardiorespiratory and spinal cord blood flow effects of intrathecal neostigmine methylsulfate, clonidine, and their combination in sheep. ANESTHESIOLOGY 82:428-435, 1995.
Hood DD, Eisenach JC, Turtle R: Phase I safety assessment of intrathecal neostigmine methylsulfate in humans. ANESTHESIOLOGY 82:331-343, 1995.
Pierce PA, Levine JD: Serotonin-induced inflammation: Involvement of sympathetic efferent terrainals (abstract). ANESTHESIOLOGY 81:A921, 1994.
Melzack R, Wall PD: Pain mechanisms: A new theory. Science 150:971-979, 1965.
Besson JM, Wyon-Maillard MC, Benoist JM, Consellier C, Hamann KF: Effects of phenoperidine on lamina V cells in the cat dorsal horn. J Pharmacol Exp Ther 187:239-245, 1973.
Kitahata LM, Kosaka Y, Taub A, Boniko C, Hoffert M: Lamina-specific suppression of dorsal horn unit activity by morphine sulfate. ANESTHESIOLOGY 41:39-48, 1974.
Calvillo O, Henry JL, Neuman RS: Effects of morphine and naloxone on dorsal horn neurons in the cat. Can J Physiol Pharmacol 52:1207-1211, 1974.
Yaksh TL, Rudy TA: Analgesia mediated by a direct spinal action of narcotics. Science 192:1357-1358, 1976.
Wang JK: Analgesic effect of intrathecally administered morphine. Reg Anesth 2:2-8, 1977.
Willis WD, Coggeshall RE: Sensory Mechanisms of the Spinal Cord, New York, Plenum, 1991, pp 132-148.
Dickenson AH: The pharmacology of pain. Trends in Pharmacol Sci Receptor Nomenclature Suppl:1-43, 1993.
Yaksh TL, Collins JG: Studies in animals should precede human use of spinally administered drugs. ANESTHESIOLOGY 70:4-6, 1989.
Yaksh TL: Spinal somatostatin for patients with cancer risk benefit assessment of an analgesic. ANESTHESIOLOGY 81:531-533, 1994.
Eisenach JC: Spinal delivery of sufentanil, alfentanil, and morphine in dogs: Physiologic and toxicologic investigations (abstract). ANESTHESIOLOGY 81:A28, 1994.