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Correspondence  |   January 2005
Amitriptyline Neurotoxicity
Author Affiliations & Notes
  • Robert R. Myers, Ph.D.
    *
  • * University of California, San Diego, School of Medicine, San Diego, California.
Article Information
Correspondence
Correspondence   |   January 2005
Amitriptyline Neurotoxicity
Anesthesiology 1 2005, Vol.102, 241. doi:
Anesthesiology 1 2005, Vol.102, 241. doi:
In Reply:—
We thank Dr. Sawynok for the interest in our study1 and for correcting an error in the conversion of our doses from mM to nmol. Fortunately, the experimental protocol, preparation and dosing of drug, and results and conclusions of our article remain unchanged, as this error was only one of unit conversion for the reader. The error does not affect the experimental paradigm or significance of the results. We also thank Dr. Sawynok for comparing the dose used in several studies of amitriptyline in their table, as this helps place our experiments in context. The range of dose evaluated in our study was in accordance with the doses previously used in studies that reported a prolongation of sciatic nerve blockade2 (i.e.  , 5–0.625 mg or 16,000–2,000 nmol; each dose administered in a 0.2-ml volume adjacent to rat sciatic nerve). Our data clearly demonstrate that amitriptyline causes a dose-related neuropathologic change if it is administered in the immediate vicinity of a nerve, and suggests that it should not be used as a local anesthetic agent. This conclusion remains unchanged. Moreover, it has recently been reported in a volunteer study that amitriptyline (25.2 mg to 6.3 mg) did not provide better ulnar nerve blockade at the wrist level than current local anesthetics.3 Indeed, amitriptyline has a reduced margin of safety and an increased potential for neurotoxic injury.
We did not test the neurotoxic effect of a 100 nmol dose used by Sawynok et al.  4 and Esser and Sawynok5 because that dose is not associated with neural blockade of major nerve bundles. A 100-nmol dose produces an analgesic effect of uncertain mechanism, as Dr. Sawynok notes. However, the point should be made that local neurotoxic injury is concentration-dependent and that there may be subclinical neurotoxic injury with even small doses of high concentration solutions. Although the analgesic effect of amitriptyline is of considerable interest, it should also be noted that adverse effects were reported when slightly higher doses (0.3 ml of 500 mm) were administered transdermally6 or by subcutaneous injection (300 to 1000 nmol).7 
Thus, we believe there is consensus that the use of amitriptyline as a local agent in clinical situations for analgesia or anesthesia requires additional experimental study that includes a neuropathologic and a behavioral or electrophysiologic endpoint. We support these studies and regret that our conversion error may have introduced some confusion in the literature.
* University of California, San Diego, School of Medicine, San Diego, California.
References
Estebe JP, Myers RR: Amitriptyline neurotoxicity: Dose-related pathology after topical application to rat sciatic nerve. Anesthesiology 2004; 100:1519–25Estebe, JP Myers, RR
Gerner P, Mujtaba M, Sinnott CJ, Wang GK: Amitriptyline versus bupivacaine in rat sciatic nerve blockade. Anesthesiology 2001; 94:661–7Gerner, P Mujtaba, M Sinnott, CJ Wang, GK
Fridrich P, Eappen S, Jaeger W, Schemhammer E, Zizza A, Wang GK, Gerner P: Phase Ia and Ib of amitriptyline for ulnar nerve block in humans. Anesthesiology 2004; 100:1511–8Fridrich, P Eappen, S Jaeger, W Schemhammer, E Zizza, A Wang, GK Gerner, P
Sawynok J, Reid AR, Esser MJ: Peripheral antinociceptive action of amitriptyline in the rat formalin test: involvement of adenosine. Pain 1999; 80:45–55Sawynok, J Reid, AR Esser, MJ
Esser MJ, Sawynok J: Caffeine blockade of the thermal antihyperalgesic effect of acute amitriptyline in a rat model of neuropathic pain. Eur J Pharmacol 2000; 399:131–9Esser, MJ Sawynok, J
Haderer A, Gerner P, Kao G, Srinivasa V, Wang GK: Cutaneous analgesia after transdermal application of amitriptyline versus lidocaine in rats. Anesth Analg 2003; 96:1707–10Haderer, A Gerner, P Kao, G Srinivasa, V Wang, GK
Oatway M, Reid A, Sawynok J: Peripheral antihyperalgesic and analgesic actions of ketamine and amitriptyline in a model of mild thermal injury in the rat. Anesth Analg 2003; 97:168–73Oatway, M Reid, A Sawynok, J