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ANESTHETIC PHARMACOLOGY

Local Anesthetic Properties of a Novel Derivative, N-Methyl Doxepin, Versus Doxepin and Bupivacaine

Yukari Sudoh, MD^*, Elaine Elliott Cahoon, BS^*, Umberto De Girolami, MD, and Ging Kuo Wang, PhD^*

*Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital; and Department of Pathology, Brigham and Women’s Hospital and Children’s Hospital and Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Ging Kuo Wang, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. Address e-mail to wang{at}zeus.bwh.harvard.edu

Among various tricyclic antidepressants, doxepin and amitriptyline are also long-acting local anesthetics. We synthesized a new compound, N-methyl doxepin, and investigated whether this derivative possesses local anesthetic properties. N-methyl doxepin and doxepin were tested in a rat sciatic nerve model at 2.5, 5.0, and 10 mM. Proprioceptive, motor, and nociceptive blockade were evaluated and compared with those induced by 0.5% bupivacaine. Block of Na⁺ channels by N-methyl doxepin and doxepin was assessed in cultured pituitary tumor cells under voltage clamp conditions. N-methyl doxepin elicited complete nociceptive blockade that generally lasted longer than that caused by doxepin (e.g., approximately 7.4 h versus 5.3 h at 10 mM). Significant differences were observed for full recovery of function at all concentrations and for the duration of complete blockade except at 2.5 mM. Bupivacaine at 0.5% (15.4 mM) was less effective in producing complete blockade (approximately 1.5 h) than N-methyl doxepin and doxepin. Both doxepin and N-methyl doxepin were potent Na⁺ channel blockers, although N-methyl doxepin displayed a slower wash-in rate. No morphological alterations were detected in cross-sectioned sciatic nerve specimens with these three drugs. We conclude that N-methyl doxepin is a potent Na⁺ channel blocker and a long-acting local anesthetic for rat sciatic nerve blockade.

IMPLICATIONS: N-methyl doxepin and doxepin are both potent Na⁺ channel blockers; they elicit rat sciatic nerve block lasting longer than that induced by bupivacaine and seem to be nontoxic to peripheral nerves at concentrations up to 10 mM.

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