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R-Duloxetine and N-Methyl Duloxetine as Novel Analgesics Against Experimental Postincisional Pain

Wang, Chi-Fei MD; Russell, Gabriella BFA; Wang, Sho-Ya PhD; Strichartz, Gary R. PhD; Wang, Ging Kuo PhD

doi: 10.1213/ANE.0000000000001086
Anesthetic Pharmacology: Research Report

BACKGROUND: Antidepressant S-duloxetine alleviates intractable pain associated with diabetic peripheral neuropathy and fibromyalgia. It also reduces both acute and persistent pain in various animal models. This study addresses whether the enantiomer, R-duloxetine, and the homolog, N-methyl duloxetine, could act as analgesics and whether they block neuronal Na+ channels.

METHODS: The rat incision plus extension model on the dorsothoracic skin was applied to evoke postoperative mechanoallodynia and hyperalgesia, measured for 5 days postoperatively by local responses to von Frey filaments. R-Duloxetine and N-methyl duloxetine were administered systemically (intraperitoneal) or locally (subcutaneous [SC]) 1 hour before the surgery. The block of Na+ currents in rat neuronal GH3 cells was determined under the whole-cell configuration.

RESULTS: Ipsilateral SC injections (2 mg/0.4 mL) of R-duloxetine and N-methyl duloxetine reduced both postoperative allodynia and hyperalgesia by approximately 89% to 99% in the area under the curve of skin responses next to incision over 5 days. Systemic intraperitoneal injections at a higher dosage (10 mg) had smaller analgesic effects (reduced by approximately 53%–69%), whereas contralateral SC injections (10 mg) were ineffective. Both R-duloxetine and N-methyl duloxetine blocked neuronal Na+ currents, with a higher affinity for the inactivated than the resting states. In addition, both drugs elicited significant use-dependent block of Na+ currents when stimulated at 5 Hz.

CONCLUSIONS: R-Duloxetine and N-methyl duloxetine are highly effective against postoperative pain using the skin incision model, and they elicit both tonic and use-dependent block of neuronal Na+ channels. Our results suggest that R-duloxetine and N-methyl duloxetine are applicable as novel analgesics.

Published ahead of print December 7, 2015

From the *College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham & Women’s Hospital, Boston, Massachusetts; and Department of Biological Sciences, SUNY at Albany, Albany, New York.

Accepted for publication September 14, 2015.

Published ahead of print December 7, 2015

Funding: This research was funded by National Institutes of Health grant number GM094152 and CA080153.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Sho-Ya Wang, PhD, Department of Biological Sciences, SUNY at Albany, 1400 Washington Ave., Albany, NY 12222. Address e-mail to sywang@albany.edu.

© 2016 International Anesthesia Research Society