RESULTS Cutaneous Analgesia Induced by SC R-Duloxetine and N-Methyl Duloxetine for Postoperative Pain

March 2016 • Volume 122 • Number 3 www.anesthesia-analgesia.org 719 Copyright © 2015 International Anesthesia Research Society DOI: 10.1213/ANE.0000000000001086 Duloxetine (an S-enantiomer drug) is a mixed serotonin-norepinephrine reuptake inhibitor and is widely prescribed for major depressive and anxiety disorders. The drug was originally developed as a serotonin-norepinephrine reuptake inhibitor antidepressant because it is twice as potent as the enantiomer R-duloxetine1 in reducing serotonin uptake. Duloxetine is also an US Food and Drug Administration–approved analgesic used for various pain syndromes, including diabetic peripheral neuropathy and fibromyalgia. The underlying mechanism for duloxetine against these pain syndromes remains unclear, but it may involve multiple central nervous system (CNS) targets.2,3 Duloxetine, by the oral gavage or by the intraperitoneal (IP) route, is effective in reducing pain in several animal models. For example, duloxetine (5–30 mg/kg oral) reversed mechanical allodynia behavior in the L5/L6 spinal nerve ligation model of neuropathic pain.4 Likewise, both mechanical and thermal hyperalgesia from inflammation of hind paw by formalin injection5,6 were significantly attenuated by acute systemic duloxetine (30–100 mg/kg, IP). In the tibial neuroma transposition model, duloxetine attenuated the mechanical allodynia effectively when applied IP at 25 to 50 mg/kg.7 Duloxetine has 3 major CNS targets: (1) serotonin transporter (Ki, 4.6 nM), (2) norepinephrine transporter (Ki, 16 nM), and (3) dopamine transporter (Ki, 370 nM).3 In the past, the antidepressant action was often thought to be the primary mechanism for its analgesic efficacy. This theory was addressed later by “Path Analysis,” and the result showed that duloxetine affected pain directly rather than indirectly through mood improvement.8 This article suggested that the analgesic action of duloxetine is because of its ability to enhance both serotonin and norepinephrine neurotransmission in descending modulatory pain pathways. In addition to these multiple CNS targets, duloxetine, like the antidepressant amitriptyline and the local anesthetic bupivacaine, blocks voltage-gated Na+ channels.9 Because neuronal Na+ channels are present in both CNS and peripheral nervous systems, such a finding expands the possible analgesic action and locus of duloxetine. Recently, we provided evidence that local subcutaneous (SC) duloxetine was effective for cutaneous antihyperalgesia after rat skin incision.10 In contrast, contralateral SC injections of duloxetine failed to reduce postincisional hyperalgesia or allodynia. This observation is consistent with the notion that duloxetine may also act on peripheral targets. In this report, we explore whether the enantiomer, R-duloxetine, and the homolog, N-methyl duloxetine, could act as novel analgesics via systemic and SC routes. Furthermore, we explore whether both these drugs are also potent Na+ channel blockers. 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. (Anesth Analg 2016;122:719–29) R-Duloxetine and N-Methyl Duloxetine as Novel Analgesics Against Experimental Postincisional Pain