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Relationship between antidepressant and analgesic responses with the dual reuptake inhibitor duloxetine hydrochloride
David A. Fishbain, MD, FAPA1, Michael Detke, MD, PhD2, Joachim Wernicke, MD, PhD2, Amy Chappell, MD2, and Daniel Kajdasz, PhD2. (1) University of Miami, School of Medicine, 1400 N.W. 10th Avenue, Miami, FL 33136, (2) Department of Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285
Many antidepressants, especially those with both serotonergic and noradrenergic activity, have been shown to have significant analgesic effects. With such antidepressants, debate continues regarding the independence of these effects and their relational onset of action. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, is effective in treating major depressive disorder (MDD) and managing diabetic peripheral neuropathic pain. These analyses of 6 randomized, double-blind, parallel trials assessing the safety and efficacy of duloxetine in patients with DSM-IV-defined MDD were designed to systematically assess both MDD symptoms and pain severity while also allowing for determining the level of independence of these responses. To test these findings, data from 2 sister studies comparing duloxetine 60mgQD with placebo for 9 weeks were pooled, while 4 similar studies comparing duloxetine at doses of 20-60mgBID with placebo for 8 weeks were separately pooled. The primary depression measure was the 17-item Hamilton Depression Scale (HAMD17); pain severity was assessed using visual analog scales (VAS) measuring overall pain, headache, back and shoulder pain, and pain while awake. The presence of pain was not an enrollment requirement for any study. Clinically significant responses for MDD and pain severity were defined as ≥ 50% reduction from baseline in HAMD17 and VAS scores, respectively. The time course of improvement was profiled using repeated measures modeling, and time to initial response (onset) was assessed using the Kaplan-Meier method. Significant reductions in mean HAMD17 and VAS scores were initially seen within 14 days of treatment except for headache severity in one data pool. Median time to pain response was consistently shorter than that for MDD response for all 5 VAS measures in patients with moderate to severe pain at baseline. Regression analyses consistently demonstrated small associations between analgesic and antidepressant responses, providing further support that the analgesic effect of duloxetine is independent of its antidepressant effect.