Duloxetine vs. placebo in patients with painful diabetic neuropathy

Abstract

The aim of this study was to examine the efficacy and safety of duloxetine, a balanced and potent dual reuptake inhibitor of serotonin and norepinephrine, in the management of diabetic peripheral neuropathic pain. Serotonin and norepinephrine are thought to inhibit pain via descending pain pathways. In a 12-week, multicenter, double-blind study, 457 patients experiencing pain due to polyneuropathy caused by Type 1 or Type 2 diabetes mellitus were randomly assigned to treatment with duloxetine 20 mg/d (20 mg QD), 60 mg/d (60 mg QD), 120 mg/d (60 mg BID), or placebo. The diagnosis was confirmed by a score of at least 3 on the Michigan Neuropathy Screening Instrument. The primary efficacy measure was the weekly mean score of the 24-h Average Pain Score, which was rated on an 11-point (0–10) Likert scale (no pain to worst possible pain) and computed from diary scores between two site visits. Duloxetine 60 and 120 mg/d demonstrated statistically significant greater improvement compared with placebo on the 24-h Average Pain Score, beginning 1 week after randomization and continuing through the 12-week trial. Duloxetine also separated from placebo on nearly all the secondary measures including health-related outcome measures. Significantly more patients in all three active-treatment groups achieved a 50% reduction in the 24-h Average Pain Score compared with placebo. Duloxetine treatment was considered to be safe and well tolerated with less than 20 percent discontinuation due to adverse events. Duloxetine at 60 and 120 mg/d was safe and effective in the management of diabetic peripheral neuropathic pain. Keywords Duloxetine Cymbalta ® Diabetic neuropathy Antidepressant Pain Efficacy Safety/tolerability 1 Introduction Diabetes is commonly associated with a peripheral neuropathy that often results in significant pain. The pain has been described as an ‘aching, burning, stabbing, or tingling’ sensation, and often affects sleep. Tricyclic antidepressants (TCAs), certain anticonvulsants (e.g. gabapentin), and opioid analgesics are currently used to treat the neuropathic pain due to diabetic peripheral neuropathy, but often are limited by efficacy or significant side effects ( Kapur et al., 1992; McQuay et al., 1996 ). Serotonin (5-HT) and norepinephrine (NE) have been implicated in the modulation of endogenous analgesic mechanisms via the descending inhibitory pain pathways in the brain and spinal cord ( Basbaum and Fields, 1984; Clark and Proudfit, 1993; Fields and Basbaum, 1999; Fields et al., 1991 ). An imbalance in these inhibitory mechanisms may contribute to central sensitization and hyperexcitability of the spinal and supraspinal pain transmitting pathways leading to persistent pain [reviewed by Coderre and Katz (1997) ] ( Ren and Dubner, 2002 ). Duloxetine hydrochloride [(Cymbalta ® ), (+)- N -methyl-γ-(1-naphthalenyloxy)-3-(2-thiopene)-propanamine] is a relatively balanced and potent dual reuptake inhibitor of both 5-HT and NE (SNRI) transporters with weak affinity for the dopamine transporter and insignificant affinity at more than 60 neurotransmitter receptors including muscarinic, histamine, opioid, glutamate and GABA receptors and sodium, potassium, and calcium channel sites ( Wong and Bymaster, 2002 ). Duloxetine is effective in animal models of persistent and neuropathic pain ( Iyengar et al., 2004 ) suggesting that duloxetine could be efficacious in the treatment of persistent pain conditions in humans. Since efficacy occurs at doses that do not impair performance on the rotorod test of neurological function, duloxetine is likely to be non-sedating and non-ataxic ( Iyengar et al., 2004 ), making it a good clinical candidate. In several randomized, double-blind, placebo-controlled studies, duloxetine at 60–120 mg per day ( Detke et al., 2002a,b; Goldstein et al., 2002; Nemeroff et al., 2002 ) was an effective treatment for major depressive disorder (MDD) based on traditional measures of efficacy, such as the Hamilton Depression Rating Scale. Duloxetine also produced significant improvement on visual analog scales (VAS) ratings of painful physical symptoms associated with depression, including overall pain, back pain, shoulder pain, headache, and general somatic symptoms, despite the fact that patients were not selected for pain type or pain severity and the studies were not statistically powered for these measures. Path analysis demonstrated that greater than 50% of the reduction in painful physical symptoms of MDD was a direct effect of duloxetine, rather than a secondary effect of improving depression. Consistent with duloxetine's effects on the painful physical symptoms in MDD and the existing evidence that dual 5-HT and NE reuptake inhibitors are effective in treating pure pain disorders such as neuropathic pain conditions ( Sindrup and Jensen, 1999 ), the potential analgesic efficacy of duloxetine was evaluated in patients with neuropathic pain due to diabetic peripheral neuropathy who did not have depression. The current study describes the efficacy and safety of duloxetine in reducing pain severity in diabetic peripheral neuropathic pain (DPNP) patients. 2 Methods 2.1 Study design This was a parallel-group, double-blind, randomized, placebo-controlled study of patients who met criteria for diabetic neuropathy as assessed by history and the physical exam portion of the Michigan Neuropathy Screening Instrument (MNSI) ( Sheehan et al., 1998 ). The primary objective was to evaluate the efficacy of duloxetine 20, 60, or 120 mg/d (administered 20 mg QD, 60 mg QD and 60 mg BID, respectively), on the treatment of pain associated with diabetic neuropathy as compared with placebo. Each site's ethics committee approved the study protocol in accordance with the principles of the Declaration of Helsinki. Patients provided written informed consent prior to participation in any study-related procedures. 2.2 Patients Patients, at least 18 years of...