Smriti Iyengar

Duloxetine vs. placebo in patients with painful diabetic neuropathy.

&NA; 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.

A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder

&NA; This was a 12‐week, randomized, double‐blind, placebo‐controlled trial to assess the efficacy and safety of duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, in 354 female patients with primary fibromyalgia, with or without current major depressive disorder. Patients (90% Caucasian; mean age, 49.6 years; 26% with current major depressive disorder) received duloxetine 60 mg once daily (QD) (N=118), duloxetine 60 mg twice daily (BID) (N=116), or placebo (N=120). The primary outcome was the Brief Pain Inventory average pain severity score. Response to treatment was defined as ≥30% reduction in this score. Compared with placebo, both duloxetine‐treated groups improved significantly more (P<0.001) on the Brief Pain Inventory average pain severity score. A significantly higher percentage of duloxetine‐treated patients had a decrease of ≥30% in this score (duloxetine 60 mg QD (55%; P<0.001); duloxetine 60 mg BID (54%; P=0.002); placebo (33%)). The treatment effect of duloxetine on pain reduction was independent of the effect on mood and the presence of major depressive disorder. Compared with patients on placebo, patients treated with duloxetine 60 mg QD or duloxetine 60 mg BID had significantly greater improvement in remaining Brief Pain Inventory pain severity and interference scores, Fibromyalgia Impact Questionnaire, Clinical Global Impression of Severity, Patient Global Impression of Improvement, and several quality‐of‐life measures. Both doses of duloxetine were safely administered and well tolerated. In conclusion, both duloxetine 60 mg QD and duloxetine 60 mg BID were effective and safe in the treatment of fibromyalgia in female patients with or without major depressive disorder.

Neurobiology of depression: an integrated view of key findings

Aims:  The objectives of the present review were to summarise the key findings from the clinical literature regarding the neurobiology of major depressive disorder (MDD) and their implications for maximising treatment outcomes. Several neuroanatomical structures in the prefrontal and limbic areas of the brain are involved in affective regulation. In patients with MDD, alterations in the dynamic patterns of activity among these structures have profound implications for the pathogenesis of this illness.

Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial.

ABSTRACT Pain is a common cause of disability in osteoarthritis. Duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), has demonstrated analgesic effects in diabetic peripheral neuropathy and fibromyalgia. Considering its central mechanism of action, duloxetine may be effective in other pain states with evidence of central sensitization. Herein, we report the results of a 13‐week, randomized, double‐blind, placebo‐controlled trial of duloxetine (60–120 mg/day) versus placebo in the treatment of knee pain in 231 patients meeting clinical and radiographic criteria for osteoarthritis of the knee. Duloxetine was superior to placebo on the primary efficacy measure (weekly mean 24‐h pain scores) beginning at Week 1 and continuing through the treatment period (P ⩽ .05). There was also a significant improvement in the WOMAC physical functioning subscale and several other secondary outcomes. Adverse‐event rates did not differ significantly between treatment groups (49.5% for duloxetine 60–120 mg/day, and 40.8% for placebo).

Kainate GluR5 receptor subtype mediates the nociceptive response to formalin in the rat

In order to study the roles of the AMPA and kainate subtypes of non-NMDA glutamate receptors in the processing of persistent nociceptive information, compounds with varying activities at these receptors were examined for effects on the formalin-induced paw-licking behavior in rats. The selective AMPA antagonist, LY300164 and the mixed AMPA/kainate antagonist, NBQX, were compared for their effects on formalin-induced pain behavior. NBQX (3, 10, 20 mg/kg, i.p.), caused antinociception as well as ataxia whereas the selective AMPA antagonist, LY300164 (3,5,10 mg/kg, i.p.), did not cause antinociception at doses that did not produce ataxia. In view of the well documented distribution of kainate receptors on C fibres and of the kainate-preferring iGluR5 subtype on dorsal root ganglia (DRG), we tested a series of three decahydroisoquinolines with different profiles of activity between iGluR5 and AMPA receptors and all without activity on iGluR6, iGluR7 or KA2 subtypes. LY293558 (0.1, 1, 3, 5 mg/kg, i.p.), which had low micromolar affinity for both iGluR5 and 2 caused, like NBQX, both antinociceptive and ataxic effects. However, the selective iGluR5 antagonist LY382884 (5, 10, 30, 100 mg/kg, i.p.), exhibited antinociceptive actions without ataxia while the iGluR2 preferring antagonist LY302679 (5 mg/kg, i.p), caused ataxia but did not produce antinociceptive effects at that dose. These actions were stereoselective since the enantiomeric compounds, LY293559 and LY302680, were ineffective in these tests. The data strongly suggest an involvement of iGluR5 in the processing of nociceptive information.

Analyzing multiple endpoints in clinical trials of pain treatments: IMMPACT recommendations

Abstract The increasing complexity of randomized clinical trials and the practice of obtaining a wide variety of measurements from study participants have made the consideration of multiple endpoints a critically important issue in the design, analysis, and interpretation of clinical trials. Failure to consider important outcomes can limit the validity and utility of clinical trials; specifying multiple endpoints for the evaluation of treatment efficacy, however, can increase the rate of false positive conclusions about the efficacy of a treatment. We describe the use of multiple endpoints in the design, analysis, and interpretation of pain clinical trials, and review available strategies and methods for addressing multiplicity. To decrease the probability of a Type I error (i.e., the likelihood of obtaining statistically significant results by chance) in pain clinical trials, the use of gatekeeping procedures and other methods that correct for multiple analyses is recommended when a single primary endpoint does not adequately reflect the overall benefits of treatment. We emphasize the importance of specifying in advance the outcomes and clinical decision rule that will serve as the basis for determining that a treatment is efficacious and the methods that will be used to control the overall Type I error rate.

Group II mGluR receptor agonists are effective in persistent and neuropathic pain models in rats.

The involvement of Group II metabotropic receptors in acute and persistent pain states was evaluated in several in vivo models of pain with selective and potent Group II metabotropic glutamate (mGlu) 2,3 agonists. LY354740, LY379268 and LY389795 attenuated late-phase paw-licking pain behavior in a dose-dependent manner in the formalin model of persistent pain. Effects occurred in the absence of overt neuromuscular deficits as measured by performance in the rotorod test for ataxia. The effects of LY354740 and LY379268 were also stereoselective. The order of potency of the agonists was LY389795>LY379268>LY354740. The attenuation of licking behavior by LY379268 (3 mg/kg) in the formalin model was reversed by a potent and selective mGlu2,3 receptor antagonist, LY341495 (1 mg/kg). In the L5/L6 spinal nerve ligation model of neuropathic pain in rats, LY379268 significantly reversed mechanical allodynia behavior in a dose-related manner. In contrast, LY379268 had no significant effects on the tail flick test or paw withdrawal test of acute thermal nociceptive function. These results support the involvement of Group II mGlu2,3 receptors in persistent pain mechanisms and suggest the potential utility of selective Group II mGlu agonists for the treatment of persistent pain.

Duloxetine for the Management of Diabetic Peripheral Neuropathic Pain: Evidence-Based Findings from Post Hoc Analysis of Three Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Studies

OBJECTIVE This post hoc analysis was aimed to summarize the efficacy and tolerability of duloxetine as represented by number needed to treat (NNT) and number needed to harm (NNH) to provide a clinically useful assessment of the position of duloxetine among current agents used to treat diabetic peripheral neuropathic pain (DPNP). METHODS Data were pooled from three 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies in which patients received 60 mg duloxetine either QD or BID or placebo. NNT was calculated based on rates of response (defined as >or=30% and >or=50% reductions from baseline in the weekly mean of the 24-hour average pain severity scores); NNH was calculated based on rates of discontinuation due to adverse events (AEs). RESULTS Patients receiving duloxetine 60 mg QD and 60 mg BID had NNTs (95% CI) of 5.2 (3.8-8.3) and 4.9 (3.6-7.6), respectively, based on last observation carried forward; NNTs of 5.3 (3.8-8.3) for 60 mg QD and 5.7 (4.1-9.7) for 60 mg BID were obtained based on baseline observations carried forward. The NNHs (95% CI) based on discontinuation due to AEs were 17.5 (10.2-58.8) in the duloxetine 60-mg QD group and 8.8 (6.3-14.7) in the 60-mg BID group. CONCLUSION These post hoc results suggest that duloxetine was effective and well tolerated for the management of DPNP and further support the importance of duloxetine as a treatment option for clinicians and patients to assist with the management of DPNP.

Depression and pain.

Depression and pain disorders are often diagnosed in the same patients. Here we summarize the shared pathophysiology between both disorders and the importance of addressing all symptoms in patients with comorbid pain and depression. We describe anatomical structures that are activated and/or altered in response to both depression and pain--examples include the insular cortex, the prefrontal cortex, the anterior cingulate cortex, the amygdala, and the hippocampus. Both disorders activate common neurocircuitries (e.g. the hypothalamic-pituitary-adrenal axis, limbic and paralimbic structures, ascending and descending pain tracks), common neurochemicals (e.g. monoamines, cytokines, and neurotrophic factors), and are associated with common psychological alterations. One explanation for the interaction and potentiation of the disease burden experienced by patients affected by both pain and depression is provided by the concept of allostasis. In this model, patients accumulate allostatic load through internal and external stressors, which makes them more susceptible to disease. To break this cycle, it is important to treat all symptoms of a patient. Therapeutic approaches that address symptoms of both depression and pain include psychotherapy, exercise, and pharmacotherapy.

The Dual Transporter Inhibitor Duloxetine: A Review of its Preclinical Pharmacology, Pharmacokinetic Profile, and Clinical Results in Depression

Major depressive disorder (MDD) poses a significant health problem and is estimated to be the third most costly and disabling disorder in the United States. Pharmacotherapy of depression has been successful, but improvements in response rates, remission rates, side effects, compliance and faster onset of therapeutic action have become prime objectives in drug development. There is considerable support for the hypothesis that dysfunctional serotonergic or noradrenergic neurotransmission may be etiological in depressed patients. Duloxetine is a balanced and potent reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE) being studied as an antidepressant medication. In this review, we highlight the preclinical pharmacology, pharmacokinetic profile, and effects of duloxetine in the pharmacotherapy of depression. Evidence for 5-HT and NE reuptake inhibition by duloxetine comes from in vitro and in vivo transporter binding and functional uptake studies. Taken together with efficacy data from in vivo microdialysis, electrophysiological and behavioral studies, it is evident that duloxetine is balanced as a dual serotonin norepinephrine uptake inhibitor in vivo. The clinical efficacy and safety of duloxetine in the treatment of MDD has been studied in 6 multicenter, randomized, double-blind, placebo-controlled trials. In these studies, duloxetine was found to be effective in the treatment of emotional/psychological and painful physical symptoms associated with depression. More importantly, duloxetine appears to have better response rates and remission from depressive symptoms, perhaps due to its ability to treat a wider range of symptoms.