Effect Of Duloxetine Research Articles

Cost effectiveness of duloxetine for osteoarthritis: a Quebec societal perspective.

To assess the cost effectiveness of duloxetine compared to other oral postacetaminophen treatments for osteoarthritis (OA) from a Quebec societal perspective. A cost-utility analysis was performed enhancing the Markov model from the 2008 OA guidelines of the National Institute for Health and Clinical Excellence (NICE). The NICE model was extended to include opioid and antidepressant comparators, adding titration, discontinuation, and relevant adverse events (AEs). Comparators included duloxetine, celecoxib, diclofenac, naproxen, hydromorphone, and oxycodone extended release (oxycodone). AEs included gastrointestinal and cardiovascular events associated with nonsteroidal antiinflammatory drugs (NSAIDs), as well as fracture, opioid abuse, and constipation, among others. Costs and incremental cost-effectiveness ratios (ICERs) were estimated in 2011 Canadian dollars. The base case modeled a cohort of 55-year-old patients with OA for a 12-month period of treatment, followed by treatment from a basket of post-discontinuation oral therapies until death. Sensitivity analyses (one-way and probabilistic) were conducted. Overall, naproxen was the least expensive treatment, whereas oxycodone was the most expensive. Duloxetine accumulated the highest number of quality-adjusted life years (QALYs), with an ICER of $36,291 per QALY versus celecoxib. Duloxetine was dominant over opioids. In subgroup analyses, ICERs for duloxetine versus celecoxib were $15,619 and $20,463 for patients at high risk of NSAID-related AEs and patients ages >65 years, respectively. Duloxetine was cost effective for a cohort of 55-year-old patients with OA, and more so in older patients and those with greater AE risks.

Impact of comorbidities on pharmacotherapy of painful diabetic neuropathy in clinical practice

AimsWe evaluated the impact of baseline comorbidities on the effectiveness of duloxetine and anticonvulsants (pregabalin/gabapentin) in patients with painful diabetic neuropathy in clinical care. MethodsOutcomes from a 6-month, observational study with 2575 patients initiating/switching DPNP treatment were analyzed post-hoc. Propensity scoring was used to adjust for baseline factors influencing treatment choice in 1523 patients receiving duloxetine or anticonvulsants. Analysis of covariance models with fixed effects for baseline pain, treatment, propensity score, baseline characteristics or comorbidities, and their interaction with treatment were used to estimate LSmean effects on Brief Pain Inventory (BPI) average pain and interference scores. Results89.5% of patients reported comorbidities, including hypertension (70.5%), hyperlipidemia (39.2%), and depression (24.8%). Macrovascular complications (37.0%) and ‘other chronic pain’ (41.5%), particularly joint pain had an impact on both pain treatments, i.e. less improvement of average pain and interference of pain. Better treatment responses with duloxetine vs. anticonvulsants were observed in patients with depression, those with high baseline BPI total interference score, especially general activity, and in patients with joint pain. ConclusionsComorbidities such as macroangiopathy and depression as well as pain characteristics should be considered in the treatment of DPNP as they may predict the effectiveness of duloxetine and anticonvulsants.

Agomelatine and Duloxetine Synergistically Modulates Apoptotic Pathway by Inhibiting Oxidative Stress Triggered Intracellular Calcium Entry in Neuronal PC12 Cells: Role of TRPM2 and Voltage-Gated Calcium Channels

Calcium ion (Ca(2+)) is one of the universal second messengers, which acts in a wide range of cellular processes. Results of recent studies indicated that ROS generated by depression leads to loss of endoplasmic reticulum-Ca(2+) homeostasis, oxidative stress, and apoptosis. Agomelatine and duloxetine are novel antidepressant and antioxidant drugs and may reduce oxidative stress, apoptosis, and Ca(2+) entry through TRPM2 and voltage-gated calcium channels. We tested the effects of agomelatine, duloxetine, and their combination on oxidative stress, Ca(2+) influx, mitochondrial depolarization, apoptosis, and caspase values in the PC-12 neuronal cells. PC-12 neuronal cells were exposed in cell culture and exposed to appropriate non-toxic concentrations and incubation times for agomelatine were determined in the neurons by assessing cell viability. Then PC-12 cells were incubated with agomelatine and duloxetine for 24 h. Treatment of cultured PC-12 cells with agomelatine, duloxetine, and their combination results in a protection on apoptosis, caspase-3, caspase-9, mitochondrial membrane depolarization, cytosolic ROS production, glutathione peroxidase, reduced glutathione, and lipid peroxidation, values. Ca(2+) entry through non-specific TRPM2 channel blocker (2-APB) and voltage-gated Ca(2+) channel blockers (verapamil and diltiazem) was modulated by agomelatine and duloxetine. However, effects of duloxetine on the Ca(2+) entry through TRPM2 channels were higher than in agomelatine. Results of current study suggest that the agomelatine and duloxetine are useful against apoptotic cell death and oxidative stress in PC-12 cells, which seem to be dependent on mitochondrial damage and increased levels of intracellular Ca(2+) through activation of TRPM2 and voltage-gated Ca(2+) channels.

The analgesia effect of duloxetine on post-operative pain via intrathecal or intraperitoneal administration

One promising strategy to prevent the chronicity of post-operative pain (POP) is to attenuate acute POP during the early phase by efficacious medications with fewer side effects. Duloxetine, one of the serotonin (5-HT)-norepinephrine (NE) reuptake inhibitors (SNRI), is used to treat a wide range of acute and chronic pain. However, its effect on POP has not been investigated. In the present study, we investigated the anti-hypersensitivity effect of duloxetine using a rat model of POP. The possible involvement of spinal 5-HT2A and α2-noradrenergic receptors were also evaluated by using antagonists for 5-HT2A (ketanserin) or α2-noradrenergic receptors (idazoxan). Finally, with the method of in vivo microdialysis, the increase in spinal NA and 5-HT levels after intraperitoneal (i.p.) delivery of duloxetine were investigated. The results showed that intrathecal (i.t.) or i.p. delivery of duloxetine produced an anti-hyperalgesic effect in a dose-dependent manner. The anti-hypersensitivity effect of duloxetine was partly attenuated by pretreatment with ketanserin or idazoxane. Microdialysis study revealed that 5-HT and NA concentrations at the spinal dorsal horn were increased, peaking at 30min after i.p. injection of 20mg/kg duloxetine. These findings indicate that duloxetine inhibits POP by increasing spinal NA and 5-HT levels and activating spinal 5-HT2A or α2-noradrenergic receptors.

Effects of Duloxetine and WAY100635 on Pudendal Inhibition of Bladder Overactivity in Cats

This study was aimed at determining the effect of duloxetine (a serotonin-norepinephrine reuptake inhibitor) on pudendal inhibition of bladder overactivity. Cystometrograms were performed on 15 cats under α-chloralose anesthesia by infusing saline and then 0.25% acetic acid (AA) to induce bladder overactivity. To inhibit bladder overactivity, pudendal nerve stimulation (PNS) at 5 Hz was applied to the right pudendal nerve at two and four times the threshold (T) intensity for inducing anal twitch. Duloxetine (0.03-3 mg/kg) was administered intravenously to determine the effect on PNS inhibition. AA irritation significantly (P < 0.01) reduced bladder capacity to 27.9 ± 4.6% of saline control capacity. PNS alone at both 2T and 4T significantly (P < 0.01) inhibited bladder overactivity and increased bladder capacity to 83.6 ± 7.6% and 87.5 ± 7.7% of saline control, respectively. Duloxetine at low doses (0.03-0.3 mg/kg) caused a significant reduction in PNS inhibition without changing bladder capacity. However, at high doses (1-3 mg/kg) duloxetine significantly increased bladder capacity but still failed to enhance PNS inhibition. WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide; a 5-HT1A receptor antagonist, 0.5-1 mg/kg i.v.) reversed the suppressive effect of duloxetine on PNS inhibition and significantly (P < 0.05) increased the inhibitory effect of duloxetine on bladder overactivity but did not enhance the effect of PNS. These results indicate that activation of 5-HT1A autoreceptors on the serotonergic neurons in the raphe nucleus may suppress duloxetine and PNS inhibition, suggesting that the coadministration of a 5-HT1A antagonist drug might be useful in enhancing the efficacy of duloxetine alone and/or the additive effect of PNS-duloxetine combination for the treatment of overactive bladder symptoms.

P.3.021 The effects of duloxetine on subjective, autonomic and neurocognitive response to 7.5% carbon dioxide challenge

The cytokine theory of depression no longer brings about any doubts. Experiments and research studies conducted in the last ten years have confirmed that both physical and psychological (emotional) stress increases the likelihood of occurrence of mental disorders (including depressive disorders) owing to the action of a series of hormonal and biochemical mechanisms.Selective serotonin reuptake inhibitors (SSRI) as well as serotonin and norepinephrine reuptake inhibitors (SNRIs) are some of the most commonly applied drugs in the world during pharmacotherapy of recurrent depressive disorder.The underestimated anti-inflammatory and anti-oxidative effect may be one of the potential mechanisms of action of the preparations mentioned above. The detailed specificity of action of this mechanism still remains unknown. The aim of our work will be to perform a review of contemporary literature in order to present the latest scientific reports regarding the anti-inflammatory effects of SSRIs and SNRIs.The mechanism of anti-inflammatory action may serve as a possible explanation for the efficacy of antidepressants from the groups of SSRIs and SNRIs.

Does Early Improvement in Anxiety Symptoms in Patients with Major Depressive Disorder Affect Remission Rates? A Post-Hoc Analysis of Pooled Duloxetine Clinic Trials

Objectives: Patients with major depressive disorder (MDD) and a comorbid anxiety disorder or significant anxiety symptoms have decreased functioning, increased risk of suicidality, and worse post-treatment outcomes. This pooled analysis of 8 duloxetine MDD trials was designed to determine whether early improvement in anxiety symptoms predicts MDD remission. Methods: Eight trials were pooled. Patients with a baseline 17-item Hamilton Rating Scale for Depression (HA-MD17) anxiety/somatization factor score ≥7 were considered to have anxious depression. Early response on the HAMD17 total score was defined as a 20% reduction at weeks 2 or 4, a 30% reduction at weeks 2 or 4, or a 50% reduction at weeks 2 or 4 in the HAMD17 anxiety subscale. Each category was analyzed separately for all patients. MDD remission is a score of ≤7 on the HAMD17 total score at study endpoint. Results: The early responder group in each analysis showed greater numerical improvement at endpoint on the HAMD17 total score than the nonresponder group. Duloxetine showed statistically significantly greater improvement than placebo in most nonresponder and responder subgroups. There were no statistically significant interaction effects for the difference between duloxetine and placebo for any of the anxious categories. Conclusion: Although patients who responded in the various response categories had greater numerical improvement and greater remission rates than nonresponding patients, the response and nonresponse groups did not differ statistically regarding the treatment effect of duloxetine. Therefore, early improvement in anxiety symptoms was not a predictor of greater endpoint remission of depressive symptoms for duloxetine treatment.

Antidepressants in the Treatment for Chronic Low Back Pain: Questioning the Validity of Meta‐Analyses

To contrast the analgesic effect of duloxetine with antidepressants reported in other published randomized clinical trials (RCTs) and review articles in patients with chronic low back pain (CLBP). In this narrative review, the results of 13 RCTs and 5 systematic reviews examining the analgesic effect of various antidepressants in CLBP were contrasted with those of 3 placebo-controlled duloxetine RCTs. Treatment effects based on the Brief Pain Inventory (BPI) average score in the duloxetine RCTs were assessed in all completers (by study and overall) and in last-observation-carried-forward (LOCF) analyses (extracted from study reports). 30%- and 50%-reduction response rates were compared between duloxetine and placebo. Eleven different antidepressants were examined in 13 individual RCTs. Sample sizes, treatment durations, and analysis methods varied across studies. Reviews each included 5 to 9 of the RCTs and came to different conclusions regarding the analgesic effect of antidepressants: 2 found no evidence while 3 reported some evidence. The completer analysis showed greater improvements in BPI average scores with duloxetine vs. placebo (significant in 2 studies). Overall, the least square mean (standard error) difference between treatments was - 0.7 (0.15) (P < 0.0001). Overall response rates were significantly larger with duloxetine than with placebo. Due to the diversity of previous studies and the pooling methods used, the conclusions regarding the analgesic effect of antidepressants in CLBP drawn from systematic reviews must be interpreted with caution. Appropriately designed and powered studies similar to recently published duloxetine studies are recommended to demonstrate the analgesic effect of antidepressants.

VEGF plasma level variations in duloxetine-treated patients with major depression

BackgroundThe vascular endothelial growth factor (VEGF) signaling, which modulates angiogenesis and neurogenesis within the neurovascular unit, might play an important role in the neuro-endocrine-immune (NEI) stress-adaptation system. Recent evidence suggests that VEGF is involved in the pathophysiology of a number of diseases including major depressive disorder (MDD) and is affected by some treatments, including antidepressants. The objective of the study was to investigate the VEGF level variations in MDD patients during antidepressant treatment with duloxetine, a relatively new SNRI. MethodsA total of 30 MDD patients and 32 healthy controls were assessed using the Hamilton Depression Scale (HAM-D) and monitored for VEGF plasma levels at baseline, week 6 and week 12 of duloxetine treatment (60mg/day) and at baseline, respectively. ResultsAccording to early clinical response to duloxetine (defined at week 6 by reduction>50% of baseline HAM-D score), the MDD patients were divided into early responders (ER) and early non-responders (ENR). During duloxetine treatment, we found an opposite trend in the VEGF levels between ER and ENR: in ER the VEGF levels significantly increased in association with clinical response at W6, while in ENR the VEGF levels significantly decreased in association with an overall clinical response at W12. LimitationsSmall sample size. ConclusionsThe opposite trends in VEGF levels, increasing in ER and decreasing in ENR, might reflect differential Norepinephrine/Serotonin effects of duloxetine on differential neurobiological backgrounds of depressive syndromes. Overall, the modulation of VEGF signaling within the neurovascular unit during antidepressant treatment could hypothetically favor the remodeling of neural circuitry, contributing to adaptive adjustment of the NEI stress-adaptation system.

Effectiveness and cost-effectiveness of transmural collaborative care with consultation letter (TCCCL) and duloxetine for major depressive disorder (MDD) and (sub)chronic pain in collaboration with primary care: design of a randomized placebo-controlled multi-Centre trial: TCC:PAINDIP.

BackgroundThe comorbidity of pain and depression is associated with high disease burden for patients in terms of disability, wellbeing, and use of medical care. Patients with major and minor depression often present themselves with pain to a general practitioner and recognition of depression in such cases is low, but evolving. Also, physical symptoms, including pain, in major depressive disorder, predict a poorer response to treatment. A multi-faceted, patient-tailored treatment programme, like collaborative care, is promising. However, treatment of chronic pain conditions in depressive patients has, so far, received limited attention in research. Cost effectiveness of an integrated approach of pain in depressed patients has not been studied.This article describes the aims and design of a study to evaluate effects and costs of collaborative care with the antidepressant duloxetine for patients with pain symptoms and a depressive disorder, compared to collaborative care with placebo and compared to duloxetine alone.Methods/DesignThis study is a placebo controlled double blind, three armed randomized multi centre trial. Patients with (sub)chronic pain and a depressive disorder are randomized to either a) collaborative care with duloxetine, b) collaborative care with placebo or c) duloxetine alone. 189 completers are needed to attain sufficient power to show a clinically significant effect of 0.6 SD on the primary outcome measures (PHQ-9 score). Data on depression, anxiety, mental and physical health, medication adherence, medication tolerability, quality of life, patient-doctor relationship, coping, health resource use and productivity will be collected at baseline and after three, six, nine and twelve months.In the collaborative care conditions a) and b), a care-manager provides Problem Solving Treatment and integrated symptom management guidance with a self-help manual, monitors depressive and pain symptoms, and refers patients to a physiotherapist for treatment according to a 'Graded Activity' protocol. A psychiatrist provides duloxetine or placebo and pain medication according to algorithms, and also monitors pain and depressive symptoms. In condition c), the psychiatrist prescribes duloxetine without collaborative care. After 12 weeks, the patient is referred back to the general practitioner with a consultation letter, with information for further treatment of the patient.DiscussionThis study enables us to show the value of a closely monitored integrated treatment model above usual pharmacological treatment. Furthermore, a comparison with a placebo arm enables us to evaluate effectiveness of duloxetine in this population in a real life setting. Also, this study will provide evidence-based treatments and tools for their implementation in practice. This will facilitate generalization and implementation of results of this study. Moreover, patients included in this study are screened for pain symptoms, differentiating between nociceptive and neuropathic pain. Therefore, pain relief can be thoroughly evaluated.Trial registrationNTR1089

Acute and subacute effects of the selective serotonin–noradrenaline reuptake inhibitor duloxetine on cardiac hERG channels

Duloxetine is a selective serotonin-noradrenaline reuptake inhibitor approved for treatment of major depressive disorder. So far, duloxetine has been found to be well tolerated and reported cardiac side effects were negligible. However, pharmacological effects on cardiac hERG channels have not been properly addressed yet. hERG channels were expressed in Xenopus oocytes and a human embryonic kidney (HEK) cell line. Currents were measured using voltage clamp and patch clamp techniques. Channel surface expression was quantified using Western blot analysis. We found that duloxetine inhibits heterologously expressed hERG channels in a concentration-dependent manner, yielding an IC50 of 142.8 μM in Xenopus oocytes. Inhibitory effects were even more pronounced when using a mammalian cell line resulting in a 34 or 59% current decrease by 10 or 30 μM duloxetine, respectively. Duloxetine did not affect channel activation or inactivation kinetics. However, channel deactivation was accelerated by duloxetine. We further showed that inhibition occurs in the open and inactivated, but not closed, states. There was no frequency dependence of block. However, effects of duloxetine were significantly attenuated when using the hERG pore mutants Y652A and F656A. Subacute effects of duloxetine on hERG channel expression were analyzed using the Western blot technique. We found that incubation with duloxetine results in a concentration-dependent decrease of channel surface expression. Whereas inhibitory effects of duloxetine seem negligible under therapeutically relevant concentrations, hERG block should be considered in cases of duloxetine overdose and when administering duloxetine to patients susceptible to drug-induced QT prolongation.

Cost-Utility Analysis of Duloxetine in Osteoarthritis: A US Private Payer Perspective

Duloxetine has recently been approved in the USA for chronic musculoskeletal pain, including osteoarthritis and chronic low back pain. The cost effectiveness of duloxetine in osteoarthritis has not previously been assessed. Duloxetine is targeted as post first-line (after acetaminophen) treatment of moderate to severe pain. The objective of this study was to estimate the cost effectiveness of duloxetine in the treatment of osteoarthritis from a US private payer perspective compared with other post first-line oral treatments, including nonsteroidal anti-inflammatory drugs (NSAIDs), and both strong and weak opioids. A cost-utility analysis was performed using a discrete-state, time-dependent semi-Markov model based on the National Institute for Health and Clinical Excellence (NICE) model documented in its 2008 osteoarthritis guidelines. The model was extended for opioids by adding titration, discontinuation and additional adverse events (AEs). A life-long time horizon was adopted to capture the full consequences of NSAID-induced AEs. Fourteen health states comprised the structure of the model: treatment without persistent AE, six during-AE states, six post-AE states and death. Treatment-specific utilities were calculated using the transfer-to-utility method and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total scores from a meta-analysis of osteoarthritis clinical trials of 12 weeks and longer. Costs for 2011 were estimated using Red Book, The Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project database, the literature and, sparingly, expert opinion. One-way and probabilistic sensitivity analyses were undertaken, as well as subgroup analyses of patients over 65 years old and a population at greater risk of NSAID-related AEs. In the base case the model estimated naproxen to be the lowest total-cost treatment, tapentadol the highest cost, and duloxetine the most effective after considering AEs. Duloxetine accumulated 0.027 discounted quality-adjusted life-years (QALYs) more than naproxen and 0.013 more than oxycodone. Celecoxib was dominated by naproxen, tramadol was subject to extended dominance, and strong opioids were dominated by duloxetine. The model estimated an incremental cost-effectiveness ratio (ICER) of US$47,678 per QALY for duloxetine versus naproxen. One-way sensitivity analysis identified the probabilities of NSAID-related cardiovascular AEs as the inputs to which the ICER was most sensitive when duloxetine was compared with an NSAID. When compared with a strong opioid, duloxetine dominated the opioid under nearly all sensitivity analysis scenarios. When compared with tramadol, the ICER was most sensitive to the costs of duloxetine and tramadol. In subgroup analysis, the cost per QALY for duloxetine versus naproxen fell to US$24,125 for patients over 65 years and to US$18,472 for a population at high risk of cardiovascular and gastrointestinal AEs. The model estimated that duloxetine was potentially cost effective in the base-case population and more cost effective for subgroups over 65 years or at high risk of NSAID-related AEs. In sensitivity analysis, duloxetine dominated all strong opioids in nearly all scenarios.

Baseline patient characteristics associated with placebo remission and their impact on remission with duloxetine and selected SSRI antidepressants

Objective:We examined whether identification of patients with placebo-remitter characteristics and placebo-nonremitter characteristics enhances the ability to identify drug–placebo treatment differences and, perhaps, differences between agents in major depressive disorder (MDD). We hypothesized: 1) that drug–placebo differences in remission rates would be greater for both duloxetine and selective serotonin reuptake inhibitors (SSRIs) among placebo nonremitters than placebo remitters and: 2) that the difference between active treatments would also be greater in placebo nonremitters than placebo remitters.Data and methods:Data were obtained from seven randomized, parallel, double-blind MDD studies which compared the effects of duloxetine (N = 795), placebo (N = 510), and SSRIs (N = 551). The 17-item Hamilton depression rating scale (HAMD) was used to assess depression severity. The classification of participants as having placebo-remitter or placebo-nonremitter characteristics was based on age, duration of current MDD episode, HAMD anxiety score, and HAMD core score. Odds ratios (ORs) for remission comparing active treatment and placebo were obtained from logistic regression models. Tests of homogeneity were used for between-group comparisons.Results:For placebo nonremitters, both duloxetine (OR = 3.52 [95% CI: 2.21, 5.62; P < 0.0001]) and SSRIs (OR = 2.38 [95% CI: 1.45, 3.89; P = 0.0006]) showed significantly higher remission rates compared to placebo. Drug–placebo differences in remission were significantly greater for placebo nonremitters than for placebo remitters for both duloxetine (P = 0.02) and SSRIs (P = 0.049). For placebo remitters, remission with duloxetine (OR = 1.83 [95% CI: 1.35, 2.47; P = 0.0001]), but not the SSRIs selected for this study (OR = 1.31 [95% CI: 0.93, 1.84; P = 0.12]), was significantly greater than placebo. Contrary to expectation, the advantage of duloxetine over the SSRIs was not greater in placebo nonremitters. However, the fact that our analysis required patient-level data limited the number of agents studied, compromising generalization.Conclusions:Our study suggests that drug–placebo differences in remission rates will be greater in subjects with placebo-nonremitter than with placebo-remitter characteristics.

Cardiac syncope due to pain

Neurocardiogenic syncope comprises situations triggered by neurological reflexes resulting in abnormal responses of the neurocardiovascular system that cause loss of consciousness. A vast number of clinical conditions may cause this disorder including pain, defecation, micturition, swallowing, cough, sudden fear or excitement, exercise, and long-time standing. Treatment options for syncope prevention are not satisfactory. Several agents were used for pharmacological treatment without success. Selective inhibitors of neuronal norepinephrine transporter (NET) like duloxetine may play a role in neurally mediated syncope by increasing synaptic norepinephrine levels. Therefore, we report the effect of duloxetine in a patient with pain-induced syncope resistant to standard regimens.

Effect of Duloxetine on Pain, Function, and Quality of Life Among Patients With Chemotherapy-Induced Painful Peripheral Neuropathy

There are no known effective treatments for painful chemotherapy-induced peripheral neuropathy. To determine the effect of duloxetine, 60 mg daily, on average pain severity. Randomized, double-blind, placebo-controlled crossover trial at 8 National Cancer Institute (NCI)-funded cooperative research networks that enrolled 231 patients who were 25 years or older being treated at community and academic settings between April 2008 and March 2011. Study follow-up was completed July 2012. Stratified by chemotherapeutic drug and comorbid pain risk, patients were randomized to receive either duloxetine followed by placebo or placebo followed by duloxetine. Eligibility required that patients have grade 1 or higher sensory neuropathy according to the NCI Common Terminology Criteria for Adverse Events and at least 4 on a scale of 0 to 10, representing average chemotherapy-induced pain, after paclitaxel, other taxane, or oxaliplatin treatment. The initial treatment consisted of taking 1 capsule daily of either 30 mg of duloxetine or placebo for the first week and 2 capsules of either 30 mg of duloxetine or placebo daily for 4 additional weeks. The primary hypothesis was that duloxetine would be more effective than placebo in decreasing chemotherapy-induced peripheral neuropathic pain. Pain severity was assessed using the Brief Pain Inventory-Short Form "average pain" item with 0 representing no pain and 10 representing as bad as can be imagined. Individuals receiving duloxetine as their initial 5-week treatment reported a mean decrease in average pain of 1.06 (95% CI, 0.72-1.40) vs 0.34 (95% CI, 0.01-0.66) among those who received placebo (P = .003; effect size, 0.513). The observed mean difference in the average pain score between duloxetine and placebo was 0.73 (95% CI, 0.26-1.20). Fifty-nine percent of those initially receiving duloxetine vs 38% of those initially receiving placebo reported decreased pain of any amount. Among patients with painful chemotherapy-induced peripheral neuropathy, the use of duloxetine compared with placebo for 5 weeks resulted in a greater reduction in pain. clinicaltrials.gov Identifier: NCT00489411.

Comparison of safety outcomes among Caucasian, Hispanic, Black, and Asian patients in duloxetine studies of chronic painful conditions

Objective:This post-hoc analysis was conducted to investigate if safety outcomes differed among race/ethnic subgroups of patients treated with duloxetine for chronic painful conditions.Research design and methods:Pooled data from 15 placebo-controlled clinical trials were used to compare the safety outcomes of duloxetine among patients of Caucasian, Hispanic, Asian, and Black race/ethnic origins. Patients were randomized to receive placebo (n = 2199) or duloxetine (n = 3148) for treatment of diabetic peripheral neuropathic pain, fibromyalgia, osteoarthritis pain, or chronic low back pain. For categorical outcomes such as study discontinuation, adverse events leading to discontinuation, and treatment-emergent adverse events, incidence rates were summarized by race/ethnic subgroups. The Breslow–Day test was used to assess the homogeneity of treatment odds ratios across the four subgroups. For continuous outcomes such as changes in vital signs, body weight, and laboratory measures, an analysis of covariance or analysis of variance model was used and duloxetine effects were compared among race/ethnic subgroups based on the test of treatment-by-subgroup interaction.Results:No significant differences were found among race/ethnic subgroups for discontinuation due to adverse events except for anxiety (p = 0.040). Rates of nausea and decreased appetite were significantly higher (p ≤ 0.05) in duloxetine-treated patients compared with placebo-treated patients within each race/ethnic subgroup. The Breslow-Day test was not significant for most safety outcomes, nor were treatment-by-race/ethnic subgroup interactions (p > 0.1), which suggested duloxetine effects were not significantly different among race/ethnic subgroups.Conclusion:Overall, these results detected only minimal differences among safety outcomes assessed in these race/ethnic subgroups in patients treated with duloxetine for chronic painful conditions. The unbalanced sample sizes among the race/ethnic subgroups may have limited the power to detect treatment by race subgroup interactions. These post-hoc subgroup analyses were of an exploratory nature and the results should be interpreted with appropriate caution.

Impact of duloxetine on depression and anxiety in patients with ankylosing spondylitis: a case-control study

To evaluate the effects of duloxetine on depression, anxiety, pain, disease activity and function in patients with ankylosing spondylitis (AS). A total of 55 AS patients with concurrent depression disorders were randomized into treatment and control groups. Both were given conventional therapy of AS while duloxetine was administered in treatment group. Bath ankylosing spondylitis disease activity index (BASDAI), functional Index (BASFI) and metrology Index (BASMI), spinal pain, self-rating anxiety scale (SAS), self-rating depression scale (SDS) and Hamilton depression scale (HAMD) were recorded before and Weeks 4 and 8 weeks post-treatment. (1) Spinal pain, BASDAI, BASFI and SDS scores significantly declined by repeated measurement data analysis of variance in treatment group (P < 0.05). And no statistical difference existed between BASMI and SAS (P > 0.05). (2) The reduced rates of spinal pain and BASDAI were positively correlated with those of SDS and SAS. And the reduced rate of BASFI was positively correlated with SDS and HAMD reduced rate. However, no relationship existed between BASMI, SDS, SAS or HAMD. (3) The remission rate of AS symptoms and depression disorders were both significantly higher in treatment group than that in control group (P < 0.01, P < 0.05). The combined regimen of duloxetine and conventional therapy is significantly effective in the treatment of AS patients with depression and anxiety.

Effects of duloxetine in rats trained to discriminate between 22 and 2 hours food deprivation

Duloxetine is a serotonin and norepinephrine reuptake inhibitor used clinically to treat depression and generalized anxiety disorder. We tested the effects of duloxetine in rats trained to discriminate 22 hr food deprivation from 2 hr food deprivation in a two‐lever, operant choice task. After rats acquired the discrimination, subjects were food restricted for 22 hr and administered saline and duloxetine (3.2–17.8 mg/kg, s.c.) before generalization tests. Food intake was measured for 1 hr after generalization tests. Duloxetine (10–17.8 mg/kg) significantly reduced the discriminative stimulus effects of 22 hr deprivation, rates of lever pressing, and food intake induced by 22 hr deprivation. The present findings are consistent with our previous research with sibutramine and offer further evidence that serotonin and norepinephrine are important regulators of both food intake and internal states associated with food deprivation.

Influence of Duloxetine on the in-vivo pharmacokinetics of Metoprolol in rat model

BackgroundIt is widely accepted that Duloxetine and Metoprolol are concomitantly administered for clinical conditions like diabetic neuropathic pain and diabetic cardiovascular disorders respectively. Since these two drugs interfere with Cytochrome P2D6 (CYP2D6), there is likelihood of possible potential drug–drug interactions between these two drugs. Hence, this study was undertaken to investigate the effect of Duloxetine on the in-vivo pharmacokinetics of Metoprolol in rat models. MethodsIn-vivo pharmacokinetic studies were performed on rats. Rats were treated with Duloxetine (20 mg/kg) and Metoprolol (25 mg/kg) orally and blood samples were collected (0), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12 and 24 h post treatment. Plasma concentration of Metoprolol was estimated by Reverse Phase High Performance Liquid Chromatography (RP-HPLC) method. ResultsDuloxetine treatment along with Metoprolol results in 3.38 fold significant (p < 0.01) increase in the area under the curve (AUC0–24) of Metoprolol, three fold significant (p < 0.01) increase in the AUC0–α of Metoprolol, 3.4 fold increase in T1/2 of Metoprolol without significant alteration in maximum concentration (Cmax) of Metoprolol. ConclusionsConcomitant administration of Duloxetine and Metoprolol orally in rat models results in increased exposure (AUC) of Metoprolol without significant increase in maximum concentration. This interaction could be of clinical significance if it is confirmed in human studies.

Efficacy and safety of duloxetine 60 mg once daily in major depressive disorder: a review with expert commentary

Objective:Major depressive disorder (MDD) is a significant public health concern and challenges health care providers to intervene with appropriate treatment. This article provides an overview of efficacy and safety information for duloxetine 60 mg/day in the treatment of MDD, including its effect on painful physical symptoms (PPS).Design:A literature search was conducted for articles and pooled analyses reporting information regarding the use of duloxetine 60 mg/day in placebo-controlled trials.Setting:Placebo-controlled, active-comparator, short- and long-term studies were reviewed.Participants:Adult (≥18 years) patients with MDD.Measurements:Effect sizes for continuous outcome (change from baseline to endpoint) and categorical outcome (response and remission rates) were calculated using the primary measures of 17-item Hamilton Rating Scale for Depression (HAMD-17) or Montgomery–Åsberg Depression Rating Scale (MADRS) total score. The Brief Pain Inventory and Visual Analogue Scales were used to assess improvements in PPS. Glass estimation method was used to calculate effect sizes, and numbers needed to treat (NNT) were calculated based on HAMD-17 and MADRS total scores for remission and response rates. Safety data were examined via the incidence of treatment-emergent adverse events and by mean changes in vital-sign measures.Results:Treatment with duloxetine was associated with small-to-moderate effect sizes in the range of 0.12 to 0.72 for response rate and 0.07 to 0.65 for remission rate. NNTs were in the range of 3 to 16 for response and 3 to 29 for remission. Statistically significant improvements (p≤0.05) were observed in duloxetine-treated patients compared to placebo-treated patients in PPS and quality of life. The safety profile of the 60-mg dose was consistent with duloxetine labeling, with the most commonly observed significant adverse events being nausea, dry mouth, diarrhea, dizziness, constipation, fatigue, and decreased appetite.Conclusion:These results reinforce the efficacy and tolerability of duloxetine 60 mg/day as an effective short- and long-term treatment for adults with MDD. The evidence of the independent analgesic effect of duloxetine 60 mg/day supports its use as a treatment for patients with PPS associated with depression. This review is limited by the fact that it included randomized clinical trials with different study designs. Furthermore, data from randomized controlled trials may not generalize well to real clinical practice.