Dose Of Duloxetine Research Articles

Observational study on safety and tolerability of duloxetine in the treatment of female stress urinary incontinence in German routine practice.

To evaluate the safety and tolerability of duloxetine during routine clinical care in women with stress urinary incontinence (SUI) in Germany, and in particular, to identify previously unrecognized safety issues as uncommon adverse reactions, and the influence of confounding factors present in clinical practice on the safety profile of duloxetine. Office-based urologists, gynaecologists and primary care physicians were asked to document women newly started on treatment for moderate to severe symptoms of SUI. Six thousand eight hundred and fifty-four patients from urologist/gynaecologist practices and 5879 primary care patients were assessed. In a two-armed, observational study with parallel 12 week (urologists and gynaecologists) or 24 week (primary care physicians) design, patients were treated with duloxetine or other conservative treatment. The main outcome measure was the occurrence of adverse events (AEs). Baseline characteristics differed slightly between patient groups and studies. Duloxetine doses in most patients were lower than recommended. Overall, AE frequency with duloxetine was lower than in controlled studies (15.9% (95% CI 14.9, 16.9) and 9.1% (95% CI 8.2, 10.0) in the 12 and 24 week treatment groups, respectively), but exhibited a similar qualitative spectrum. In the logistic regression models, the following factors were associated with greater AE risk: investigator specialization (gynaecologist vs. urologist and primary care physician), initial duloxetine dose (80 vs. 20 mg day(-1) ) and use of any concomitant medication. Within the 24 week study, a positive screen for depressive disorder was surprisingly common, but no case of attempted suicide was reported in either study. Our results from German clinical practice show that women with SUI were often treated with duloxetine doses lower than recommended. This was associated with a low incidence of AEs. Suicide attempts were not reported.

Assessment of falls in older patients treated with duloxetine: a secondary analysis of a 24-week randomized, placebo-controlled trial.

To assess fall events in older depressed patients during treatment with duloxetine. Post hoc analysis of solicited fall events collected at each study visit using a questionnaire during a 24-week, multicenter, randomized, placebo-controlled, double-blind, phase 4 trial (November 2006 to November 2009). Older outpatients (≥ 65 years) with major depressive disorder (DSM-IV criteria) were randomly assigned to duloxetine 60 mg/d (n = 249) or placebo (n = 121) for the 12-week acute phase, after which the duloxetine dose could be increased to 120 mg/d and nonresponding placebo patients could be switched to duloxetine 60 mg/d. Between-treatment differences in percentages of patients with fall events were compared by Fisher exact test. Exposure-adjusted incidence rates (EAIRs) of falls per patient-year were also estimated. In the acute phase, 17.3% of patients treated with duloxetine 60 mg versus 11.6% treated with placebo (P = .170) experienced a fall event. Over 24 weeks, the percentage of patients with a fall while taking duloxetine 60 mg versus placebo was 24.0% versus 15.7% (P = .078), and the percentage was significantly higher in patients taking duloxetine regardless of dose (25.3%) than with placebo (15.7%, P = .045). Between-treatment differences in EAIRs over 12 weeks (0.26; 95% CI, -0.20 to 0.72) and over 24 weeks (0.27; 95% CI, -0.10 to 0.65) were not significant. Direct assessment of fall events greatly increases the number of falls reported by patients. Although the EAIR of falls per patient-year associated with duloxetine was not significant in this trial, clinicians should remain vigilant about the possibility of falls in older patients with duloxetine or any antidepressant treatment. ClinicalTrials.gov identifier NCT00406848.

P1-110 - Use of Duloxetine for Treatment of Neuropathic Pain in Cancer Patients

ABSTRACT Purpose Neuropathic pain frequently occurs in cancer patients, but the mechanism has yet to be clarified and no drug therapy has been established. The purpose of this study was to investigate the effect of duloxetine on neuropathic pain in cancer patients. Methods The subjects were 15 cancer patients (9 males) with neuropathic pain who visited the Kinki University Faculty of Medicine Hospital between April 2011 and October 2011 and met the IASP diagnostic criteria for neuropathic pain. Duloxetine was administered in patients in whom pregabalin could not be administered, was ineffective, or was effective but the dose could not be elevated due to an adverse effect. The influence of duloxetine on pain and adverse effects was investigated retrospectively. Results Pain was reduced in 7 of the 15 patients. Sleepiness and a light-headed feeling were improved in three in whom pain was not reduced. Thus, the duloxetine was judged to be effective in 10 patients. The maintenance dose of duloxetine was 20–40 mg/day in patients who took the drug for 2 weeks or longer. Conclusion Duloxetine administration may be effective for neuropathic pain in cancer patients who cannot tolerate pregabalin administration.

The role of the NMDA receptors and l-arginine–nitric oxide–cyclic guanosine monophosphate pathway in the antidepressant-like effect of duloxetine in the forced swimming test

Duloxetine is a selective serotonin and noradrenaline reuptake inhibitor used as antidepressant. However, its mechanisms of action are not fully understood. This study investigated the effect of duloxetine in the mouse forced swimming test (FST) and in the tail suspension test (TST) and the involvement of the NMDA receptors and the l-arginine–NO–cGMP pathway in its effect in the FST. Duloxetine reduced the immobility time both in the FST and in the TST (dose range of 1–30mg/kg, i.p.), without changing locomotion in an open-field. Duloxetine administered orally (1–30mg/kg) also reduced the immobility time in the FST. The effect of duloxetine (10mg/kg, p.o.) in the FST was prevented by pre-treatment with NMDA (0.1pmol/site, i.c.v.), d-serine (30μg/site, i.c.v.), (l-arginine (750mg/kg, i.p.), S-nitroso-N-acetyl-penicillamine (SNAP, 25μg/site, i.c.v) or sildenafil (5mg/kg, i.p.). The administration of MK-801 (0.001mg/kg, i.p.), 7-nitroindazole (50mg/kg, i.p.), methylene blue (20mg/kg, i.p.) or 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) (30pmol/site i.c.v.) in combination with a sub-effective dose of duloxetine (0.3mg/kg, p.o.) reduced the immobility time in the FST. Moreover, the administration of duloxetine (10mg/kg) produced a reduction in NOx levels in the hippocampus and cerebral cortex. Altogether the results suggest that the effect of duloxetine in the FST is dependent on either a blockade of NMDA receptors or an inhibition of NO. In addition, our results further reinforce the role of NMDA receptors and l-arginine–NO–cGMP pathway, besides the monoaminergic systems, in the mechanism of action of current prescribed antidepressant agents.

Tolerability aspects in duloxetine-treated patients with depression: should one use a lower starting dose in clinical practice?

Objective: This study questions whether a lower starting dose of duloxetine (DLX) could be beneficial for patients with depression, in terms of tolerability and safety in routine clinical care.Research design and methods: Post-hoc analyses of a multicenter, prospective, non-interventional, 6-month study in adult outpatients with a depressive episode was undertaken.Main outcome measures: Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), discontinuations due to TEAEs and hospitalizations due to depression, were all documented at 2 weeks, 4 weeks, 3 months and 6 months after treatment initiation/switch to DLX.Results: Of 4517 patients enrolled, 4313 were included for TEAE evaluation. TEAEs occurred in 17.2% of patients, and SAEs occurred in 0.79% of patients, including one case of suicidal ideation. 1404 patients discontinued within 6 months (TEAEs: n = 119). Starting treatment with 30 mg/day DLX (72.7%) was favored in females, or after inadequate efficacy of previous antidepressant treatment; 60 mg/day DLX was favored in more severe depression and patients receiving concomitant pain medication.Conclusion: Initiating treatment with 60 mg/day DLX was not associated with poorer tolerability in this study. Physicians may be guided by their clinical experience to carefully consider the individual benefit/risk ratio and TEAE susceptibility when deciding to start treatment with a higher or a lower dose of DLX.

A Cost-Utility Analysis of Pregabalin Versus Duloxetine for the Treatment of Painful Diabetic Neuropathy

ABSTRACTThe objective of the current study was to determine the cost-utility of pregabalin versus duloxetine for treating painful diabetic neuropathy (PDN) using a decision tree analysis. Literature searches identified clinical trials and real-world studies reporting the efficacy, tolerability, safety, adherence, opioid usage, health care utilization, and costs of pregabalin and duloxetine. The proportions of patients reported in the included studies were used to determine probabilities in the decision tree model. The base-case model included the Food and Drug Administration (FDA)-approved doses of pregabalin (300 mg/day) and duloxetine (60 mg/day), whereas “real-world” sensitivity analyses explored the effects over a range of doses (pregabalin 75–600 mg/day, duloxetine 20–120 mg/day). A 6-month time horizon and a US third-party payer perspective were chosen for the study. Outcomes from the model were expressed as cost per quality-adjusted life-year (QALY). In the base-case model, duloxetine cost less and was more effective than pregabalin (incremental cost −$187, incremental effectiveness 0.011 QALYs). Results from two real-world sensitivity analyses indicated that duloxetine cost $16,300 and $20,667 more per additional QALY than pregabalin. Using a decision tree model that incorporated both clinical trial and real-world data, duloxetine was a more cost-effective option than pregabalin in the treatment of PDN from the perspective of third-party payers.

An Open-Label Safety and Pharmacokinetics Study of Duloxetine in Pediatric Patients with Major Depression

This preliminary, 32-week study assessed the safety, tolerability, and pharmacokinetics of duloxetine in pediatric patients (aged 7-17 years) with major depressive disorder. Patients received flexible duloxetine doses of 20-120 mg once daily, with dose changes made based on clinical improvement and tolerability. Pharmacokinetic samples were collected across all duloxetine doses, and data were analyzed using population modeling. Primary outcome measures included treatment-emergent adverse events (TEAEs), vital signs, and Columbia-Suicide Severity Rating Scale (C-SSRS). Of the 72 enrolled patients, 48 (66.7%) completed acute treatment (18 weeks) and 42 (58.3%) completed extended treatment. Most patients (55/72; 76%) required doses ≥ 60 mg once daily to optimize efficacy based on investigator judgment and Clinical Global Impressions-Severity score. Body weight and age did not significantly affect duloxetine pharmacokinetic parameters. Typical duloxetine clearance in pediatric patients was ≈ 42%-60% higher than that in adults. Four patients (5.6%) discontinued due to TEAEs. Many (36/72, 50%) patients experienced potentially clinically significant (PCS) elevations in blood pressure, with most cases (21/36, 58%) being transient. As assessed via C-SSRS, one nonfatal suicidal attempt occurred, two patients (2.8%) experienced worsening of suicidal ideation, and among the 19 patients reporting suicidal ideation at baseline, 17 (90%) reported improvement in suicidal ideation. Results suggested that pediatric patients generally tolerated duloxetine doses of 30 to 120 mg once daily, although transient PCS elevations in blood pressure were observed in many patients. Pharmacokinetic results suggested that adjustment of total daily dose based on body weight or age is not warranted for pediatric patients and different total daily doses may not be warranted for pediatric patients relative to adults.

The Effect of Initial Duloxetine Dosing Strategy on Nausea in Korean Patients with Major Depressive Disorder

ObjectiveTo assess the relative severity of nausea in patients from Korea with major depressive disorder (MDD) who were treated with duloxetine at low (30 mg) or high (60 mg) doses, with or without food, for the first week of an 8 week treatment.MethodsAdult patients (n=249), with MDD and a 17-item Hamilton Rating Scale for Depression (HAMD17) score of ≥15, received open-label once daily duloxetine. At Week 0, patients were randomized to 4 groups: 30 mg with food (n=63), 60 mg with food (n=59), 30 mg without food (n=64), and 60 mg without food (n=63). At Week 1, all patients switched to duloxetine 60 mg for 7 weeks. The primary outcome measure was item 112 (nausea) of the Association for Methodology and Documentation in Psychiatry adverse event scale. Effectiveness was assessed by change in HAMD17 total score.ResultsOverall, 94.4% (235/249) of patients completed Week 1 and 55.0% (137/249) of patients completed the study. For Week 1, nausea was significantly less severe for patients who received 30 mg compared with 60 mg duloxetine (p=0.003), regardless of food intake. In all groups, nausea severity was highest at Week 1 and declined throughout the study. HAMD17 score was reduced in all groups and the most common adverse event reported was nausea (145/249; 58.2%).ConclusionTo minimize nausea, Korean patients with MDD who require duloxetine treatment could be given 30 mg once daily, regardless of food, for the first week followed by 60 mg once daily for the course of therapy.

Dosing Patterns for Duloxetine and Predictors of High-Dose Prescriptions in Patients With Major Depressive Disorder: Analysis from a United States Third-Party Payer Perspective

Background Major depressive disorder (MDD) is a common illness that affects ∼7% of adults in the United States each year. Duloxetine is a dual reuptake inhibitor of serotonin and norepinephrine that has demonstrated efficacy and tolerability in the treatment of MDD. Objective The purpose of our study was to examine dosing patterns and pretreatment predictors of high-dose duloxetine therapy for patients with MDD in the usual clinical setting. Methods Data were from 6132 commercially insured patients with MDD initiated on duloxetine during 2005 and 2006. Patients had no duloxetine use in the previous 6 months and had continuous enrollment in a health plan for the 12 months immediately preceding and following initiation. Dosing patterns and predictors of high-dose therapy with duloxetine were examined. Results Initial doses of duloxetine were <60 mg/d, 60 mg/d, 90 mg/d, and ≥120 mg/d for 32.4%, 60.9%, 3.1%, and 3.5% of patients, respectively. Maximum daily doses were <60 mg, 60 mg, 90 mg, and ≥120 mg for 16.3%, 59.3%, 11.0%, and 13.3% of patients, respectively. Patients treated with >60 mg/d for at least 2 months were older, were more likely to have been treated by a psychiatrist, had greater comorbidity, and had used more health care resources and psychotropic and pain medications in the previous year. The following factors were independently associated with doses of >60 mg/d: older age (odds ratio [OR] = 1.33–1.46); comorbid neuropathic pain (OR = 1.88); fibromyalgia (OR = 1.36); dysthymic disorder (OR = 1.24); prior injury/poisoning (OR = 1.19); physician specialty (psychiatrist, OR = 1.55); and prior use of psychostimulants (OR = 1.26), benzodiazepines (OR = 1.19), venlafaxine (OR = 1.35), or atypical antipsychotics (OR = 1.35). Conclusions Most of the commercially insured patients in this dataset were initiated and maintained on a duloxetine dose of 60 mg/d. Although the data are limited in their generalizability, the characteristics associated with higher dose therapy describe a complex group of patients who may require more intensive drug treatment and monitoring.

An open pilot study of zonisamide augmentation in major depressive patients not responding to a low dose trial with duloxetine: preliminary results on tolerability and clinical effects

BackgroundDespite multiple antidepressant options, major depressive disorder (MDD) still faces high non-response rates, eventually requiring anticonvulsant augmentation strategies too. The aim of this study was to explore such a potential role for zonisamide.MethodsA total of 40 MDD outpatients diagnosed using the Diagnostic and Statistical Manual for Mental Disorders, fourth edition criteria entered a 24 week open trial receiving duloxetine 60 mg/day for the first 12 weeks and subsequently (weeks 12 to 24) augmentation with zonisamide 75 mg/day if they did not respond to the initial monotherapy. Efficacy and tolerability were assessed using the Hamilton Scales for Anxiety and Depression (a 12 week score ≥50% vs baseline defined 'non-response'), the Arizona Sexual Experience Scale, the Patient Rated Inventory of Side Effects and the Young Mania Rating Scale.ResultsAt week 12, 15 patients out of 39 (38.5%) were responders, and 1 had dropped out; remarkably, 14 patients out of 24 (58.3%) had achieved response by week 24. Poor concentration and general malaise were associated with non-response both at week 12 and 24 (P = 0.001), while loss of libido and reduced energy were prominent among final timepoint non-responders. Patients receiving zonisamide also experienced weight reduction (2.09 ± 12.14 kg; P = 0.001) independently of the outcome.ConclusionsAlthough only a preliminary study due to strong methodological limitations, and thus requiring confirmation by further controlled investigations, the current results indicate zonisamide may be a potential augmentation option for some depressed patients receiving low doses of duloxetine.

A Systematic Review and Mixed Treatment Comparison of the Efficacy of Pharmacological Treatments for Fibromyalgia

To review the literature on pharmacological treatments for fibromyalgia. Relative efficacy was estimated in terms of outcome measures highlighted by the Outcome Measures in Rheumatology Network using a Bayesian mixed treatment comparison (MTC) meta-analysis. Randomized controlled trials reporting treatments for fibromyalgia were identified by systematically reviewing electronic databases (Cochrane Library, Medline, EMBASE; accessed February 2008) and conducting manual bibliographic searches. Forty-five randomized controlled trials met the prespecified inclusion criteria for the systematic review. There were limited robust clinical data for some therapeutic classes (tricyclic antidepressants, analgesics, sedative hypnotics, monoamine oxidase inhibitors) and only 21 studies met the more stringent criteria for inclusion in the MTC. The majority of studies included in the MTC assessed the anticonvulsant pregabalin (n = 5) or the serotonin norepinephrine reuptake inhibitors (SNRIs) duloxetine (n = 3) and milnacipran (n = 3). Licensed doses of pregabalin and duloxetine were significantly (P < 0.05) more efficacious than placebo in terms of absolute reduction in pain, number of "responders" (≥30% reduction in pain), or change in Fibromyalgia Impact Questionnaire score (pregabalin 450 mg/d only). There was no significant difference between licensed doses of pregabalin and duloxetine for these outcomes. However licensed doses of pregabalin produced significantly greater improvements in sleep compared with milnacipran (as measured by Medical Outcomes Study Sleep Scale). The current study confirms the therapeutic efficacy of pregabalin and the SNRIs, duloxetine and milnacipran, in the treatment of fibromyalgia. Given their different modes of action, combination therapy with pregabalin plus an SNRI should be investigated in future research.

Duloxetine in the management of diabetic peripheral neuropathic pain.

Diabetic neuropathy affects up to 70% of diabetics, and diabetic peripheral neuropathic pain (DPNP) is the most common and debilitating of the diabetic neuropathies. DPNP significantly reduces quality of life and increases management costs in affected patients. Despite the impact of DPNP, management is poor with one-quarter of patients receiving no treatment and many treated with medications having little or no efficacy in managing DPNP. Duloxetine is one of two drugs approved by the United States Food and Drug Administration for DPNP management. Duloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI) proven safe, effective, and cost-saving in reducing DPNP symptoms at a dose of 60 mg/day. Duloxetine doses greater than 60 mg/day for DPNP management are not recommended since they are no more efficacious and associated with more side effects; addition of pregabalin or gabapentin for these patients may be beneficial. Side effects of duloxetine are generally mild and typical for the SNRI class including nausea, dizziness, somnolence, fatigue, sweating, dry mouth, constipation, and diarrhea. Given its other indications, duloxetine is a particularly good choice for DPNP treatment in patients with coexisting depression, anxiety, fibromyalgia, or chronic musculoskeletal pain. Duloxetine treatment had no clinically significant effect on glycemic control and did not increase the risk of cardiovascular events in diabetes patients. However, duloxetine use should be avoided in patients with hepatic disease or severe renal impairment. Given its safety, efficacy, and tolerability, duloxetine is an excellent choice for DPNP treatment in many patients.

Postprostatectomy Established Stress Urinary Incontinence Treated With Duloxetine

To evaluate the efficacy of duloxetine to treat stress urinary incontinence, 1 of the most frequent complications after radical prostatectomy. Conservative measures and surgery are well-established treatments. However, drug treatment could be an intermediate option. All patients had >1 year of follow-up after radical prostatectomy to avoid interfering with the natural recovery period (established stress urinary incontinence). Continence was measured by the average daily use of pads and the International Consultation on Incontinence Questionnaire-short form. In Spain, it is necessary to proceed with off-label use formality, and all patients were informed and agreed. The initial dose of duloxetine was 30 mg once daily and was increased to 60 mg/d. Drug treatment was maintained for 9 months. From June 2006 to July 2007, 68 patients were included. The median age was 68 years (range 52-79). The median duration of duloxetine treatment was 5.56 months (range 1-18). A statistically significant decrease in the International Consultation on Incontinence Questionnaire-Urinary Incontinence-short form (from 13 to 9; P < .001) and the average number of pads/d (from 2 to 1; P < .001) was observed between the initial and 3-month visit. At the end of the follow-up period, 74% and 57% of the patients had a reduced International Consultation on Incontinence Questionnaire-Urinary Incontinence-short form score and a decrease in the number of pads used daily, respectively. Of the 68 patients, 32 (47%) presented with some side effects and 17 patients stopped the treatment because of adverse effects (25%). Our results suggest that duloxetine is a possible alternative treatment of postprostatectomy established stress urinary incontinence. The continence improvement results were mild and conditioned in part by the frequency of the side effects. Provided that duloxetine does not preclude later continence surgery and the benefits are observed at the first visit, we believe it can be a treatment option for selected patients.

Serotonin Syndrome Due to Duloxetine

Serotonin syndrome is a toxic condition due to serotoninergic hyperstimulation, which is caused mostly by serotonergic agents either in overdose or in combination. The diagnosis is purely clinical and poorly validated. We described a patient with tremor, mydriatic pupils, clonus, and ataxia after a single dose of duloxetine; on the dosage of admission. Duloxetine belongs to a large class of antidepressants called reuptake inhibitors. The case is presented to emphasize this possible toxicity due to increasing availability of serotonergic agents. It is a complex but easily preventable and recognizable condition. We believe this to be one of the rare reports of serotonin syndrome associated with duloxetine.

Average daily dose, medication adherence, and healthcare costs among commercially-insured patients with fibromyalgia treated with duloxetine

Objective:What is the relationship between average daily dose (ADD) of duloxetine, adherence to therapy, and healthcare costs among patients with fibromyalgia?Methods:Employing a retrospective cohort design, this study assessed administrative claims data for commercially-insured fibromyalgia patients who initiated duloxetine in 2006. Initiation was defined as a 90-day clean period without access to duloxetine. Five study cohorts were constructed based on the ADD of duloxetine, calculated from all prescriptions dispensed over the 12-month follow-up period: <30 mg, 30 mg, 31–59 mg, 60 mg, and >60 mg (duloxetine starting dose: 30 mg/day; target dose: 60 mg/day). Medication possession ration (MPR) was used to assess duloxetine adherence, with MPR ≥0.8 as ‘high’ adherence. Multivariate regressions were applied to examine the association between ADD, duloxetine adherence, and healthcare costs (total, inpatient, outpatient, and pharmacy), adjusting for differences in demographic and clinical characteristics between cohorts.Results:Of the 4869 patients with fibromyalgia, 3% had an ADD of <30 mg, 12% had 30 mg, 21% had 31–59 mg, 46% had 60 mg, and 18% had >60 mg. High adherence to duloxetine ranged from 16% to 41% across cohorts. Controlling for demographic and clinical characteristics, patients with an ADD of 31–59 mg or >60 mg were more likely to adhere to duloxetine therapy than those in the 60 mg cohort, while patients in the <30 mg cohort were less likely to adhere to duloxetine (all p < 0.05). Total costs were significantly higher for individuals in the 31–59 mg or >60 mg ADD cohorts ($1834 and $5766) than those maintaining an ADD of 60 mg, as were outpatient ($1167 and $2275) and pharmacy costs ($502 and $2983) (all p < 0.05). Patients with an ADD of 30 mg had significantly lower total (−$1770), inpatient (−$1524), and pharmacy (−$827) costs (all p < 0.05) than those with an ADD of 60 mg.Limitations:This study is subject to selection bias because some confounders might be unobserved in the administrative claims database. Indirect costs or over-the-counter medication costs were also not available.Conclusions:Fibromyalgia patients with an ADD of 60 mg of duloxetine had better adherence than patients with an ADD ≤30 mg. Duloxetine patients with an ADD of 30 mg (31–59 or >60 mg) had significantly lower (higher) healthcare costs than those maintaining an ADD of 60 mg.

Trajectory analysis of healthcare costs for patients with major depressive disorder treated with high doses of duloxetine

Objective:To examine healthcare cost patterns prior to and following duloxetine initiation in patients with major depressive disorder (MDD), focusing on patients initiated at or titrated to high doses.Research design and methods:Retrospective analysis of 10,987 outpatients, aged 18–64 years, who were enrolled in health insurance for 6 months preceding and 12 months following duloxetine initiation.Outcome measures:Repeated measures and pre–post analyses were used to examine healthcare cost trajectories before and after initiation of low- (<60 mg/day), standard- (60 mg/day), and high-dose (>60 mg/day) duloxetine therapy. Decision tree analysis was used to identify patient characteristics that might explain heterogeneity in economic outcomes following titration to high-dose therapy.Results:Low-, standard-, and high-dose duloxetine were initiated for 29.6%, 60.9%, and 9.5% of patients, respectively. Within 6 months, 13.7% of patients had dose increases to > 60 mg/day. Regardless of dose, total costs increased prior to and decreased following initiation of treatment. The High Initial Dose Cohort had higher costs both prior to and throughout treatment compared to the other two cohorts. Following escalation to > 60 mg/day, higher medication costs were balanced by lower inpatient costs. Titration to high-dose therapy was cost-beneficial for patients with histories of a mental disorder in addition to MDD and higher prior medical costs.Limitations:Conclusions are limited by a lack of supporting clinical information and may not apply to patients who are not privately insured.Conclusions:In data taken from insured patients with MDD who were started on duloxetine in a clinical setting, healthcare costs increased prior to and decreased following initiation of therapy. Compared to patients initiated at low- and standard-doses, costs were greater prior to and following initiation for patients initiated at high doses. Increases in pharmacy costs associated with escalation to high-dose therapy were offset by reduced inpatient expenses.

Duloxetine in patients with central neuropathic pain caused by spinal cord injury or stroke: A randomized, double-blind, placebo-controlled trial

The mechanisms underlying central neuropathic pain are poorly understood. Pain inhibitory mechanisms including sertononergic and norepinephrine systems may be dysfunctional. In this randomized, double-blinded, placebo-controlled trial we evaluated the effects of duloxetine on pain relief (spontaneous pain and evoked pain), tolerability, health status, and quality of life in patients with central pain related to cerebrovascular lesions or spinal cord lesions. At baseline and eight weeks following start of treatment subjects were evaluated with standard measures of efficacy: pain intensity (primary efficacy variable), quantitative sensory testing, health status and quality of life (secondary efficacy variables). Forty-eight patients received escalating doses of either duloxetine (60 and 120mg/day) or matching placebo capsules. In both groups, patients started with 1 capsule per day. If pain relief was insufficient, patients were titrated to a higher dose. A trend towards a decrease in mean pain score after eight weeks was observed for duloxetine treatment (p=0.056). Duloxetine alleviated dynamic (p=0.035) and cold allodynia (p<0.001) significantly better than placebo. Tactile pain and pressure pain thresholds did not improve significantly. The duloxetine group showed a significant improvement for the bodily pain domain of the SF36 (p=0.035). No significant differences were observed in the other domains of the SF36, the Pain Disability Index, and the EQ-5D. While this trial showed no significant effect on pain intensity, duloxetine revealed a biologic effect. It would be worthwhile to suspend our judgement and to perform more studies to evaluate the role of duloxetine in modulation of the symptoms of central neuropathic pain.

Duloxetine reduces morphine requirements after knee replacement surgery

BackgroundMultimodal analgesia is advocated for perioperative pain management to reduce opioid use and its associated adverse effects. Serotonin and norepinephrine are involved in the modulation of endogenous analgesic mechanisms via descending inhibitory pain pathways in the brain and spinal cord. An increase in serotonin and norepinephrine may increase inhibition of nociceptive input and improve pain relief. Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, has demonstrated efficacy in chronic pain conditions such as painful diabetic neuropathy and post-herpetic neuralgia. The objective of the study was to evaluate the efficacy of duloxetine in reducing morphine requirements in patients after knee replacement surgery. MethodsFifty patients received either two doses of oral duloxetine 60 mg (2 h before surgery and on first postoperative day) or placebo. All patients received patient-controlled analgesia with morphine for 48 h after operation. Pain and adverse effects were assessed at 0.5, 1, 2, 6, 12, 24, and 48 h after surgery on an 11-point numeric rating scale. ResultsTwenty-three patients in the duloxetine group and 24 patients in the placebo group completed the study. Morphine requirements during the 48 h after surgery were significantly lower in the duloxetine group [19.5 mg, standard deviation (sd) 14.5 mg] compared with the placebo group (30.3 mg, sd 18.1 mg) (P=0.017). There were no statistically significant differences between the groups in pain scores (at rest and on movement) or in adverse effects. ConclusionsPerioperative administration of duloxetine reduced postoperative morphine requirements during the first 48 h after knee replacement surgery, without significant adverse effects.

α 2-Adrenoceptor Blockade Potentiates the Effect of Duloxetine on Sneeze Induced Urethral Continence Reflex in Rats

Serotonin and norepinephrine reuptake inhibitors such as duloxetine have clinical efficacy for stress urinary incontinence. However, the therapeutic dose of duloxetine is often associated with unwanted side effects. We examined whether combined alpha(2)-adrenoceptor antagonists could decrease the duloxetine dose due to synergistic effects. We used normal female rats and rats with stress urinary incontinence induced by vaginal distention. Urethral responses were measured using a microtransducer tipped catheter. We evaluated the effect of low dose duloxetine (0.1 mg/kg), alpha(2)-adrenoceptor antagonists (idazoxan or yohimbine) and sequential administration of drugs on urethral pressure response amplitude during sneezing and urethral baseline pressure. Sneeze induced leak point pressure was also measured. In normal and vaginally distended rats low dose duloxetine did not alter urethral pressure response amplitude during sneezing but it significantly increased urethral baseline pressure. When low dose duloxetine was co-applied with alpha(2)-adrenoceptor antagonists, urethral pressure response amplitude during sneezing was significantly increased. In all 7 vaginally distended rats leakage was observed during sneezing. After low dose duloxetine administration fluid leakage still occurred during sneezing. However, after low dose duloxetine and idazoxan co-administration fluid leakage disappeared in 2 of 7 rats and sneeze induced leak point pressure was significantly increased in the remaining incontinent rats with vaginal distention. Findings support the concept that combination therapy with alpha(2)-adrenoceptor antagonists may be an effective, novel strategy to reinforce the clinical efficacy of serotonin and norepinephrine reuptake inhibitors for stress urinary incontinence.

Efficacy and Safety of Duloxetine in Patients With Chronic Low Back Pain

This was a randomized, double-blind, placebo-controlled clinical trial. To assess the efficacy and safety of duloxetine in the treatment of chronic low back pain (CLBP). Imbalance of serotonin and norepinephrine within modulatory pain pathways has been implicated in the development and maintenance of chronic pain. Duloxetine, a selective reuptake inhibitor of serotonin and norepinephrine, has demonstrated clinical efficacy in 3 distinct chronic pain conditions: diabetic peripheral neuropathic pain, fibromyalgia, and chronic pain because of osteoarthritis. In this randomized double-blind trial, adult nondepressed patients with a non-neuropathic CLBP and a weekly mean of the 24-hour average pain score>or=4 at baseline (0-10 scale) were treated with either duloxetine or placebo for 13 weeks. The dose of duloxetine during first 7 weeks was 60 mg once daily. At week 7, patients reporting<30% pain reduction had their dose increased to 120 mg. The primary outcome measure was the Brief Pain Inventory (BPI) 24-hour average pain rating. Secondary measures included Roland-Morris Disability Questionnaire-24; Patient's Global Impressions of Improvement; Clinical Global Impressions-Severity (CGI-S); BPI-Severity and -Interference (BPI-I); and weekly means of the 24-hour average pain, night pain, and worst pain scores from patient diaries. Quality-of-life, safety, and tolerability outcomes were also assessed. Compared with placebo-treated patients (least-squares mean change of -1.50), patients on duloxetine (least-squares mean change of -2.32) had a significantly greater reduction in the BPI 24-hour average pain from baseline to endpoint (P=0.004 at week 13). Additionally, the duloxetine group significantly improved on Patient's Global Impressions of Improvement; Roland-Morris Disability Questionnaire-24; BPI-Severity and average BPI-Interference; weekly mean of the 24-hour average pain, night pain, and worst pain. Significantly more patients in the duloxetine group (13.9%) compared with placebo (5.8%) discontinued because of adverse events (P=0.047). The most common treatment-emergent adverse events in the duloxetine group included nausea, dry mouth, fatigue, diarrhea, hyperhidrosis, dizziness, and constipation. Duloxetine significantly reduced pain and improved functioning in patients with CLBP. The safety and tolerability were similar to those reported in earlier studies.