Duloxetine

Also known under the names Cymbalta, Ariclaim, Xeristar, Yentreve, and Duzela Duloxetine is a serotonin norepinephrine reuptake inhibitor manufactured and marketed by Eli Lily It is effective for major depressive disorder and generalizedanxiety disorder Duloxetine failed the US approval for stress urinary incontinence amidst concerns over liver toxicity and suicidal events However it was approved for this indication in Europe, where it is recommended as an add on medication in stress urinary incotinece instead of surgery

Medical uses
The main uses of duloxetine are in [|major depressive disorder], [|general anxiety disorder] , [|stress urinary incontinence] , painful [|peripheral neuropathy] , [|fibromyalgia] , and chronic musculoskeletal pain associated with [|osteoarthritis] and chronic lower back pain. It is being studied for various other indications.

Major depressive disorder
Duloxetine has demonstrated efficacy for the treatment of [|major depressive disorder]. Recently, duloxetine was shown to be effective in elderly with recurrent major depressive disorder where it improved cognition, depression, and some pain measures. [|[4]]

Stress urinary incontinence
Duloxetine was first reported to improve outcomes in [|stress urinary incontinence] (SUI) in 1998. [|[5]] [|Systematic reviews] with meta-analysis, conducted in 2005 by [|Cochrane Collaboration] [|[6]] and in 2008 by [|University of Minnesota], [|[7]] concluded that duloxetine failed to cure SUI better than placebo. According to the Cochrane review, some studies showed that episodes of incontinence were reduced by about 50%. This was associated with an improvement in [|quality of life] measurements. [|[6]] According to the University of Minnesota review, duloxetine performed worse than [|oxybutynin] (Ditropan) or [|tolterodine] (Detrol) that cured 18% of the cases, or than [|pelvic floor muscle training] + bladder training, which cured 13% of the cases. In terms of "improvement", that is incomplete cure, duloxetine showed improvement in 11% of patients while [|pelvic floor] muscle training + bladder training showed improvement in 36% of the cases. [|[7]] Significant side effects were common with duloxetine; they were reported as acceptable and about a fifth had to discontinue the medication because of poor tolerance. [|[6]] In addition, the full report prepared by Minnesota Evidence-based Practice Center for the U.S. government, on which the University of Minnesota review is based, notes that weight reduction would result in improved SUI in 990 adults per 1,000 treated. [|[8]] In the light of the cited data, the report does not mention duloxetine in its policy recommendations. The only recommended interventions are early behavioral changes in weight, physical activity, and pelvic floor muscle training. [|[8]] The only clinical trial, which directly compared duloxetine with the gold standard of the SUI treatment pelvic floor muscle training (PFMT) was conducted by [|Eli Lilly] and gave mixed results. The incontinence episode frequency in duloxetine group decreased by 57% vs. 35% in the PFTM group. However, the differences in the pad use and quality of life were not statistically significant. To the contrary, 65% patients doing PFTM reported feeling better vs 54% of the patients on duloxetine. 31% of the patients on duloxetine discontinued the trial due to the side effects during the first 12 weeks. [|[9]] In the continuation of this trial more than 91% of the patients on duloxetine experienced side effects. [|[10]] Summing up the existing evidence, a review in Prescrire International recommends pelvic floor exercises, which are "risk-free and effective in two-thirds to three-quarters of cases", as the first line treatment of SUI. Duloxetine use reduced the frequency of stress incontinence by one episode a day as compared with placebo. "The tangible effect of duloxetine on the quality of life is doubtful, with a maximum gain of five points on a 100-point scale." The review notes that, at best, duloxetine efficacy is "modest and transient, while its adverse effects are numerous and potentially severe." [|[11]]

Diabetic peripheral neuropathy
Duloxetine was approved for the pain associated with diabetic peripheral neuropathy (DPN) based on the positive results of two clinical trials. The average daily pain was measured using 11-point scale, and duloxetine treatment resulted in an additional 1–1.7 points decrease of pain as compared with placebo. [|[12]] [|[13]] [|[14]] At least 50% pain relief was achieved in 40–45% of the duloxetine patients vs. 20–22% of placebo patients. The pain almost completely disappeared, decreasing by more than 90%, in 9–14% of duloxetine patients vs. 2–4% of placebo patients. Most of the response was achieved in the first two weeks on the medication. Duloxetine slightly increased the fasting serum glucose; however this effect was deemed to be of "minimal clinical significance". [|[12]] Duloxetine was not effective for the numbness or tingling, nor for the other [|complications of diabetes]. It reduced the pain without treating the underlying nerve damage. [|[15]] Only tight glycemic control was unequivocally demonstrated to slow the progression of neuropathy. [|[16]] [|[17]] [|Benfotiamine], [|alpha-lipoic acid] , and [|ranirestat] have also shown some promise. [|[17]] The comparative efficacy of duloxetine and established pain-relief medications for DPN is unclear. An independent systematic review in BMJ noted that tricyclic antidepressants (imimpramine and amitriptyline), traditional anticonvulsants and opioids have better efficacy than duloxetine. Duloxetine, tricyclic antidepressants and anticonvulsants have similar tolerability while the opioids caused more side effects. [|[16]] A review in Drug and Therapeutic Bulletin saw no place for duloxetine in the treatment of DPN, based on its high cost and insufficient evidence of the comparative efficacy with tricyclic antidepressants. [|[18]] Another independent review in Prescrire International, considered the moderate pain relief achieved with duloxetine to be clinically insignificant and the results of the clinical trials—unconvincing. The reviewer saw no reason to prescribe duloxetine in practice. [|[19]] The comparative data collected by reviewers in BMC Neurology indicated that amitriptyline, other tricyclic antidepressants and venlafaxine may be more effective. However, the authors noted that the evidence in favor of duloxetine is much more solid. [|[20]]

Generalized anxiety disorder
Duloxetine is as effective as [|venlafaxine] in the treatment of [|generalized anxiety disorder] with demonstrated improvements in function and quality of life for sufferers. Long-term use of duloxetine prevents relapse of generalized anxiety disorder. Although this view was repeated in a recent independent review, [|[21]] the major guidelines such as Maudsley Prescribing Guidelines, [|[22]] Mayo Clinic Health Information [|[23]] and Canadian Psychiatric Association Guidelines [|[24]] do not mention duloxetine among the recommended treatment options.

Fibromyalgia
On October 19, 2006, Eli Lilly issued a press release saying they had done trials which found that Cymbalta (duloxetine), at 60 mg once or twice daily, significantly reduced pain in more than half of women treated for [|fibromyalgia] (FM), with and without major depression, according to 12-week data presented at the annual meeting of the [|American College of Rheumatology]. Eli Lilly has been promoting Cymbalta for FM since 2004. [|[25]] Duloxetine is superior to many other medications for the treatment of fibromyalgia due to its freedom from [|muscarinic], [|histaminergic] and [|adrenergic] adverse reactions. Its effectiveness in pain relief is believed to be due to its modulation of the [|nociception] system. A [|meta-analysis] of clinical trials has confirmed its pain relief, fatigue reducing properties as well as its effectiveness in improving physical and mental performance. [|[26]] In the study testing the efficacy of Cymbalta for FM, participants completed several questionnaires to measure the amount of pain and discomfort the disease caused them at the beginning of the study, and then at the end of each of the first two weeks and every second week for the remaining 12 weeks of the study. Researchers also tested the participants for depression. [|[25]] Women who took Cymbalta had significantly less pain and discomfort than those who took the placebo. For men, who made up only 11% of the study, there was no effect from taking the medication compared with a placebo. Reportedly, depression played no part in whether or not the drug worked to control pain. The change in the level of women's pain was particularly pronounced after a month of taking the drug, then leveled off a bit before dropping again near the end of the study. [|[25]] However, in one of the primary measures of pain there was no significant difference between the two groups at the end of the 12-week trial. Also, because the trial lasted only 12 weeks, it is impossible to tell how well the drug would control treatment for a longer period of time. [|[25]] The Food and Drug Administration regulators approved the drug for the treatment of fibromyalgia in June 2008. [|[27]]