duloxetine duloxetine duloxetine, sold under the brand name cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, fibromyalgia, neuropathic pain and central sensitization. it is taken by mouth. not to be confused with dapoxetine. duloxetineclinical datatrade namescymbalta, ariclaim, yentreve, othersahfs/drugs.commonographmedlineplusa604030license data eu ema: by inn us dailymed: duloxetine us fda: duloxetine pregnancycategory au: b3 routes ofadministrationby mouthdrug classserotonin–norepinephrine reuptake inhibitoratc coden06ax21 (who) legal statuslegal status au: s4 (prescription only) ca: ℞-only uk: pom (prescription only) us: ℞-only eu: rx-only pharmacokinetic databioavailability~ 50% (32% to 80%)protein binding~ 95%metabolismliver, two p450 isozymes, cyp2d6 and cyp1a2elimination half-life12 hoursexcretion70% in urine, 20% in fecesidentifiers iupac name (+)-(s)-n-methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine cas number116539-59-4 yas hcl: 136434-34-9 ypubchem cid60835iuphar/bps202drugbankdb00476 ychemspider54822 yuniio5tnm5n07uas hcl: 9044sc542w ykeggd07880 yas hcl: d01179 ychebichebi:36795 yas hcl: chebi:31526 ychemblchembl1175 yas hcl: chembl1200328 ypdb ligand29e (pdbe, rcsb pdb)comptox dashboard (epa)dtxsid6048385 echa infocard100.116.825 chemical and physical dataformulac18h19nosmolar mass297.42 g·mol−13d model (jsmol)interactive image smiles cncc(c1=cc=cs1)oc2=cc=cc3=cc=cc=c32 inchi inchi=1s/c18h19nos/c1-19-12-11-17(18-10-5-13-21-18)20-16-9-4-7-14-6-2-3-8-15(14)16/h2-10,13,17,19h,11-12h2,1h3/t17-/m0/s1 ykey:zeuitgriyctcem-krwdzbqosa-n y ny (what is this?) (verify) duloxetine is a serotonin–norepinephrine reuptake inhibitor (snri). similarly to ssris and other snris, the precise mechanism for its antidepressant and anxiolytic effects is not known. common side effects include dry mouth, nausea, feeling tired, dizziness, agitation, sexual problems, and increased sweating. severe side effects include an increased risk of suicide, serotonin syndrome, mania, and liver problems. antidepressant withdrawal syndrome may occur if stopped. there are concerns that use during the later part of pregnancy can harm the developing fetus. duloxetine was approved for medical use in the united states and in the european union in 2004. it is available as a generic medication. in 2020, it was the 27th most commonly prescribed medication in the united states, with more than 22 million prescriptions. medical uses the main uses of duloxetine are in major depressive disorder, generalized anxiety disorder, neuropathic pain, chronic musculoskeletal pain, and fibromyalgia. duloxetine is recommended as a first-line agent for the treatment of chemotherapy-induced neuropathy by the american society of clinical oncology, as a first-line therapy for fibromyalgia in the presence of mood disorders by the german interdisciplinary association for pain therapy, as a grade b recommendation for the treatment of diabetic neuropathy by the american association for neurology and as a level a recommendation in certain neuropathic states by the european federation of neurological societies. a 2014 cochrane review concluded that duloxetine is beneficial in the treatment of diabetic neuropathy and fibromyalgia but that more comparative studies with other medicines are needed. the french medical journal prescrire concluded that duloxetine is no better than other available agents and has a greater risk of side effects. major depressive disorder duloxetine was approved for the treatment of major depression in 2004. while duloxetine has demonstrated improvement in depression-related symptoms compared to placebo, comparisons of duloxetine to other antidepressant medications have been less successful. a 2012 cochrane review did not find greater efficacy of duloxetine compared to ssris and newer antidepressants. additionally, the review found evidence that duloxetine has increased side effects and reduced tolerability compared to other antidepressants. it thus did not recommend duloxetine as a first line treatment for major depressive disorder, given the (then) high cost of duloxetine compared to inexpensive off-patent antidepressants and lack of increased efficacy. duloxetine appears less tolerable than some other antidepressants. generic duloxetine became available in 2013. generalized anxiety disorder duloxetine is more effective than placebo in the treatment of generalized anxiety disorder (gad). a review from the annals of internal medicine lists duloxetine among the first line drug treatments along with citalopram, escitalopram, sertraline, paroxetine, and venlafaxine. diabetic 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 an 11-point scale, and duloxetine treatment resulted in an additional 1–1.7 points decrease of pain as compared with placebo. at least 50% pain relief was achieved in 40–45% of the duloxetine patients vs. 20–22% of placebo patients. pain decreased 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; this effect was deemed to be of "minimal clinical significance", however. the comparative efficacy of duloxetine and established pain-relief medications for dpn is unclear. a systematic review noted that tricyclic antidepressants (imipramine 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. another 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. the comparative data collected by reviewers in bmc neurology indicated that amitriptyline, other tricyclic antidepressants and venlafaxine may be more effective. the authors noted that the evidence in favor of duloxetine is much more solid, however. a cochrane review concluded that the evidence in support of duloxetine's efficacy in treating painful diabetic neuropathy was adequate, and that further trials should focus on comparisons with other medications. a crossover trial found that duloxetine, pregabalin, and amitripyline offered similar levels of pain relief. combination treatment of duloxetine and pregabalin offered additional pain relief for people whose pain is not adequately controlled with one medication, and was safe. fibromyalgia and chronic pain a review of duloxetine found that it reduced pain and fatigue, and improved physical and mental performance compared to placebo. the u.s. food and drug administration (fda) approved the drug for the treatment of fibromyalgia in june 2008. it may be useful for chronic pain from osteoarthritis. on 4 november 2010, the u.s. food and drug administration (fda) approved duloxetine to treat chronic musculoskeletal pain, including discomfort from osteoarthritis and chronic lower back pain. stress urinary incontinence duloxetine failed to receive us approval for stress urinary incontinence amid concerns over liver toxicity and suicidal events; it was approved for this use in the uk, however, where it is recommended as an add-on medication in stress urinary incontinence instead of surgery. the safety and utility of duloxetine in the treatment of incontinence has been evaluated in a series of meta analyses and practice guidelines. a 2017 meta-analysis found that harms are at least as great if not greater than the benefits. a 2013 meta-analysis concluded that duloxetine decreased incontinence episodes more than placebo with people about 56% more likely than placebo to experience a 50% decrease in episodes. adverse effects were experienced by 83% of duloxetine-treated subjects and by 45% of placebo-treated subjects. a 2012 review and practice guideline published by the european association of urology concluded that the clinical trial data provides grade 1a evidence that duloxetine improves but does not cure urinary incontinence, and that it causes a high rate of gastrointestinal side effects (mainly nausea and vomiting) leading to a high rate of treatment discontinuation. the national institute for clinical and health excellence recommends (as of september 2013) that duloxetine not be routinely offered as first line treatment, and that it only be offered as second line therapy in women wishing to avoid therapy. the guideline further states that women should be counseled regarding the drug's side effects. contraindications the following contraindications are listed by the manufacturer: hypersensitivity: duloxetine is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients. monoamine oxidase inhibitors (maois): concomitant use in patients taking maois is contraindicated. uncontrolled narrow-angle glaucoma: in clinical trials, cymbalta use was associated with an increased risk of mydriasis (dilation of the pupil); therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma, in which mydriasis can cause sudden worsening. central nervous system (cns) acting drugs: given the primary cns effects of duloxetine, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action. duloxetine and thioridazine should not be co-administered. in addition, the fda has reported on life-threatening drug interactions that may be possible when co-administered with triptans and other drugs acting on serotonin pathways leading to increased risk for serotonin syndrome. adverse effects nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10% to 20% of patients. in a trial for major depressive disorder (mdd), the most commonly reported treatment-emergent adverse events among duloxetine-treated patients were nausea (34.7%), dry mouth (22.7%), headache (20.0%) and dizziness (18.7%), and except for headache, these were reported significantly more often than in the placebo group. in a long-term study of fibromyalgia patients receiving duloxetine, frequency and type of adverse effects was similar to that reported in the mdd trial above. side effects tended to be mild-to-moderate, and tended to decrease in intensity over time. in four clinical trials of duloxetine for the treatment of mdd, sexual dysfunction occurred significantly more frequently in patients treated with duloxetine than those treated with placebo, and this difference occurred only in men. specifically, common side effects include difficulty becoming aroused, lack of interest in sex, and anorgasmia (trouble achieving orgasm). loss of or decreased response to sexual stimuli and ejaculatory anhedonia are also reported. frequency of treatment-emergent sexual dysfunction were similar for duloxetine and ssris when compared in a 6-month observational study in depressed patients. rates of sexual dysfunction in mdd patients treated with duloxetine vs escitalopram did not differ significantly at 4, 8, and 12 weeks of treatment, although the trend favored duloxetine (33.3% of duloxetine patients experienced sexual side effects compared to 43.6% of those receiving escitalopram and 25% of those receiving placebo). discontinuation syndrome further information: ssri discontinuation syndrome during marketing of other ssris and snris, there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as brain zap electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. the withdrawal syndrome from duloxetine resembles the ssri discontinuation syndrome. when discontinuing treatment with duloxetine, the manufacturer recommends a gradual reduction in the dose, rather than abrupt cessation, whenever possible. if intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. subsequently, the physician may continue decreasing the dose but at a more gradual rate. in placebo-controlled clinical trials of up to nine weeks' duration of patients with mdd, a systematic evaluation of discontinuation symptoms in patients taking duloxetine following abrupt discontinuation found the following symptoms occurring at a rate greater than or equal to 2% and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paresthesia, vomiting, irritability, and nightmare. in 2012 the institute for safe medical practices (ismp) published a report: “duloxetine and serious withdrawal symptoms”. the report highlights early clinical studies which found “abrupt discontinuation showed that withdrawal effects occurred in 40-50% of patients, that 10% of those were severe and approximately half were not resolved when side effects monitoring had ended after one or two weeks”. withdrawal symptoms listed in 48 case reports (in the first quarter of 2012) included anger, crying, dizziness and suicidal ideation. the report concluded there was insufficient information and a lack of clear warnings about the effects of discontinuing duloxetine and that in many cases withdrawal symptoms may be “severe, persistent, or both”, adding “the prescribing information for physicians and pharmacists does not provide realistic schedules for tapering or a clear picture of the likely incidence of these reactions”. suicidality in the united states all antidepressants, including duloxetine carry a black box warning stating that antidepressants may increase the risk of suicide in persons younger than 25. this warning is based on statistical analyses conducted by two independent groups of the fda experts that found a 2-fold increase of the suicidal ideation and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group. to obtain statistically significant results the fda combined the results of 295 trials of 11 antidepressants for psychiatric indications. as suicidal ideation and behavior in clinical trials are rare, the results for any drug taken separately usually do not reach statistical significance. in 2005, the united states