Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, obsessive–compulsive disorder, fibromyalgia, neuropathic pain, and other types of chronic pain. It is taken by mouth.
Duloxetine is a serotonin–norepinephrine reuptake inhibitor (SNRI). The precise mechanism for its antidepressant and anxiolytic effects is not known.
Common side effects include dry mouth, nausea, constipation, loss of appetite, drowsiness, sexual problems, and increased sweating. In some patients, sexual dysfunction may persist even after the drug is discontinued, a condition known as post-SSRI sexual dysfunction. Severe side effects include an increased risk of suicide, serotonin syndrome, mania, and liver problems. Antidepressant withdrawal syndrome may occur if stopped. Use during the later part of pregnancy may increase the risk of bleeding or cause complications for the fetus.
Duloxetine was approved for medical use in the United States and the European Union in 2004. It is available as a generic medication. In 2023, it was the 31st most commonly prescribed medication in the United States, with more than 18million 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.
Painful diabetic peripheral neuropathy 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. Whereas duloxetine has shown efficacy in treating painful diabetic peripheral neuropathy by blocking late Nav 1.7 sodium ion channels and increasing norepinephrine, serotonin, and dopamine in the central nervous system and while improving mean NPRS scores and achieving a ≥50% pain response in more patients compared to placebo, it has been associated with potentially serious adverse reactions including hepatotoxicity, serotonin syndrome, severe skin reactions, increased risk of bleeding, increased blood pressure and sexual dysfunction.
Major depressive disorder Duloxetine was approved for the treatment of major depression in 2004. A 2025 systematic review assessing the benefits and harms of duloxetine in depression found an average change of 1.81 points on the 53-point Hamilton Depression Rating Scale and a small beneficial effect on quality of life, effects below the review's predefined minimal clinically important differences. There was insufficient data to assess suicide or other serious adverse events. All results assessed were at a high risk of bias. 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.
Neuropathic pain Duloxetine was approved for the pain associated with diabetic peripheral neuropathy (DPN) by the US Food and Drug Administration (FDA). The response is achieved in the first two weeks on the medication. Duloxetine slightly increased the fasting serum glucose.
The comparative efficacy of duloxetine and established pain-relief medications for diabetic peripheral neuropathy 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 opioids cause 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 amitriptyline offered similar levels of pain relief. Duloxetine also has similar effect on pain relief in diabetic neuropathic pain as gabapentin. Comparing at various doses, the strongest effect on relieving diabetic neuropathic pain is on dose. Combination treatment of duloxetine and pregabalin offered additional pain relief for people whose pain is not adequately controlled with one medication and was safe.
Duloxetine is also an option for the management of neuropathic pain in multiple sclerosis patients.
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 US Food and Drug Administration (FDA) approved the drug for the treatment of fibromyalgia in June 2008.
Duloxetine may be useful for chronic pain from osteoarthritis.
In November 2010, the FDA approved duloxetine to treat chronic musculoskeletal pain, including discomfort from osteoarthritis and chronic lower back pain.
Stress urinary incontinence Duloxetine failed to receive FDA approval for stress urinary incontinence amid concerns over liver toxicity and suicidal events; it was approved for this use in the United Kingdom, 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 have been evaluated in a series of meta-analyses and practice guidelines. A 2017 meta-analysis found that the 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.
Duloxetine should also be avoided in hepatic impairment such as cirrhosis.
Adverse effects Nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10–20% of patients.Cymbalta package insert. Indianapolis, IN: Eli Lilly Pharmaceuticals; 2004, September.
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.
Sexual dysfunction 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 versus 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).
Post-SSRI sexual dysfunction