BrandWikiReturn

Duloxetine

Duloxetine, sold under the brand name Cymbalta among others,[4] is a medication used to treat major depressive disorder, generalized anxiety disorder, obsessive–compulsive disorder, fibromyalgia, neuropathic pain, central sensitization, and other types of chronic pain.[5][6] It is taken by mouth.[5]

Duloxetine is a serotonin–norepinephrine reuptake inhibitor (SNRI).[7] The precise mechanism for its antidepressant and anxiolytic effects is not known.[5]

Common side effects include dry mouth, nausea, constipation, loss of appetite, drowsiness, sexual problems, and increased sweating.[8] 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.[5] Antidepressant withdrawal syndrome may occur if stopped.[5] Use during the later part of pregnancy may increase the risk of bleeding or cause complications for the fetus.[8]

Duloxetine was approved for medical use in the United States[5] and the European Union in 2004.[9] It is available as a generic medication.[7] In 2023, it was the 31st most commonly prescribed medication in the United States, with more than 18million prescriptions.[10][11]

Medical uses

The main uses of duloxetine are in major depressive disorder, generalized anxiety disorder, neuropathic pain, chronic musculoskeletal pain, and fibromyalgia.[12][5][13][14]

Duloxetine is recommended as a first-line agent for the treatment of chemotherapy-induced neuropathy by the American Society of Clinical Oncology,[15] as a first-line therapy for fibromyalgia in the presence of mood disorders by the German Interdisciplinary Association for Pain Therapy,[16] as a Grade B recommendation for the treatment of diabetic neuropathy by the American Association for Neurology[17] and as a level A recommendation in certain neuropathic states by the European Federation of Neurological Societies.[18]

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.[19] The French medical journal Prescrire concluded that duloxetine is no better than other available agents and has a greater risk of side effects.[20] 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 (CNS) 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.[21]

Major depressive disorder

Duloxetine was approved for the treatment of major depression in 2004.[12][9] 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.[22] 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.[23] Duloxetine appears less tolerable than some other antidepressants.[24] Generic duloxetine became available in 2013.[25]

Generalized anxiety disorder

Duloxetine is more effective than placebo in the treatment of generalized anxiety disorder (GAD).[26] A review from the Annals of Internal Medicine lists duloxetine among the first line drug treatments along with citalopram, escitalopram, sertraline, paroxetine, and venlafaxine.[27]

Neuropathic pain

Duloxetine was approved for the pain associated with diabetic peripheral neuropathy (DPN) by the US FDA.[28][29][30] The response is achieved in the first two weeks on the medication. Duloxetine slightly increased the fasting serum glucose.[31]

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.[32] 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.[33] 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.[34] 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.[19] 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.[35] Comparing at various doses, the strongest effect on relieving diabetic neuropathic pain is on 120 mg/d dose.[35] Combination treatment of duloxetine and pregabalin offered additional pain relief for people whose pain is not adequately controlled with one medication and was safe.[36][37]

Duloxetine is also an option for the management of neuropathic pain in multiple sclerosis patients.[38]

Fibromyalgia and chronic pain

A review of duloxetine found that it reduced pain and fatigue, and improved physical and mental performance compared to placebo.[39]

The US Food and Drug Administration (FDA) approved the drug for the treatment of fibromyalgia in June 2008.[40][41]

It may be useful for chronic pain from osteoarthritis.[42][43]

In November 2010, the US Food and Drug Administration (FDA) approved duloxetine to treat chronic musculoskeletal pain, including discomfort from osteoarthritis and chronic lower back pain.[44][45]

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.[46]

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.[47]
  • 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.[48]
  • 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.[49]
  • 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.[50]

Contraindications

The following contraindications are listed by the manufacturer:[51]

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.[53]

Duloxetine should also be avoided in hepatic impairment such as cirrhosis.[54]

  • 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.

Adverse effects

Nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10% to 20% of patients.[55]

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.[56] 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.[57][58]

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.[59][58] 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.[60] Frequency of treatment-emergent sexual dysfunction were similar for duloxetine and SSRIs when compared in a 6-month observational study in depressed patients.[61] 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).[60]

Post-SSRI sexual dysfunction

Post-SSRI sexual dysfunction (PSSD) is an iatrogenic condition in which sexual side effects persist after discontinuation of serotonin reuptake inhibiting antidepressants, including duloxetine.[62][63] Characteristic symptoms include genital numbness, pleasureless or weak orgasm, loss of libido, and erectile dysfunction; non-sexual symptoms such as emotional blunting and cognitive impairment may also occur.[63] The condition can arise after even brief exposure to a serotonin reuptake inhibitor and may persist indefinitely; there is currently no established treatment.[64] The DSM-5 noted in 2013 that serotonin reuptake inhibitor–induced sexual dysfunction may persist after the agent is discontinued.[65] A 2023 retrospective cohort study of over 12,000 males estimated the risk of irreversible sexual dysfunction at approximately 0.46% of patients treated with serotonergic antidepressants, including SNRIs, though the actual prevalence remains uncertain and the condition is likely underreported.[66][65]

In 2019, the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) reviewed evidence including data on duloxetine specifically and recommended that product labels for all SSRIs and SNRIs be updated to state that sexual dysfunction may be long-lasting even after treatment is stopped.[67] Health Canada followed with similar label updates in 2021.[65] In 2024, Australia's Therapeutic Goods Administration aligned all SSRI and SNRI product information to reflect this risk, noting that duloxetine was among the products requiring updated warnings about persistent sexual dysfunction.[68]

Increased sweating

Duloxetine may also cause sweating more than usual (hyperhidrosis).[69][70]

The exact mechanism behind why duloxetine increases sweating is still not fully understood. However, a possible explanation is in duloxetine's action on the sympathetic nervous system. Sympathetic nerves control thermoregulation and sweating in humans; when increased levels of noradrenaline are present (as seen with SNRIs), this can stimulate sweat gland activity, leading to an increase in perspiration. Noradrenaline release may also cause increased serotonin availability that results from inhibiting reuptake. Such release enhances and further facilitates the activation of post-synaptic α-adrenoceptors by noradrenaline, which can stimulate sweat gland activity, leading to more significant amounts of copious liquid secretion mainly at higher duloxetine dosages above certain thresholds. The amount of sweating experienced may be influenced by the noradrenergic tone, which is determined by the interaction between noradrenergic and serotonergic neurons.[71] Therefore, at higher serum doses or concentrations (above certain thresholds) resulting from therapeutic antidepressant treatment, patients may show more perspiration than at lower doses.[72]

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.[73]

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 FDA experts that found a 2-fold increase in the risk of suicidal ideation and behavior in children and adolescents, and a 1.5-fold increase in suicidality in the 18–24 age group.[74][75][76] 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 FDA released a public health advisory noting that there had been eleven reports of suicide attempts and three reports of suicidality within the mostly middle-aged women participating in the open-label extension trials of duloxetine for the treatment of stress urinary incontinence (SUI). The FDA described the potential role of confounding social stressors as "unclear". The suicide attempt rate in the SUI study population (based on 9,400 patients) was calculated to be 400 per 100,000 person-years. This rate is more than 2.5 times greater than the suicide attempt rate among middle-aged US women that has been reported in published studies, i.e., 150 to 160 per 100,000 person-years. In addition, one death from suicide was reported in a Cymbalta clinical pharmacology study in a healthy female volunteer without SUI. No increase in suicidality was reported in controlled trials of Cymbalta for depression or diabetic neuropathic pain.[77]

Postmarketing reports

Reported adverse events that were temporally correlated to duloxetine therapy include rash, reported rarely, and the following adverse events, reported very rarely: alanine aminotransferase increased, alkaline phosphatase increased, anaphylactic reaction, angioneurotic edema, aspartate aminotransferase increased, bilirubin increased, glaucoma, hepatotoxicity, hyponatremia, jaundice, orthostatic hypotension (especially at the initiation of treatment), Stevens–Johnson syndrome, syncope (especially at initiation of treatment), and urticaria.[78]

Pharmacology

Mechanism of action

Duloxetine inhibits the reuptake of serotonin and norepinephrine (NE) in the central nervous system. Duloxetine increases dopamine (DA) specifically in the prefrontal cortex, where there are few DA reuptake pumps, via the inhibition of NE reuptake pumps (NET), which is believed to mediate the reuptake of DA and NE.[81] Duloxetine has no significant affinity for dopaminergic, cholinergic, histaminergic, opioid, glutamate, and GABA reuptake transporters, however, and can therefore be considered to be a selective reuptake inhibitor at the 5-HT and NE transporters. Duloxetine undergoes extensive metabolism, but the major circulating metabolites do not contribute significantly to the pharmacologic activity.[82][83]

In vitro binding studies using synaptosomal preparations isolated from rat cerebral cortex indicated that duloxetine was approximately 3 fold more potent at inhibiting serotonin uptake than norepinephrine uptake.[84]

Pharmacokinetics

Absorption

Duloxetine is acid labile, and is formulated with an enteric coating to prevent degradation in the stomach. Duloxetine has good oral bioavailability, averaging 50% after one 60 mg dose. There is an average 2-hour lag until absorption begins with maximum plasma concentrations occurring about 6 hours post-dose. Food or bedtime administration has no significant impact on the Cmax of duloxetine, but delay time to reach peak concentration by 4 hours.[83] This delay is caused by reduced gastrointestinal motility, and reduce area under curve and half-life by only 11% and 18%, respectively; as such, no dose adjustments or time-of-day restrictions are necessary. Depending on condition being treated, duloxetine is taken once a day or twice a day.[12]

Distribution

Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. Volume of distribution is about 1,640 liters.[12]

Metabolism

Duloxetine undergoes predominately hepatic metabolism via two cytochrome P450 isozymes, CYP2D6 and CYP1A2. Circulating metabolites are pharmacologically inactive. Duloxetine is a moderate CYP2D6 inhibitor.[12]

Elimination

Duloxetine, administered in a single oral dose of 20 mg or 40 mg has plasma elimination half-life of 10 hours[12] and its pharmacokinetics are dose proportional over the therapeutic range.[12] Steady-state concentration is usually achieved after 3 days.[12] Only trace amounts (<1%) of unchanged duloxetine are present in the urine and most of the dose (approx. 70%) appears in the urine as metabolites of duloxetine with about 20% excreted in the feces.[12]

Smoking is associated with a decrease in duloxetine concentration.[85][86][87]

Absorption

Duloxetine is acid labile, and is formulated with an enteric coating to prevent degradation in the stomach. Duloxetine has good oral bioavailability, averaging 50% after one 60 mg dose. There is an average 2-hour lag until absorption begins with maximum plasma concentrations occurring about 6 hours post-dose. Food or bedtime administration has no significant impact on the Cmax of duloxetine, but delay time to reach peak concentration by 4 hours.[83] This delay is caused by reduced gastrointestinal motility, and reduce area under curve and half-life by only 11% and 18%, respectively; as such, no dose adjustments or time-of-day restrictions are necessary. Depending on condition being treated, duloxetine is taken once a day or twice a day.[12]

Distribution

Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. Volume of distribution is about 1,640 liters.[12]

Metabolism

Duloxetine undergoes predominately hepatic metabolism via two cytochrome P450 isozymes, CYP2D6 and CYP1A2. Circulating metabolites are pharmacologically inactive. Duloxetine is a moderate CYP2D6 inhibitor.[12]

Elimination

Duloxetine, administered in a single oral dose of 20 mg or 40 mg has plasma elimination half-life of 10 hours[12] and its pharmacokinetics are dose proportional over the therapeutic range.[12] Steady-state concentration is usually achieved after 3 days.[12] Only trace amounts (<1%) of unchanged duloxetine are present in the urine and most of the dose (approx. 70%) appears in the urine as metabolites of duloxetine with about 20% excreted in the feces.[12]

Smoking is associated with a decrease in duloxetine concentration.[85][86][87]

Research directions

Major depressive disorder is believed to be due in part to an increase in pro-inflammatory cytokines within the central nervous system.[88][89] Antidepressants including ones with a similar mechanism of action as duloxetine, i.e., serotonin metabolism inhibition, cause a decrease in proinflammatory cytokine activity and an increase in anti-inflammatory cytokines;[90] this mechanism may apply to duloxetine in its effect on depression but research on cytokines specific to duloxetine therapy is insufficient.[91][92] Cytokines are immunoregulatory molecules that play a key role in the human immune response. Some cytokines are proinflammatory and contribute to the development of inflammation, while others are anti-inflammatory and help to control the proinflammatory response.[93] Duloxetine can reduce the production of pro-inflammatory cytokines such as interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) and may increase the production of anti-inflammatory cytokines such as interleukin 10 (IL-10),[90][94][95] however, mechanisms behind these effects are not well elucidated, there have been mixed findings regarding duloxetine's impact on cytokine production in different contexts, and the results are inconclusive.[96][97][98][99]

Duloxetine is being investigated for its potential to decrease opioid use in the perioperative period because duloxetine administration can help reduce opioid consumption and mitigate the risk of opioid-related side effects and dependence. In total hip arthroplasty (THA) or total knee arthroplasty (TKA), duloxetine is researched to provide pain relief; studies demonstrated that it can reduce pain for several weeks post-surgery without an increased risk of adverse drug events, suggesting that duloxetine could be a valuable component of a multimodal management regimen for patients undergoing THA or TKA. Also, duloxetine can reduce postoperative nausea and vomiting after THA or TKA, which are common side effects of anesthesia and opioids: this additional benefit could improve patient comfort and satisfaction, potentially enhancing recovery outcomes.[100]

History

Duloxetine was created by Eli Lilly and Company researchers. David Robertson; David Wong, a co-inventor of fluoxetine; and Joseph Krushinski are listed as inventors on the patent application filed in 1986 and granted in 1990.[101] The first publication on the invention of the racemic form of duloxetine known as LY227942, was made in 1988.[102] The (+)-enantiomer, assigned LY248686, was chosen for further studies, because it inhibited serotonin reuptake in rat synaptosomes to twice the degree of the (–)-enantiomer. This molecule was subsequently named duloxetine.[103]

In 2001, Lilly filed a New Drug Application (NDA) for duloxetine with the US Food and Drug Administration. In 2003, however, the FDA "recommended this application as not approvable from the manufacturing and control standpoint" because of "significant cGMP (current Good Manufacturing Practice) violations at the finished product manufacturing facility" of Eli Lilly in Indianapolis. Additionally, "potential liver toxicity" and QTc interval prolongation appeared as a concern. The FDA experts concluded that "duloxetine can cause hepatotoxicity in the form of transaminase elevations. It may also be a factor in causing more severe liver injury, but there are no cases in the NDA database that clearly demonstrate this. Use of duloxetine in the presence of ethanol may potentiate the deleterious effect of ethanol on the liver." The FDA also recommended "routine blood pressure monitoring", since there was a dose-dependent increase in elevated blood pressure readings, including at the new highest recommended dose of 120 mg "where 24% of patients had one or more [elevated] blood pressure readings of 140/90 vs. 9% of placebo patients."[104][105]

After the manufacturing issues were resolved, the liver toxicity warning included in the prescribing information, and the follow-up studies showed that duloxetine does not cause QTc interval prolongation, duloxetine was approved by the FDA for depression and diabetic neuropathy in 2004.[106] In 2007, Health Canada approved duloxetine for the treatment of depression and diabetic peripheral neuropathic pain.[107]

Duloxetine was approved for use of stress urinary incontinence (SUI) in the EU in 2004.[108] In 2005, Lilly withdrew the duloxetine application for stress urinary incontinence (SUI) in the US, stating that discussions with the FDA indicated "the agency is not prepared at this time to grant approval ... based on the data package submitted." A year later Lilly abandoned the pursuit of this indication in the US market.[109][110]

The FDA approved duloxetine for the treatment of generalized anxiety disorder in February 2007.[111]

Cymbalta generated sales of nearly US$5 billion in 2012, with $4 billion of that in the US, but its patent protection terminated 1 January 2014. Lilly received a six-month extension beyond 30 June 2013, after testing for the treatment of depression in adolescents, which may produce US$1.5 billion in added sales.[112][113]

The first generic duloxetine was marketed by an Indian pharmaceutical company Dr. Reddy's Laboratories.[114]

See also

  • List of antidepressants

Explanatory notes

References

  1. RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial Diário Oficial da União, 31 March 2023, retrieved 16 August 2023^
  2. Cymbalta PI Union Register of medicinal products, 22 December 2004, retrieved 19 December 2024^
  3. Yentreve PI Union Register of medicinal products, 13 August 2004, retrieved 19 December 2024^
  4. Duloxetine Drugs.com, retrieved 24 December 2018^
  5. Duloxetine Monograph, The American Society of Health-System Pharmacists, retrieved 24 December 2018^
  6. Medications for OCD International OCD Foundation, retrieved 25 February 2024^
  7. British national formulary: BNF 76 Pharmaceutical Press, 2018^
  8. Duloxetine: Uses, Side Effects, Dosage, Warnings Drugs.com, retrieved 30 May 2025^
  9. Cymbalta EPAR European Medicines Agency (EMA), 17 September 2018, retrieved 30 September 2020^
  10. Top 300 of 2023 ClinCalc, retrieved 12 August 2025^
  11. Duloxetine Drug Usage Statistics, United States, 2014 - 2023 ClinCalc, retrieved 13 August 2025^
  12. Cymbalta- duloxetine hydrochloride capsule, delayed release DailyMed, retrieved 29 September 2020^
  13. {{NICE|96|Neuropathic pain – pharmacological management|2010}}^
  14. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation Neurology, May 2011^
  15. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline Journal of Clinical Oncology, June 2014^
  16. [Drug therapy of fibromyalgia syndrome. Systematic review, meta-analysis and guideline] Schmerz, June 2012^
  17. Evidence-based guideline: treatment of painful diabetic neuropathy--report of the American Association of Neuromuscular and Electrodiagnostic Medicine, the American Academy of Neurology, and the American Academy of Physical Medicine & Rehabilitation Muscle & Nerve, June 2011^
  18. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision European Journal of Neurology, September 2010^
  19. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia The Cochrane Database of Systematic Reviews, January 2014^
  20. Towards better patient care: drugs to avoid in 2014 Prescrire International, June 2014, retrieved 28 June 2014^
  21. Update on Treating Painful Diabetic Peripheral Neuropathy: A Review of Current US Guidelines with a Focus on the Most Recently Approved Management Options J Pain Res, 2024^
  22. Beneficial and harmful effects of duloxetine versus placebo, 'active placebo' or no intervention for adults with major depressive disorder: a systematic review with meta-analysis and trial sequential analysis of randomised clinical trials BMJ Open, February 2025^
  23. Duloxetine versus other anti-depressive agents for depression The Cochrane Database of Systematic Reviews, October 2012^
  24. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis Lancet, April 2018^
  25. Loss of Cymbalta patent a major blow for Eli Lilly Indianapolis Star, 13 October 2013, retrieved 27 February 2015^
  26. Duloxetine: a review of its use in the treatment of generalized anxiety disorder CNS Drugs, 2009^
  27. Generalized anxiety disorder Annals of Internal Medicine, December 2013^
  28. Pharmacological and Nonpharmacological Treatments for Painful Diabetic Peripheral Neuropathy Diabetes Metab J, November 2023^
  29. Duloxetine vs. placebo in patients with painful diabetic neuropathy Pain, July 2005^
  30. A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain Pain Medicine, 2005^
  31. Application number 21-733. Medical review(s). U.S. Food and Drug Administration (FDA), 3 September 2004, retrieved 14 April 2009^
  32. Effects of treatments for symptoms of painful diabetic neuropathy: systematic review BMJ, July 2007^
  33. Duloxetine: new indication. Depression and diabetic neuropathy: too many adverse effects Prescrire International, October 2006^
  34. Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials BMC Neurology, August 2008^
  35. Effectiveness of Duloxetine versus Other Therapeutic Modalities in Patients with Diabetic Neuropathic Pain: A Systematic Review and Meta-Analysis Pharmaceuticals (Basel), June 2024^
  36. Combination therapy for painful diabetic neuropathy is safe and effective NIHR Evidence, 6 April 2023, retrieved 28 April 2023^
  37. Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial Lancet, August 2022^
  38. Pharmacological and Non-pharmacological Approaches for the Management of Neuropathic Pain in Multiple Sclerosis CNS Drugs, March 2024^
  39. Duloxetine for the treatment of fibromyalgia Drugs of Today, October 2008^
  40. FDA Approves Cymbalta for the Management of Fibromyalgia Eli Lilly Co., 16 June 2008, retrieved 17 June 2008^
  41. Drug Approval Package: Cymbalta (duloxetine hydrochloride) NDA #022148 U.S. Food and Drug Administration (FDA), retrieved 30 September 2020^
  42. A systematic review of duloxetine for osteoarthritic pain: what is the number needed to treat, number needed to harm, and likelihood to be helped or harmed? Postgraduate Medicine, January 2012^
  43. The efficacy of duloxetine, non-steroidal anti-inflammatory drugs, and opioids in osteoarthritis: a systematic literature review and meta-analysis BMC Musculoskeletal Disorders, March 2014^
  44. FDA clears Cymbalta to treat chronic musculoskeletal pain U.S. Food and Drug Administration (FDA), Food and Drug Administration, 4 November 2010, retrieved 19 August 2013^
  45. Drug Approval Package: Cymbalta (duloxetine hydrochloride) NDA #022516 U.S. Food and Drug Administration (FDA), 16 September 2011, retrieved 29 September 2020^
  46. {{NICE|40|Urinary incontinence|2006}}^
  47. Considering benefits and harms of duloxetine for treatment of stress urinary incontinence: a meta-analysis of clinical study reports CMAJ, February 2017^
  48. The role of duloxetine in stress urinary incontinence: a systematic review and meta-analysis International Urology and Nephrology, June 2013^
  49. www.uroweb.org^
  50. Urinary incontinence Introduction CG171^
  51. Eli Lilly and Company retrieved 15 May 2010^
  52. The effects of supratherapeutic doses of duloxetine on blood pressure and pulse rate Journal of Cardiovascular Pharmacology, June 2007^
  53. Information for Healthcare Professionals: Duloxetine (marketed as Cymbalta) – Selective Serotonin Reuptake Inhibitors (SSRIs) or Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) and 5-Hydroxytryptamine Receptor Agonists (Triptans) U.S. Food and Drug Administration (FDA), 14 August 2013, retrieved 18 September 2013^
  54. The Safe Use of Analgesics in Patients with Cirrhosis: A Narrative Review Am J Med, February 2024^
  55. Cymbalta package insert. Indianapolis, IN: Eli Lilly Pharmaceuticals; 2004, September.^
  56. Duloxetine 60 mg once daily in the treatment of milder major depressive disorder International Journal of Clinical Practice, May 2006^
  57. A 1-year safety and efficacy study of duloxetine in patients with fibromyalgia The Clinical Journal of Pain, June 2009^
  58. Cymbalta - FDA prescribing information, side effects and uses Drugs.com, retrieved 14 September 2018^
  59. The safety and tolerability of duloxetine compared with paroxetine and placebo: a pooled analysis of 4 clinical trials Primary Care Companion to the Journal of Clinical Psychiatry, 2006^
  60. Changes in sexual functioning associated with duloxetine, escitalopram, and placebo in the treatment of patients with major depressive disorder The Journal of Sexual Medicine, July 2007^
  61. Treatment-emergent sexual dysfunction with SSRIs and duloxetine: effectiveness and functional outcomes over a 6-month observational period International Journal of Psychiatry in Clinical Practice, November 2011^
  62. Post-SSRI Sexual Dysfunction: A Literature Review Sexual Medicine Reviews, January 2018^
  63. Diagnostic criteria for enduring sexual dysfunction after treatment with antidepressants, finasteride and isotretinoin International Journal of Risk & Safety in Medicine, 2022^
  64. Enduring sexual dysfunction after treatment with antidepressants, 5α-reductake inhibitors and isotretinoin: 300 cases International Journal of Risk & Safety in Medicine, 2018^
  65. Post-SSRI sexual dysfunction: barriers to quantifying incidence and prevalence Epidemiology and Psychiatric Sciences, 2024^
  66. Estimating the risk of irreversible post-SSRI sexual dysfunction (PSSD) due to serotonergic antidepressants Annals of General Psychiatry, April 2023^
  67. PRAC recommendations on signals adopted at the 13–16 May 2019 PRAC meeting European Medicines Agency, 11 June 2019, retrieved 8 April 2026^
  68. Updated warnings about persistent sexual dysfunction for antidepressants Therapeutic Goods Administration, 23 May 2024, retrieved 8 April 2026^
  69. Duloxetine (Oral Route) Side Effects - Mayo Clinic Mayo Clinic, retrieved 1 October 2023^
  70. Excessive sweating induced by interaction between agomelatine and duloxetine hydrochloride: case report and review of the literature Wien Klin Wochenschr, September 2015^
  71. Hyperhidrosis in sleep disorders – A narrative review of mechanisms and clinical significance Journal of Sleep Research, 2023^
  72. To sweat or not to sweat? A hypothesis on the effects of venlafaxine and SSRIs Med Hypotheses, January 2010^
  73. Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder Journal of Affective Disorders, December 2005^
  74. Antidepressants and Suicidality in Adults: Statistical Evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006) Food and Drug Administration, retrieved 13 May 2007^
  75. Clinical review: relationship between antidepressant drugs and suicidality in adults Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC), U.S. Food and Drug Administration (FDA), 17 November 2006, retrieved 22 September 2007^
  76. Statistical Evaluation of Suicidality in Adults Treated with Antidepressants Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC), U.S. Food and Drug Administration (FDA), 17 November 2006, retrieved 22 September 2007^
  77. Historical Information on Duloxetine hydrochloride (marketed as Cymbalta) U.S. Food and Drug Administration (FDA), retrieved 16 December 2019^
  78. Duloxetine Side Effects, and Drug Interactions RxList Monographs^
  79. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors Neuropsychopharmacology, December 2001^
  80. Top Drugs: Their History, Pharmacology, and Syntheses Oxford University Press, 2015, retrieved 20 October 2020^
  81. Stahl's Essential Pharmacology Cambridge University Press, 2013^
  82. SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants CNS Spectrums, September 2005^
  83. The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression Current Pharmaceutical Design, 2005^
  84. Duloxetine, an antidepressant with analgesic properties - a preliminary analysis Romanian Journal of Anaesthesia and Intensive Care, October 2015^
  85. Duloxetine: clinical pharmacokinetics and drug interactions Clinical Pharmacokinetics, May 2011^
  86. The influence of smoking on the serum level of duloxetine Pharmacopsychiatry, July 2008^
  87. Duloxetine 60mg gastro-resistant capsules - Summary of Product Characteristics (SmPC) - (emc) www.medicines.org.uk, retrieved 21 March 2020^
  88. Inflammatory cytokine-associated depression Brain Res, August 2015^
  89. Cytokine imbalance in the pathophysiology of major depressive disorder Prog Neuropsychopharmacol Biol Psychiatry, June 2007^
  90. Might different cytokine trends in depressed patients receiving duloxetine indicate differential biological backgrounds J Affect Disord, March 2013^
  91. The effect of newer serotonin-noradrenalin antidepressants on cytokine production: a review of the current literature International Journal of Immunopathology and Pharmacology, 2010^
  92. The Effect of Antidepressant Medication Treatment on Serum Levels of Inflammatory Cytokines: A Meta-Analysis Neuropsychopharmacology, November 2011^
  93. Anti-inflammatory cytokines Chest, April 2000^
  94. Association between TNF-α & IL-6 level changes and remission from depression with duloxetine treatment Int J Neurosci, October 2024^
  95. Effect of duloxetine on changes in serum proinflammatory cytokine levels in patients with major depressive disorder BMC Psychiatry, June 2024^
  96. Clinical effect of flunarizine combined with duloxetine in the treatment of chronic migraine comorbidity of depression and anxiety disorder Brain Behav, August 2022^
  97. Genetic variation in IL-1β, IL-2, IL-6, TSPO and BDNF and response to duloxetine or placebo treatment in major depressive disorder Pharmacogenomics, November 2015^
  98. Effect of antidepressant treatment on plasma levels of neuroinflammation-associated molecules in patients with somatic symptom disorder with predominant pain around the orofacial region Hum Psychopharmacol, July 2019^
  99. Maternal fluoxetine reduces hippocampal inflammation and neurogenesis in adult offspring with sex-specific effects of periadolescent oxytocin Brain Behav Immun, October 2021^
  100. Duloxetine reduces opioid consumption and pain after total hip or knee arthroplasty: a meta-analysis of randomized controlled trials J Orthop Surg Res, March 2024^
  101. United States Patent 4,956,388: 3-Aryloxy-3-substituted propanamines USPTO, 11 September 1990, retrieved 17 May 2008^
  102. LY227942, an inhibitor of serotonin and norepinephrine uptake: biochemical pharmacology of a potential antidepressant drug Life Sciences, 1988^
  103. Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake Bioorganic & Medicinal Chemistry Letters, December 2003^
  104. Approval package for: application number NDA 721-427. Administrative/Correspondence #2 U.S. Food and Drug Administration (FDA), 2003, retrieved 18 May 2008^
  105. Drug Approval Package: Cymbalta (Duloxetine Hydrochloride) NDA #021427 U.S. Food and Drug Administration (FDA), 24 December 1999, retrieved 29 September 2020^
  106. FDA news Food and Drug Administration, retrieved 16 December 2019^
  107. Summary Basis of Decision (SBD): Cymbalta Health Canada, 5 May 2008, retrieved 27 February 2015^
  108. Yentreve EPAR European Medicines Agency (EMA), 17 September 2018, retrieved 30 September 2020^
  109. Lilly Won't Pursue Yentreve for U.S. TheStreet, TheStreet.com, 15 February 2006, retrieved 18 May 2008^
  110. FDA warns that antidepressants may increase suicidality in adults BMJ, July 2005^
  111. FDA approves antidepressant Cymbalta (duloxetine HCl) for treatment of generalized anxiety disorder News-Medical, 26 February 2007, retrieved 25 December 2013^
  112. Lilly could net $1.5B-plus from Cymbalta extension FiercePharma, 9 July 2012, retrieved 25 December 2013^
  113. Eli Lilly to lay off hundreds in sales as Cymbalta nears edge of patent cliff FiercePharma, 11 April 2013, retrieved 25 December 2013^
  114. Generic Cheaper Versions of Cymbalta Approved National Pain Report, 12 December 2013, retrieved 2 January 2014^