[10] Common side effects include dry mouth, nausea, feeling tired, dizziness, agitation, sexual problems, and increased sweating.

[10] Severe side effects include an increased risk of suicide, serotonin syndrome, mania, and liver problems.

[21] 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.

[22] The French medical journal Prescrire concluded that duloxetine is no better than other available agents and has a greater risk of side effects.

[23] 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.

[4][5] 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.

Additionally, the review found evidence that duloxetine has increased side effects and reduced tolerability compared to other antidepressants.

[29] A review from the Annals of Internal Medicine lists duloxetine among the first line drug treatments along with citalopram, escitalopram, sertraline, paroxetine, and venlafaxine.

A systematic review noted that tricyclic antidepressants (imipramine and amitriptyline), traditional anticonvulsants and opioids have better efficacy than duloxetine.

[36] The comparative data collected by reviewers in BMC Neurology indicated that amitriptyline, other tricyclic antidepressants, and venlafaxine may be more effective.

[37] 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.

[22] A crossover trial found that duloxetine, pregabalin, and amitriptyline offered similar levels of pain relief.

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

[59] 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.

[62][61] Specifically, common side effects include difficulty becoming aroused, lack of interest in sex, and anorgasmia (trouble achieving orgasm).

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

[67] 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.

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".

As suicidal ideation and behavior in clinical trials are rare, the results for any drug taken separately usually do not reach statistical significance.

In addition, one death from suicide was reported in a Cymbalta clinical pharmacology study in a healthy female volunteer without SUI.

Food or bedtime administration has no significant impact on the Cmax of duloxetine, but delay time to reach peak concentration by 4 hours.

[9][81][82] Major depressive disorder is believed to be due in part to an increase in pro-inflammatory cytokines within the central nervous system.

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.

[95] 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.

[7] 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."

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.