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Duloxetine: Mechanism, Adverse Effects, Contraindications, and Dosage

Mechanism of action

Duloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI). It inhibits the presynaptic reuptake of serotonin and norepinephrine, thereby increasing their concentrations in the synaptic cleft and prolonging their effects at postsynaptic receptors. Within the central nervous system, duloxetine exerts antidepressant, anxiolytic, and analgesic effects. In the lower urinary tract, duloxetine increases functional bladder capacity and enhances the tone of the striated external urethral sphincter (Thor and Donatucci, 2004).

Urological Indications for Duloxetine:

Duloxetine is approved in Europe and Canada for the treatment of moderate to severe stress urinary incontinence of women. In appropriately selected patients, it can reduce the number of incontinence episodes by approximately 50–60%, compared with a reduction of about 20–40% with placebo (Mariappan et al., 2007). For the indication of stress urinary incontinence, the FDA has not approved duloxetine, primarily because they considered the adverse effect profile and overall benefit–risk balance to be unfavorable.

For male stress urinary incontinence in men, particularly after radical prostatectomy, no regulatory approval exists; duloxetine may be used off label in this setting. Randomized controlled trials demonstrate only modest efficacy, with a reduction in the duration and severity of postprostatectomy incontinence but also a 38% discontinuation rate due to adverse effects (Cornu et al., 2011) (Kotecha et al., 2021).

With different dosing regimens, duloxetine is also indicated for psychiatric and neurologic disorders, such as major depressive disorder, generalized anxiety disorder, and diabetic peripheral neuropathic pain.

Pharmacokinetics of duloxetine:

Duloxetine is well absorbed after oral administration. It undergoes extensive hepatic metabolism primarily via cytochrome P450 (CYP) 1A2 and CYP2D6, and its inactive metabolites are excreted predominantly in the urine. The elimination half-life is approximately 12 hours.

Adverse Effects of Duloxetine

The rate of treatment discontinuation due to adverse effects is high. Common adverse effects of duloxetine include nausea, fatigue, insomnia or somnolence, dry mouth, constipation, diarrhea, dizziness, headache, blurred vision, increased sweating, and decreased appetite. Other clinically important adverse reactions include psychomotor agitation or akathisia, sexual dysfunction, increases in blood pressure up to frank hypertension, hyponatremia (often due to the syndrome of inappropriate antidiuretic hormone secretion [SIADH]), and elevations of liver enzymes up to drug-induced hepatitis. As with other antidepressants, duloxetine may precipitate or worsen depressive symptoms, suicidal ideation, and suicidal behavior, particularly at the beginning of treatment or after dose adjustments; monitor patients closely during these periods.

Drug Interactions of Duloxetine:

• There is a risk of serotonin syndrome. Concomitant use with nonselective monoamine oxidase inhibitors (MAOIs) is absolutely contraindicated. Clinicians must exercise particular caution when combining duloxetine with other serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs), other SNRIs, tricyclic antidepressants, St. John’s wort, tramadol, or triptans.
• Duloxetine should not be coadministered with potent CYP1A2 inhibitors such as ciprofloxacin or enoxacin, because these drugs can markedly increase duloxetine plasma concentrations.
• Concomitant use of duloxetine with anticoagulants or antiplatelet agents increases the risk of bleeding, and clinicians should monitor for signs of hemorrhage.
• Use caution when combining duloxetine with other central nervous system depressants (such as alcohol, sedative–hypnotics, or opioids) because of the risk of additive CNS depression.
• Duloxetine is a moderate CYP2D6 inhibitor and can increase levels of CYP2D6 substrates.

Contraindications for Duloxetine:

• Clinically significant hepatic impairment.
• Severe renal impairment with an estimated glomerular filtration rate (eGFR) or creatinine clearance below 30 mL/min.
• Uncontrolled arterial hypertension.
• Concomitant treatment with nonselective monoamine oxidase inhibitors (MAOIs) or potent CYP1A2 inhibitors. Combined use with selective serotonin reuptake inhibitors (SSRIs) and other serotonergic antidepressants is generally avoided because of the risk of serotonin syndrome and should, if considered at all, occur only with careful monitoring.
• Uncontrolled narrow-angle glaucoma.
• Known hypersensitivity to duloxetine.
• For the use of duloxetine in the treatment of stress urinary incontinence: acute suicidality or untreated major depression, pregnancy, breastfeeding, children and adolescents, and men.

Dosage of duloxetine:

Administer 20 mg orally twice daily for the first two weeks. If the patient tolerates this dose, increase the dose to 40 mg orally twice daily. Reassess the clinical efficacy after approximately four weeks; if there is no meaningful improvement in symptoms, discontinue treatment. When discontinuing therapy, the dose must be tapered gradually over at least two weeks to minimize discontinuation symptoms.

References

Thor, K. B. & Donatucci, C. Central nervous system control of the lower urinary tract: new pharmacological approaches to stress urinary incontinence in women.
J Urol, 2004, 172, 27-33.

Cornu, J.; Merlet, B.; Ciofu, C.; Mouly, S.; Peyrat, L.; Sèbe, P.; Yiou, R.; Vallancien, G.; Debrix, I.; Laribi, K.; Cussenot, O. & Haab, F. Duloxetine for mild to moderate postprostatectomy incontinence: preliminary results of a randomised, placebo-controlled trial.
Eur Urol, 2011, 59, 148-154.

Kotecha P, Sahai A, Malde S. Use of Duloxetine for Postprostatectomy Stress Urinary Incontinence: A Systematic Review. Eur Urol Focus. 2021 May;7(3):618-628. doi: 10.1016/j.euf.2020.06.007.

Mariappan, P.; Alhasso, A.; Ballantyne, Z.; Grant, A. & N'Dow, J. Duloxetine, a serotonin and noradrenaline reuptake inhibitor (SNRI) for the treatment of stress urinary incontinence: a systematic review.
Eur Urol, 2007, 51, 67-74.

  Deutsche Version: Nebenwirkungen und Kontraindikationen von Duloxetin

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