Skip to content

Duloxetine (Cymbalta)

SNRI • Last reviewed 2025-09-26

General information

Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) approved for major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain. Its broader pain indications make it a common choice when depression coexists with neuropathic or somatic symptoms.

Enteric-coated delayed-release capsules (20, 30, 40, 60 mg) protect duloxetine from gastric degradation. The medication may be taken once daily, or in divided doses if tolerability issues arise.

Efficacy data show dose-dependent improvements in mood and pain measures up to 120 mg/day, though doses above 60 mg/day offer diminishing returns for pure depression. Hepatotoxicity, orthostatic changes, and blood pressure increases are notable safety considerations.

Because duloxetine inhibits CYP2D6 moderately, clinicians should review for interactions with tricyclics, antipsychotics, and tamoxifen.

Dosing & administration

Start 30 mg once daily for 1 week, then increase to 60 mg once daily.

May increase to 90–120 mg/day based on response; divide doses >60 mg/day.

Avoid use in patients with severe hepatic impairment or heavy alcohol use.

Mechanism of action

Duloxetine inhibits serotonin and norepinephrine reuptake transporters with a 10:1 ratio at clinical doses. Minimal affinity exists for muscarinic, histamine, or adrenergic receptors, limiting anticholinergic effects.

Metabolism & pharmacokinetics

Absolute bioavailability is ~50% due to first-pass metabolism. Peak plasma concentrations occur ~6 hours post-dose. Extensive hepatic metabolism via CYP1A2 and CYP2D6 generates multiple inactive metabolites eliminated in urine (70%) and feces (20%). Half-life averages 12 hours with steady state in 3 days.

Drug interactions

Avoid MAOIs, linezolid, or IV methylene blue (serotonin syndrome risk).

CYP1A2 inhibitors (fluvoxamine, ciprofloxacin) increase exposure; consider dose reduction.

Moderate CYP2D6 inhibitor—monitor levels of TCAs, antipsychotics, and tamoxifen.

Monitoring & safety checks

  • Blood pressure and heart rate at baseline and periodically

  • Liver enzymes with baseline risk factors or symptoms

  • Assess for suicidality/activation during initiation

Discontinuation guidance

Taper over ≥2 weeks to reduce discontinuation symptoms (dizziness, paresthesias, irritability). Longer tapers are recommended after long-term therapy.

References

  1. Duloxetine Prescribing Information — DailyMed
  2. Duloxetine for chronic pain and depression: An evidence review — Pain Medicine (2022)
  3. APA Guideline: Pharmacologic treatment of depressive disorders (2023)

Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.