Duloxetine

SNRI, Antidepressant, Anxiolytic

Duloxetine

Cymbalta, Drizalma Sprinkle, Irenka, Yentreve

Duloxetine is a serotonin–norepinephrine reuptake inhibitor (SNRI) with a relatively balanced affinity for the serotonin (SERT) and norepinephrine (NET) transporters, distinguishing it from venlafaxine, which is primarily serotonergic at low doses. Beyond its psychiatric problems, duloxetine is one of the most commonly prescribed agents for chronic pain syndromes, particularly diabetic peripheral neuropathy and fibromyalgia, where its norepinephrine activity in descending inhibitory pain pathways is thought to underlie analgesic efficacy.

Experience

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Problems

• Major depressive disorder
• Generalized anxiety disorder
• Diabetic peripheral neuropathic pain
• Fibromyalgia
• Chronic musculoskeletal pain (osteoarthritis, chronic low back pain)
• Stress urinary incontinence (approved in Europe; not FDA-approved)

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Titration strategies

Start: 30 mg PO daily × 1 week, then increase to 60 mg daily (target dose for most problems). Range: 60–120 mg/day. Higher doses (>60 mg) often add modest benefit at the cost of more side effects. Renal/hepatic: avoid in CrCl <30 mL/min or significant hepatic impairment. Discontinuation: taper gradually over ≥2 weeks; abrupt cessation produces notable discontinuation syndrome.

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Effects

Therapeutic: improved mood, reduced anxiety, reduced neuropathic and musculoskeletal pain. Common adverse: nausea (~25%, usually improves over 1–2 weeks), dry mouth, somnolence, fatigue, constipation, decreased appetite, hyperhidrosis, sexual dysfunction, insomnia.

• Hepatotoxicity, rare but well-documented; avoid in significant alcohol use or chronic liver disease
• Elevated blood pressure, dose-dependent; monitor especially at doses >60 mg
• Serotonin syndrome, especially with concurrent serotonergic agents
• Suicidality warning in patients under 25
• Hyponatremia / SIADH, especially in elderly
• Bleeding risk, additive with anticoagulants/NSAIDs
• Mydriasis / angle-closure glaucoma, caution in untreated narrow-angle glaucoma
• Urinary hesitancy
• Discontinuation syndrome, among the more pronounced of the SNRI/SSRI class; dizziness, paresthesias ("brain zaps"), irritability, nausea

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Pharmacokinetics

Well-absorbed orally with ~50% bioavailability, though substantial interindividual variability. Extensive first-pass metabolism, primarily via CYP1A2 (major) and CYP2D6 (minor). Highly protein-bound (>90%). Half-life ~12 hours; steady state in ~3 days. No active metabolites of clinical significance. Capsules are enteric-coated, should not be crushed or chewed.

Pharmacodynamics

Inhibits reuptake of both serotonin and norepinephrine at the synaptic cleft via SERT and NET. The serotonergic and noradrenergic effects are relatively balanced across the clinical dose range (60–120 mg/day), unlike venlafaxine. Modest indirect dopaminergic activity in the prefrontal cortex (via NET inhibition, since DA reuptake in PFC depends partly on NET). Minimal affinity for muscarinic, histaminic, or alpha-adrenergic receptors.

Interactions

• MAOIs, serotonin syndrome; contraindicated
• CYP1A2 inhibitors (ciprofloxacin, fluvoxamine, enoxacin), substantially increase duloxetine levels; avoid combination
• Other serotonergic agents, triptans, tramadol, linezolid, lithium, St. John's wort
• Anticoagulants / antiplatelets / NSAIDs, additive bleeding risk
• CYP2D6 substrates, duloxetine is a moderate CYP2D6 inhibitor; can elevate levels of metoprolol, propafenone, flecainide, certain TCAs

Fluoxetine via Category:Antidepressants👤 exp n/a/5 outcome n/a (n=1)⚕️ exp 1.0/5 outcome +33.0 (n=1)RateNotes (1)×

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Pregnancy and lactation

Category C. Third-trimester use associated with persistent pulmonary hypertension of the newborn (PPHN) and neonatal adaptation syndrome (jitteriness, feeding difficulty, respiratory distress). Risk-benefit decision; if continuation is needed, sertraline is often preferred among SNRIs/SSRIs in pregnancy. Excreted in breast milk in low amounts.

Monitoring

• Blood pressure at initiation and dose changes
• LFTs at baseline and if symptoms develop; avoid in heavy alcohol use
• Mood and suicidality, particularly first 4 weeks
• Sodium in elderly patients
• Response and adverse effects at each follow-up

  Patient counseling

• Take with or without food, at the same time each day.
• Swallow the capsule whole, do not crush or chew (enteric-coated).
• Full mood effect emerges over 2–4 weeks; pain relief is often faster.
• Do not stop abruptly, taper gradually to minimize discontinuation symptoms.
• Avoid heavy alcohol use due to liver toxicity risk.
• Report symptoms of serotonin syndrome (agitation, hyperthermia, tremor, diarrhea) or hepatotoxicity (jaundice, dark urine, upper abdominal pain).

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See also

Venlafaxine, Desvenlafaxine, Levomilnacipran, Milnacipran, Fluoxetine, Sertraline

Summary

Classes

SNRI, Antidepressant, Anxiolytic

Common uses

Depression, anxiety, neuropathic pain, fibromyalgia, chronic musculoskeletal pain

Pharmacy

Pharmacology

Routes

Oral

Onset

Mood: 2–4 weeks. Pain: often within 1–2 weeks.

Duration

Chronic daily dosing

Half-life

~12 hours

Bioavailability

~50% (highly variable)

Pregnancy

Category C

Legal status

Rx-only

Purported mechanism

Serotonin–norepinephrine reuptake inhibition (balanced)