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)

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).
Relevant anecdote

Duloxetine

Experience

Problems

Titration strategies

Effects

Pharmacokinetics

Pharmacodynamics

Interactions

Pregnancy and lactation

Monitoring

Patient counseling

Relevant anecdote

Relevant Literature

See also