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Duloxetine

Duloxetine

Cymbalta Drizalma Irenka

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Updated: December 06, 2025

Overview

Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant with multiple FDA-approved indications. It is widely used for major depressive disorder, generalized anxiety disorder, and various chronic pain conditions including diabetic peripheral neuropathy and fibromyalgia. The drug exerts its therapeutic effects by increasing synaptic concentrations of serotonin and norepinephrine in the central nervous system. Duloxetine has demonstrated efficacy in both psychiatric conditions and chronic pain management, with its analgesic effects believed to be mediated through central pain modulation pathways.

Drug Class

Serotonin-norepinephrine reuptake inhibitor (SNRI), Antidepressant, Analgesic (for neuropathic pain)

Mechanism of Action

Duloxetine potently inhibits the reuptake of serotonin and norepinephrine by blocking the serotonin transporter (SERT) and norepinephrine transporter (NET). This dual action increases the availability of these neurotransmitters in the synaptic cleft, enhancing neurotransmission. • Serotonin modulation: Improves mood regulation and emotional processing • Norepinephrine modulation: Enhances attention and pain inhibition pathways • Combined effects: Produces both antidepressant and analgesic effects

Pharmacokinetics

Absorption: Well absorbed orally with 50% bioavailability. Food delays absorption by 3 hours but does not affect total absorption. Distribution: Highly protein-bound (>90%), primarily to albumin and α1-acid glycoprotein. Volume of distribution is 1640 L. Metabolism: Extensively metabolized in the liver via CYP1A2 and CYP2D6 isoenzymes. Excretion: 70% excreted in urine as metabolites, 20% in feces. Half-life: Approximately 12 hours (range 8-17 hours). Steady state achieved in 3 days.

Pharmacodynamics

• Central nervous system: Improves mood, reduces anxiety, and modulates pain perception • Cardiovascular: May increase blood pressure and heart rate • Gastrointestinal: Can delay gastric emptying • Analgesic effects: Reduces central sensitization in chronic pain conditions

Indications

• Major depressive disorder (MDD): Treatment of adults with MDD • Generalized anxiety disorder (GAD): Acute and maintenance treatment in adults • Diabetic peripheral neuropathic pain: Management of neuropathic pain associated with diabetes • Fibromyalgia: Management of chronic widespread pain • Chronic musculoskeletal pain: Management of chronic osteoarthritis pain and chronic low back pain

Contraindications

Absolute: • Concurrent use with MAO inhibitors or within 14 days of discontinuation • Uncontrolled narrow-angle glaucoma Relative: • Severe hepatic impairment • Uncontrolled hypertension • History of mania or seizures

Dosage & Administration

Major depressive disorder: Initial dose 20-30 mg once daily, increase to 60 mg/day as tolerated. Generalized anxiety disorder: Start at 30-60 mg once daily, may increase to 120 mg/day if needed. Diabetic neuropathy: 60 mg once daily (lower starting doses may reduce side effects). Fibromyalgia: 30 mg once daily for 1 week, then increase to 60 mg/day. Chronic musculoskeletal pain: 30 mg once daily, may increase to 60 mg/day after 1 week.

Special Populations

Pediatric: Safety and efficacy not established for most indications. Geriatric: Use with caution; consider lower starting doses due to increased sensitivity. Renal impairment: Not recommended for severe renal impairment (CrCl <30 mL/min). Hepatic impairment: Avoid in chronic liver disease or cirrhosis; reduce dose in mild-moderate impairment.

Adverse Effects

Common (>10%): • Nausea (20-30%) • Dry mouth (15-20%) • Fatigue (10-15%) • Constipation (10-15%) Serious (<1%): • Hepatotoxicity • Serotonin syndrome • Severe skin reactions • Hyponatremia • Increased suicide risk in young adults

Drug Interactions

• MAO inhibitors: Risk of serotonin syndrome (contraindicated) • CYP1A2 inhibitors (e.g., fluvoxamine): May increase duloxetine levels • Anticoagulants: May increase bleeding risk • Other serotonergic drugs: Increased risk of serotonin syndrome • NSAIDs: Increased risk of GI bleeding

Warnings & Precautions

• Black Box Warning: Increased risk of suicidal thinking and behavior in children, adolescents, and young adults • May cause hepatotoxicity; avoid in chronic liver disease • Can increase blood pressure; monitor regularly • Risk of serotonin syndrome, especially with other serotonergic drugs • May cause activation of mania in bipolar disorder • Discontinuation syndrome with abrupt withdrawal

Pregnancy & Lactation

Pregnancy: Category C. Potential neonatal complications with third trimester use. Risk-benefit assessment required. Lactation: Excreted in breast milk. Not recommended due to potential adverse effects in nursing infants.

Monitoring Parameters

• Blood pressure at baseline and periodically • Liver function tests at baseline and when clinically indicated • Mood changes and suicidality, especially in first few months • Serum sodium in elderly or at-risk patients • Pain assessment in chronic pain conditions • Weight changes

Patient Counseling

• Take at same time each day, with or without food • Do not crush or chew capsules • Report any unusual bleeding, jaundice, or mood changes • Avoid abrupt discontinuation • Caution with alcohol use • May take 2-4 weeks for full therapeutic effect • Report severe nausea or persistent side effects

Storage & Stability

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture and light. Keep in original container with desiccant.

Clinical Pearls

• Start low and go slow in elderly patients • Consider bedtime dosing if sedation occurs • Nausea often improves with continued use • Taper gradually when discontinuing (over at least 2 weeks) • More effective for pain at lower doses than required for depression • Monitor for urinary hesitation, especially in men with BPH

References

• Micromedex® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA • UpToDate, Duloxetine: Drug information • FDA Prescribing Information for Cymbalta (2023) • Stahl SM. Essential Psychopharmacology (2021) • Bymaster FP, et al. Neuropsychopharmacology (2005)