What are the indications and dosing guidelines for Duloxetine (Cymbalta)?

Duloxetine: Indications and Dosing Guidelines

Duloxetine is FDA-approved for major depressive disorder, generalized anxiety disorder (adults and children ≥7 years), diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain in adults, with 60 mg once daily being the target therapeutic dose for most indications. 1

FDA-Approved Indications

Duloxetine is indicated for: 1

• Major depressive disorder in adults
• Generalized anxiety disorder in adults and pediatric patients ≥7 years
• Diabetic peripheral neuropathic pain in adults
• Fibromyalgia in adults
• Chronic musculoskeletal pain in adults (including osteoarthritis and chronic low back pain)

Standard Dosing Regimens

Major Depressive Disorder

• Starting dose: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or 30 mg twice daily) 1
• Alternative initiation: 30 mg once daily for 1 week to improve tolerability, then increase to 60 mg once daily 1
• Maximum dose: 120 mg/day, though no evidence supports additional benefit beyond 60 mg/day 1

Generalized Anxiety Disorder

Adults <65 years: 1

• Start at 60 mg once daily (or 30 mg once daily for 1 week if tolerability is a concern)
• Target dose: 60 mg once daily
• May increase in 30 mg increments if needed, up to 120 mg/day

Geriatric patients (≥65 years): 1

• Start at 30 mg once daily for 2 weeks
• Increase to target dose of 60 mg/day
• May increase beyond 60 mg in 30 mg increments (maximum 120 mg/day studied)

Pediatric patients (7-17 years): 1

• Start at 30 mg once daily for 2 weeks
• Recommended range: 30-60 mg once daily
• May increase beyond 60 mg in 30 mg increments if needed (maximum 120 mg/day studied)

Diabetic Peripheral Neuropathic Pain

• Standard dose: 60 mg once daily 1
• No benefit from doses >60 mg/day, with higher doses being less well tolerated 1
• For tolerability concerns: Consider lower starting dose 1
• Efficacy data: Approximately 50% of patients achieve ≥50% pain reduction at 12 weeks, with NNT of 5.2 for 60 mg/day and 4.9 for 120 mg/day 2, 3

Fibromyalgia

• Starting dose: 30 mg once daily for 1 week 1
• Target dose: 60 mg once daily 1
• Key point: No evidence that doses >60 mg/day provide additional benefit, even in non-responders, and higher doses increase adverse events 1
• Efficacy: NNT of 8 for ≥50% pain reduction at 12 weeks 3

Chronic Musculoskeletal Pain (Osteoarthritis and Low Back Pain)

• Starting dose: 30 mg once daily for 1 week 2
• Target dose: 60 mg once daily 2
• Dose escalation: May increase to 120 mg daily after 7 weeks at 60 mg if response is suboptimal 2
• CDC recommendation: Consider duloxetine when NSAIDs are contraindicated, ineffective, or not tolerated 4

Critical Dosing Principles

The 30 mg Starting Strategy

Starting at 30 mg once daily for 1 week significantly reduces treatment-emergent nausea (the most common adverse effect) while producing only a transient delay in therapeutic effect compared to starting at 60 mg daily. 5, 6 This approach improves medication adherence and reduces early discontinuation. 5

Dose Escalation Guidelines

• Increment size: Increase in 30 mg increments 2
• Timing: Allow at least 1-2 weeks at each dose level to assess response 2
• Maximum dose: 120 mg/day across all indications 1
• Reassessment: If no response after 4-8 weeks at 120 mg once daily, switch to a different medication class rather than further dose increases 2

Administration Instructions

• Take with or without food 1
• Swallow capsules whole—do not chew, crush, open, or sprinkle contents 1
• Timing: Can be taken at any time of day 2
• Missed dose: Take as soon as remembered unless almost time for next dose; never double dose 1

Special Population Considerations

Renal Impairment

• Not recommended for creatinine clearance <30 mL/min 5
• Consider lower starting dose and gradual titration in patients with renal disease (common in diabetes) 1

Hepatic Impairment

• Dose reduction required in hepatic disease 5

Older Adults

• Require lower starting doses and slower titration 5
• Increased risk of adverse effects including cognitive impairment, falls, and drug-drug interactions 2

Monitoring Requirements

• Blood pressure: Monitor at each visit, as duloxetine can cause modest hypertension 5
• Therapeutic response: Evaluate using standardized pain or depression scales 5
• Adverse effects: Assess at each follow-up visit, particularly with higher doses 5
• Mood changes: Watch closely in young adults during first few months of treatment 5
• Liver enzymes: Consider checking within 2 months if using concomitantly with CBD-containing products (13% develop transaminase elevations) 2

Common Adverse Effects

Most common treatment-emergent adverse events include: 2, 7

• Nausea (most common, reduced by starting at 30 mg)
• Dry mouth
• Headache
• Constipation
• Dizziness
• Fatigue
• Decreased appetite
• Somnolence

Discontinuation rate: Approximately 16% stop due to adverse effects 3

Discontinuation Protocol

Taper duloxetine gradually over at least 2-4 weeks when discontinuing after more than 3 weeks of treatment to minimize withdrawal symptoms. 2, 5

Standard Taper

• Reduce dose in 30 mg decrements 2
• Allow at least 1 week at each dose level 2

Slower Taper (for patients with history of withdrawal symptoms)

• Taper over 3-4 weeks with smaller decrements (e.g., 120→100→80→60 mg) 5
• Use small increments with adequate observation time 5

Common Discontinuation-Emergent Symptoms

• Nausea and dizziness (most common, occurring in up to one-third of patients) 7

Drug Interactions

• CYP1A2 inhibitors: Avoid concomitant use 2
• CYP2D6 substrates: Use with caution, particularly drugs with narrow therapeutic index 2
• MAO inhibitors: Contraindicated (nonselective, irreversible MAOIs) 6
• NSAIDs: Use with caution due to increased cardiovascular risk; duloxetine can increase blood pressure and heart rate 2
• Cannabis/CBD: May increase duloxetine levels via CYP1A2 inhibition; start cannabis at lowest dose and monitor for duloxetine toxicity 2

Clinical Context and Evidence Quality

The CDC guidelines recommend duloxetine as a first-line option for diabetic neuropathy and fibromyalgia, and as a second-line option for chronic low back pain and osteoarthritis when NSAIDs are inadequate. 4 Moderate-quality evidence supports duloxetine at 60-120 mg daily for diabetic neuropathy, with lower-quality evidence for fibromyalgia. 4 The evidence base consists primarily of manufacturer-sponsored trials, though the consistency of findings across multiple studies supports efficacy. 3

For osteoarthritis, duloxetine is the only centrally acting agent with adequate evidence, making it the preferred choice over alternatives like pregabalin or gabapentin when NSAIDs fail. 2