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

Duloxetine (Cymbalta): Indications and Dosing Guidelines

FDA-Approved Indications

Duloxetine is FDA-approved for major depressive disorder in adults, generalized anxiety disorder in adults and children ≥7 years, diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain in adults. 1

• Major depressive disorder (adults) 1
• Generalized anxiety disorder (adults and pediatric patients ≥7 years) 1
• Diabetic peripheral neuropathic pain (adults) 1
• Fibromyalgia (adults) 1
• Chronic musculoskeletal pain including chronic low back pain and osteoarthritis (adults) 1

Standard Dosing Regimens

Major Depressive Disorder

• Start at 40 mg/day (20 mg twice daily) or 60 mg/day (once daily or 30 mg twice daily). 1
• For improved tolerability, start at 30 mg once daily for 1 week before increasing to 60 mg once daily. 1
• Maximum effective dose is 60 mg/day; doses >60 mg/day provide no additional benefit. 1

Generalized Anxiety Disorder

Adults <65 years:

• Initiate at 60 mg once daily. 1
• For improved tolerability, start at 30 mg once daily for 1 week before increasing to 60 mg. 1
• May increase in 30 mg increments if needed, though no evidence supports benefit beyond 60 mg/day. 1
• Maximum studied dose: 120 mg/day. 1

Geriatric patients ≥65 years:

• Start at 30 mg once daily for 2 weeks before increasing to target dose of 60 mg/day. 1
• May increase in 30 mg increments beyond 60 mg if needed. 1

Pediatric patients 7-17 years:

• Start at 30 mg once daily for 2 weeks before considering increase to 60 mg. 1
• Recommended range: 30-60 mg once daily. 1
• May increase in 30 mg increments; maximum studied dose 120 mg/day. 1

Diabetic Peripheral Neuropathic Pain

• Administer 60 mg once daily. 1
• No evidence that doses >60 mg/day provide additional benefit, and higher doses are less well tolerated. 1
• For patients with tolerability concerns or renal impairment, consider lower starting dose with gradual titration. 1
• Number needed to treat (NNT) for 50% pain reduction: 4.9 for 120 mg/day and 5.2 for 60 mg/day, with approximately 50% of patients achieving ≥50% pain reduction at 12 weeks. 2

Fibromyalgia

• Start at 30 mg once daily for 1 week, then increase to 60 mg once daily. 1
• Some patients respond to the 30 mg starting dose. 1
• Doses >60 mg/day provide no additional benefit and increase adverse events. 1
• The CDC recommends duloxetine as a treatment option for fibromyalgia, with moderate-quality evidence showing small to moderate improvements in pain, function, and quality of life. 3

Chronic Musculoskeletal Pain (Low Back Pain and Osteoarthritis)

• Start at 30 mg once daily for 1 week to reduce nausea, then increase to 60 mg once daily. 2, 4
• For suboptimal response after 7 weeks at 60 mg, may increase to 120 mg daily. 2
• For osteoarthritis with one or few affected joints, topical NSAIDs are recommended first; duloxetine is used when topical NSAIDs are insufficient or multiple joints are affected. 3
• Moderate-quality evidence demonstrates small improvements in chronic low back pain with duloxetine. 3

Administration Guidelines

• Administer orally with or without meals; swallow capsules whole. 1
• Do not chew, crush, or open capsules, as this affects the enteric coating. 1
• If a dose is missed, take as soon as remembered unless it's almost time for the next dose; never double dose. 1

Special Population Considerations

Renal Impairment

• Not recommended for patients with creatinine clearance <30 mL/min. 4
• Consider lower starting dose and gradual titration for patients with renal impairment. 1

Hepatic Impairment

• Dose reduction required in hepatic disease. 4

Geriatric Patients

• Require lower starting doses and slower titration. 4
• For GAD, start at 30 mg once daily for 2 weeks before increasing. 1

Safety Monitoring and Adverse Effects

Common Adverse Effects

• Nausea (most common), dry mouth, headache, constipation, dizziness, decreased appetite, and somnolence. 2
• Most prominent in the first week and generally mild to moderate. 2
• Starting at 30 mg once daily for 1 week significantly reduces treatment-emergent nausea. 2, 4

Serious but Rare Adverse Effects

• Hepatic failure, severe skin reactions, suicidal thinking and behavior, and serotonin syndrome. 2
• Monitor blood pressure as duloxetine can cause modest hypertension. 4
• When combining with NSAIDs, use caution in patients with cardiovascular comorbidities, as duloxetine can increase systolic BP, diastolic BP, and heart rate. 2

Discontinuation Rate

• Approximately 16% of participants stop the drug due to adverse effects. 5

Drug Interactions

• Avoid concomitant use with potent CYP1A2 inhibitors. 2
• Use with caution in patients receiving drugs extensively metabolized by CYP2D6, particularly those with narrow therapeutic index. 2
• Do not use with nonselective, irreversible monoamine oxidase inhibitors. 6

Discontinuation Protocol

• Taper gradually over at least 2-4 weeks when discontinuing after >3 weeks of treatment. 2, 4
• For patients with history of withdrawal symptoms, consider slower taper over 3-4 weeks with smaller dose decrements (e.g., 120 mg → 100 mg → 80 mg → 60 mg). 4
• Use small increments at intervals of at least one week at each dose level. 4
• Common discontinuation-emergent adverse events include nausea and dizziness. 7

Evidence Quality and Clinical Context

• High-quality evidence supports duloxetine 60-120 mg daily for diabetic peripheral neuropathy, with NNT of 5 for ≥50% pain reduction at 12 weeks. 3
• Moderate-quality evidence supports duloxetine for fibromyalgia with NNT of 8 for ≥50% pain reduction. 3, 5
• The CDC 2022 guideline recommends duloxetine as a nonopioid option for chronic musculoskeletal pain when nonpharmacologic approaches are insufficient. 3
• Duloxetine is not a controlled substance and has no significant abuse liability. 2