What is the usage and dosage of Cymbalta (duloxetine) for various medical conditions?

Cymbalta (Duloxetine): Clinical Applications and Dosing

Primary FDA-Approved Indications

Duloxetine is FDA-approved for major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain (including chronic low back pain and osteoarthritis) at doses of 60-120 mg daily. 1

Major Depressive Disorder

• Start at 30 mg once daily for 1 week, then increase to 60 mg once daily 1
• Maximum dose: 120 mg/day, though doses above 60 mg/day show no clear additional benefit 1
• Duloxetine demonstrates efficacy within 1-2 weeks at 60 mg once daily 2
• Particularly effective for patients with painful physical symptoms accompanying depression 3, 4

Generalized Anxiety Disorder

• For adults under 65 years: initiate at 60 mg once daily (may start at 30 mg for 1 week to improve tolerability) 1
• For geriatric patients: start at 30 mg once daily for 2 weeks before increasing to 60 mg/day 1
• For pediatric patients (7-17 years): start at 30 mg once daily for 2 weeks, then consider increasing to 60 mg once daily 1
• Recommended dosage range for pediatrics: 30-60 mg once daily, with maximum studied dose of 120 mg/day 1
• While 120 mg/day is effective, no evidence supports additional benefit over 60 mg/day 1, 5

Diabetic Peripheral Neuropathic Pain

• Administer 60 mg once daily as the standard dose 1
• No evidence that doses higher than 60 mg/day provide additional significant benefit, and higher doses are clearly less well tolerated 1
• This is the only drug with Level I, B evidence for painful diabetic neuropathy 6
• Number needed to treat (NNT) for 50% pain reduction: 5 at 60 mg/day 3
• Approximately 50% of patients achieve at least 50% pain reduction at 12 weeks 3
• For patients with tolerability concerns, start at 30 mg once daily 1
• Since diabetes frequently involves renal disease, consider lower starting dose with gradual titration in patients with renal impairment 1

Fibromyalgia

• Begin at 30 mg once daily for 1 week, then increase to 60 mg once daily 1
• Target dose: 60 mg once daily 1
• Some patients respond to the 30 mg starting dose 1
• No evidence that doses greater than 60 mg/day confer additional benefit, even in non-responders 1
• NNT for 50% pain reduction: 8 at 12 weeks 4
• Effects sustained through 28 weeks 4
• Pain reduction may be greater in patients with comorbid depression 3

Chronic Musculoskeletal Pain (Low Back Pain and Osteoarthritis)

• Begin at 30 mg once daily for 1 week, then increase to 60 mg once daily 1
• Target dose: 60 mg once daily 1
• No evidence that higher doses provide additional benefit, even in non-responders 1
• Higher doses associated with increased adverse reactions 1
• For osteoarthritis: particularly indicated when NSAIDs are contraindicated, ineffective, or not tolerated 3
• Consider as second-line when first-line therapies (NSAIDs, acetaminophen, intra-articular corticosteroids) have failed 3

Chemotherapy-Induced Peripheral Neuropathy (CIPN)

• Duloxetine is the only drug with large randomized trial evidence showing moderate clinical benefit for CIPN 6, 4
• 59% pain reduction with duloxetine versus 38% with placebo 6, 4
• Recommended as first-line treatment with Level I, B evidence 6, 4
• Effect more pronounced in platinum-based CIPN than taxane-induced CIPN 6
• Standard dose: 60 mg once daily 6

Critical Dosing Principles

Starting Low to Minimize Nausea

• Nausea is the most common adverse effect and can be mitigated by starting at 30 mg once daily for 1 week before increasing to 60 mg 3, 7
• This titration strategy significantly reduces nausea incidence 3
• Most adverse effects are mild to moderate and most prominent in the first week 3

Dose Escalation Strategy

• If 60 mg once daily is insufficient after 4-8 weeks, increase in 30 mg increments 3
• Allow at least 1-2 weeks at each dose level to assess response 3
• Maximum dose: 120 mg/day 3, 1
• In older adults, use cautious dose escalation with small increments at intervals of at least one week 3

When to Switch Rather Than Escalate

• If no response after reaching 120 mg once daily for 4-8 weeks, switch to a different medication class rather than further dose increases 3
• Alternative options include pregabalin, gabapentin, or alternative antidepressants 3

Special Populations and Contraindications

Hepatic Impairment

• Avoid use in patients with chronic liver disease or cirrhosis 1
• Duloxetine is contraindicated in severe hepatic impairment 8

Renal Impairment

• Avoid use in patients with severe renal impairment (GFR <30 mL/minute) 1
• Use caution and consider lower starting doses in patients with renal insufficiency 3, 1

Geriatric Patients

• Start at lower doses (30 mg once daily) and titrate more slowly 3, 8
• Increased risk of adverse effects including cognitive impairment, falls, and drug-drug interactions 3

Discontinuation Protocol

Taper gradually over at least 2-4 weeks to minimize withdrawal symptoms, especially after treatment longer than 3 weeks 3, 1

Common discontinuation-emergent adverse events include:

• Dizziness, headache, nausea, diarrhea 1
• Paresthesia, irritability, vomiting 1
• Insomnia, anxiety, hyperhidrosis, fatigue 1

Drug Interactions and Safety Monitoring

MAOI Interactions

• Allow at least 14 days between discontinuing an MAOI and starting duloxetine 1
• Allow at least 5 days after stopping duloxetine before starting an MAOI 1
• Do not start duloxetine in patients receiving linezolid or IV methylene blue due to serotonin syndrome risk 1

CYP450 Interactions

• Duloxetine is metabolized by CYP1A2 and CYP2D6 6, 3
• Avoid concomitant use with potent CYP1A2 inhibitors 5
• Use caution with drugs extensively metabolized by CYP2D6, particularly those with narrow therapeutic index 5

Cannabis Interaction

• Cannabis inhibits CYP1A2, which could theoretically increase duloxetine levels and risk of adverse effects 3
• Start cannabis at lowest possible dose if duloxetine is already established 3
• Monitor for signs of duloxetine toxicity 3
• Consider checking liver enzymes within 2 months if using CBD-containing products, as 13% of patients on therapeutic CBD develop transaminase elevations 3

Cardiovascular Considerations

• Duloxetine does not typically produce clinically important ECG or blood pressure changes 4, 8
• Unlike tricyclic antidepressants, not contraindicated in cardiac disease 4
• When combining with NSAIDs, use caution in patients with cardiovascular comorbidities as duloxetine can increase systolic BP, diastolic BP, and heart rate 3

Common Adverse Effects

Most common treatment-emergent adverse events include:

• Nausea (most common) 3, 1, 7
• Dry mouth, headache, constipation 3, 1
• Dizziness, decreased appetite, somnolence 3
• Fatigue 3, 1

Serious but rare adverse effects:

• Hepatic failure 3
• Severe skin reactions 3
• Suicidal thinking and behavior 3
• Serotonin syndrome 3

Key Clinical Pitfalls to Avoid

• Do not start at 60 mg/day in all patients—this increases discontinuation due to adverse events 2
• Do not assume all patients need dose escalation beyond 60 mg/day—there is no evidence of additional benefit for most indications 1, 9
• Do not abruptly discontinue—always taper gradually 1
• Do not overlook comorbid depression in pain patients—these patients derive particular benefit from duloxetine 4
• Do not require sequential failure of all therapies—weigh expected benefits against risks without mandating stepwise progression 4

Monitoring Recommendations

• Weekly contact during titration phase to assess target symptoms using standardized scales 3
• Monthly follow-up until symptoms stabilized 3
• Regular monitoring for improvement in pain scores and functional status 8
• Periodic reassessment to determine continued need for maintenance treatment 1
• Aminotransferase monitoring generally unnecessary according to recent reviews 4