What is the recommended use and dosage of Duloxetine (Serotonin-Norepinephrine Reuptake Inhibitor)?

Duloxetine: Recommended Use and Dosing

FDA-Approved Indications

Duloxetine is FDA-approved for major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain (including osteoarthritis and chronic low back pain), with a standard therapeutic dose of 60 mg once daily for most indications. 1

Approved Indications by Population:

• Adults: Major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, chronic musculoskeletal pain 1
• Pediatric patients (7-17 years): Generalized anxiety disorder only 2, 1

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Standard Dosing Protocol

Initial Dosing Strategy

Start with 30 mg once daily for 1 week before increasing to the target dose of 60 mg once daily to minimize nausea, the most common adverse effect. 3, 4, 5, 1

• This titration approach significantly reduces treatment-emergent nausea while producing only a transient delay in therapeutic effect compared to starting at 60 mg daily 4
• The 30 mg starting dose allows patients to adjust to the medication before reaching therapeutic levels 5

Target Therapeutic Doses by Indication:

Major Depressive Disorder:

• Starting dose: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or 30 mg twice daily) 1
• For improved tolerability, start at 30 mg once daily for 1 week, then increase to 60 mg once daily 1
• Maximum studied dose: 120 mg/day, though no evidence suggests doses >60 mg/day provide additional benefit 1

Generalized Anxiety Disorder (Adults <65 years):

• Initial dose: 60 mg once daily 1
• May start at 30 mg once daily for 1 week to improve tolerability 1
• Maximum studied dose: 120 mg/day 1

Diabetic Peripheral Neuropathic Pain:

• Target dose: 60 mg once daily 1, 6
• No evidence that doses >60 mg/day confer additional benefit, and higher doses are less well tolerated 1
• For tolerability concerns, consider lower starting dose 1
• This is the only dose with proven efficacy (NNTB = 5) 6

Fibromyalgia:

• Start at 30 mg once daily for 1 week, then increase to 60 mg once daily 1
• Target dose: 60 mg once daily 1, 6
• No evidence that doses >60 mg/day provide additional benefit 1
• NNTB = 8 at 12 weeks 6

Chronic Musculoskeletal Pain (Osteoarthritis/Low Back Pain):

• Start at 30 mg once daily for 1 week, then increase to 60 mg once daily 5, 1
• Target dose: 60 mg once daily 5, 1
• Higher doses show no additional benefit and increased adverse reactions 1

Chemotherapy-Induced Peripheral Neuropathy:

• Duloxetine is the only drug with large randomized trial evidence showing moderate clinical benefit for painful CIPN 2
• Dosing: 30 mg daily for 1 week, then 60 mg daily 2, 4
• More effective for platinum-based chemotherapy than taxanes 2, 4
• Recommendation level: I, B 2

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Special Populations

Geriatric Patients (≥65 years):

• Start at 30 mg once daily for 2 weeks before increasing to target dose of 60 mg/day 3, 1
• Titrate more slowly than younger adults 3, 5
• May benefit from doses >60 mg once daily; if increasing, use 30 mg increments 1

Pediatric Patients (7-17 years) with Generalized Anxiety Disorder:

• Start at 30 mg once daily for 2 weeks before considering increase to 60 mg 1
• Recommended range: 30-60 mg once daily 1
• Maximum studied dose: 120 mg/day 1
• Monitor closely for mood changes, particularly during first few months of treatment 4

Renal Impairment:

• Avoid use in severe renal impairment (GFR <30 mL/min) 4, 1
• For patients with renal insufficiency, consider lower starting dose and gradual titration 4, 5
• Since diabetes frequently causes renal disease, consider lower starting dose in diabetic patients 1

Hepatic Impairment:

• Avoid use in patients with chronic liver disease or cirrhosis 4, 1
• Dose reduction required in hepatic disease 4

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Administration Guidelines

How to Take:

• Administer orally with or without meals 1
• Swallow capsules whole—do not chew, crush, or open capsules 1
• Opening capsules or mixing contents with food/liquids affects the enteric coating 1
• Can be given once daily due to sufficiently long elimination half-life 2

Missed Dose:

• Take missed dose as soon as remembered 1
• If almost time for next dose, skip the missed dose 1
• Never take two doses at the same time 1

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Monitoring Requirements

Routine Monitoring:

• Monitor blood pressure at follow-up visits, as duloxetine can cause modest hypertension 2, 4
• Assess for adverse effects at each visit, particularly with higher doses 4
• Evaluate therapeutic response using standardized pain or depression scales 4
• Routine aminotransferase monitoring is generally unnecessary 5

Safety Monitoring:

• Watch for suicidal thinking and behavior in patients up to age 24 years 2
• Monitor for behavioral activation, agitation, hypomania, or mania 2
• Discontinue immediately if jaundice, hepatomegaly, or elevated transaminases develop 2
• Discontinue at first sign of blisters, peeling rash, mucosal erosions, or Stevens-Johnson syndrome 2

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Discontinuation Protocol

When discontinuing duloxetine after >3 weeks of treatment, taper gradually over at least 2-4 weeks to minimize withdrawal symptoms. 4, 5, 1

Recommended Tapering Approach:

• For patients with history of withdrawal symptoms, use 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 allowing adequate observation, usually at least one week at each dose level 4
• Common discontinuation symptoms include dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue 1

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Contraindications and Drug Interactions

Absolute Contraindications:

• Do not use with MAOIs due to risk of serotonin syndrome 3
• Do not combine with CYP1A2 inhibitors 7

Relative Contraindications:

• Severe renal impairment (GFR <30 mL/min) 4, 1
• Chronic liver disease or cirrhosis 4, 1

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Common Adverse Effects

Most Frequent Side Effects:

• Nausea (most common): 37.8% at 60 mg QD vs. 16.4% at 40 mg/day 3, 8
• Dry mouth 2, 3
• Constipation 3
• Dizziness 2, 3
• Headache 2
• Fatigue 3
• Insomnia 2
• Somnolence 2
• Decreased appetite and weight loss 2
• Diaphoresis 2

Discontinuation Rate:

• 16% of patients stop due to adverse effects 6
• 13.1% discontinuation rate at 60 mg QD 8
• Serious adverse events are rare 6

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Clinical Pearls

Analgesic Properties:

• The analgesic effectiveness of duloxetine is independent of its antidepressant activity 5
• Effective analgesic dose is often lower than that required to treat depression 5
• Onset of analgesic action typically occurs earlier than antidepressant effects 5
• Frequently used as coanalgesic in combination with opioids for neuropathic pain 5

Efficacy Timeline:

• Pain relief can occur within one week at 60 mg/day 7
• Improvements in efficacy measures apparent after 1-2 weeks at 60 mg once daily 9
• For CIPN, apply pharmacologic treatment for at least 2 weeks at appropriate dose before changing to another option 2