What are the indications, dosing, and potential side effects of Duloxetine (SNRI)?

Duloxetine (SNRI): Indications, Dosing, and Side Effects

FDA-Approved Indications

Duloxetine is FDA-approved for generalized anxiety disorder in children and adolescents ≥7 years old, making it the only SNRI with this pediatric anxiety indication. 1 In adults, duloxetine is approved for major depressive disorder, diabetic peripheral neuropathic pain, fibromyalgia, generalized anxiety disorder, and chronic musculoskeletal pain. 2

Dosing Recommendations

Standard Initiation Protocol

Start duloxetine at 30 mg once daily for 1 week, then increase to the therapeutic dose of 60 mg once daily. 2, 3 This approach significantly reduces treatment-emergent nausea while producing only a transient delay in therapeutic effect compared to starting at 60 mg daily. 3

• The 30 mg starting dose for one week allows patients to adjust before reaching therapeutic levels, with nausea being the most common adverse effect that benefits from this gradual approach. 3
• Duloxetine has a sufficiently long elimination half-life to permit single daily dosing. 1
• The medication may be taken with or without food and at any time of day. 4

Condition-Specific Dosing

For diabetic peripheral neuropathy: 60-120 mg daily is the FDA-approved range, with approximately 50% of patients achieving at least 50% pain reduction at 12 weeks. 2 The number needed to treat (NNT) for 50% pain reduction is 4.9 for 120 mg/day and 5.2 for 60 mg/day. 2

For fibromyalgia: 60 mg once daily is the optimal dose, with no additional benefit demonstrated at 120 mg. 2 Pain reduction may be greater in patients with comorbid depression. 2

For osteoarthritis and chronic low back pain: Start at 30 mg daily for one week, then 60 mg daily, with the option to increase to 120 mg daily if response is suboptimal after 7 weeks at 60 mg. 2

For generalized anxiety disorder: 60-120 mg once daily has demonstrated efficacy in short-term (9-10 weeks) and longer-term (26 weeks) trials. 1

Dose Escalation

If escalation beyond 60 mg is needed, increase in 30 mg increments, allowing at least 1-2 weeks at each dose level to assess response, with a maximum dose of 120 mg/day. 2 If no response occurs after reaching 120 mg once daily for 4-8 weeks, switch to a different medication class rather than further dose increases. 2

Special Populations

Duloxetine is not recommended for patients with creatinine clearance <30 mL/min. 3 Dose reduction is required in hepatic disease. 3 In older adults, use cautious dose escalation with small increments at intervals allowing adequate observation, usually at least one week at each dose level. 2

Monitoring Requirements

Monitor height, weight, pulse, and blood pressure at baseline and throughout treatment; no specific laboratory tests are routinely recommended. 1

• Duloxetine can cause sustained clinical hypertension, increased blood pressure, and increased pulse. 1
• In pediatric patients, height and weight should be monitored regularly, as duloxetine-treated children experienced a 0.1 kg mean decrease in weight at 10 weeks compared with 0.9 kg gain in placebo-treated patients. 4
• Watch closely for mood changes, particularly in young adults during the first few months of treatment. 3

Common Adverse Effects

The most common adverse effects include nausea (37.8% at 60 mg QD), dry mouth, headache, constipation, dizziness, fatigue, decreased appetite, insomnia, somnolence, and increased sweating. 1, 4

• Nausea is the most common side effect but occurs less frequently when treatment is initiated at 30 mg daily and titrated after one week to 60 mg daily. 5
• Most adverse events are mild to moderate in severity and are most prominent in the first week. 2
• Approximately 16% of participants stop the drug due to adverse effects. 6
• The incidence of treatment-emergent nausea is 37.8% at 60 mg QD compared with 16.4% at 40 mg daily (20 mg BID). 7

Serious Adverse Effects (Rare but Critical)

Hepatotoxicity

Duloxetine has been associated with hepatic failure presenting as abdominal pain, hepatomegaly, and elevation of transaminase levels. 1 Cholestatic jaundice has also been reported. 1 Discontinue duloxetine immediately and do not restart in patients who develop jaundice or other evidence of clinically significant liver dysfunction. 1

Severe Skin Reactions

Severe skin reactions, including erythema multiforme and Stevens-Johnson syndrome, can occur with duloxetine. 1 Discontinue duloxetine immediately and do not restart at the first appearance of blisters, peeling rash, mucosal erosions, or other signs of hypersensitivity. 1

Psychiatric Effects

Uncommon but potentially serious adverse effects include suicidal thinking and behavior (through age 24 years), behavioral activation/agitation, hypomania, and mania. 1 Two episodes of attempted suicide and one completed suicide occurred in duloxetine recipients during longer-term trials. 8

Serotonin Syndrome

Serotonin syndrome is a life-threatening condition that can occur, particularly when duloxetine is combined with other serotonergic agents. 4 Symptoms include agitation, hallucinations, coordination problems, racing heartbeat, high or low blood pressure, sweating, fever, nausea, vomiting, diarrhea, muscle rigidity, dizziness, flushing, tremor, and seizures. 4

Other Serious Effects

• Abnormal bleeding: Increased risk when combined with warfarin, NSAIDs, or aspirin. 4
• Seizures or convulsions 4
• Hyponatremia: Elderly people are at greater risk, presenting with headache, weakness, confusion, or memory problems. 4
• Angle-closure glaucoma: Eye pain, vision changes, swelling or redness in or around the eye. 4
• Urinary retention: Decreased urine flow or inability to pass urine. 4

Drug Interactions

Contraindications

Concomitant administration of duloxetine and any MAOIs is absolutely contraindicated due to increased risk of serotonin syndrome. 1

Significant Interactions

Duloxetine may interact with drugs metabolized by CYP1A2 and CYP2D6. 1 Avoid concomitant use with potent CYP1A2 inhibitors (such as ciprofloxacin, enoxacin). 4 Use caution with drugs extensively metabolized by CYP2D6, particularly those with a narrow therapeutic index (propafenone, flecainide, quinidine). 4

Exercise caution when combining with:

• Triptans (migraine medications) 4
• Other serotonergic agents (SSRIs, SNRIs, tricyclics, lithium, buspirone, tramadol, fentanyl) 4
• Amphetamines 4
• Warfarin and NSAIDs (increased bleeding risk) 4
• Thioridazine (serious heart rhythm problems or sudden death) 4
• St. John's Wort or tryptophan 4

Cannabis Interaction

Cannabis inhibits CYP1A2, which could theoretically increase duloxetine levels and risk of adverse effects. 2 The combination may increase risk of hepatotoxicity, as both can cause liver enzyme elevations. 2 Start cannabis at the lowest possible dose if duloxetine is already established, and consider checking liver enzymes within 2 months if using CBD-containing products. 2

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, 3 A discontinuation syndrome has been reported following missed doses or acute discontinuation. 1

Discontinuation symptoms include:

• Anxiety, irritability 4
• Fatigue, sleep problems 4
• Headache 4
• Sweating, dizziness 4
• Electric shock-like sensations 4
• Vomiting, nausea, diarrhea 4

For patients with a history of withdrawal symptoms, consider a slower taper over 3-4 weeks with smaller dose decrements (e.g., 120 mg → 100 mg → 80 mg → 60 mg). 3

Critical Clinical Pitfalls to Avoid

• Do not crush, chew, or open capsules: Swallow whole, as opening the capsule may affect how duloxetine works. 4
• Avoid heavy alcohol use: Concomitant use with heavy alcohol intake may be associated with severe liver injury. 4
• Do not combine with other duloxetine-containing products 4
• Do not abruptly discontinue: Always taper to prevent withdrawal syndrome. 1
• Monitor for hepatotoxicity: Discontinue immediately if jaundice or liver dysfunction develops. 1
• Watch for skin reactions: Discontinue at first sign of blisters or severe rash. 1

Overdose Management

Fatal outcomes have been reported with duloxetine overdoses, including with 1000 mg (approximately 8.3 times the maximum recommended dosage). 4 Signs include somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting. 4 There is no specific antidote; treatment consists of general supportive measures, gastric lavage if performed soon after ingestion, and activated charcoal (which decreases duloxetine AUC and Cmax by an average of one-third). 4 Contact poison control (1-800-222-1222) for additional guidance. 4