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

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

FDA-Approved Indications

Duloxetine is FDA-approved for major depressive disorder, generalized anxiety disorder (specifically in children and adolescents ≥7 years old), diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain. 1, 2

Pain Conditions with Evidence of Efficacy

• Diabetic peripheral neuropathy: Duloxetine 60 mg and 120 mg daily (but not lower doses) demonstrate moderate-quality evidence for pain reduction 1
• Fibromyalgia: Small improvements in pain with duloxetine compared to placebo, though evidence quality is lower than for diabetic neuropathy 1
• Osteoarthritis: Small to moderate benefits for pain and function at 60 mg daily, with evidence showing greater effectiveness in patients >65 years and those with knee osteoarthritis 1
• Chronic low back pain: Small improvements demonstrated at standard doses 1
• Chemotherapy-induced peripheral neuropathy: Efficacy shown at 30 mg daily for 1 week, then 60 mg daily, with better response in cisplatin-treated versus taxane-treated patients 3

Dosing Recommendations

Initiation Strategy

Start duloxetine at 30 mg once daily for 1 week before increasing to 60 mg once daily to minimize nausea, the most common adverse effect. 3, 4 This approach significantly improves tolerability and reduces treatment discontinuation 3.

Therapeutic Dosing by Indication

• Diabetic peripheral neuropathic pain: 60 mg once daily is the recommended dose; no evidence that higher doses provide additional significant benefit 5, 6
• Fibromyalgia and generalized anxiety disorder: 60-120 mg once daily 1, 7
• Osteoarthritis and chronic low back pain: 60 mg once daily 1
• Chemotherapy-induced peripheral neuropathy: 30 mg daily for 1 week, then 60 mg daily 3

Administration Details

• May be taken with or without food 2
• Swallow capsules whole; do not chew, crush, open, or mix with liquids as this affects drug delivery 2
• Once-daily dosing is appropriate due to the 12-hour elimination half-life 7

Special Population Considerations

• Renal impairment: Not recommended for creatinine clearance <30 mL/min 3
• Hepatic impairment: Dose reduction required 3
• Elderly patients: Monitor closely for hyponatremia, falls, and blood pressure changes 2

Monitoring Requirements

Essential Monitoring Parameters

• Blood pressure: Check before starting and throughout treatment, as duloxetine can cause modest hypertension or orthostatic hypotension 1, 3, 2
• Weight and height in pediatric patients: Monitor regularly as decreased appetite and weight loss are common 2
• Therapeutic response: Evaluate using standardized pain or depression scales at each follow-up 3
• Liver function: Discontinue immediately if jaundice or signs of liver dysfunction develop 1, 2

Adverse Effects

Common Side Effects (Occurring in >5% of Patients)

The most frequent adverse effects include 2, 4:

• Nausea (most common, reduced by starting at 30 mg)
• Dry mouth
• Constipation
• Decreased appetite and weight loss
• Dizziness
• Fatigue/somnolence
• Increased sweating (hyperhidrosis)
• Headache
• Insomnia

Serious Adverse Effects Requiring Immediate Action

Duloxetine must be discontinued immediately and never restarted if the following occur: 1, 2

• Hepatic failure: Presenting as abdominal pain, hepatomegaly, elevated transaminases, or jaundice
• Severe skin reactions: Including erythema multiforme, Stevens-Johnson syndrome, blisters, peeling rash, or mucosal erosions
• Serotonin syndrome: Agitation, hallucinations, tachycardia, hyperthermia, muscle rigidity, seizures (life-threatening)

Other Potentially Serious Effects

• Suicidal thinking and behavior: Increased risk in patients ≤24 years old; requires close monitoring 1, 2
• Abnormal bleeding: Increased risk, especially with concomitant warfarin, NSAIDs, or aspirin 2
• Hypertension and orthostatic hypotension: Can cause both sustained blood pressure elevation and postural drops leading to falls 2
• Angle-closure glaucoma: Eye pain, vision changes, or eye swelling warrant immediate ophthalmologic evaluation 2
• Seizures: Rare but reported 2
• Hyponatremia: Particularly in elderly patients; symptoms include headache, confusion, weakness, or unsteadiness 2
• Urinary retention: Decreased urine flow or inability to void 2

Discontinuation Syndrome

Abrupt discontinuation causes withdrawal symptoms in a significant proportion of patients. 1, 2 Common discontinuation-emergent symptoms include:

• Dizziness and electric shock-like sensations
• Nausea, vomiting, diarrhea
• Headache
• Anxiety and irritability
• Insomnia and fatigue
• Sweating

Discontinuation Protocol

Taper duloxetine gradually over 3-4 weeks using small dose decrements (e.g., 120 mg → 100 mg → 80 mg → 60 mg → 30 mg) with at least one week at each dose level. 3 This approach is particularly important for patients with a history of withdrawal symptoms 3.

Critical Drug Interactions

Absolute Contraindications

• MAOIs: Concomitant use is contraindicated due to risk of fatal serotonin syndrome 1, 2
• Thioridazine: Can cause serious cardiac arrhythmias or sudden death 2
• Potent CYP1A2 inhibitors: Should be avoided (e.g., ciprofloxacin, enoxacin) 1, 2

Use with Caution

• CYP2D6 substrates with narrow therapeutic index: Duloxetine is a moderate CYP2D6 inhibitor 1, 7
• Serotonergic drugs: SSRIs, SNRIs, triptans, tramadol, fentanyl, amphetamines, tryptophan, St. John's Wort increase serotonin syndrome risk 2
• Anticoagulants and antiplatelet agents: Increased bleeding risk 2
• Alcohol: Avoid heavy alcohol use due to risk of severe liver injury 2

Efficacy Timeline and Magnitude

Pain relief with duloxetine 60 mg daily can occur within one week of reaching therapeutic dose. 4 For diabetic peripheral neuropathy, the number needed to treat (NNT) for 50% pain reduction at 12 weeks is 5-6, indicating robust efficacy 1, 6, 8. For fibromyalgia, the NNT is 8, suggesting more modest benefit 1, 6.

Overdose Management

Fatal outcomes have been reported with duloxetine overdoses, particularly in mixed overdoses 2. Signs include somnolence, coma, serotonin syndrome, seizures, tachycardia, and blood pressure abnormalities 2. There is no specific antidote; treatment consists of supportive care, airway protection, and activated charcoal if administered soon after ingestion 2. Contact poison control (1-800-222-1222) for guidance 2.

Clinical Pearls

• Approximately 16% of patients discontinue duloxetine due to adverse effects, with nausea being the most common reason 6, 8
• Serious adverse events are rare in clinical trials 6, 8
• The 60 mg dose is generally optimal; higher doses (120 mg) increase adverse effects without proportional benefit for most indications 5
• Duloxetine may be particularly useful for patients with comorbid depression and chronic pain 9