Generic Name

Cymbalta (duloxetine)

Mechanism

Cymbalta (duloxetine) is a *serotonin‑norepinephrine reuptake inhibitor* (SNRI).
• Inhibits reuptake transporters:
• *Serotonin transporter (SERT)* – 65–84 % relative potency.
• *Norepinephrine transporter (NET)* – 20–30 % relative potency.
• Resulting in increased extracellular serotonin and norepinephrine at synaptic clefts.
• Synergistic action improves mood, pain perception, and modulates autonomic function.

Pharmacokinetics

Indications

• Major depressive disorder (MDD)
• Generalized anxiety disorder (GAD)
• Diabetic peripheral neuropathic pain (DPNP)
• Fibromyalgia
• Chronic musculoskeletal pain in osteoarthritis or low‑back pain (off‑label but widely used)

Contraindications

• Contraindications:
• Known hypersensitivity to duloxetine or any excipient.
• Use of monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI discontinuation.
• Co‑administration with linezolid, fluoroquinolones, or other serotonergic agents (risk of serotonin syndrome).
• Warnings:
• Serotonin syndrome – monitor for agitation, hyperthermia, neuromuscular abnormalities.
• Hypertension – raises blood pressure in susceptible patients.
• Suicidal ideation – monitor all patients under 25 years of age.
• Abnormal hepatic transaminases – avoid in moderate to severe hepatic impairment.
• Pregnancy: Category C; use only if benefits outweigh risks.
• Breastfeeding: Unknown safety; generally contraindicated.

Dosing

• Adults:
• *MDD/GAD*: start 20 mg PO once daily; increase to 40 mg after 1–2 weeks if needed.
• *DPNP/Fibromyalgia*: 30 mg once daily; upgrade to 60 mg after 2 weeks if tolerable.
• Elderly: Initiate at lowest dose; gradual titration.
• Renal impairment: Dose adjustment based on creatinine clearance.
• Administration: With or without food; avoid alcohol.
• Discontinuation: Taper over 2–4 weeks to avoid withdrawal—cough, nausea, dizziness, anterograde loss of bladder control.

Adverse Effects

• Common (≥10 %): nausea, dry mouth, fatigue, dizziness, constipation, decreased appetite.
• Serious (≤1 %): serotonin syndrome, severe hypertension, hepatotoxicity, suicidal ideation.

Monitoring

• Baseline:
• BP, headache or dizziness history, liver function tests (ALT/AST), ECG in CHD patients.
• Follow‑up:
• BP every 2–4 weeks during titration.
• Liver enzymes every 3 months or sooner if symptomatic.
• Serotonin Syndrome Signs: agitation, myoclonus, hyperreflexia, fever.
• Suicidal ideation: frequent assessment especially first 3 months.

Clinical Pearls

• Citrus Interference: Grapefruit juice *increases* duloxetine levels via CYP3A4 inhibition. Avoid concurrently.
• Polypharmacy & CNS Depressants: Combining with opioids or benzodiazepines heightens sedation; dose adjustments or monitoring required.
• Drug‑Drug Interaction Matrix: CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) elevate duloxetine; consider dose reduction.
• Weight & Gastrointestinal Effects: Weight loss can occur; monitor in weight‑sensitive patients (anorexia, pregnancy).
• Off‑Label Use: Adequate evidence supports duloxetine for neuropathic pain and fibromyalgia; document indication for insurance coverage.
• Patient Education: Stress the importance of adherence due to delayed onset of efficacy (~4–6 weeks).

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• References

1. FDA label – Cymbalta (duloxetine HCl) 2023.

2. Katzung & Trevor’s Pharmacology Examination and Board Review, 15th ed. 2022.

Keywords: Cymbalta, duloxetine, SNRI, pharmacology, depression, anxiety, neuropathic pain, dosing, contraindications, monitoring.