Generic Name

Duloxetine

Mechanism

• Selective inhibition of the serotonin transporter (SERT) and norepinephrine transporter (NET) → ↑ synaptic serotonin and norepinephrine levels.
• Modulates descending pain pathways and mood circuits.
• Partial inhibition of monoamine oxidase A (MAO‑A) at therapeutic doses; clinically relevant only with strong MAO‑A inhibitors.

Pharmacokinetics

• Absorption: Oral bioavailability ≈ 60 % (food increases Cmax by ~30 %), peak concentration in 6–12 h.
• Distribution: Highly protein‑bound (> 94 %); volume of distribution 45 L/kg.
• Metabolism: Liver‑mediated via CYP2D6 (major), CYP1A2, CYP2C19 → active metabolite GS‑331, primarily glucuronidation.
• Elimination: 70 % renal excretion, 30 % hepatic; terminal half‑life 12–17 h.
• Drug interactions: Strong CYP2D6 inhibitors ↑ duloxetine levels; MAO‑A inhibitors, SSRIs, SNRIs, tramadol, and CYP2D6 substrates increase risk of serotonin syndrome.

Indications

• Major depressive disorder (MDD) – *Uniq®*
• Generalized anxiety disorder (GAD) – *Uniq®*
• Diabetic peripheral neuropathic pain – *Unisom®*
• Fibromyalgia – *Unisom®*
• Chronic musculoskeletal pain (e.g., osteoarthritis, chronic low back pain) – *Unisom®*
• Post‑herpetic neuralgia (off‑label, extended‑release formulations)

Contraindications

• Contraindications: Severe hepatic impairment, uncontrolled hypertension, concomitant treatment with strong MAO‑A inhibitors, or opioids/dextromethorphan (serotonin‑syndrome risk).
• Warnings:
• Hypertension and excessive fluid retention → monitor BP and weight.
• Risk of suicidality in patients < 24 yrs; see prescribing information.
• Possible hepatotoxicity; baseline LFTs recommended for chronic users.
• Abrupt cessation → discontinuation syndrome (nausea, dizziness, flu‑like symptoms).

Dosing

• Prefer once‑daily dosing to improve adherence.
• Take with food to reduce GI symptoms.

Adverse Effects

• Common (≥ 10 %):
• Nausea, dry mouth, dizziness, constipation, fatigue, insomnia.
• ↑ blood pressure (mild systolic or diastolic rise ~5 mm Hg).
• Serious (≤ 1 %):
• Serotonin syndrome (especially with MAOI, tramadol, dextromethorphan).
• Severe hypertension or hypertensive crisis.
• Hepatotoxicity (elevated ALT/AST > 3× ULN).
• Suicidal ideation/behaviour (especially in younger adults).
• Severe rash/SCARs (rare).

Monitoring

• Baseline: BP, weight, LFTs, serum creatinine, psychiatric history.
• During therapy:
• BP/lab ad: every 4–6 wk for first 3 mo, then every 6–12 mo.
• LFTs: every 3 mo for first 6 mo if chronic use.
• Screen for suicidality at baseline, 2 wk, and monthly thereafter.
• Optional: CYP2D6 genotyping in poor metabolizers when therapeutic failure or adverse reactions suspected.

Clinical Pearls

• Start low, go slow: 20 mg qd or 10 mg BID prevents nausea, allows tolerability; essential for patients with GI distress.
• Blood‑pressure bump: Check BP before initiation and after each dose increase; consider antihypertensives if ≥ 140/90 mm Hg.
• Serotonin‑syndrome worry: Avoid combining with MAO‑A inhibitors, tramadol, or other serotonergic agents unless washout ≥ 14 days.
• Pregnancy: Category C; not recommended for first trimester; monitor fetal growth if continued.
• Hepatic impairment: Reduce dose to 20 mg qd; further titration may be difficult; monitor LFTs closely.
• CYP2D6 poor metabolizers: Higher systemic exposure (~2–3×); consider dosing every other day or switch to alternative SNRI.
• Pregnancy + lactation: Breast‑milk excretion minimal but advise caution; milk‑milk cautions not warranted unless high risk.
• If dizziness or orthostatic hypotension: Evaluate for concurrent antihypertensives or diuretics; adjust accordingly.

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• References
• Lexicomp®: Duloxetine (Uniq®/Unisom®).
• National Comprehensive Cancer Network (NCCN) Guidelines for MDD and GAD.
• FDA prescribing information, *Uniq®* and *Unisom®* (CYP2D6 data).