Duloxetine

Indications

• FDA-approved for major depressive disorder in adults at 40-60 mg/day, with no added antidepressant benefit demonstrated above 60 mg/day.
• FDA-approved for generalized anxiety disorder in adults and in pediatric patients aged 7 years and older, dosed at 30 to 120 mg/day.
• FDA-approved for diabetic peripheral neuropathic pain in adults at 60 mg once daily, the dose at which the pivotal trials were run.
• FDA-approved for fibromyalgia in adults and in adolescents aged 13 to 17, and for chronic musculoskeletal pain including osteoarthritis and low back pain.
• Off-label for stress urinary incontinence, an approved indication in Europe but never granted in the United States.
• Off-label for chemotherapy-induced peripheral neuropathy, where it has the strongest randomized evidence of any pharmacologic option.

Mechanism of action

• Balanced inhibitor of the serotonin and norepinephrine transporters, with meaningful noradrenergic activity at standard clinical doses.
• Descending noradrenergic and serotonergic pathways from the brainstem to the dorsal horn are the substrate for its analgesic effect.
• That descending inhibition explains why pain responds at doses comparable to those used for mood rather than at higher doses.
• Weak dopamine transporter inhibition contributes little, and there is no clinically relevant muscarinic, histaminic, or adrenergic blockade.
• Noradrenergic tone drives its characteristic effects on blood pressure, sweating, urinary hesitancy, and dry mouth.

Pharmacokinetics

• Delivered as enteric-coated pellets because the drug degrades in gastric acid, so capsules must not be crushed or chewed.
• Half-life is about 12 hours, and although dosed once daily, that short half-life underlies its frequent discontinuation symptoms.
• Metabolized by both CYP1A2 and CYP2D6 into inactive metabolites, with less than 1 percent excreted unchanged in urine.
• It is a moderate CYP2D6 inhibitor, so it raises levels of tricyclics, metoprolol, atomoxetine, and other 2D6 substrates.
• Exposure rises roughly fivefold in end-stage renal disease and about threefold in cirrhosis, which underlies both use restrictions.

Dosing

• For depression start 30 mg PO daily for one week to limit nausea, then increase to the usual target of 60 mg once daily.
• Generalized anxiety may be started at 30 or 60 mg daily; the labeled maximum is 120 mg/day, though benefit above 60 mg is limited.
• For neuropathic pain, fibromyalgia, and chronic musculoskeletal pain the target is 60 mg once daily, with no added benefit at 120 mg/day.
• Pediatric generalized anxiety starts at 30 mg once daily for two weeks, then 60 mg daily, with a range of 30 to 120 mg/day.
• Not recommended when creatinine clearance is under 30 mL/min or in any hepatic insufficiency or chronic liver disease.
• Taper over at least two weeks, using 20 or 30 mg steps, because abrupt discontinuation causes dizziness and paresthesia in many patients.

Adverse effects

• Nausea affects roughly 25 percent of patients and is worst in the first week, which is the reason for the 30 mg lead-in dose.
• Dry mouth, constipation, somnolence, fatigue, decreased appetite, and hyperhidrosis are common and largely noradrenergically driven.
• Hepatotoxicity ranging from transaminase elevation to rare hepatic failure led to the warning against use in liver disease or heavy alcohol use.
• Blood pressure rises modestly and dose-dependently; sustained hypertension is less frequent than with venlafaxine but still requires monitoring.
• Discontinuation syndrome is common and prominent, with dizziness, nausea, headache, paresthesia, and irritability within days of stopping.
• Sexual dysfunction, hyponatremia, urinary hesitancy, mydriasis, and increased bleeding risk round out the prescribing-relevant effects.

Monitoring

• Obtain baseline liver enzymes in anyone with alcohol use, hepatitis, or fatty liver, and recheck if abdominal pain or jaundice develops.
• Check blood pressure at baseline and periodically, particularly during dose escalation above 60 mg/day.
• Estimate creatinine clearance before starting, since duloxetine is not recommended below 30 mL/min.
• Assess suicidality, activation, and agitation weekly for the first four weeks and after each dose change, especially under age 25.
• Track pain with a numeric rating scale alongside PHQ-9 or GAD-7, since mood and pain responses do not always move together.

Interactions

• Contraindicated with MAOIs and within 14 days of stopping one, and with linezolid or intravenous methylene blue.
• Strong CYP1A2 inhibitors, especially fluvoxamine and ciprofloxacin, can raise duloxetine exposure severalfold and should be avoided.
• Moderate CYP2D6 inhibition raises levels of tricyclics, metoprolol, atomoxetine, risperidone, and thioridazine, which should be avoided outright.
• Additive serotonin syndrome risk with triptans, tramadol, fentanyl, lithium, and St. John's wort, and additive bleeding risk with NSAIDs.
• Combined use with substantial alcohol intake is discouraged because of the added hepatotoxic risk.

Special populations

• Pregnancy cohort data show no clear teratogenic signal, though late exposure carries neonatal adaptation and postpartum hemorrhage concerns.
• Relative infant dose in breast milk is under 1 percent, so duloxetine is generally considered acceptable during lactation if needed.
• Approved from age 7 for generalized anxiety and from age 13 for fibromyalgia, making it one of the few SNRIs with pediatric labeling.
• In older adults start at 20-30 mg/day and watch for hyponatremia, falls, urinary retention, and blood pressure elevation.
• Avoid entirely in severe renal impairment and in any hepatic impairment, where exposure rises three to five times over normal.

Clinical pearls

• Best choice when depression rides with neuropathic pain or fibromyalgia; 60 mg/day covers both.
• Avoid in liver disease or heavy alcohol use; hepatotoxicity is the label warning that changes practice.
• Do not use below a creatinine clearance of 30 mL/min, and never crush the enteric-coated pellets.