Milnacipran

Milnacipran is an SNRI licensed for fibromyalgia in some regions and for depression in others. It has a stronger noradrenaline than serotonin effect, almost no hepatic metabolism, and mainly renal elimination, so kidney function sets the dose. Availability is limited in many regions.

Classification. SNRI.

Mechanism. Inhibits noradrenaline and serotonin reuptake, with noradrenaline reuptake inhibition somewhat stronger. It does not act on muscarinic, histaminergic or adrenergic receptors.

Pharmacokinetics. Bioavailability about 85%, unaffected by food. Minimal CYP metabolism; about 55% is excreted unchanged in urine. Half-life 6 to 8 hours. Few CYP-mediated interactions.

All regimens are oral with no loading dose.

Fibromyalgia, adults.

• Day 1: 12.5 mg once.
• Days 2 to 3: 12.5 mg twice daily.
• Days 4 to 7: 25 mg twice daily.
• After day 7: 50 mg twice daily.
• Titration: may increase to 100 mg twice daily if response is inadequate. Maximum 200 mg daily.

Major depression, adults (licensed in some regions).

• Day 1: 50 mg once; from day 2: 50 mg twice daily (100 mg daily).
• Maintenance 100 mg daily in two divided doses; may increase to a maximum of 200 mg daily.
• Duration: at least 6 months after remission.

Dose limits. Creatinine clearance 30 to 50 mL/min: use with caution and consider a lower dose. Creatinine clearance 5 to 29 mL/min: reduce the maintenance dose by half to 25 mg twice daily. End-stage kidney disease: not advised. Liver impairment: caution and use the lowest effective dose.

Contraindications. MAOI use now or within 14 days of stopping it, uncontrolled hypertension, uncontrolled narrow-angle glaucoma, severe kidney impairment in some labels, hypersensitivity.

Serious adverse effects. Boxed-warning-level risk of suicidal thinking and behaviour in under 25 years. Hypertension, tachycardia and palpitations, serotonin syndrome, hyponatraemia, bleeding, urinary retention, mania, seizures, hepatotoxicity (rare), severe discontinuation syndrome.

Common adverse effects. Nausea, headache, constipation, hot flushes, hyperhidrosis, palpitations, insomnia, dizziness.

Interactions. Serotonin syndrome risk rises with tramadol, triptans and linezolid. Parenteral digoxin may cause hypotension and arrhythmia. Noradrenaline and adrenaline given parenterally can cause hypertensive reactions. Clonidine effect is reduced. Bleeding risk rises with NSAIDs and anticoagulants.

Common prescribing errors. Not adjusting for kidney function; not checking blood pressure; stopping abruptly.

Special groups.

• Pregnancy: limited data; avoid unless the benefit clearly outweighs the risk.
• Breastfeeding: limited data; generally avoided.
• Children: not advised in under 18 years.
• Older adults: raised risk of hyponatraemia and urinary retention; creatinine clearance often limits the dose.
• Kidney impairment: caution when creatinine clearance is 30 to 50 mL/min; halve the maintenance dose to 25 mg twice daily when it is 5 to 29 mL/min; avoid in end-stage kidney disease.
• Liver impairment: caution, lowest effective dose.

Formulations. Tablets 12.5 mg, 25 mg, 50 mg and 100 mg. Take with food in divided doses.

Baseline. Blood pressure and pulse (control hypertension first), creatinine clearance, mood history including past mania, suicide risk, sodium in older adults, bladder outlet symptoms.

Monitoring. Blood pressure and pulse at baseline, after each dose increase and at reviews; reduce the dose or stop if sustained hypertension develops. Review within 1 to 2 weeks and after each dose change for suicidality. Check sodium 2 to 4 weeks after starting in high-risk patients; review the need for the drug if sodium falls under 130 mmol/L and stop it if under 125 mmol/L or if symptomatic. Repeat kidney function if illness reduces fluid intake.

Stopping. Taper over at least 2 weeks, ideally 4 weeks.

Referral and escalation. Refer to psychiatry for suicidal intent, psychosis, mania, or failure of two adequate courses. Suspected serotonin syndrome or hypertensive crisis needs emergency care.