Serotonin Noradrenaline Reuptake Inhibitors

Serotonin noradrenaline reuptake inhibitors (venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran) treat depression, generalised anxiety and social anxiety disorder, and duloxetine and venlafaxine are also used in neuropathic pain. They are second-line after an SSRI in most patients, and are first-line when pain is a prominent feature.

Mechanism. They block serotonin and noradrenaline transporters. Venlafaxine acts mainly on serotonin up to about 150 mg daily, and adds noradrenergic effect at higher doses.

Pharmacokinetics. Venlafaxine half-life 5 hours (desvenlafaxine 11 hours), duloxetine 12 hours. Venlafaxine is metabolised by CYP2D6. Duloxetine is metabolised by CYP1A2 and CYP2D6.

Differences. Venlafaxine has higher efficacy at high doses but raises blood pressure and is more dangerous in overdose. Duloxetine has less hypertension but causes more nausea and liver effects. Desvenlafaxine is the active metabolite of venlafaxine.

• Depression: after an SSRI has failed or caused side effects; venlafaxine for severe depression.
• Generalised anxiety, panic and social anxiety: venlafaxine extended release and duloxetine.
• Neuropathic pain, including diabetic neuropathy, and chronic musculoskeletal pain: duloxetine 60 mg daily.
• Stress urinary incontinence: duloxetine 40 mg twice daily (some regions).
• Menopausal vasomotor symptoms: venlafaxine 37.5 to 75 mg daily.
• Stopping: taper over at least 4 weeks, because discontinuation symptoms are frequent and severe, especially with venlafaxine.

Special groups.

• Pregnancy: use only if benefit outweighs risk; neonatal adaptation and, with late exposure, hypertension.
• Breastfeeding: small amounts in milk; use with caution.
• Children: not routinely used.
• Older adults: check blood pressure and sodium.
• Kidney impairment: reduce venlafaxine by 25 to 50% when creatinine clearance is under 30 mL/min; avoid duloxetine under 30 mL/min.
• Liver impairment: avoid duloxetine in chronic liver disease or alcohol excess; reduce venlafaxine by 50%.
• Regional: duloxetine and venlafaxine are less widely stocked than amitriptyline, and cost limits use.

Adverse effects. Nausea, sweating, dry mouth, constipation, insomnia, sexual dysfunction, dose-related hypertension (venlafaxine above 150 mg), tachycardia, urinary hesitancy, hyponatraemia, bleeding, and with duloxetine raised liver enzymes.

Overdose. Venlafaxine causes seizures, QRS and QT prolongation and arrhythmias at doses over about 1 to 2 g, a greater risk than SSRIs.

Contraindications. Monoamine oxidase inhibitors within 14 days, uncontrolled hypertension (venlafaxine), and narrow-angle glaucoma.

Interactions. Linezolid, tramadol and triptans (serotonin syndrome); fluvoxamine and ciprofloxacin raise duloxetine levels; NSAIDs and anticoagulants increase bleeding.

Monitoring. Blood pressure at baseline and after each dose increase, sodium in older adults, liver enzymes with duloxetine, and suicidality.

Referral and escalation. Sustained hypertension, severe discontinuation symptoms, jaundice, or overdose.