Which medications are serotonin‑norepinephrine reuptake inhibitors (SNRIs) and what are their typical adult dosing regimens?

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

The SNRI class comprises four medications available in the United States: venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran, all of which inhibit the reuptake of both serotonin and norepinephrine with varying selectivity ratios. 1, 2

SNRI Medications and Their Characteristics

Venlafaxine

• Selectivity profile: 30-fold higher affinity for serotonin than norepinephrine, making it predominantly serotonergic at lower doses with increasing noradrenergic effects as dose escalates 3, 2, 4
• Metabolism: Converted to active metabolite O-desmethylvenlafaxine (desvenlafaxine) by CYP2D6, resulting in significant inter-individual variation in blood levels 2
• Half-life: Short at approximately 5 hours for parent compound, 12 hours for active metabolite 2
• Typical dosing: Dose-dependent efficacy with ascending dose-response curve; approved for major depressive disorder, generalized anxiety disorder, social anxiety disorder, and panic disorder 2
• Key consideration: Potential for dose-dependent blood pressure elevation, though infrequently observed below 225 mg/day 2

Desvenlafaxine

• Selectivity profile: Primary metabolite of venlafaxine; relatively low-potency serotonin and norepinephrine reuptake inhibitor 2, 5
• Metabolism: Subject to CYP3A4 metabolism, but primary pathway is direct conjugation and renal elimination 2, 5
• Half-life: Achieves steady-state plasma concentrations within 4-5 days 5
• Typical dosing: Approved in narrow dose range of 50-100 mg daily, with 50 mg/day clearly distinguished from placebo in clinical trials 2, 5
• Key consideration: Favorable drug-drug interaction profile with minimal impact on cytochrome P450 enzyme system 5

Duloxetine

• Selectivity profile: 10-fold selectivity for serotonin over norepinephrine, representing a more balanced profile than venlafaxine 1, 3, 2, 4
• Metabolism: Moderate inhibitor of CYP2D6, requiring dose adjustments when combined with drugs metabolized by this enzyme 2
• Typical dosing: Start at 30 mg once daily for one week, then increase to target dose of 60 mg once daily; maximum 120 mg/day 1
• FDA-approved indications: Major depressive disorder, generalized anxiety disorder (including pediatric patients ≥7 years), diabetic peripheral neuropathic pain, fibromyalgia, chronic musculoskeletal pain (including chronic low back pain and osteoarthritis) 6, 1, 2
• Key consideration: Only SNRI with FDA approval for anxiety disorders in children and adolescents 1

Levomilnacipran

• Selectivity profile: Levorotary enantiomer of milnacipran with pharmacologically similar properties but potentially milder side effects within approved dosing range 2
• Key consideration: May increase blood pressure and pulse less than other norepinephrine reuptake inhibitors 2

Milnacipran

• Selectivity profile: Approximately equal potency for inhibition of serotonin and norepinephrine reuptake both in vitro and in vivo, making it the only truly balanced SNRI 3, 2, 4
• Metabolism: Metabolized by CYP3A4, but major pathway is direct conjugation and renal elimination 2
• Half-life: Approximately 10 hours, requiring twice-daily administration 2
• Typical dosing: 100 or 200 mg/day for fibromyalgia 6
• Key consideration: Not marketed as an antidepressant in the United States but approved for fibromyalgia treatment 2

Clinical Context and Comparative Efficacy

SNRIs demonstrate efficacy comparable to SSRIs for anxiety disorders but superior efficacy for chronic pain conditions, where SSRIs are generally ineffective. 3

• At usual doses, milnacipran appears more effective than SSRIs with efficacy similar to tricyclic antidepressants but with lower side effect burden 4
• Venlafaxine and duloxetine at high doses appear superior to SSRIs, though duloxetine is not licensed at higher doses in the EU 4
• All three SNRIs (venlafaxine, duloxetine, milnacipran) are helpful in relieving chronic pain associated with and independent of depression 3

Common Adverse Effects and Safety Considerations

All SNRIs can cause serotonin syndrome when combined with MAOIs, and this combination is contraindicated. 2

• Common adverse effects include nausea, dry mouth, dizziness, constipation, insomnia, fatigue, and sexual dysfunction 6, 2
• Duloxetine and milnacipran have higher dropout rates due to side effects compared with placebo, though no difference in serious adverse events 6
• Venlafaxine combines serotonergic adverse effects (nausea, sexual dysfunction, withdrawal problems) with dose-dependent cardiovascular effects, principally hypertension 3
• Duloxetine and milnacipran appear better tolerated and essentially devoid of cardiovascular toxicity 3

Critical Prescribing Pitfalls

• Never abruptly discontinue SNRIs: Taper gradually over at least 2-4 weeks to minimize discontinuation syndrome, which includes dizziness, fatigue, myalgias, headaches, and gastrointestinal disturbances 6, 7, 1
• Monitor for serotonin syndrome: Particularly when combining with other serotonergic medications including SSRIs, tricyclic antidepressants, tramadol, and certain analgesics 6
• Consider CYP2D6 interactions: Duloxetine requires dose reductions when combined with drugs metabolized by CYP2D6; venlafaxine is subject to drug-drug interactions with CYP2D6 inhibitors 2
• Monitor blood pressure: Particularly with venlafaxine at doses above 225 mg/day and with all SNRIs in patients with cardiovascular comorbidities 6, 2