What other serotonin‑norepinephrine reuptake inhibitors (SNRIs) could be used?

Available SNRIs for Clinical Use

The SNRIs currently marketed in the United States are venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran. 1

FDA-Approved SNRI Options

Primary SNRI Medications

• Venlafaxine (available in immediate-release and extended-release formulations) 1

  • Extended-release formulation permits once-daily dosing due to sufficiently long elimination half-life 1
  • Immediate-release formulation may require twice- or thrice-daily dosing due to short elimination half-life 1
  • Has the least effect on CYP450 system compared to other SNRIs, potentially reducing drug-drug interaction risk 1
  • Important caveat: Associated with greater suicide risk than other SNRIs and has been linked to overdose fatalities 1
  • Associated with discontinuation symptoms requiring slow taper 1

• Desvenlafaxine (active metabolite of venlafaxine) 1

  • Permits single daily dosing due to long elimination half-life 1
  • Important caveat: Associated with overdose fatalities 1

• Duloxetine 1

  • Only SNRI with FDA indication for anxiety disorders (specifically generalized anxiety disorder in children and adolescents ≥7 years old) 1
  • Permits single daily dosing due to long elimination half-life 1
  • May interact with drugs metabolized by CYP1A2 and CYP2D6 1
  • Critical safety concern: Associated with hepatic failure (abdominal pain, hepatomegaly, elevated transaminases, cholestatic jaundice) - must discontinue and not restart if jaundice or liver dysfunction develops 1
  • Critical safety concern: Associated with severe skin reactions including erythema multiforme and Stevens-Johnson syndrome - must discontinue at first appearance of blisters, peeling rash, or mucosal erosions 1
  • Strongest evidence for analgesic properties among SNRIs 1, 2

• Levomilnacipran 1

  • Limited data available for most clinical applications 1

Alternative SNRI-Related Medications

• Milnacipran 1, 2
  • FDA-approved for fibromyalgia 2
  • Less robust evidence for depression compared to duloxetine and venlafaxine 1
  • No demonstrated superiority over SSRIs in depression treatment 3, 4

Class-Wide Considerations

Common Adverse Effects

All SNRIs share potential for: 1

• Diaphoresis, dry mouth, gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal discomfort)
• Neurological effects (dizziness, headache, tremor, insomnia, somnolence)
• Decreased appetite and weight loss
• Cardiovascular effects: Sustained hypertension, increased blood pressure and pulse (requires monitoring)

Serious Adverse Effects Across Class

• Suicidal thinking and behavior (through age 24 years) 1
• Behavioral activation/agitation, hypomania, mania 1
• Sexual dysfunction, seizures, abnormal bleeding 1
• Serotonin syndrome (especially with MAOIs or multiple serotonergic agents) 1

Contraindications

Concomitant administration of any SNRI with any MAOI is absolutely contraindicated due to increased risk of serotonin syndrome 1

Required Monitoring

For all SNRIs, medical monitoring should include: 1

• Height and weight
• Pulse and blood pressure
• No specific laboratory tests routinely recommended (except monitor liver function if using duloxetine and symptoms develop)

Discontinuation Protocol

All SNRIs warrant slow discontinuation taper to minimize risk of discontinuation syndrome 1