By Chris Faubel, MD —

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) have gained popularily with pain physicians in the treatment of neuropathic pain and fibromyalgia in recent years.

The first SNRI, venlafaxine (Effexor), has been joined by an ever-increasing number of others (see list below).

Mechanism of action

  • As a class, they all increase the amount of serotonin (S) and norepinephrine (NE) in the brain.
  • By decreasing the reuptake of these two neurotransmitters after they’ve been release from the presynaptic terminals, the SNRIs allow the S and NE to remain in the synaptic cleft longer, thereby giving them a longer chance to bind to postsynaptic receptors.
  • These medications differ from each other in the relative reuptake inhibition ratio of serotonin and norepinephrine.  See below for the differences.
It is this increase in NE that is believed to be the reason why SNRIs are more effective than SSRIs in treating pain.
Serotonin syndrome is an adverse effect that is possible with all SNRIs.  Learn out what other medications will increase the risk, how to diagnose it, and how to treat it.  Click here

Venlafaxine (Effexor)

  • Uses(off-label) [2]
    • Neuropathic pain (diabetic neuropathy)
    • Migraines (prophylactic)
    • Tension headaches
    • Chronic pain syndromes
    • Fibromyalgia [1]
    • Chronic fatigue syndrome
  • Increases serotonin much more than norepinephrine (S>>>NE)
    • 75mg BID is believed to only increase serotonin –> better for depression
    • 150-300mg/day (in BID or TID dosing) will increase both S and NE
  • Dosing
    • Immediate-release formulation: Start with 37.5mg BID, and increase every 4-7 days (if tolerated) [max of 100mg TID]
    • Extended-release: Start 37.5 to 75mg daily, and increase by 75mg every 4-7 days [max of 225-mg]
    • Note: taper dose over 2-weeks to discontinue

Desvenlafaxine (Pristiq)

  • The active metabolite  of venlafaxine.
  • Not used as commonly in pain medicine

Duloxetine (Cymbalta)

  • Uses(FDA-approved)
    • Diabetic painful peripheral neuropathy
    • Fibromyalgia
    • Major depressive disorder and generalized anxiety disorder
  • The effectiveness in treating fibromyalgia are independent of whether the patient also has depression. (3)
  • Thought to have a more NE reuptake effects than venlafaxine, but still less NE than S.   (S > NE)
  • Dosing
    • Start with 60mg daily.
    • May be better to start with 30mg daily for a week to minimize side effects.
    • Taper dose gradually to discontinue
  • Adverse effects
    • Weight gain (with long-term use)
    • Nausea (seen early in course, but tends to resolve)
    • Liver toxicity (in patients with pre-existing liver disease)
    • Increased blood pressure (because of the increase in NE reuptake)

Milnacipran (Savella)

  • Uses(FDA-approved)
    • Fibromyalgia
    • Also used for major depressive disorder in other countries
  • 3:1 norepinephrine to serotonin reuptake inhibition ratio (Note: this is the only SNRI which has more effect on NE reuptake than S) (NE>>>S)
  • Dosing
    • Titrated up slowly to minimize adverse effects.
    • Starter pack includes pills for:  12.5mg x 1 day, then 12.5mg bid x 2 days, then 25mg bid x 4 days, then 50mg bid.  Max dose of 100mg bid.
    • Note: Many practitioners are now doubling the length of time to titrate up.  So, instead of 12.5mg for 1 day, they recommend 12.5mg for two days.  Therefore, instead of getting up to 50mg bid in 7 days, it would now take 14 days.
    • Taper dose gradually to discontinue
  • Adverse effects(most common)
    • Nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increase, dry mouth, and hypertension.
    • More caution with patients that are already hypertensive, because of the increased norepinephrine reuptake inhibition.
  • Absolute contraindications
    • Migraine patients taking triptan medications (ex: sumatriptan, rizatriptan, zolmitriptan, etc)
    • Pregnancy
    • Caution with advanced renal disease (use a smaller dose)


1) Venlafaxine Treatment of Fibromyalgia:




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