SNRIs are established, guideline-approved treatment options for both psychiatric and chronic pain diagnoses. When to use them, when to avoid them.

Two for the price of one. Buy one, get one free. Everyone loves a good deal, right? Chronic pain and mental health diagnoses are highly comorbid and it is well known that chronic pain and mental health feed into each other.1

Why I Convert from SSRIs to SNRIs

Many times, patients may already be on a selective serotonin reuptake inhibitor (SSRI) for a mental health diagnosis, and I will convert them to an SNRI instead to target mental and health and pain with one medication (see Table II).7 Of note, a patient does not have to have a comorbid mental health diagnosis to receive analgesic benefit from SNRIs. SNRIs are thought to provide analgesia through activity in the descending pain pathway.8 SSRIs have limited value in managing chronic pain.

Several clinical practice guidelines include recommendations for the use of SNRIs for low back pain, diabetic peripheral neuropathy, osteoarthritis, and fibromyalgia (see Table III).9-12 A Cochrane Database of Systematic Review meta-analysis examining antidepressants in the treatment of chronic pain was recently published. This review confirms moderate evidence supporting duloxetine primarily in treating fibromyalgia, neuropathic pain, and musculoskeletal pain, with outcomes of pain relief and improvement in continuous pain intensity. The SNRI milnacipran also showed a small effect in improving pain intensity. Other antidepressants had low levels of certainty of benefit. Additionally, the review stated that no antidepressant had evidence demonstrating long-term efficacy.13

When I Avoid SNRIs

It would be imprudent to fail to mention when not to use SNRIs. Prior to initiation or conversion to an SNRI, check the patient’s blood pressure, sodium level, renal function, and hepatic function. All SNRIs can contribute to hypertension through their effects on norepinephrine, so I would recommend initiation of a SNRI only if a patient’s blood pressure is controlled.

SNRIs may also contribute to hyponatremia so again, I would not initiate in someone with preexisting hyponatremia. Duloxetine should be avoided in severe renal dysfunction (EGFR < 30 mL/min) or chronic liver disease/cirrhosis. Venlafaxine and milnacipran carry dose adjustments for both renal and hepatic failure. A drug-drug interaction check is always a good idea especially with duloxetine given that it’s metabolized primarily by CYP1A2 with some contribution by CYP2D6. Venlafaxine can be impacted by pharmacogenomics via CYP2D6 variants.

Overall, SNRIs are established treatment options for both numerous psychiatric diagnoses and chronic pain diagnoses in clinical practice guidelines. While a mental health diagnosis is not needed for benefit, why not capitalize on the multiple uses of SNRIs?

SNRI FDA-Approved Indications Dosing
desvenlafaxine major depressive disorder 50 mg PO daily
max 200 mg/day
duloxetine major depressive disorder
generalized anxiety disorder
diabetic peripheral neuropathy
chronic musculoskeletal pain
MDD: 20 mg BID initial
Others: 30 mg/day x 1 weeks then 60 mg/day
If ≥65, 30 mg/day x 2 weeks, then 60 mg/day
Max 120 mg/day
levomilnacipran major depressive disorder Initial: 20 mg daily x 2 days then 40 mg daily
Titration: 40 mg/day q2 or more days
Max: 120 mg/day
milnacipran fibromyalgia Day 1: 12.5 mg once
Days 2-3: 25 mg/day (12.5 mg twice daily)
Days 4-7: 50 mg/day (25 mg twice daily)
After day 7: 100 mg/day (50 mg twice daily)
Max: 200 mg/day
venlafaxine XR major depressive disorder
generalized anxiety disorder
social anxiety disorder
panic disorder
Initial: 75 mg PO daily
Most would benefit from starting with 37.5 mg x 4–7 days
Titration: 75 mg/day q4 days or more
Max: 225 mg/day

Table II: Switching Between SSRI and SNRI Antidepressants.7

Initial Medication Method of Switching Equivalent Dose
citalopram direct switch direct switch 20 mg
duloxetine cross-taper direct switch 30 mg
escitalopram direct switch direct switch 10 mg
fluoxetine direct switch direct switch 20 mg
paroxetine direct switch direct switch 20 mg
sertraline direct switch direct switch 50-75 mg
venlafaxine cross-taper direct switch 75 mg

Steps: 1. Identify the medication the patient is currently on (initial medication). 2. Determine class of medication you are switching to (eg, for chronic pain, we will be switching to an SNRI) as this step determines the method of conversion. For a cross-taper, reduce current medication by 50% and then initiate 50% of the new medication over 2 weeks. 3. This determines the dose equivalent between different SSRIs and SNRIs.

Table III: SNRIs in Pain Management Guidelines.9-12

Guideline Diagnoses Summary of Recommendations
American College of Physicians, 2017 chronic low back pain duloxetine second-line after trial of nonpharmacologic options and oral NSAIDs
American Academy of Neurology, 2022 painful diabetic polyneuropathy SNRI first-line with tricyclic antidepressants, sodium channel blockers, and gabapentinoids
American College of Rheumatology/Arthritis Foundation, 2019 hand, hip, and knee osteoarthritis conditionally recommend use of duloxetine
European Alliance of Associations for Rheumatology (EULAR), 2017 fibromyalgia weak for duloxetine for severe pain


  1. Bonilla-Jaime H, Sánchez-Salcedo JA, Estevez-Cabrera MM, Molina-Jiménez T, Cortes-Altamirano JL, Alfaro-Rodríguez A. Depression and Pain: Use of Antidepressants. Curr Neuropharmacol. 2022;20(2):384-402. doi:10.2174/1570159X19666210609161447
  2. Pristiq package insert. New York, NY: Pfizer Inc; September 2021.
  3. Cymbalta package insert. Indianapolis, IN: Lilly USA, LLC 2021; September 2021.
  4. Fetzima package insert. North Chicago, IL: AbbVie, Inc; March 2023.
  5. Savella package insert. Madison, NJ; Allergan USA, Inc: December 2022.
  6. Effexor XR package insert. Philadelphia, PA: Wyeth Pharmaceuticals, Inc: August 2022.
  7. Veterans Health Administration. Pharmacy Benefits Management Academic Detailing Service. Posttraumatic stress disorder: A VA clinician’s guide to optimal treatment of posttraumatic stress disorder (PTSD) – a quick reference guide. 2019. Available at: Accessed 21 May 2023.
  8. Tao ZY, Wang PX, Wei SQ, et al. The role of descending pain modulation in chronic primary pain: Potential application of drugs targeting serotonergic system. Neural Plast. 2019;2019:1389296. Published 2019 Dec 17. doi:10.1155/2019/1389296
  9. Qaseem A, Wilt TJ, McLean RM, et al. Noninvasive treatments for acute, subacute, and chronic low back pain: A clinical practice guideline from the American College of Physicians. Ann Intern Med. 2017;166(7):514-530. doi:10.7326/M16-2367
  10. Price R, Smith D, Franklin G, et al. Oral and topical treatment of painful diabetic polyneuropathy: Practice guideline update summary: Report of the AAN guideline subcommittee. Neurology. 2022;98(1):31-43. doi:10.1212/WNL.0000000000013038
  11. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee [published correction appears in Arthritis Care Res (Hoboken). 2021 May;73(5):764]. Arthritis Care Res (Hoboken). 2020;72(2):149-162. doi:10.1002/acr.24131
  12. Macfarlane GJ, Kronisch C, Dean LE, et al. EULAR revised recommendations for the management of fibromyalgia. Ann Rheum Dis. 2017;76(2):318-328. doi:10.1136/annrheumdis-2016-209724
  13. Birkinshaw H, Friedrich CM, Cole P, et al. Antidepressants for pain management in adults with chronic pain: a network meta-analysis. Cochrane Database Syst Rev. 2023;5(5):CD014682.