Duloxetine (Cymbalta®) vs Pregabalin (Lyrica®)

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD

Difference between Duloxetine and Pregabalin

  Duloxetine Pregabalin
Drug class Antidepressant,
Serotonin-Norepinephrine Reuptake inhibitor
Gamma-Aminobutiric Acid (GABA) analog
Legal status Non-controlled substance Schedule V controlled substance (may cause euphoria)
Common FDA approved indications • Fibromyalgia
• Diabetic peripheral neuropathy
Other FDA-approved indications • Anxiety
• Depression
• Musculoskeletal pain
• Postherpetic neuralgia
• Partial onset seizures
• Neuropathic pain associated with spinal cord injury
"Off-label" uses • Preoperative analgesia8
Mechanism of action Inhibits reuptake of norepinephrine and serotonin.
Has analgesic, antidepressant, anxiolytic activity.
Binds to the alpha2-delta subunit of voltage-sensitive calcium channels, modulating neuronal excitability.
Has analgesic, anticonvulsant, and anxiolytic activity.
Metabolism Hepatic, via CYP1A2 and CYP2D6; forms multiple metabolites Negligible
Side effects, safety Insomnia, nausea, dry mouth, constipation, dizziness. Dizziness, somnolence weight gain, blurred vision, peripheral edema1.
Discontinuation of drug Neither duloxetine nor pregabalin should be discontinued abruptly because of possible withdrawal effects.
Special populations Advantageous in patients with depressed mood. Can be useful in patients in whom antidepressants are contraindicated.
Contraindications/warnings Use of MAOIs,
Uncontrolled narrow-angle glaucoma,
Substantial alcohol use,
Hepatic insufficiency,
Severe renal impairment
Hypersensitivity to pregabalin
Drug interactions Major substrate of CYP1A2 and CYP2D6.

Risk of serotonin syndrome with SSRIs, MAOIs and other serotonergic drugs.
Pregabalin can be useful in patients taking multiple medications because of its renal clearance, resulting in low risk of interactions with drugs metabolized by liver enzymes.

Thiazolidinediones may have additive effect on weight gain/edema when used concurrently.

Duloxetine vs Pregabalin for Fibromyalgia

In patients with fibromyalgia duloxetine is superior to pregabalin in reducing depressed mood2. Pregabalin is superior in reducing fatigue.


Patients with fibromyalgia taking duloxetine have better medication compliance and lower total medical costs (1 year following the initiation of the drug) than those who take pregabalin5.


Duloxetine vs Pregabalin for Diabetic Peripheral Neuropathy

Duloxetine and pregabalin generally provide comparable analgesic efficacy in the treatment of diabetic peripheral neuropathic pain (DPNP)6. Duloxetine may provide better effects on quality of life measures7.

Duloxetine may be more effective than pregabalin for DPNP in patients with an inadequate response to anticonvulsant. A 12-week open-label, randomized, noninferiority study4 compared duloxetine and pregabalin in the treatment of diabetic peripheral neuropathic pain. The mean change in the pain rating at end point was -2.6 for duloxetine and -2.1 for pregabalin.

Daytime performance
There is evidence that duloxetine improves mental processing speed, possibly due to CNS activation6. Pregabalin has been reported to increase tracking error on a divided attention task.

Effects on sleep
Duloxetine may reduce total sleep time, increase the amount of wake, increase time to fall asleep, and substantially disrupt REM sleep6. Pregabalin improves sleep continuity, reducing wake after sleep onset.

Results of randomized, open-label study of comparative safety and tolerability of duloxetine vs. pregabalin in DPNP3 Duloxetine Pregabalin
Discontinuation because of adverse events
Adverse events nausea, insomnia, hyperhidrosis,
decreased appetite
Weight changes
Weight loss
-2.39 ± 0.04
Weight gain
+1.0 ± 0.04 kg

Further reading


  • 1. Lyrica FDA prescribing information.
  • 2. Häuser W, Petzke F, Sommer C. Comparative efficacy and harms of duloxetine, milnacipran, and pregabalin in fibromyalgia syndrome. J Pain. 2010 Jun;11(6):505-21. PubMed
  • 3. Irving G, Tanenberg RJ, Raskin J, Risser RC, Malcolm S. Comparative safety and tolerability of duloxetine vs. pregabalin in patients with diabetic peripheral neuropathic pain. Int J Clin Pract. 2014 May PubMed
  • 4. Tanenberg RJ, Irving GA, Risser RC, Ahl J, Robinson MJ, Skljarevski V, Malcolm SK. Duloxetine, pregabalin for diabetic peripheral neuropathic pain management in patients with inadequate pain response to anticonvulsant treatment: an open-label, randomized, noninferiority comparison. Mayo Clin Proc. 2011 Jul;86(7):615-26. PubMed
  • 5. Sun P, Peng X, Sun S, Novick D, Faries DE, Andrews JS, Wohlreich MM, Wu A. Direct medical costs and medication compliance among fibromyalgia patients: duloxetine initiators vs. pregabalin initiators. Pain Pract. 2014 Jan;14(1):22-31. PubMed
  • 6. Boyle J, Eriksson ME, Gribble L, Gouni R, Johnsen S, Coppini DV, Kerr D. Randomized, placebo-controlled comparison of duloxetine and pregabalin in patients with chronic diabetic peripheral neuropathic pain: impact on pain, polysomnographic sleep, daytime functioning, and quality of life. Diabetes Care. 2012 Dec;35(12):2451-8. PubMed
  • 7. Roy MK, Kuriakose AS, Varma SK, Jacob LA, Beegum NJ. A study on comparative efficacy and cost effectiveness of Pregabalin and Duloxetine used in diabetic neuropathic pain. Diabetes Metab Syndr. 2016 Jul 27. pii: S1871-4021(16)30177-1. PubMed
  • 8. Altıparmak B, Güzel Ç, Gümüş Demirbilek S. Comparison of Preoperative Pregabalin and Duloxetine on Cognitive Functions and Pain Management after Spinal Surgery: A Randomized Double-blind Placebo-controlled Study. Clin J Pain. 2018 Jul 16.

Published: June 14, 2014
Last reviewed: August 14, 2018


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