Adding Duloxetine to a Multimodal Pain Management Protocol for TKA Patients

Multiple medications have been proposed as adjuncts to more-traditional anesthetics and analgesics for relieving postoperative pain following total knee arthroplasty (TKA), including the antidepressant duloxetine (Cymbalta).

Prescribed to treat major depressive disorder and anxiety, duloxetine has also been used to manage musculoskeletal pain, fibromyalgia, and neuropathic pain. Building on this, for several years surgeons have investigated duloxetine for the treatment of acute pain associated with procedures like TKA, with mixed results.

A recent study from Hospital for Special Surgery (HSS) provides support for using duloxetine, finding that not only can duloxetine help to reduce pain after TKA, but it can also reduce the number of opioids that these patients take postoperatively. A 29% reduction in opioids was achieved without an increase in pain scores when duloxetine was added to the HSS multimodal pain management protocol for TKA patients.

“A multimodal pain management regimen often includes opioids, but they are associated with side effects and the potential for physical dependence and tolerance,” said Geoffrey Westrich, MD, a Professor of Clinical Orthopedic Surgery at HSS and the senior study author.

“Given the link between the opioid epidemic and opioid over-prescription, it is desirable to find methods to reduce postoperative opioid use.”

The study from HSS has been published online ahead of print by The Journal of Arthroplasty. Early results of the study have previously been reported at the 2021 Annual Meeting of the American Association of Hip & Knee Surgeons and at the American Society of Regional Anesthesia and Pain Medicine’s 46th Annual Regional Anesthesiology and Acute Pain Medicine Meeting. [1,2]

Study Methods

For the study, the researchers randomized 160 TKA patients at HSS to receive either 60 mg of duloxetine in pill form or a placebo daily, starting on the day of surgery and continuing for 14 days postoperatively. This was a triple-blinded study, with patients, surgeons, and research assistants blinded to who was receiving duloxetine versus placebo.

In addition, all patients received multimodal analgesia that included:

  • Spinal epidural anesthesia and peripheral nerve blocks during surgery
  • Acetaminophen, non-steroidal anti-inflammatory drugs, and oral opioids after surgery as needed

The researchers were interested in 2 primary outcomes:

  • Pain rated on a 1 to 10 numeric rating scale (NRS) on POD1, POD2, and POD14
  • Cumulative opioid consumption from the day of surgery through POD14

Study Findings

The researchers found that patients taking duloxetine needed fewer opioids to reach similar pain scores on the NRS compared with patients taking the placebo. The 29% reduction in opioid use corresponded with 17 fewer oxycodone pills per patient without an increase in pain scores.

Patients in the duloxetine group also reported higher satisfaction with pain management and found that pain was less likely to interfere with their mood, walking, work, relations with other people, sleep, and enjoyment of life. No major side effects were noted. Patients in the placebo group reported more adverse events than patients in the duloxetine group.

“Our research found that duloxetine can be used to reduce opioid usage after total knee replacement in selected patients who can be appropriately monitored for any potential side effects of the medication,” Dr. Westrich said.

“Additional studies are needed to define the optimal duration of treatment, to assess for rare side effects, and to examine the applicability of postoperative duloxetine for other surgical procedures.”


YaDeau JT, Mayman DJ, Jules-Elysee KM, et al. Effect of duloxetine on opioid use and pain after total knee arthroplasty: a triple-blinded randomized controlled trial. J Arthroplasty. 2022 Feb 18:S0883-5403(22)00133-4. doi: 10.1016/j.arth.2022.02.022. Online ahead of print.


  1. YaDeau J, Westrich GH, Jules-Elysee K, Lin Y, Padgett DE, Goytizolo E, Sculco TP, Kahn R, Haskins S, Brummett C. Effect of Duloxetin on Opioid Use and Pain After Total Knee Arthroplasty: A Triple-Blinded Trial (Poster 155). Presented at the 2021 AAHKS Annual Meeting, November 11-14, 2021, in Dallas, Texas.
  2. DeMeo DA, Gbaje E, Ya Deau JT, Jules-Elysee KM, Lin Y, Goytizolo EA, Kim D, Kahn RL, Haskin SC, Mayman DJ, Padgett DE, Sculco TP, Brummett CM, Westrich G. Effect of Duloxetine on Opioid Use After Total Knee Arthroplasty. A Double-Blinded Randomized Control Trial. Presented at the American Society of Regional Anesthesia and Pain Medicine’s 46th Annual Regional Anesthesiology and Acute Pain Medicine Meeting, May 13-15, 2021, in Orlando, Florida.

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