The aim of this study is to determine if duloxetine is associated with differences in post-operative pain, patient-reported outcome measures, and opioid consumption in patients undergoing primary total knee arthroplasty compared to patients who do not receive the medication. If so, duloxetine has the potential to become widely incorporated into the multi-modal analgesic regimen given to patients following knee replacements.

Despite advances in surgical techniques and multimodal analgesia, many patients experience severe pain following total knee arthroplasty (TKA). In addition, chronic osteoarthritis, the most common reason patients undergo arthroplasty, predisposes patients to neuropathic pain with an estimated 23% of osteoarthritic patients suffering from neuropathic pain in addition to their nociceptive pain. This process is believed to lower the pain threshold and may lead to central sensitization, a condition defined as "the increase in the excitability and synaptic efficacy of neurons in the central nociceptive pathways that manifests as pain hypersensitivity." Central sensitization is present in 20% to 40% of patients with advanced knee osteoarthritis and believed to predispose them to increased preoperative and postoperative levels of pain.

In previous studies, duloxetine has been shown to reduce postoperative pain and opioid consumption. In a 2019 randomized controlled trial (RCT), Ko et al. reported that 30 milligrams (mg) of duloxetine administered one day prior to surgery and continued for 6 weeks after surgery decreased pain scores in patients with central sensitization who underwent TKA. Duloxetine administered for a shorter duration of time has also shown beneficial results. In their 2010 study, Ho et al. found that although 60 mg of duloxetine administered prior to surgery and on the first postoperative day did not significantly improve postoperative pain scores, it significantly reduced postoperative inpatient morphine requirements following TKA. Similarly, in a 2016, triple-blinded, randomized, placebo-controlled trial, YaDeau et al. found that 60 mg of duloxetine given for 15 days following surgery did not significantly impact pain scores but did significantly reduce opioid consumption in the two weeks following TKA. Although promising, these previous studies are difficult to interpret as they evaluated different patient populations, used different dosages of duloxetine, and administered for different lengths of time.

To our knowledge, all previous prospective, randomized controlled trials have examined only patients undergoing TKA, either focused only on patients with central sensitization or failed to differentiate between patients with and without central sensitization in their study population, or failed to administer duloxetine for the 4-8 week duration that has been traditionally recommended to assess the efficacy of SNRIs for other clinical indications.

The researchers propose to fill this knowledge gap by conducting a study that evaluates TKA patients, includes and differentiates patients with and without central sensitization, and administers duloxetine for the full recommended trial duration.

Inclusion Criteria:

• Any patient undergoing primary total knee arthroplasty for osteoarthritis
• Age ≥ 18 years old
• Willingness to undergo randomization and return for all scheduled visits
• English speaking

Exclusion Criteria:

• Age > 80 years old
• American Society of Anesthesiologists (ASA) Score ≥ 4
• Prior use of SSRIs or SNRIs
• Use of serotonergic drugs in the past 6 months with the exception of tramadol
• Known psychiatric disorder (specifically: generalized anxiety disorder, major depressive disorder, type I or type II bipolar disorder, and schizophrenia)
• Heavy alcohol consumption defined as ≥ 14 drinks per week for men and ≥ 7 drinks per week for women
• Opioid tolerant patients defined as ≥ 60 morphine equivalents (MEQs) per day within 90 days prior to surgery
• Renal impairment defined as a glomerular filtration rate (GFR) < 30 mL/minute or creatinine >1.3 mg/dL
• Non-English speaking
• Non-independent (i.e. requires a caretaker to make medical decisions on their behalf)

This study will be triple-blind, thus, the patients, clinicians, and study members involved will be unaware of patient allocation during this study. After the patient completes his or her Central Sensitization Inventory, a study coordinator will grade the survey to determine if the patient should be allocated to the groups with central sensitization or without. Each patient will receive a study ID based on his or her group (detailed in Section XIV). A computer randomization system will be used to allocate patients to receive either duloxetine or a placebo based on their study ID. Only members of the Rush pharmacy staff will possess the list matching the study ID to the study group assignment, ensuring that the study remains triple-blinded and that study coordinators are unaware of a patient's assignment when he or she picks up the study medication from the pharmacy.