## 1 Background  
Total knee primary arthroplasty (TKA) is a common orthopedic operation to eliminate pain due to arthrosis or other severe knee pathology, allowing for better mobility and improvement of the quality of life [1; 2; 3]. Joint replacement surgery is considered one of the most painful orthopedic procedures. After TKA, the control of pain with effective analgesic treatment allows early functional recovery and patient satisfaction. Moreover, adequate treatment of postoperative pain significantly reduces the incidence of postoperative complications, the length of stay, and the consequent costs [4]. The postoperative period is often uncomfortable due to inadequate pain treatment, despite the fact that pain after surgery is controllable, predictable, and almost totally preventable [4]. However, the therapy is complex and linked to patient-specific factors: psychologic conditions, previous and concomitant medications, substance abuse disorders, and history of pain central sensitization. Acute postoperative pain is classified as moderate (30%) to severe (60%) and consists of nociceptive, neuropathic, and psychogenic pathways that are differently combined according to preoperative pain, orthopedic diagnosis, surgery (approach and intraoperative anesthetic treatment), and the pain threshold of the patient (psychological status) [5]. The complexity of postoperative pain needs a comprehensive assessment of the patient including psychologic conditions, concomitant medications, substance abuse disorders, and previous postoperative treatment regimens in case of history of chronic pain [5]. The pain caused by TKA surgery is often acute over chronic because many patients have chronic joint pain and have already performed unsuccessful analgesic treatments. When the surgery patients are on chronic opioid treatment, postoperative analgesic treatment is more complex. These data help to define a tailored and individualized pain management plan, according to the \"around the clock concept\" and not just \"as required\" (\"pro re nata\",PRN) [6]. A validated pain assessment tool to define the intensity of pain is essential to track responses to analgesic treatments (e.g., Visual Analogic Scale, Numeric Rating Scale). Education of the patient and the caregivers (information on treatment options for managing postoperative pain) is useful to improve patient satisfaction [5; 7]. A possible solution to the inadequate treatment of postoperative pain lies in better organization and utilization of the existing techniques. A multidisciplinary approach (surgeons, anesthesiologists, internists, nurses, physiotherapists), not yet widespread, seems fundamental to apply and coordinate all categories of pain medications to obtain a better outcome [8; 9]. Historically, opioids have been widely used for perioperative pain management of surgery patients [10]. The exponential rise of synthetic opioid-related overdose deaths in recent years has forced a review of the opioid-only postoperative analgesic protocols, already in question for related adverse effects (drowsiness, fatigue, confusion, delirium, nausea, vomiting, ileus, urinary retention) that obstruct a rapid functional recovery after surgery [10]. Monotherapy with opioids is not enough to provide satisfactory postoperative pain relief after TKA, but it is widespread in the management of postoperative pain [11]. Considering the various postoperative pain mechanisms, it seems reasonable to use a multimodal analgesic approach [12]. Multimodal analgesia was first introduced by [PERSON] in 1999, referring to a combination of several types of medications and delivery routes [12]. Multimodal treatment is based on the synergism of submaximal doses of painkillers, with different mechanisms of action, to increase therapeutic power and reduce adverse effects [12].