## 5 Systemic Drugs  
Acetaminophen reduces nociceptive pain through selective inhibition of COX enzyme activity in the central nervous system [41]. It is efficacious, inexpensive, and has a favorable safety profile with relatively few adverse effects. IV acetaminophen use should be reserved only for patients unable to swallow tablets as the efficacy of the IV and oral form is the same. However, IV administration does have more rapid and predictable onset of effect than oral administration (5-10 vs. 10-60 min, respectively) [41]. In the postoperative period, the recommended acetaminophen dose is 650 mg per os every 6 h or 1000 mg per os every 8 h (not to exceed 3000 mg per day). A reduced dose of acetaminophen should be used in patients with body weight \(\leq\) 50 kg, or mild-moderate hepatic insufficiency, or chronic alcoholism, malnutrition, or dehydration. If creatinine clearance is less than 30 mL/min, the dose is the same. Acetaminophen is contraindicated in patients with severe hepatic insufficiency [42]. Combination with NSAIDS or COX-2 inhibitors for postoperative pain is more effective than acetaminophen alone. This should be continued for another 2 weeks after discharge [41]. NSAIDs and COX-2 inhibitors are the main tools of multimodal analgesia in TKA; they reduce the inflammation from surgery, the postoperative pain (by approximately 30%), and the opioid consumption with relatively low adverse effects [43]. However, the individual patient risk should be assessed, including gastroduodenal ulcer history, cardiovascular morbidity, renal and hepatic dysfunction, and aspirin-induced asthma. Due to their side effect profile, judicious use and appropriate molecule selection are required. NSAIDs are unlikely to be the cause of postoperative bleeding complications in patients with adequate gastric acid inhibitor activity. The \"black-box\" warning about COX-2 inhibitors is related to cardiovascular risk, although this risk appears to be associated with long-term use [18; 44]. For example, in the postoperative period, ketorolac should be administered 30 mg IV every 6 h for a maximum of 4 days. The dose of ketorolac should be reduced to 15 mg every 6 h if patients are over 65 years old or have mildly impaired renal function. It should not be used in patients with acute or chronic kidney disease or ulcerative gastrointestinal disease. After discharge, it is recommended to follow anti-inflammatory therapy with meloxicam 15 mg per os daily, or celecoxib 200 mg per os every 12 h. The use of these drugs beyond the hospital stay (for up to 6 weeks) alleviates pain and facilitates postoperative rehabilitation [44]. Opioids. Although opioids are effective in pain management after TKA, adverse effects such as nausea, vomiting, somnolence, sedation, respiratory depression, retention of urine, and constipation must be considered [10]. In addition, long-term use of opioid medications may lead to tolerance and dependence. According to enhanced recovery after surgery (ERAS) protocols, the use of opioids as first-line or primary analgesics for perioperative pain must be reconsidered and daily opioid dosage and duration must be limited (opioid sparing) [45]. Opioids should be prescribed carefully, starting with the minimum dose needed to alleviate pain and only after exhausting nonopioid analgesic options. Monitoring opioid use after discharge is designed to stop its use as soon as possible. This is accomplished by the surgeon, the anesthesiologist, and the general practitioner working together. More attention is needed in opioid-naive patients where the prescription should be limited to a maximum of 7 days. Patients who receive an initial opioid prescription of 10 days have almost a 20% probability of still taking opioids 1 year later, and the probability increases to about 35% at 1 year with a 30-day supply [45; 46]. Opioids should be administered by continuous IV only in a monitored setting (intensive care unit) and with small bolus doses with a fixed lockout interval (patient-controlled analgesia--PCA).