## 5 Systemic Drugs
PCA is useful in conscious patients who cannot take oral medications and are capable of understanding instructions for use of the pump. Any opioid can be administered via PCA. Opioids administered as PCA cause less severe adverse effects than conventional opioid treatment. The pump can be discontinued when the patient is able to tolerate oral analgesics. When the patient can tolerate oral medication, the opioid regimen can be changed from IV to oral. The opioid dose (e.g., codeine, tramadol, oxycodone, hydromorphone, morphine) should be calculated based on 24 h opioid consumption and with the appropriate conversions [13]. In addition, patients on opioids should not take benzodiazepines. If discharged on opioids, patients should receive a co-prescription of nasal naloxone if MME is greater than 50 mg per day (Table 1). Tramadol in combination with acetaminophen and/or NSAIDs after TKA significantly improves pain control and early ambulation. Tramadol has a lower affinity for the mu opioid receptor than full mu receptor agonists (e.g., morphine, oxicodone) which means less efficacy in pain control and lower opioid side effects. It can still be addictive. In the postoperative period after TKA, tramadol should be limited to moderate pain and/or as needed (breakthrough pain); the recommended dose is 50 mg orally every 6 h and every 8 h after discharge from hospital [47] (Table 1). Oxycodone should be limited to severe pain and/or as needed (breakthrough pain); the recommended dose is 5-10 mg orally every 4-6 h both in the postoperative period and after hospital discharge [47] (Table 1). Gabapentins control neuropathic pain. Opinions vary in the literature about the routine use of gabapentin due to the lack of certain clinical efficacy. Compared to the use of the basic analgesia regimen (acetaminophen, NSAIDs/COX-2-specific inhibitors, and LIA), gabapentins reduce the postoperative opioid consumption, but do not significantly reduce the pain score. Their potential side effects (e.g., sedation, dizziness, visual disturbances) are amplified when they are taken together with opioids. Recently, [PERSON] et al. in a meta-analysis analyzed side effects of gabapentin. The authors concluded that although pruritus is a side effect during the administration of gabapentin, gabapentin can significantly decrease the incident rate of postoperative pruritus. Other side effects such as nausea, sedation, and dizziness in the gabapentin group shared the same incident rate with the placebo group [48]. It is useful to limit their use to patients younger than 75 years who are already taking them before surgery or have chronic neuropathic pain conditions. In the postoperative TKA period, the recommended dosage of pregabalin is 75 mg per os every 12 h and gabapentin 300 mg per os every 12 h, to be continued for 2 weeks after discharge [48; 49]. 1284 patients, demonstrated the viability of ketamine as a safe and effective alternative to opioids in the perioperative setting with major total joint arthroplasty surgery [52]. Magnesium sulfate is an antagonist of the NMDA receptor. Intraoperative and perioperative IV magnesium has been found to be an effective adjuvant for reduction of opioid requirement. Both bolus and continuous infusion regimens are effective. The optimal dose has not been determined [53]. Alpha-2 receptor agonists. Clonidine produces analgesia in the perioperative period and especially in association with opioids. The mechanism by which alpha-2 agonists produce analgesia remains unknown (likely with the release of acetylcholine). Although not routinely used, preoperative oral 150-200 mcg clonidine reduces the requirement of postoperative opioids. Dexmedetomidine is not recommended because of limited and conflicting evidence and concerns of adverse effects, such as bradycardia and hypotension [50]. Serotonin-norepinephrine reuptake inhibitors. Few studies have demonstrated the use of the duloxetine in post-TKA patients.