TITLE: Epidural morphine combined with single-injection femoral nerve block for postoperative analgesia in patients after total knee arthroplasty: a randomized controlled trial
AUTHORS: Zhao-Ting Meng, Fan Cui, Xue-Ying Li, Dong-Xin Wang

[DESCRIPTION]
<div class = "text-blocks"><div class = "text-block">Total knee arthroplasty (TKA) is an important therapy for patients with serious knee osteoarthritis in order to improve quality of life and relieve pain. But a large number of patients who undergo this surgery experience moderate to severe postoperative pain. Previously, the investigators used single femoral nerve blockade combined with patient-controlled intravenous analgesia for postoperative analgesia for patients after TKA. Although this method provides acceptable analgesia, the incidence of opioid-associated side effects is relatively high. Low-dose epidural morphine is commonly used in postoperative analgesia after cesarean section, and the effect of single dose morphine lasts more than 20 hours, with low incidences of itching, nausea, vomiting, and respiratory depression. The investigators hypothesize that, for patients undergoing TKA, the addition of low-dose epidural morphine to single femoral nerve block and intravenous opioids can improve the postoperative analgesia, reduce the consumption of intravenous opioids and decrease opioid-associated side effects.</div></div>

[STEPS]
?. [Enrollment]
Patients will be screened the day before surgery. And eligible patients will be enrolled for their consent in advance and written informed consent will be signed.
?. [Randomization]
This is a randomized, double-blind, and placebo-controlled one-center trial. The random numbers were generated in a 1:1 ratio with a block size of 4 by an independent biostatistician using the SAS statistical package version 9.3 (SAS Institute, Cary, NC, USA). Each enrolled patient will be assigned a number according to the sequence of recruitment. The study drugs, either 2 mg morphine in 5 mL normal saline or 5 mL normal saline, will be prepared according to the randomization results by a study coordinator who will not participate in the rest of the study. The prepared drugs will be contained in 5 mL syringes with same appearance, labeled with the number of recruitments, and provided to the anesthesiologists taking care of the enrolled patients. The results of randomization and the preparation of study drugs will be recorded and sealed in sequentially numbered letters and stored at the site of investigation until the end of the study.
?. [Intervention and anesthesia management]
Combined spinal (with 0.5% hyperbaric bupivacaine) and epidural (with 2% lidocaine) anesthesia will be performed for all patients. The dosage of local anesthetics (either spinal bupivacaine or epidural lidocaine) will be determined by the anesthesiologists. Intraoperative sedation will be provided with dexmedetomidine infusion (a loading dose of 0.4 μg/kg in 10 minutes, followed by a 0.2 μg/kg/h infusion) which will be started once patients become hemodynamically stable after spinal anesthesia, and stopped before the end of surgery. The study drugs (morphine for patients in the epidural morphine [EDMO] group and normal saline for those in the control [CTRL] group) will be administered at the end of surgery through the indwelling epidural catheter which will be removed afterwards.
?. [Intervention and anesthesia management]
Patients will be transferred to the post-anesthetic care unit (PACU), where single-injection femoral nerve block will be performed with 20 mL of 0.5% ropivacaine under the guidance of ultrasonography and a nerve stimulator. A patient-controlled intravenous analgesia (PCIA) pump will also be provided, which is established with 100 mL of 0.5 mg/mL morphine and programmed to deliver a 2 mL bolus with a lockout interval of 8–10 min and a background infusion of 0.5 mL/h. The PCIA pump will be stopped at 48 hours after surgery. If the morphine solution in the pump is exhausted before that time, supplemental morphine of same concentration will be provided to ensure a 48-hour postoperative patient-controlled analgesia.
?. [Outcome assessment and follow-up schedule]
After obtaining the written informed consents, detailed baseline data including demographic characteristics, diagnosis, comorbidities, current medication, NYHA classification, American Society of Anesthesiologists (ASA) classification, history of previous surgery and anesthesia, as well as important laboratory test results will be collected.
?. [Outcome assessment and follow-up schedule]
Intraoperative data including duration of anesthesia and surgery, name of surgery, types and doses of anesthetic drugs, and fluid balance will be recorded. After surgery, patients will be monitored in PACU for at least 30 minutes. Motor blockade of the lower limbs will be estimated using a modified Bromage scale (0 = no motor block, able to lift extended limb off the bed; 1 = partial block, able to flex/extend the knee and ankle; 2 = partial block, only plantar flexion of the ankle possible; 3 = complete block, no voluntary movement of the limb) at PACU arrival and 30 minutes.
?. [Outcome assessment and follow-up schedule]
After surgery, investigators will visit patients at 6, 12, 24, 36, and 48 hours after surgery (1 hour earlier or later is allowed). The severity of pain at rest and with movement will be assessed with the numerical rating scale (NRS, an 11-point scale where 0 = no pain and 10 = the most severe pain). Motor blockade of the lower limbs will be estimated using a modified Bromage scale. The numbers of required and given bolus injections by the PCIA pumps between the neighbouring time-points will be counted. The occurrence of side effects (nausea, vomiting, pruritus, and dizziness), the uses and dosages of other analgesics, the volume of drainage, and the requirement of blood transfusion within 48 hours will be recorded. The score of patients’ satisfactions (1 = poor, 2 = fair, 3 = good, 4 = excellent) will be evaluated at 48 hours after surgery. Other postoperative date including time to ambulation, length of postoperative hospital stays, occurrence of complications within 30 days, and 30-day mortality after surgery will be documented.
?. [Outcome assessment and follow-up schedule]
At 30 days after surgery, the quality of life will be assessed with 12-item short-form; the severity of arthritic symptoms will be assessed with WOMAC osteoarthritis index. 30-day followed-up will be performed by face-to-face interview, when patients come back to the hospital for a re-examination.