{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T21:23:23Z","timestamp":1772659403789,"version":"3.50.1"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T00:00:00Z","timestamp":1682553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Rebound pain, transient and acute postoperative pain after the disappearance of regional block anesthesia, has been a concern in recent years. Insufficient preemptive analgesia and hyperalgesia induced by regional block are the main mechanisms. At present, the evidence for the treatment of rebound pain is limited. The esketamine, as an antagonist of the N-methyl-D-aspartate receptor, has been proven to prevent hyperalgesia. Therefore, this trial aims to evaluate the impact of esketamine on postoperative rebound pain in patients undergoing total knee arthroplasty.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods\/design<\/jats:title><jats:p>This study is a single-center, prospective, double-blind, randomized, placebo-controlled trial. Participants who plan to undergo total knee arthroplasty will be randomly assigned to the esketamine group (<jats:italic>N<\/jats:italic>\u2009=\u2009178) and placebo group (<jats:italic>N<\/jats:italic>\u2009=\u2009178) in a ratio of 1:1. This trial aims to evaluate the impact of esketamine on postoperative rebound pain in patients undergoing total knee arthroplasty. The primary outcome of this trial is the incidence of rebound pain within 12 h after the operation in the esketamine group and the placebo group. The secondary outcome will be to compare (1) the incidence of rebound pain 24 h after the operation; (2) the time to enter the pain cycle for the first time within 24 h after the procedure; (3) the first time of rebound pain occurred within 24 h after surgery; (4) the modified rebound pain score; (5) NRS score under rest and exercise at different time points; (6) the cumulative opioid consumption at different time points; (7) patient\u2019s prognosis and knee joint function evaluation; (8) blood glucose and cortisol concentration; (9) patient\u2019s satisfaction score; (10) adverse reactions and adverse events.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The effect of ketamine on preventing postoperative rebound pain is contradictory and uncertain. The affinity of esketamine to the N-methyl-D-aspartate receptor is about four times higher than levo-ketamine, the analgesic effect is 3 times higher than levo-ketamine, and there are fewer adverse mental reactions. To our knowledge, there is no randomized controlled trial to verify the impact of esketamine on postoperative rebound pain in patients undergoing total knee arthroplasty. Therefore, this trial is expected to fill an important gap in relevant fields and provide novel evidence for individualized pain management.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical Trial Registration<\/jats:title><jats:p><jats:ext-link>http:\/\/www.chictr.org.cn<\/jats:ext-link>, identifier ChiCTR2300069044.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2023.1179673","type":"journal-article","created":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T04:30:35Z","timestamp":1682569835000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Effects of esketamine on postoperative rebound pain in patients undergoing unilateral total knee arthroplasty: a single-center, randomized, double-blind, placebo-controlled trial protocol"],"prefix":"10.3389","volume":"14","author":[{"given":"Youzhuang","family":"Zhu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qun","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guilin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaotian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lili","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaona","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianshuai","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhijin","family":"Zou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baobo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changyao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,4,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1016\/j.bja.2020.12.034","article-title":"Rebound pain: distinct pain phenomenon or nonentity?","volume":"126","author":"Hamilton","year":"2021","journal-title":"Br J Anaesth"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1016\/j.bja.2020.10.035","article-title":"Factors associated with rebound pain after peripheral nerve block for ambulatory surgery","volume":"126","author":"Barry","year":"2021","journal-title":"Br J Anaesth"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1097\/AAP.0b013e3182176f5a","article-title":"Transient heat hyperalgesia during resolution of ropivacaine sciatic nerve block in the rat","volume":"36","author":"Kolarczyk","year":"2011","journal-title":"Reg Anesth Pain Med"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"372","DOI":"10.4097\/kja.20436","article-title":"Managing rebound pain after regional anesthesia","volume":"73","author":"Mu\u00f1oz-Leyva","year":"2020","journal-title":"Korean J Anesthesiol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1111\/os.12535","article-title":"Postoperative pain Management in Total Knee Arthroplasty","volume":"11","author":"Li","year":"2019","journal-title":"Orthop Surg"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/j.bjan.2019.05.001","article-title":"Peripheral nerve block and rebound pain: literature review","volume":"69","author":"Nobre","year":"2019","journal-title":"Braz J Anesthesiol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1136\/rapm-2021-102795","article-title":"Perineural dexamethasone reduces rebound pain after ropivacaine single injection interscalene block for arthroscopic shoulder surgery: a randomized controlled trial","volume":"46","author":"Woo","year":"2021","journal-title":"Reg Anesth Pain Med"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.2147\/JPR.S370589","article-title":"Effect of Transauricular Vagus nerve stimulation on rebound pain after Ropivacaine single injection femoral nerve block for anterior cruciate ligament reconstruction: a randomized controlled trial","volume":"15","author":"Zhou","year":"2022","journal-title":"J Pain Res"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"4022","DOI":"10.1007\/s00167-020-06288-8","article-title":"Dexmedetomidine combined with suprascapular nerve block and axillary nerve block has a synergistic effect on relieving postoperative pain after arthroscopic rotator cuff repair","volume":"29","author":"Lee","year":"2021","journal-title":"Knee Surg Sports Traumatol Arthrosc"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2343","DOI":"10.1007\/s00167-019-05799-3","article-title":"Dexmedetomidine combined with interscalene brachial plexus block has a synergistic effect on relieving postoperative pain after arthroscopic rotator cuff repair","volume":"28","author":"Hwang","year":"2020","journal-title":"Knee Surg Sports Traumatol Arthrosc"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1016\/j.arthro.2014.03.014","article-title":"Effect of ultrasonographically guided axillary nerve block combined with suprascapular nerve block in arthroscopic rotator cuff repair: a randomized controlled trial","volume":"30","author":"Lee","year":"2014","journal-title":"Arthroscopy"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1097\/00115550-200705000-00003","article-title":"Rebound pain scores as a function of femoral nerve block duration after anterior cruciate ligament reconstruction: retrospective analysis of a prospective, randomized clinical trial","volume":"32","author":"Williams","year":"2007","journal-title":"Reg Anesth Pain Med"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1097\/BOT.0000000000000374","article-title":"Continuous popliteal sciatic nerve block versus single injection nerve block for ankle fracture surgery: a prospective randomized comparative trial","volume":"29","author":"Ding","year":"2015","journal-title":"J Orthop Trauma"},{"key":"ref14","first-page":"1069","article-title":"The effects of minimal-dose versus low-dose S-ketamine on opioid consumption, hyperalgesia, and postoperative delirium: a triple-blinded, randomized, active- and placebo-controlled clinical trial","volume":"82","author":"Bornemann-Cimenti","year":"2016","journal-title":"Minerva Anestesiol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1016\/j.bja.2021.11.043","article-title":"Evaluation of intraoperative ketamine on the prevention of severe rebound pain upon cessation of peripheral nerve block: a prospective randomised, double-blind, placebo-controlled study","volume":"128","author":"Touil","year":"2022","journal-title":"Br J Anaesth"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1111\/j.1365-2044.2008.05831.x","article-title":"Subacute pain and function after fast-track hip and knee arthroplasty","volume":"64","author":"Andersen","year":"2009","journal-title":"Anaesthesia"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1093\/bja\/aet441","article-title":"Effect of adductor canal block on pain in patients with severe pain after total knee arthroplasty: a randomized study with individual patient analysis","volume":"112","author":"Grevstad","year":"2014","journal-title":"Br J Anaesth"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1097\/00000542-200307000-00025","article-title":"Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans","volume":"99","author":"Koppert","year":"2003","journal-title":"Anesthesiology"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1007\/s00508-017-1299-3","article-title":"S(+)-ketamine: current trends in emergency and intensive care medicine","volume":"130","author":"Trimmel","year":"2018","journal-title":"Wien Klin Wochenschr"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1093\/bja\/aer221","article-title":"Ketamine: new uses for an old drug?","volume":"107","author":"Hirota","year":"2011","journal-title":"Br J Anaesth"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1744-8069-7-20","DOI":"10.1186\/1744-8069-7-20","article-title":"Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy","volume":"7","author":"Ruscheweyh","year":"2011","journal-title":"Mol Pain"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.coph.2011.10.018","article-title":"Hyperalgesia by synaptic long-term potentiation (LTP): an update","volume":"12","author":"Sandk\u00fchler","year":"2012","journal-title":"Curr Opin Pharmacol"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"Cd012033","DOI":"10.1002\/14651858.CD012033.pub4","article-title":"Perioperative intravenous ketamine for acute postoperative pain in adults","volume":"12","author":"Brinck","year":"2018","journal-title":"Cochrane Database Syst Rev"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"e0252626","DOI":"10.1371\/journal.pone.0252626","article-title":"S-ketamine in patient-controlled analgesia reduces opioid consumption in a dose-dependent manner after major lumbar fusion surgery: a randomized, double-blind, placebo-controlled clinical trial","volume":"16","author":"Brinck","year":"2021","journal-title":"PLoS One"},{"key":"ref25","first-page":"757","article-title":"S(+)-ketamine for control of perioperative pain and prevention of post thoracotomy pain syndrome: a randomized, double-blind study","volume":"78","author":"Mendola","year":"2012","journal-title":"Minerva Anestesiol"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"45","DOI":"10.21037\/apm-21-3343","article-title":"Effect of low-dose esketamine on pain control and postpartum depression after cesarean section: a retrospective cohort study","volume":"11","author":"Wang","year":"2022","journal-title":"Ann Palliat Med"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.medcli.2017.10.001","article-title":"Diagnosis and medical treatment of breakthrough pain","volume":"150","author":"Esparza-Mi\u00f1ana","year":"2018","journal-title":"Med Clin (Barc)"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1016\/j.jpainsymman.2021.04.018","article-title":"A systematic review of measures of breakthrough pain and their psychometric properties","volume":"62","author":"Liossi","year":"2021","journal-title":"J Pain Symptom Manag"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1179673\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T04:30:38Z","timestamp":1682569838000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1179673\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,27]]},"references-count":28,"alternative-id":["10.3389\/fneur.2023.1179673"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2023.1179673","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,27]]},"article-number":"1179673"}}