Dexmedetomidine-esketamine Combination and Moderate-to-severe Pain After Spinal Surgery

Summary

Spinal surgery is generally followed by severe postoperative pain, and poor pain control may cause adverse outcomes such as cardiovascular events, neurocognitive disorders, and chronic postsurgical pain (CPSP). In previous studies, perioperative use of dexmedetomidine or esketamine is each associated with improved analgesia after surgery. Recent studies suggest that combined use of dexmedetomidine and esketamine may produce synergetic effects in improving analgesia. This trial is designed to test the hypothesis that perioperative combined use of dexmedetomidine and esketamine may improve analgesia and reduce moderate-to-severe pain in patients after spinal surgery.

Timeline

Start

2026-04

Primary completion

2027-04

Completion

2027-05

Publications

• Background Austin PC. An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies. Multivariate Behav Res. 2011 May;46(3):399-424. doi: 10.1080/00273171.2011.568786. Epub 2011 Jun 8.
• Background Ruetzler K, Smilowitz NR, Berger JS, Devereaux PJ, Maron BA, Newby LK, de Jesus Perez V, Sessler DI, Wijeysundera DN. Diagnosis and Management of Patients With Myocardial Injury After Noncardiac Surgery: A Scientific Statement From the American Heart Association. Circulation. 2021 Nov 9;144(19):e287-e305. doi: 10.1161/CIR.0000000000001024. Epub 2021 Oct 4.
• Background Weir S, Samnaliev M, Kuo TC, Ni Choitir C, Tierney TS, Cumming D, Bruce J, Manca A, Taylor RS, Eldabe S. The incidence and healthcare costs of persistent postoperative pain following lumbar spine surgery in the UK: a cohort study using the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES). BMJ Open. 2017 Sep 11;7(9):e017585. doi: 10.1136/bmjopen-2017-017585.
• Background Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, Cohen M, Evers S, Finnerup NB, First MB, Giamberardino MA, Kaasa S, Kosek E, Lavand'homme P, Nicholas M, Perrot S, Scholz J, Schug S, Smith BH, Svensson P, Vlaeyen JWS, Wang SJ. A classification of chronic pain for ICD-11. Pain. 2015 Jun;156(6):1003-1007. doi: 10.1097/j.pain.0000000000000160. No abstract available.
• Background Rodrigues NB, McIntyre RS, Lipsitz O, Lee Y, Cha DS, Shekotikhina M, Vinberg M, Gill H, Subramaniapillai M, Kratiuk K, Lin K, Ho R, Mansur RB, Rosenblat JD. A simplified 6-Item clinician administered dissociative symptom scale (CADSS-6) for monitoring dissociative effects of sub-anesthetic ketamine infusions. J Affect Disord. 2021 Mar 1;282:160-164. doi: 10.1016/j.jad.2020.12.119. Epub 2020 Dec 29.
• Background Busse JW, Bartlett SJ, Dougados M, Johnston BC, Guyatt GH, Kirwan JR, Kwoh K, Maxwell LJ, Moore A, Singh JA, Stevens R, Strand V, Suarez-Almazor ME, Tugwell P, Wells GA. Optimal Strategies for Reporting Pain in Clinical Trials and Systematic Reviews: Recommendations from an OMERACT 12 Workshop. J Rheumatol. 2015 Oct;42(10):1962-1970. doi: 10.3899/jrheum.141440. Epub 2015 May 15.
• Background Zhang Y, Cui F, Ma JH, Wang DX. Mini-dose esketamine-dexmedetomidine combination to supplement analgesia for patients after scoliosis correction surgery: a double-blind randomised trial. Br J Anaesth. 2023 Aug;131(2):385-396. doi: 10.1016/j.bja.2023.05.001. Epub 2023 Jun 9.
• Background Junior AB Jr, Bendazzoli PS, Ferreira Melo FW Jr, Porto Franco RM, de Sousa Rocha EM, Matos Lima RD, Brondi EB. Efficacy and Safety of the Ketamine-Dexmedetomidine Combination in Adult Sedation and Anesthesia: A Systematic Review and Single-Arm Meta-Analysis of Randomized Controlled Trials. Cureus. 2025 Nov 21;17(11):e97432. doi: 10.7759/cureus.97432. eCollection 2025 Nov.
• Background Raymond BL, Allen BFS, Freundlich RE, McEvoy MD, Parrish CG, Ruble SR, Scharfman KH, Wanderer JP, Gao Y, Choi L, Dear ML, Master H, Rice TW, Kertai MD; Vanderbilt Learning Healthcare System Platform Investigators. IMpact of PerioperAtive KeTamine on Enhanced Recovery After abdominal Surgery (IMPAKT ERAS): a pragmatic randomised single-cluster trial. Br J Anaesth. 2025 Dec;135(6):1770-1778. doi: 10.1016/j.bja.2025.08.001. Epub 2025 Sep 3.
• Background Verret M, Le JBP, Lalu MM, Jeffers MS, McIsaac DI, Nicholls SG, Turgeon AF, Ramchandani R, Li H, Hutton B, Zivkovic F, Graham M, Le M, Geist A, Berube M, O'Hearn K, Gilron I, Poulin P, Daudt H, Martel G, McVicar J, Moloo H, Fergusson DA. Effectiveness of dexmedetomidine on patient-centred outcomes in surgical patients: a systematic review and Bayesian meta-analysis. Br J Anaesth. 2024 Sep;133(3):615-627. doi: 10.1016/j.bja.2024.06.007. Epub 2024 Jul 16.
• Background Brinck ECV, Virtanen T, Makela S, Soini V, Hynninen VV, Mulo J, Savolainen U, Rantakokko J, Maisniemi K, Liukas A, Olkkola KT, Kontinen V, Tarkkila P, Peltoniemi M, Saari TI. 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. PLoS One. 2021 Jun 7;16(6):e0252626. doi: 10.1371/journal.pone.0252626. eCollection 2021.
• Background Hou NN, Zhang MY, Zhang YW, Wu HJ, Luo H, Yang H. Safety and efficacy of low-dose esketamine weakly opioidized anesthesia in elderly patients with lumbar spinal stenosis undergoing surgery: a prospective, double-blind randomized controlled trial. BMC Anesthesiol. 2025 Feb 5;25(1):57. doi: 10.1186/s12871-025-02908-3.
• Background Liu J, Wang T, Song J, Cao L. Effect of esketamine on postoperative analgesia and postoperative delirium in elderly patients undergoing gastrointestinal surgery. BMC Anesthesiol. 2024 Feb 1;24(1):46. doi: 10.1186/s12871-024-02424-w.
• Background O'Sullivan R, Inouye SK, Meagher D. Delirium and depression: inter-relationship and clinical overlap in elderly people. Lancet Psychiatry. 2014 Sep;1(4):303-11. doi: 10.1016/S2215-0366(14)70281-0. Epub 2014 Aug 10.
• Background Elsamadicy AA, Adogwa O, Lydon E, Sergesketter A, Kaakati R, Mehta AI, Vasquez RA, Cheng J, Bagley CA, Karikari IO. Depression as an independent predictor of postoperative delirium in spine deformity patients undergoing elective spine surgery. J Neurosurg Spine. 2017 Aug;27(2):209-214. doi: 10.3171/2017.4.SPINE161012. Epub 2017 Jun 2.
• Background Wang S, Deng CM, Zeng Y, Chen XZ, Li AY, Feng SW, Xu LL, Chen L, Yuan HM, Hu H, Yang T, Han T, Zhang HY, Jiang M, Sun XY, Guo HN, Sessler DI, Wang DX. Efficacy of a single low dose of esketamine after childbirth for mothers with symptoms of prenatal depression: randomised clinical trial. BMJ. 2024 Apr 10;385:e078218. doi: 10.1136/bmj-2023-078218.
• Background Persson J, Hasselstrom J, Maurset A, Oye I, Svensson JO, Almqvist O, Scheinin H, Gustafsson LL, Almqvist O. Pharmacokinetics and non-analgesic effects of S- and R-ketamines in healthy volunteers with normal and reduced metabolic capacity. Eur J Clin Pharmacol. 2002 Feb;57(12):869-75. doi: 10.1007/s002280100353.
• Background Segmiller F, Ruther T, Linhardt A, Padberg F, Berger M, Pogarell O, Moller HJ, Kohler C, Schule C. Repeated S-ketamine infusions in therapy resistant depression: a case series. J Clin Pharmacol. 2013 Sep;53(9):996-8. doi: 10.1002/jcph.122. Epub 2013 Jul 24. No abstract available.
• Background Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, Pinter C, Hough D, Sanacora G, Manji H, Drevets WC. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Focus (Am Psychiatr Publ). 2019 Jan;17(1):55-65. doi: 10.1176/appi.focus.17105. Epub 2019 Jan 7.
• Background Molero P, Ramos-Quiroga JA, Martin-Santos R, Calvo-Sanchez E, Gutierrez-Rojas L, Meana JJ. Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review. CNS Drugs. 2018 May;32(5):411-420. doi: 10.1007/s40263-018-0519-3.
• Background Bartova L, Papageorgiou K, Milenkovic I, Dold M, Weidenauer A, Willeit M, Winkler D, Kasper S. Rapid antidepressant effect of S-ketamine in schizophrenia. Eur Neuropsychopharmacol. 2018 Aug;28(8):980-982. doi: 10.1016/j.euroneuro.2018.05.007. Epub 2018 Jul 2.
• Background Smith-Apeldoorn SY, Veraart JK, Spijker J, Kamphuis J, Schoevers RA. Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. Lancet Psychiatry. 2022 Nov;9(11):907-921. doi: 10.1016/S2215-0366(22)00317-0.
• Background Ma S, Chen M, Jiang Y, Xiang X, Wang S, Wu Z, Li S, Cui Y, Wang J, Zhu Y, Zhang Y, Ma H, Duan S, Li H, Yang Y, Lingle CJ, Hu H. Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb. Nature. 2023 Oct;622(7984):802-809. doi: 10.1038/s41586-023-06624-1. Epub 2023 Oct 18.
• Background Brinck EC, Tiippana E, Heesen M, Bell RF, Straube S, Moore RA, Kontinen V. Perioperative intravenous ketamine for acute postoperative pain in adults. Cochrane Database Syst Rev. 2018 Dec 20;12(12):CD012033. doi: 10.1002/14651858.CD012033.pub4.
• Background Su X, Meng ZT, Wu XH, Cui F, Li HL, Wang DX, Zhu X, Zhu SN, Maze M, Ma D. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet. 2016 Oct 15;388(10054):1893-1902. doi: 10.1016/S0140-6736(16)30580-3. Epub 2016 Aug 16.
• Background Wu XH, Cui F, Zhang C, Meng ZT, Wang DX, Ma J, Wang GF, Zhu SN, Ma D. Low-dose Dexmedetomidine Improves Sleep Quality Pattern in Elderly Patients after Noncardiac Surgery in the Intensive Care Unit: A Pilot Randomized Controlled Trial. Anesthesiology. 2016 Nov;125(5):979-991. doi: 10.1097/ALN.0000000000001325.
• Background Lu W, Fu Q, Luo X, Fu S, Hu K. Effects of dexmedetomidine on sleep quality of patients after surgery without mechanical ventilation in ICU. Medicine (Baltimore). 2017 Jun;96(23):e7081. doi: 10.1097/MD.0000000000007081.
• Background Huupponen E, Maksimow A, Lapinlampi P, Sarkela M, Saastamoinen A, Snapir A, Scheinin H, Scheinin M, Merilainen P, Himanen SL, Jaaskelainen S. Electroencephalogram spindle activity during dexmedetomidine sedation and physiological sleep. Acta Anaesthesiol Scand. 2008 Feb;52(2):289-94. doi: 10.1111/j.1399-6576.2007.01537.x. Epub 2007 Nov 14.
• Background Tasbihgou SR, Barends CRM, Absalom AR. The role of dexmedetomidine in neurosurgery. Best Pract Res Clin Anaesthesiol. 2021 Jul;35(2):221-229. doi: 10.1016/j.bpa.2020.10.002. Epub 2020 Oct 14.
• Background Mo Y, Zimmermann AE. Role of dexmedetomidine for the prevention and treatment of delirium in intensive care unit patients. Ann Pharmacother. 2013 Jun;47(6):869-76. doi: 10.1345/aph.1AR708.
• Background Swarbrick CJ, Partridge JSL. Evidence-based strategies to reduce the incidence of postoperative delirium: a narrative review. Anaesthesia. 2022 Jan;77 Suppl 1:92-101. doi: 10.1111/anae.15607.
• Background Dinges HC, Otto S, Stay DK, Baumlein S, Waldmann S, Kranke P, Wulf HF, Eberhart LH. Side Effect Rates of Opioids in Equianalgesic Doses via Intravenous Patient-Controlled Analgesia: A Systematic Review and Network Meta-analysis. Anesth Analg. 2019 Oct;129(4):1153-1162. doi: 10.1213/ANE.0000000000003887.
• Background Duprey MS, Dijkstra-Kersten SMA, Zaal IJ, Briesacher BA, Saczynski JS, Griffith JL, Devlin JW, Slooter AJC. Opioid Use Increases the Risk of Delirium in Critically Ill Adults Independently of Pain. Am J Respir Crit Care Med. 2021 Sep 1;204(5):566-572. doi: 10.1164/rccm.202010-3794OC.
• Background Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology. 2000 Oct;93(4):1123-33. doi: 10.1097/00000542-200010000-00038. No abstract available.
• Background Orhurhu VJ, Chu R, Gill J. Failed Back Surgery Syndrome. 2023 May 1. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK539777/
• Background Ruhnau J, Muller J, Nowak S, Strack S, Sperlich D, Pohl A, Dilz J, Rehberg S, Usichenko T, Hahnenkamp K, Weidemeier M, Ehler J, Floel A, Schroeder HWS, Muller JU, Fleischmann R, Vogelgesang A. Exploring Neuroinflammation and Its Role in Postoperative Cognitive Dysfunction following Spine Surgery. Gerontology. 2026;72(1):29-40. doi: 10.1159/000548923. Epub 2025 Oct 20.
• Background Morrison RS, Magaziner J, Gilbert M, Koval KJ, McLaughlin MA, Orosz G, Strauss E, Siu AL. Relationship between pain and opioid analgesics on the development of delirium following hip fracture. J Gerontol A Biol Sci Med Sci. 2003 Jan;58(1):76-81. doi: 10.1093/gerona/58.1.m76.
• Background Turan A, Leung S, Bajracharya GR, Babazade R, Barnes T, Schacham YN, Mao G, Zimmerman N, Ruetzler K, Maheshwari K, Esa WAS, Sessler DI. Acute Postoperative Pain Is Associated With Myocardial Injury After Noncardiac Surgery. Anesth Analg. 2020 Sep;131(3):822-829. doi: 10.1213/ANE.0000000000005033.
• Background Bernholm KF, Meyhoff CS, Bickler P. Association between tissue oxygenation and myocardial injury in patients undergoing major spine surgery: a prospective cohort study. BMJ Open. 2021 Sep 17;11(9):e044342. doi: 10.1136/bmjopen-2020-044342.
• Background Writing Committee for the VISION Study Investigators; Devereaux PJ, Biccard BM, Sigamani A, Xavier D, Chan MTV, Srinathan SK, Walsh M, Abraham V, Pearse R, Wang CY, Sessler DI, Kurz A, Szczeklik W, Berwanger O, Villar JC, Malaga G, Garg AX, Chow CK, Ackland G, Patel A, Borges FK, Belley-Cote EP, Duceppe E, Spence J, Tandon V, Williams C, Sapsford RJ, Polanczyk CA, Tiboni M, Alonso-Coello P, Faruqui A, Heels-Ansdell D, Lamy A, Whitlock R, LeManach Y, Roshanov PS, McGillion M, Kavsak P, McQueen MJ, Thabane L, Rodseth RN, Buse GAL, Bhandari M, Garutti I, Jacka MJ, Schunemann HJ, Cortes OL, Coriat P, Dvirnik N, Botto F, Pettit S, Jaffe AS, Guyatt GH. Association of Postoperative High-Sensitivity Troponin Levels With Myocardial Injury and 30-Day Mortality Among Patients Undergoing Noncardiac Surgery. JAMA. 2017 Apr 25;317(16):1642-1651. doi: 10.1001/jama.2017.4360.
• Background Mastrokostas PG, Mastrokostas LE, Lavi AB, Razi A, Houten JK, Saleh A, Bou Monsef J, Razi AE, Ng MK. Postoperative complications, length of stay, and discharge disposition following single-level anterior lumbar interbody fusion in elderly and octogenarian patients. J Orthop. 2025 Aug 7;69:311-316. doi: 10.1016/j.jor.2025.08.002. eCollection 2025 Nov.
• Background Gerbershagen HJ, Pogatzki-Zahn E, Aduckathil S, Peelen LM, Kappen TH, van Wijck AJ, Kalkman CJ, Meissner W. Procedure-specific risk factor analysis for the development of severe postoperative pain. Anesthesiology. 2014 May;120(5):1237-45. doi: 10.1097/ALN.0000000000000108.
• Background Hah JM, Cramer E, Hilmoe H, Schmidt P, McCue R, Trafton J, Clay D, Sharifzadeh Y, Ruchelli G, Goodman S, Huddleston J, Maloney WJ, Dirbas FM, Shrager J, Costouros JG, Curtin C, Mackey SC, Carroll I. Factors Associated With Acute Pain Estimation, Postoperative Pain Resolution, Opioid Cessation, and Recovery: Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2019 Mar 1;2(3):e190168. doi: 10.1001/jamanetworkopen.2019.0168.
• Background Yang MMH, Hartley RL, Leung AA, Ronksley PE, Jette N, Casha S, Riva-Cambrin J. Preoperative predictors of poor acute postoperative pain control: a systematic review and meta-analysis. BMJ Open. 2019 Apr 1;9(4):e025091. doi: 10.1136/bmjopen-2018-025091.
• Background Yang MMH, Riva-Cambrin J, Cunningham J, Jette N, Sajobi TT, Soroceanu A, Lewkonia P, Jacobs WB, Casha S. Development and validation of a clinical prediction score for poor postoperative pain control following elective spine surgery. J Neurosurg Spine. 2020 Sep 15;34(1):3-12. doi: 10.3171/2020.5.SPINE20347. Print 2021 Jan 1.
• Background Tsaousi GG, Pourzitaki C, Aloisio S, Bilotta F. Dexmedetomidine as a sedative and analgesic adjuvant in spine surgery: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Pharmacol. 2018 Nov;74(11):1377-1389. doi: 10.1007/s00228-018-2520-7. Epub 2018 Jul 14.
• Background Mathiesen O, Dahl B, Thomsen BA, Kitter B, Sonne N, Dahl JB, Kehlet H. A comprehensive multimodal pain treatment reduces opioid consumption after multilevel spine surgery. Eur Spine J. 2013 Sep;22(9):2089-96. doi: 10.1007/s00586-013-2826-1. Epub 2013 May 17.
• Background Sharma S, Balireddy RK, Vorenkamp KE, Durieux ME. Beyond opioid patient-controlled analgesia: a systematic review of analgesia after major spine surgery. Reg Anesth Pain Med. 2012 Jan-Feb;37(1):79-98. doi: 10.1097/AAP.0b013e3182340869.

Drugs

Indications

No indication recorded.