The Archives of Bone and Joint Surgery

The Archives of Bone and Joint Surgery

Perioperative Ketamine and Esketamine for Postoperative Mood Symptoms After Orthopaedic Surgery: A Systematic Review of Randomized Controlled Trials

Document Type : SYSTEMATIC REVIEW

Authors
Ali Dabbagh 1
Firoozeh Madadi 1
Maryam Fallah 2
Negarsadat Namazi 1
1 Department of Anesthesiology, School of Medicine, Anesthesiology Research Center, Ayatollah Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Shahid Beheshti University of Medical Sciences, Tehran, Iran
10.22038/abjs.2026.94686.4270
Abstract
Objectives: Perioperative anxiety and depression are common following major orthopaedic surgery and may adversely affect postoperative recovery. Ketamine and esketamine have rapid psychotropic effects; however, their effectiveness in reducing postoperative mood symptoms in orthopaedic patients remains uncertain. We systematically reviewed randomized evidence on the effects of these agents on postoperative anxiety, depression, and adverse events.
Methods: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials enrolling adults undergoing major orthopaedic procedures. Eligible studies compared ketamine or esketamine administered preoperatively, intraoperatively, or postoperatively with placebo or no ketamine-class agent. The primary outcomes were postoperative anxiety and depression assessed using validated scales. Secondary outcomes included drug-related adverse events.
Results: Nine randomized controlled trials were included, with follow-up durations ranging from 24 hours to 12 months. Five trials assessed postoperative anxiety using validated scales; four reported significantly lower anxiety scores with ketamine or esketamine at early postoperative time points, whereas one trial using a single preoperative dose of ketamine found no significant anxiolytic effect. Overall, perioperative ketamine or esketamine may be associated with lower early postoperative anxiety and depressive symptom scores in selected orthopaedic populations. Regarding safety, ketamine or esketamine did not appear to increase the incidence of common adverse events.
Conclusion: Perioperative ketamine or esketamine appears to reduce early postoperative anxiety and depressive symptoms in orthopaedic patients without increasing postoperative nausea, vomiting, or dizziness. Further standardized trials are needed before firm conclusions can be drawn.
Level of evidence: II
Keywords
Anxiety
Depression
Ketamine
Orthopaedic
Perioperative
Subjects
1.    El-Gabalawy R, Sommer JL, Pietrzak R, et al. Stress post-traumatique en période postopératoire: état de la situation et orientations futures. Can J Anaesth. 2019;66(11):1385-1395. doi:10.1007/s12630-019-01418-4.
2.    Srifuengfung M, Abraham J, Avidan MS, Lenze EJ. Perioperative Anxiety and Depression in Older Adults: Epidemiology and Treatment. Am J Geriatr Psychiatry. 2023;31(11):996-1008. doi:10.1016/j.jagp.2023.07.002.
3.    Hooker JE, Jochimsen KN, Mace RA, Doorley JD, Brewer JR, Vranceanu AM. Clinical Presentation of Adults with Traumatic Orthopedic Injuries Enrolled in a Multisite Psychosocial Trial. Arch Bone Jt Surg. 2024;12(12):826-834. doi:10.22038/abjs.2024.76953.3559.
4.    O'Connor JP, Holden P, Gagnier JJ. Systematic review: preoperative psychological factors and total hip arthroplasty outcomes. J Orthop Surg Res. 2022;17(1):457. doi:10.1186/s13018-022-03355-3.
5.    Cai J, Chen X, Jin Z, Chi Z, Xiong J. Effects of adjunctive esketamine on depression in elderly patients undergoing hip fracture surgery: a randomized controlled trial. BMC Anesthesiol. 2024;24(1):340. doi:10.1186/s12871-024-02733-0.
6.    Smith C, Ades R, Lo Y, Stallone S, Khokhar S, Gruson KI. Predictors of Return to Emergency Department and Readmission Following Primary Elective Total Shoulder Arthroplasty. Arch Bone Jt Surg. 2024;12(7):477-486. doi:10.22038/abjs.2024.77508.3581.
7.    Ripoll-Romero E, Agüera Z, Puig-Llobet M, Galimany-Masclans J. The impact of nursing-led emotional preparation on mental health after total hip arthroplasty. Front Psychol. 2025;16:1693111. doi:10.3389/fpsyg.2025.1693111.
8.    Namazi N, Khani Y, Salmannezhad A, et al. Virtual and augmented reality for anxiety reduction in orthopedic patients and providers: a systematic review. J Orthop Surg Res. 2025;20(1):327. doi:10.1186/s13018-025-05690-7.
9.    Li S, Zhuo Z, Li R, Guo K. Efficacy of esketamine for the treatment of postpartum depression and pain control following cesarean section: a randomized, double-blind, controlled clinical trial. BMC Anesthesiol. 2024;24(1):52. doi:10.1186/s12871-024-02436-6.
 
10.  Krystal JH, Kavalali ET, Monteggia LM. Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms. Neuropsychopharmacology. 2024;49(1):41-50. doi:10.1038/s41386-023-01629-w.
11.  Rosenbaum SB, Gupta V, Patel P, Palacios JL. Ketamine. InStatPearls [Internet] 2024. StatPearls Publishing.
12.  Dahi-Taleghani M, Fazli B, Ghasemi M, Vosoughian M, Dabbagh A. Effect of intravenous patient controlled ketamine analgesiaon postoperative pain in opium abusers. Anesth Pain Med. 2014;4(1):e14129. doi:10.5812/aapm.14129.
13.  Magruder T, Isenhart M, Striepe MV, et al. Ketamine - An Imperfect Wonder Drug? Biochem Pharmacol. 2024;229:116516. doi:10.1016/j.bcp.2024.116516.
14.  Abdallah CG, Adams TG, Kelmendi B, Esterlis I, Sanacora G, Krystal JH. Ketamine's mechanism of action: a path to rapid‐acting antidepressants. Depress Anxiety. 2016;33(8):689-97. doi:10.1002/da.22501.
15.  Guo J, Qiu D, Gu HW, et al. Efficacy and safety of perioperative application of ketamine on postoperative depression: A meta-analysis of randomized controlled studies. Mol Psychiatry. 2023;28(6):2266-2276. doi:10.1038/s41380-023-01945-z.
16.  Tang L, Qu S, Du Z, Zhu Y, Wu L, Wang J. Efficacy of esketamine in reducing nausea and vomiting after anesthesia: a systematic review and meta-analysis of randomized controlled trials. Ann Med. 2026;58(1):2604409. doi:10.1080/07853890.2025.2604409.
17.  Verdonk F, Lambert P, Gakuba C, et al. Preoperative ketamine administration for prevention of postoperative neurocognitive disorders after major orthopedic surgery in elderly patients: A multicenter randomized blinded placebo-controlled trial. Anaesth Crit Care Pain Med. 2024;43(4):101387. doi:10.1016/j.accpm.2024.101387.
18.  Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj. 2021;372:n71. doi:10.1136/bmj.n71.
19.  Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev. 2016;5(1):210. doi:10.1186/s13643-016-0384-4.
20.  Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. Bmj. 2019;366:l4898. doi:10.1136/bmj.l4898.
21.  Zhao Y, Ye C, He Y, Bao M, Liu Y, Yan M. Effect of Esketamine for Patient-Controlled Intravenous Analgesia on Postoperative Sleep Disturbance in the Elderly After Total Hip or Knee Arthroplasty: A Prospective, Randomized, Double-Blind, and Controlled Trial. J Arthroplasty. 2026;41(1):81-89. doi:10.1016/j.arth.2025.06.009.
22.  Min M, Du C, Chen X, Xin W. Effect of subanesthetic dose of esketamine on postoperative rehabilitation in elderly patients undergoing hip arthroplasty. J Orthop Surg Res. 2023;18(1):268. doi:10.1186/s13018-023-03728-2.
23.  Qu S, Zhang WJ, Zhou HJ, Deng F, Liu RJ, Yan WJ. The efficacy and safety of patient-controlled intravenous analgesia with esketamine after total hip arthroplasty: a randomized controlled trial. BMC Anesthesiol. 2025;25(1):31. doi:10.1186/s12871-025-02894-6.
24.  Wilson JA, Nimmo AF, Fleetwood-Walker SM, Colvin LA. A randomised double blind trial of the effect of pre-emptive epidural ketamine on persistent pain after lower limb amputation. Pain. 2008;135(1-2):108-18. doi:10.1016/j.pain.2007.05.011.
25.  Kudoh A, Takahira Y, Katagai H, Takazawa T. Small-dose ketamine improves the postoperative state of depressed patients. Anesth Analg. 2002;95(1):114-8, table of contents. doi:10.1097/00000539-200207000-00020.
26.  Jiang M, Wang MH, Wang XB, et al. Effect of intraoperative application of ketamine on postoperative depressed mood in patients undergoing elective orthopedic surgery. J Anesth. 2016;30(2):232-7. doi:10.1007/s00540-015-2096-7.
27.  Liu Z, Xu J, Zhang M, Zhou T. Effect of esketamine on postoperative pain relief and depressive status in patients with traumatic fractures. Front Med (Lausanne). 2025;12:1684134. doi:10.3389/fmed.2025.1684134.
28.  Li S, Zhou W, Li P, Lin R. Effects of ketamine and esketamine on preventing postpartum depression after cesarean delivery: A meta-analysis. J Affect Disord. 2024;351:720-728. doi:10.1016/j.jad.2024.01.202.
29.  Sun X, Li C, Xu L, et al. Effect and safety of perioperative ketamine/esketamine administration on postoperative pain and depression after breast cancer surgery: a systematic review and meta-analysis. Front Pharmacol. 2025;16:1532524. doi:10.3389/fphar.2025.1532524.
30.  Wang H, Wang L, Gao J, Zhou F. Effect of intravenous esketamine on postoperative sleep disturbance, anxiety, and depression in elderly patients undergoing laparoscopic abdominal surgery: a randomized controlled trial. BMC Geriatr. 2025;25(1):148. doi:10.1186/s12877-025-05787-y.
31.  Zhou D, Liu F, Jiang F, Ye X, Gong X, Zhang M. Sub-Anesthesia Dose of S-Ketamine Reduces Postoperative Pain and Anxiety in Patients Receiving Breast and Thyroid Surgery: A Randomized, Controlled Trial. Pain Physician. 2023;26(3):257-264.
32.  Wang J, Xu Z, Feng Z, Ma R, Zhang X. Impact of Ketamine on Pain Management in Cesarean Section: A Systematic Review and Meta-Analysis. Pain Physician. 2020;23(2):135-148.
33.  Khashan M, Dolkart O, Amar E, et al. Effect of preemptive intra-articular morphine and ketamine on pain after arthroscopic rotator cuff repair: a prospective, double-blind, randomized controlled study. Arch Orthop Trauma Surg. 2016;136(2):233-9. doi:10.1007/s00402-015-2346-z.
 
 
 
The Archives of Bone and Joint Surgery
Volume 14, Issue 9
September 2026
Pages 561-570

  • Receive Date 24 March 2026
  • Revise Date 24 May 2026
  • Accept Date 25 May 2026