Analgesic Effects of Low-dose S-ketamine in Major Spine Fusion Surgery

Postoperative Analgesia Clinical Trial

Official title:

Analgesic Effects of Low-dose S-ketamine in Patients Undergoing Major Spine Fusion Surgery: A Double-blinded, Randomized Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04964219
• Other study ID #: 2021-272
• Status: Recruiting
• Phase: Phase 4
• Start date: February 8, 2022
• Est. completion date: December 30, 2024

Study information

• Verified date: May 2024
• Source: Peking University First Hospital
• Contact: Dong-Xin Wang, MD, PhD
• Phone: +8610-83572784
• Email: wangdongxin[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Despite opioid-based multimodal analgesia, moderate-to-severe pain remains a big problem in patients following multi-segment spinal fusion. As a N-methyl-D-aspartate receptor antagonist, S-ketamine has prominent analgesic effects through activating receptors both in the brain and in the spinal cord, inhibiting the excitatory postsynaptic potential, and thus blunting nociception transmission.

This randomized controlled trial is designed to investigate whether perioperative S-ketamine infusion can decrease pain intensity after major spine fusion surgery.

Description:

Multi-segment spinal fusion usually lasts long and produces significant trauma. Patients following this surgery are at high risk of developing moderate-to-severe pain. In a large sample size cohort study investigating pain severity following 179 kinds of surgical procedures, multi-segment spinal fusion ranked the third with a median pain score of 6.6 (assessed with an 11-point scale, where 0=no pain and 10= the worst pain) and a median morphine consumption of 27 mg during the first postoperative day.

High-dose opioids are associated with adverse effects including respiratory depression, sedation, nausea and vomiting, pruritus, and constipation, which are harmful for early postoperative recovery. A previous study showed that about 50% of patients are taking opioids for chronic pain at 3 months after spinal fusion surgery. Chronic pain is considered to be a result of poorly controlled acute postoperative pain. Thus, multimodal analgesia aiming at improving analgesia while decreasing opioid consumption is advocated to control acute postsurgical pain, in order to promote perioperative recovery and prevent chronic pain.

Racemic ketamine, a commonly used N-methyl-D-aspartate receptor antagonist, is a mixture of equal parts of two optical isomers including R-(-)-ketamine and S-(+)-ketamine. It has prominent analgesic effects through activating receptors both in the brain and in the spinal cord, inhibiting the excitatory postsynaptic potential, and thus blunting nociception transmission. Additionally, studies also showed that, when used within the appropriate time, ketamine reduces pain-related sensitization that aggravates postoperative pain. Thus, ketamine is recommended as a part of a multimodal analgesia regimen in clinical practice, especially for patients undergoing major orthopedic surgery. However, the reported psychotropic side effects limit the clinical use of racemic ketamine.

S-ketamine, an S-isomer of ketamine, is twice as potent as the racemic mixture in analgesia, and produces fewer side effects than the racemic ketamine. How, there are only a few studies exploring analgesic effect of S-ketamine in spine fusion surgery. In opioid-dependent patients, Nielsen et al. reported that intraoperative S-ketamine infusion reduced opioid consumption within 24 hours and relieved back pain intensity at 6 months, it also decreased the daily opioid use at 1 year after spinal surgery. On the other hand, the study of Brinck et al. did not found any superiority of intraoperative S-ketamine in reducing oxycodone consumption within 48 hours after lumbar fusion surgery in opioid-naive patients.

Considering these inconsistent results, the effects of S-ketamine in spinal surgery require further clarification. This trial is designed to investigate the analgesic effect of S-ketamine infused both intraoperatively and postoperatively in patients undergoing multi-segment spine infusion surgery.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 164
• Est. completion date: December 30, 2024
• Est. primary completion date: December 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Patients aged between 18 and 80 years.

• Scheduled to undergo multi-segment (=2) spine fusion surgery.

• Agreed to receive postoperative patient-controlled analgesia.

Exclusion Criteria:

• Refused to participant in this trial.

• Poor blood pressure control in those with hypertension (BP >160/100 mmHg in the ward).

• Previous history of hyperthyroidism or pheochromocytoma.

• Previous history of schizophrenia, epilepsy or Parkinson disease.

• History of sick sinus syndrome, bradycardia (HR <50 beat per min), or atrioventricular block of grade II or higher without pacemaker.

• Severe heart dysfunction (New York Heart Association functional classification 4), hepatic insufficiency (Child-Pugh grade C), renal insufficiency (serum creatinine of 442 µmol/L or above, or requirement of renal replacement therapy), or ASA classification IV or above.

• Unable to complete preoperative assessment due to severe dementia or language barrier.

• Any other conditions that were considered unsuitable for the study participation.

Related Conditions & MeSH terms

• Postoperative Analgesia
• S-ketamine
• Spine Fusion

Intervention

Drug:
• S-ketamine
After anesthesia induction, a bolus of 0.15 mg/kg S-ketamine is injected intravenously about 30 min before incision; this is followed by a continuous infusion at a rate of 0.15 mg/kg/h until 1 hour before the end of surgery. After surgery, patient-controlled analgesia is provided. The pump is established with S-ketamine 25 mg, dexmedetomidine 100 microgram, and sufentanil 100 microgram, diluted with normal saline to 100 ml. The pump is programmed to deliver 2-ml boluses with a background infusion rate at 1 ml /h and a 10-min lockout interval.
• Placebo
After anesthesia induction, a bolus of placebo (normal saline) in the same volume is injected intravenously about 30 min before incision; this is followed by a continuous infusion of placebo at the same rate until 1 hour before the end of surgery. After surgery, patient-controlled analgesia is provided. The pump is established with placebo, dexmedetomidine 100 microgram and sufentanil 100 microgram, diluted with normal saline to 100 ml. The pump is programmed to deliver 2-ml boluses with a background infusion rate at 1 ml /h and a 10-min lockout interval.

Locations

Country	Name	City	State
China	Beijing University First Hospital	Beijing	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
Peking University First Hospital

Country where clinical trial is conducted

China, 

References & Publications (17)

Adams HA, Thiel A, Jung A, Fengler G, Hempelmann G. [Studies using S-(+)-ketamine on probands. Endocrine and circulatory reactions, recovery and dream experiences]. Anaesthesist. 1992 Oct;41(10):588-96. German. — View Citation

Adams HA, Werner C. [From the racemate to the eutomer: (S)-ketamine. Renaissance of a substance?]. Anaesthesist. 1997 Dec;46(12):1026-42. doi: 10.1007/s001010050503. German. — View Citation

Arendt-Nielsen L, Nielsen J, Petersen-Felix S, Schnider TW, Zbinden AM. Effect of racemic mixture and the (S+)-isomer of ketamine on temporal and spatial summation of pain. Br J Anaesth. 1996 Nov;77(5):625-31. doi: 10.1093/bja/77.5.625. — View Citation

Avidan MS, Maybrier HR, Abdallah AB, Jacobsohn E, Vlisides PE, Pryor KO, Veselis RA, Grocott HP, Emmert DA, Rogers EM, Downey RJ, Yulico H, Noh GJ, Lee YH, Waszynski CM, Arya VK, Pagel PS, Hudetz JA, Muench MR, Fritz BA, Waberski W, Inouye SK, Mashour GA; PODCAST Research Group. Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. Lancet. 2017 Jul 15;390(10091):267-275. doi: 10.1016/S0140-6736(17)31467-8. Epub 2017 May 30. Erratum In: Lancet. 2017 Jul 15;390(10091):230. — View Citation

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. — View Citation

Brinck ECV, Maisniemi K, Kankare J, Tielinen L, Tarkkila P, Kontinen VK. Analgesic Effect of Intraoperative Intravenous S-Ketamine in Opioid-Naive Patients After Major Lumbar Fusion Surgery Is Temporary and Not Dose-Dependent: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Anesth Analg. 2021 Jan;132(1):69-79. doi: 10.1213/ANE.0000000000004729. — View Citation

Connolly J 3rd, Javed Z, Raji MA, Chan W, Kuo YF, Baillargeon J. Predictors of Long-term Opioid Use Following Lumbar Fusion Surgery. Spine (Phila Pa 1976). 2017 Sep 15;42(18):1405-1411. doi: 10.1097/BRS.0000000000002133. — View Citation

Cozowicz C, Bekeris J, Poeran J, Zubizarreta N, Schwenk E, Girardi F, Memtsoudis SG. Multimodal Pain Management and Postoperative Outcomes in Lumbar Spine Fusion Surgery: A Population-based Cohort Study. Spine (Phila Pa 1976). 2020 May 1;45(9):580-589. doi: 10.1097/BRS.0000000000003320. — View Citation

Doan LV, Wang J. An Update on the Basic and Clinical Science of Ketamine Analgesia. Clin J Pain. 2018 Nov;34(11):1077-1088. doi: 10.1097/AJP.0000000000000635. — View Citation

Gerbershagen HJ, Aduckathil S, van Wijck AJ, Peelen LM, Kalkman CJ, Meissner W. Pain intensity on the first day after surgery: a prospective cohort study comparing 179 surgical procedures. Anesthesiology. 2013 Apr;118(4):934-44. doi: 10.1097/ALN.0b013e31828866b3. — View Citation

Nielsen RV, Fomsgaard JS, Nikolajsen L, Dahl JB, Mathiesen O. Intraoperative S-ketamine for the reduction of opioid consumption and pain one year after spine surgery: A randomized clinical trial of opioid-dependent patients. Eur J Pain. 2019 Mar;23(3):455-460. doi: 10.1002/ejp.1317. Epub 2018 Oct 14. — View Citation

Nielsen RV, Fomsgaard JS, Siegel H, Martusevicius R, Nikolajsen L, Dahl JB, Mathiesen O. Intraoperative ketamine reduces immediate postoperative opioid consumption after spinal fusion surgery in chronic pain patients with opioid dependency: a randomized, blinded trial. Pain. 2017 Mar;158(3):463-470. doi: 10.1097/j.pain.0000000000000782. — View Citation

Ocay DD, Li MMJ, Ingelmo P, Ouellet JA, Page MG, Ferland CE. Predicting Acute Postoperative Pain Trajectories and Long-Term Outcomes of Adolescents after Spinal Fusion Surgery. Pain Res Manag. 2020 Feb 24;2020:9874739. doi: 10.1155/2020/9874739. eCollection 2020. — View Citation

Park PJ, Makhni MC, Cerpa M, Lehman RA, Lenke LG. The role of perioperative ketamine in postoperative pain control following spinal surgery. J Spine Surg. 2020 Sep;6(3):591-597. doi: 10.21037/jss-19-306. — View Citation

Pfenninger E, Baier C, Claus S, Hege G. [Psychometric changes as well as analgesic action and cardiovascular adverse effects of ketamine racemate versus s-(+)-ketamine in subanesthetic doses]. Anaesthesist. 1994 Nov;43 Suppl 2:S68-75. German. — View Citation

Stein C. New concepts in opioid analgesia. Expert Opin Investig Drugs. 2018 Oct;27(10):765-775. doi: 10.1080/13543784.2018.1516204. Epub 2018 Sep 7. — View Citation

Walker CT, Gullotti DM, Prendergast V, Radosevich J, Grimm D, Cole TS, Godzik J, Patel AA, Whiting AC, Little A, Uribe JS, Kakarla UK, Turner JD. Implementation of a Standardized Multimodal Postoperative Analgesia Protocol Improves Pain Control, Reduces Opioid Consumption, and Shortens Length of Hospital Stay After Posterior Lumbar Spinal Fusion. Neurosurgery. 2020 Jul 1;87(1):130-136. doi: 10.1093/neuros/nyz312. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Sedation or agitation level	Sedation or agitation was assessed using the Richmond Agitation Sedation Scale (RASS), with scores ranging from -5 (unarousable) to +4 (combative) and 0 indicates alert and calm	Up to 5 days after surgery
Other	The incidence of postoperative nausea and vomiting	The incidence of postoperative nausea and vomiting	Up to 5 days after surgery
Other	The incidence of delirium	The incidence of delirium	Up to 5 days after surgery
Other	The incidence of other adverse events (dizziness, nightmares, hallucination and etc.)	Other adverse events include dizziness, nightmares, hallucination, and others	Up to 5 days after surgery
Other	The percentage of adverse events requiring therapeutic intervention	The percentage of adverse events requiring therapeutic intervention	Up to 5 days after surgery
Primary	The percentage of patients with moderate-to-severe pain in the first 48 hours after surgery.	Moderate-to-severe pain is defined as a numeric rating scale (NRS; an 11-point scale where 0=no pain and 10=the worst pain) pain score =4.	Up to 48 hours after surgery
Secondary	Opioid consumption during anesthesia	Opioid consumption in equivalent-dose of sufentanil	From induction to end of anesthesia
Secondary	Cumulative opioid consumption after surgery	Opioid consumption in equivalent-dose of sufentanil	From end of anesthesia to the 5th day after surgery
Secondary	NRS pain score at rest and with movement	Pain is assessed with a numeric rating scale (NRS; an 11-point scale where 0=no pain and 10=the worst pain)	Up to postoperative day 5
Secondary	The percentage of using rescue analgesics	The percentage of using rescue analgesics	Up to postoperative day 5
Secondary	Subjective sleep quality	Subjective sleep quality is assessed with NRS scale (0 indicates the best sleep and 10 indicates the worst sleep)	Up to postoperative day 5
Secondary	Time to first ambulation	Time to first ambulation	Up to 30 days after surgery
Secondary	Quality of recover after surgery	Quality of recover is assessed with the Quality of Recovery scale, a 15-item Q-15 questionnaire with score ranges from 0 to 150, with higher score indicating better recovery.	On the third day after surgery
Secondary	Length of hospital stay after surgery	Length of hospital stay after surgery	Up to 30 days after surgery
Secondary	The percentage of taking oral analgesics	The percentage of taking oral analgesics	On the 30th day after surgery
Secondary	The severity of anxiety and depression	The severity of anxiety and depression is assessed with the Hospital Anxiety and Depression Scale, a 14-item questionnaire with scores range from 0 to 21 for either anxiety or depression. Higher score indicates more severe symptom.	On the 30th day after surgery
Secondary	The incidence of postoperative complications and mortality	The incidence of postoperative complications and mortality	Up to 30 days after surgery