Esketamine combined with pregabalin on acute postoperative pain in patients undergoing resection of spinal neoplasms: study protocol for a randomized controlled trial

doi:10.21203/rs.3.rs-1120347/v1

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Esketamine combined with pregabalin on acute postoperative pain in patients undergoing resection of spinal neoplasms: study protocol for a randomized controlled trial

https://doi.org/10.21203/rs.3.rs-1120347/v1

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published 25 Feb, 2023

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Background

Perioperative pain management is one of the most challenging issues for patients with spinal neoplasms. Inadequate postoperative analgesia usually leads to severe postsurgical pain, which could cause patients to suffer from many other related complications. Meanwhile, there is no appropriate analgesic strategy for patients with spinal neoplasms.

Methods/design:

This is a protocol for a randomized double-blind controlled trial to evaluate the effect of esketamine combined with pregabalin on postsurgical pain in spinal surgery. Patients aged 18 to 65 years scheduled for spinal neoplasm resection will be randomly allocated into the combined and control groups in a 1:1 ratio. In the combined group, esketamine will be given during the 48-h postoperative period, and pregabalin will be taken from 2 hours before the surgery to 2 weeks postoperatively. The control group will receive normal saline and placebo capsules at the same time points. To ensure the accuracy and reliability of this trial, all the researchers and patients will be blinded until the completion of this study. The primary outcome will be the proportion of patients with acute moderate-to-severe postsurgical pain (Visual Analogue Scale, VAS ≥ 40) during the 48-hr postoperative period. The secondary outcomes will include the maximal VAS scores during the 2-h, 1-d, 2-d, 3-d postoperative periods and discharge, the incidence of acute postsurgical pain at each other time point, chronic postsurgical pain assessment, neuropathic pain assessment, and the incidence of drug-related adverse events and other postoperative complications, such as postoperative delirium and postoperative nausea and vomiting(PONV).

Discussion

The aim of this study is to evaluate the effect of esketamine combined with pregabalin on acute postsurgical pain in patients undergoing resection of spinal neoplasms. The safety of this perioperative pain management strategy will also be examined.

Trial registration:

ClinicalTrials.gov, NCT05096468. Registered on October 26, 2021.

Esketamine

Pregabalin

Acute postoperative pain

Spinal neoplasms

Pain is one of the most common complications for patients undergoing surgery. According to previous studies, almost 80% of patients undergoing spinal surgery suffer from acute postoperative pain^[1], and over 60% of these patients might have persistent postoperative pain^[2]. Poor perioperative pain management was an independent risk factor for persistent postoperative pain^[3] and could increase the risk by 3 times^[4]. Elderly patients with postoperative pain might have impaired cognitive function^[5], which increases the risk of senile dementia ^[6]. Severe postoperative pain could also influence the emotional and mental health of patients^{[7, 8]}, which could be associated with unfavorable prognoses for the patients. Moreover, inadequate acute postsurgical pain management could result in longer hospitalization, decreased satisfaction and higher hospital costs. Therefore, effective perioperative pain management, especially appropriate management of acute postoperative pain, is one of the most important links to help enhance the recovery of surgical patients.

One of the most challenging issues during the perioperative period is providing appropriate pain control measures to enhance the recovery of patients. Over the last decade, opioids have been the most commonly used drug in perioperative pain management strategies. However, administration of opioids could be compounded by aspects of misuse, overdose, and addiction. Furthermore, clinical adverse events such as nausea and vomiting and respiratory depression have limited the use of opioids. In 2016, the American Society of Anesthesiologists (ASA) and American Society of Regional Anesthesia and Pain Medicine (ASRAPM) jointly published the consensus guidelines of acute pain management. These guidelines pointed out that ketamine^[9] and pregabalin^[10] can be used for the treatment of postsurgical pain.

The mechanisms underlying postsurgical pain might be peripheral and central sensitization because of nerve injury and inflammatory responses at the operative site. Previously, researchers have suggested that central pain sensitization might be related to N-methyl-D-aspartate (NMDA) receptor activation^[11]. Ketamine, an NMDA receptor antagonist, reduces central pain sensitization by blocking the activity of NMDA receptors. A related meta-analysis found that intravenous ketamine could reduce VAS scores in the 24 ~ 48-h postoperative period and decrease opioid consumption^[12]. S-ketamine, one of the enantiomers of ketamine, is a more effective analgesic and has fewer side effects than ketamine. Regarding the effects of S-ketamine on acute postsurgical pain, a meta-analysis of 12 randomized controlled trials showed that intravenous S-ketamine could decrease the intensity of pain and opioid requirements only in the 24 h after surgery and may increase the incidence of psychotomimetic adverse events^[13]. Meanwhile, it was unfortunate that the evidence level was only moderate or even low. Due to the differences in the S-ketamine intervention protocols and the types of surgery, more high-quality studies are needed.

At the same time, gabapentinoids (gabapentin and pregabalin) have gained more attention by researchers for their significant effect on neuralgia. These compounds can inhibit the modulation of neuronal excitability by blocking α2–δ subunits of presynaptic, voltage-dependent calcium channels, which are upregulated in central sensitization processes^[11]. A meta-analysis of preoperative gabapentinoids for acute postoperative pain reported that gabapentinoids were associated with reduced pain scores and cumulative morphine consumption during the 48-h postoperative period^[1]. In the same year, another meta-analysis showed the effectiveness of preoperative pregabalin on acute postsurgical pain^[14]. In contrast, in 2020, a meta-analysis including 281 trials investigated the effect of perioperative gabapentinoids on postoperative acute pain and reported the noneffective analgesic effects of gabapentinoids in adult patients during the postoperative period^[15].

Thus, we designed a randomized controlled study to explore the analgesic effects of a combination of esketamine and pregabalin after resection of spinal neoplasms to investigate whether there is a synergistic effect on acute postoperative pain following the combined application of these two different analgesics. The fundamental aim of this study was to find an effective and safe analgesic treatment to help patients undergoing spinal surgery and provide a new perspective regarding perioperative pain management strategies.

Study design

This study will be a single-center, randomized, double-blind, controlled trial to evaluate the analgesic effects of esketamine in combination with pregabalin after resection of spinal neoplasms. It was approved by the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University, Beijing, China (KY-2021-081-02). This study (protocol version 1.4 / Date 2021.10.08) was registered on Clinicaltrials.gov on October 26, 2021 (NCT05096468). All participants or their legal representatives will provide written informed consent after screening and before randomization.

Study setting and recruitment procedure

The trial will be conducted in Beijing Tiantan Hospital from 30 November 2021 to 31 December 2022. Based on the electronic medical records of the hospital, potential participants will be individually screened after admission. Participants meeting the eligibility criteria will be visited by the research staff to sign informed consent forms and provide baseline information. The flow chart of study see figure 1.

Study population

Patients meeting with the following inclusion criteria and not meeting the exclusion criteria at the time of randomization will be considered for enrollment.

Inclusion Criteria:

Scheduled to undergo elective resection of spinal neoplasms.
Age between 18 and 65 years old.
ASA I-III.
Signed informed consent.

Exclusion Criteria:

Previous adverse reaction to ketamine, S-ketamine or pregabalin.
A diagnosed history of severe chronic pain.
Long-term medical history of analgesic treatment (gabapentin/opioids/ketamine).
Aphasia or inability to cooperate with the pain assessments.
Known severe insufficiency of vitals (such as heart failure/renal dysfunction/hepatic failure).
A diagnosed history of psychiatric disorder.
Treated with gabapentin/pregabalin in the last three months.
Drug use disorder.
Body mass index > 35 kg/m².
Pregnancy or lactation.

Randomization and blinding

Patients will be randomized 1 day before surgery using blocked, stratified randomization by independent research staff to 1 of 2 treatment groups (the combined group or the control group) after study enrollment. We will randomize the patients in a 1:1 ratio in blocks of four. The randomized allocation list will be generated by using a computer-generated randomization sequence in Microsoft Excel 2020. The randomization results will be maintained by independent researcher who will not participate in any other work of this study to guarantee allocation blinding. The presence of moderate or severe preoperative pain will be used as a basis for the stratification of patients (moderate or severe preoperative pain is defined by a VAS score equal to or more than 40 mm).

Allocation concealment will be achieved using study capsules and intravenous infusions with identical appearance for placebo and drugs. All of the trial drugs will be provided by a medicine company (Hengrui Induction, Jiangsu, China) with no other contribution to this trial. The appearance of all trial capsules (placebo capsules containing starch and pregabalin capsules) will be the same. Esketamine will be diluted to a concentration of 0.5 mg/ml with normal saline. Colorless 50 ml syringes containing clear esketamine or placebo (normal saline) solution will be prepared in a blinded manner by an independent research assistant. The randomization code will be marked on the syringes and the drug bottles of study capsules. All the researchers and patients will be blinded until the study is complete.

Intervention

This study is an interventional trial with two groups.

In the combined group, the patients will be given both esketamine and pregabalin during the perioperative period: The patients will receive 2 capsules of pregabalin (75 mg/capsule, 150 mg total) 1~2 h before the surgery and 1 capsule twice daily during the 7-d postoperative period (75 mg/capsule, BID; 150 mg total; POD 1~7), followed by dose reduction to 1 capsule once daily for 7 days (75 mg/capsule, QD; 75 mg total; POD 8~14). At the same time, patients will be administered a bolus dose of 0.5 mg/kg esketamine after the induction of anesthesia and then receive continuous intravenous infusion at 0.12 mg/kg·h (2 mg/kg·min) during the 48-h postoperative period.

In the control group, the patients will be given the same number of placebo capsules as the combined group at the same time points (two placebo capsules 1~2 h preoperatively and twice daily postoperatively for 7 days, followed by reduction to a single capsule once daily for 7 days), alongside a normal saline bolus after induction of anesthesia and intravenous saline infusion for the 48-h postoperative period.

Perioperative anesthesia management

Perioperative anesthesia management will be standardized. After entering the operating room, the patients will be given standard electrocardiography monitoring. Anesthesia will be induced with propofol, sufentanil and rocuronium/cisatracurium. Total intravenous anesthesia depends on target-controlled infusions and will be chosen to maintain anesthesia with propofol and sufentanil and keep the bispectral index between 40~60. Remifentanil will be prohibited in this study. All the participants will be given the usual postoperative analgesia therapy by postoperative patient-controlled intravenous analgesia (PCIA, 0.5 ml per bolus with a lockout period of 15 min, 100 ml total), which will include 100 µg sufentanil and 16 mg ondansetron during the 2-d postoperative period. If the patients are experiencing moderate or severe pain (VAS score ≥ 40 mm), rescue analgesia will be given, and the dose and name of the analgesic will be clearly recorded.

Outcomes

The primary outcome was the proportion of patients with acute moderate-to-severe postsurgical pain during the 48-h postoperative period (defined as a VAS score ≥ 40 mm). The schedule of enrollment, intervention, and assessments is presented in Figure 2.

Secondary outcomes include the following:

Acute pain assessment: the maximal VAS score within the 2-h, 1-d, 2-d and 3-d postoperative period and at discharge; the incidence of acute postsurgical pain at each other time point (defined as the VAS score≥ 40 mm).
Subacute or chronic pain assessment: the incidence of postsurgical pain was assessed by a number rating scale (NRS: 0~10) at the 1-month, 3-month, and 6-month postoperative time points (defined as an NRS score > 3).
Neuropathic pain assessment: the short-form McGill pain questionnaire-2 (SF-MPQ-2) scores at the 1-month, 3-month, and 6-month postoperative period.
Total opioid consumption within the 48-h period after surgery.
Effective or noneffective button presses for PCIA.
Quality of anesthesia emergence evaluated by a 15-item quality of recovery scale (QoR-15) at the 3-d postoperative time point and at discharge.
The incidence of psychotic side effects (such as manic symptoms and dissociative symptoms) determined using the 11-item Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS) and Clinician-Administered Dissociative States Scale (CADSS) within the first 3 days after surgery.
Adverse events including drug-related (palpitation, hypertension, dizziness, diplopia) and operation- or anesthesia-related complications; the incidence of PONV during the 3-d postoperative period; and the incidence of postsurgical delirium within the three-day postoperative period.
Other outcomes: perioperative depressive/anxious symptoms assessed by Patient Health Questionnaire 9 (PHQ-9), Hospital Anxiety and Depression Scale (HADS), and Generalized Anxiety Disorder scale (GAD-7) during hospitalization; hospitalization expenses.

Data management

All the clinical information will be recorded in the unified case report forms designed specifically for this project, other paper documents including informed consent forms and the protocol. An electronic database will be set up. The data will be entered twice by two different data operators soon after completion of this study. All this material will be taken care of by the primary investigator and stored carefully in a single secure office in Beijing Tiantan Hospital.

Statistical analysis

Continuous data will be described as the mean with standard deviation (SD) or median with inter quartile range (IQR) based on its distribution. The histogram and Kolmogorov–Smirnov tests will be used to evaluate the normality of the data distribution. Categorical variables will be summarized as counts and percentages. The primary outcome is categorical and will be analyzed by using the chi-square test or Fisher’s exact test. Regarding the secondary outcomes, based on the type of each variable, the difference between groups will be analyzed using t tests, Mann–Whitney U tests, and chi-square or Fisher’s exact tests as appropriate. Sensitivity analyses will be applied to determine the statistical nature of the missing data. A two-sided P value of 0.05 was considered statistically significant for the primary outcome. Because of the repeated measurement, the Holm–Bonferroni method will be used to adjust the P value for secondary outcomes. Statistical analysis will be implemented using SPSS version 23.0 software and Stata version 14.0.

Sample size calculation

According to a previous randomized controlled trial that investigated the effect of combined ketamine and pregabalin on persistent postoperative pain, the prevalence of moderate-to-severe acute postoperative pain at 24 h after surgery was 42% in the combined group and 78% in the control group^[16]. The incidence of acute moderate-to-severe postsurgical pain in the population undergoing spinal surgery was nearly 80%^[1]. Based on the above data and the current clinical situation, we estimate that the incidence of acute moderate-to-severe postsurgical pain will be 30% in the combined group and 60% in the control group, with a total 2-sided type I error rate of 0.05 and a 20% withdrawal rate. Ninety patients will have to be enrolled to achieve a statistical power of 80% (p values of 0.05).

Safety consideration

If any adverse events (AEs) take place and in the unlikely event that harm is experienced, there will be professional doctors from various fields to immediately help the patients. Based on the relationships between AEs or serious adverse events (SAEs) and the drugs being assessed in this study, the project management team will consider whether unblinding allocated interventions is required. All AEs will be followed up until resolution. All adverse events will be documented in the final written report of this study and will be reported to the Institutional Review Board by the principal investigator.

Patient and public involvement

Patients and the public were not involved in the trial design. Participants will have access to the findings of the study on request.

This proposed study will measure the efficacy and safety of esketamine combined with pregabalin on postsurgical pain in patients undergoing elective resection of spinal neoplasms. The participants will receive esketamine from the beginning of surgery until 48 h post operation, along with a total dose of 150 mg pregabalin for one week postoperatively (POD 1 ~ 7, including the operation day) followed by a reduced dose of 75 mg pregabalin for the next week (POD 8 ~ 14). Both acute and chronic postoperative pain will be assessed during the 6 months after surgery. Other complications and safety outcomes will also be observed.

The primary concern is the potential inadequate analgesia in the control group after the surgery. The PCIA device is not a regular part of the therapeutic regimen during the postoperative period in this study hospital. As a result, we designed a usual PCIA procedure for all the participants to ensure basic postoperative analgesic treatment. If the participants experience a moderate or severe level of pain, rescue analgesia will be administered. The secondary concern is in regard to active placebo for the preoperative pregabalin capsule. In 2017, Hah's team designed a randomized clinical trial to evaluate the effects of perioperative gabapentin on pain resolution in a mixed surgical population^[17]. The researchers considered the sedating effects of preoperative gabapentin, so they chose lorazepam as the preoperative active placebo. Sleepiness is one of the common side effects of this kind of drug. However, in our pilot study, we did not observe obvious sleepiness in the participants before the surgery after taking pregabalin, and we will administer an injection of midazolam as a standard step after the patients enter the operating room; therefore, our research team decided to use the starch capsule as the placebo capsule at all time points. Furthermore, we chose total intravenous anesthesia as the standard maintenance of anesthesia with propofol and sufentanil, and propofol injection depends on target-controlled infusion (TCI). Our anesthesia management protocols might be different from previous studies. However, total intravenous anesthesia dependent on TCI technology can be more convenient to calculate and analyze possible drug interactions after the completion of the study. Moreover, we did not previously find any adverse events during the pilot study that are of concern, such as intraoperative awareness or delayed recovery.

The choice of the dosages of these two trial drugs was deliberate. Based on a related meta-analysis^[3], intravenous ketamine does not increase complications related to the central nervous system (such as delirium and hallucinations). A meta-analysis^[18] on the effect of pregabalin on chronic pain suggested that doses as high as 300 ~ 600 mg pregabalin per day does not increase the incidence of severe adverse events. Moreover, the guidelines on pain management^[10] have suggested the following recommended dosages of these two drugs: a 0.5 mg/kg bolus of ketamine with a continuous intravenous infusion dose of 0.12 mg/kg·h (2 µg/kg·min) and a maximum continuous infusion dose that does not go over 10 µg/kg·min; a 150 ~ 300 mg preoperative dose of pregabalin and a postoperative dose of 150 ~ 300 mg per day. Based on the above information, these two trial drugs in our study will be used at lower dosages. The purpose of this dose design is to keep the participants as safe as possible while releasing postsurgical pain.

In conclusion, this study is a randomized controlled trial to explore a better method to treat postsurgical pain. The expected outcome is that perioperative esketamine combined with pregabalin can release postsurgical pain safely and effectively, and the results of this study can expand the understanding of perioperative pain management.

Trial Status

This study was approved by the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University, Beijing, China on November 20, 2021 (KY-2021-081-02). It was registered on Clinicaltrials.gov on October 26, 2021 (NCT05096468). The first participant will be recruited on November 30, 2021. The conclusions of this study will be published in peer-reviewed journals.

VAS

Visual Analogue Scale

PONV

Postoperative nausea and vomiting

ASA

American Society of Anesthesiologists

ASRAPM

American Society of Regional Anesthesia and Pain Medicine

NMDA

N-methyl-D-aspartate

POD

Postoperative day

NRS

Number rating scale

SF-MPQ-2

the short-form McGill pain questionnaire-2

PCIA

Postoperative patient-controlled intravenous analgesia

QoR-15

15-item quality of recovery scale

YMRS

Young Mania Rating Scale

BPRS

Brief Psychiatric Rating Scale

CADSS

Clinician-Administered Dissociative States Scale

PHQ-9

Patient Health Questionnaire 9

GAD-7

Generalized Anxiety Disorder scale 7

Standard Deviation

IQR

Inter Quartile Range

AEs

adverse events

SAEs

serious adverse events

TCI

target-controlled infusion

Acknowledgments: Not applicable.

Authors Contributions: RH: Conceptualization and design. WS, JW, JW, and JF: Investigation. YZ: Statistical analyses. YW: Supervision. WS and JW: Writing - Original draft of the manuscript. YW and RH: Writing - Review & Editing. RH: funding acquisition and project administration.

Funding: This study was supported by funding from Beijing Clinical Medicine Development of Special Funding Support (DFL20180502).

Availability of data and materials: The datasets will be available from the primary investigator (Ruquan Han, Email: [email protected]) upon reasonable request after the publication of the study results.

Ethics approval and consent to participate: This study was approved by the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University, Beijing, China (KY-2021-081-02). All participants will provide written informed consent before enrollment.

Consent for publication: Written informed consent for publication will be obtained from all participants.

Competing interests: The authors declare that they have no competing interests.

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Download PDF

Journal Publication

published 25 Feb, 2023

Read the published version in Trials →

Editorial decision: Major revision
15 Nov, 2022
Reviewers agreed at journal
07 Jul, 2022
Reviewers invited by journal
07 Jul, 2022
Editor assigned by journal
06 Jul, 2022
First submitted to journal
01 May, 2022

You are reading this latest preprint version

Esketamine combined with pregabalin on acute postoperative pain in patients undergoing resection of spinal neoplasms: study protocol for a randomized controlled trial

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Background

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