Analgesic efficacy of intravenous nefopam after spine surgery: a randomized, double-blind, placebo-controlled trial

Ethical issues

The study was a randomized, double-blinded, placebo-controlled trial. It was approved by the Institutional Review Board of Prasat Neurological Institute (IRBPNI) [Bangkok] and informed consent was obtained from all patients. The patients enrolled in the study comprised all patients undergoing spine surgery at Prasat Neurological Institute, February 2018 to March 2019.

Recruitment and allocation

Inclusion criteria were patient with age >18 years, who were undergoing lumbosacral spine surgery under general anesthesia; elective case; not more than three-level spinal surgery; ASA physical status I-III; expected length of operation of 4–6 hours; and no history of nefopam or morphine allergy. Exclusion criteria were: patients with ischemic heart disease or arrhythmia; epilepsy; liver disease; creatinine clearance <30 ml/min; receiving nefopam within 24 hours or five elimination half-lives of nefopam; received strong opioids for more than 2 weeks or received monoamine oxidase inhibitor within 2 weeks before surgery; and who are unable to use a patient-controlled analgesia (PCA) device.

Patients were allocated into four treatment groups by the computer-generated random sequence and their allocation placed in a sealed envelope. A total of 96 patients were randomized into 4 treatment groups: 24 in placebo-placebo, 24 in nefopam-placebo, 24 in placebo-nefopam and 24 in nefopam-nefopam groups. The envelopes were opened only after the enrolled participants by the nurse anesthetists who was not involved in the study. All participants and researchers were blinded to the group allocation. At enrolment, patients were explained on a 0 to 10 numerical rating scale (NRS): 0 corresponds to no pain and 10 to the worst imaginable pain for postoperative pain assessment, and how to use the patient-controlled analgesia device on a day before surgery. Patients received premedication with 7.5 mg of midazolam within 30 – 60 minutes before anesthesia. No patients received NSAIDs, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressant, gabapentinoid or opioids on the morning of surgery.

Intervention

When the patients arrived at the operating theatre, each group of patients received two treatment timings: period A, 30 minutes before surgical incision; or period B, 30 minutes before the end of surgery or both timings compared with matching placebo. Nurse anesthetists not involved in the research project opened sealed envelopes containing the allocation to group in the order of patients. Study medications were in identical appearance bottles; 100 ml of transparent, colorless solution, containing either 30 mg of nefopam (Acupan® BIOCODEX) or placebo, which was prepared in sealed envelopes by the nurse anesthetist who was not involved in the study. Study medications were given intravenously within 20 minutes each time. The treatment team and the data collector will not know which group of participants is in the study group. The patients were withdrawn and labels were opened if they exhibited a heart rate >150/min, arrhythmia, development of extreme unexpected events (such as acute ischemic heart disease, pulmonary embolism), and if the patient stopped using the PCA device before 24 hours after surgery.

In the operating theatre, Patients were monitored routinely with an electrocardiogram, noninvasive blood pressure, and pulse oximetry. Additionally, a bispectral index (BIS) monitor was utilized to assess the depth of anesthesia. Pre-oxygenation with high-flow oxygen through a facemask was given for 3 to 5 minutes. Anesthesia was then induced with intravenous propofol (1.5–2 mg/kg), and intravenous cisatracurium (0.15–0.2 mg/kg) was administered to facilitate the endotracheal intubation. Anesthesia was maintained at 1 MAC of desflurane with oxygen and nitrous oxide. Anesthesiologists provided cisatracurium and morphine by adjusting the depth of anesthesia to the Bispectral index (BIS) of 40–60. All patients received local wound infiltration with 20 ml of 0.5% bupivacaine at the end of the operation. At the recovery room, the patients were asked pain scores every 15 minutes using a numerical rating scale. If the pain score is greater than or equal to 4 points, the patients were injected with 2 mg of morphine every 10 minutes until the patients reported pain scores of less than 4. Then, the patients started to use the PCA device in the post-operative period. The PCA devices used in this study were IVAC® PCAM® Syringe Pumps (Alaris, United Kingdom). The protocol PCA setting of morphine 1 mg/ml; no basal rate, bolus dose of 1 mg, lockout interval of 5 minutes, 4-hour limit of 40 mg. If the patients required more than 40 mg of morphine within 4 hours, the cause of pain was reevaluated and neuropathic pain was ruled out by using the Thai-language Neuropathic Pain Diagnostic Questionnaire (Thai DN4)²⁴. Any other analgesics were not permitted during the study period.

Outcomes

Demographic data, American Society of Anesthesiologist (ASA) Physical status, comorbid disease, average pain score in a 24-hour period before surgery, operation, anesthetic time, duration of surgery, vital signs every 2.5 minutes during nefopam administration, intraoperative and 24 hours postoperative morphine consumption, first time to rescue morphine, pain score during postoperative 24 hours and side effects were recorded.

The primary outcome of the study was to determine the analgesic efficacy. The primary efficacy was defined as the cumulative morphine dose received 24 hours postoperatively by PCA during each time of nefopam administration. Secondary outcome comparisons were 24-hour postoperative pain score, and incidence of side effects such as tachycardia, sedation, sweating and nausea/vomiting. Sedation was defined as a Pasero Opioid-induced Sedation Scale (POSS) score that was greater than or equal to 3²⁵. Clinically important postoperative nausea and vomiting (PONV) were defined as PONV intensity scale of ≥75²⁶.

Sample size calculation and statistical analysis

Previous studies have shown that when nefopam was given before the end of surgery, postoperatively 24-hour morphine consumption was 21.2 (15.3) mg. Morphine dose received 24 hours postoperatively in control group was 27.3 (19.2) mg¹⁷. The sample size was determined from total postoperatively 24-hour morphine consumption. Neither the mean of 24-hour morphine consumption in the group receiving nefopam before surgical incision nor the group receiving nefopam before surgical incision plus at the end of surgery compared with placebo was reported in these previous studies. Therefore, this sample size estimated the level of reduction in 24-hour morphine consumption in both groups. The sample size gives the trial a power of 80%, sets a two-tailed α at 0.05 in means characterized by a variance of means of 11.792, assuming that the common standard deviation is 9.12. The calculation resulted in 21 patients per group. To compensate for 10% attrition rate, we included 24 patients per group. The total sample size is 96 patients. Criteria for interim analysis and early termination of the study were as follows: 1) a heart rate of more than 150 beats per minute; 2) arrhythmias; and 3) patients developed extreme unexpected events such as acute ischemic heart disease, pulmonary embolism. Analysis of the analgesic efficacy measures was performed by the Kruskal-Wallis test. Descriptive statistical analyses were performed and expressed in median (IQR) for continuous variables and number (percent) for categorical variables as appropriate. The software program SPSS version 16 was used. Safety data analysis was analyzed by a statistical chi-square test. Statistically significance was considered if p-value < 0.05

Patient eligibility and background

A total of 112 patients were eligible; 12 patients did not meet inclusion criteria and 4 patients declined to participate. As such, 96 patients were randomly assigned to the four groups: 21 in placebo-placebo, 22 in nefopam-placebo, 22 in placebo-nefopam and 21 in nefopam-nefopam groups. There were three patients in the placebo-placebo group, two patients in nefopam-placebo group, two patients in placebo-nefopam group, and three patients in nefopam-nefopam group were excluded from the analysis. Because 10 patients were unable to use patient-controlled analgesia device postoperatively. The total number of patients assessed was 86 (Figure 1).

Figure 1. Study flow diagram.

Demographic characteristics of patients, preoperative pain score, number of surgical levels, surgery time and anesthetic time are shown in Table 1. The four groups are comparable in age, sex, body mass index, ASA Classification, type of operation, number of levels of spinal surgery, surgery time and anesthetic time. The demographic characteristics and baseline clinical characteristics of patients are similar.

The postoperative 24-hour morphine consumption (median [IQR]) for the placebo-placebo, nefopam-placebo, placebo-nefopam and nefopam-nefopam groups were not different, at 18 [13.5–29], 20 [11–28.3], 17 [11.5–28.5], 13 [8.5–18.5] mg, respectively (p = 0.223). Time to first dose of morphine were not different, at 30 [7.5–85], 16.5 [10–41], 30 [12.5–67.5], 30 [12.5–91.5] min, respectively (p = 0.710). Pain score and total intraoperative morphine for four treatment groups were not different (Table 2). All raw data are available from Figshare²⁷.

The incidence of sedation, nausea and vomiting, sweating and intraoperative arrhythmia did not differ significantly between the groups (Table 3). No patients in four groups developed tachycardia. There was no statistically significant difference in heart rate between the four groups (Figure 2). No patients discontinued the treatment due to adverse events.

Figure 2. Heart rate in each group (median) before surgical incision (left) and at the end of surgery (right).

Group 1: Placebo - Placebo; Group 2: Nefopam - Placebo; Group 3: Placebo - Nefopam; Group 4: Nefopam - Nefopam. There was no statistically significant difference in heart rate between groups.

Underlying data

Figshare: Raw Data: Analgesic Efficacy of Intravenous Nefopam after Spine Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial. https://doi.org/10.6084/m9.figshare.12029256.²⁷

This project contains the individual-level data for each participant.

Figshare: Information of abbreviation data set Title: Analgesic Efficacy of Intravenous Nefopam after Spine Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial Untitled Item. https://doi.org/10.6084/m9.figshare.12090753.v1³².

This project contains definitions used in the above dataset²⁷.

Reporting guidelines

Figshare: CONSORT checklist for ‘Analgesic efficacy of intravenous nefopam after spine surgery: a randomized, double-blind, placebo-controlled trial’. https://doi.org/10.6084/m9.figshare.12033693.v4³³.

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).