The protocol for this study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand (IRB approval no., 377/62), and complied with the Declaration of Helsinki guidelines. This study was registered prior to patient enrollment at clinicaltrials.in.th (Thai Clinical Trials Registry no., TCTR20190525001). It was a randomized, double-blind, placebo-control study. This manuscript adheres to the applicable CONSORT (Consolidated Standards of Reporting Trials) guidelines. Informed consent was obtained from 100 patients aged between 20 and 80 years old with the American Society of Anesthesiologists physical status I and III undergoing elective minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) under general anesthesia at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. The exclusion criteria were patients with a history of chronic pain, epilepsy, coronary artery disease, glaucoma, severe liver, and kidney dysfunction, use of monoamine oxidase inhibitors, allergic to medications, and impaired cognitive function. The operations were performed by two surgeons (W.S. and W.Y.) with the same surgical technique. Their levels of experience and skill in MISS were similar.

After obtaining informed consent, the patients were asked to complete the painDETECT Questionnaire (PDQ) to assess preoperative neuropathic pain [9]. This questionnaire classifies lower back and leg pain into three groups: neuropathic pain, unclear, and non-neuropathic pain. Patient education, including a rehabilitation program, was performed by a spine nurse and a physiotherapist perioperatively. The patients were randomized using computer-generated blocked randomization with randomly selected block sizes into two groups: a nefopam group and a control group. Sealed envelopes were prepared by a research assistant and were opened on the day of surgery by a nurse anesthetist, who prepared both nefopam and normal saline. The solutions of nefopam and normal saline were identical in volume and color. Both solutions were labeled as a study drug so that the anesthesiologist, the surgeon, and the pain assessor could not identify the solutions. In the operating room, the patients were not premedicated and received standard monitoring. All patients were given 2–3 mg/kg propofol and 0.15–0.2 mg/kg cisatracurium intravenously for the induction of anesthesia, followed by desflurane for the maintenance of anesthesia. After the induction of anesthesia, 10 mg of dexamethasone was given intravenously to all patients for antiemetic, anti-inflammatory, and analgesic purposes. Intravenous fentanyl (no more than 5 μg/kg) was allowed during intubation and throughout the surgery. The last dose of fentanyl was given 45 minutes prior to extubation, according to the judgment of the anesthesiologist. At the end of the surgery, patients in the nefopam group received 20 mg of intravenous nefopam diluted in 100 mL of normal saline intraoperatively [10]. The control group received an identical solution of normal saline in the same manner. Anesthesiologists, surgeons, pain assessors, and patients were blinded to the study groups. All patients received 40 mg of intravenous parecoxib (or 30 mg of ketorolac in sulfa allergic patients), 8 mg of ondansetron for antiemetic prophylaxis, and local infiltration of 10 mL of 0.25% bupivacaine immediately prior to skin closure. Normothermia and normovolemia were maintained throughout the perioperative period. After extubation, all patients were transferred to the postanesthetic care unit (PACU).

Patients were discharged from the PACU when a modified Aldrete score of ≥9 was achieved. At the ward, patients in the nefopam group received 80 mg of nefopam diluted in 500 mL of normal saline infused in 24 hours postoperatively [10], while the control group received an identical solution of normal saline. Both groups received 1,000 mg of paracetamol orally every 6 hours, 90 mg of etoricoxib once daily in the morning, and 75 mg of pregabalin at bedtime. Rescue pain was managed by patient-controlled analgesia with morphine (1 mg bolus, 6-minute lockout, no continuous infusion). A numerical rating scale of 0–10 was used to assess the severity of pain both at rest and upon movement at the PACU and on postoperative days 1, 2, and 3. Pain upon movement was defined as pain upon changing position, sitting, or walking. The PDQ was repeated on postoperative day 1. All patients were encouraged to have early mobilization and nutrition. Morphine consumption in the first 24 hours and during the postoperative period was recorded as the primary outcome. Secondary outcomes regarding ERAS were collected, including the time to PACU discharge, first sitting (defined as the interval from the end of surgery to sitting), first walking (defined as the interval from the end of surgery to walking), time to discontinuing Foley catheter use and drain removal, and length of hospital stay (defined as the time between the end of surgery until readiness for discharge from hospital). The adverse effects of pain medications, including nausea/vomiting, dizziness, drowsiness, tachycardia, and hypertension, were closely observed.

The sample size was calculated using 17 mg of morphine, as the average opioid consumption in patients undergoing spine surgery. The power analysis was performed using 9 mg of morphine as the minimum clinical difference and 90% power. It was hypothesized that adding nefopam perioperatively would reduce morphine intake to 8 mg. On this basis, a sample size of 46 patients per group was required; after accounting for a 10% dropout rate, a total of 100 patients were required. Categorical data were compared using chi-square test or Fisher’s exact test. Continuous data were compared between groups by unpaired t-test or Mann-Whitney test using Stata ver. 14.0 (Stata Corp., College Station, TX, USA). A p-value of <0.05 was considered to indicate a statistically significant difference.