Abstract
Background:
Pain-free and relief are one of the anesthesiologist’s most important concerns during the operation. General aim is always to effectively control pain but while simultaneously reducing opioid requirements to reduce opioid related side effects and mortality. Patients undergoing orthopedic operations tend to have high pain scores and analgesic requirements.
Objective:
In this study, we aim to investigate the effect of adding nefopam on reducing the postoperative pain scores and the need for opioids.
Methods:
This double-blind placebo-controlled prospective study aims to determine the effectiveness of nefopam in relieving the pain resulting from the operation in addition to the pain resulting from tourniquet. The unlabeled drug solution was administered one at the beginning of surgery. A 10 mL solution containing nefopam 20 mg or placebo diluted with normal saline was infused over 20 min. 11-point visual analogue scale was utilized to assess the pain score.
Results:
Forty-nine participants enrolled in the study, 24 received nefopam. The mean age was 40.45 years. Participants received nefopam achieved better postoperative surgical site pain score, less intraoperative and postoperative opioids use. Nefopam utilization was the single independent factor affecting the postoperative pain score.
Conclusions:
Compared with placebo, opioid requirement was decreased, the pain resulting from operation and tourniquet pain were decreased.
Keywords: opioid, nefopam, tourniquet, orthopedic
1. BACKGROUND
Pain relief is one of the most important concerns of anesthesiologists during the operation. Pain control postoperatively contributed greatly to the patient’s recovery. Opioids are considered a mainstay in treatment of postoperative pain, although opioids are markedly effective but also have many serious side effects (1-3). Therefore, it is necessary to find alternatives that are equally effective but with fewer and less serious side effects. Postoperative pain is not always due to the operation alone. It may have other causes, such as tourniquet insertion in orthopedic operations. Peripheral nerve blocks improve pain control and reduce opioid requirements (4). Although peripheral nerve block reduces pain significantly, the majority of patients prefer to use oral or intravenous medications because of the risks that may arise from it. Peripheral nerve blocks’ side effects include nerve injury, hematoma formation, vascular injury, and systemic absorption with subsequent toxicity. Furthermore, the peripheral nerve blocks may result in complications related to the specific site such as femoral muscles weakness in patients receiving femoral nerve block, and pleural injury in patients with interscalene block (4). Therefore, safer alternatives must be found.
During the 1960s, nefopam was developed from a non-sedative benzoxazocine, known as fenazocine. Nefopam is a centrally acting, non-opioid, non-steroidal analgesic medication with poorly understood mechanisms of analgesic action. Two mechanisms were postulated regarding the mechanism of action of nefopam, first it may act on the modulation of the descending pain through inhibition of triple neurotransmitter reuptake. Second, nefopam may have the ability to inhibit calcium influx with subsequent inhibition of long-term potentiation mediated by N-methyl-D-aspartate (NMDA) (1). Therefore, nefopam has been utilized mainly for neuropathic pain, and a treatment for postoperative shivering and hiccups (1, 4-6). We believe that nefopam could be a viable, safe and cost-effective choice to reduce pain scores resulting from orthopedic surgeries in addition to pain resulting from tourniquet insertion and reduce opioid requirements simultaneously with minimal side effects.
2. OBJECTIVE
In this study, we aim to investigate the effect of adding nefopam on reducing the postoperative pain scores and the need for opioids.
3. MATERIAL AND METHODS
Study design and participants
This study was a prospective, double-blind, case-control study conducted at the King Abdullah University Hospital in Jordan during the period of June 2023 to December 2023. The study protocol was approved by the Institutional Review Board of King Abdullah University Hospital and registered at the Clinical Research Information Service. Written informed consent was obtained from all participants before enrollment.
Eligible participants for this study included patients undergoing orthopedic surgery which involved usage of tourniquet under general anesthesia. Only patients aged 15–60 were included in the study. The exclusion criteria were as follows: patients with any contraindication to nefopam, surgery with tourniquet time more than 180 min, patients on opioid medications, patients with preexisting chronic pain syndromes, patients refuse to participate in the study and patients with psychiatric diseases. Moreover, patients who underwent operations under neuro-axial anesthesia were excluded from the study. Furthermore, operations which required different anesthetic plans or protocols (such as children, geriatric patients, operations requiring prone position, patients with GERD, morbid obesity, hiatal hernia, gastroparesis) were excluded. All participants were randomly divided into two groups (control and nefopam) in a 1:1 ratio using computer-generated randomization. A pharmacist who was not involved in this study handled normal saline or nefopam to the anesthesiologist according to the assigned group with the same drug labeling to ensure double blindness.
Intervention and anesthetic protocol
Standard monitoring including electrocardiography, non-invasive blood pressure monitor, pulse oximetry, capnography, and neuromuscular monitoring, was applied to the patients throughout the procedure. Induction was performed using propofol 2mg/kg fentanyl 2 μg/kg and atracurium 0.5mg /kg. Inhalational anesthesia using isoflurane 1- minimum alveolar concentration (MAC) with atracurium was performed to maintain general anesthesia. Mechanical ventilation was controlled to maintain the end-tidal carbon dioxide partial pressure at 35–45 mmHg with an inhaled oxygen fraction of 40%-50%. Neostigmine 2.5 mg with atropine 1mg was used to reverse muscle relaxation at the end of surgery.
The unlabeled interventional drug solution was administered one at the beginning of surgery. A 10 mL solution containing nefopam 20 mg or placebo diluted with normal saline was infused over 20 min. At the end of surgery, all patients were given morphine 0.1 mg/kg or tramadol 1mg/kg for postoperative pain control. Morphine (5 mg) was provided as a rescue analgesic upon the patient’s request when the postoperative pain score exceeded 3.
Clinical assessments and outcomes
The primary outcome was to compare the severity of pain at the site of surgery and at the site of tourniquet insertion by the use of an 11-point visual analogue scale (VAS) ranging from 0 (no discomfort) to 10 points (most extreme discomfort).
The secondary outcomes were the amount of opioids used intraoperatively and immediately postoperatively by calculating oral morphine equivalent and the sedation score using postoperative Richmond Agitation-Sedation Scores (RASS).
Statistical Analysis
The collected data was entered into a spreadsheet and analyzed using the IBM SPSS statistical package for Windows v.29 (Armonk, New York, USA). Nominal variables were expressed as the frequency (percentage) and continuous variables as the mean ± standard error of the mean (SEM). Data normality was tested using the Kolmogorov-Smirnov test. The statistical significance between the study groups was determined by using the Chi-square test for categorical variables and the student’s t-test for continuous variables. A statistically significant result was considered if p ≤ 0.05. Power testing was performed based on post operative pain scores and intra and post operative opioid requirements, and the sample size of 23 was required based on a power of 80%, P value of 0.05 and accounting for 10% dropouts. Therefore, 49 participants were enrolled: 24 for the nefopam group and 25 for the placebo group.
4. RESULTS
Participant characteristics and demographics
Forty-nine participants were enrolled in the study. Twenty-six participants (53.1%) were males. The mean age of the participants was 40.45 years, the mean weight was 78.7 kg, and almost all participants (except two) had American Society of Anesthesiologists (ASA) score of 1 or 2.
Regarding the operative details, the most commonly encountered operations were knee operations, either arthroscopic operations or open knee operations. The mean tourniquet time was 77.78 minutes. In addition, the intraoperative opioids dose measured in oral morphine equivalent dose was 59.57 mg/day. Nefopam was utilized in 24 participants (49%), while placebo saline was given in 25 (51%) participants.
The postoperative outcome was measured in multiple approaches. The postoperative opioids measured in oral morphine equivalent dose was 6.3 mg/day. Moreover, the mean postoperative tourniquet site pain score measured by VAS scoring system was 0.53. Furthermore, the mean postoperative surgical site pain score measured by VAS scoring system was 4.2. The postoperative sedation score was 0. Table 1 summarizes the general characteristics of the participants.
Table 1. General demographical and clinical characteristics. Abbreviations: SEM: standard error; VAS: visual analogue scale.
| Variables | Number* | Percentage (%) |
|---|---|---|
| Mean ± SEM | ||
| Sex | ||
| Male | 26 | 53.1 |
| Female | 23 | 46.9 |
| Age (years) | 40.45 ± 2.3 | |
| Patients weight (Kg) | 78.67 ± 1.7 | |
| Type of operation | ||
| Arthroscopic knee operation | 16 | 32.7 |
| Open knee operation | 7 | 14.3 |
| Trauma operations | 12 | 24.5 |
| Small joints operations | 11 | 22.4 |
| Tumor operations | 3 | 6.1 |
| American society of anesthesia score | ||
| One | 21 | 42.8 |
| Two | 26 | 53.1 |
| Three | 2 | 4.1 |
| Intraoperative parameters | ||
| Torniquet time (minutes) | 77.78 ± 4.5 | |
| Intraoperative opioids use (oral morphine equivalent, mg/day) | 59.57 ± 1.8 | |
| Postoperative outcome scores | ||
| Postoperative opioids use (oral morphine equivalent, mg/day) | 6.31 ± 1.1 | |
| Postoperative sedation score (RASS) | 0.0 | |
| Postoperative torniquet pain score (VAS) | 0.53 ± 0.3 | |
| Postoperative surgical site pain score (VAS) | 4.20 ± 0.5 | |
| Type of analgesia | ||
| Nefopam | 24 | 51.0 |
| Control placebo | 25 | 49.0 |
Nefopam versus placebo groups
There was no difference between both groups in terms of sex, age, and body weight. In addition, type of operations, ASA assessment score, and torniquet time were similar between both groups.
Participants received nefopam significantly required less intraoperative and postoperative opioids than participants received placebo. Moreover, participants received nefopam achieved significantly better postoperative surgical site pain score measured by VAS score. Table 2 summarizes the differences between the nefopam and placebo groups.
Table 2. Nefopam versus placebo. Abbreviations: SEM: standard error; VAS: visual analogue scale.
| Variables | Number (percentage) or mean ± SEM | ||
|---|---|---|---|
| Nefopam (n = 24) |
Placebo (n = 25) |
P-value | |
| Sex | |||
| Male | 11 (45.8) | 15 (60.0) | NS |
| Female | 13 (54.2) | 10 (40.0) | |
| Age (years) | 43.3 ± 3.5 | 37.7 ± 2.9 | NS |
| Patients weight (Kg) | 75.8 ± 1.9 | 81.4 ± 2.9 | NS |
| Type of operation | |||
| Arthroscopic knee operation | 6 (25.0) | 10 (40.0) | NS |
| Open knee operation | 3 (12.5) | 4 (16.0) | |
| Trauma operations | 6 (25.0) | 6 (24.0) | |
| Small joints operations | 8 (33.3) | 3 (12.0) | |
| Tumor operations | 1 (4.2) | 2 (66.7) | |
| American society of anesthesia score | |||
| One | 10 (41.6) | 11 (44.0) | NS |
| Two | 13 (54.2) | 13 (52.0) | |
| Three | 1 (4.2) | 1 (4.0) | |
| Intraoperative parameters | |||
| Torniquet time (minutes) | 75.1 ± 5.4 | 80.4 ± 5.6 | NS |
| Intraoperative opioids use (oral morphine equivalent, mg/day) | 54.0 ± 2.1 | 64.9 ± 2.0 | 0.001 |
| Postoperative outcome scores | |||
| Postoperative opioids use (oral morphine equivalent, mg/day) | 0.6 ± 0.4 | 11.8 ± 1.4 | 0.0001 |
| Postoperative sedation score (RASS) | 0.0 | 0.0 | - |
| Postoperative torniquet pain score (VAS) | 0.04 ± 0.002 | 1.0 ± 0.5 | NS |
| Postoperative surgical site pain score (VAS) | 1.6 ± 0.3 | 6.7 ± 0.6 | 0.001 |
Factors affecting the postoperative surgical site pain score
The sex, age, and body weight of the participants did not contribute to the postoperative surgical site pain score. Furthermore, torniquet time, ASA score, and type of operation were not involved with the postoperative pain score. It was revealed that postoperative surgical site pain score was related to the intra- and postoperative opioids use. Nefopam was associated significantly with less postoperative surgical site pain score. On multiple regression analysis, the use of nefopam was the single independent factor affecting the postoperative surgical site pain score in this study. Table 3 summarizes the factors affecting the postoperative surgical site pain score.
Table 3. Factors affecting the postoperative surgical site pain score. Abbreviations: SEM: standard error; VAS: visual analogue scale.
| Variables | Mean ± SEM* or B Regression Coefficient ± SEM ** | |
|---|---|---|
| Postoperative surgical site pain score (VAS score) | P-value | |
| Sex | ||
| Male | 4.04 ± 0.7 | NS |
| Female | 4.39 ± 0.7 | |
| Age (years) | -0.021 ± 0.032 | NS |
| Patients weight (Kg) | 0.073 ± 0.04 | NS |
| Type of operation | ||
| Arthroscopic knee operation | 5.38 ± 0.9 | |
| Open knee operation | 5.43 ± 1.1 | |
| Trauma operations | 3.25 ± 1.2 | NS |
| Small joints operations | 2.45 ± 0.6 | |
| Tumor operations | 5.33 ± 0.4 | |
| American society of anesthesia score | ||
| One | 3.95 ± 0.8 | NS |
| Two | 4.38 ± 0.7 | |
| Three | 4.50 ± 1.3 | |
| Nefopam versus placebo | ||
| Nefopam | 1.6 ± 0.3 | 0.0001 |
| Placebo | 6.7 ± 0.6 | |
| Intraoperative parameters | ||
| Torniquet time (minutes) | 0.025 ± 0.015 | NS |
| Intraoperative opioids use (oral morphine equivalent, mg/day) | 0.12 ± 0.03 | 0.002 |
| Postoperative outcome scores | ||
| Postoperative opioids use (oral morphine equivalent, mg/day) | 0.40 ± 0.03 | 0.0001 |
| Postoperative torniquet pain score (VAS) | 0.79 ± 0.04 | 0.004 |
5. DISCUSSION
To the best of our knowledge, this is the first study conducted in Jordan to investigate the effect of the use of nefopam; a non-opioid, non-steroid analgesic; in the management of intraoperative and postoperative pain responses. It was revealed that the use of nefopam was associated with better postoperative surgical site pain score, and with less intraoperative and postoperative utilization of opioids.
A study conducted by Evans et al showed that nefopam; compared with placebo; had a less cumulative 24 hours morphine consumption. Pain intensity at 24 hours was also decreased: on a 100 mm VAS score (6). On the other hand, they reported an increased risk of tachycardia and sweating. They concluded that nefopam had similar analgesic potency to non-steroidal anti-inflammatory drugs. However, dose adjustment and side effects profile need more investigations (6).
The aim of the study conducted by Beloeil et al was to characterize the nature of analgesic interaction between nefopam and morphine administered intravenously for postoperative pain after minor surgery (7). Their study revealed that the combination of morphine and nefopam was not superior to the administration of each medication alone after minor procedures. Moreover, the reported side effects for nefopam, morphine, and the combination of nefopam and morphine were similar (7). A double-blind, two-dose (15 and 30 mg of nefopam, and 50 and 100 mg of pethidine) comparison was performed with pethidine and nefopam in 100 subjects in a study conducted by Tigerstedt et al (8). They found that pethidine 100 mg was significantly more efficient in pain relief than nefopam 30 mg and 15 mg. Nefopam 30 mg and 15 mg had similar analgesic potency while nefopam 30 mg had longer duration of pain relief (8). Regarding side effects, pethidine and nefopam had similar incidences of nausea and vomiting. However, the incidence of sweating and tachycardia were more frequently documented after nefopam, whereas sedative side-effects were more common after pethidine (8). Zhao et al investigated the efficacy and safety of nefopam for pain relief during laparoscopic cholecystectomy (9). They showed that intravenous nefopam infusion resulted in significant reduction in postoperative pain scores and opioid requirements while decreasing opioid-related adverse effects. Additionally, no increased risk of venous thromboembolism was found (9).
Du Manoir et al conducted a similar randomized prospective study regarding the analgesic effect of nefopam after orthopedic surgery. They showed that in combination with morphine, nefopam gave significant morphine‐sparing with lower immediate postoperative pain scores without major side‐effects (10). This analgesic effect seems to be particularly notable for patients with intense preoperative pain (10). This was consistent with the study of Kapfer et al in where the ketamine 10 mg and nefopam 20 mg comparably potentiate opioid analgesia, each reducing the need for opioid by approximately 40% (11). Ketamine administration was associated with sedation, whereas nefopam produced tachycardia and sweating (11). However, none of the observed side effects was serious. The concomitant administration of nefopam with fentanyl for postoperative pain management may allow reduction of fentanyl dose, thereby reducing the risk of opioid-related adverse effects (12).
Nefopam and ketorolac were similarly effective in reducing postoperative pain after thyroid surgery. Postoperative nausea was less in patients who took nefopam 20 mg within 6 hours postoperatively, especially one hour. Nefopam was favored for pain management after thyroidectomy (13). In a study performed by Jin et al on operative patients with lumbar spinal stenosis regarding the analgesic contribution of nefopam for postoperative pain and lower extremities dysesthesia, they demonstrated a significant lower reported incidence of postoperative dysesthesia in the the nefopam group compared to the control group (a reduction of about 30%) with more satisfaction (14). However, there were no significant reduction in the surgical-site pain or the need for analgesics (14).
Regarding the acute and chronic postoperative pain in patients with colorectal cancer, Lim et al revealed that preoperatively administered nefopam reduced exertional pain compared to intraoperative administration although postoperative analgesic consumption was similar between two groups (15). The administration of nefopam after major anorectal surgery is beneficially evident in reducing postoperative opioid requirements (16). A study investigated the role of nefopam in cardiac surgery patients, the investigator randomly assigned patients scheduled for cardiac surgery between three groups (nefopam, fentanyl or nefopam + fentanyl). Pain was assessed at rest and during movement at 12, 24, 36, 48 and 72 hours after surgery using a VAS score. There were no significant differences between the three group in VAS score or number of rescue injections. Nausea was significantly more common in the fentanyl group compared with both other groups (17).
A study about post-operative intravenous patient-controlled analgesic efficacy of morphine with ketorolac versus nefopam after laparoscopic gynecologic surgery resulted in the conclusion that using nefopam alone had a non-inferior analgesic efficacy and produced a lower incidence of postoperative nausea and vomiting in comparison with a combination of morphine and ketorolac after laparoscopic gynecologic surgery (18). A study bout nefopam after total hip arthroplasty showed that nefopam added to the paracetamol–ketoprofen–ketamine combination provided no additional analgesia after total hip arthroplasty. However, nefopam can decrease or minimize some of the side effects of morphine despite the absence of a morphine-sparing effect (19). A study investigated the use of ramosetron as nausea and vomiting prophylactic in patients receiving the combination of nefopam with fentanyl versus patients receiving the combination of ketorolac and fentanyl, and they reported similar incidence of nausea and vomiting between both groups (20).
6. CONCLUSION
We preferred to assess orthopedic surgeries that involve torniquet because they are among the most painful surgeries and therefore require high doses of opioids. It was found the addition of nefopam may decrease the postoperative surgical site pain score and decrease the intraoperative and postoperative opioids use. Larger clinical trials are needed to justify this effect and to assess the possible uncommon side effects.
List of abbreviations: NMDA: N-methyl-D-aspartate; MAC: alveolar concentration; ASA: American Society of Anesthesiologists; RASS: Richmond Agitation-Sedation Scores; VAS: visual analogue scale
Ethical Approval and consent to participate:
The KAUH Institutional Review Board (IRB) and research committee approved the study’s ethical conduct. Under the approval number (52/163/2023). The study is carried out in compliance with the ethical guidelines in place at our institute, taking the Helsinki Declaration as an ethical guideline for research involving human subjects. This study was conducted with adherence to the CONSORT guidelines.
Consent for publication:
Written informed consent was obtained from all participants before enrollment.
Availability of data and materials:
Data are available upon request from the corresponding author.
Authors’ contribution:
All authors contributed significantly and in agreement with the content of the article. All authors were involved in project design, data collection, analysis, statistical analysis, data interpretation and writing the manuscript. All authors presented substantial contributions to the article and participated of correction and final approval of the version to be submitted.
Competing interests:
The authors declare no conflict of interest.
Funding:
This research was not received no funding
Clinical Trial Registration:
The trial was registered retrospectively in the https://clinicaltrials.gov registry with NCT06680609 on 02/11/2024
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Data Availability Statement
Data are available upon request from the corresponding author.