The effect of the addition of nefopam to intraoperative ketoprofen and acetaminophen on postoperative morphine requirements after laparoscopic cholecystectomy: a randomized controlled trial.

BACKGROUND: Few studies investigated the use of nefopam for pain control after laparoscopic cholecystectomy in the context of multimodal analgesia. The aim of this study was to evaluate the effect of adding nefopam to ketoprofen and acetaminophen given before the end of laparoscopic cholecystectomy. METHODS: In this double-blind, controlled study, 90 patients undergoing laparoscopic cholecystectomy during sevoflurane-dexmedetomidine-based anesthesia were randomized to receive either ketoprofen and acetaminophen or nefopam, ketoprofen, and acetaminophen for postoperative pain control before the end of surgery. The primary outcome was total morphine consumption in the Postanesthesia Care Unit (PACU). RESULTS: PACU morphine consumption was significantly lower in the experimental group compared to the control group (0.9±1.8 mg vs. 2.3±2.4 mg, respectively; P=0.004, Cohen's d=0.63). In the experimental group, a smaller proportion of patients received morphine in PACU (24% vs. 60%, respectively; P=0.001), morphine during the first 24 hours after surgery (47% vs. 77%, respectively; P=0.004), and acetaminophen on the floor (76% vs. 93%, respectively; P=0.039) compared with the control group. The average pain score during PACU stay was also significantly lower in the experimental group (1.7±2.0 vs. 2.7±2.0, P=0.01). Median time to first morphine requirement (44.0 minutes, 95% CI [(31.96 to, 52.21)] was shorter in the control group than in the experimental group (higher than the 90 minutes-last time point taken in PACU). CONCLUSIONS: Adding nefopam to ketoprofen and acetaminophen before the end of laparoscopic cholecystectomy provides a reduction in morphine consumption with superior analgesia in PACU.

Antinociceptive effects of nefopam activating descending serotonergic modulation via 5-HT2 receptors in the nucleus raphe magnus.

BACKGROUND: Nefopam is a centrally acting antinociceptive drug; however, the underlying mechanisms are not fully understood. This study investigated the supraspinal mechanisms of nefopam. METHODS: The effects of intraperitoneally administered nefopam were assessed in rats using the formalin test, and the mechanisms were investigated by intrathecal or intra-nucleus raphe magnus (NRM) pre-treatment with the serotonin (5-HT) receptor antagonist or 5-HT2 receptor antagonist. The change in extracellular 5-HT levels was measured by spinal cord microdialysis. RESULTS: Intraperitoneally administered nefopam showed antinociceptive effects in the rat formalin test, which were reversed by intrathecal pre-treatment with 5-HT receptor antagonist dihydroergocristine. Microdialysis study revealed that systemic nefopam significantly increased 5-HT level in the spinal dorsal horn. Pretreatment of cinanserin, a 5-HT2 receptor antagonist, into the NRM blocked the antinociceptive effects of intraperitoneally delivered nefopam. Direct injection of nefopam into the NRM mimicked the effects of systemic nefopam, and this effect was reversed by intra-NRM cinanserin pre-treatment. The increase in spinal level of 5-HT by systemic nefopam was attenuated by intra-NRM cinanserin pre-treatment. CONCLUSION: The antinociceptive effects of systemically administered nefopam are mediated by 5-HT2 receptors in the NRM, which recruit the descending serotonergic fibres to increase the release of 5-HT into the spinal dorsal horn. SIGNIFICANCE: This study revealed supraspinal mechanisms of nefopam-produced analgesia mediated by 5-HT2 receptors in the NRM recruiting the descending serotonergic fibres to increase the release of 5-HT into the spinal dorsal horn. These observations support a potential role for nefopam in multimodal analgesia based on its distinct mechanisms of action that are not shared by the other analgesics.

Changes in hospital consumption of opioid and non-opioid analgesics after colorectal endometriosis surgery.

The aim of this study was to analyze postoperative consumption of analgesics during hospitalization following colorectal surgery for endometriosis. We conducted a retrospective study at Tenon University Hospital, Paris, France from February 2019 to December 2021. One hundred sixty-two patients underwent colorectal surgery: eighty-nine (55%) by robotic and seventy-three (45%) by conventional laparoscopy. The type of procedure had an impact on acetaminophen and nefopam consumed per day: consumption for colorectal shaving, discoid resection, and segmental resection was, respectively, 2(0.5), 2.1(0.6), 2.4(0.6) g/day (p = 10-3), and 25(7), 30(14), 31(11) mg/day (p = 0.03). The total amount of tramadol consumed was greater following robotic surgery compared with conventional laparoscopy (322(222) mg vs 242(292) mg, p = 0.04). We observed a switch in analgesic consumption over the years: tramadol was used by 70% of patients in 2019 but only by 7.1% in 2021 (p < 10-3); conversely, ketoprofen was not used in 2019, but was consumed by 57% of patients in 2021 (p < 10-3). A history of abdominal surgery (OR = 0.37 (0.16-0.78, p = 0.011) and having surgery in 2020 rather than in 2019 (OR = 0.10 (0.04-0.24, p < 10-3)) and in 2021 than in 2019 (OR = 0.08 (0.03-0.20, p < 10-3)) were the only variables independently associated with the risk of opioid use. We found that neither clinical characteristics nor intraoperative findings had an impact on opioid consumption in this setting, and that it was possible to rapidly modify in-hospital analgesic consumption modalities by significantly reducing opioid consumption in favor of NSAIDS or nefopam.

Pharmacologic interventions for the therapy of postanesthetic shivering in adults: a systematic review and network meta-analysis.

INTRODUCTION: Shivering is a common side effect after general anesthesia. Risk factors are hypothermia, young age and postoperative pain. Severe complications of shivering are rare but can occur due to increased oxygen consumption. Previous systematic reviews are outdated and have summarized the evidence on the topic using only pairwise comparisons. The objective of this manuscript was a quantitative synthesis of evidence on pharmacological interventions to treat postanesthetic shivering. EVIDENCE ACQUSITION: Systematic review and frequentist network meta-analysis using the R package netmeta. Endpoints were the risk ratio (RR) of persistent shivering at one, five and 10 minutes after treatment with saline/placebo as the comparator. Data were retrieved from Medline, Embase, Central and Web of Science up to January 2022. Eligibility criteria were: randomized, controlled, and blinded trials comparing pharmacological interventions to treat shivering after general anesthesia. Studies on shivering during or after any type of regional anesthesia were excluded as well as sedated patients after cardiac surgery. EVIDENCE SYNTHESIS: Thirty-two trials were eligible for data synthesis, including 28 pharmacological interventions. The largest network included 1431 patients. The network geometry was two-centered with most comparisons linked to saline/placebo or pethidine. The best interventions were after one minute: doxapram 2 mg/kg, tramadol 2 mg/kg and nefopam 10 mg, after 5 minutes: tramadol 2 mg/kg, nefopam 10 mg and clonidine 150 µg and after 10 minutes: nefopam 10 mg, methylphenidate 20 mg and tramadol 1 mg/kg, all reaching statistical significance. Pethidine 25 mg and clonidine 75 µg also performed well and with statistical significance in all networks. CONCLUSIONS: Nefopam, tramadol, pethidine and clonidine are the most effective treatments to stop postanesthetic shivering. The efficacy of doxapram is uncertain since different doses showed contradictory effects and the evidence for methylphenidate is based on a single comparison in only one network. Furthermore, both lack data on side effects. Further studies are needed to clarify the efficacy of dexmedetomidine to treat postanesthetic shivering.

Comparative effectiveness of interventions for managing urological postoperative catheter-related bladder discomfort: a systematic review and network meta-analysis.

BACKGROUND: Catheter-related bladder discomfort (CRBD) is a common postoperative bladder pain syndrome. Many drugs and interventions for managing CRBD have been studied, but their comparative effectiveness remains controversial. We made a study to assess the comparative effectiveness of interventions included Ketorolac, Lidocaine, Chlorpheniramine, Gabapentin, Magnesium, Nefopam, Oxycodone, Parecoxib, Solifenacin, Tolterodine, Bupivancaine, Dexmedetomidine, Hyoscine N-butyl bromide, Ketamine, Penile nerve block on urological postoperative CRBD. METHODS: We performed a network meta-analysis via Aggregate Data Drug Inormation System software included 18 studies with 1816 patients and assessed the risk of bias by Cochrane Collaboration tool. The incidence of moderate to severe CRBD at 0, 1, and 6 h after surgery and the incidence severe CRBD at 1 h after surgery were compared. RESULT: The number of best rank is 0.48(Nefopam) and 0.22(Nefopam) in the incidence of moderate to severe CRBD at 1 h and incidence severe CRBD at 1 h. More than half of studies at unclear or high risk of bias. CONCLUSION: Nefopam reduced the incidence of CRBD and prevented severe events, but limited by the small number of studies for each intervention and heterogeneous patients.

Single-dose intravenous nefopam on postoperative catheter-related bladder discomfort in patients undergoing transurethral resection of prostate: a randomized, double-blind placebo-controlled trial.

PURPOSE: Transurethral resection of prostate (TURP) with postoperative catheter traction can lead to significant catheter-related bladder discomfort (CRBD). This condition causes many postoperative complications and low patient satisfaction. This study aimed to evaluate the effectiveness of preoperative single-dose intravenous nefopam on the incidence and severity of CRBD and its adverse effects. METHODS: This randomized, controlled, double-blind study included patients who underwent TURP under spinal anesthesia with postoperative urinary catheter traction. Patients were allocated into nefopam (NF) and normal saline (NS) groups. Twenty mg of nefopam in normal saline solution (NSS) 100 mL or NSS 100 mL were given intravenously before TURP. The primary outcome was the incidence of CRBD. RESULTS: Seventy-three patients were randomized into NF (n = 37) and NS (n = 36) groups. There were 35 and 33 patients in the NF and NS groups, respectively, in the final analysis. The incidences of CRBD were 45.71% and 84.85% in the NF and NS groups at 6 h after operation, respectively, OR 0.54 (95% CI 0.36, 0.73), while before the end of catheter traction, the corresponding incidences were 37.14% and 75.76%, respectively, OR 0.49 (95% CI 0.28, 0.84). The CRBD scores were statistically significantly lower in the NF group at both time points. Morphine consumptions and adverse effects were not different between groups. Patient satisfaction was higher in the NF group. CONCLUSIONS: Single-dose nefopam significantly reduced the incidence and severity of CRBD in patients undergoing TURP with urinary catheter traction at 6 h after the procedure and before the end of catheter traction without increasing the adverse effects.

Postoperative analgesia of intraoperative nefopam in patients undergoing anterior cervical spine surgery: A prospective randomized controlled trial.

BACKGROUND: Nefopam is a non-opioid, non-nonsteroidal anti-imflammatory drug, analgesic drug that inhibits the reuptake of serotonin, norepinephrine, and dopamine. It is widely used as an adjuvant for pain. This study investigated whether the intraoperative, intravenous infusion of nefopam (20 mg) reduces postoperative morphine consumption, pain scores, and alleviates neuropathic pain in patients undergoing cervical spine surgery. METHODS: A prospective, paralleled design, randomized study was conducted on 50 patients (aged 18-75 years) in a university-based hospital. The patients were assigned to an intervention or a control group (25 patients in each). The intervention group received a 1-hour infusion of nefopam (20 mg) before the end of surgery. The control group received normal saline (NSS). The outcome measures were morphine consumption during the first 24 postoperative hours, numerical rating scale (NRS) pain scores, and scores for the Thai version of the Neuropathic Pain Symptom Inventory (NPSI-T) in patients with neuropathic pain and adverse drug reactions. The NPSI-T scores were assessed on the preoperative day, postoperative day 1, 3, 15, and 30. The outcome assessors were blinded to group allocation. RESULTS: Fifty patients were analyzed. During the first 24 postoperative hours, morphine consumption was 8 mg (nefopam) and 12 mg (NSS; P = .130). The intervention and control groups demonstrated no significant differences in the median NRS scores or total NPSI-T scores or adverse drug reactions. CONCLUSIONS: A single, intraoperative infusion of 20 mg of nefopam did not significantly reduce postoperative (24 hours) morphine consumption in patients undergoing anterior cervical spine surgery.

Effect of Continuous Infusion of Intravenous Nefopam on Postoperative Opioid Consumption After Video-assisted Thoracic Surgery: A Double-blind Randomized Controlled Trial.

BACKGROUND: Although nefopam has been reported to have opioid-sparing and analgesic effects in postsurgical patients, its effectiveness in video-assisted thoracoscopic surgery (VATS) is unknown. OBJECTIVES: This study aimed to investigate the opioid-sparing and analgesic effects of perioperative nefopam infusion for lung resection. STUDY DESIGN: Double-blinded randomized controlled trial. SETTING: Operating room, postoperative recovery room, and ward at a single tertiary university hospital. METHODS: Ninety patients scheduled for elective VATS for lung resection were randomized to either the nefopam (group N) or control group (group C). Group N received 20 mg nefopam over 30 minutes immediately after the induction of anesthesia. Nefopam was administered continuously for 24 hours postoperative, using a dual-channel elastomeric infusion pump combined with fentanyl-based intravenous patient-controlled analgesia. Group C received the same volume of normal saline as nefopam solution administered in the same manner. The primary outcome measure was fentanyl consumption for the first postoperative 24 hours. The secondary outcome measures were the cumulative fentanyl consumption during the first postoperative 48 hours, pain intensity at rest and during coughing evaluated using an 11-point numeric rating scale, quality of recovery at postoperative time points 24 hours and 48 hours, and the occurrence of analgesic-related side effects during the first postoperative 24 hours and postoperative 24 to 48 hour period. Variables related to chronic postsurgical pain (CPSP) were also investigated by telephone interviews with patients at 3 months postoperative. This prospective randomized trial was approved by the appropriate institutional review board and was registered in the ClinicalTrials.gov registry. RESULTS: A total of 83 patients were enrolled. Group N showed significantly lower fentanyl consumption during the first postoperative 24 hours and 48 hours (24 hours: median difference: -270 µg [95%CI, -400 to -150 µg], P < 0.001); 48 hours: median difference: -365 µg [95% CI: -610 to -140 µg], P < 0.001). Group N also showed a significantly lower pain score during coughing at 24 hours postoperative (median difference, -1 [corrected 95% CI: -2.5 to 0], adjusted P = 0.040). However, there were no significant between-group differences in the postoperative quality of recovery, occurrence of analgesic-related side effects, length of hospital stay, and occurrence of CPSP. LIMITATIONS: Despite the significant opioid-sparing effect of perioperative nefopam infusion, it would have been difficult to observe significant improvements in other postoperative outcomes owing to the modest sample size. CONCLUSION: Perioperative nefopam infusion using a dual-channel elastomeric infusion pump has a significant opioid-sparing effect in patients undergoing VATS for lung resection. Therefore, it could be a feasible option for multimodal analgesia in these patients.

Nefopam prescribing preferences in French hospitals: results of a survey.

Introduction: nefopam is a non-opioid, centrally-acting analgesic, frequently prescribed in France for acute pain and postoperatively. Only intravenous (IV) formulation is available, however the off-label oral use is frequent in surgical and medical patients. There is no data on the actual in-hospital prescription preferences in French physicians regarding nefopam. We wish to identify nefopam prescription habits for acute and chronic pain among hospital physicians. Methods: an online survey was sent to physicians via professional emails. Frequency of prescription, indication, preferred and prescribed administration route, dose regimen, and personal perception of the nefopam tolerance and efficiency were examined. Results: a total of 527 responses were analysed. Nefopam was mostly prescribed by senior hospital physicians, for acute pain, orally (85%), 20 mg/6h with 120 mg maximal daily dose. For chronic pain, the oral administration was more frequent. More than half of prescribers considered the efficacy of the oral route was similar to intravenous, and better tolerated compared to intravenous administration. Forty-eight percent of responders would change their prescription attitude in case of oral route approval of nefopam. Conclusion: oral prescription of intravenous formulation of nefopam is frequent, especially for acute pain, and has the same dose and regimen pattern as for intravenous route. Prescribers consider oral nefopam efficient and safe for patients. Regulatory actions regarding the oral nefopam prescription authorization and duration of such prescription are needed.

Effect of remifentanil on post-operative analgesic consumption in patients undergoing shoulder arthroplasty after interscalene brachial plexus block: a randomized controlled trial.

PURPOSE: Remifentanil is useful in balanced anesthesia; however, there is concern regarding opioid-induced hyperalgesia. The effect of remifentanil on rebound pain, characterized by hyperalgesia after peripheral nerve block has rarely been studied. This study evaluated whether intraoperative remifentanil infusion may increase postoperative analgesic requirement in patients receiving preoperative interscalene brachial plexus block (IBP). METHODS: Sixty-eight patients undergoing arthroscopic shoulder surgery under general anesthesia were randomly allocated to remifentanil (R) or control (C) group. Preoperative IBP with 0.5% ropivacaine 15 mL was performed in all patients. Intraoperative remifentanil was administered only in the R group. Postoperative pain was controlled using intravenous patient-controlled analgesia (IV-PCA) and rescue analgesics. The primary outcome was the dosage of fentanyl-nefopam IV-PCA infused over 24 h postoperatively. The secondary outcomes included the numeric rating scale (NRS) score recorded at 4-h intervals over 24 h, amount of rescue analgesics and total postoperative analgesics used over 24 h, occurrence of intraoperative hypotension, postoperative nausea and vomiting (PONV) and delirium. RESULTS: The dosage of fentanyl-nefopam IV-PCA was significantly less in C group than R group for postoperative 24 h. Fentanyl 101 [63-158] (median [interquartile range]) µg was used in the C group, while fentanyl 161 [103-285] µg was used in the R group (median difference 64 µg, 95% CI 10-121 µg, P = 0.02). Nefopam 8.1 [5.0-12.6] mg was used in the C group, while nefopam 12.9 [8.2-22.8] mg was used in the R group (median difference 5.1 mg, 95% CI 0.8-9.7 mg, P = 0.02). The total analgesic consumption: the sum of PCA consumption and administered rescue analgesic dose, converted to morphine milligram equivalents, was higher in the R group than C group (median difference 10.9 mg, 95% CI 3.0-19.0 mg, P = 0.01). The average NRS score, the incidence of PONV and delirium, were similar in both groups. The incidence of intraoperative hypotension was higher in R group than C group (47.1% vs. 20.6%, P = 0.005). CONCLUSIONS: Remifentanil administration during arthroscopic shoulder surgery in patients undergoing preoperative IBP increased postoperative analgesic consumption.

Does Nefopam Provide Analgesic Effect and Reduce Morphine Consumption After Primary Total Knee Arthroplasty? A Prospective, Double-Blind, Randomized Controlled Trial.

BACKGROUND: One of the most undesirable results after total knee arthroplasty (TKA) is severe immediate postoperative pain, resulting in patient dissatisfaction. We aimed to evaluate nefopam's analgesic efficacy after primary TKA along with related outcomes, including morphine consumption and adverse events. METHODS: We conducted a double-blind, randomized controlled trial of patients undergoing unilateral primary TKA, comparing 24 hours of 80 mg of continuous intravenous nefopam to placebo infusion. A 100-mm Visual Analog Scale (VAS) for pain-at-rest and in-motion ≤48 hours was the primary outcome measure. Secondary outcomes were morphine and antiemetic consumption, adverse events, and functional outcomes: time-to-walk, timed up-and-go test, postoperative knee range of motion at 24 and 48 hours, time-to-discharge, and patient satisfaction scores. RESULTS: Patients in the nefopam group had significantly lower VAS at rest 6 hours postop (20.3 ± 27.3 vs 35 ± 24.3, P = .01). Other timepoints and in-motion VAS did not significantly differ. Total morphine consumption (0-48 hours) was 37% less, significantly lower, in the nefopam group (5.3 ± 4.5 vs 8.4 ± 7.5 mg, P = .03). Antiemetic consumption was also 61% lower in the nefopam group but not statistically significant (0.8 ± 2.3 vs 2.0 ± 3.8 mg, P = .08). There were no variations in adverse events, functional outcomes, and satisfaction scores between groups. CONCLUSION: Continuous nefopam administration as part of multimodal analgesia for 24 hours post-TKA produced a significant analgesic effect but only within the first 6 hours. However, there was a notable reduction in morphine use 48 hours postop. Nefopam is a useful agent for contemporary pain control after TKA. LEVEL OF EVIDENCE: Therapeutic Level I.

Different interventions for preventing postoperative catheter-related bladder discomfort: a systematic review and meta-analysis.

OBJECTIVE: Catheter-related bladder discomfort (CRBD) is a common complication of intraoperative urinary catheterization. Various studies have evaluated the efficacy of different interventions in postoperative CRBD. The present review was performed to assess the efficacy of these interventions. METHODS: PubMed, Embase, and CENTRAL (Cochrane Central Register of Controlled Trials) databases were systematically searched to identify randomized controlled trials (RCTs) investigating the efficacy of different drugs for the prevention of postoperative CRBD. This review evaluated the incidence and severity of CRBD after different interventions at 0, 1, 2, and 6 h postoperatively. RESULTS: Forty-five studies including 31 different drugs were analyzed. Eleven drugs were investigated in more than two RCTs, of which dexmedetomidine, gabapentin, tolterodine, tramadol, ketamine, nefopam, oxybutynin, pregabalin, and pudendal nerve block (PNB) generally showed significantly higher efficacy than controls postoperatively. Solifenacin only showed significant efficacy compared with the control at 0 h, and intravenous lidocaine only showed significant efficacy compared with the control at 6 h. There were insufficient trials to draw conclusions regarding atropine, butylscopolamine, chlorpheniramine, clonidine, darifenacin, diphenhydramine, glycopyrrolate, intravesical bupivacaine, ketamine-haloperidol, pethidine-haloperidol, ketorolac, lidocaine-prilocaine cream, magnesium, hyoscine n-butyl bromide, oxycodone, paracetamol, parecoxib, trospium, resiniferatoxin, or amikacin. However, all but pethidine-haloperidol and chlorpheniramine showed some efficacy at various time points compared with controls. CONCLUSION: This review suggests that dexmedetomidine, gabapentin, tolterodine, tramadol, ketamine, nefopam, oxybutynin, pregabalin, and PNB are effective in preventing postoperative CRBD. Considering the efficacy and adverse effects of all drugs, dexmedetomidine and gabapentin were ranked best.

Assessment of surface water quality and mercury levels from Artisanal and small-scale gold mining (ASGM) along Acupan River, Benguet, Philippines.

Artisanal and small-scale mining activities are most evident among communities surrounding the Acupan River in Itogon Benguet. The mining activities include manual extraction of gold ores, use of improvised ball/rod mills and sluice boxes, and metallurgical processing such as cyanidation, carbon-in-pulp (CIP) and amalgamation. This study evaluates the influence of small-scale mining and the geology/mineralization of the Acupan Au-Ag-Te deposit to the water quality of the Acupan River and to the possible human exposures to Hg within the small-scale mining community. Different water quality parameters were monitored along selected sites along the Acupan River for a year and the results showed that the low average values of dissolve oxygen (DO) (2.54-4.53 mg L-1) and the relatively high average values of pH (8.84-10.10), sulfate (300.00-1133.33 mg L-1), nitrate (11.33-134.67 mg L-1), arsenic (As) (0.227-0.574 mg L-1) and mercury (Hg) (0.004-0.054 mg L-1) have exceeded the acceptable criteria limit of the Department of Environment and Natural Resources for Class C waters. The exceeded values are noted to occur in areas where extensive small-scale mining activities are being done and have affected as well the downstream areas. To test possible human contamination in the use of Hg, hair samples from 56 volunteers were analyzed for total Hg (T-Hg) following standard protocols. The T-Hg concentrations in hair samples are mostly inorganic and are determined in various parameters such as sex, geographic location, occupation, age, fish consumption and localization in hair. Though not significantly different, higher Hg values are noted in males (1.280 ± 0.446 ng mg-1) than among females (0.651 ± 0.163 ng mg-1) as well as those with ages 41-50 years (3.130 ± 2.330 ng mg-1) as compared to other age groups. The higher amounts of inorganic Hg in human hairs could be attributed to the discrete yet prevalent use of amalgamation. The findings of this study emphasize the need for better regulations of the small-scale mining activities and for stricter implementation of the total ban on the use of Hg in ore processing to ensure better water quality of Acupan River as well as the health and safety of the communities surrounding the river.

Effect of Nefopam-Based Patient-Controlled Analgesia with and without Fentanyl on Postoperative Pain Intensity in Patients Following Laparoscopic Cholecystectomy: A Prospective, Randomized, Controlled, Double-Blind Non-Inferiority Trial.

Background and Objectives: We investigated the non-inferiority of patient-controlled analgesia (PCA), using either nefopam alone or combined nefopam-fentanyl for postoperative analgesia in patients undergoing laparoscopic cholecystectomy. Materials and Methods: In this prospective, randomized, controlled study, 78 patients were allocated to receive nefopam 240 mg (Group N240) or nefopam 120 mg with fentanyl 600 µg (Group NF), equivalent to fentanyl 1200 µg, with a total PCA volume of 120 mL. Patients were given a loading dose (0.1 mL/kg) from the PCA device along with ramosetron (0.3 mg) and connected to a PCA device with a background infusion rate of 2 mL/h, bolus dose amount set at 2 mL, and lockout interval set at 15 min. Pain scores were obtained using the numeric rating scale (NRS) at 30 min after recovery room (RR) admission, as well as 8 and 24 h postoperatively. The primary outcome was analgesic efficacy evaluated using NRS-rated 8 h postoperatively. Other evaluated outcomes included the incidence rate of bolus demand, rescue analgesic and antiemetic requirements, and postoperative adverse effects. Results: NRS scores were not significantly different between the groups throughout the postoperative period (p = 0.539). NRS scores of group N240 were not inferior to those of group NF at 30 min after RR admission, or at 8 and 24 h postoperatively (mean difference [95% CI], -0.05 [-0.73 to 0.63], 0.10 [-0.29 to 0.50], and 0.28 [-0.06 to 0.62], respectively). Postoperative adverse effects were not significantly different between the two groups (p = 1.000) and other outcomes were also not significantly different between the two groups (p ≥ 0.225). Conclusions: PCA using nefopam alone has a non-inferior and effective analgesic efficacy and produces a lower incidence of postoperative adverse effects compared to a combination of fentanyl and nefopam after laparoscopic cholecystectomy.

Synergism between oral paracetamol and nefopam in a murine model of postoperative pain.

BACKGROUND: The use of paracetamol or nefopam for postoperative pain control is limited by the need of high doses associated with unwanted effects. Previous works suggest positive interactions between both compounds that may be exploited to obtain potentiation of antinociception. METHODS: Mechanical and heat antinociception induced by oral doses of paracetamol, nefopam or their combination was studied by isobolographic analysis in a murine model of postsurgical pain. The effective doses that produced 50% antinociception (ED50 ) were calculated from the log dose-response curves for each compound. Subsequently, the effects of ED8.7 s, ED12.5 s, ED17.5 s and ED35 s of nefopam and paracetamol combined were assessed. RESULTS: Oral paracetamol induced dose-dependent relief of postoperative sensitivity and showed higher efficacy reducing mechanical hypersensitivity (ED50 177.3 ± 15.4 mg/kg) than heat hyperalgesia (ED50 278.6 ± 43 mg/kg). Oral nefopam induced dose-dependent antinociception with similar efficacy for mechanical and heat hypersensitivity (ED50 s 5.42 ± 0.81 vs. 5.83 ± 0.72). Combinations of increasing isoeffective doses revealed that combined ED17.5 s (85.76 mg/kg paracetamol and 1.9 mg/kg nefopam) and ED35 s (132.67 mg/kg and 3.73 mg/kg) showed synergistic effects leading to 75% and 90% mechanical antinociception, respectively. These mixtures were defined by interaction indexes of 0.43 and 0.41 and ratios 45:1 and 35:1 paracetamol:nefopam, respectively. The same combinations showed additive effects for the inhibition of incisional thermal hyperalgesia. CONCLUSIONS AND LIMITATIONS: This work describes a synergistic antinociceptive interaction between low doses of nefopam and paracetamol for the treatment of postoperative hypersensitivity to peripheral stimuli. The promising results obtained on reflexive nociceptive responses of young male mice subjected to plantar surgery highlight the interest of further research evaluating the effects of this mixture on the affective-motivational component of pain and in females and additional age groups. Confirmation of pain-relieving efficacy and safety of this oral combination clinically available in European and Asian countries could provide a useful tool for postsurgical pain management. SIGNIFICANCE: Early postoperative pain is currently undertreated and has been recognized as a relevant source of chronic postsurgical pain. Oral efficient treatments could facilitate fast-track surgeries and patient recovery at home. Here, we identify in a mouse model of postoperative pain a potent synergistic oral combination consisting of low paracetamol and nefopam doses that provides relief of postsurgical hypersensitivity to mechanical and thermal stimuli. Oral multimodal paracetamol-nefopam mixtures represent a potential clinically available pharmacological strategy for the relief of incisional sensitivity and the promotion of patient recovery.

[Thirty years of nefopam abuse in France]. / Trente ans d'abus de néfopam en France.

AIM OF THE STUDY: The use of nefopam is constantly increasing in France. The objectives of this study were to quantify the intensity of the drug dependence signal, to identify the populations at risk and the risk factors of dependence. METHODS: All serious and non-serious cases of misuse, abuse, drug dependence, overdose and withdrawal syndrome reported to the French Addictovigilance Network since 1988 were reviewed. An analysis of nefopam reimbursement data from the French national EGB (échantillon généraliste des bénéficiaires) database for the period 2006-2017 was also performed. RESULTS: The drug dependence profile of nefopam is close to that of a psychostimulant. Our literature review and the analysis of spontaneous reports confirm the risk of abuse and dependence of nefopam. In addition to a frequent psychiatric history (depression, psychosis, anxiety), nearly half of the patients also present addictive disorders, including more than one-third with opioid-dependence. In almost half of the 120 reported cases, the main adverse reaction was dependence and the frequency of serious effects was greater than 40%. In nearly 70% of the reported cases, the use was associated with chronic pain, which might explain the prolonged use. Moreover, the analysis of data on the reimbursement of nefopam in the general population showed that one French person out of two, having a prescription for nefopam, presented chronic pain. However, nefopam is only indicated in the treatment of acute painful conditions. Although it does not seem to be associated with a greater risk of abuse or dependence, taking the drug orally is another very frequent off-label use that needs to be regulated. CONCLUSION: In France, the prescription of nefopam outside of its marketing authorization is regrettable, because it contributes to the development of abuse and drug dependence.

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

Background: The incidence of moderate to severe pain is high among patients undergoing spinal surgery. Nefopam can be used as an adjuvant analgesic postoperatively after spine surgery. The study aimed to assess the analgesic efficacy and side effects of nefopam on 24-hour postoperative morphine consumption after spine surgery. Methods: The study is a randomized, double-blinded, placebo-controlled trial. A total of 96 patients were randomized into 4 treatment groups, 24 each. In group 1, patients received normal saline before surgical incision and before the end of surgery. In group 2, patients received 30 mg nefopam before surgical incision and normal saline before the end of surgery. In group 3, patients received normal saline before surgical incision and 30 mg of nefopam before the end of surgery. In group 4, patients received 30 mg of nefopam in both timings. Patient-controlled analgesia morphine was used for the postoperative period. Outcomes were to determine 24-hour morphine consumption and incidence of side effects.  Results: Of 96 patients enrolled, 21 in placebo-placebo, 22 in nefopam-placebo, 22 in placebo-nefopam and 21 in nefopam-nefopam groups completed the study.  Analysis of the Kruskal-Wallis test on the intention-to-treat basis shows no significant difference in 24-hour postoperative morphine consumption between four groups, which were 18 [IQR 13.5-29], 20 [IQR 11-28.3], 17 [IQR 11.5-28.5], 13 [IQR 8.5-18.5] mg., respectively (p = 0.223). Incidence of side effects, including tachycardia, sedation, sweating and nausea/ vomiting, did not differ. Conclusions: Adding perioperative nefopam to opioid analgesic does not improve analgesic efficacy in patients who underwent spine surgery. Registration: Thai Clinical Trials Registry ID TCTR20171115001; registered on 15 November 2017.

A Comprehensive Review of the Diagnosis, Treatment, and Management of Postmastectomy Pain Syndrome.

PURPOSE OF REVIEW: Postmastectomy pain syndrome (PMPS) remains poorly defined, although it is applied to chronic neuropathic pain following surgical procedures of the breast, including mastectomy and lumpectomy in breast-conserving surgery. It is characterized by persistent pain affecting the anterior thorax, axilla, and/or medial upper arm following mastectomy or lumpectomy. Though the onset of pain is most likely to occur after surgery, there may also be a new onset of symptoms following adjuvant therapy, including chemotherapy or radiation therapy. RECENT FINDINGS: The underlying pathophysiology is likely multifactorial, although exact mechanisms have yet to be elucidated. In this regard, neuralgia of the intercostobrachial nerve is currently implicated as the most common cause of PMPS. Numerous pharmacological options are available in the treatment of PMPS, including gabapentinoids, tricyclic antidepressants, selective serotonin reuptake inhibitors, NMDA receptor antagonists, and nefopam (a non-opioid, non-steroidal benzoxazocine analgesic). Minimally invasive interventional treatment including injection therapy, regional anesthesia, botulinum toxin, and neuromodulation has been demonstrated to have some beneficial effect. A comprehensive update highlighting current perspectives on the treatment of postmastectomy pain syndrome is presented with emphasis on treatments currently available and newer therapeutics currently being evaluated to alleviate this complex and multifactorial condition.