Postoperative analgesic efficacy of nefopam after anorectal surgery: a retrospective observational study

Objective: To examine the effectiveness of nefopam on postoperative pain control after anorectal surgeries. Methods: We retrospectively reviewed the electronic medical records of patients who underwent anorectal surgeries from January 2019 to March 2022 at two medical centers. The data were divided into nefopam and conventional groups. The primary outcome was the number of patients who requested additional opioids in the 24-h postoperative period. The secondary outcomes were numeric rating pain scores (NRPS) within a 24-h postoperative period and analgesic drugs-related side effects. Results: Eighty-seven patients in the conventional group and 60 in the nefopam group were recruited. The nefopam group reported less additional opioid consumption than the conventional group in all dimensions of analysis, including overall, adjusted to anesthetic techniques and types of surgery. However, these did not reach statistical significance (P = 0.093). Only patients in the nefopam group who underwent hemorrhoidectomy under TIVA or spinal anesthesia significantly required fewer additional opioids (P = 0.016, 60% mean difference). Similarly, the 24-h postoperative morphine consumption was lower in the nefopam group (mean difference = -3.4, 95%CI: 0.72,6.08). Furthermore, significantly lower NRPS were reported in the nefopam group during the 12-18 h postoperative period (P = 0.009). On the other hand, analgesic drugs related side effects were similar in both groups. Conclusions: The administration of nefopam after major anorectal surgery is beneficially evident in reducing postoperative opioid requirements. (AU)

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.

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.

Association of nefopam use with postoperative nausea and vomiting in gynecological patients receiving prophylactic ramosetron: A retrospective study.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a common adverse effect of opioid-based intravenous patient-controlled analgesia (IV PCA). Nefopam has been considered as a good candidate for inclusion in multimodal analgesia because of its opioid sparing effect, but it can be emetic. This study aims to examine whether the use of nefopam combined with fentanyl in IV PCA was associated with the higher incidence of PONV in patients receiving prophylactic ramosetron after gynecological surgery. METHODS: Data from 296 patients who underwent gynecological surgery were retrospectively reviewed. The patients received IV PCA containing either fentanyl 1500 µg and ketorolac 90 mg (Group K) or fentanyl 1500 µg and nefopam 80 mg (Group N). All patients in both groups received 0.3 mg of ramosetron at the end of surgery. The primary outcome measure was the incidence of PONV during the 3-day postoperative period. RESULTS: No difference was observed in the incidence of PONV during the 3-day postoperative period between the two groups. However, the incidence of nausea on postoperative day 2 was significantly higher in Group N (10.3%) than in Group K (2.8%) (P = 0.016). Multivariable logistic regression analysis showed that the use of nefopam was not associated with a higher incidence of PONV (adjusted odds ratio, 1.616; 95% confidence interval, 0.952-2.743, P = 0.076). There were no differences in postoperative pain scores between the two groups. CONCLUSION: The combined use of nefopam with fentanyl in IV PCA was not associated with the higher incidence of PONV compared with the use of ketorolac and fentanyl combination in patients who received ramosetron as PONV prophylactic agent. However, prospective trials are required for a confirmative conclusion.

Opioid sparing effect and safety of nefopam in patient controlled analgesia after laparotomy: A randomized, double blind study.

OBJECTIVES: A double-blind randomised study to evaluate the opioid sparing effect and safety of nefopam when administered via intravenous patient controlled analgesia (PCA) with fentanyl. METHODS: Patients planned for elective open laparotomy, were randomly assigned to receive into fentanyl 25 µg/ml (SF group) or nefopam 2.4 mg/ml plus fentanyl 25 µg/ml (NF group). Patients were assessed before surgery and for 24 h postoperatively. RESULTS: Total PCA fentanyl consumption was significantly lower in the NF group (n = 35) than the SF group (n = 36). Pain scores were significantly lower and patients' satisfaction with treatment significantly better in the NF group than the SF group. Dry mouth and dizziness were significantly more frequent in the NF group than the SF group. There were no other statistically significant between-group differences in the incidence of adverse events. CONCLUSIONS: Intravenous PCA using nefopam + fentanyl following laparotomy has an opioid sparing effect and is associated with a low incidence of some of the typical opioid related adverse events. TRIAL REGISTRY: Clinicaltrials.gov Registration No: NCT02596269.

Nefopam for the prevention of perioperative shivering: a meta-analysis of randomized controlled trials.

BACKGROUND: Shivering is a frequent complication following surgery and anaesthesia. A large variety of studies have been reported that nefopam may be efficacious for the prevention and treatment of perioperative shivering. Regrettably, there is still no conclusion of the efficacy and safety of nefopam for the prevention of perioperative shivering. The aim of this analysis is to evaluate the efficacy of nefopam for the prevention of perioperative shivering in patients undergoing different types of anaesthesia compared with placebo group and other active interventions. METHODS: PubMed, EMBASE, Cochrane Central Register of Control Trials were systematically searched for potentially relevant trials. Trial quality and extracted data were evaluated by two authors independently. Dichotomous data on the absence of shivering was extracted and analysed by using relative risk (RR) with 95% confidence interval (CI). Continuous outcome was abstracted and analysed by using weighted mean difference (WMD) with 95% confidence interval (CI). Outcome data was analysed by using random effect model or fixed effect model in accordance with heterogeneity. RESULTS: Compared with placebo, prophylactic administration of nefopam significantly reduced the risk of perioperative shivering not only in the patients under general anaesthesia but also neuraxial anaesthesia (RR 0.08; 95% CI 0.05-0.13). As compared with clonidine, nefopam was more efficacious in the prevention of perioperative shivering (RR 0.34; 95% CI 0.17-0.70). Nefopam has no influence on the extubation time (WMD 0.92; 95% CI -0.15-1.99). CONCLUSION: Our analysis has demonstrated that nefopam is associated with the decrease of risk of perioperative shivering following anaesthesia without influencing the extubation time.

The analgesic efficacy and safety of nefopam in patient-controlled analgesia after cardiac surgery: A randomized, double-blind, prospective study.

OBJECTIVE: The efficacy and side-effects of nefopam were prospectively compared with those of fentanyl for patient-controlled analgesia (PCA) following cardiac surgery. METHODS: Patients scheduled to undergo cardiac surgery were randomly assigned between three PCA groups (nefopam, fentanyl or nefopam + fentanyl). Pain was assessed at rest and during movement at 12, 24, 36, 48 and 72 h after surgery using a visual analogue scale (VAS). Total infused PCA volume, number of rescue drug injections, duration of intubation and length of stay in the intensive care unit were recorded. The incidence of adverse effects was noted at 48 h postoperatively. RESULTS: There were no significant between-group differences in VAS score, total PCA infusion volume or number of rescue injections (n = 92 per group). Nausea was significantly more common in the fentanyl group compared with both other groups. CONCLUSIONS: PCA with nefopam alone provides suitable postoperative analgesia after cardiac surgery.

[Postoperative analgesia with nefopam and non-steroidal anti-inflammatory drugs in patients after surgery for tumors of head and neck].

MATERIALS AND METHODS: 83 adult patients included in the study were divided into two groups. Patients of the group-1 (n-49) had medium level of pain after cancer head and neck surgery. Patients of the group-2 (n-34) had severe pain. Three first postoperative days their post-operative multimodal analgesia started with tenoxycam 20 mg i.m. after induction of anesthesia, then every 24 hour (58 patients). 25 patients got ketoprofen 100 mg i.m. every 8-12 hours instead of tenoxycam. All patients had nefopam 30 mg i.m. 30 min prior the end of surgery procedure, and every 8 hours afterwards. 7 patients of the group-1 had more than 4 pain scores (day 1), 4 patients--at the day 2. They received tramadol or paracetamol additionally. 7 patients (group-2) also had up to 5 pain scores on the day 1, 5 patients had 4 pain scores on the day 2, and 3 patients 4 pain scores on the day 3. All that patients received additional analgesia with tramadol or trimeperidine once a day. 8.4% of patients suffered from adverse reactions (tachycardia, PONV and sweating). CONCLUSION: This method of multimodal postoperative analgesia is very simple and fairly efficient.

[Thrombocytopenia and postoperative analgesia].

OBJECTIVE: To develop effective and safe measures of postoperative multimodal analgesia (optimizing the use of narcotic analgesics) in surgical treatment of hematological patients with thrombocytopenia. DESIGN: A pilot and prospective comparative controlled study. METHODS: We studied 27 patients with acquired thrombocytopenia who underwent laparoscopic splenectomy. Three schemes of anesthesia were used: 1) Nefopam 20 mg/day + trimeperidin (n = 7); 2) Paracetamol 4 g/day + trimeperidin (n = 10); 3) paracetamol + trimeperidin + glucocorticosteroids (GC) (through treatment of the underlying disease) (n = 10). Analgesic properties and effect of each scheme were assessed according to a rating scale of pain NRS (10 points) and VAS (100 points) studied. Additionally we evaluated the effect of nefopam and paracetamol on the functional properties of platelets and hemostasis, platelet levels while monitoring and indicators of thromboelastogram (TEG). RESULTS: Application of paracetamol + trimeperidin accompanied with effectively reducing of postoperative pain (less than 5 points on the NRS). The level of postoperative pain was lower in patients who were treated with corticosteroids within the therapy of the underlying disease before surgery and who continued to receive it in postoperative period (2-3 points NRS). Nefopam use in the perioperative period is not only inferior to the analgesic effect of paracetamol, but also causes frequent side effects. Consumption of narcotic analgesic--trimeperidin when applying nefopam averaged 43 mg/day, the appointment of paracetamol--28 mg/day, using a combination of paracetamol + GC--20 mg/day. Thus, GC within the underlying disease treatment substantially reduces the need for opioid analgesics. A monitoring of the number of platelets and TEG did not shows negative effect of paracetamol and nefopam on platelet and plasma hemostasis. CONCLUSIONS: Nefopam and paracetamol may be used in patients with thrombocytopenia, as do not affect the hemostasis and platelet count. Application of postoperative analgesia scheme paracetamol + trimeperidin in patients receiving corticosteroids provides the maximum reduction of pain with the least consumption of narcotic analgesics.

Ondansetron does not attenuate the analgesic efficacy of nefopam.

OBJECTIVES: The aim of this study was to investigate if there is any interaction between ondansetron and nefopam when they are continuously co-administrated during patient-controlled intravenous analgesia (PCIA). METHODS: The study was a prospective, randomized, controlled, non-inferiority clinical trial comparing nefopam-plus-ondansetron to nefopam alone. A total of 230 postoperative patients using nefopam for PCIA, were randomly assigned either to a group receiving continuous infusion of ondansetron (Group O) or to the other group receiving the same volume of normal saline continuously (Group N). Postoperative pain intensity scores, the sum of pain intensity difference over 24 hours postoperatively (SPID24hr), the incidence of adverse events, and the total consumption of nefopam were evaluated respectively. RESULTS: Postoperative pain was treated successfully in both groups. The mean SPID24hr scores were 95.6 mm in Group N and 109.3mm in Group O [95% confidence interval (CI) -14.28, 24.32]. The lower margin of the 95% CI was above the pre-determined non-inferiority margin (-30mm) for SPID24hr, which indicated that nefopam-plus-ondansetron was not worse than the nefopam alone in term of analgesic efficacy. In addition, there was no statistical difference between the two groups in term of cumulative consumption of nefopam. Compared with Group N, postoperative vomiting was significantly reduced in Group O during the postoperative 24 hours (P < 0.05). Less rescue antiemetics were given to patients in Group O than those receiving nefopam alone (P < 0.05). There were no differences in postoperative nausea between the two groups. CONCLUSION: Nefopam-plus-ondansetron is not inferior to nefopam alone in relieving the pain in PCIA after minimally invasive surgery. In addition, adverse events are reduced without compromising analgesic efficacy.

[The use of central acting analgesic nefopam in postoperative analgesia in cardiac surgery patients].

A prospective, randomized, comparative study was conducted. 3 analgesia protocols were used: 1) patient controlled analgesia (PCA) with trimeperidine in combination with a nefopam constant infusion; 2) PCA with trimeperidine in combination with a nefopam bolus; 3) PCA with trimeperidine separately during early postoperative period in cardiac surgery patients. The study included 60 patients agedf rom 40 to 65 years of age (20 patients in each group). The analgesia efficacy was evaluated with a 5-point verbal rating scale (VRS) for pain intensity and inspiratory lung capacity (ILC), measured with incentive spirometer. The safety of nefopam during early postoperative period in cardiac surgery patients was shown. The combination of nefopam and trimeperidine led to a more pronounced analgetic effect. Trimeperidine consumption was significantly lower in nefopam groups than in the group of isolated PCA. Wholly adverse effects were associated with trimeperidine and were dose-related The incidence of nausea, vomiting, dizziness, weakness, bowel paresis was significantly higher in isolated PCA group than in the other two groups.

Median effective dose (ED50) of paracetamol and nefopam for postoperative pain: isobolographic analysis of their antinociceptive interaction.

BACKGROUND: The analgesic efficacy of nefopam and of paracetamol has been shown in the postoperative period after mild- and moderate-pain surgery. The aim of this study was to define the median effective analgesic doses of each drug and of their combination, in order to determine the nature of their interaction. METHODS: Ninety adult patients scheduled to undergo tonsillectomy under general anesthesia were enrolled in one out of three groups: nefopam group, or paracetamol group, or nefopam-paracetamol group. The median effective dose for each drug and also for their combination was defined using an up-and-down sequential allocation technique. The analgesic interaction of their combination was assessed using an isobolographic analysis. RESULTS: The median effective analgesic dose (median value and 95% confidence interval) of nefopam and paracetamol were 21.7 mg (21.1-22.3 mg) and 628 mg (600-656 mg), respectively. The median effective analgesic doses of the combination were 8.9 mg (8.7-9.1 mg) for nefopam and 265 mg (256-274 mg) for paracetamol. The isobolographic analysis demonstrated a supra-additive interaction of the two drugs. CONCLUSION: The combination of nefopam and paracetamol produces effective analgesia with a synergistic interaction.

Nefopam pharmacokinetics in patients with end-stage renal disease.

BACKGROUND: Treatment of intense postoperative pain in patients with end-stage renal disease (ESRD) is a recurrent problem for anesthesiologists because of the risk of accumulation of numerous molecules and their metabolites. Nefopam is a potent analgesic metabolized by the liver and weakly eliminated intact in urine that may offer advantages for use in patients with ESRD because it lacks respiratory-depressive effects. However, the effects of renal failure on nefopam disposition have never been investigated. METHODS: We studied 12 ESRD patients (creatinine clearance < 20 mL/min, mean age 57 ± 13 years) having surgery under general anesthesia to create or repair an arteriovenous fistula. Postoperatively, after complete recovery from anesthesia, each patient received a single 20-mg dose of nefopam IV over 30 minutes. Nefopam and desmethyl-nefopam concentrations in plasma samples obtained over 48 hours were determined by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameter values obtained were compared with those of 12 healthy 50- to 60-year-old volunteers who also received a single 20-mg nefopam infusion over 30 minutes using a population pharmacokinetic approach. RESULTS: Healthy volunteers and ESRD patients had comparable demographic characteristics. In comparison with those volunteers, ESRD patients had a lower volume of central compartment (115 and 53 L vs. 264 L for patients not yet hemodialyzed and on chronic hemodialysis, respectively; P < 0.001) and lower mean nefopam clearance (37.0 and 27.3 L/h vs. 52.9 L/h, P < 0.001), resulting in higher mean nefopam peak concentration (121 and 223 ng/mL vs. 61 ng/mL, P < 0.001). CONCLUSIONS: Nefopam distribution and elimination are altered in patients with ESRD, resulting in heightened exposure. To avoid too-high concentration peaks, it is suggested that the daily nefopam dose be reduced by 50%.

Postoperative analgesia and early rehabilitation after total knee replacement: a comparison of continuous low-dose intravenous ketamine versus nefopam.

The effects of nefopam and ketamine on pain control and rehabilitation after total knee replacement were compared in a prospective, double blinded study. Seventy-five patients were randomly assigned to receive a 0.2mg kg(-1) bolus of nefopam or ketamine, followed by a 120microg kg(-1) h(-1) continuous infusion until the end of surgery, and 60microg kg(-1) h(-1) until the second postoperative day, or an equal volume of saline considered as placebo. Pain scores measured on a visual analog scale at rest and on mobilization, and patient-controlled intravenous morphine consumption, were assessed during 48h. We measured the maximal knee flexion on the third postoperative day, and the delay to obtain a 90 degrees flexion. Ketamine and nefopam reduced morphine consumption (p<0.0001). Pain scores, were lower at rest and on mobilization in the ketamine group compared to the two other groups at all times of measurement. Pain score were lower in patients receiving nefopam compared to placebo, on arrival in the recovery room and at 2h. Ketamine improved knee flexion on post operative day 3 (59 degrees [33-63] vs. 50 degrees [47-55] and 50 degrees [44-55] in ketamine, placebo and nefopam groups, respectively, p<0.0002) and decreased the delay to flex the knee at 90 degrees (9.1+/-4.2 vs. 12.3+/-4.0 days, in ketamine and placebo groups, respectively, p=0.01). Ketamine produces opioid-sparing, decreases pain intensity, and improves mobilization after total knee replacement. Nefopam achieves less significant results in that circumstances.

[Analgesic effect of continuous intravenous nefopam after urological surgery]. / Effets analgésiques de l'administration intraveineuse continue de néfopam après chirurgie urologique.

OBJECTIVES: To evaluate the efficacy of continuous infusion of nefopam. Indeed this analgesic is commonly used by continuous infusion by many anaesthetists to reduce its adverse effects. However whether the analgesic effect of an intermittent administration of nefopam has been proven, the efficacy of continuous infusion has not been established. STUDY DESIGN: Double-blind placebo controlled prospective randomised study. PATIENTS AND METHODS: Sixty patients ASA 1 to 3 undergoing planned urological surgery with laparotomy were included. At the end of surgery, bolus doses of placebo (Group 3) or nefopam 20 mg (Group 1 and 2) were administered to all the patients. Placebo (Group 3), nefopam 80 mg (Group 1) or 120 mg (Group 2) was thereafter continuously infused over 24 hours. All patients received additional analgesia with PCA morphine. We measured pain at rest and on cough with VAS. Adverse side effects such as nausea and vomiting, sedation and respiratory depression were evaluated. Mental performance was measured with mini mental status tests. RESULTS: Patients were older in the placebo group by approximately six years but anesthetic and surgical variables were not different between groups. Pain at rest and on cough was not statistically different between groups. In the placebo group, the median (interquartile range) morphine consumption reached 29 mg (13-53) whereas in patients receiving 80 and 120 mg nefopam, it levelled to 44 mg (11-54) and 35 mg (9-82) respectively (p > 0.05). Patients needed morphine during the same time period whether they received nefopam or not. Patients suffering from adverse effects were similar between groups. CONCLUSION: In this study, continuous administration of nefopam did not reduce morphine consumption nor ameliorate analgesia and thus may not be recommended in urological surgery. Nefopam pharmacokinetics when used with continuous infusion as well as surgery types and differences in age between groups may explain these results.

Nefopam and ketamine comparably enhance postoperative analgesia.

Opioids alone sometimes provide insufficient postoperative analgesia. Coadministration of drugs may reduce opioid use and improve opioid efficacy. We therefore tested the hypothesis that the administration of ketamine or nefopam to postoperative patients with pain only partly alleviated by morphine reduces the amount of subsequent opioid necessary to produce adequate analgesia. Patients (n=77) recovering from major surgery were given up to 9 mg of IV morphine. Those who still had pain were randomly assigned to blinded administration of 1) isotonic saline (control group; n=21), 2) ketamine 10 mg (ketamine group; n=22), or 3) nefopam 20 mg (nefopam group; n=22). Three-milligram morphine boluses were subsequently given at 5-min intervals until adequate analgesia was obtained, until 60 min elapsed after the beginning of study drug administration, or until ventilation became insufficient (respiratory rate <10 breaths/min or saturation by pulse oximetry <95%). Supplemental morphine (i.e., after test drug administration) requirements were significantly more in the control group (mean +/- sd; 17 +/- 10 mg) than in the nefopam (10 +/- 5 mg; P <0.005) or ketamine (9 +/- 5 mg; P <0.001) groups. Morphine titration was successful in all ketamine and nefopam patients but failed in four control patients (two because of respiratory toxicity and two because of persistent pain). Tachycardia and profuse sweating were more frequent in patients given nefopam, and sedation was more intense with ketamine; however, the incidence of other potential complications did not differ among groups.

The median effective dose of nefopam and morphine administered intravenously for postoperative pain after minor surgery: a prospective randomized double-blinded isobolographic study of their analgesic action.

UNLABELLED: The aim of this study was to characterize the nature of analgesic interaction between nefopam and morphine administered i.v. for postoperative pain after minor surgery. To do so, we defined the median effective analgesic dose (ED(50)) for each drug and also the median ED(50) of their combination and compared them using the isobolographic method. Determination of median effective doses was performed by the up-and-down sequential drug administration in a two-stage study. First, in a prospective, randomized, double-blinded study, we enrolled 60 patients with mild to moderate pain after minor surgery; this was followed by an open study enrolling 30 patients. The end-point was a pain score less than 3 on a Numerical Pain Scale (0-10). Initial doses were 16 mg in group N, 5 mg in group M, and 7.5 mg of N combined with 2.5 mg of M in group N+M. The testing interval was 2 mg in group N, 1 mg in group M, and 1.5 mg of N combined with 0.5 mg of M in group N+M. ED(50) (95% confidence interval) was 5 mg (4-6 mg) for morphine, 18 mg (16-18 mg) for nefopam, and 4 mg (3.5-4.5 mg) with 12 mg (10.5-13.5 mg) for the combination of morphine and nefopam administered at a 3:1 dose ratio. Isobolographic analysis demonstrated a significant infra-additive interaction. The incidence of side effects did not differ significantly among morphine, nefopam, and their combination. These findings suggest that the combination of nefopam and morphine does not offer any advantage compared to each drug administered i.v. or alone after minor surgery. This study is the first to define the ED(50) of nefopam and morphine in postoperative patients. In conclusion, the addition of nefopam has a morphine-sparing effect, but the combination is infra-additive. IMPLICATIONS: Pharmacologic interaction between nefopam and morphine shows infra-additivity but their combination may be clinically useful as morphine consumption is decreased in postoperative patients.

Randomized prospective study of the analgesic effect of nefopam after orthopaedic surgery.

BACKGROUND: Balanced postoperative analgesia combines non-narcotic drugs and opioids. We organized a large study to evaluate nefopam analgesia and tolerance in combination with morphine for patient-controlled analgesia (PCA) after orthopaedic surgery. METHODS: Two hundred and one patients scheduled to undergo hip arthroplasty were included in this multicentre (n=24), double-blind, randomized study comparing nefopam (20 mg every 4 h for 24 h) with placebo, the first dose being infused peroperatively. The primary outcome measure was the cumulative morphine dose received postoperatively by PCA over 24 h. Secondary outcome measures were the amount of morphine received as a loading dose in the postanaesthesia care unit (PACU) and during the 24-h observation period, and pain assessments using a visual analogue scale (VAS) and a verbal pain scale (VPS), patient's satisfaction with analgesia and treatment tolerance. RESULTS: The two groups were comparable with respect to their characteristics and preoperative pain assessment. PCA-administered morphine over 24 h was significantly less for the nefopam group than the control group (21.2 (15.3) and 27.3 (19.2) mg respectively; P=0.02). This morphine-sparing effect was greater (35.1%) for patients with severe preoperative pain (VAS>30/100). For the entire study period (loading dose and PCA), morphine use was less for the nefopam group (34.5 (19.6) vs 42.7 (23.6) mg; P=0.01). Pain VAS at PACU arrival and during the whole PACU period was significantly lower for the nefopam than for the placebo group (P=0.002 and 0.04 respectively). Patient satisfaction was similar for the nefopam and placebo groups. CONCLUSION: In combination with PCA morphine, nefopam gives significant morphine-sparing with lower immediate postoperative pain scores without major side-effects. This analgesic effect seems to be particularly notable for patients with intense preoperative pain.