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Pain is a common public health problem and remains as an unmet medical need. Currently available analgesics usually have limited efficacy or are accompanied by many adverse side effects. To achieve satisfactory pain relief by multimodal analgesia, new combinations of nefopam and gabapentinoids (pregabalin/gabapentin) were designed and assessed in inflammatory, osteoarthritis and neuropathic pain. Isobolographic analysis was performed to analyze the interactions between nefopam and gabapentinoids in carrageenan-induced inflammatory pain, mono-iodoacetate-induced osteoarthritis pain and paclitaxel-induced peripheral neuropathic pain in mice. The anti-inflammatory effect and motor performance of monotherapy or their combinations were evaluated in the carrageenan-induced inflammatory responses and rotarod test, respectively. Nefopam (1, 3, 5, 10, 30 mg/kg, p.o.), pregabalin (3, 6, 12, 24 mg/kg, p.o.) or gabapentin (25, 50, 75, 100 mg/kg, p.o.) dose-dependently reversed mechanical allodynia in three pain models. Isobolographic analysis indicated that the combinations of nefopam and gabapentinoids exerted synergistic anti-nociceptive effects in inflammatory, osteoarthritis, and neuropathic pain mouse models, as evidenced by the experimental ED 50 (median effective dose) falling below the predicted additive line. Moreover, the combination of nefopam-pregabalin/gabapentin alleviated carrageenan-induced inflammation and edema, and also prevented gabapentinoids-related sedation or ataxia by lowering their effective doses. Collectively, the co-administration of nefopam and gabapentinoids showed synergistic analgesic effects and may result in improved therapeutic benefits for treating pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Multimodal analgesia is central to pain management after total knee arthroplasty (TKA). This study aimed to evaluate the efficacy of adding oral nefopam to multimodal analgesia for post-TKA pain management., Methods: In this prospective, double-blind, placebo-controlled, randomized trial, 100 patients who underwent TKA at our hospital were randomized to either the nefopam or the control group. After surgery, patients in the nefopam group received 200 mg of celecoxib, 150 mg of pregabalin, and 40 mg of nefopam twice daily to control postoperative pain. Patients in the control group received 200 mg of celecoxib, 150 mg of pregabalin, and a placebo. Oxycodone hydrochloride (10 mg) was used as the rescue analgesic. If the pain remained poorly controlled, 10 mg of morphine hydrochloride was injected subcutaneously as a secondary rescue analgesic. The primary outcome was the postoperative consumption of oxycodone and morphine as rescue analgesics. Secondary outcomes were postoperative pain assessed using the visual analogue scale (VAS), functional recovery assessed by the range of knee motion and ambulation distance, time until hospital discharge, indicators of liver function, and complication rates., Results: Patients in the nefopam group had significantly lower postoperative oxycodone and morphine consumption within 24 hours after surgery and during hospitalization, lower VAS pain scores at rest and during motion within 24 h after surgery, better functional recovery on postoperative days 1 and 2, and a shorter hospital stay. However, the absolute reduction in 0 to 24 h opioid consumption, VAS pain scores, and knee range of motion did not exceed the reported minimal clinically important difference. Both groups had similar indicators of liver function and complication rates., Conclusions: Adding oral nefopam to multimodal analgesia resulted in statistically significant improvements in opioid consumption, VAS pain scores, and functional recovery. However, the amount of improvement may not be clinically important., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To assess the efficacy and adverse events linked to the utilization of fentanyl for perioperative pain management in dentistry., Methods: This systematic review of randomized clinical trials (RCTs) adhered to the PRISMA guidelines and incorporated various databases., Results: Eleven RCTs studying 674 patients were analyzed. Perioperative pain was predominantly evaluated in patients undergoing surgery for impacted molars, although some studies also included patients with other conditions such as oral submucous fibrosis, maxillary cancer, bony temporomandibular joint ankylosis, irreversible pulpitis, among others. Combined with dexmedetomidine, fentanyl produced enhanced analgesic effects. It demonstrated comparable efficacy when compared to nefopam and nalbuphine. Both intranasal and intravenous administration routes proved equally effective. In four RCTs, the transdermal fentanyl patch outperformed the control group, except in the clinical trial where it was compared to ropivacaine. The main adverse events associated with the use of fentanyl included nausea, vomiting, drowsiness, delirium, and respiratory depression; however, they were like those reported in the comparison groups., Conclusions: While fentanyl demonstrated satisfactory perioperative analgesic efficacy, there were other alternatives that displayed better or comparable outcomes. Due to the risks and potential for misuse of fentanyl, these alternatives must be considered although adverse events were also reported., (© 2023 Wiley Periodicals LLC.)

Background and Objectives : This study explored how nefopam, a non-opioid analgesic in a multimodal regimen, impacts postoperative pain, opioid use, and recovery quality in single-port robot-assisted laparoscopic cholecystectomy (RALC) patients with a parietal pain block, addressing challenges in postoperative pain management. Materials and Methods : Forty patients scheduled for elective single-port RALC were enrolled and randomized to receive either nefopam or normal saline intravenously. Parietal pain relief was provided through a rectus sheath block (RSB). Postoperative pain was assessed using a numeric rating scale (NRS) in the right upper quadrant (RUQ) of the abdomen, at the umbilicus, and at the shoulder. Opioid consumption and recovery quality, measured using the QoR-15K questionnaire, were also recorded. Results : The 40 patients had a mean age of 48.3 years and an average body mass index (BMI) of 26.2 kg/m 2 . There were no significant differences in the pre- or intraoperative variables between groups. Patients receiving nefopam reported significantly lower RUQ pain scores compared to the controls, while the umbilicus and shoulder pain scores were similar. Rescue fentanyl requirements were lower in the nefopam group in both the PACU and ward. The QoR-15K questionnaire scores for nausea and vomiting were better in the nefopam group, but the overall recovery quality scores were comparable between the groups. Conclusions : Nefopam reduces RUQ pain and opioid use post-single-port RALC with a parietal pain block without markedly boosting RSB's effect on umbilicus or shoulder pain. It may also better manage postoperative nausea and vomiting, underscoring its role in analgesia strategies for this surgery.

Purpose: To identify pharmacological and nonpharmacological interventions adopted for pain relief in the postoperative period of coronary artery bypass graft surgery., Design: Integrative review., Methods: Studies published in English, Spanish, and Portuguese from January 2010 to December 2019 in Cumulative Index to Nursing and Allied Health Literature (CINAHL), Latin American and Caribbean Literature on Health Science, PubMed, and Web of Science. Two hundred studies were identified and eleven were included. Methodological analysis was performed using the Medical Education Research Study Quality Instrument., Findings: The studies found were organized into three thematic categories: pharmacological interventions (methadone, morphine, lidocaine gel, remifentanil, sufentanil, and nefopam), nonpharmacological interventions (low-level laser therapy, light-emitting diode, Class IV laser, and transcutaneous nerve stimulation) and anesthetic techniques (dexmedetomidine, ultrasound-guided pectoral nerve block, high thoracic epidural analgesia, and perioperative parasternal block with levobupivacaine)., Conclusions: A greater tendency to use drug strategies for postoperative pain relief was identified. The drugs used demonstrated efficacy and safety in the treatment of pain, with the exception of nefopam, which showed little benefit in this population. Nonpharmacological interventions, used as adjuvants to drug treatment, were shown to be safe, effective, and well tolerated by the patients., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest related to this article., (Copyright © 2024 The American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.)

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., (© 2023 European Pain Federation - EFIC ®.)

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.

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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

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.

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare no competing interests., (Copyright: Thomas Schulz et al.)

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.

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.

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., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Eiamcharoenwit J et al.)

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 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., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Eiamcharoenwit J et al.)

Background: Nefopam is a non-opioid, non-steroidal, central acting drug used effectively for postoperative pain. The efficacy of nefopam for cancer pain remains unclear. We aimed to evaluate the analgesic efficacy of nefopam for cancer pain in a randomized controlled trial. Methods : Patients with moderate to severe cancer pain (n=40) were randomly divided into two groups. The nefopam group (n=20) received three 20 mg doses of nefopam every 8 hours. The placebo group (n=20) received normal saline. Intravenous patient-controlled analgesia with morphine was given for breakthrough pain for 48 hours. The primary outcome was significant pain reduction. Secondary outcomes were morphine consumption over 48 hours and incidence of side effects. Results: The nefopam group showed pain reduction at 12 hours (65% of patients), 24 hours (80%), 36 hours (85%), and 48 hours (65%). The placebo group showed pain reduction at 12 hours (70%), 24 hours (75%), 36 hours (80%), and 48 hours (60%). However, there were no statistically significant differences between the groups (p>0.05). The median dosage of morphine consumption in 48 hours was lower in the nefopam group (25.5 mg) compared with the placebo group (37 mg), but this was not statistically significant (p=0.499). There were no statistically significant differences in blood pressure and heart rate between the groups. Side effects in both groups were comparable. Conclusions: At dosage of 60 mg in 24 hours, nefopam did not provide significant pain reduction in moderate to severe cancer pain patients. However, there was a trend of reduced opioid consumption. Further studies with larger sample sizes, longer duration, or higher doses of nefopam are warranted. Registration: Thai Clinical Trail Registry (TCTR) ID TCTR20181016001; registered on 12 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Pasutharnchat K et al.)

Shivering is a common postoperative complication that occurs after both general and regional anesthesia even in the cases when hypothermia during surgery has been averted. Patients describe it as a highly unpleasant experience, while clinicians are concerned due to its adverse effects such as increased oxygen consumption. In this article, we present a summary of the pathophysiological mechanisms involved in postoperative shivering (POS), risk factors, and inadvertent effects. The major objective of this article was to review the existing literature on the effi ciency of various drug interventions as a prophylactic measure against POS. Since α2-adrenergic, opioid, anticholinergic, and serotonergic pathways are thought to play a role in the pathogenesis of POS, a wide variety of drugs has been investigated in this regard. Although the methodological diversity of the study designs and regimens does not support drawing defi nite conclusions, there is evidence indicating a benefi cial effect of dexmedetomidine, ketamine, tramadol, meperidine, dexamethasone, nefopam, granisetron, and ondansetron in the prevention of POS. The purpose of this review is to provide a thorough insight on various drug options and to serve as an aid for clinicians for careful analysis of the advantages and disadvantages of each regimen to decide which regimen will be ideally suited for the medical profi le of each patient.

Background: Head-to-head comparisons of combinations of more than one non-opioid analgesic (NOA) with morphine alone, for postoperative analgesia, are lacking. The objective of this multicentre, randomised, double-blind controlled trial was to compare the morphine-sparing effects of different combinations of three NOAs-paracetamol (P), nefopam (N), and ketoprofen (K)-for postoperative analgesia., Methods: Patients from 10 hospitals were randomised to one of eight groups: control (C) received saline as placebo, P, N, K, PN, PK, NK, and PNK. Treatments were given intravenously four times a day during the first 48 h after surgery, and morphine patient-controlled analgesia was used as rescue analgesia. The outcome measures were morphine consumption, pain scores, and morphine-related side-effects evaluated 24 and 48 h after surgery., Results: Two hundred and thirty-seven patients undergoing a major surgical procedure were included between July 2013 and November 2016. Despite a failure to reach a calculated sample size, 24 h morphine consumption [median (inter-quartile range)] was significantly reduced in the PNK group [5 (1-11) mg] compared with either the C group [27 (11-42) mg; P<0.05] or the N group [21 (12-29) mg; P<0.05]. Results were similar 48 h after surgery. Patients experienced less pain in the PNK group compared with the C, N, and P groups. No difference was observed in the incidence of morphine-related side-effects., Conclusions: Combining three NOAs with morphine allows a significant morphine sparing for 48 h after surgery associated with superior analgesia the first 24 h when compared with morphine alone., Clinical Trial Registration: EudraCT: 2012-004219-30; NCT01882530., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Catheter-related bladder discomfort (C.R.B.D.) is a risk factor for emergence agitation and delirium in postoperative phase. It may be resistant to conventional analgesic therapy such as opioids. This study evaluated the role of preoperative treatment using intravenous 20 mg nefopam in reducing the incidence and severity of C.R.B.D. during the first postoperative 24 h after urinary catheterization when compared with placebo., Methods: Seventy adult males undergoing elective transurethral resection of bladder tumor requiring urinary bladder catheterization intraoperatively were randomly divided into two groups of 35 patients. In the intervention group (Group N), intravenous 20 mg nefopam in 100 mL normal saline was administered before spinal anesthesia. The placebo group (Group P) received intravenous normal saline 100 mL instead. The incidence and severity of side-effects, including C.R.B.D. at 1, 2, 6, and 24 h after surgery, was evaluated., Results: The incidence of C.R.B.D. was reduced in Group N compared with Group P during the first postoperative 24 h (6/33 [18.2%] vs 22/35 [62.9%], Group N vs Group P, p = .000). The severity of C.R.B.D. also varied significantly at postoperative 1, 2, and 6 h. The use of postoperative analgesics was reduced in Group N compared with Group P (8/33 [24.2%] vs 25/35 [71.4%], Group N vs Group P, p = .000)., Conclusions: The preoperative administration of single-dose intravenous nefopam reduced the incidence and severity of C.R.B.D. in the early postoperative period in patients undergoing T.U.R.-B. under spinal anesthesia.

Objective Nefopam is thought to reduce postoperative pain; however, the evidence is insufficient. The recommended dose is 20 mg, and the median effective dose (ED50) in the surgical setting reportedly ranges from 17 to 28 mg. However, nefopam frequently produces inadequate postoperative analgesia. We evaluated the ED50 of nefopam as a single agent in patients undergoing laparoscopic cholecystectomy. Methods Twenty-nine patients were scheduled for laparoscopic cholecystectomy. Postoperative pain was evaluated using a numerical pain scale (NPS). When the NPS score was >3, patients were administered a predetermined dose of nefopam. The dose was calculated using the up-and-down allocation technique based on the previous response. The initial dose was 28 mg, with adjustment intervals of 5 mg. An effective response was defined as a decrease in the NPS score to <3 at 30 minutes after infusion. Results The ED50 of nefopam was 62.1 mg (95% confidence interval, 52.9-72.9 mg). Eight patients reported pain upon injection, and three were excluded due to severe injection pain and phlebitis. Conclusions The estimated ED50 was higher than the predetermined dose based on previous studies. We recommend that the dose of nefopam be chosen after careful consideration of individual variations and clinical settings.

Background: Acute postoperative pain and chronic discomfort are reported after robotic or endoscopic thyroidectomy. The purpose of this prospective, randomized, and double-blinded clinical trial was to investigate whether intraoperative infusion of nefopam decreases acute postoperative pain and chronic discomfort following either a robotic or endoscopic thyroidectomy via the bilateral axillo-breast approach (BABA)., Methods: Patients were randomized into two groups: The control group (n = 29) or the nefopam group (n = 29). Patients in each group were infused with the same volume of saline or nefopam (0.2 mg/kg bolus, 120 μg/kg/h continuous infusion) during surgery. Acute postoperative pain, the need for rescue analgesics, and other postoperative adverse effects were assessed at 1, 6, 24, and 48 h postoperatively. Chronic pain and discomfort was recorded at 3 months after surgery., Results: Patients in the nefopam group reported lower pain scores in the neck, as well as the axilla and anterior chest areas at 1, 6, 24, and 48 h postoperatively, when compared with the control group (P < 0.05 at each time points). Rescue analgesics were required less in the nefopam group than in the control group (1.4 [1] vs. 2.3 [1.5]; P = 0.001). The degree of chronic pain and discomfort were relatively lower in the nefopam group (P < 0.05)., Conclusion: We report that intravenous nefopam infusion during surgery decreased acute postoperative pain and the need for rescue analgesics, as well as chronic discomfort, following BABA robotic or endoscopic thyroidectomy without adverse events.

Background: We assessed whether intraoperative nefopam would reduce opioid consumption and relieve postoperative pain in patients undergoing laparoscopic gastrectomy., Methods: The 60 enrolled patients were randomly assigned to the control (n = 32) or nefopam (n = 28) group. All patients were blinded to their group assignment. We administered 100 ml of normal saline only (control group) or 20 mg of nefopam mixed in 100 ml normal saline (nefopam group) after anesthesia induction and at the end of surgery. The cumulative amount of fentanyl via intravenous patient-controlled analgesia (PCA), incidence of rescue analgesic medication, and numerical rating scale (NRS) for postoperative pain were evaluated along with the total remifentanil consumption., Results: The mean infusion rate of remifentanil was significantly lower in the nefopam group (0.08 ± 0.05 μg/kg/min) than in the control group (0.13 ± 0.06 μg/kg/min) (P < 0.001). Patients in the nefopam group required less fentanyl via intravenous PCA than those in the control group during the first 6 h after surgery (323.8 ± 119.3 μg vs. 421.2 ± 151.6 μg, P = 0.009). Additionally, fewer patients in the nefopam group than in the control group received a rescue analgesic during the initial 6 h postoperatively (78.6 vs. 96.9%, P = 0.028). The NRS measured while patients were in the post-anesthetic care unit was significantly lower in the nefopam group than in the control group (3.8 ± 1.1 vs. 4.8 ± 1.4, P = 0.012). The subsequent NRS obtained after patients had been transferred to the general ward was comparable between the two groups during the following postoperative period., Conclusions: Intraoperative nefopam decreased postoperative pain and opioid consumption in the acute postoperative period after laparoscopic gastrectomy. Hence, nefopam may be considered as a component of multimodal analgesia after laparoscopic gastrectomy.

Background/aim: We performed this prospective randomized double-blind study to compare the effects of nefopam versus ketorolac in intravenous fentanyl-based patient-controlled analgesia (PCA) after shoulder arthroscopic orthopedic surgery. Materials and methods: Ninety-two patients were randomly divided into two groups to receive intravenous PCA. Patients were assigned to either the nefopam group (nefopam 120 mg and fentanyl 20 µg/kg) or the ketorolac group (ketorolac 2 mg/kg and fentanyl 20 µg/kg). Pain was assessed on a visual analogue scale (VAS) and a numeric rating scale (NRS). Additionally, patient satisfaction, adverse events, and vital signs were monitored. Results: There were no significant differences in VAS score (P = 0.48) or NRS score (P = 0.15) between the two groups. Similarly, patient satisfaction did not differ between the two groups [8.5(0.8) vs. 8.2(1.0), P = 0.14]. There were no statistically significant differences in the incidence of nausea (P = 0.72), vomiting (P = 0.46), urinary retention (P = 0.82), sweating (P = 0.49), or dizziness (P = 0.45) between the two groups. Likewise, there were no differences in heart rate [78.2(7.7) vs. 75.2(6.5), P = 0.18] or SpO2 [98.4(1.8) vs. 98.5(1.9), P = 0.83]. Conclusion: Nefopam is an appropriate alternative for co-administration with fentanyl-based PCA in patients who have difficulty using nonsteroidal antiinflammatory drugs.

Once-daily oral dosage of nefopam hydrochloride loaded sustained release microspheres (NPH-MS) was investigated as novel therapeutic strategy for post-operative pain management. Microspheres were synthesized using poly-3-hydroxybutyrate and poly-(ɛ-caprolactone) by double emulsion solvent evaporation technique. NPH-MS were characterized through FTIR, PXRD and SEM. In-vitro drug release study revealed sustained behavior till 24 h. Haemolysis was <5% which signified haemocompatibility of formulation. ED50 in rat tail-flick anti-nociceptive test was found ∼18.12 mg/kg. In post-operative pain model, reversal of mechanical allodynia and thermal hyperalgesia by NPH-MS was statistically significant (p < .001) as compared with NPH till 24 h post-dose.

Background: Nefopam is a centrally acting analgesic which has a theoretical risk of stopping lactation due to its anticholinergic and dopaminergic effects. The aim of this study was to evaluate the effect of nefopam on lactation and to investigate potential adverse effects on newborns., Methods: Seventy-two women, scheduled to undergo a caesarean delivery under spinal anaesthesia and wanting to breastfeed, were randomised to one of two groups: nefopam (20mg, six hourly) or paracetamol (1g, six hourly). In both groups, postoperative analgesia was supplemented with ketoprofen (50mg, six hourly) in conjunction with intrathecal morphine 0.1mg. The primary outcome was onset of lactation, estimated by weighing the newborns before and after feeding; by maternal perception of breast fullness and based on serum prolactin concentration 48hours postpartum. Secondary outcomes were neonatal adverse effects evaluated by neurobehavioural score at 12, 24, 48, and 72hours after birth. Statistical analyses were performed using Chi-squared, Fisher exact and Student t tests as appropriate. P<0.05 was considered statistically significant., Results: The difference in the weight of the newborn before and after each feed, maternal perception of breast fullness and serum prolactin did not significantly differ between groups. The volume of artificial milk given to newborns of mothers in the nefopam group on days two and three was significantly greater than for the paracetamol group. Neurobehavioural scores were comparable at each time point., Conclusion: Nefopam does not appear to delay the onset of lactation or present any clear risk to the newborn., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: There has been a growing interest in continuous local anaesthetic wound infiltration as a non-opioid technique for postoperative pain relief. The impact of this modality on baseline analgesia after spinal fusion surgery has however been inconclusive. We tested whether continuous wound infiltration with ropivacaine can enhance postoperative analgesia compared to a baseline intravenous multimodal analgesia protocol after spinal fusion surgery., Methods: In this randomized, double-blinded, placebo-controlled study, a multiholed 19-gauge catheter was placed at the end of the surgical procedure through the wound to permit the continuous administration (8 ml/h) of ropivacaine 0.2 % (ropivacaine group; n = 19 patients) or saline (control group; n = 20 patients) during the first 48 postoperative hours (H48). Both groups received intraoperative low-dose ketamine, a combination of acetaminophen, non-steroidal anti-inflammatory drug, and nefopam over the same postoperative period, and morphine delivered by a patient-controlled analgesia (PCA) device., Results: Morphine consumption was comparable between the two groups both at H48, 38 mg (26:52) (median, 25th:75th percentile) (control group) versus 43 mg (19:74) (ropivacaine group), and at H24, 18 mg (16:22) versus 22 mg (9:35) respectively. Pain scores at rest and during mobilization, quality of postoperative sleep, and morphine-related side effects were comparable between the two groups at H24 and H48., Conclusion: Our findings indicate that no additional analgesia was provided with continuous wound infiltration of ropivacaine compared to a baseline intravenous multimodal analgesia protocol after spinal fusion surgery., Trial Registration: Clinicaltrials.gov #NCT01743794.

Background: Morphine, and analgesics other than morphine (AOM), are commonly used to treat postoperative pain after major surgery. However, which AOM provides the best efficacy-safety profile remains unclear., Methods: Randomized trials of any AOM alone or any combination of AOM compared with placebo or another AOM in adults undergoing major surgery and receiving morphine patient-controlled analgesia were included in a network meta-analysis. The outcomes were morphine consumption, pain, incidence of nausea, vomiting at 24 h and severe adverse effects., Results: 135 trials (13,287 patients) assessing 14 AOM alone or in combination were included. For all outcomes, comparisons with placebo were over-represented. Few trials assessed combinations of two AOM and none the combination of three or more. Network meta-analysis found morphine consumption reduction was greatest with the combination of two AOM (acetaminophen + nefopam, acetaminophen + NSAID, and tramadol + metamizol): -23.9 (95% CI -40;-7.7), -22.8 (-31.5;-14) and -19.8 (35.4;-4.2) mg per 24 h, respectively. For AOM used alone, morphine consumption reduction was greatest with α-2 agonists, NSAIDs, and COX-2 inhibitors. When considering the risk of nausea, NSAIDs, corticosteroids and α-2 agonists used alone were the most efficacious (OR 0.7 [95% CI: 0.6-0.8], 0.36 [0.18-0.79], 0.41 [0.15-.64], respectively). The paucity of severe adverse effects data did not allow assessment of efficacy-safety balance., Conclusions: A combination of aetaminophen with either an NSAID or nefopam was superior to most AOM used alone, in reducing morphine consumption. Efficacy was best with three AOM used alone (α-2 agonists, NSAIDs and COX-2 inhibitors) and least with tramadol and acetaminophen. There is insufficient trial data reporting adverse events., Clinical Trial Registration: PROSPERO: CRD42013003912., (© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Nefopam hydrochloride is a centrally acting compound that induces antinociceptive and antihyperalgesic properties in neuropathic pain models. Previous reports have shown that activation of adenosine triphosphate (ATP)-sensitive and calcium-activated potassium (KATP and KCa2+) channels has antiallodynic effects in neuropathic pain. In the present study, we evaluated the relationship between potassium channels and nefopam to determine whether the antiallodynic effects of nefopam are mediated by potassium channels in a neuropathic pain model., Methods: Mechanical allodynia was induced by spinal nerve ligation (SNL) in rats, and the paw withdrawal threshold (PWT) was evaluated by the use of von Frey filaments. Nefopam was administered intraperitoneally before or after SNL. We assessed the relationship between nefopam and intrathecal injection of the KCa2+ channel antagonists apamin and charybdotoxin, and the KATP channel blocker glibenclamide to assess their abilities to reverse the antiallodynic effects of nefopam. In addition, we evaluated whether the KATP channel opener pinacidil had antiallodynic effects and promoted the antiallodynic effects of nefopam., Results: Administration of nefopam before and after SNL induced significant antiallodynic effects (P < .01, respectively), which were significantly reduced by glibenclamide (P < .01). Pinacidil improved the antiallodynic effects of nefopam (P < .01); however, apamin and charybdotoxin had little effects on the antiallodynic properties of nefopam., Conclusions: The antiallodynic effects of nefopam are increased by a KATP channel agonist and reversed by a KATP channel antagonist. These data suggest that the KATP channel is involved in the antiallodynic effects of nefopam in a neuropathic pain model.

Breast cancer surgery is known to cause severe acute postoperative pain, which can persist for a long time. We administered nefopam preventively to patients undergoing lumpectomy with axillary lymph node dissection or sentinel lymph node biopsy, and evaluated its efficacy on acute and chronic postoperative pain.Enrolled patients were assigned to the nefopam (n = 41) or the control (n = 42) group. Before initiating the operation, 20 mg of nefopam was given to the patients of the nefopam group, and normal saline was used in the control group. Ketorolac was given at the end of surgery, and meloxicam was prescribed in the postoperative period to all patients in both groups. Pain was assessed using a numerical rating scale (NRS), and the rescue analgesic drug was given when the NRS was >5. Implementation of postoperative chemotherapy, radiotherapy (RT), or hormone therapy was evaluated.The NRS of postoperative pain was significantly lower in the nefopam than in the control group in the postanesthetic care unit (4.5 ± 2.2 vs 5.7 ± 1.5, respectively; P = 0.01), at postoperative 6 h (3.0 ± 1.6 vs 4.5 ± 1.3, respectively; P < 0.001), and at postoperative 24 h (3.1 ± 1.1 vs 3.8 ± 1.5, respectively; P = 0.01) with reduced use of rescue analgesic drugs. Significantly fewer patients suffered from chronic postoperative pain in the nefopam than in the control group at postoperative 3 months (36.6% vs 59.5%, P = 0.04). Considering only the cohort without postoperative adjuvant RT, the difference in the proportion of patients reporting chronic pain increased (23.5% in the nefopam group vs 61.5% in the control group, P = 0.04).Preventive nefopam was helpful in reducing the acute postoperative pain, with reduced use of rescue analgesic drugs, and it contributed to reduced occurrence of chronic pain at postoperative 3 months after breast cancer surgery.

Objective: Neuraxial morphine is considered as a "gold standard" for pain relief after cesarean section, however it causes bothersome side effects. Alternative analgesia including nonsteroidal antiinflammatory drugs (NSAID) has been proposed. We aimed to assess the morphine sparing effect of continuous wound infiltration with a local anesthetic, when added to multimodal systemic analgesia including NSAID without subarachnoid morphine., Study Design: Sixty-eight women scheduled for elective cesarean section under spinal anesthesia were included in a randomized controlled open-label trial. Patients received bupivacaine spinal anesthesia without intrathecal morphine. Postoperative analgesia consisted for all patients in multimodal systemic analgesia with acetaminophen, nefopam, celecoxib, and patient-controlled intravenous morphine for 24h. The intervention group also received subfascial levobupivacaine infiltration through a multi-holed catheter, at 6.25mg/h for 48h. The primary endpoint was total morphine consumption at 24h postoperatively; and secondary endpoints were pain scores, side effects, breastfeeding comfort, maternal satisfaction, and nurse workload. Student t test, Mann-Whitney test or χ(2) test were used when appropriate., Results: The intervention group had 6.7mg less morphine consumption (95%CI -1.3mg; -12mg, P=0.02), and 0.8 pain point less at rest on the numerical rating scale 0-10 (95%CI -0.3; -1.3, P=0.002). The intervention was associated with significantly better breastfeeding comfort (+1.7 at numerical rating scale score 0-10, 95%CI +0; +3.3, P=0.0498). Wound dressing changes were required in a significantly higher proportion of intervention-group women (12/34 vs. 1/34, P=0.002)., Conclusion: Adding continuous levobupivacaine infiltration to multimodal analgesia after cesarean section without subarachnoid morphine decreased postoperative morphine consumption and pain, facilitated breastfeeding initial comfort, and slightly increased nurse workload., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Nefopam has been used as an adjuvant to opioid analgesia after operation. We investigated the efficacy of nefopam as an adjunct to fentanyl-based intravenous patient-controlled analgesia (IV PCA) on post-operative pain relief in patients undergoing renal transplantation., Methods: Ninety-eight patients undergoing elective renal transplantation were randomised into two groups: nefopam or control groups. The former received nefopam (160 mg in 200 ml at a rate of 4 ml/h) whereas the latter received normal saline during the first 48 h after reperfusion of grafted kidney. Pain intensity scores, cumulative dose of fentanyl, and the incidence of adverse events were assessed at 1, 6, 12, 24, and 48 h post-operatively. Serum creatinine and estimated glomerular filtration rate were evaluated on post-operative days 1, 2, 4, and 7., Results: The cumulative fentanyl consumption during the first 48 h after operation was 19% less in the nefopam group than that in the control group (1005 ± 344 μg vs. 1246 ± 486 μg, mean ± SD; P = 0.006). Pain intensity scores at rest and on coughing were significantly lower in the nefopam group throughout the first 12 and 48 h after operation, respectively. Adverse events and early graft function were comparable between the groups, except a significantly lower incidence of drowsiness observed in the nefopam group (4% vs. 21%, P = 0.027)., Conclusion: In combination with fentanyl PCA, nefopam reduced post-operative fentanyl consumption with superior analgesia after renal transplantation., (© 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

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.

We examined the involvement of spinal 5-HT(5-hydroxytryptamine) receptor 3(5-HT3R) and 7(5-HT7R) as well as the overall role of descending serotonergic projections in the analgesic effects of intrathecal(i.t.) nefopam for two rat models of formalin and paw incision test. I.t. nefopam produced an antinociceptive effect in a dose-dependent manner in both tests. Lesioning the spinal serotonergic projections using i.t. 5,7-dihydroxytryptamine(5,7-DHT) did not influence the intensity of allodynia in the paw incision test, but i.t. 5,7-DHT abolished the effect of nefopam. In the formain test, i.t. 5,7-DHT alone significantly diminished the flinches, but the effect of nefopam was not affected by i.t. 5,7-DHT. Antagonism study showed that i.t. 5-HT7R antagonist, SB269970 significantly blocked the antinociceptive effect of nefopam in both tests, but i.t. 5-HT3R antagonist, ondansetron has no influence on the effect of nefopam. The present study demonstrates that descending spinal serotonergic projections play a vital role in antinociceptive effect of i.t. nefopam in the paw incision test, but indeterminate in the formalin test. In both tests, the antinociceptive effect of i.t. nefopam involves the spinal 5-HT7R, but not 5-HT3R., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

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.

Objectives: Ketamine and nefopam has been documented to decrease pain intensity and improve rehabilitation after total knee arthroplasty (TKA). We conducted a follow-up study of a previously randomized clinical trial to determine the prevalence and risk factors of chronic pain 1 year after TKA and to assess the role of perioperative administration of ketamine and nefopam., Materials and Methods: The original randomized, double-blind trial evaluated postoperative pain in 75 patients scheduled for TKA who received either a 48-hour infusion of ketamine or nefopam compared with placebo. The current study has evaluated patients at 6 and 12 months for the presence of chronic pain defined as a visual analogue scale ≥40 mm during a stair-climbing test. Other outcomes were incidence of neuropathic pain evaluated (DN4 score), active flexion of the knee, and functional outcome (KOOS-PS score)., Results: A total of 69 patients completed the trial. The prevalence of chronic pain at 12 months was 17.4% (95% confidence interval [CI], 10.2%-27.9%) without difference between the ketamine (12.5%), nefopam (13.7%), and placebo groups (26.1%). Prevalence of neuropathic pain was 10.2% (95% CI, 3%-17.3%). Ketamine reduced DN4 scores (P=0.02), increased knee flexion (P=0.0007), and KOOS-PS scores (P<0.0001) compared with placebo. A visual analogue scale score ≥60 mm in the postoperative period was the only risk factor associated with the occurrence of chronic pain (odds ratio 4.54; 95% CI, 1.17-17.67)., Discussion: After TKA, the intensity of postoperative pain is a risk factor of chronic pain on movement. Intraoperative ketamine seems to improve long-term results of rehabilitation in this setting.

Purpose: We aimed to investigate the frequency and severity of pain associated with intravenous injection of nefopam and to determine whether a slow rate of administration can effectively reduce such pain., Methods: We used a solution containing 30 mg nefopam diluted to 20 ml in saline. In all, 102 adult patients undergoing minor surgery were randomly allocated to one of three administration groups: A (60 ml/h, n = 34); B (120 ml/h, n = 34); or C (180 ml/h, n = 34). All patients scored the maximal pain experienced during the 120-s infusion period, using the visual analogue scale (VAS) and the verbal pain score (VPS). Adverse events including phlebitis were recorded., Results: Eighty-three patients (29 in group A, 27 each in groups B and C) were included in the final analysis. The incidence of injection pain was lower in group A (86.2 %) than in groups B (96.3 %) and C (100 %), but this difference was not statistically significant. The proportion of patients with a tolerable level of pain (VAS 0-3 and VPS 0-1) was significantly higher in group A (79.3 %) versus groups B (7.4 %) and C (3.7 %). The mean VAS scores for groups A, B, and C were 2.2 ± 1.3, 5.1 ± 1.6, and 7.2 ± 1.7, respectively, and these differences were statistically significant., Conclusions: At the slower rate of infusion (60 ml/h) of the 1.5 mg/ml nefopam solution, injection pain intensity was attenuated to a significantly greater degree than at the faster rates.

Nefopam is a non-opioid analgesic drug, used widely in European countries to control postoperative pain. However, its mechanism of action remains unclear. In this study, the effects of intrathecal nefopam on spinal nerve-ligated induced neuropathic pain in rats were examined and the involvement of the 5-HT7 receptor at the spinal level was determined. Next, a 5-HT7 receptor antagonist (SB-269970) or descending serotonergic pathway ablation agent (5,7-DHT) was administered intrathecally before delivery of the nefopam to determine the contribution of spinal 5-HT7 receptors or descending serotonergic pathway to the activity of nefopam. The concentrations of 5-HT were measured. Intrathecal nefopam dose-dependently produced the antiallodynic effect. Pre-treatment with intrathecal SB-269970 reversed the antiallodynic effect of the nefopam. 5,7-DHT failed to affect the effect of nefopam. The concentrations of 5-HT in the spinal cord and plasma were decreased in neuropathic pain. Intrathecal nefopam increased the levels of 5-HT in the spinal cord and plasma. Intrathecal nefopam is effective in the attenuation of neuropathic pain induced by spinal nerve ligation and nefopam increases the level of 5-HT. Additionally, the 5-HT7 receptor is involved in the antiallodynic action of nefopam in the spinal cord., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

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.

4 combinations of analgesia were studied: 1) Nefopam and patient-controlled analgesia (PCA) with Trimeperidine; 2) Ketoprofen (100 microg each 12 hours intramuscular) and PCA with Trimeperidine; 3) Nefopam, Ketoprofen and PCA with Trimeperidine; 4) PCA with Trimeperidine as monotherapy in early postoperative period in cardio-surgical patients. 80 patients (age from 40 to 70) were divided into 4 groups, 20 patients in each group. Administration of Nefopam and Ketoprofen before extubation reduced the intensity of pain syndrome (in average on 90%) and promoted the early stirring up of patients. Combination of Nefopam and Ketoprofen provided the most expressed analgesic and opioids-saving effects. In this group average amount of Trimeperidine per 24 hours was 14.7 microg that was 4.9 times less than in group of PCA with Trimeperidine as monotherapy. Dynamics of maximal inspiratory capacity of the lungs in the first three groups was better than in group of PCA with Trimeperidine as monotherapy beginning from 6th hour of study. In common undesirable effects was connected with Trimeperidine administration and depended on its dose. The frequency of nausea, vomit, dizziness and weakness was authentically higher in the group of PCA with Trimeperidine as monotherapy than in other groups.

Objective: The purpose of this randomized, double-blind placebo-controlled study was to evaluate the effect of nefopam, a centrally acting antinociceptive compound, on the development of hyperalgesia after sternotomy. Preventive strategy giving nefopam from the early stage of anesthesia was compared with a postoperative strategy only and placebo., Design: This study was double-blinded and randomized., Setting: It was conducted in a single university hospital., Participants: Ninety American Society of Anesthesiologists II to III patients scheduled for elective cardiac surgery., Interventions: Patients were assigned randomly to receive a 0.3-mg/kg bolus of nefopam at the induction of anesthesia followed by a continuous infusion of 0.065 mg/kg/h for 48 hours (G1), a 0.3-mg/kg bolus of nefopam at the end of surgery followed by a continuous infusion of 0.065 mg/kg/h for 48 hours (G2), or a placebo (G3). Postoperative analgesia was based on morphine patient-controlled analgesia and rescue analgesia when necessary. Postoperative hyperalgesia, pain scores, morphine consumption, and postoperative cognitive dysfunction were assessed for the first 48 hours and thereafter on postoperative days 4 and 7., Measurements and Main Results: The postoperative extent of dynamic hyperalgesia and the decrease of the nociceptive threshold evaluated by von Frey filaments at the sternal midline were smaller in group 1 and group 2 compared with the placebo group at the 24th hour. The primary objective was the extent of hyperalgesia at the midline given as the mean (standard deviation [SD]) (4.4 [2.5] cm for G1, 4.1 [2.7] for G2, and 6.1 [2.7] cm for G3. The punctuate is given as mean (SD) (64 [43] g for G1, 68 [40.8] g for G2, and 32 [27] g for G3; with p < 0.05 for the comparisons of extent and punctuate hyperalgesia between G1 and G3 and G2 and G3). The extent of hyperalgesia was not significantly different among the 3 groups on days 2, 4, and 7 after surgery. There were no significant differences in pain scores, morphine consumption, or postoperative cognitive dysfunctions., Conclusions: Nefopam administered during the perioperative period slightly reduced acute hyperalgesia after cardiac surgery, but this was not associated with improved analgesic efficacy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To assess the improvement of practices in postoperative analgesia after a cesarean section post implementation of a corrective program., Study Design: Prospective impact study., Patients and Methods: After obtaining ethics approval, we included all patients undergoing a cesarean section at Montpellier University Hospital during February 2011 (PRE group) and March 2012 (POST group). The patients were interviewed on the fourth day postpartum about pain management and related data was collected from the chart. From March 2011 to February 2012, training sessions were held for the paramedical and medical teams., Results: Sixty patients were included in each group. The two groups were not significantly different. The mean overall numeric rating scale worst pain score between Day 0 and Day 4 in POST group was lower (5.5±2.5 vs. 6.5±2.4 p<0.01) and impairment during mobilization decreased significantly. Compliance with protocols improved in the POST group: the number of women receiving full analgesia regiment increased from 12% to 68% between PRE and POST period., Conclusion: After an awareness campaign of the paramedical and medical staff, we succeeded in improving significantly the routine use of analgesics regardless of their level. Nevertheless healthcare professionals still seem reluctant to administer opioids., (Copyright © 2013 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.)

Background: Multimodal analgesia combining several non-opioid analgesics is recommended for pain control after surgery. In one study of total hip arthroplasty (THA), pain relief achieved by adding ketamine to the paracetamol-ketoprofen combination was statistically significant but remained inadequate in most patients. In two other studies, the analgesic effect of nefopam was synergistic with that of ketoprofen and additive with that of paracetamol. Adding nefopam to the paracetamol-ketoprofen-ketamine combination has not been evaluated., Hypothesis: Adding nefopam to the paracetamol-ketoprofen-ketamine combination significantly improves analgesia after THA., Material and Methods: A prospective single-centre comparative non-randomised study (control group then nefopam group) was conducted in patients undergoing THA under general anaesthesia. All patients received paracetamol-ketoprofen-ketamine and morphine/droperidol patient-controlled analgesia. The nefopam group also received a continuous infusion of nefopam (120 mg/d for 48 h). Pain was evaluated daily for 7 days. The main evaluation criteria were morphine consumption, and pain intensity evaluated using a numerical rating scale and a validated questionnaire. To detect a 40% morphine-sparing effect by H24 (α=0.05 and β=0.2), 85 patients were needed in each group., Results: The two groups (90 patients/group) had no significant differences for perioperative characteristics, pain scores, morphine consumption at H24 (nefopam, 13 ± 12 mg and control, 14 ± 13 mg, P=0.39), or functional recovery. Compared to the control group, the nefopam group had lower rates of nausea/vomiting (P<0.0001), pruritus (P=0.002), and visual disturbances (P=0.02)., Discussion: Nefopam failed to improve pain relief when added to a multimodal analgesia regimen but alleviated several morphine-induced side effects. Redundancy between nefopam and ketamine may explain the absence of greater pain relief. This study emphasises the need for clinical evaluations of every analgesic regimen, as the available data were not sufficient to predict these results., Level of Evidence: Level III, case-control study., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

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.

Whether intestinal toxicity of preferential or selective COX-2 inhibitors is reduced compared with that of standard NSAIDs is controversial. A 26-year-old woman presented with acute abdominal pain and bloody diarrhoea a few days after beginning meloxicam treatment. Endoscopic examination of the colon showed erythematous and ulcerative lesions involving 15 cm of the left colon. No aetiology has been found for colitis. Diarrhea disappeared 1 week after meloxicam was stopped. Total colonoscopy 3 months and 2 years later was normal. The role of meloxicam in the etiology of colitis was considered plausible. This report and a few other cases in the literature suggest that cyclooxygenase-2 selective non-steroidal anti-inflammatory drug inhibitor toxicity should be investigated in case of unexplained acute colitis., (Copyright © 2013. Published by Elsevier Masson SAS.)

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.

Background: Renal colic pain is a frequent cause of emergency department admissions (1-2% of admissions). It is extremely painful, often requiring intravenous morphine titration. The aim of this study was to estimate the effect of adding nefopam to ketoprofen upon subsequent morphine consumption and the time needed to achieve adequate analgesia in renal colic., Methods: The authors undertook a prospective, monocentric, randomised, double-blind, placebo-controlled, parallel-group study, using an intent-to-treat analysis. Patients admitted to the emergency department for suspected hyperalgesic (evaluated with a visual analogue scale (VAS)) renal colic were enrolled in the study. They were administered an initial treatment of ketoprofen before being randomly assigned to either the placebo or nefopam group., Results: Thirty patients admitted to the emergency department were enrolled in the study. Morphine analgesia was necessary for 10 patients (66.6%) (95% CI 40% to 90%) in the nefopam group and 8 (53.3%) (95% CI 30% to 80%) in the placebo group, with no statistically significant difference found (difference 13.3%, 95% CI -51% to 24%). The time needed to achieve adequate analgesia in the case of morphine titration was 8.3 min (95% CI 4.2 to 12.5) in the nefopam group and 9 min (95% CI 2.7 to 15.3) in the placebo group, with no statistically significant difference (difference 0.7, 95% CI 7.25 to 8.58)., Conclusion: This study did not reveal any significant difference between nefopam and placebo. This may be due to lack of statistical power or lack of effectiveness., Clinical Trial Registration Number: http://ClinicalTrials.gov ID number NCT00639574.

Objective: To determine the efficacy and safety of neuromodulators for pain management in patients with inflammatory arthritis., Methods: A Cochrane systematic review was performed as part of the 3e Initiative on pain management in inflammatory arthritis. We searched Medline, Embase, and Cochrane Central for studies to November 2010, and American College of Rheumatology/European League Against Rheumatism meeting abstracts published in 2008-2009. Studies were included if they were randomized or quasirandomized controlled trials that compared any neuromodulator (excluding cannabis) to another therapy (active or placebo, including nonpharmacological therapies) for pain in patients with RA, psoriatic arthritis, ankylosing spondylitis, or spondyloarthritis. Primary outcomes of interest were patient-reported pain relief of 30% or greater and withdrawals due to adverse events. Two authors independently extracted data and assessed methodological quality. A risk of bias assessment was performed using the methods recommended by the Cochrane Collaboration., Results: Three trials, all in RA and all at high risk of bias, were included in this review. Two placebo-controlled trials evaluated nefopam (52 participants) and one placebo-controlled trial evaluated topical capsaicin 0.025% (31 participants). Pooled analysis showed a significant reduction in pain levels favoring nefopam over placebo after 2 weeks [weighted mean difference -21.2, 95% CI -35.6 to -6.7; number needed to treat (NNT) 2, 95% CI 1.4 to 9.5]. However, nefopam was associated with significantly more adverse events (RR 4.1, 95% CI 1.6 to 10.7; number needed to harm 9, 95% CI 2 to 367), predominantly nausea and sweating. In one trial, capsaicin reduced pain more than placebo at 1 and 2 weeks (MD -23.8, 95% CI -44.8 to -2.8; NNT 3, 95% CI 2-47, and -34.4, 95% CI -54.7 to -14.14; NNT 2, 95% CI 1.4 to 6, respectively). Of those who received capsaicin, 44% developed burning at the site of application and 2% withdrew as a result., Conclusion: Based on 3 small trials, which were all at high risk of bias, there is weak evidence that nefopam and capsaicin are superior to placebo in reducing pain in patients with RA, but both are associated with a significant side effect profile. There are no available data for other types of IA or for newer agents such as gabapentin or pregabalin.

Background: Pain management is a high priority for patients with rheumatoid arthritis (RA). Despite deficiencies in research data, neuromodulators have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain., Objectives: The aim of this review was to determine the efficacy and safety of neuromodulators in pain management in patients with RA. Neuromodulators included in this review were anticonvulsants (gabapentin, pregabalin, phenytoin, sodium valproate, lamotrigine, carbamazepine, levetiracetam, oxcarbazepine, tiagabine and topiramate), ketamine, bupropion, methylphenidate, nefopam, capsaicin and the cannabinoids., Search Methods: We performed a computer-assisted search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, 4th quarter), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44, 2010) and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 and 2009 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) conference abstracts and performed a handsearch of reference lists of articles., Selection Criteria: We included randomised controlled trials which compared any neuromodulator to another therapy (active or placebo, including non-pharmacological therapies) in adult patients with RA that had at least one clinically relevant outcome measure., Data Collection and Analysis: Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of a neuromodulator on pain, depression and function as well as their safety., Main Results: Four trials with high risk of bias were included in this review. Two trials evaluated oral nefopam (52 participants) and one trial each evaluated topical capsaicin (31 participants) and oromucosal cannabis (58 participants).The pooled analyses identified a significant reduction in pain levels favouring nefopam over placebo (weighted mean difference (WMD) -21.16, 95% CI -35.61 to -6.71; number needed to treat (NNT) 2, 95% CI 1.4 to 9.5) after two weeks. There were insufficient data to assess withdrawals due to adverse events. Nefopam was associated with significantly more adverse events (RR 4.11, 95% CI 1.58 to 10.69; NNTH 9, 95% CI 2 to 367), which were predominantly nausea and sweating.In a mixed population trial, qualitative analysis of patients with RA showed a significantly greater reduction in pain favouring topical capsaicin over placebo at one and two weeks (MD -23.80, 95% CI -44.81 to -2.79; NNT 3, 95% CI 2 to 47; MD -34.40, 95% CI -54.66 to -14.14; NNT 2, 95% CI 1.4 to 6 respectively). No separate safety data were available for patients with RA, however 44% of patients developed burning at the site of application and 2% withdrew because of this.One small, low quality trial assessed oromucosal cannabis against placebo and found a small, significant difference favouring cannabis in the verbal rating score 'pain at present' (MD -0.72, 95% CI -1.31 to -0.13) after five weeks. Patients receiving cannabis were significantly more likely to suffer an adverse event (risk ratio (RR) 1.82, 95% CI 1.10 to 3.00; NNTH 3, 95% CI 3 to 13). These were most commonly dizziness (26%), dry mouth (13%) and light headedness (10%)., Authors' Conclusions: There is currently weak evidence that oral nefopam, topical capsaicin and oromucosal cannabis are all superior to placebo in reducing pain in patients with RA. However, each agent is associated with a significant side effect profile. The confidence in our estimates is not strong given the difficulties with blinding, the small numbers of participants evaluated and the lack of adverse event data. In some patients, however, even a small degree of pain relief may be considered worthwhile. Until further research is available, given the relatively mild nature of the adverse events, capsaicin could be considered as an add-on therapy for patients with persistent local pain and inadequate response or intolerance to other treatments. Oral nefopam and oromucosal cannabis have more significant side effect profiles however and the potential harms seem to outweigh any modest benefit achieved.