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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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Our study indicated nefopam exerted significant anti-allodynic effects in osteoarthritis pain model for the first time. • Nefopam and gabapentinoids exerted synergistic anti-nociceptive effects in inflammatory, osteoarthritis and neuropathic pain. • Nefopam–gabapentinoids showed significantly improved anti-inflammatory effects than the equimolar dose of monotherapy. • Nefopam–gabapentinoids can alleviate gabapentinoids-induced sedation or ataxia by lowering their effective doses. [ABSTRACT FROM AUTHOR]

Pain control and quality of recovery (QoR) at home remains a challenge after ambulatory shoulder arthroscopy. This study aims to assess the QoR and pain relief using a sequential implementation strategy for rescue analgesic drugs. After institutional review board approval, patients (>18 years, American Society of Anesthesiology [ASA] score 1-3 stable) scheduled for ambulatory surgery under general anesthesia with a single-shot interscalene nerve block were enrolled. After discharge, patients received standard information regarding the postoperative recovery and care consisting of a multimodal analgesic regime (acetaminophen and ketoprofen for 5 days). The first 48 postoperative hours allowed us to compare 3 different rescue drug regimes with a control group, in sequential order: tramadol (control group), tramadol + nefopam, immediate-release oxycodone (IR), and extended-release oxycodone (ER). The primary endpoint was the QoR 40 score at 48 hours after surgery. Secondary endpoints were pain relief and adverse events over a 7-day period. An intention-to-treat statistical analysis was performed with sequential analysis (as an interim analysis) every 20 patients. Results were recorded as medians and interquartiles (25-75). We analyzed 109 patients with similar characteristics among groups. The QoR 40 scores were similar for the tramadol group (168 [161-172]), the tramadol + nefopam group (161 [151-173], P =.09), and the IR group (164 [153-169], P =.17), but higher for the ER group (176 [167-181], P =.03). Concerning adverse events, drugs were interrupted more frequently in the tramadol + nefopam group (36 %). In the ER group, a higher quality of postoperative relief was attained in the domains of pain and sleep. The present study shows that a combination of IR and ER oxycodone over a short period of time (<48 hours) is associated with a better QoR at home after ambulatory shoulder surgery. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Patients with Neurofibromatosis type 1 display delayed fracture healing and the increased deposition of fibrous tissue at the fracture site. Severe cases can lead to non-union and even congenital pseudarthrosis. Neurofibromatosis type 1 is caused by a mutation in the NF1 gene and mice lacking the Nf1 gene show a fracture repair phenotype similar to that seen in patients. Tissue from the fracture site of patients with Neurofibromatosis type 1 and from mice deficient in the Nf1 gene both show elevated levels of β-catenin protein and activation of β-catenin mediated signaling. Constitutively elevated β-catenin leads to a delayed and fibrous fracture repair process, and ( RS )-5-methyl-1-phenyl-1,3,4,6-tetrahydro-2,5-benzoxazocine (Nefopam, a centrally-acting, non-narcotic analgesic agent) inhibits β-catenin mediated signaling during skin wound repair. Here we investigate Nefopam's potential as a modulator of bone repair in mice deficient in Nf1 . Mice were treated with Nefopam and investigated for bone fracture repair. Bone marrow stromal cells flushed from the long bones of unfractured mice were treated with Nefopam and investigated for osteogenic potential. Treatment with Nefopam was able to lower the β-catenin level and the Axin2 transcript level in the fracture calluses of Nf1 deficient mice. Cultures from the bone marrow of Nf1 − / − mice had significantly lower osteoblastic colonies and mineralized nodules, which was increased when cells were cultured in the presence of Nefopam. Fracture calluses were harvested and analyzed 14 days and 21 days after injury. Nf1 − / − calluses had less bone, less cartilage, and higher fibrous tissue content than control calluses. Treatment with Nefopam increased the bone and cartilage content and decreased the fibrous tissue content in Nf1 − / − calluses. These findings present a potential treatment for patients with Neurofibromatosis 1 in the context of bone repair. Since Nefopam is already in use in patient care, it could be rapidly translated to the clinical setting. [ABSTRACT FROM AUTHOR]

Purpose Many studies have examined the postoperative analgesic effects of nefopam in various settings. However, although nefopam is expected to be useful in bimaxillary osteotomy, no published data are available. Material and methods We divided 42 patients into nefopam [n = 21, nefopam 20 mg intravenous (i.v.) 30 min before surgery, followed by an i.v. infusion (5 mg/h) beginning immediately postoperatively for 24 h] and control [n = 21, normal saline] groups. Then we compared the analgesic efficacy, side effects, and degree of patient satisfaction with postoperative analgesia. Results Pain was lower in the nefopam group than in the controls in the recovery room [4.6 (3.0–6.0) vs. 6.0 (5.5–7.0), median (interquartile range), P = 0.002] and on the ward. Fewer patients in the nefopam group required rescue analgesics, and the degree of patient satisfaction was significantly higher in the nefopam group ( P < 0.001). There were no significant differences in other side effects between the groups. However, the control group showed more sedation 1 h postoperatively ( P = 0.009). Conclusion Nefopam is an effective analgesic in bimaxillary osteotomy in that it can reduce the use of opioids and nonsteroidal anti-inflammatory drugs, thereby reducing the side effects of conventional analgesics. (Trial Registration: ClinicalTrials.gov (NCT 01461031)) [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Highlights: [•] Intrathecal nefopam attenuated mechanical allodynia by spinal nerve ligation. [•] The effect of nefopam was antagonized by 5-HT7 receptor antagonist. [•] Descending serotonergic pathway ablation drug failed to affect the effect of nefopam. [•] The level of 5-HT in the spinal cord and plasma was decreased in neuropathic pain. [•] Intrathecal nefopam increased the level of 5-HT in the spinal cord and plasma. [ABSTRACT FROM AUTHOR]

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 &y& Elsevier]

Background Nefopam is a non-opioid, non-steroidal, centrally acting analgesic which has an opioid-sparing effect. It also reduces the threshold (triggering core temperature) for shivering without causing sedation or respiratory depression. The drug is therefore useful as both an analgesic and to facilitate induction of therapeutic hypothermia. However, compartmental pharmacokinetics during hypothermia are lacking for nefopam. Methods We conducted a prospective, randomized, blinded study in eight volunteers. On two different occasions, one of two nefopam concentrations was administered and more than 30 arterial blood samples were gathered during 12 h. Plasma concentrations were determined using gas chromatography/mass spectrometry to investigate the pharmacokinetics of nefopam with non-linear mixed-effect modelling. Results A two-compartment mammillary model with moderate inter-individual variability and inter-occasional variability independent of covariates was found to best describe the data [mean (se): V1=24.13 (2.8) litre; V2=183.34 (13.5) litre; Clel=0.54 (0.07) litre min−1; Cldist=2.84 (0.42) litre min−1]. Conclusions The compartmental data set describing a two-compartment model was determined and could be implemented to drive automated pumps. Thus, work load could be distributed to a pump establishing and maintaining any desired plasma concentration deemed necessary for a treatment with therapeutical hypothermia. [ABSTRACT FROM AUTHOR]

Background Pain management is challenging in intensive care unit (ICU) patients. The analgesic efficacy, tolerance, and haemodynamic effects of nefopam have never been described in critically ill patients. Methods In consecutive medical–surgical ICU patients who received 20 mg of nefopam i.v. over 30 min, we measured pain, Richmond Agitation Sedation Scale (RASS), respiratory parameters, and adverse drug events at T0 (baseline), T30 (end-of-infusion), T60, and T90 min. Haemodynamic variables were assessed every 15 min from T0 to T60 and T90. Pain was evaluated by the behavioural pain scale (BPS, 3–12) or by the self-reported visual numeric rating scale (NRS, 0–10) according to communication capacity. Results Data were analysed for 59 patients. As early as T30, median NRS and BPS decreased significantly from T0 to a minimum level at T60 for NRS [5 (4–7) vs 1 (1–3), P<0.001] and T90 for BPS [5 (5–6) vs 3 (3–4), P<0.001]. No significant changes were detected for RASS, ventilatory frequency, or oxygen saturation. Increased heart rate and decreased mean arterial pressure, defined as a change ≥15% from baseline, were found in 29% and 27% of patients, respectively. For the 18 patients monitored, cardiac output increased by 19 (7–29)% and systemic vascular resistance decreased by 20 (8–28)%, both maximally at T30. Heat sensation, nausea/vomiting, sweating, and mouth dryness were found, respectively, in 6%, 9%, 22%, and 38% of patients. Conclusions A single slow infusion of nefopam is effective in critically ill patients who have moderate pain. The risk of tachycardia and increased cardiac output and also hypotension and decreased systemic vascular resistance should be known to evaluate the benefit/risk ratio of its prescription. [ABSTRACT FROM AUTHOR]

Abstract: Nefopam, a non-opioid, centrally acting benzoxazocine analgesic, proved to be as efficient in treatment of postanaesthetic thermoregulatory shivering as clonidine or meperidine. However, its exact mechanism of action is still unclear. Potent anti-shivering activity was also demonstrated for physostigmine primarily based on cholinergic but probably also different additional mechanisms of action. Hypothesizing an involvement of α2-adrenoceptors we studied their role in nefopam- and physostigmine-mediated thermoregulation in a mouse model of nonshivering thermogenesis. To differentiate possible α2-adrenoceptor subtype-specific interactions, we analysed wildtype mice and mice with deletion of the α2A-, α2B- or α2C-adrenoceptor (knock out). Ten mice of each genotype (n = 40) were administered saline, saline plus atipamezole, 1 mg/kg nefopam, 25 mg/kg nefopam, 25 mg/kg nefopam plus atipamezole, physostigmine and physostigmine plus atipamezole intraperitoneally. Each mouse was randomly subjected to each of the seven different treatments. Afterwards, the mice were positioned into a plexiglas chamber where rectal temperature and mixed expired carbon dioxide were measured during following whole body cooling. Thermoregulatory threshold temperature of nonshivering thermogenesis and maximum response intensity were analysed. Nefopam decreased the thermoregulatory threshold temperature in wildtype, α2B- and α2C-adrenoceptor mice. This effect was partially abolished by additional administration of the α2-adrenoceptor antagonist atipamezole. In α2A-adrenoceptor knock out mice, nefopam did not affect the thermoregulatory threshold. In contrast, physostigmine decreased the thermoregulatory threshold in wildtype and all α2-adrenoceptor knock out mice independently from additional atipamezole administration. Our results indicate an important role of the α2A-adrenoceptor in the thermoregulatory response induced by nefopam but not by physostigmine in mice. [Copyright &y& Elsevier]

In recent years the use of mild therapeutic hypothermia as a means of neuroprotection has become an important concept for treatment after cerebral ischemic hypoxic injury. Mild therapeutic hypothermia has been shown to improve outcome after out-of-hospital cardiac arrest, and many studies suggest a beneficial effect of mild therapeutic hypothermia on patient outcome after traumatic brain injury, cerebrovascular damage and neonatal asphyxia. This review article explores the numerous possibilities and methods for the induction of mild therapeutic hypothermia, reviews thermoregulatory management during maintenance and discusses associated risks and complications. [Copyright &y& Elsevier]

Abstract: Objectives: The combination of non-opioid analgesic drugs (P: paracetamol, K: ketoprofen and N: nefopam) is currently recommended for postoperative pain control. In practice, these analgesics are often administered in the same solution. We investigated the chemical stability and sterility of three mixtures of analgesics (P+K, P+N and K+N). Methods: For each mixture, concentrations of active principles were measured using high-performance liquid chromatography over 24 hours. These mixtures were cultured for microbiological colonization. Results: Our study demonstrated chemical and bacteriologic stability of these three mixtures over a 24-hour period. The results allow the use of P+K, P+N and K+N in the same ready to use solution. [Copyright &y& Elsevier]

Abstract: Combinations of analgesics with different mechanisms of action offer the possibility of efficient analgesia with a decrease in side effects as a result of reduced dosages of one or both compounds. Based on a clinical observation of synergism between nefopam, a centrally acting non-opioid that inhibits monoamines reuptake, and ketoprofen, a non-steroidal anti-inflammatory drug, the objective of this study was to further explore this antinociceptive synergy in four distinct animal models of pain (both drugs were administered subcutaneously). Strong antinociceptive properties were observed in the mouse writhing abdominal test with ED50 values of 2.56±0.38 and 1.41±0.41 mg/kg for nefopam and ketoprofen, respectively. In the inflammatory phase of the mouse formalin test, both compounds significantly inhibited the licking time of the injected hind-paw with ED50 of 4.32±0.17 mg/kg for nefopam and 49.56±15.81 mg/kg for ketoprofen. Isobolographic analysis revealed that this drug combination is synergistic in the formalin test and additive in the writhing test. In rat carrageenan-induced tactile allodynia, single administration of nefopam or ketoprofen only partially reduced allodynia. Combination of low analgesic doses of nefopam (10 or 30 mg/kg) with low analgesic doses of ketoprofen (30 or 100 mg/kg) significantly reduced or reversed allodynia, with a more pronounced anti-allodynic effect and a longer duration efficacy. In a rat model of postoperative thermal hyperalgesia induced by incision, co-administration of nefopam at a low analgesic dose (10 mg/kg) with ketoprofen at non-analgesic doses (30 or 100 mg/kg) showed the appearance of a strong anti-hyperalgesic effect, maintained during at least 3 h. In conclusion, co-administration of nefopam with ketoprofen is synergistic, and should allow either to increase their analgesic efficacy and/or to reduce their side effects. [Copyright &y& Elsevier]

Abstract: The effects of opiate analgesics and non-steroidal anti-inflammatory drugs on the immune functions have been reported. The effect of the non-opiate analgesic nefopam on the immune functions has not yet been investigated. Male Swiss albino mice were treated with either heat killed E. coli or saline. They were classified into 12 groups. The effects of subacute (15 mg/kg/12 h S.C. daily for one week) and chronic (10 mg/kg/12 h S.C. daily for one month) treatment with nefopam on the levels of interferon-gamma (IFN-γ) and total immunoglobulins were examined in both normal and immunized mice. Also, the effect of the chronic administration of nefopam on the phagocytic activity of peritoneal macrophage was evaluated in both normal and immunized mice. Subacute and chronic administration of nefopam induced no significant raise in the level of interferon-gamma (IFN-γ) or in the level of total immunoglobulins in non-immunized animals, while subacute and chronic treatment with nefopam augmented markedly the immunization induced increase of level of interferon-gamma (IFN-γ). Furthermore, chronic treatment with nefopam potentiated significantly the production of total immunoglobulin induced by heat killed E. coli. Chronic treatment with nefopam also was associated with significant enhancement of innate immune response reflected in the pronounced increase in the phagocytic activity of macrophages in non-immunized and immunized animals. The enhancement of phagocytic activity of macrophages by nefopam in immunized animals was significantly higher than that of non-immunized animals. These findings revealed that nefopam has the ability to trigger the immune response for bacterial antigen. The mechanism behind the immunostimulatory effect of nefopam requires further investigation, but it may be due, at least in part, to the inhibitory effect of nefopam on the serotonin and norepinephrine reuptake at nerve endings. In conclusion, our findings postulated that nefopam stimulated the immune functions and improved the defence mechanism. This information may be of future therapeutic value in diseases that need immunologic enhancement. [Copyright &y& Elsevier]

Abstract: A specific and sensitive liquid chromatography–tandem mass spectrometric (LC–MS–MS) method using an ion trap spectrometer was developed for quantitation of nefopam and desmethyl-nefopam in human plasma. Nefopam, desmethyl-nefopam and the internal standard (ethyl loflazepate) were extracted in a single step with diethyl ether from 1mL of alkalinized plasma. The mobile phase consisted of acetonitrile with 0.1% formic acid (50:50, v:v). It was delivered at a flow-rate of 0.3mL/min. The effluent was monitored by MS–MS in positive-ion mode. Ionisation was performed using an electrospray ion source operating at 200°C. Nefopam and desmethyl-nefopam were identified and quantified in full scan MS–MS mode using a homemade MS–MS library. Calibration curves were linear over the concentration range of 0.78–100ng/mL with determination coefficients >0.996. This method was fast (total run time<6min), accurate (bias<12.5%), and reproducible (intra- and inter-assay precision<17.5%) with a quantitation limit of 0.78ng/mL. The high specificity and sensitivity achieved by this method allowed the determination of nefopam and desmethyl-nefopam plasma levels in patients following either intermittent or continuous intravenous administration of nefopam. [Copyright &y& Elsevier]

Résumé: Objectifs. – Évaluer l’efficacité analgésique du néfopam en perfusion continue en chirurgie urologique. En effet, le néfopam est utilisé en injection continue par de nombreux anesthésistes pour réduire ses effets indésirables. Type d’étude. – Étude prospective randomisée contrôlée en double insu contre placebo. Patients et méthodes. – Soixante patients opérés par laparotomie d’une chirugie urologique réglée. À la fin de la chirurgie, les patients recevaient une dose de placebo en bolus (groupe 3) ou 20 mg de néfopam (groupes 1 et 2) puis de façon continue sur 24 heures soit du placebo (groupe 3), soit 80 mg (groupe 1) ou 120 mg (groupe 2) de néfopam. Chez tous les patients, une analgésie de complément était assurée par l’administration de morphine en mode ACP. La douleur au repos et à la toux a été mesurée grâce aux échelles visuelles analogiques (EVA). Les effets indésirables tels que nausées/vomissements, sédation et dépression respiratoire ont été évalués. Les performances psychiques ont été mesurées grâce au mini mental status test (MMS-tests). Résultats. – Les patients du groupe placebo étaient plus âgés en moyenne de six ans mais les données chirurgicales et anesthésiques n’étaient pas statistiquement différentes entre les groupes. La douleur au repos et à la toux n''était pas statistiquement différente entre les groupes. Dans le groupe placebo, la médiane (25e–75e quartiles) de la consommation de morphine était égale à 29 mg (13–53) alors que chez les patients recevant 80 et 120 mg de néfopam, cette consommation a atteint respectivement 44 mg (11–54) et 35 mg (9–82) (p > 0,05). Les patients ont eu besoin de morphine durant la même période qu''ils recevaient ou non du néfopam. L''incidence des effets indésirables était similaire dans les différents groupes. Conclusion. – L''administration continue de néfopam ne réduit pas la consommation de morphine et n''améliore pas l''analgésie ni les effets indésirables lors de la chirurgie urologique lourde. La discordance de ces résultats avec ceux obtenus en chirurgie abdominale lourde peut résulter du mode d’administration du néfopam, de l’intensité douloureuse différente entre les deux types de chirurgie ainsi que par une population plus âgée. [Copyright &y& Elsevier]

The present study explored the role of the histaminergic system in nefopam analgesia based on the structural relationship between nefopam and diphenhydramine. In vitro binding assays revealed that nefopam possesses moderate affinity for histamine H1 and H2 receptor subtypes, with IC50 of 0.8 and 6.9 μM, respectively, but no affinity for histamine H3 receptor subtype until 100 μM. Subcutaneous nefopam administration dose-dependently inhibited pain in acetic acid-induced writhing (1–30 mg/kg) and formalin (1–10 mg/kg) tests in the mouse. Pretreatment with the histamine-depleting agent α-fluoromethylhistidine (α-FMH, 50 mg/kg), the histamine H1 receptor antagonist pyrilamine (3 or 10 mg/kg), or the histamine H2 receptor antagonists cimetidine (100 mg/kg) and zolantidine (10 or 30 mg/kg) did not significantly modify nefopam antinociception in both tests. The histamine H3 receptor agonist R(−)α-methylhistamine (RAMH, 10 mg/kg) did not significantly modify the nefopam analgesic activity in the writhing test. At 25 mg/kg, RAMH inhibited nefopam antinociception at 3 mg/kg, but not at 10 mg/kg in the formalin test. However, pretreatment with the histamine H3 receptor antagonist thioperamide (25 mg/kg) inhibited nefopam antinociception in the writhing test, but not in the formalin test. In conclusion, nefopam analgesic activity is not mediated by histamine H1 or H2 receptors, but can be slightly modulated by histamine H3 receptors in mouse pain tests. [Copyright &y& Elsevier]

In order to specify the nature of interactions between the analgesic compound nefopam and the glutamatergic system, we examined the effects of nefopam on binding of specific ligands on the three main subtypes ionotropic glutamate receptors: N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), or quisqualic acid (QA) and kainic acid (KA) in rat brain membrane preparations. Functionally, we investigated the effects of nefopam against the seizures induced by agonists of these excitatory glutamate receptors in mice. Since the synaptic release of glutamate mainly depends upon the activation of membrane voltage-sensitive sodium channels (VSSCs), the nature of interactions between nefopam and these ionic channels was studied by evaluating the effects of nefopam on binding of 3H-batrachotoxinin, a specific ligand of the VSSCs in rat brain membrane preparations. The functional counterpart of the binding of nefopam on VSSCs was evaluated by its effects on the 22Na uptake-stimulated by veratridine on human neuroblastoma cells and in the maximal electroshock test in mice. Nefopam showed no affinity for the subtypes of ionotropic glutamate receptors up to 100 μM. On the other hand, nefopam was effective against NMDA, QA and KA induced clonic seizures in mice. Nefopam displaced 3H-batrachotoxinin and inhibited the uptake of 22Na in the micromolar range and it protected mice against electroshock induced seizures. Nefopam may block the VSSCs activity: consequently, at the presynaptic level, this effect led to a reduction of glutamate release and at the postsynaptic level, it led to a decrease of the neuronal excitability following activation of the glutamate receptors. [Copyright &y& Elsevier]

The objective of this study was to resolve discrepancies regarding the possible antinociceptive synergy between morphine and nefopam in animal models of pain. Firstly, we have examined the antinociceptive activity of nefopam, a nonopioid antinociceptive compound that inhibits monoamine reuptake, in pain models of allodynia and hyperalgesia induced by carrageenan injection, or skin and muscle incision of the rat hind paw. Single subcutaneous administration of nefopam at 30 mg/kg blocked carrageenan- and incision-induced thermal hyperalgesia, and weakly but significantly diminished carrageenan-induced tactile allodynia. A weaker dose of nefopam (10 mg/kg) only reduced carrageenan-induced tactile allodynia and incision-induced thermal hyperalgesia. Secondly, we assessed the usefulness of the coadministration of nefopam with morphine. Combination of a nonanalgesic dose of nefopam (10 mg/kg) with a nonanalgesic dose of morphine (0.3 or 1.0 mg/kg) completely inhibited carrageenan- or incision-induced thermal hyperalgesia, respectively. In carrageenan-induced tactile allodynia, coadministration of weak analgesic doses of nefopam (10 and 30 mg/kg) with a nonanalgesic dose (1 mg/kg) or moderately analgesic dose (3 mg/kg) of morphine significantly reduced or reversed allodynia, respectively. In conclusion, coadministration of nefopam with morphine enhances the analgesic potency of morphine, indicating a morphine sparing effect of nefopam. [Copyright &y& Elsevier]

Nefopam (NEF) and desmethyl-nefopam (DMN) were assayed simultaneously in plasma, globule and urine samples using imipramine as internal standard. A liquid–liquid extraction procedure was coupled with a reverse phase high-performance liquid chromatography system. This system requires a mobile phase containing buffer (15 mM KH2PO4 with 5 mM octane sulfonic acid: pH 3.7) and acetonitrile (77:33, v/v) through (flow rate=1.5 ml/min) a C18 Symmetry column (150×4.6 I.D., 5 μm particle size: Waters) and a UV detector set at 210 nm. Internal standard was added to 1 ml of plasma or globule sample or 0.5 ml of urine sample, prior to the extraction under alkaline ambiance with n-hexane. The limits of quantification were 1 and 2 ng/ml for both molecules in plasma and globule, respectively; 5 and 10 ng/ml for NEF and DMN in urine, respectively. The method proved to be accurate and precise: the relative error at three concentrations ranged from −13.0 to +12.3% of the nominal concentration for all molecule and biological fluid; the within-day and between-day precision (relative standard deviation %) ranged from 1.0 to 10.1% for all the molecules and biological fluids. The method was linear between 1 and 60 ng/ml for both molecules in the plasma; 2 and 25 ng/ml for both molecules in the globule; 25 and 250 ng/ml for NEF and 50 and 500 ng/ml for DMN in the urine: correlation coefficients of calibration curves (determined by least-squares regression) of each molecule were higher than 0.992 whatever the biological fluid and during the pre-study and in-study validations. This method was successfully applied to a bio-availability study of NEF in healthy subjects. [Copyright &y& Elsevier]

• In France, foot surgery represents 100,000 procedures per year, of which over 60% concern the first ray. • The rate of outpatient stays increases regularly with a national target of 70% in 2022 for all surgeries combined. • One of the limiting factors in outpatient care is the management of post-operative pain. • The patients' pain assessment was performed upon return home by the patient's nurse and repeated on D1, D5, D7 and D15. • Nefopam IV infusion has proven effective and is well tolerated. At present, health facilities are forced to switch to outpatient care. While it lends itself well to this organizational arrangement, first ray surgery is broadly considered as painful by patients, who are often reluctant to this treatment. The evolution of post-operative pain in patients who underwent operations for first ray surgery from D0 to D15 were studied. Secondly, the duration of the oral analgesic treatment, the patient's satisfaction level, and searched for complications were assessed. This is an observational, single-center and single-operator study. Between July and December 2019, forty patients who underwent first ray surgery (hallux valgus or rigidus) and eligible for outpatient treatment were included. The surgical technique of the hallux valgus treatment consisted of open surgery via double metatarsal and phalangeal osteotomy. The hallux rigidus surgery consisted of arthrodesis using an open dorsal plate. Home monitoring was carried out by a healthcare provider (e-HORUS). The protocol provided for pain management by means of a diffuser of Nefopam IV for a maximum of 5 days, combined with alleviating oral analgesics 1 and 2 and NSAIDs. The pain was evaluated on D0, D1, D3, D5, D8 and D15, using a numerical scale (NS) from 0 to 10. The degree of patient satisfaction was recorded at 1 month. 35 patients were followed. 5 patients were excluded due to incomplete data. The series included 26 women and 9 men, with an average age of 59.9 years. There were 30 hallux valgus and 5 hallux rigidus. The pain analyzed by the NS was 5.37 on D0, 3.34 on D1, 1.83 on D3, 1.43 on D5, 1.06 on D8 and 2.2 on D15. The average duration of Nefopam infusions was 3.89 days, and the average duration of oral analgesics was 17.7 days. The tolerance of the treatment was satisfactory in 79% of the cases. 69% of patients were very satisfied with the management of their pain. There were no scar complications or infections. No re-hospitalization was necessary. 3 algoneurodystrophies were identified. The existence of fibromyalgia or Parkinsonian syndrome was correlated with higher pain. Pain management after outpatient first ray surgery using the injectable Nefopam protocol was satisfactory in the majority of cases, with a high degree of patient satisfaction. This protocol is routinely offered to our patients who must undergo first ray surgery. [ABSTRACT FROM AUTHOR]

Abstract: We report the case of a 77-year-old man, with nefopam postoperative analgesia, who developed subacute neurological symptoms, whereas he had profound hypoprotidemia and acute renal failure. Chronological, semiological and bibliographical criteria are in favour of causality assessment. The plasma nefopam concentration (135 ng/ml) during the neurological symptoms is another argument. [Copyright &y& Elsevier]

• Intrathecal nefopam effectively attenuated formalin-induced pain behavior. • Intrathecal nefopam inhibited the reuptake of 5-HT and NE and reduced glutamate release after formalin injection. • The blockade of serotonergic, adrenergic, or group III metabotropic glutamate receptors partially reversed the analgesic effects of nefopam. The present study investigated the effects of intrathecal nefopam on the pain behavior and on the extracellular levels of serotonin (5-HT), norepinephrine (NE), and glutamate in the spinal cord, in a rat model of pain induced by formalin. Nefopam was intrathecally administered 10 min prior to the formalin test to assess its antinociceptive effects. In another cohorts of animals, dihydroergocristine, yohimbine, or (RS)-α-Methylserine-O-phosphate (MSOP), a serotonergic, α-2 adrenergic receptor, or group III metabotropic glutamate receptor antagonist, respectively, were administered prior to the application of nefopam in the formalin test. Microdialysis studies were conducted to measure the extracellular levels of 5-HT, NE, and glutamate in the spinal cord following nefopam administration. Intrathecal nefopam reduced formalin-induced behavior in both phases of the test. The blockade of serotonergic or adrenergic receptors partially reversed the analgesic effects of nefopam in the first phase of the formalin test whereas MSOP reversed these effects in both phases. The microdialysis results revealed that intrathecal nefopam significantly increased 5-HT and NE levels and attenuated the formalin-induced release of glutamate in the spinal cord. Thus, the present data suggest that the increase in the extracellular levels of 5-HT and NE, and reductions in glutamate release in the spinal cord, may have contributed to the analgesic effects of nefopam. [ABSTRACT FROM AUTHOR]

In the present paper, for the first time, the electrochemical behavior and determination of a highly oxidizable non-opioid painkilling medication Nefopam (NEF) has been reported. The outcomes revealed that NEF presented one diffusion-controlled anodic signal at very positive potential of about +1.7 V in 1 M HClO 4 on the boron-doped diamond electrode (BDDE). The impact of the electrochemical (anodic and cathodic) pretreatment of the BDDE surface was evaluated. The cathodic pretreatment after anodic one was considered as the most suitable choice due to the improved charge transfer and the enhanced surface activity. Under optimized experimental conditions and operating parameters, the calibration curves were linear over concentration ranges of 2.00–59.7 μM and 0.99–77.1 μM with similar detection limits of 0.5 μM for differential pulse (DPV) and square-wave (SWV) voltammetry, respectively. Moreover, the electroanalytical determination of NEF in the presence of human urine matrix was also found to be possible in the linear concentration ranges from 3.8 to 64.8 μM and from 4.9 to 47.2 μM with detection limits of 1.7 μM and 1.8 μM for DPV and SWV, respectively. The practical feasibility of the introduced method was successfully confirmed by the quantification of NEF amount in commercial pharmaceutical dosage with the result in a good agreement with that specified in analytical normative documentation. The developed procedure can be easily implemented for control analysis also with the use of miniaturized thick-film BDDE without additional optimization steps. Unlabelled Image • The first report on the electrochemical behavior of Nefopam • BDDE as sensitive electrochemical sensor for highly oxidizable analytes • The impact of various electrochemical pretreatments was investigated. • The method applicability in pharmaceutical, biological and environmental samples [ABSTRACT FROM AUTHOR]

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We report a case of nefopam intoxication in a severely malnourished postoperative intensive care patient with profound hypoprotidemia. Nefopam induced agitation and confusion associated with anticholinergic symptoms such as tremor, hypertonia, mydriasis, and tachycardia. All these symptoms disappeared after withdrawal of the drug. Nefopam should be considered as a possible cause of confusion in postoperative patients. [Copyright &y& Elsevier]

Abstract: Acute glaucoma angle closure is a rare complication of anaesthesia and multimodal analgesia. However it is a medical emergency, hence any delay in its treatment may have catastrophic consequences. We present a case of postoperative glaucoma, which had evolved to permanent blindness. We also reviewed the French pharmacovigilance database between 1996 and 2006 and found four other cases of acute glaucoma angle closure in postoperative period possibly related to the administration of nefopam. [Copyright &y& Elsevier]