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Jeanmarie Gillardin - One of the best experts on this subject based on the ideXlab platform.
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Nefopam and ketoprofen synergy in rodent models of antinociception
European Journal of Pharmacology, 2008Co-Authors: Philippe Girard, Danielle Verniers, Marieclaude Coppe, Yannick Pansart, Jeanmarie GillardinAbstract: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.
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role of catecholamines and serotonin receptor subtypes in Nefopam induced antinociception
Pharmacological Research, 2006Co-Authors: Philippe Girard, Danielle Verniers, Marieclaude Coppe, Yannick Pansart, Jeanmarie GillardinAbstract:The non-opiate analgesic Nefopam has been shown to inhibit monoamines uptake, but little is known about receptor subtypes effectively involved in its analgesic effect. In vitro binding assays yielded the following measures of affinity (IC(50)): serotonergic 5-HT(2C) (1.4 microM), 5-HT(2A) (5.1 microM), 5-HT(3) (22.3 microM), 5-HT(1B) (41.7 microM), 5-HT(1A) (64.9 microM), adrenergic alpha(1) (15.0 microM) and dopaminergic D(1) (100 microM). Subcutaneous Nefopam administration dose-dependently inhibited pain in acetic acid-induced writhing (1-30 mg kg(-1)) and formalin (1-10 mg kg(-1)) tests in the mouse. Pretreatments with adrenergic alpha(1) (prazosin) and alpha(2) (yohimbine), and serotonergic 5-HT(1B) (GR127935) receptor antagonists significantly increased the Nefopam ED(50) in the writhing test. The serotonergic 5-HT(2C) (RS102221) and the dopaminergic D(2) (sulpiride) receptor antagonists inhibited Nefopam antinociception in the formalin test. However, in both tests, Nefopam analgesic activity was not modified by the following receptor antagonists: dopaminergic D(1) (SCH23390), serotonergic 5-HT(1A) (NAN-190, WAY100635), 5-HT(2A) (R96544, ketanserin), 5-HT(3) (tropisetron), and 5-HT(4) (SDZ205557). In conclusion, Nefopam analgesic activity could be modulated by the adrenergic alpha(1) and alpha(2) receptors, the dopaminergic D(2) receptors, and the serotonergic 5-HT(1B) and 5-HT(2C) receptor subtypes.
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role of the histamine system in Nefopam induced antinociception in mice
European Journal of Pharmacology, 2004Co-Authors: Philippe Girard, Danielle Verniers, Marieclaude Coppe, Yannick Pansart, Jeanmarie GillardinAbstract: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 microM, respectively, but no affinity for histamine H(3) receptor subtype until 100 microM. 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 alpha-fluoromethylhistidine (alpha-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(-)alpha-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.
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Nefopam blocks voltage sensitive sodium channels and modulates glutamatergic transmission in rodents
Brain Research, 2004Co-Authors: Marc Verleye, Nathalie Andre, Isabelle Heulard, Jeanmarie GillardinAbstract:Abstract 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.
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Nefopam potentiates morphine antinociception in allodynia and hyperalgesia in the rat
Pharmacology Biochemistry and Behavior, 2004Co-Authors: Philippe Girard, Yannick Pansart, Jeanmarie GillardinAbstract: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.
Myung Ha Yoon - One of the best experts on this subject based on the ideXlab platform.
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antinociceptive effects of Nefopam modulating serotonergic adrenergic and glutamatergic neurotransmission in the spinal cord
Neuroscience Letters, 2020Co-Authors: Joo Wung Chae, Hyung Gon Lee, Jeong Il Choi, Myung Ha Yoon, Dong Ho Kang, Seung Hoon Kim, Woong Mo KimAbstract:Abstract 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.
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Nefopam downregulates autophagy and c jun n terminal kinase activity in the regulation of neuropathic pain development following spinal nerve ligation
BMC Anesthesiology, 2018Co-Authors: Myung Ha Yoon, Kyung Joon Lim, In Gook Jee, Ki Tae JungAbstract:Neurodegeneration is associated with changes in basal cellular function due to the dysregulation of autophagy. A recent study introduced the involvement of autophagy during spinal nerve ligation (SNL). Nefopam has shown potential for reducing neuropathic pain, but the underlying mechanisms are unknown. Here, we investigated the effects of Nefopam on neuropathic pain development following SNL, focusing on the involvement of autophagy. The functional role of Nefopam in capsaicin-induced autophagy was assessed by human glioblastoma M059 K cells. The neuropathic pain model was used to determine whether the effect of Nefopam on pain control was mediated through autophagy control. Neuropathic pain was induced by L5 and L6 SNL in male rats randomized into three groups: Group S (sham-operated), Group C (received normal saline), and Group E (received Nefopam). A behavioral test using a von Frey was examined. Expression changes of autophagy in response to Nefopam was analyzed in spinal cord tissues (L4-L6) by immunoblotting and immunohistochemistry. The paw withdrawal threshold examined on days 3, 5, 7, and 14 post-SNL was significantly higher in Group E than in Group C. SNL increased the levels of microtubule-associated protein 1 light chain 3B (LC3B-1), with concomitant reduction of sequestosome 1 (SQTSM1/p62), compared with Group S, indicating that SNL induced autophagy. These effects were reversed by Nefopam injection, and the results were confirmed by immunohistochemistry for LC3-I/II. Furthermore, SNL-mediated JNK activation was markedly decreased following Nefopam injection. Hematoxylin and eosin staining on Day 14 post-SNL revealed that SNL caused lymphocyte infiltration and oligodendrocyte localization in the substantia gelatinosa of the dorsal gray horn, which were reduced by Nefopam injection. Collectively, the mode of action of Nefopam on neuropathic pain appears to be associated with downregulation of phospho-JNK and autophagy, as well as modulation of the immune response.
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Nefopam downregulates autophagy and c-Jun N-terminal kinase activity in the regulation of neuropathic pain development following spinal nerve ligation
BMC, 2018Co-Authors: Myung Ha Yoon, Kyung Joon Lim, In Gook Jee, Ki Tae JungAbstract:Abstract Background Neurodegeneration is associated with changes in basal cellular function due to the dysregulation of autophagy. A recent study introduced the involvement of autophagy during spinal nerve ligation (SNL). Nefopam has shown potential for reducing neuropathic pain, but the underlying mechanisms are unknown. Here, we investigated the effects of Nefopam on neuropathic pain development following SNL, focusing on the involvement of autophagy. Methods The functional role of Nefopam in capsaicin-induced autophagy was assessed by human glioblastoma M059 K cells. The neuropathic pain model was used to determine whether the effect of Nefopam on pain control was mediated through autophagy control. Neuropathic pain was induced by L5 and L6 SNL in male rats randomized into three groups: Group S (sham-operated), Group C (received normal saline), and Group E (received Nefopam). A behavioral test using a von Frey was examined. Expression changes of autophagy in response to Nefopam was analyzed in spinal cord tissues (L4-L6) by immunoblotting and immunohistochemistry. Results The paw withdrawal threshold examined on days 3, 5, 7, and 14 post-SNL was significantly higher in Group E than in Group C. SNL increased the levels of microtubule-associated protein 1 light chain 3B (LC3B-1), with concomitant reduction of sequestosome 1 (SQTSM1/p62), compared with Group S, indicating that SNL induced autophagy. These effects were reversed by Nefopam injection, and the results were confirmed by immunohistochemistry for LC3-I/II. Furthermore, SNL-mediated JNK activation was markedly decreased following Nefopam injection. Hematoxylin and eosin staining on Day 14 post-SNL revealed that SNL caused lymphocyte infiltration and oligodendrocyte localization in the substantia gelatinosa of the dorsal gray horn, which were reduced by Nefopam injection. Conclusion Collectively, the mode of action of Nefopam on neuropathic pain appears to be associated with downregulation of phospho-JNK and autophagy, as well as modulation of the immune response
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comparison of effects of intraoperative Nefopam and ketamine infusion on managing postoperative pain after laparoscopic cholecystectomy administered remifentanil
Korean Journal of Anesthesiology, 2016Co-Authors: Sung Kwan Choi, Bong Ha Heo, Myung Ha Yoon, Woong Mo Kim, Jung Il Choi, Keun Seok Park, Ji A SongAbstract:Background Although intraoperative opioids provide more comfortable anesthesia and reduce the use of postoperative analgesics, it may cause opioid induced hyperalgesia (OIH). OIH is an increased pain response to opioids and it may be associated with N-methyl-D-aspartate (NMDA) receptor. This study aimed to determine whether intraoperative Nefopam or ketamine, known being related on NMDA receptor, affects postoperative pain and OIH after continuous infusion of intraoperative remifentanil. Methods Fifty-four patients undergoing laparoscopic cholecystectomy were randomized into three groups. In the Nefopam group (N group), patients received Nefopam 0.3 mg/kg at the induction of anesthesia followed by a continuous infusion of 0.065 mg/kg/h. In the ketamine group (K group), patients received ketamine 0.3 mg/kg at the induction of anesthesia followed by a continuous infusion of 3 µg/kg/min. The control group did not received any other agents except for the standard anesthetic regimen. Postoperative pain score, first time and number of demanding rescue analgesia, OIH and degrees of drowsiness/sedation scale were examined. Results Co-administrated Nefopam or ketamine significantly reduced the total amount of intraoperative remifentanil and postoperative supplemental morphine. Nefopam group showed superior property over control and ketamine group in the postoperative VAS score and recovery index (alertness and respiratory drive), respectively. Nefopam group showed lower morphine consumption than ketamine group, but not significant. Conclusions Both Nefopam and ketamine infusion may be useful in managing in postoperative pain control under concomitant infusion of remifentanil. However, Nefopam may be preferred to ketamine in terms of sedation.
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The Role of Spinal Dopaminergic Transmission in the Analgesic Effect of Nefopam on Rat Inflammatory Pain.
The Korean journal of pain, 2016Co-Authors: Yun Kim, Joo Wung Chae, Chang Hun Lim, Bong Ha Heo, Keun Suk Park, Hyung Gon Lee, Jeong Il Choi, Myung Ha Yoon, Woong Mo KimAbstract:BACKGROUND Nefopam has been known as an inhibitor of the reuptake of monoamines, and the noradrenergic and/or serotonergic system has been focused on as a mechanism of its analgesic action. Here we investigated the role of the spinal dopaminergic neurotransmission in the antinociceptive effect of Nefopam administered intravenously or intrathecally. METHODS The effects of intravenously and intrathecally administered Nefopam were examined using the rat formalin test. Then we performed a microdialysis study to confirm the change of extracellular dopamine concentration in the spinal dorsal horn by Nefopam. To determine whether the changes of dopamine level are associated with the Nefopam analgesia, its mechanism was investigated pharmacologically via pretreatment with sulpiride, a dopaminergic D2 receptor antagonist. RESULTS When Nefopam was administered intravenously the flinching responses in phase I of the formalin test were decreased, but not those in phase II of the formalin test were decreased. Intrathecally injected Nefopam reduced the flinching responses in both phases of the formalin test in a dose dependent manner. Microdialysis study revealed a significant increase of the level of dopamine in the spinal cord by intrathecally administered Nefopam (about 3.8 fold the baseline value) but not by that administered intravenously. The analgesic effects of intrathecally injected Nefopam were not affected by pretreatment with sulpiride, and neither were those of the intravenous Nefopam. CONCLUSIONS Both the intravenously and intrathecally administered Nefopam effectively relieved inflammatory pain in rats. Nefopam may act as an inhibitor of dopamine reuptake when delivered into the spinal cord. However, the analgesic mechanism of Nefopam may not involve the dopaminergic transmission at the spinal level.
Benjamin A Alman - One of the best experts on this subject based on the ideXlab platform.
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A High Throughput Screen Identifies Nefopam as Targeting Cell Proliferation in b-Catenin Driven Neoplastic and Reactive Fibroproliferative Disorders
2016Co-Authors: Raymond Poon, Helen Hong, Xin Wei, James Pan, Benjamin A AlmanAbstract:Fibroproliferative disorders include neoplastic and reactive processes (e.g. desmoid tumor and hypertrophic scars). They are characterized by activation of b-catenin signaling, and effective pharmacologic approaches are lacking. Here we undertook a high throughput screen using human desmoid tumor cell cultures to identify agents that would inhibit cell viability in tumor cells but not normal fibroblasts. Agents were then tested in additional cell cultures for an effect on cell proliferation, apoptosis, and b-catenin protein level. Ultimately they were tested in Apc1638N mice, which develop desmoid tumors, as well as in wild type mice subjected to full thickness skin wounds. The screen identified Neofopam, as an agent that inhibited cell numbers to 42 % of baseline in cell cultures from b-catenin driven fibroproliferative disorders. Nefopam decreased cell proliferation and b-catenin protein level to 50 % of baseline in these same cell cultures. The half maximal effective concentration in-vitro was 0.5 uM and there was a plateau in the effect after 48 hours of treatment. Nefopam caused a 45% decline in tumor number, 33 % decline in tumor volume, and a 40 % decline in scar size when tested in mice. There was also a 50 % decline in b-catenin level in-vivo. Nefopam targets b-catenin protein level in mesenchymal cells in-vitro and in-vivo
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Nefopam regulates scar size and β-catenin level in cutaneous wound repair.
2013Co-Authors: Raymond Poon, Helen Hong, Xin Wei, James Pan, Benjamin A AlmanAbstract:A to D) Representative histologic sections through the widest margin of scars 14 days after wounding. A) A wound from a mouse treated with TGF-β. B) A wound in a mice treated with carrier only. C) A wound from a mouse treated with TGF-β and Nefopam. D) A wound from a mouse treated with Nefopam. Arrows show the widest width of the scar. The black line is 500 µm in length. E) A graphical representation of the mean and 95% confidence intervals of the widest diameter of the scars in µms. F) A representative Western blot mice showing the β-catenin protein levels in wounds from mice treated with TGF-β, Nefopam, or both, showing that Nefopam decreases β-catenin protein level in the wounds.
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a high throughput screen identifies Nefopam as targeting cell proliferation in β catenin driven neoplastic and reactive fibroproliferative disorders
PLOS ONE, 2012Co-Authors: Raymond Poon, Helen Hong, Xin Wei, James Pan, Benjamin A AlmanAbstract:Fibroproliferative disorders include neoplastic and reactive processes (e.g. desmoid tumor and hypertrophic scars). They are characterized by activation of β-catenin signaling, and effective pharmacologic approaches are lacking. Here we undertook a high throughput screen using human desmoid tumor cell cultures to identify agents that would inhibit cell viability in tumor cells but not normal fibroblasts. Agents were then tested in additional cell cultures for an effect on cell proliferation, apoptosis, and β-catenin protein level. Ultimately they were tested in Apc1638N mice, which develop desmoid tumors, as well as in wild type mice subjected to full thickness skin wounds. The screen identified Neofopam, as an agent that inhibited cell numbers to 42% of baseline in cell cultures from β-catenin driven fibroproliferative disorders. Nefopam decreased cell proliferation and β-catenin protein level to 50% of baseline in these same cell cultures. The half maximal effective concentration in-vitro was 0.5 uM and there was a plateau in the effect after 48 hours of treatment. Nefopam caused a 45% decline in tumor number, 33% decline in tumor volume, and a 40% decline in scar size when tested in mice. There was also a 50% decline in β-catenin level in-vivo. Nefopam targets β-catenin protein level in mesenchymal cells in-vitro and in-vivo, and may be an effective therapy for neoplastic and reactive processes driven by β-catenin mediated signaling.
Philippe Girard - One of the best experts on this subject based on the ideXlab platform.
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Nefopam analgesia and its role in multimodal analgesia a review of preclinical and clinical studies
Clinical and Experimental Pharmacology and Physiology, 2016Co-Authors: Philippe Girard, Marcel Chauvin, Marc VerleyeAbstract:Nefopam is a non-opioid, non-steroidal, centrally acting analgesic drug used to prevent postoperative pain, primarily in the context of multimodal analgesia. This paper reviews preclinical and clinical studies in which Nefopam has been combined with opioids, non-steroidal anti-inflammatory compounds, and paracetamol. This report focuses on the literature during the last decade and discusses the translational efforts between animal and clinical studies in the context of multimodal or balanced analgesia. In preclinical rodent models of acute and inflammatory pain, Nefopam combinations including opioids revealed a synergistic interaction or enhanced morphine analgesia in six out of seven studies. Nefopam combinations including non-steroidal anti-inflammatory drugs (NSAIDs) (aspirin, ketoprofen or nimesulide) or paracetamol likewise showed enhanced analgesic effects for the associated compound in all instances. Clinical studies have been performed in various types of surgeries involving different pain intensities. Nefopam combinations including opioids resulted in a reduction in morphine consumption in 8 out of 10 studies of severe or moderate pain. Nefopam combinations including NSAIDs (ketoprofen or tenoxicam) or paracetamol also demonstrated a synergic interaction or an enhancement of the analgesic effect of the associated compound. In conclusion, this review of Nefopam combinations including various analgesic drugs (opioids, NSAIDs and paracetamol) reveals that enhanced analgesia was demonstrated in most preclinical and clinical studies, suggesting a role for Nefopam in multimodal analgesia based on its distinct characteristics as an analgesic. Further clinical studies are needed to evaluate the analgesic effects of Nefopam combinations including NSAIDs or paracetamol.
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systematic evaluation of the Nefopam paracetamol combination in rodent models of antinociception
Clinical and Experimental Pharmacology and Physiology, 2011Co-Authors: Philippe Girard, Marieclaude Coppe, Yannick Pansart, Betty Niedergang, Marc VerleyeAbstract:1. The aim of the present study was to explore the concept of multimodal anaesthesia using a combination of two non-opioid analgesics, namely Nefopam, a centrally acting non-opioid that inhibits monoamine reuptake, and paracetamol, an inhibitor of central cyclo-oxygenases. The antinociceptive characteristics of the combination were evaluated using four different animal models of pain. 2. In the mouse writhing test, antinociceptive properties were observed with ED50 values of 1.5 ± 0.2 and 120.9 ± 14.8 mg/kg for Nefopam and paracetamol, respectively. In the mouse formalin test, both compounds significantly inhibited the licking time of the injected hind paw, with ED50 values in the early phase of 4.5 ± 1.1 and 330.7 ± 80.3 mg/kg for Nefopam and paracetamol, respectively, compared with 4.3 ± 0.2 and 206.1 ± 45.1 mg/kg for Nefopam and paracetamol, respectively, in the inflammatory phase. Isobolographic analysis revealed that this drug combination was synergistic in the writhing test and additive in the formalin test. 3. In a rat incision model of postoperative thermal hyperalgesia, coadministration of Nefopam at a non-analgesic dose (3 mg/kg) with paracetamol at a low analgesic dose (300 mg/kg) showed the appearance of a strong antihyperalgesic effect, maintained for at least 3 h. In rat carrageenan-induced tactile allodynia, the combination of low analgesic doses of Nefopam (10 or 30 mg/kg) with a non-analgesic dose of paracetamol (30 mg/kg), significantly blocked allodynia with a longer duration of efficacy. 4. In conclusion, coadministration of Nefopam with paracetamol is worthy of clinical evaluation.
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Nefopam and ketoprofen synergy in rodent models of antinociception
European Journal of Pharmacology, 2008Co-Authors: Philippe Girard, Danielle Verniers, Marieclaude Coppe, Yannick Pansart, Jeanmarie GillardinAbstract: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.
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role of catecholamines and serotonin receptor subtypes in Nefopam induced antinociception
Pharmacological Research, 2006Co-Authors: Philippe Girard, Danielle Verniers, Marieclaude Coppe, Yannick Pansart, Jeanmarie GillardinAbstract:The non-opiate analgesic Nefopam has been shown to inhibit monoamines uptake, but little is known about receptor subtypes effectively involved in its analgesic effect. In vitro binding assays yielded the following measures of affinity (IC(50)): serotonergic 5-HT(2C) (1.4 microM), 5-HT(2A) (5.1 microM), 5-HT(3) (22.3 microM), 5-HT(1B) (41.7 microM), 5-HT(1A) (64.9 microM), adrenergic alpha(1) (15.0 microM) and dopaminergic D(1) (100 microM). Subcutaneous Nefopam administration dose-dependently inhibited pain in acetic acid-induced writhing (1-30 mg kg(-1)) and formalin (1-10 mg kg(-1)) tests in the mouse. Pretreatments with adrenergic alpha(1) (prazosin) and alpha(2) (yohimbine), and serotonergic 5-HT(1B) (GR127935) receptor antagonists significantly increased the Nefopam ED(50) in the writhing test. The serotonergic 5-HT(2C) (RS102221) and the dopaminergic D(2) (sulpiride) receptor antagonists inhibited Nefopam antinociception in the formalin test. However, in both tests, Nefopam analgesic activity was not modified by the following receptor antagonists: dopaminergic D(1) (SCH23390), serotonergic 5-HT(1A) (NAN-190, WAY100635), 5-HT(2A) (R96544, ketanserin), 5-HT(3) (tropisetron), and 5-HT(4) (SDZ205557). In conclusion, Nefopam analgesic activity could be modulated by the adrenergic alpha(1) and alpha(2) receptors, the dopaminergic D(2) receptors, and the serotonergic 5-HT(1B) and 5-HT(2C) receptor subtypes.
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role of the histamine system in Nefopam induced antinociception in mice
European Journal of Pharmacology, 2004Co-Authors: Philippe Girard, Danielle Verniers, Marieclaude Coppe, Yannick Pansart, Jeanmarie GillardinAbstract: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 microM, respectively, but no affinity for histamine H(3) receptor subtype until 100 microM. 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 alpha-fluoromethylhistidine (alpha-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(-)alpha-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.
Capucine Morelotpanzini - One of the best experts on this subject based on the ideXlab platform.
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Nefopam a non opioid analgesic does not alleviate experimental work effort dyspnoea in healthy humans a randomised controlled trial
Pulmonary Pharmacology & Therapeutics, 2016Co-Authors: Laurence Dangers, Louis Laviolette, Beny Charbit, Thomas Similowski, Capucine MorelotpanziniAbstract:Abstract Background Dyspnoea is a distressing and debilitating symptom with a major impact on quality of life. Alleviation of dyspnoea therefore constitutes a major clinical challenge. When causative physiological disorders cannot be corrected (“persistent dyspnoea”), nonspecific treatment must be considered. Morphine alleviates dyspnoea but has numerous side-effects including ventilatory depression, which justifies looking for alternatives. Certain forms of dyspnoea involve C-fibres, and can be attenuated by C-fibres blockade. We hypothesised that Nefopam, a non-sedative benzoxazocine analgesic known to block the transient receptor potential vanilloid subtype 1 abundantly present on C-fibres, would attenuate dyspnoea. Methods We conducted a randomised, double-blind, placebo-controlled crossover study of Nefopam in healthy subjects submitted to experimental work/effort dyspnoea by inspiratory threshold loading (15 healthy male volunteers; age 23–41). We studied a perceptual outcome (dyspnoea visual analogue scale —D-VAS—) and a neurophysiological outcome (effect of Nefopam on dyspnoea-pain counter-irritation as assessed by laser-evoked potentials; an effect of Nefopam on dyspnoea was hypothetised to reduce the ability of dyspnoea to inhibit pain). Somaesthetic evoked potentials (SEPs) were studied as a control. Results A statistically significant decrease in LEP amplitude was observed in response to loading with Nefopam (F = 19.1; p Conclusions In this study, Nefopam did not exhibit any effects on dyspnoea.
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effects of a non opioid analgesic on experimental work effort dyspnea in healthy volunteers a laser evoked potential study
European Respiratory Journal, 2013Co-Authors: Laurence Dangers, Louis Laviolette, Beny Charbit, Thomas Similowski, Capucine MorelotpanziniAbstract:Background. Counter-irritation is the attenuation of a painful sensation by a newly occurring heterotopic stimulus that must be noxious in nature. Dyspnea-pain counter-irritation, arising from C-fibers stimulation, has been described with experimental dyspnea of the work/effort type, which inhibits laser evoked cortical potentials (LEPs). Thus, an experimental dyspnea (work/effort) might be relieved by a non-opioid analgesic. Dyspnea-induced counter irritation should then be attenuated, with a lesser degree of LEPs inhibition. Methods. In this randomized, double-blind, placebo-controlled cross-over study, a non opioid analgesic (Nefopam) was administrated by intravenous infusion over 30 min to fifteen healthy naive male subjects, according to power calculations based on available results. The N2P2 component of LEPs was obtained using CO2 laser stimulation on the hand and recorded using EEG. LEPs were acquired during three conditions: spontaneous breathing, spontaneous breathing under Nefopam/placebo and experimental dyspnea induced by inspiratory threshold loading under Nefopam/placebo. Results. The intensity of experimental dyspnea was not different (p=0.88) between Nefopam and placebo (VAS rating 3.7 ± 2 cm versus 4 ± 1.9 cm). The amplitude of N2P2 during experimental dyspnea was reduced by 35 ± 18% and 25 ± 21 % (Δ = 37%, p = 0.23) with placebo and Nefopam respectively (power 0. 74). Conclusion. There was no statistically significant effect of Nefopam on experimental dyspnea and on dyspnea-pain counter-irritation assessed by LEPs, but the study proved underpowered. How interfering with C-fibers function could alleviate dyspnea should be further studied.
