Expanding Role of NMDA Receptor Antagonists in the Management of Pain

Kreutzwiser, Denise; Tawfic, Qutaiba A.

doi:10.1007/s40263-019-00618-2

Cited by 59 publications

(54 citation statements)

References 157 publications

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“…This contrasts with gabapentin and pregabalin, which do not notably cause dissociative effects, disrupt memory nor cause agitation or psychosis in clinical use. Although ketamine (the most widely studied NMDA antagonist for treating pain) is used primarily for perisurgical pain (Kreutzwiser and Tawfic, 2019) and increasingly for treatment-resistant depression (Murrough et al, 2013;van Schalkwyk et al, 2018), it is not used for chronic neuropathic pain (Gilron, 2007), and it has strong psychotomimetic properties (Sos et al, 2013).…”

Section: Analgesia Produced By Gabapentinoids Compared To Known Nmda mentioning

confidence: 99%

Analgesia with Gabapentin and Pregabalin May Involve N-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins

Taylor¹,

Harris²

2020

J Pharmacol Exp Ther

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The gabapentinoid drugs gabapentin and pregabalin (Neurontin® and Lyrica®) are mainstay treatments for neuropathic pain and for preventing focal seizures. Both drugs have similar effects to each other in animal models and clinically. Studies have shown that a protein first identified as an auxiliary subunit of voltage-gated calcium channels (the alpha2-delta subunit, 2-1 or CaVa2d1) is the high-affinity binding site for gabapentin and pregabalin, and is required for the efficacy of these drugs. The 2-1 protein is required for the ability of gabapentin and pregabalin to reduce neurotransmitter release in neuronal tissue, consistent with a therapeutic mechanism of action via voltage-gated calcium channels. However, recent studies have revealed that 2-1 interacts with several proteins in addition to voltage-gated calcium channels, and these additional proteins could be involved in gabapentinoid pharmacology. Furthermore, gabapentin and pregabalin have been shown to modify the action of a subset of NMDAsensitive glutamate receptors, neurexin-1, and thrombospondin proteins by binding to 2-1. Thus, these effects may contribute substantially to gabapentinoid therapeutic mechanism of action. Significance Statement It is widely believed that gabapentin and pregabalin act by modestly reducing the membrane localization and activation of voltage-gated calcium channels at synaptic endings in spinal cord and neocortex via binding to the 2-1 protein. However, recent findings show that the 2-1 protein also interacts with NMDA-sensitive glutamate receptors, neurexin-1, thrombospondins (adhesion molecules), and other presynaptic proteins. These newly discovered interactions, in addition to actions at calcium channels, may be important mediators of gabapentin and pregabalin therapeutic effects.

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Section: Analgesia Produced By Gabapentinoids Compared To Known Nmda mentioning

confidence: 99%

Analgesia with Gabapentin and Pregabalin May Involve N-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins

Taylor¹,

Harris²

2020

J Pharmacol Exp Ther

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“…NMDA receptor antagonists have therefore garnered increasing attention over recent years as an adjunctive/alternative pain treatment modality, as blockage of NMDA receptors prohibits central sensitization of nociceptors and thus the interception of nociceptive input. Despite its attractive analgesic profile, ketamine has been postulated to trigger undesired augmentation of systemic hemodynamics, PONV, and psychomimetic manifestations, with hallucinations being the predominant one among them . Yet, a bulk of evidence demonstrates that the risk of the aforementioned side‐effects becomes trivial when analgesic doses of ketamine (<2 mg/kg) are applied .…”

Section: Discussionmentioning

confidence: 70%

“…Despite its attractive analgesic profile, ketamine has been postulated to trigger undesired augmentation of systemic hemodynamics, PONV, and psychomimetic manifestations, with hallucinations being the predominant one among them . Yet, a bulk of evidence demonstrates that the risk of the aforementioned side‐effects becomes trivial when analgesic doses of ketamine (<2 mg/kg) are applied . Our results showed that the combined use of pre‐incisional infiltration of tramadol with local or intravenous ketamine provided better postoperative pain control and quality of recovery than using each drug separately, with minor adverse effects .…”

Section: Discussionmentioning

confidence: 70%

“…Ketamine hydrochloride is a nonbarbiturate anesthetic drug whose anesthetic and analgesic effects are mediated primarily by a noncompetitive antagonism at NMDA receptors . NMDA receptor antagonists have therefore garnered increasing attention over recent years as an adjunctive/alternative pain treatment modality, as blockage of NMDA receptors prohibits central sensitization of nociceptors and thus the interception of nociceptive input.…”

Section: Discussionmentioning

confidence: 99%

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Analgesic Efficacy and Safety of Local Infiltration of Tramadol in Pediatric Tonsillectomy Pain: A Systematic Review and Meta‐Analysis

et al. 2020

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Objectives The aim of this systematic review and meta‐analysis was to appraise clinical evidence of the impact of peritonsillar infiltration of tramadol, on postoperative pain control and the occurrence of adverse effects in children undergoing tonsillectomy. Methods A database search was conducted to identify randomized controlled trials (RCTs) pertinent to peritonsillar infiltration of tramadol compared to no treatment (placebo) or other analgesic regimens. The outcomes of interest were postoperative pain intensity, time to first analgesic demand, rescue analgesic consumption up to 24 hours after intervention, and the occurrence of adverse events. Results Twelve RCTs enrolling 972 pediatric patients were selected for qualitative analysis, among which eight were suitable for meta‐analysis. Tramadol infiltration induced a significant reduction of pain intensity up to 24 hours post‐tonsillectomy (mean difference [MD], −2.31; 95% confidence interval [CI], −3.49 to −1.12; P < 0.001; I2 = 97%) and time to first analgesic (MD 180.54; 95% CI, 56.91 to 304.18; P = 0.004; I2 = 99%), with no profound impact on postoperative nausea and vomiting (risk ratio [RR] 0.98; 95% CI, 0.73 to 1.32; P = 0.90; I2 = 0%) compared to the placebo group. The analgesic efficacy of tramadol infiltration was equivalent to the local or systematic use of ketamine or infiltration with local anesthetics. This effect was further enhanced when tramadol infiltration served as an adjunct to other analgesic interventions. No serious adverse events were reported. Conclusions In children undergoing tonsillectomy, peritonsillar infiltration of tramadol is associated with a postoperative analgesic benefit when compared to placebo, with negligible adverse events. Yet, no definite conclusion can be drawn due to the low quality, considerable heterogeneity, and paucity of the available data.

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“…Magnesium ions are coactivators of the activity of many enzymes and regulate the conductance of the NMDA receptor channel in the central nervous system (Swaminathan, 2003;Seo and Park, 2008), which play a crucial role in the mechanisms of chronic pain. Clinical trials showed that systemic Mg 2+ , used as adjuvant medication of opioids (mostly morphine, but also fentanyl and tramadol), significantly reduced opioid consumption in acute intraoperative and post-operative pain complaints (Bujalska-Zadrozṅy et al, 2017), but no similar data exist regarding chronic pain syndromes (Kreutzwiser and Tawfic, 2019). On the other hand, copper has demonstrated antinociceptive properties against various pain modalities in preclinical studies hot plate, tail flick tests, and in the writhing test (Tamba et al, 2013), formalin test (Cazanga et al, 2018), adjuvant arthritic rat pain model (Okuyama et al, 1987), and that it may enhance the peripheral analgesic effect of fenoprofen (Gumilar et al, 2012)) and the central analgesic effect of ketamine (Cazanga et al, 2018), but copper has not yet been tested as antinociceptive agent in humans via systemic route.…”

Section: Introductionmentioning

confidence: 99%

Magnesium Salt, a Simple Strategy to Improve Methadone Analgesia in Chronic Pain: An Isobolographic Preclinical Study in Neuropathic Mice

et al. 2020

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Analgesic efficacy of methadone in cancer and chronic non-cancer pains is greater than that of other opioids, probably because of its unique pharmacokinetics properties and also because it targets glutamatergic receptors in addition to µ-opioid receptors. However, methadone has drawbacks which are clearly related to dosing and treatment duration. The authors hypothesized that the antinociceptive efficacy of methadone could be synergistically potentiated by magnesium and copper salts in a preclinical mouse model of chronic pain, using the intraplantar formalin test as algesimetric tool. The spared nerve injury mice model was used to generate mononeuropathy. A low dose (0.25%) formalin was injected in the neuropathic limb in order to give rise only to Phase I response, resulting from direct activation by formalin of nociceptive primary afferents. Licking/biting of the formalin-injected limb was evaluated as nociceptive behavior during a 35-min observation period. Dose-response curves for intraperitoneal magnesium sulfate (10, 30, 100, and 300 mg/kg i.p.), copper sulfate (0.1, 0.3, 1, and 3 mg/kg i.p.) and methadone (0.1, 0.3, 1, and 3 mg/kg i.p.) allowed to combine them in equieffective doses and to determine their interaction by isobolographic analysis. Magnesium sulfate, copper sulfate and methadone dose-dependently decreased the nociceptive response evoked by formalin injection, the respective ED 50 being 76.38, 1.18, and 0.50 mg/kg i.p. Isobolographic analysis showed a superadditive interaction for magnesium and methadone. Indeed, despite that both ED 50 are obviously equieffective, the ED 50 for the MgSO4/methadone combination contained less than one third of the methadone having the ED 50 for methadone alone. For the CuSO 4 /methadone combination, the interaction was only additive. Extrapolated to clinical settings, the results suggest that magnesium salts might be used to improve synergistically the efficacy of methadone in neuropathy, which would allow to reduce the dose of methadone and its associated side effects.

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Expanding Role of NMDA Receptor Antagonists in the Management of Pain

Cited by 59 publications

References 157 publications

Analgesia with Gabapentin and Pregabalin May Involve N-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins

Analgesia with Gabapentin and Pregabalin May Involve N-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins

Analgesic Efficacy and Safety of Local Infiltration of Tramadol in Pediatric Tonsillectomy Pain: A Systematic Review and Meta‐Analysis

Magnesium Salt, a Simple Strategy to Improve Methadone Analgesia in Chronic Pain: An Isobolographic Preclinical Study in Neuropathic Mice

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