Mechanisms of tramadol-related neurotoxicity in the rat: Does diazepam/tramadol combination play a worsening role in overdose?

Lagard, Camille; Chevillard, L; Malissin, Isabelle; Risède, Patricia; Crinon, Jacques; Labat, Laurence; Launay, Jean‐Marie; Laplanche, Jean‐Louis; Mégarbane, Bruno

doi:10.1016/j.taap.2016.09.013

Cited by 46 publications

(49 citation statements)

References 50 publications

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“…Rat pretreatment with cyproheptadine, a serotonin receptor antagonist, did not abolish tramadol-induced seizures 4 while 5-hydroxytryptophane/benserazide, a combination enhancing brain serotonin concentration, was protective 5 or without effects on seizures. 4 These observations contrasted with the preventive effects of cyproheptadine on seizures induced by citalopram, a serotoninreuptake inhibitor, 6 suggesting that drug-related SS is a heterogeneous entity. Including seizures in the SS should not be systematic but depending on the responsible drug.…”

Section: To the Editormentioning

confidence: 99%

Tramadol: Distinguishing the Pathophysiology of Serotonin Syndrome and Seizures

Mégarbane

Lagard

Chevillard

2018

The American Journal of Medicine

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Section: To the Editormentioning

confidence: 99%

Tramadol: Distinguishing the Pathophysiology of Serotonin Syndrome and Seizures

Mégarbane

Lagard

Chevillard

2018

The American Journal of Medicine

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“…Nearly every opioid has shown at least some degree of neurotoxicity, including hydromorphone, tramadol, oxycodone, fentanyl, sufentanil and buprenorphine [25][26][27][28][29][30][31][32][33][34][35]. For neuraxial morphine, this is less consistent [26,36].…”

Section: Neurotoxicitymentioning

confidence: 99%

“…We suggest avoiding all widely used opioids that are proven neurotoxic and have no proven benefit when administered epidurally, being hydromorphone [64], buprenorphine [62] and tramadol [29,30].…”

Section: Clinical Implicationmentioning

confidence: 99%

Safety of epidural drugs: a narrative review

Zuylen

Hoope

Bos

et al. 2019

Expert Opinion on Drug Safety

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Introduction: Epidural analgesia is a popular approach to postoperative and labor pain. Neurotoxicity and drug-specific systemic side effects can occur after epidural administration. As an increasing number of epidural drugs are studied and clinically applied, drug efficacy and safety evaluation are crucial. Areas covered: In this narrative review, the authors provide a thorough overview on the safety of the most widely used epidural drugs, focusing on potential neurotoxicity, side effects, and complications in the adult, non-pregnant population. A combined text and MeSH heading search strategy was used to identify relevant publications. Expert opinion: The search for the ideal epidural medication has resulted in a surplus of drug combinations with extensive heterogeneity amongst studies, while the value of investigating these is not always evident. Epidural drugs pose a potential threat of neurotoxicity and other side effects. Consequently, we should pursue safe epidural drug administration to patients and refrain from drugs with minimal proven benefit. Also, studies should compare epidural with systemic application. Because why use a drug epidurally, which can be safely used systemically? Future research should focus on providing solid evidence regarding efficacy of epidural analgesia compared to new and already existing modalities and optimizing presently used medicinal regimens.

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“…7 Although TR, as opposed to typical opioids, does not have a remarkable opioid side effects (eg, respiratory depression, sedation, constipation), sometimes it has unfavorable side effects with respect to seizure potential. 8,9 At therapeutic doses, TR slightly suppresses the severity of seizure. However, at high doses, TR paradoxically induces seizure.…”

Section: Introductionmentioning

confidence: 99%

“…10 Two important mechanisms of action for TR are weak agonistic effect at the m-opioid receptors and inhibition of the monoamines (serotonin, norepinephrine) reabsorption. 8,11 The neurotoxicity of TR mostly occurs within 24 hours of drug administration and 84.6% of seizures occur within 6 hours after TR consumption. The minimum dose of TR that may induce convulsion is not so clear, but in various studies, it has been reported to be about 200 mg. 12,13 The exact mechanism of TR in the generation of seizure remains to be elucidated, but some studies show the involvement of opioid receptor activation-linked g-aminobutyric acid (GABA) inhibitory pathway in the convulsant effects of TR.…”

Section: Introductionmentioning

confidence: 99%

Evidence for the Involvement of the Dopaminergic System in Seizure and Oxidative Damage Induced by Tramadol

et al. 2018

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Tramadol (TR) is a synthetic analgesic drug with central function that can induce seizures even at therapeutic doses. The exact mechanism of TR effect on seizure generation is not clear, but inhibition of the serotonin and nitric oxide pathways and inhibitory effects on GABA receptors are the most common hypotheses about the seizure-inducing mechanism of the TR. This study aimed to evaluate the role of dopaminergic system on the seizure and oxidative damage induced by TR using agonist and antagonist drugs of this system in the Albino mice. Clonic seizure induced by TR was evaluated as seizure threshold. Haloperidol (0.2 mg/kg, IP), a predominantly D receptor antagonist, and cabergolin (0.5 mg/kg, IP), a dopamine agonist specific for the D receptors, were injected 60 minutes before the seizure induction. The seizure threshold was significantly increased by dopaminergic antagonist, but it was decreased significantly by pretreatment with the selective agonist. Oxidative stress biomarkers (reactive oxygen species, lipid peroxidation, and protein carbonyl content) significantly increased and glutathione content significantly decreased in brain mitochondria by TR compared with the control group, whereas oxidative markers were decreased significantly after pretreatment with haloperidol compared with the TR group. This study revealed that the dopaminergic system is involved in TR-induced seizure, and meanwhile, inhibition of dopamine D receptors can increase the TR threshold seizure and decrease the oxidative damage in the brain mitochondria. Conversely, stimulation of dopamine D receptors by cabergolin can decrease the TR threshold seizure and glutathione content in the brain mitochondria.

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Mechanisms of tramadol-related neurotoxicity in the rat: Does diazepam/tramadol combination play a worsening role in overdose?

Cited by 46 publications

References 50 publications

Tramadol: Distinguishing the Pathophysiology of Serotonin Syndrome and Seizures

Tramadol: Distinguishing the Pathophysiology of Serotonin Syndrome and Seizures

Safety of epidural drugs: a narrative review

Evidence for the Involvement of the Dopaminergic System in Seizure and Oxidative Damage Induced by Tramadol

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