Tramadol‐Induced Seizurogenic Effect: A Possible Role of Opioid‐Dependent γ‐Aminobutyric Acid Inhibitory Pathway

Abstract

The present study has been designed to pharmacologically investigate the role of opioid and γ -aminobutyric acid receptors on the seizurogenic effect of tramadol. A single injection of pentylenetetrazole (80 mg/kg) was used to elicit seizure activity in mice. Seizures were assessed in terms of the time latency of the onset of Straub's tail phenomenon, onset of jerky movements of whole body, convulsions and death. Tramadol administration (50 mg/kg) caused a marked increase in seizurogenic activity of pentylenetetrazole as measured in terms of a significant decrease in the time latency of the onset of Straub's tail phenomenon, jerky movements of whole body, convulsions and death. Moreover, prior administration of naloxone (2 mg/kg) and gabapentin (25 mg/kg), respectively, attenuated the seizurogenic activity that tramadol exerted on pentylenetetrazole-treated mice. Furthermore, prior administration of naloxone (2 mg/kg) and gabapentin (25 mg/kg), respectively, also attenuated the seizurogenic activity exerted by tramadol per se . Therefore, it is suggested that tramadol exerts a seizurogenic effect on mice possibly via an opioid-dependent γ -aminobutyric acid inhibitory pathway., is a centrally acting analgesic used clinically for the treatment of postoperative and cancer pain. Tramadol binds to opioid receptors with low affinity and inhibits reuptake of monoamines such as norepinephrine and serotonin in the central nervous system, resulting in the activation of the descending inhibitory system [1,2]. These actions are believed to primarily contribute to tramadol's antinociceptive effect. At clinically relevant doses, tramadol has been shown to slightly suppress the severity of seizures [3]. However, at relatively higher doses, tramadol has paradoxically been proven to induce seizures [3]. Although γ -aminobutyric acid (GABA) receptors were not affected by tramadol at clinical doses, at higher concentrations tramadol has been shown to exert an inhibitory effect on GABA receptors [4]. Moreover, pharmacological inhibition of GABA receptors has been reported to potentiate the severity of seizures in various animal models [5]. Furthermore, this inhibition of GABA receptors induced by tramadol has been shown to be secondary to its opioid receptor agonist activity. In addition, continued pharmacological opioid receptor agonist activity has been proven to precipitate seizures via a GABA inhibitory pathway [6,7]. Therefore, the present study has been designed to pharmacologically investigate the role of opioid and GABA receptors in the seizurogenic effect of tramadol on pentylenetetrazole-treated mice and on seizure-like behavioural symptomatology precipitated per se by tramadol. Materials and MethodsMale inbred Swiss albino mice, weighing 25 ± 2 g, maintained on a standard laboratory diet (Kisan Feeds Ltd., Mumbai, India) with free access to tap water, were employed in the present study. They were housed in the departmental animal house and were exposed to a 12-hr light:dark cycle. The experiments were conducte...

Factors Related to Seizure in Tramadol Poisoning and Its Blood Concentration

“…The exact mechanism of tramadol in induction of seizure remains to be elucidated yet. Research indicates that in high concentrations tramadol exerts an inhibitory effect on gammaaminobutyric acid (GABA) receptors [12,13]. Inhibition of GABA receptors has been found to potentiate the severity of seizures in animal models [13,14].…”

“…Research indicates that in high concentrations tramadol exerts an inhibitory effect on gammaaminobutyric acid (GABA) receptors [12,13]. Inhibition of GABA receptors has been found to potentiate the severity of seizures in animal models [13,14]. In addition, GABA receptor inhibition induced by tramadol can be secondary to its opioid receptor agonist activity [13], and continuing this agonist activity on opioid receptor has been proven to precipitate seizure due to inhibition of GABA pathways [15,16].…”

“…Inhibition of GABA receptors has been found to potentiate the severity of seizures in animal models [13,14]. In addition, GABA receptor inhibition induced by tramadol can be secondary to its opioid receptor agonist activity [13], and continuing this agonist activity on opioid receptor has been proven to precipitate seizure due to inhibition of GABA pathways [15,16]. In addition to overdose, seizures have been reported in patients receiving tramadol at recommended doses [17].…”

Severe acute lactic acidosis and hypoglycemia due to isolate tramadol poisoning

“…2 It has also been demonstrated that tramadol stimulates the dopamine (D2) receptors and inhibits the gamma amino butyric acid (GABA) release in central nervous system. 3,4 This pharmacodynamic complexity translates into a wide range of clinical actions and even toxic effects, which are often not fully predictable. Briefly, tramadol is an increasingly used analgesic drug, available as both parenteral and enteral formulations, originally introduced in Germany in the late 1970s as a weak opioid with atypical clinical profile.…”

Tramadol Induced Partial Seizure: A Rare Adverse Drug Reaction - Case Report

“…[3,4] Smallest amount of tramadol associated with seizure was 200 mg, and 84.6% of seizures occurred within 6 hours administration. When tramadol is used for long-term, suicide attempts, intentional abuse or misuse, and tachycardia have been reported.…”