Tramadol toxicity and risk of seizures: mechanisms and suggested management

1. Tramadol toxicity and risk of seizures: mechanisms and
suggested management
Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA
Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of
Medical Sciences, Iran
By:
Omid Mehrpour, MD, FACMT
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2. Tramadol toxicity:
 Tramadol is one of the most commonly prescribed central nervous system (CNS)
analgesics used globally.
 It is widely prescribed for the treatment of moderate to severe pain
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3. Schematic diagram of tramadol metabolism
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4. (Subedi M. et al, 2019)
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Mechanism of action of tramadol

5. Mechanism of action of opioids
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6. Mechanism of action of opioids
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7. 7

8. Signs and symptoms of
Tramadol toxicity:
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9. Common signs and symptoms of tramadol toxicity:
Tramadol overdose can lead to:
 Tachycardia
Miosis or mydriasis
Loss of consciousness
Seizures
Respiratory depression
Serotonin syndrome
Hypoglycemia in diabetic patients 9

10. The characteristics of tramadol induced seizure:
Seizure as a serious nervous disturbance is more common in
tramadol intoxication than with other opioids
Tramadol induced seizures may occur in the first 6h after
ingestion of tramadol.
Seizures are typically single tonic-clonic type
Seizure may happen at doses as low as 100-200 mg.
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11. The incidence of seizure:
The incidence of seizure has been reported to be 0.32% to 81.08%
with tramadol overdose
The rate of seizures with therapeutic tramadol use was reported to
range from 0.025% to 14.6%
Reported incidence of seizures in tramadol dependent patients
ranged from 0.86% to 52.4%.
Seizures may occur in infants and children, as well.
Most patients will have a normal EEG and CT scan of the brain.
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12. Tramadol dose and seizures:
Tramadol induced seizure is dose dependent?
Some studies reported a non-significant difference of serum
tramadol concentrations between patients with seizures and
those without seizures.
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13. Risk factors of seizures
The seizure risk is more significant with these conditions:
An existing seizure disorder or a history of previous seizures.
Patients with a history of tramadol abuse or intoxication
Chronic tramadol users.
Tramadol may also increase the seizure risk with concurrent use
of serotonergic medications
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14. Mechanism of tramadol induced- seizure:
Possible systems have been proposed as being involved in precipitating tramadol-induced
seizures, including:
 Serotonin and norepinephrine reuptake inhibition
 Histaminergic
 Dopaminergic
 Nitric oxide pathway
 Opioid receptors(mu and delta)
 Inhibition of GABAergic neurons
 Activation of glutamatergic
 Dual effects on G proteins
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15. (Subedi M. et al, 2019)
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Serotonin and norepinephrine reuptake inhibition

16. Dopaminergic/serotonergic pathway pathway
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17. The role of nitric oxide (NO)
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18. Opioids and nitric oxide interaction:
(Khan et al. 2020)
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19. Mechanism of tramadol induced- seizure:
Tramadol and metabolite M1 inhibit GABAA receptors at high
concentrations and NMDA receptors at clinical concentrations .
So, in low doses, tramadol has some anti-seizure properties and high
doses have some seizuregenic effects.
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20. Dual effects on G proteins
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21. Role of Norepinephrine reuptake inhibition /alpha2
contribution
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(Chang et al, 2016)

22. Management of tramadol induced-seizures
 Treatment of tramadol toxicity should be based on conservative approaches
 Maintenance of airway and breathing,
 Maintain circulation
 Fluid resuscitation if needed
 Oxygen therapy
 Diazepam administration for the managing of seizure and agitation .
 Because of the early onset of seizures following tramadol ingestion, it has been
suggested to administer charcoal after securing the airway.
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23. Measure Blood glucose levels and treat
hypoglycemia.
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24. Role of naloxone administration in tramadol induced-seizures:
 Naloxone is an opioid receptor antagonist that reverses opioid-induced respiratory
depression.
 However, there are conflicting findings on its use in tramadol poisoning and its
effect on seizures.
 Previous experimental and human investigations have shown that naloxone may
reduce, increase, or have no impact on the risk of tramadol-induced seizures.
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25. 25

26. (Lagard .et al, 2016)
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27. Prophylactic anticonvulsant treatment ?
 Due to the low risk of multiple seizures in tramadol toxicity, prophylactic
anticonvulsant treatment should not be routinely prescribed even for cases of
initial seizures.
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28. Different treatments for tramadol-induced seizure in an animal model:
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29. Management of tramadol induced-seizures
A combination of diazepam/naloxone is reported as an efficient treatment to
reverse tramadol-induced seizure.
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30. References:
 Lagard C, Chevillard L, Malissin I, Risède P, Callebert J, Labat L, Launay JM, Laplanche JL,
Mégarbane B. Mechanisms of tramadol-related neurotoxicity in the rat: Does diazepam/tramadol
combination play a worsening role in overdose?. Toxicology and applied pharmacology. 2016
Nov 1;310:108-19
 Subedi M, Bajaj S, Kumar MS, Mayur YC. An overview of tramadol and its usage in pain
management and future perspective. Biomedicine & Pharmacotherapy. 2019 Mar 1;111:443-51.
 Khan MI, Shah FU, Wahab A, Nikoui V, Dehpour AR. The role of opioid and nitrergic systems
in dual modulation of seizure susceptibility. Advancements in Life Sciences. 2020 Sep
2;7(4):193-201.
 Eipe N. Peri-operative Ketamine for Acute Pain Management. InAnalgesia in Major Abdominal
Surgery 2018 (pp. 65-82). Springer, Cham.
 Rehni AK, Singh TG, Singh N, Arora S. Tramadol-induced seizurogenic effect: a possible role of
opioid-dependent histamine (H 1) receptor activation-linked mechanism. Naunyn-
Schmiedeberg's archives of pharmacology. 2010 Jan 1;381(1):11.
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31. References:
 Faria J, Barbosa J, Moreira R, Queirós O, Carvalho F, Dinis‐Oliveira RJ. Comparative
pharmacology and toxicology of tramadol and tapentadol. European Journal of Pain. 2018
May;22(5):827-44.
 Hara K, Minami K, Sata T. The effects of tramadol and its metabolite on glycine, γ-aminobutyric
AcidA, and N-methyl-d-aspartate receptors expressed in Xenopus oocytes. Anesthesia &
Analgesia. 2005 May 1;100(5):1400-5.
 Bameri B, Shaki F, Ahangar N, Ataee R, Samadi M, Mohammadi H. Evidence for the
involvement of the dopaminergic system in seizure and oxidative damage induced by tramadol.
International journal of toxicology. 2018 Mar;37(2):164-70.
 Chang EJ, Choi EJ, Kim KH. Tapentadol: can it kill two birds with one stone without breaking
windows?. The Korean journal of pain. 2016 Jul;29(3):153.
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