Tramadol-Induced Seizures: Incidence and Seizure Threshold Risk
Direct Answer
Tramadol lowers the seizure threshold and causes seizures even at therapeutic doses, with the FDA issuing a boxed warning about this risk; however, the absolute incidence in clinical practice appears relatively low (approximately 1-2% at therapeutic doses), though it increases substantially with higher doses, overdose, and when combined with other seizure threshold-lowering medications. 1
Seizure Risk Profile
FDA Boxed Warning and Mechanism
The FDA has issued a boxed warning stating that seizures have been reported in patients receiving tramadol within the recommended dosage range, and that seizure risk is increased with doses above the recommended range. 1
Tramadol's dual mechanism—weak mu-opioid receptor agonism plus norepinephrine and serotonin reuptake inhibition—contributes to its seizure-lowering properties through effects on monoamine neurotransmission. 2, 3
Incidence Data
In overdose settings, seizure prevalence is substantial: 58% of tramadol-intoxicated patients presenting to emergency departments experienced seizures. 4
In therapeutic use, a large nested case-control study of nearly 1 million patients found a 41% increased risk of seizures requiring hospitalization with tramadol compared to codeine (OR 1.41,95% CI 1.11-1.79), though no significant association was found when using broader seizure definitions including outpatient diagnoses. 5
A nationwide Korean study using case-case-time-control methodology found no significant association between transient tramadol use and seizure incidence in routine clinical practice (aOR 0.94,95% CI 0.98-1.43). 6
Dose-Response Relationship
History of seizure increases the risk of tramadol-induced seizures 3.7-fold (OR 3.71,95% CI 1.17-11.76). 4
Higher tramadol doses correlate significantly with increased seizure frequency—patients with multiple seizure episodes had ingested a median of 2800 mg compared to 850 mg in those with single episodes. 4
The maximum recommended daily dose is 400 mg for immediate-release and 300 mg for extended-release formulations to minimize seizure risk. 2, 3
High-Risk Populations and Drug Interactions
Medications That Increase Seizure Risk
The FDA warns that concomitant use of tramadol significantly increases seizure risk with: 1
- SSRIs and SNRIs (antidepressants)
- Tricyclic antidepressants (TCAs) and other tricyclic compounds (cyclobenzaprine, promethazine)
- MAO inhibitors
- Other opioids
- Neuroleptics
- Any drugs that reduce seizure threshold
Patient-Specific Risk Factors
Administration of tramadol may enhance seizure risk in patients with: 1
- Epilepsy or history of seizures
- Head trauma
- Metabolic disorders
- Alcohol and drug withdrawal
- CNS infections
Special Populations Requiring Dose Reduction
- Older adults (≥75 years) require reduced dosing to minimize seizure risk. 2, 3
- Patients with hepatic or renal dysfunction need lower doses due to drug accumulation. 2, 3
- Starting dose should be 50 mg once or twice daily, gradually titrated to maximum 400 mg/day in adults with normal organ function. 2
Clinical Management Considerations
Recurrent Seizure Risk
Only 7% of tramadol-intoxicated patients who had an initial seizure experienced recurrent seizures, and all recovered without sequelae in a cohort of 100 patients. 7
Prophylactic anticonvulsant therapy after a first tramadol-induced seizure is unnecessary given the low recurrence rate and lack of morbidity. 7
Naloxone Caution
- In tramadol overdose, naloxone administration may paradoxically increase the risk of seizures and should be used cautiously. 1
Trauma Risk
- Tramadol-induced seizures result in trauma in 24.6% of cases, most commonly facial injuries (9.5%), with serious head injury occurring in approximately 1% of patients. 8
Practical Prescribing Recommendations
When prescribing tramadol, the Mayo Clinic Proceedings guidelines recommend: 2
- Avoid tramadol in patients taking SSRIs, SNRIs, or TCAs due to both seizure risk and serotonin syndrome risk
- Consider tramadol as second-line therapy, reserved for patients who have not responded to first-line medications
- Use as first-line only for acute neuropathic pain, cancer-related pain, or episodic severe pain exacerbations
- Monitor closely for seizure activity in patients with pre-existing seizure disorders
The ACEP guidelines note that prescribed medications like tramadol can lower seizure threshold, complicating emergency management of seizure patients. 2