What is the significance of the seizure threshold lowering effect of tramadol (tramadol hydrochloride)?

From the Guidelines

Tramadol's seizure threshold lowering effect is a significant concern that should be taken seriously when prescribing this medication, particularly at doses exceeding 400mg daily or in patients with predisposing factors such as epilepsy, prior head trauma, or when combined with other medications that lower seizure threshold. The seizure risk is substantially higher in these patients due to tramadol's inhibition of serotonin and norepinephrine reuptake, as noted in the 2024 guidelines on the management of trauma in elderly and frail patients 1. According to the 2019 NCCN clinical practice guidelines in oncology, tramadol is a weak mu-opioid receptor agonist with some norepinephrine and serotonin reuptake inhibition, and its use should be cautious or avoided in patients taking other serotonergic or monoamine oxidase inhibitors (MAOI)-like medications due to the risk of serotonin syndrome 1.

Key Considerations

• Tramadol causes seizures through its inhibition of serotonin and norepinephrine reuptake, with the seizure risk estimated at approximately 1 per 1000 patients at therapeutic doses but increasing dramatically with overdose.
• The risk of seizures is higher in patients with predisposing factors such as epilepsy, prior head trauma, or when combined with other medications that lower seizure threshold (including SSRIs, SNRIs, tricyclic antidepressants, and antipsychotics).
• For patients requiring pain management with risk factors for seizures, alternative analgesics such as acetaminophen, NSAIDs, or certain opioids with lower seizure risk (like morphine or hydrocodone) should be considered.
• Always start tramadol at the lowest effective dose, avoid rapid dose escalation, and counsel patients to never exceed prescribed dosages to minimize this serious adverse effect.

Recommendations

• Use tramadol with caution in patients with a history of seizures or predisposing factors, and consider alternative analgesics when possible.
• Monitor patients closely for signs of serotonin syndrome when combining tramadol with other serotonergic or MAOI-like medications.
• Follow the recommended maximum daily dose of 400 mg for IR formulations or 300 mg/day for ER formulations, and adjust doses accordingly for older adults or patients with hepatic and/or renal dysfunction to reduce the risk of seizures, as recommended by the 2019 NCCN clinical practice guidelines in oncology 1.

From the FDA Drug Label

WARNING Seizures have been reported in patients receiving Tramadol hydrochloride within the recommended dosage range. Concomitant use of tramadol hydrochloride increases the seizure risk in patients taking: Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics), Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine , promethazine, etc.), or Other opioids. Administration of tramadol hydrochloride may enhance the seizure risk in patients taking: MAO inhibitors (see alsoWARNINGS, Use with MAO Inhibitors and Serotonin Re-Uptake Inhibitors), Neuroleptics, or Other drugs that reduce the seizure threshold Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections).

The significance of the seizure threshold lowering effect of tramadol (tramadol hydrochloride) is that it increases the risk of seizures in patients taking certain medications, such as SSRIs, TCAs, and MAO inhibitors, as well as in patients with a history of seizures or epilepsy. This effect is a serious safety concern and requires cautious use of tramadol hydrochloride in these patients 2. Key points to consider include:

• Concomitant use of tramadol hydrochloride with certain medications increases the seizure risk
• Patients with epilepsy or a history of seizures are at increased risk
• Other drugs that reduce the seizure threshold may also increase the risk of seizures when used with tramadol hydrochloride

From the Research

Seizure Threshold Lowering Effect of Tramadol

• The seizure threshold lowering effect of tramadol is a significant concern, as seizures can occur even at therapeutic doses 3, 4.
• Studies have shown that the risk of seizure is increased in patients with a history of seizure, and the increase in dose correlates with a significant increase in seizure frequency 3.
• However, some studies suggest that the incidence of seizure with tramadol is not dose-dependent 4, while others found no significant association between transient use of tramadol and incidence of seizures 5.
• Electrocardiographic changes have been observed in patients with tramadol-induced idiosyncratic seizures, including terminal S wave, sinus tachycardia, and terminal R wave in the lead aVR 6.
• Tramadol-induced seizures are often generalized tonic-clonic seizures that occur within 24 hours of tramadol intake, and are more common in subjects concomitantly consuming other substances such as alcohol, illicit drugs, anti-psychotics, or anti-depressants 7.

Factors Influencing Seizure Risk

• History of seizure: increases the risk of seizure in patients taking tramadol 3.
• Dose: increase in dose correlates with a significant increase in seizure frequency 3, but some studies suggest that the incidence of seizure is not dose-dependent 4.
• Concomitant use of other substances: increases the risk of seizure 7.
• Age and sex: younger patients and males are more likely to experience seizures 4, 6.

Clinical Implications

• Patients with a history of seizure or those taking high doses of tramadol should be closely monitored for signs of seizure activity 3, 4.
• Electrocardiographic changes should be assessed in patients with tramadol-induced seizures 6.
• Concomitant use of other substances should be avoided in patients taking tramadol 7.