What is the risk of seizure associated with Tramadol (Ultram) use?

From the Guidelines

Tramadol can cause seizures, especially at higher doses or in patients with risk factors, and if a patient experiences a seizure while taking tramadol, the medication should be discontinued immediately and emergency medical attention sought. The risk of seizures increases with doses above 400mg per day, in patients with epilepsy, head trauma, metabolic disorders, or when combined with medications that lower seizure threshold (like antidepressants, antipsychotics, or other opioids) 1. According to the NCCN clinical practice guidelines, tramadol is a weak mu-opioid receptor agonist with some norepinephrine and serotonin reuptake inhibition, which can increase neuronal excitability and lower the seizure threshold, particularly in susceptible individuals 1.

Treatment for tramadol-induced seizures involves stopping the medication, providing supportive care, and administering benzodiazepines like diazepam (5-10mg IV) or lorazepam (2-4mg IV) to control the seizure, as recommended by the American College of Emergency Physicians (ACEP) clinical policy 2. After the acute event, the patient should not restart tramadol and should discuss alternative pain management options with their healthcare provider. Key considerations for managing seizures include:

• Discontinuing tramadol immediately
• Providing supportive care
• Administering benzodiazepines to control the seizure
• Discussing alternative pain management options with the healthcare provider

It is essential to note that tramadol is less potent than other opioids and is considered to be approximately one tenth as potent as morphine, and its use should be carefully evaluated in patients with risk factors for seizures 1. The ACEP clinical policy also highlights the importance of considering the potential for noncompliance with antiseizure drug therapy and the impact of prescribed and illicit substance use on seizure threshold 2.

From the FDA Drug Label

WARNING Seizures have been reported in patients receiving Tramadol hydrochloride within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol hydrochloride above the recommended 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). In tramadol hydrochloride overdose, naloxone administration may increase the risk of seizure

Tramadol Seizure Risk: Tramadol may increase the risk of seizures, especially when used with other medications that reduce the seizure threshold, such as SSRIs, TCAs, MAO inhibitors, and other opioids. The risk of seizures is also higher in patients with a history of epilepsy, head trauma, or other conditions that increase the risk of seizures.

• Key Factors that Increase Seizure Risk: + Doses of tramadol above the recommended range + Concomitant use of certain medications (e.g., SSRIs, TCAs, MAO inhibitors, other opioids) + History of epilepsy or seizures + Head trauma or other conditions that increase the risk of seizures + Administration of naloxone in overdose situations 3

From the Research

Tramadol Seizure Risk

• Tramadol is an atypical opioid analgesic that can cause seizures as a prominent complication with its therapeutic use, abuse, or overdose 4.
• The likelihood of recurrent seizures in patients who have had a tramadol-induced seizure is low, with only 7% of patients experiencing recurrent seizures in one study 4.
• Tramadol's potential to lower seizure threshold is a concern, particularly in patients with a history of seizure disorders 5.
• The prevalence of tramadol-induced seizures is modest in the general population, but if left untreated, the morbidity and mortality can be high 6.
• Risk factors for tramadol-induced seizures include medical comorbidities, use or abuse of supratherapeutic doses of tramadol, and concomitant administration of proconvulsant serotonergic cytochrome P-450 inhibitors 6.

Tramadol-Induced Seizure Studies

• A 3-year study found that tramadol-induced seizures commonly manifest as generalized tonic-clonic seizures, most frequently within 24 hours after tramadol intake 7.
• A nested case-control study found no association between risk of seizure and exposure to tramadol compared with codeine, but this finding was sensitive to the outcome definition used 8.
• Another study found that tramadol may be useful as part of multi-modal analgesia in moderate to severe pain in specific contexts, but greater awareness of its potential adverse effects, particularly its potential to lower seizure threshold, is warranted 5.

Management of Tramadol-Induced Seizures

• Tramadol-induced seizures can be effectively treated by administering benzodiazepines, providing supportive care, and discontinuing tramadol and other contributing agents 6.
• Cyproheptadine should be administered in moderate to severe cases of serotonin syndrome, which can be a complication of tramadol-induced seizures 6.