Tramadol

*Tramadol is a centrally acting opioid analgesic used to treat moderate to moderately severe pain
* Seizures can occur with tramadol, particularly if high doses are used (however this is not always the
case)
Should be used with caution in epileptic patients or if there is concomitant use of medicines that lower
the seizure threshold (particularly SSRIs/SNRIs and TCAs)
*One possible mechanism = all commonly metabolized by cytochrome P450 2D6 (CYP2D6) and
there may be competition when all administered concomitantly
*Seizures were generalized tonic–clonic, without auras or focal features; Should be treated with
benzodiazepenes
*Tramadol’s opioid activity is due to : agonist for μ-opioid receptors; as well as inhibits reuptake of
serotonin and NE
* In view of the complex effects of tramadol on opioid receptors and monoamine uptake, it is not
possible to conclude which mechanism is primarily responsible for the observed effects in kindled rats.

*5-HT2C blockade may also account for its lowering of the seizure threshold, as 5-HT2C knockout
mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in
spontaneous death.

*Tramadol's major active metabolite, O-desmethyltramadol, is a high-affinity ligand of the δ- and κ-

opioid receptors, and activity at the former receptor could be involved in tramadol's ability to provoke
seizures in some individuals, as δ-opioid receptor agonists are well known to induce seizures

*Could be attributed to tramadol's putative inhibition of GABAA receptors at high doses. Tramadol
has no effect on GABA receptors at clinically acceptable doses. However, at high concentrations,
tramadol has an inhibitory effect. The GABA receptor inhibition, which is induced by tramadol, is
secondary to its opioid agonist activity. In other words, the opioid receptor activation, which is
generated by tramadol, causes an inhibition in GABA neurotransmitter system and this considered to be
the responsible for epileptogenic effect of tramadol

Histamine

* Antihistamines also are known to increase electroencephalographic (EEG) abnormalities and are
suspected to produce seizures in patients with epilepsy
*Has been demonstrated that increased histamine levels elevate the seizure threshold and reduce the
severity and duration of seizures,4 whereas decreased histamine levels have the opposite effect
*Possible mechanism: natural anticonvulsant role of histamine because H1 receptors coalesce around
epileptogenic foci in the brain and inhibit generalization of seizure activity
*One study was investigating the effect of chronic antihistamine treatment and seizure susceptibility
after drug withdrawal
*Found that chronic antihistamine treatment is associated with increased seizure susceptibility due to
inhibition of glutamine synthase => Marked decline in GABA and glutamine synthesis
*Confirmed with reversal of seizure susceptibility with glutamine administration