Neuroexcitatory Phenomena
Fentanyl can cause neuroexcitation ranging from delirium to grand
mal seizure-like activity.[127]
It was reported
that fentanyl causes EEG seizure activity in animals, but EEG evidence of seizure
activity after fentanyl, alfentanil, and sufentanil is generally lacking in humans.
Remifentanil was reported to induce generalized tonic-clonic seizure-like activity
in an otherwise healthy adult.[128]
Animal studies demonstrate that in certain species, opioids cause
focal CNS excitation rather than global CNS depression.[129]
Focal neuroexcitation (e.g., sharp and spike wave activity) is noted occasionally
on EEG in humans after large doses of fentanyl, sufentanil, and alfentanil. Morphine
has also been reported to produce tonic-clonic activity after epidural and intrathecal
administration.[130]
Meperidine also may cause
CNS excitability. The mechanism is related to its N-desmethyl
metabolite, normeperidine, which is twice as potent in causing CNS excitation and
convulsions as meperidine.[131]
Naloxone administration
for the CNS adverse effects of meperidine should be avoided, because naloxone can
elicit seizures by unmasking the excitatory effects of meperidine when its depressant
effects are antagonized.[131]
The mechanisms underlying opioid-induced neuroexcitatory phenomena
are not completely clear. More recent work suggests that excitatory opioid actions
may be related to their coupling to mitogen-activated protein kinase cascades.[132]
Local increases in CBF and metabolism are also of theoretical concern because prolonged
seizure activity, even if focal, can lead to neuronal injury and/or cellular death.
Fentanyl, alfentanil, and sufentanil in large doses also induce hypermetabolism
and histopathologic alterations of the limbic system in rats.[133]
In rats, midazolam, naloxone, and phenytoin prevented EEG seizure activity and histologically
evident brain damage induced by large-dose fentanyl.[134]
