Case study and review article: epilepsy-like movements induced by fentanyl analgesia

Epilepsy-like movements are observed immediately after the administration of fentanyl as well as its derivatives. Although the event has no serious outcomes, it is so worrisome that it has garnered the attention of many authors to publish case reports of such events. Despite the presence of cerebral lesions in some cases, epileptic focus cannot be attributed to such lesions. Radiological and electrophysiological studies have failed to reveal abnormal cerebral activity during such events. The reported activity is usually generalized tonic–clonic convulsions. Epileptic convulsive movements were observed with low doses of fentanyl and its derivatives. Previous studies on animals have supported the occurrence of such epileptiform movements in corresponding doses. Idiosyncrasy and narcotic-related muscle rigidity did not satisfactorily explain the seizures. Our case report represents the occurrence of epileptiform movements twice in and an old patient with no cerebral insult. The past history was epileptic activity under control with lamotrigine for last 2 years.


Fentanyl analgesia
It has been noticed that administration of fentanyl during anesthesia is accompanied by epilepsy-like movements. Evaluation of brain activity using conventional electroencephalogram (EEG) showed no epileptic activity or focal epileptic wave changes. These findings cast on the nature, and hence the diagnosis of these observed abnormal movements.
Epilepsy is not a well-known side-effect of fentanyl. There are only observations of abnormal muscle contractions that are interpreted as convulsions [1]. However, EEG performed during such episodes show normal tracing [2].
Case reports are the only available data sources on epilepsy-like events that start a few minutes after administration of fentanyl or its analogs [3].

Case report Subjective data
We report the case of a 71-year-old man weighing 80 kg. He had a past history of angina pectoris for 20 years and was maintained on nifedipine, metoprolol, and transdermal nitroglycerine. The patient has Epilepsy for 14 years before and currently on Lamotrigine 150 mg a day is correct. No permanent neurological deficit ensued. No history of any epileptic activity during the past 2 years was reported or documented. The patient was referred for elective gastroscopy and colonoscopy for investigation of mild anemia (hemoglobin 11.3 g/dl, ferritin 15, mean corpuscular volume 71).

Anesthetic events
The patient was assessed and found to have normal blood pressure of 124/86, O 2 saturation of 98% on room air, and his heart rate was 84 beats/min. He provided formal consent for the procedure. Fentanyl 50 mg intravenously was administered, and the patient developed tremulous movements in the left hand immediately, followed by the left arm and left foot. Subsequently, all four limbs were involved in grand mal seizure with tonic-clonic contractions. The patient was given 2 mg of midazolam intravenously, and the seizure stopped. During that episode, the patient was vitally stable. He was admitted to the recovery room for observation before discharge.
A computed tomographic scan of the head was performed 2 weeks later and the results were normal.

Learning point
We can avoid using fentanyl as a sedative in epileptic patients, or it can be administered at lower doses with extreme caution.

Fentanyl: drug information
Pharmacological aspects of fentanyl Clinical pharmacology Fentanyl belongs to the family of anilidopiperidine opioids used for general anesthesia. Fentanyl exerts its analgesic action by binding to stereospecific receptors leading to increased pain threshold, depression of ascending pain pathways, and changes in reception of pain. μ-Opiate receptors that are located in the periphery mediate the analgesic effects of fentanyl as well as respiratory depression [4].
It is a good practice to titrate the dose of fentanyl to alleviate and/or prevent pain with monitoring of vital signs. During surgery, fentanyl is usually administered at a dose of 50-100 mcg by intramuscular or slow intravenous route in 30-60 min before surgery or 25-50 mcg by slow intravenous soon before induction [5]. Doses and dosage interval vary according to the severity of pain [6] and the critical condition of the patient [7]. Fentanyl can also be given to children aged more than 2 years and adolescents, as an adjunct to anesthesia [8], at a dose of 2-3 mcg/kg/dose by intravenous route, to be repeated every 1-2 h when appropriate. No dose adjustment is needed in patients with renal or hepatic impairment [1].
Fentanyl is used to relieve preoperative and postoperative pain, adjunct to general or regional anesthesia, acute or chronic pain, and cancer pain. It is worth mentioning that the Benzodiazepines and Opioid Medicine Safety Alert August 2016 focused on the combination of opioid medications with benzodiazepines or other central nervous system depressants. Respiratory compromise and death are the most serious adverse effects of such combinations [9]. Other adverse effect worth attention are listed collectively in Table 1 [4].

Pharmacodynamics and pharmacokinetics
The onset of action varies with age and route of administration. Children aged 3-12 years show the effects of fentanyl in 5-10 min by the intranasal route. Fentanyl administration in adults by intramuscular route takes about 8 min to exert full effect and it is immediate by intravenous route. A transdermal patch takes 6 h, and the transmucosal route takes 5-15 min to exert the full effect of fentanyl.
The duration of fentanyl effect is 1-2 h by intramuscular route and 0.5-1 h by intravenous route. The duration reaches up to 96 h through the transdermal route and even longer by the transmucosal route.
Fentanyl absorption varies with the route of administration. The drug is released from the transdermal patch and accumulates in the outer layers of the skin, from which the drug is released into the circulation, leading to constant circulating levels for 12-24 h. Transdermal devices release fentanyl within 10 min, and the amount of drug in blood keeps increasing for about 5 min after that. Nearly 50% of buccal tablets and films are rapidly absorbed from the buccal mucosa, and the remaining is swallowed and absorbed from gut. Lozenges has about 25% absorption from the buccal mucosa, and the rest is absorbed from gut.
Fentanyl is highly lipophilic. It shows a threecompartment distribution mode affected by blood pH. V dss ranges from 5 to 30 l/kg in children and from 4 to 6 l/kg in adults. Fentanyl binds to α-1 acid glycoprotein, albumin, and erythrocytes (79-87%).
It is metabolized in the liver by CYP3A4 by N-dealkylation into inactive metabolites: norfentanyl and hydroxylated compounds.
The half-life of fentanyl varies by age ( Table 2). The normal range is 2-4 h; however, it increases with continuous infusion because of its large volume of distribution [10].
Fentanyl is excreted in urine mostly as inactive metabolites (75%) and in its native form (7-10%) Excretion through feces is around 9%. Fentanyl clearance in newborn infants is related to gestational age and birth weight [11].

Discussion
Many studies have been continuously reporting epilepsy-like movements and muscle activity related to fentanyl administration. Safwat et al. [12] reported on the occurrence of grand mal epilepsy in a 71-yearold woman, who was scheduled for hysterectomy, after administration of 200 μg fentanyl. Brian and Seifen [13] observed tonic-clonic activity in a 69-year-old man, who was scheduled for coronary artery bypass grafting operation, after administering 58 μg of sufentanil. A recent study by Haber and Litman [14] reported generalized tonic-clonic convulsive episodes associated with loss of consciousness in a 42-year-old woman scheduled for hysteroscopy and polypectomy, after using remifentanil, a fentanyl analog, at a dose of 10 μg/kg/min by continuous infusion. Moreover, administering fentanyl in young children has the same effect as in adults. Hsieh et al. [15] reported the occurrence of generalized tonic-clonic convulsions in a 10-year-old girl scheduled for elective tenectomy, after receiving fentanyl and lidocaine. EEG tracing during the epileptiform activity showed no significant abnormality (Fig. 1) [3,16]. Epilepsy occurs with low doses of narcotic anesthesia ranging from 44 to 78.1 μg/kg for fentanyl [17] and 0.7 μg/kg for sufentanil [13]. Doses as low as 100 μg of fentanyl can induce grand mal epilepsy in patients with previous neurological deficits [15]. In agreement with most of the previously reported cases, our case showed no epileptic seizures for 2 years or neurological abnormalities.
Thorough clinical history taking and review of medical records fail to show the occurrence of epilepsy in otherwise healthy individuals. Most events of epilepsy related to fentanyl or its analogs were accidentally discovered and managed accordingly by postponing surgery. This case report of a 71-year-old man with past history of healed cerebral infarct is one example of many such cases [3].
A long-term, retrospective, matched cohort study showed that the initial therapy for epilepsy with enzyme-induced antiepileptic drugs (EIAED) causes a serious impact on patient health compared with non-EAAED [18].
Other explanations have been provided by Scott and Sarnquist [19]. The first suggestion presumed an exaggeration of narcotic-induced muscle rigidity, whereas the second suggestion was about a kind of myoclonus secondary to inhibitory neuronal depression induced by narcotics. However, the first suggestion can be ruled out by the observation that the patient received 2 mg of vecuronium, which inhibits narcotic rigidity and ventilation can be easily provided through a mask. Therefore, it lacks evidence for muscle rigidity. The duration of the seizure cannot be estimated in our case because of the paralyzing effect of using 8 mg vecuronium. The second suggestion is strongly related to our case report. Myoclonic activity [20] is highly related to narcotic anesthesia [21]. In contrast to epileptic seizure, myoclonic movements are related to either rhythmic or arrhythmic contractions of the muscles. Findings on EEG determine whether the myoclonus activity is epileptic or nonepileptic [22].
Fentanyl is one of the drugs whose concentrations can be decreased by co-administration with EIAED (carbamazepine, phenobarbital, phenytoin, and primidone) [23] and lamotrigine is not an exception [24]. Lamotrigine's side-effect that enforces cessation of the drug is rash. The most commonly reported side-effects of lamotrigine were dizziness, nausea, and somnolence. Epilepsy has not been mentioned frequently, however [25]. Lamotrigine has not been mentioned as having negative drug interactions or is not contraindicated for administration along with fentanyl; even epilepsy is not proved to be one of the documented side-effect of fentanyl and its analogs [26]. Both lamotrigine and fentanyl have similar impact on the brain. However, no evidence-based study has revealed that such an impact is synchronized or augmented. Further studies are needed in this field to document observations and side-effects.

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Conflicts of interest
There are no conflicts of interest.