|Year : 2017 | Volume
| Issue : 2 | Page : 86-90
Case study and review article: epilepsy-like movements induced by fentanyl analgesia
Mahmoud El-Karamany MRCPI, MD
Department of Gastroenterology, Hull and East Yorkshire Hospitals NHS Trust, Hull, UK
|Date of Submission||03-Apr-2017|
|Date of Acceptance||02-May-2017|
|Date of Web Publication||14-Aug-2017|
Department of Gastroenterology, Hull and East Yorkshire Hospitals NHS Trust, UK, Anlaby Road, Hull HU3 2JZ
Source of Support: None, Conflict of Interest: None
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.
Keywords: analgesics, convulsions, epilepsy, fentanyl, seizures
|How to cite this article:|
El-Karamany M. Case study and review article: epilepsy-like movements induced by fentanyl analgesia. Egypt J Intern Med 2017;29:86-90
|How to cite this URL:|
El-Karamany M. Case study and review article: epilepsy-like movements induced by fentanyl analgesia. Egypt J Intern Med [serial online] 2017 [cited 2019 Sep 16];29:86-90. Available from: http://www.esim.eg.net/text.asp?2017/29/2/86/212931
| 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 . However, EEG performed during such episodes show normal tracing .
Case reports are the only available data sources on epilepsy-like events that start a few minutes after administration of fentanyl or its analogs .
| Case report|| |
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).
The patient was assessed and found to have normal blood pressure of 124/86, O2 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.
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
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 .
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 . Doses and dosage interval vary according to the severity of pain  and the critical condition of the patient . Fentanyl can also be given to children aged more than 2 years and adolescents, as an adjunct to anesthesia , 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 .
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 . Other adverse effect worth attention are listed collectively in [Table 1] .
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 three-compartment distribution mode affected by blood pH. Vdss 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 buccal film has 40% exposure systemically (area under the curve), which is higher compared with transmucosal lozenge. The bioavailability of buccal tablets is 65%, lozenge 50%, sublingual spray 76%, and sublingual tablet 54%.
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 .
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 .
| Discussion|| |
Many studies have been continuously reporting epilepsy-like movements and muscle activity related to fentanyl administration. Safwat et al.  reported on the occurrence of grand mal epilepsy in a 71-year-old woman, who was scheduled for hysterectomy, after administration of 200 µg fentanyl. Brian and Seifen  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  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.  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 ([Figure 1]) ,. Epilepsy occurs with low doses of narcotic anesthesia ranging from 44 to 78.1 µg/kg for fentanyl  and 0.7 µg/kg for sufentanil . Doses as low as 100 µg of fentanyl can induce grand mal epilepsy in patients with previous neurological deficits . In agreement with most of the previously reported cases, our case showed no epileptic seizures for 2 years or neurological abnormalities.
|Figure 1 The electroencephalogram (EEG) tracing of the 79-year-old man, weighing 54 kg, who was scheduled for elective laminoplasty at the level of C3–C7. (a) EEG 1 year preoperatively showing normal βwave tracing. (b). EEG during fentanyl induction showing αwaves.|
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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 .
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 .
Other explanations have been provided by Scott and Sarnquist . 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  is highly related to narcotic anesthesia . 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 .
Fentanyl is one of the drugs whose concentrations can be decreased by co-administration with EIAED (carbamazepine, phenobarbital, phenytoin, and primidone)  and lamotrigine is not an exception . 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 . 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 . 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.
| References|| |
Bowdle T, Rooke G. Postoperative myoclonus and rigidity after anesthesia with opioids. Anesth Analg 1994; 78:783–786.
Hsieh X, Hsu Y, Cherng C, Lin C, Huang G, Lin S et al.
Grand mal seizure induced by low-dose fentanyl and lidocaine in a young child. Acta Anaesthesiol Taiwan 2015; 53:105–108.
Katz R, Eide T, Hartman A, Poppers P. Two instances of seizure-like activity in the same patient associated with two different narcotics. Anesth Analg 1988; 67:289–290.
Henderson F, May W, Gruber DJ, Puskovic Y, Young A. Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats. Respir Physiol Neurobiol 2014; 191:95–105.
Barash P, Cullen B, Stoelting R. Clinical anesthesia. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009.
Barr J, Fraser G, Gilles L, Puntillo K, Ely W, Gélinas C et al.
Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41:263–306.
Liu L, Gropper M. Postoperative analgesia and sedation in the adult intensive care unit. Drugs 2003; 63:755–767.
Sessler C, Varney K. Patient-focused sedation and analgesia in the ICU. Chest 2008; 133:552–565.
Saarenmaa E, Neuvonen P, Fellman V. Gestational age and birth weight effects on plasma clearance of fentanyl in newborn infants. J Pediatr 2000; 136:0767–0770.
Safwat A, Daniel D. Grand mal seizure after fentanyl administration. Anesthesiology 1983; 59:78.
Brian J, Seifen A. Tonic-clonic activity after sufentanil. Anesth Analg 1987; 66:481.
Haber G, Litman R. Generalized tonic-clonic activity after remifentanil administration. Anesth Analg 2001; 93:1532–1533.
Hsieh X, Hsu Y, Cherng C, Lin C, Huang G, Lin S. Grand mal seizure induced by low-dose fentanyl and lidocaine in a young child. Acta Anaesthesiol Taiwan 2015; 53:105–108.
Scott JF. Seizure-like movements during a fentanyl infusion with absence of seizure activity in a simulataneous EEG recording. Anesthesiology 1985; 62:812–813.
Fujimoto T, Nishiyama T, Hanaoka K. Seizure induced by a small dose of fentanyl. J Anesth 2003; 17:55–56.
Borghs S, Thieffry S, Noack-Rink M, Dedeken P, Hong L, Byram L et al.
Health care cost associated with the use of enzyme-inducing and non-enzyme-active antiepileptic drugs in the UK: a long-term retrospective matched cohort study. BMC Neurol 2017; 17:1.
Scott J, Sarnquist F. Seizure-like movements during a fentanyl infusion with absence of seizure activity in a simulataneous EEG recording. Anesthesiology 1985; 62:812–813.
Larson K, Wittwer E, Nicholson W, Weingarten T, Price D, Sprung J. Myoclonus in patient on fluoxetine after receiving fentanyl and low-dose methylene blue during sentinel lymph node biopsy. J Clin Anesth 2015; 27:247–251.
Richardson S, Egan T. The safety of remifentanil by bolus injection. Expert Opin Drug Saf 2005; 4:643–651.
Modica P, Tempelhoff R, White P. Pro- and anticonvulsant effects of anesthetics (part I). Anesth Analg 1990; 70:303–315.
Patsalos P, Perucca E. Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurol 2003; 2:473–481.
Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 2006; 61:246–255.
Szaflarski J, Linda Steinbaugh MD. Adjunctive therapy for the treatment of primary generalized tonic–clonic seizures: focus on once-daily lamotrigine. Drug Des Devel Ther 2010; 4:337–342.
[Table 1], [Table 2]