Anesth Analg 2003;96:1374-1376
© 2003 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Extrapyramidal Reactions to Ondansetron: Cross-Reactivity Between Ondansetron and Prochlorperazine?
Juraj Sprung, MD PhD,
Faisal M. Choudhry, MD, and
Brian A. Hall, MD
Department of Anesthesiology, Mayo Clinic, Rochester, MN
Address correspondence and reprint requests to Juraj Sprung, MD, PhD, Mayo Medical School, Department of Anesthesiology, MB-2–752, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Address e-mail to Sprung.juraj{at}mayo.edu
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Abstract
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IMPLICATIONS: Ondansetron can rarely induce extrapyramidal reactions in susceptible individuals. Our patient had a history of drug-induced dystonic reaction; therefore, these patients may be susceptible to extrapyramidal adverse reactions after ondansetron.
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Introduction
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Ondansetron, a 5-hydroxytriptamine 3 (5-HT3) receptor antagonist perioperatively used as an antiemetic, has an excellent safety record (1,2). In contrast to other antiemetic drugs (droperidol, promethazine, and metoclopramide), extrapyramidal side effects were not detected in the initial clinical trials (3–6). Ondansetron does not affect dopamine, histamine, adrenergic, or cholinergic receptor activity and is therefore "free of neurologic adverse effects (7)." However, in the 11 years since its approval by the Food and Drug Administration, ondansetron has been associated with several cases of extrapyramidal side effects (8–13). We encountered two patients who developed extrapyramidal symptoms in close temporal proximity to their ondansetron administration. Although these symptoms resolved with no long term sequelae, the presentation was dramatic and resembled seizure activity. The first case noted was especially interesting because it suggests that a patient who has experienced earlier drug-induced extrapyramidal side effects with an antiemetic may experience similar adverse effects with ondansetron.
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Case Reports
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Case 1
A 58-yr-old woman with breast cancer was admitted for mastectomy. Her other medical history was remarkable for hypertension, mitral valve prolapse with occasional palpitations, and diabetes mellitus. All vital signs and laboratory data before the operation were within the normal limits. She reported a previous episode of an acute dystonic reaction with prochlorperazine and hives with "sulfa preparations." She underwent an uneventful general anesthetic with propofol, midazolam, fentanyl, isoflurane, and nitrous oxide. After surgery, she was transferred to the recovery room where she complained of nausea. High-flow oxygen was administered via face mask, and 4 mg of ondansetron was given IV. Just minutes after the ondansetron administration, she developed an acute episode of stimulus-sensitive generalized clonus. Her lower extremities were moving in a jerking fashion, whereas tonic-clonic movements could be observed throughout her entire body with forceful plantarflexion of her feet. These movements could be largely attenuated by gently holding her legs against the bed. There was cogwheel rigidity in both wrists. She was not able to give appropriate answers to questions nor did she follow commands. She was gazing into the distance without facial expression. Diphenhydramine 50 mg and midazolam 1 mg were administered IV. Over the next 20 min, as the patient became sedated, the symptoms gradually resolved. After neurologic consultation, it was concluded that the patient had experienced a dystonic reaction to ondansetron. All postoperative lab data were within normal limits. The patient subsequently related to us that she had had a somewhat similar reaction several years ago after receiving prochlorperazine for nausea.
Case 2
A 28-yr-old woman with unremarkable medical history was admitted for nasal reconstruction. She denied history of allergies or adverse reactions to medications. Her vital signs and laboratory data before surgery were within normal limits. She was taken to the recovery room after an uneventful anesthesia (propofol, succinylcholine, fentanyl, isoflurane, and nitrous oxide) where she complained of nausea and was treated with ondansetron 4 mg over 3 min. Soon thereafter she became "stunned". Her face was expressionless; she was breathing quietly but not responding to our questions. Vigorous tonic-clonic movements were noted in the lower extremities as well as jerking movements of the head. She also had dystonia of the jaw and stiffness of her upper limbs. Oxyhemoglobin saturation as assessed by pulse oximetry remained unchanged, but her heart rate increased from 65 bpm to 95 bpm during this episode. The shaking subsided after 2 mg of midazolam, and the patient fell asleep. Attempts to arouse her resulted in a new episode of tonic-clonic movements. Gently holding her legs to the bed resulted in successful reduction of muscle movements. It was initially concluded that these movements were the manifestation of an anxiety reaction. Subsequent discovery that plantarflexion repeatedly induced whole-body tonic-clonic shake spoke against anxiety as an origin. The shaking episode resolved without sequelae 25 min after the administration of 25 mg of IV diphenhydramine. A neurologist was consulted who concluded that this clinical picture most probably represented a drug-induced dystonia. The only medication given in temporal proximity to the reaction was ondansetron.
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Discussion
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Ondansetron, a selective antagonist at 5-HT3 receptors, is effective in the treatment of perioperative nausea and vomiting. 5-HT3 receptors are ubiquitous in the enteric, sympathetic, parasympathetic, and peripheral nervous systems as well as in the central nervous system. In humans, 5-HT3 receptors are mainly situated on enterochromaffin cells in the gastrointestinal mucosa, which are innervated by vagal afferent fibers, and the area postrema of the brainstem, which forms the chemoreceptor trigger zone. Ondansetron is 100 times more potent than metoclopramide at this site (14). Ondansetron has a relatively small incidence of severe adverse effects (3) and was considered free of neurologic complications. Because ondansetron is not a central dopaminergic blocker, extrapyramidal effects similar to those seen after metoclopramide would not be expected (2,7). Indeed, extrapyramidal symptoms were not reported in original ondansetron clinical trials (3,5,15–17). The first case that suggested the possibility of ondansetron-induced extrapyramidal symptoms was published in 1991 (9). However, the patient had also received droperidol, so the reaction could not unequivocally be attributed to ondansetron (18). By 1996, there were three case reports of extrapyramidal side effects during ondansetron therapy (14). Since that time, this selective 5-HT3 receptor antagonist has been reported, albeit infrequently, to produce extrapyramidal side effects (8,12,19–21). Only two perioperative cases have been described (12,13). All other cases occurred during treatment of nausea associated with chemotherapy (8), and they evolved after several days of therapy or after larger doses of ondansetron (8). It was postulated that rare extrapyramidal side-effects may be dose-related (14) because: (a) most reports were noted after the repetitive administration of ondansetron and (b) even in individuals who experienced extrapyramidal reactions, the administration of reduced doses or slow injection of ondansetron decreased the severity of the reaction (8). Halperin and Murphy (20) demonstrated that for patients who experienced extrapyramidal side effects with ondansetron, reduction of the initial dose by 50% eliminated extrapyramidal side effects with subsequent treatment.
Although ondansetron has no appreciable affinity for dopamine receptors, animal studies have shown that it inhibits or reduces increased mesolimbic dopamine activity and antagonizes increased locomotor activity caused by mesolimbic dopamine excess (22). In another study, pretreatment with oral ondansetron prevented levodopa-associated psychosis in four patients with Parkinson’s disease who had repeatedly experienced psychotic reactions to levodopa (22). This suggests that ondansetron may play a role in dopaminergic transmission. Our first patient reported that she received prochlorperazine after a previous operation and developed side effects consistent with dystonic reaction. After the operation described here, she received a single 4-mg dose of ondansetron and developed classical extrapyramidal signs. This suggests that there may be cross-reactivity between ondansetron and other drugs that produce extrapyramidal symptoms (prochlorperazine and probably the butyrophenones, haloperidol and droperidol, as well as metoclopramide, phenothiazine, and tricyclic antidepressants). At the same time, it suggests that ondansetron, although believed not to have affinity for dopamine receptors, may produce dopamine receptor mediated side effects in certain patients. It is not known why or by what mechanism this adverse reaction occurs in susceptible individuals after ondansetron therapy.
It has been postulated that ondansetron may induce seizures (23). Sharma and Raina (23) described generalized tonic-clonic seizures on the second day of ondansetron therapy (8 mg). However, in the absence of electroencephalographic evidence, as well as other proof of seizure activity, these phenomena may well have been manifestations of a severe extrapyramidal reaction, as seen in the two patients described here. Furthermore, both our patients received propofol, which has been associated with dystonic reactions (24). However, after anesthetic emergence, neither patient had dystonic symptoms, and they both occurred in close temporal relationship to the injection of ondansetron. Based on these facts, we dismiss the possibility that propofol contributed to symptomatology in our patients.
In conclusion, ondansetron can rarely induce extrapyramidal reactions in susceptible individuals. One of our patients reported previous extrapyramidal side effects after prochlorperazine. We therefore conclude that patients with a history of drug-induced dystonic reactions may be susceptible to similar adverse reactions after ondansetron therapy.
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Accepted for publication January 14, 2003.
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M. J. Ritter, B. P. Goodman, J. Sprung, and E. F. M. Wijdicks
Ondansetron-Induced Multifocal Encephalopathy
Mayo Clin. Proc.,
September 1, 2003;
78(9):
1150 - 1152.
[Abstract]
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Abstract
Introduction
