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Intentional overdose with tiagabine: An unusual clinical presentation
The Journal of Emergency Medicine, Vol. 27, No. 3, pp. 271–272, 2004 Copyright © 2004 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/04 $–see front matter
doi:10.1016/j.jemermed.2004.06.003
Selected Topics: Toxicology
INTENTIONAL OVERDOSE WITH TIAGABINE: AN UNUSUAL CLINICAL PRESENTATION F. Lee Cantrell,
PharmD,*†
Mike Ritter,
MD,‡
and Ed Himes,
MD§
*California Poison Control System, San Diego Division, San Diego, California, †School of Pharmacy, University of California San Francisco, San Francisco, California, and ‡Department of Emergency Medicine and §Department of Internal Medicine, Mission Hospital, Mission Viejo, California Reprint Address: F. Lee Cantrell, PharmD, 200 West Arbor Drive, San Diego, CA 92103-8925
e Abstract—Tiagabine (Gabitril®) is a unique anticonvulsant that is prescribed for a variety of psychiatric disorders. We report a case of intentional self-poisoning with tiagabine. A 46-year-old woman was brought to the Emergency Department after being found confused and nonverbal while wandering in a field. Eighteen tablets (72 mg) of her tiagabine prescription were missing. Remarkable findings on initial examination were facial grimacing, flexure posturing of both upper extremities, and 7-mm, reactive pupils. She was uncommunicative and unable to follow commands. Vital signs, blood chemistries and a head CT scan were normal. Urine toxicology screening was negative. An extrapyramidal reaction was suspected and diphenhydramine 50 mg was administered without effect. Lorazepam 2 mg was given with significant improvement. She was admitted for observation and all symptoms resolved within 12 h of admission. Tiagabine overdose causes an unusual array of neurological symptoms, many similar to reported adverse effects during therapeutic use. © 2004 Elsevier Inc.
variety of psychiatric disorders (1,2). An increase in tiagabine poisonings, therefore, might be expected, similar to that seen in recent years with valproic acid (3). Due to the paucity of literature describing tiagabine toxicity, we report the clinical course in a case of intentional self-poisoning with tiagabine.
CASE REPORT A 46-year-old woman with a history of anxiety and depression was brought to the Emergency Department (ED) by paramedics after being found confused and nonverbal while wandering in a field. The patient had no other medical problems. Her current medications were tiagabine 4 mg twice daily (initiated 5 days prior for depression) and escitalopram 10 mg at bedtime. There was no indication that the patient had ingested anything more than her normal therapeutic doses based on an initial pill count. However, the patient’s husband later discovered that 18 tablets (72 mg) of tiagabine were missing from empty sample packets found in the trash at home. He also reported that his wife seemed to have a “blank stare” for a few hours the night before, after taking an extra 4 mg tiagabine (8 mg total) to relieve stress. He described her as “asleep with her eyes open” while watching television. The patient’s initial physical examination showed abnormal facial grimacing and rigid flexure posturing of both upper extremities. Motor
e Keywords—tiagabine; overdose; poisoning; anticonvulsant; neurological
INTRODUCTION Tiagabine (Gabitril®) is a unique anticonvulsant indicated as an adjunct for the treatment of refractory partial seizures in patients 12 years and older. Similar to other anticonvulsants, tiagabine is being prescribed for use in a
Selected Topics: Toxicology is coordinated by Kenneth Kulig,
RECEIVED: 28 May 2003; FINAL ACCEPTED: 6 February 2004
SUBMISSION RECEIVED:
MD,
of Denver, Colorado
31 December 2003; 271
272
F. L. Cantrell et al.
strength and deep tendon reflexes were normal in both upper and lower extremities. There was no seizure activity observed. She was able to track with her eyes and no nystagmus was noted. Her pupils were 7 mm, sluggish and reactive to light. She was uncommunicative and unable to follow any purposeful commands. Initial vital signs were: blood pressure 144/90 mm Hg, pulse 74 beats/min, respiratory rate 20 breaths/min, temperature 37°C (98.6°F) and normal oxygen saturation. An electrocardiogram (EKG) was not performed. Intravenous access was established. A finger stick done by paramedics revealed a blood glucose of 108 mg/dL. Blood chemistries and a head computed tomography (CT) scan were normal and urine and blood toxicology screens were negative for common drugs of abuse (opiates, benzodiazepines, phencyclidine, cocaine, amphetamines, tricyclic antidepressants, phenobarbital and ethanol) as well as acetaminophen and aspirin. Tiagabine blood levels are not routinely available and thus were not drawn. Because an extrapyramidal reaction was initially suspected, 50 mg of diphenhydramine was administered without effect. Ten minutes later, 2 mg of lorazepam was given with significant improvement in the patient’s clinical status. The flexure posturing resolved and she followed verbal commands immediately. Due to the bilateral posturing, the lack of postictal symptoms immediately after the administration of lorazepam, and the lack of a prior history, seizures were not suspected. Due to difficulties obtaining additional lorazepam, 2 mg of midazolam was administered in the ED over the next 2 h with continued improvement and return of speech. She ultimately admitted intentionally taking an overdose of this medication. Additionally, she did remember wandering in the field, the ambulance ride, and being in the ED. She described her symptoms as a “bad dream where you know what to do but cannot control your body.” She was admitted for overnight observation and all symptoms resolved within 12 h of admission. DISCUSSION Tiagabine inhibits the presynaptic re-uptake of gammaaminobutyric acid (GABA) in neurons and glial cells. It is a highly selective and potent inhibitor of GABA Transporter 1. The resulting increase in synaptic GABA concentrations is thought to increase the duration and intensity of inhibitory postsynaptic potentials, thereby reducing aberrant excitatory activity (4). Its use is limited to controlling partial seizures due to a tendency to aggravate certain types of seizures such as myoclonic jerks and absences (5). Subjectively reported side effects during therapeutic use include: dizziness, asthenia, confusion, language problems, tremor, visual disturbances and headache (6,7). Clinical symptoms reported in the overdose setting are: central nervous system (CNS) depres-
sion ranging from lethargy to coma, agitation, dysphagia, weakness, myoclonus, and status epilepticus (8,9). The exact mechanism of our patient’s clinical picture is difficult to determine based on the pharmacology of tiagabine. Leach and Brodie state that at serum concentrations of 100 umol/L, tiagabine weakly inhibits the binding of specific ligands for D1, D2, muscarinic, 5-HT2, GABAA and glycine receptors (10). It could be theorized that some of the specificity for GABA Transporter 1 could be lost at high concentrations. Due to the spectrum of our patient’s symptoms and her favorable response to benzodiazepines, tiagabine toxicity possibly could be mediated through GABAminergic pathways as well as non-GABAminergic pathways. The duration of our patient’s symptoms loosely correlate with the pharmacokinetics of tiagabine as her symptoms resolved completely within 12 h of admission. It is rapidly absorbed and achieves peak plasma concentrations within 2–3 h. It is extensively metabolized by cytochrome P450 (CYP) isoform 3A in the liver to the inactive metabolite 5-ox-tiagabine. It has an elimination half-life of 7–9 h in non-CYP-induced patients and 2–3 h in CYP-induced patients (10). Although our patient was concurrently taking another medication (escitalopram) that is also metabolized by CYP isoform 3A, the pharmacokinetic and pharmacodynamic impact of this combination remains undefined. Based on our limited experience and few published cases reports, tiagabine overdose seems to cause an unusual array of neurological symptoms, many similar to reported adverse effects during therapeutic use. The only required treatment was benzodiazepines and supportive care. Perhaps future experiences in treating tiagabine overdose cases will shed more light on the exact mechanism by which it causes toxicity. REFERENCES 1. Ketter TA, Wang PW. The emerging differential roles of GABAergic and antiglutamatergic agents in bipolar disorders. J Clin Psychiatry 2003;64(Suppl 3):15–20. 2. Suppes T, Chisholm KA, Dhavale D, et al. Tiagabine in treatment refractory bipolar disorder: a clinical case series. Bipolar Disord 2002;4:283–9. 3. Spiller HA, Krenzelok EP, Klein-Schwartz W, et al. Multicenter case series of valproic acid ingestion: serum concentrations and toxicity. J Toxicol Clin Toxicol 2000;38:755– 60. 4. Meldrum BS, Chapman AG. Basic mechanisms of gabitril (tiagabine) and future potential developments. Epilepsia 1999;40(Suppl 9):S2– 6. 5. Angehagen M, Ben-Menachem E, Ronnback L, Hansson E. Novel mechanisms of action of three antiepileptic drugs, vigabatrin, tiagabine, and topiramate. Neurochem Res 2003;28:333– 40. 6. Fakhoury T, Uthman B, Abou-Khalil B. Safety of long-term treatment with tiagabine. Seizure 2000;9:431–5. 7. Kalviainen R. Long-term safety of tiagabine. Epilepsia 2001; 42(Suppl 3):46 – 8. 8. Leach JP, Stolarek I, Brodie MJ. Deliberate overdose with the novel anticonvulsant tiagabine. Seizure 1995;4:155–7. 9. Ostrovskiy D, Spanaki MV, Morris GL 3rd. Tiagabine overdose can induce convulsive status epilepticus. Epilepsia 2002;43:773– 4. 10. Leach JP, Brodie MJ. Tiagabine. Lancet 1998;351:203–7.
doi:10.1016/j.jemermed.2004.06.003
Selected Topics: Toxicology
INTENTIONAL OVERDOSE WITH TIAGABINE: AN UNUSUAL CLINICAL PRESENTATION F. Lee Cantrell,
PharmD,*†
Mike Ritter,
MD,‡
and Ed Himes,
MD§
*California Poison Control System, San Diego Division, San Diego, California, †School of Pharmacy, University of California San Francisco, San Francisco, California, and ‡Department of Emergency Medicine and §Department of Internal Medicine, Mission Hospital, Mission Viejo, California Reprint Address: F. Lee Cantrell, PharmD, 200 West Arbor Drive, San Diego, CA 92103-8925
e Abstract—Tiagabine (Gabitril®) is a unique anticonvulsant that is prescribed for a variety of psychiatric disorders. We report a case of intentional self-poisoning with tiagabine. A 46-year-old woman was brought to the Emergency Department after being found confused and nonverbal while wandering in a field. Eighteen tablets (72 mg) of her tiagabine prescription were missing. Remarkable findings on initial examination were facial grimacing, flexure posturing of both upper extremities, and 7-mm, reactive pupils. She was uncommunicative and unable to follow commands. Vital signs, blood chemistries and a head CT scan were normal. Urine toxicology screening was negative. An extrapyramidal reaction was suspected and diphenhydramine 50 mg was administered without effect. Lorazepam 2 mg was given with significant improvement. She was admitted for observation and all symptoms resolved within 12 h of admission. Tiagabine overdose causes an unusual array of neurological symptoms, many similar to reported adverse effects during therapeutic use. © 2004 Elsevier Inc.
variety of psychiatric disorders (1,2). An increase in tiagabine poisonings, therefore, might be expected, similar to that seen in recent years with valproic acid (3). Due to the paucity of literature describing tiagabine toxicity, we report the clinical course in a case of intentional self-poisoning with tiagabine.
CASE REPORT A 46-year-old woman with a history of anxiety and depression was brought to the Emergency Department (ED) by paramedics after being found confused and nonverbal while wandering in a field. The patient had no other medical problems. Her current medications were tiagabine 4 mg twice daily (initiated 5 days prior for depression) and escitalopram 10 mg at bedtime. There was no indication that the patient had ingested anything more than her normal therapeutic doses based on an initial pill count. However, the patient’s husband later discovered that 18 tablets (72 mg) of tiagabine were missing from empty sample packets found in the trash at home. He also reported that his wife seemed to have a “blank stare” for a few hours the night before, after taking an extra 4 mg tiagabine (8 mg total) to relieve stress. He described her as “asleep with her eyes open” while watching television. The patient’s initial physical examination showed abnormal facial grimacing and rigid flexure posturing of both upper extremities. Motor
e Keywords—tiagabine; overdose; poisoning; anticonvulsant; neurological
INTRODUCTION Tiagabine (Gabitril®) is a unique anticonvulsant indicated as an adjunct for the treatment of refractory partial seizures in patients 12 years and older. Similar to other anticonvulsants, tiagabine is being prescribed for use in a
Selected Topics: Toxicology is coordinated by Kenneth Kulig,
RECEIVED: 28 May 2003; FINAL ACCEPTED: 6 February 2004
SUBMISSION RECEIVED:
MD,
of Denver, Colorado
31 December 2003; 271
272
F. L. Cantrell et al.
strength and deep tendon reflexes were normal in both upper and lower extremities. There was no seizure activity observed. She was able to track with her eyes and no nystagmus was noted. Her pupils were 7 mm, sluggish and reactive to light. She was uncommunicative and unable to follow any purposeful commands. Initial vital signs were: blood pressure 144/90 mm Hg, pulse 74 beats/min, respiratory rate 20 breaths/min, temperature 37°C (98.6°F) and normal oxygen saturation. An electrocardiogram (EKG) was not performed. Intravenous access was established. A finger stick done by paramedics revealed a blood glucose of 108 mg/dL. Blood chemistries and a head computed tomography (CT) scan were normal and urine and blood toxicology screens were negative for common drugs of abuse (opiates, benzodiazepines, phencyclidine, cocaine, amphetamines, tricyclic antidepressants, phenobarbital and ethanol) as well as acetaminophen and aspirin. Tiagabine blood levels are not routinely available and thus were not drawn. Because an extrapyramidal reaction was initially suspected, 50 mg of diphenhydramine was administered without effect. Ten minutes later, 2 mg of lorazepam was given with significant improvement in the patient’s clinical status. The flexure posturing resolved and she followed verbal commands immediately. Due to the bilateral posturing, the lack of postictal symptoms immediately after the administration of lorazepam, and the lack of a prior history, seizures were not suspected. Due to difficulties obtaining additional lorazepam, 2 mg of midazolam was administered in the ED over the next 2 h with continued improvement and return of speech. She ultimately admitted intentionally taking an overdose of this medication. Additionally, she did remember wandering in the field, the ambulance ride, and being in the ED. She described her symptoms as a “bad dream where you know what to do but cannot control your body.” She was admitted for overnight observation and all symptoms resolved within 12 h of admission. DISCUSSION Tiagabine inhibits the presynaptic re-uptake of gammaaminobutyric acid (GABA) in neurons and glial cells. It is a highly selective and potent inhibitor of GABA Transporter 1. The resulting increase in synaptic GABA concentrations is thought to increase the duration and intensity of inhibitory postsynaptic potentials, thereby reducing aberrant excitatory activity (4). Its use is limited to controlling partial seizures due to a tendency to aggravate certain types of seizures such as myoclonic jerks and absences (5). Subjectively reported side effects during therapeutic use include: dizziness, asthenia, confusion, language problems, tremor, visual disturbances and headache (6,7). Clinical symptoms reported in the overdose setting are: central nervous system (CNS) depres-
sion ranging from lethargy to coma, agitation, dysphagia, weakness, myoclonus, and status epilepticus (8,9). The exact mechanism of our patient’s clinical picture is difficult to determine based on the pharmacology of tiagabine. Leach and Brodie state that at serum concentrations of 100 umol/L, tiagabine weakly inhibits the binding of specific ligands for D1, D2, muscarinic, 5-HT2, GABAA and glycine receptors (10). It could be theorized that some of the specificity for GABA Transporter 1 could be lost at high concentrations. Due to the spectrum of our patient’s symptoms and her favorable response to benzodiazepines, tiagabine toxicity possibly could be mediated through GABAminergic pathways as well as non-GABAminergic pathways. The duration of our patient’s symptoms loosely correlate with the pharmacokinetics of tiagabine as her symptoms resolved completely within 12 h of admission. It is rapidly absorbed and achieves peak plasma concentrations within 2–3 h. It is extensively metabolized by cytochrome P450 (CYP) isoform 3A in the liver to the inactive metabolite 5-ox-tiagabine. It has an elimination half-life of 7–9 h in non-CYP-induced patients and 2–3 h in CYP-induced patients (10). Although our patient was concurrently taking another medication (escitalopram) that is also metabolized by CYP isoform 3A, the pharmacokinetic and pharmacodynamic impact of this combination remains undefined. Based on our limited experience and few published cases reports, tiagabine overdose seems to cause an unusual array of neurological symptoms, many similar to reported adverse effects during therapeutic use. The only required treatment was benzodiazepines and supportive care. Perhaps future experiences in treating tiagabine overdose cases will shed more light on the exact mechanism by which it causes toxicity. REFERENCES 1. Ketter TA, Wang PW. The emerging differential roles of GABAergic and antiglutamatergic agents in bipolar disorders. J Clin Psychiatry 2003;64(Suppl 3):15–20. 2. Suppes T, Chisholm KA, Dhavale D, et al. Tiagabine in treatment refractory bipolar disorder: a clinical case series. Bipolar Disord 2002;4:283–9. 3. Spiller HA, Krenzelok EP, Klein-Schwartz W, et al. Multicenter case series of valproic acid ingestion: serum concentrations and toxicity. J Toxicol Clin Toxicol 2000;38:755– 60. 4. Meldrum BS, Chapman AG. Basic mechanisms of gabitril (tiagabine) and future potential developments. Epilepsia 1999;40(Suppl 9):S2– 6. 5. Angehagen M, Ben-Menachem E, Ronnback L, Hansson E. Novel mechanisms of action of three antiepileptic drugs, vigabatrin, tiagabine, and topiramate. Neurochem Res 2003;28:333– 40. 6. Fakhoury T, Uthman B, Abou-Khalil B. Safety of long-term treatment with tiagabine. Seizure 2000;9:431–5. 7. Kalviainen R. Long-term safety of tiagabine. Epilepsia 2001; 42(Suppl 3):46 – 8. 8. Leach JP, Stolarek I, Brodie MJ. Deliberate overdose with the novel anticonvulsant tiagabine. Seizure 1995;4:155–7. 9. Ostrovskiy D, Spanaki MV, Morris GL 3rd. Tiagabine overdose can induce convulsive status epilepticus. Epilepsia 2002;43:773– 4. 10. Leach JP, Brodie MJ. Tiagabine. Lancet 1998;351:203–7.