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Intentional bupropion overdoses
The Journal of Emergency Medicine, Vol. 27, No. 2, pp. 147–151, 2004 Copyright © 2004 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/04 $–see front matter
doi:10.1016/j.jemermed.2004.02.017
Selected Topics: Toxicology
INTENTIONAL BUPROPION OVERDOSES Greene Shepherd,
PharmD,
Larissa I. Velez,
MD,
and Daniel C. Keyes,
MD
Division of Emergency Medicine, University of Texas Southwestern Medical School and The North Texas Poison Center at Parkland Memorial Hospital, Dallas, Texas Reprint Address: Greene Shepherd, PHARMD, Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, MCG, Room CJ-1020, Augusta, GA 30912
e Abstract—Bupropion is an antidepressant that has recently seen increased usage in smoking cessation. This increased usage, along with its potential for causing seizures, has renewed interest among clinicians about the effects of this drug. The purpose of this study is to describe the clinical course of intentional bupropion overdoses in adults and adolescents. This study is a retrospective review of intentional bupropion overdoses reported to regional poison centers over a 2-year period. Our review included 385 cases. Women accounted for 63% of cases and ages ranged from 12 to 57 years. Significant clinical effects were noted in 26% of cases. Seizures were reported in 11% of patients. Seizures occurred within 6 h in most patients. Other prominent effects included tachycardia, agitation, and hallucinations. In conclusion, after a bupropion overdose, patients frequently display agitation, tachycardia, hallucinations and seizures. Seizures commonly occur within 6 h of the ingestion. However, seizures may occur beyond this time frame, particularly if persistent tachycardia, agitation, or hallucinations are noted. © 2004 Elsevier Inc.
INTRODUCTION Bupropion is a novel antidepressant with a unique aminoketone structure. It is thought that its primary pharmacologic action involves the inhibition of neuronal dopamine uptake and, to a lesser extent, the blockage of the reuptake of serotonin and norepinephrine (1,2). Bupropion has an active metabolite (4-hydroxybupropion) that may be involved in producing its toxic effects (3,4). This agent was originally marketed as an antidepressant and promptly removed from the market in 1986 due to seizures occurring at doses between 400 and 600 mg per day. The greatest risk for seizures was identified in sub-populations with bulimia, epilepsy or a history of head trauma (5,6). It was reintroduced to the market in 1989 at a lower dose range and with contraindications against use in persons with seizure or eating disorders. This lower dosing regimen still poses a risk of seizures that is similar to other antidepressants at therapeutic doses (7,8). In 1997, the FDA approved bupropion as a smoking cessation therapy under the trade name Zyban威 (bupropion 150 mg SR). The use of bupropion has increased significantly since that time and, not surprisingly, reports of both intentional and unintentional exposures also have increased. Although there has been much concern regarding adverse effects, particularly seizures, resulting from acute bupropion overdoses, there is limited information describing these effects. The purpose of this
e Keywords— bupropion; poisoning; adverse effects; seizures; prognosis
Presented as a poster at the 2000 North American Congress of Clinical Toxicology, Tucson, AZ, USA.
Selected Topics: Toxicology is coordinated by Kenneth Kulig,
RECEIVED: 14 March 2003; FINAL ACCEPTED: 3 February 2004
SUBMISSION RECEIVED:
MD,
of Denver, Colorado
7 November 2003; 147
148
G. Shepherd et al.
Figure 1. Clinical outcomes after intentional bupropion overdose.
retrospective case review is to describe the clinical course of intentional bupropion overdoses reported to a Regional Poison Control Center network.
METHODS This study is a retrospective chart review of intentional bupropion ingestions by adolescents and adults that were reported to the Texas Poison Center Network during the calendar years 1998 and 1999. Cases of unintentional dosing errors and exploratory ingestions by children were excluded. All reported cases were evaluated based on the American Association of Poison Control Centers– Toxic Exposure Surveillance System (AAPCC–TESS) coding of acuity, symptoms, and outcome using a predetermined template for data collection. A review of the written case record was performed on all cases that were coded as having a moderate, major, or death outcome, as defined by AAPCC–TESS. Cases with poor follow-up or where duplicative charts existed were excluded. A panel of two physicians and one pharmacist collected data from the identified cases using a standardized tool. Reviewers were trained on data extraction using an example of a poison center record. The collected data were discussed by the group to ensure agreement of the collected facts. In cases where discrepancies were identified, the case was re-reviewed by the group to allow for consensus about the data points. The review evaluated the reported amount ingested, dosage form, co-ingestants, clinical effects, treatment, and outcome. In cases where death occurred, autopsy data were reviewed when available. This review also addressed the temporal relationship between ingestion, therapy, and clinical effects.
RESULTS Our search initially yielded 385 cases with intentional ingestions of bupropion. The majority of these cases involved women (63%). Ages ranged from 12 to 57 years old (mean ⫽ 30 ⫾ 10 years). The 150-mg sustained release tablets (75%) were the most common dosage form in our study group. The brand name Zyban (150 mg SR) accounted for 19% of the ingestions, whereas Wellbutrin (150 mg SR) accounted for 56% of cases. Outcomes (see Figure 1) according to the AAPCC–TESS format were as follows: no effect n ⫽ 80 (21%), minor effect n ⫽ 98 (25%), moderate effect n ⫽ 62 (16%), major effect n ⫽ 35(9%), and death n ⫽ 2 (1%). Unknown outcomes due to poor follow-up data were reported in 108 (28%) cases. A review of the written case record was performed on 99 case records that met our inclusion criteria of a moderate, major or death outcome. Among this group there were no cases where the coded outcome seemed incorrect. Agreement among the reviewers was 100% on the selected data points. The excluded cases lacked outcome data (n ⫽ 108) or were coded as having minimal or no effects (n ⫽ 178). Deaths were reported in two cases. In both of these cases it is difficult to state conclusively that bupropion was the main cause of death. The first case involved a 45-year-old man who was found unresponsive by paramedics. It is believed that he took 30 – 60 bupropion 150-mg SR tablets, but the time of ingestion is uncertain. His initial blood pressure was 166/84 mm Hg with a heart rate of 101 beats per minute. On arrival in the Emergency Department (ED), the blood pH was 7.04, potassium 7.9 mEq/L, and creatinine 2.5 mg/dL. Gastric lavage was performed with no return of fragments, activated charcoal (50 g) was given, and whole bowel irri-
Intentional Bupropion Overdose
gation was initiated. Shortly after admission, the patient had three tonic-clonic seizures, which were successfully treated with lorazepam and fosphenytoin. The patient’s condition worsened over the next few hours and he was declared dead approximately 12 h after arriving at the hospital. Limited information is available about this case after the patient left the ED. No autopsy was performed and blood levels for bupropion were not obtained. Results of a urine drug screen were not available. The second death case involved a 41-year-old man who took approximately a 30-day supply of each of the following medications: bupropion 150 mg SR, imipramine, diphenhydramine, thiamine and clonazepam. Before EMS arrived, the patient reportedly had a seizure. At the scene, he was disoriented and combative, and seemed to be in a post-ictal state. Upon arrival at the ED, he was described as lethargic, with “stable vital signs.” Gastric lavage was performed without return of pill fragments, activated charcoal was given and whole bowel irrigation was initiated. A urine drug screen was positive for tricyclic antidepressants and cocaine metabolite. Aspirin, acetaminophen, and ethanol were not detected in blood samples. Soon after arrival, the patient developed sinus tachycardia and became less responsive. He continued to deteriorate despite supportive care, had a cardiorespiratory arrest, and died later that day. An autopsy ruled the cause of death to be due to a mixed drug overdose. Post-mortem qualitative laboratory analysis revealed the presence of bupropion, imipramine, despiramine, cocaine metabolite, and cannabinoid. The presence of the tricyclic antidepressant imipramine and its metabolite desipramine suggest that bupropion was not the major cause of death in this case. The range of clinical effects that were observed in our study population is shown in Figure 2. Effects that were reported in less than 0.25% of cases were not included. The most frequently reported symptoms included tachycardia (23%) and gastrointestinal upset (14%). Seizures were reported in 41 (11%) cases. Of these, 9 patients had more than one seizure and one developed status epilepticus. In the group that had seizures, reported doses ranged from 600 mg to 18 g. Seizures occurred most commonly in patients falling into two categories: those who reported ingesting more than 2500 mg without coingestants or those who were also using stimulants at the time of exposure (independent of the amount ingested). Twenty-one of the seizure cases (21/41) reported ingestions that were greater than 2.5 grams. However, there were 8 cases (8/58) in which ⬎ 2.5 g (range 2.5 to 8.5 g) was reported and seizures did not occur. Coingestion was reported in 16 of the patients who had seizures (37%). The dosage forms involved in the seizure cases were as follows: 6 regular release, 29 sustained release, and 6 unknown. In 13 of the cases where seizures did develop,
149
Figure 2. Frequency of reported clinical effects after intentional bupropion overdose.
the relationship between time of ingestion and the occurrence of the seizure could not be determined due to poor recall from the patient or lack of bystander history. For the remaining 28 cases, the time of onset of seizures ranged from 1 to 14 h (mean 4.3 ⫾ 3.2 h, median 4.0 and mode 2.0) (see Figure 3). Of particular interest, all patients who developed seizures, except for one, were noted to have persistent neurologic effects before seizing. These neurologic findings included agitation, tremors, and hallucinations. The hallucinations were often described as “bugs crawling on my skin.” One case stood out as unique in that it lacked a prodrome and the onset of seizures did not occur until 9 h after the ingestion. In this case, the patient ingested 45 tablets of bupropion 150 mg extended release. He was given activated charcoal and lavaged until return was clear (within 2 h of the ingestion). The patient was monitored until 5 h post-ingestion and then was discharged home after being asymptomatic for the entire stay. However, 4 h later he returned to the ED after a witnessed seizure. A clear history of what happened between discharge and the patient’s subsequent return is not available. Most patients received some treatment after arrival at the health care facility. Decontamination therapy was used in 90% of the reviewed cases with significant outcomes. Activated charcoal was the most common intervention, n ⫽ 79, followed by orogastric lavage, n ⫽ 47, and whole bowel irrigation, n ⫽ 13. In the treatment of seizures, 20 patients (50%) received benzodiazepines, 7 received phenytoin products, 11 received no treatment, and for 8 patients it could not be determined if any therapy was administered. All patients treated with ben-
150
G. Shepherd et al.
Figure 3. Onset of seizures after intentional bupropion overdose.
zodiazepines demonstrated good response to the therapy. In the cases where multiple seizures or status epilepticus occurred, benzodiazepines had not been given until these events occurred.
DISCUSSION Pesola and Avasarala recently reported that 1.4% of new onset seizures at their institution were due to therapeutic use of bupropion (8). Based on this and previous studies, seizure seems to be the most prominent feature of bupropion overdose. Our article has focused on intentional bupropion ingestion resulting in seizures. Our results are consistent with previously reported data by Spiller et al. on 58 cases of bupropion overdose. They are also similar to Belson and Kelley’s report on bupropion poisoning cases reported to U.S. poison centers (9,10). Although seizures were reported in only 7% (41/385) of all reported bupropion overdoses in our study, they were present in 41% (41/99) of the cases with significant clinical effects. Fortunately, the majority of these patients had self-limited seizures and recovered without any permanent damage. Seizures were more common when patients had co-ingested stimulants or reported ingesting ⬎ 2.5 grams of drug. Generally, these seizures occurred within 6 h of ingestion and responded well to therapy. In all but one case of late-onset seizure, the patient had persistent neurologic symptoms preceding the convulsion. These manifestations usually consisted of tremors and hallucinations. In the case where the patient was discharged and returned later with a witnessed seizure, the possibility exists that there was a second ingestion between the time he was discharged
and readmission. Although seizures often occur early, late presentation is also possible, particularly if other symptoms are present. Significant cardiovascular toxicity was not reported unless cardiotoxic co-ingestants were present. Although electrocardiograms were not available for review in any of the cases in our series, none of the patients reported having dysrhythmia or conduction disturbances. However, there has been one case report of a 32-year-old man developing prolonged QTc and QRS intervals after ingesting 9 g of immediate-release bupropion (11). It is possible that we did not observe this effect because the majority of patients in our case series ingested less than 9 g and involved sustained-release products that could reduce peak levels. The visual hallucinations that we observed have occasionally been noted at therapeutic doses as well (12,13). Benzodiazepines were the most frequent therapeutic modality for patients who had seizures. Because a neurologic prodrome was observed before seizures occurred, early benzodiazepine administration is advisable in those patients who are having tremors, hallucinations, tachycardia or agitation. The few patients who developed late-onset seizures had all of these symptoms but did not receive benzodiazepine until after seizures developed. Although some of the patients in this series were given a loading dose of phenytoin after seizures had occurred, this practice is generally not necessary in the treatment of toxin-induced seizures due to the brief nature of these convulsive episodes. Measurement of serum bupropion concentration was not done in our series. Measuring serum bupropion concentration can serve as an academic tool to confirm ingestion but has little if any value in
Intentional Bupropion Overdose
monitoring ongoing therapy or in the management of an overdose (14). Such laboratory studies are rarely available on a same-day basis and results will not affect patient management or disposition.
Limitations This study is limited by the retrospective nature of the review. Because not all cases are reported to poison centers, it is possible that some cases that occurred during the study period were not available for review. Dose estimates relied on patient or bystander histories and were not confirmed by laboratory studies. Furthermore, because weight was not uniformly collected, weight-based dose estimates were not made. Due to this, we did not attempt to draw any conclusions regarding mg/kg doses that are likely to produce seizures.
CONCLUSIONS After a bupropion overdose, seizures are most likely to occur within 6 h, especially when stimulants are coadministered or when large ingestions (⬎ 2.5 grams) occur. Nevertheless, patients may be at risk for having a seizure for several hours beyond this time frame if they display persistent symptoms such as tachycardia, agitation, or hallucinations. Benzodiazepines were the most common intervention for bupropion-induced seizures. Their use is also advisable for patients with neurologic symptoms related to the ingestion.
151
REFERENCES 1. Nomikos GG, Damsma G, Wenkstern D, Fibiger HC. Effects of chronic bupropion on interstitial concentrations of dopamine in rat nucleus accumbens and striatum. Neuropsychopharmacology 1992;7:7–14. 2. Butz RF, Welch RM, Findlay JW. Relationship between bupropion disposition and dopamine uptake inhibition in rats and mice. J Pharmacol Exp Ther 1982;221:676 – 85. 3. Friel PN, Logan BK, Fligner CL. Three fatal drug overdoses involving bupropion. J Anal Toxicol 1993;17:436 – 8. 4. Schroeder DH. Metabolism and kinetics of bupropion. J Clin Psychiatry 1983;44:79 – 81. 5. Horne RL, Ferguson JM, Pope HG Jr, et al. Treatment of bulimia with bupropion: a multicenter controlled trial. J Clin Psychiatry 1988;49:262– 6. 6. Davidson J. Seizures and Bupropion. J Clin Psychiatry 1989;50: 256 – 61. 7. Johnston JA, Lineberry CG, Ascher JA, et al. A 102-center prospective study of seizure in association with bupropion. J Clin Psychiatry 1991;52:450 – 6. 8. Pesola GR, Avasarala J. Bupropion seizure proportion among new-onset generalized seizures and drug related seizures presenting to an emergency department. J Emerg Med 2002;22:235–9. 9. Spiller HA, Ramoska EA, Krenzelok EP, et al. Bupropion overdose: a 3-year multi-center retrospective analysis. Am J Emerg Med 1994;12:43–5. 10. Belson MG, Kelley TR. Bupropion exposures: clinical manifestations and medical outcome. J Emerg Med 2002;23:223–30. 11. Paris PA, Saucier JR. ECG conduction delays associated with massive bupropion overdose. J Toxicol Clin Toxicol 1998;36: 595– 8. 12. Ames D, Wirshing WC, Szuba MP. Organic mental disorders associated with bupropion in three patients. J Clin Psychiatry 1992;53:53–5. 13. Golden RN, James SP, Sherer MA, Rudorfer MV, Sack DA, Potter WZ. Psychoses associated with bupropion treatment. Am J Psychiatry 1985;142:1459 – 62. 14. Preskorn SH. Pharmacokinetics of antidepressants: why and how they are relevant to treatment. J Clin Psychiatry1993;54(Suppl): 14 –34; discussion 55– 6.
doi:10.1016/j.jemermed.2004.02.017
Selected Topics: Toxicology
INTENTIONAL BUPROPION OVERDOSES Greene Shepherd,
PharmD,
Larissa I. Velez,
MD,
and Daniel C. Keyes,
MD
Division of Emergency Medicine, University of Texas Southwestern Medical School and The North Texas Poison Center at Parkland Memorial Hospital, Dallas, Texas Reprint Address: Greene Shepherd, PHARMD, Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, MCG, Room CJ-1020, Augusta, GA 30912
e Abstract—Bupropion is an antidepressant that has recently seen increased usage in smoking cessation. This increased usage, along with its potential for causing seizures, has renewed interest among clinicians about the effects of this drug. The purpose of this study is to describe the clinical course of intentional bupropion overdoses in adults and adolescents. This study is a retrospective review of intentional bupropion overdoses reported to regional poison centers over a 2-year period. Our review included 385 cases. Women accounted for 63% of cases and ages ranged from 12 to 57 years. Significant clinical effects were noted in 26% of cases. Seizures were reported in 11% of patients. Seizures occurred within 6 h in most patients. Other prominent effects included tachycardia, agitation, and hallucinations. In conclusion, after a bupropion overdose, patients frequently display agitation, tachycardia, hallucinations and seizures. Seizures commonly occur within 6 h of the ingestion. However, seizures may occur beyond this time frame, particularly if persistent tachycardia, agitation, or hallucinations are noted. © 2004 Elsevier Inc.
INTRODUCTION Bupropion is a novel antidepressant with a unique aminoketone structure. It is thought that its primary pharmacologic action involves the inhibition of neuronal dopamine uptake and, to a lesser extent, the blockage of the reuptake of serotonin and norepinephrine (1,2). Bupropion has an active metabolite (4-hydroxybupropion) that may be involved in producing its toxic effects (3,4). This agent was originally marketed as an antidepressant and promptly removed from the market in 1986 due to seizures occurring at doses between 400 and 600 mg per day. The greatest risk for seizures was identified in sub-populations with bulimia, epilepsy or a history of head trauma (5,6). It was reintroduced to the market in 1989 at a lower dose range and with contraindications against use in persons with seizure or eating disorders. This lower dosing regimen still poses a risk of seizures that is similar to other antidepressants at therapeutic doses (7,8). In 1997, the FDA approved bupropion as a smoking cessation therapy under the trade name Zyban威 (bupropion 150 mg SR). The use of bupropion has increased significantly since that time and, not surprisingly, reports of both intentional and unintentional exposures also have increased. Although there has been much concern regarding adverse effects, particularly seizures, resulting from acute bupropion overdoses, there is limited information describing these effects. The purpose of this
e Keywords— bupropion; poisoning; adverse effects; seizures; prognosis
Presented as a poster at the 2000 North American Congress of Clinical Toxicology, Tucson, AZ, USA.
Selected Topics: Toxicology is coordinated by Kenneth Kulig,
RECEIVED: 14 March 2003; FINAL ACCEPTED: 3 February 2004
SUBMISSION RECEIVED:
MD,
of Denver, Colorado
7 November 2003; 147
148
G. Shepherd et al.
Figure 1. Clinical outcomes after intentional bupropion overdose.
retrospective case review is to describe the clinical course of intentional bupropion overdoses reported to a Regional Poison Control Center network.
METHODS This study is a retrospective chart review of intentional bupropion ingestions by adolescents and adults that were reported to the Texas Poison Center Network during the calendar years 1998 and 1999. Cases of unintentional dosing errors and exploratory ingestions by children were excluded. All reported cases were evaluated based on the American Association of Poison Control Centers– Toxic Exposure Surveillance System (AAPCC–TESS) coding of acuity, symptoms, and outcome using a predetermined template for data collection. A review of the written case record was performed on all cases that were coded as having a moderate, major, or death outcome, as defined by AAPCC–TESS. Cases with poor follow-up or where duplicative charts existed were excluded. A panel of two physicians and one pharmacist collected data from the identified cases using a standardized tool. Reviewers were trained on data extraction using an example of a poison center record. The collected data were discussed by the group to ensure agreement of the collected facts. In cases where discrepancies were identified, the case was re-reviewed by the group to allow for consensus about the data points. The review evaluated the reported amount ingested, dosage form, co-ingestants, clinical effects, treatment, and outcome. In cases where death occurred, autopsy data were reviewed when available. This review also addressed the temporal relationship between ingestion, therapy, and clinical effects.
RESULTS Our search initially yielded 385 cases with intentional ingestions of bupropion. The majority of these cases involved women (63%). Ages ranged from 12 to 57 years old (mean ⫽ 30 ⫾ 10 years). The 150-mg sustained release tablets (75%) were the most common dosage form in our study group. The brand name Zyban (150 mg SR) accounted for 19% of the ingestions, whereas Wellbutrin (150 mg SR) accounted for 56% of cases. Outcomes (see Figure 1) according to the AAPCC–TESS format were as follows: no effect n ⫽ 80 (21%), minor effect n ⫽ 98 (25%), moderate effect n ⫽ 62 (16%), major effect n ⫽ 35(9%), and death n ⫽ 2 (1%). Unknown outcomes due to poor follow-up data were reported in 108 (28%) cases. A review of the written case record was performed on 99 case records that met our inclusion criteria of a moderate, major or death outcome. Among this group there were no cases where the coded outcome seemed incorrect. Agreement among the reviewers was 100% on the selected data points. The excluded cases lacked outcome data (n ⫽ 108) or were coded as having minimal or no effects (n ⫽ 178). Deaths were reported in two cases. In both of these cases it is difficult to state conclusively that bupropion was the main cause of death. The first case involved a 45-year-old man who was found unresponsive by paramedics. It is believed that he took 30 – 60 bupropion 150-mg SR tablets, but the time of ingestion is uncertain. His initial blood pressure was 166/84 mm Hg with a heart rate of 101 beats per minute. On arrival in the Emergency Department (ED), the blood pH was 7.04, potassium 7.9 mEq/L, and creatinine 2.5 mg/dL. Gastric lavage was performed with no return of fragments, activated charcoal (50 g) was given, and whole bowel irri-
Intentional Bupropion Overdose
gation was initiated. Shortly after admission, the patient had three tonic-clonic seizures, which were successfully treated with lorazepam and fosphenytoin. The patient’s condition worsened over the next few hours and he was declared dead approximately 12 h after arriving at the hospital. Limited information is available about this case after the patient left the ED. No autopsy was performed and blood levels for bupropion were not obtained. Results of a urine drug screen were not available. The second death case involved a 41-year-old man who took approximately a 30-day supply of each of the following medications: bupropion 150 mg SR, imipramine, diphenhydramine, thiamine and clonazepam. Before EMS arrived, the patient reportedly had a seizure. At the scene, he was disoriented and combative, and seemed to be in a post-ictal state. Upon arrival at the ED, he was described as lethargic, with “stable vital signs.” Gastric lavage was performed without return of pill fragments, activated charcoal was given and whole bowel irrigation was initiated. A urine drug screen was positive for tricyclic antidepressants and cocaine metabolite. Aspirin, acetaminophen, and ethanol were not detected in blood samples. Soon after arrival, the patient developed sinus tachycardia and became less responsive. He continued to deteriorate despite supportive care, had a cardiorespiratory arrest, and died later that day. An autopsy ruled the cause of death to be due to a mixed drug overdose. Post-mortem qualitative laboratory analysis revealed the presence of bupropion, imipramine, despiramine, cocaine metabolite, and cannabinoid. The presence of the tricyclic antidepressant imipramine and its metabolite desipramine suggest that bupropion was not the major cause of death in this case. The range of clinical effects that were observed in our study population is shown in Figure 2. Effects that were reported in less than 0.25% of cases were not included. The most frequently reported symptoms included tachycardia (23%) and gastrointestinal upset (14%). Seizures were reported in 41 (11%) cases. Of these, 9 patients had more than one seizure and one developed status epilepticus. In the group that had seizures, reported doses ranged from 600 mg to 18 g. Seizures occurred most commonly in patients falling into two categories: those who reported ingesting more than 2500 mg without coingestants or those who were also using stimulants at the time of exposure (independent of the amount ingested). Twenty-one of the seizure cases (21/41) reported ingestions that were greater than 2.5 grams. However, there were 8 cases (8/58) in which ⬎ 2.5 g (range 2.5 to 8.5 g) was reported and seizures did not occur. Coingestion was reported in 16 of the patients who had seizures (37%). The dosage forms involved in the seizure cases were as follows: 6 regular release, 29 sustained release, and 6 unknown. In 13 of the cases where seizures did develop,
149
Figure 2. Frequency of reported clinical effects after intentional bupropion overdose.
the relationship between time of ingestion and the occurrence of the seizure could not be determined due to poor recall from the patient or lack of bystander history. For the remaining 28 cases, the time of onset of seizures ranged from 1 to 14 h (mean 4.3 ⫾ 3.2 h, median 4.0 and mode 2.0) (see Figure 3). Of particular interest, all patients who developed seizures, except for one, were noted to have persistent neurologic effects before seizing. These neurologic findings included agitation, tremors, and hallucinations. The hallucinations were often described as “bugs crawling on my skin.” One case stood out as unique in that it lacked a prodrome and the onset of seizures did not occur until 9 h after the ingestion. In this case, the patient ingested 45 tablets of bupropion 150 mg extended release. He was given activated charcoal and lavaged until return was clear (within 2 h of the ingestion). The patient was monitored until 5 h post-ingestion and then was discharged home after being asymptomatic for the entire stay. However, 4 h later he returned to the ED after a witnessed seizure. A clear history of what happened between discharge and the patient’s subsequent return is not available. Most patients received some treatment after arrival at the health care facility. Decontamination therapy was used in 90% of the reviewed cases with significant outcomes. Activated charcoal was the most common intervention, n ⫽ 79, followed by orogastric lavage, n ⫽ 47, and whole bowel irrigation, n ⫽ 13. In the treatment of seizures, 20 patients (50%) received benzodiazepines, 7 received phenytoin products, 11 received no treatment, and for 8 patients it could not be determined if any therapy was administered. All patients treated with ben-
150
G. Shepherd et al.
Figure 3. Onset of seizures after intentional bupropion overdose.
zodiazepines demonstrated good response to the therapy. In the cases where multiple seizures or status epilepticus occurred, benzodiazepines had not been given until these events occurred.
DISCUSSION Pesola and Avasarala recently reported that 1.4% of new onset seizures at their institution were due to therapeutic use of bupropion (8). Based on this and previous studies, seizure seems to be the most prominent feature of bupropion overdose. Our article has focused on intentional bupropion ingestion resulting in seizures. Our results are consistent with previously reported data by Spiller et al. on 58 cases of bupropion overdose. They are also similar to Belson and Kelley’s report on bupropion poisoning cases reported to U.S. poison centers (9,10). Although seizures were reported in only 7% (41/385) of all reported bupropion overdoses in our study, they were present in 41% (41/99) of the cases with significant clinical effects. Fortunately, the majority of these patients had self-limited seizures and recovered without any permanent damage. Seizures were more common when patients had co-ingested stimulants or reported ingesting ⬎ 2.5 grams of drug. Generally, these seizures occurred within 6 h of ingestion and responded well to therapy. In all but one case of late-onset seizure, the patient had persistent neurologic symptoms preceding the convulsion. These manifestations usually consisted of tremors and hallucinations. In the case where the patient was discharged and returned later with a witnessed seizure, the possibility exists that there was a second ingestion between the time he was discharged
and readmission. Although seizures often occur early, late presentation is also possible, particularly if other symptoms are present. Significant cardiovascular toxicity was not reported unless cardiotoxic co-ingestants were present. Although electrocardiograms were not available for review in any of the cases in our series, none of the patients reported having dysrhythmia or conduction disturbances. However, there has been one case report of a 32-year-old man developing prolonged QTc and QRS intervals after ingesting 9 g of immediate-release bupropion (11). It is possible that we did not observe this effect because the majority of patients in our case series ingested less than 9 g and involved sustained-release products that could reduce peak levels. The visual hallucinations that we observed have occasionally been noted at therapeutic doses as well (12,13). Benzodiazepines were the most frequent therapeutic modality for patients who had seizures. Because a neurologic prodrome was observed before seizures occurred, early benzodiazepine administration is advisable in those patients who are having tremors, hallucinations, tachycardia or agitation. The few patients who developed late-onset seizures had all of these symptoms but did not receive benzodiazepine until after seizures developed. Although some of the patients in this series were given a loading dose of phenytoin after seizures had occurred, this practice is generally not necessary in the treatment of toxin-induced seizures due to the brief nature of these convulsive episodes. Measurement of serum bupropion concentration was not done in our series. Measuring serum bupropion concentration can serve as an academic tool to confirm ingestion but has little if any value in
Intentional Bupropion Overdose
monitoring ongoing therapy or in the management of an overdose (14). Such laboratory studies are rarely available on a same-day basis and results will not affect patient management or disposition.
Limitations This study is limited by the retrospective nature of the review. Because not all cases are reported to poison centers, it is possible that some cases that occurred during the study period were not available for review. Dose estimates relied on patient or bystander histories and were not confirmed by laboratory studies. Furthermore, because weight was not uniformly collected, weight-based dose estimates were not made. Due to this, we did not attempt to draw any conclusions regarding mg/kg doses that are likely to produce seizures.
CONCLUSIONS After a bupropion overdose, seizures are most likely to occur within 6 h, especially when stimulants are coadministered or when large ingestions (⬎ 2.5 grams) occur. Nevertheless, patients may be at risk for having a seizure for several hours beyond this time frame if they display persistent symptoms such as tachycardia, agitation, or hallucinations. Benzodiazepines were the most common intervention for bupropion-induced seizures. Their use is also advisable for patients with neurologic symptoms related to the ingestion.
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