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New-Onset Seizure in Patient Medicated With Bupropion for Smoking Cessation: A Case Report
The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–3, 2020 Ó 2019 Elsevier Inc. All rights reserved. 0736-4679/$ - see front matter
https://doi.org/10.1016/j.jemermed.2019.12.020
Clinical Communications: Adult NEW-ONSET SEIZURE IN PATIENT MEDICATED WITH BUPROPION FOR SMOKING CESSATION: A CASE REPORT Donna Saffaei, MS,* Shannon Lovett, MD,† and Megan A. Rech, PHARMD, MS†‡ *Stritch School of Medicine, Loyola University, Chicago, Illinois, †Department of Emergency Medicine, Loyola University Medical Center, Chicago, Illinois, and ‡Department of Pharmacy, Loyola University Medical Center, Maywood, Illinois Reprint Address: Donna Saffaei, MS, Stritch School of Medicine, Loyola University Chicago, Loyola University Medical Center, 2160 S 1st Avenue, Maywood, IL 60513
, Abstract—Background: Bupropion is a pharmacologic agent approved by the U.S. Food and Drug Administration as an antidepressant and to support smoking cessation. Because reduction of seizure threshold is a rare but serious side effect of bupropion, its use in patients with a known history of seizures is contraindicated. We report a patient without seizure risk factors who presented to the emergency department (ED) with new-onset seizures secondary to bupropion use. Case Report: A 66-year-old female presented to the ED by emergency medical services with altered mental status. She was determined to be postictal after a witnessed new-onset seizure 4 days after starting bupropion for smoking cessation. She had no personal or family history of seizure disorders, although her medication list raised suspicion that recent discontinuation of alprazolam may have contributed to a reduced seizure threshold. Why Should an Emergency Physician Be Aware of This?: New-onset seizures secondary to bupropion use are less likely in patients with no personal or family history of seizure disorders. Emergency medicine clinicians should be aware, however, of the seizure risk associated with bupropion regardless of personal risk factors. Discontinuation of bupropion should be considered if determined to be a contributor to seizures. Ó 2019 Elsevier Inc. All rights reserved.
INTRODUCTION Bupropion was introduced to the United States market in 1985 and is now available in more than 50 countries as an atypical antidepressant and aid for smoking cessation (1). Its mechanism of action involves the reuptake inhibition of norepinephrine and dopamine, as well as the noncompetitive antagonism of nicotinic acetylcholine receptors, resulting in the inhibition of nicotine’s stimulant effects (2). Bupropion and varenicline are the only two nicotine-free pharmaceuticals that are approved to aid in smoking cessation (3). An 8-week regimen of bupropion has demonstrated successful smoking abstinence for up to 12 months in 23.6–33.2% of patients (4). A meta-analysis in 2006 demonstrated the ability of bupropion to double the rate of cessation in a smoking population compared to placebo (5). Bupropion has a mild side effect profile compared to similar medications, consisting largely of gastrointestinal adverse effects. Generalized seizures are a rare but serious adverse effect that warrants the attention of emergency medicine providers. The risk of seizures is dosedependent and higher among patients with risk factors for seizures, including medical history or family history of seizures, bulimia, anorexia, alcohol intake, sleep deprivation, and history of head injury. Concomitant use of other medications that lower seizure threshold or withdrawal of specific drugs, such as alcohol or
, Keywords—bupropion; new-onset seizure; smoking cessation
RECEIVED: 17 October 2019; ACCEPTED: 16 December 2019 1
2
D. Saffaei et al.
benzodiazepines, are also contributing factors (6–8). Despite this risk, bupropion-related seizures appear to be underrepresented in emergency medicine literature. A study evaluating drug-related new-onset seizures in the emergency department (ED) during a 4-year period found that therapeutic-dose bupropion was the third leading cause, after cocaine intoxication and benzodiazepine withdrawal (7). The purpose of this case report is to document a case of new-onset seizure secondary to bupropion use in the setting of no personal or family history of seizures, and to promote awareness of bupropion as a possible cause of new-onset seizures.
was thought to have had a provoked seizure in the setting of bupropion use, and the neurology team was consulted for further recommendations. Neurology was in agreement with the diagnosis and did not feel any additional workup was indicated. The seizure was thought to be from bupropion use, potentially exacerbated by withdrawal from benzodiazepines. The patient and family were counseled on the risks associated with buproprion use and the importance of gradually weaning benzodiazepines to avoid withdrawal symptoms. The patient was discharged with seizure precautions and instructed to follow-up with her primary care provider to discuss her medications further.
CASE REPORT DISCUSSION A 66-year-old Caucasian female smoker with medical history of chronic back pain, hypothyroidism, and anxiety presented to the ED by emergency medical services (EMS) with altered mental status. She arrived awake and alert, but was agitated, restless, and confused. Limited history was available from EMS and limited medical records were available. The patient’s vitals on arrival were normal, with the exception of hypertension (154/104 mm Hg) and tachycardia (heart rate 107 beats/min). On examination, she was thin and appeared restless and confused. She had an abrasion over her nose and a small laceration to her tongue. She repeatedly moved to get off the cart but was cooperative when redirected. She was oriented to person and year but could not recall her medications. She had no focal neurologic deficits and the remainder of her examination was normal. A noncontrast computed tomography (CT) head was obtained. The patient was given 2 mg of intravenous lorazepam prior to CT, with some improvement in her agitation and restlessness. Family was contacted for additional history and reported witnessing an episode of seizure-like activity that lasted approximately 5 min, followed by confusion and lethargy. Her pharmacy was contacted for a medication list that included levothyroxine 137–150 mg alternating daily, alprazolam 1 mg three times daily, and bupropion XL 150 mg daily. CT head was unremarkable. Laboratory tests were within normal limits, with the exception of elevated lactate of 4.60 U/L and mild electrolyte abnormalities, including sodium 130 mEq/L, potassium 3.1 mEq/L, bicarbonate 12 mEq/L, glucose 208 mg/dL, and magnesium 1.5 mEq/L. Toxicology workup was negative other than benzodiazepines, which were administered on arrival. Clinically, the patient’s confusion improved back to baseline mental status and she was able to provide more history. She reported not taking her alprazolam the day of the event or the day prior and confirmed initiating bupropion 4 days prior for smoking cessation. The patient
This case describes a bupropion-induced seizure in an ED patient with no history of seizures. A medical history of seizures is a known risk factor for such an event (1). Our case serves to remind emergency medicine clinicians to look for medications as a precipitating factor inciting seizures. Additionally, when initiating bupropion while on medications like benzodiazepines, it is critical to counsel patients on the potential risk of seizures with concomitant withdrawal. One year after bupropion received approval from the U.S. Food and Drug Administration, it was removed from the market due to a significant incidence of epileptic seizures, but was later reintroduced at reduced recommended doses (1). Despite these measures, therapeutic bupropion use has been found to be the third leading cause, after cocaine intoxication and benzodiazepine withdrawal, of drug-related new-onset seizures (7). A retrospective study found a 75% increase in bupropion abuse between 2000 and 2012, with 33.5% of patients experiencing seizures (9). Additionally, 10,002 patients prescribed various antidepressants in a 10-year study demonstrated that bupropion had the most significant seizure risk (odds ratio 2.23; 95% confidence interval 1.58–3.16) (10). These findings support the need for further investigation into the confounding factors affecting bupropion use, as this case report depicts a patient experiencing a bupropion-induced seizure in the setting of no known risk factors. Bupropion should therefore be prescribed at lower doses with caution to possible drug interactions, such as benzodiazepines or alcohol, which could result in a decreased seizure threshold. The reported management of bupropion-induced seizures has varied in the literature, depending on co-ingestants, although benzodiazepines are indicated in any seizing patient. In the setting of life-threatening overdose, the use of intravenous lipid emulsion is recommended to reverse acute toxicity (11,12).
New-Onset Seizures Secondary to Bupropion Use
This case was confounded by withdrawal of alprazolam, which may have lowered seizure threshold. Seizures associated with alprazolam have only been reported in the context of alprazolam withdrawal (2). Current studies hypothesize that chronic activation of the inhibitory GABAA receptors results in increased sensitivity of the excitatory glutamatergic system, thereby increasing susceptibility to seizures (13). In this case report, the patient skipped doses of alprazolam within 48 h preceding seizures, which likely lowered her seizure threshold and contributed to her presentation. While this case report is limited in that it consists of a single patient, it has important implications for emergency medicine clinicians, as this patient was on a low dose of bupropion (one-third of the recommended daily maximum) and had no risk factors for seizure disorders. This highlights the need to closely monitor patients taking bupropion, and to advise patients of other medications or conditions that may lower seizure threshold. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS? Bupropion is an effective antidepressant and aid for smoking cessation. However, a rare yet serious adverse effect is lowering seizure threshold. This case report demonstrates that bupropion at a low therapeutic dose can still potentially induce new-onset seizures in patients lacking a history of seizures. Patients should be advised of additional conditions that may contribute to a lowered seizure threshold when initiating bupropion. While there are many possible etiologies for acute seizures, emergency medicine clinicians should consider medications that lower the seizure threshold.
3
REFERENCES 1. Fava M, Rush AJ, Thase ME, et al. 15 years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL. Prim Care Companion J Clin Psychiatry 2005;7(3): 106–13. 2. Vicente Ferreira Naves P, Calderaro M, Caboclo LO. De novo myoclonic status epilepticus after benzodiazepine withdrawal. Clin Neuropharmacol 2018;41(4):142–4. 3. Baker CL, Ferrufino CP, Bruno M, Kowal S. Estimated budget impact of adopting the affordable care act’s required smoking cessation coverage on United States healthcare payers. Adv Ther 2017; 34:156–70. 4. Swan GE, McAfee T, Curry SJ, et al. Effectiveness of bupropion sustained release for smoking cessation in a health care setting. Arch Intern Med 2003;163:2337–44. 5. Wu P, Wilson K, Dimoulas P, Mills EJ. Effectiveness of smoking cessation therapies: a systematic review and meta-analysis. BMC Public Health 2006;6:300. 6. Mishra DK, Sardesai U, Rastogi P, Rhamghulam. Seizure secondary to bupropion extended release preparation: a report. Asian J Psychiatry 2017;30:86–7. 7. Pesola GR, Avasarala J. Bupropion seizure proportion among newonset generalized seizures and drug related seizures presenting to an emergency department. J Emerg Med 2002;22:235–9. 8. Tran AX, Ho TT, Varghese-Gupta S. Role of CYP2B6 pharmacogenomics in bupropion-mediated smoking cessation. J Clin Pharm Ther 2019;44:174–9. 9. Dunner DL, Zisook S, Billow AA, Batey SR, Johnston JA, Ascher JA. A prospective safety surveillance study for bupropion sustained-release in the treatment of depression. J Clin Psychiatry 1998;59:366–73. 10. Wu CS, Liu HY, Tsai HJ, Liu SK. Seizure risk associated with antidepressant treatment among patients with depressive disorders: a population-based case-crossover study. J Clin Psychiatry 2017;78: e1226–32. 11. Cave G, Harvey M. Intravenous lipid emulsion as antidote beyond local anesthetic toxicity: a systematic review. Acad Emerg Med 2009;16:815–24. 12. Baylis J. IV lipid emulsion for drug toxicity in the ED. In: CanadiEM, ed. Medical Concepts. 2017. Available at: canadiem.org/iv-lipidemulsion-for-drug-toxicity-in-the-ed/. Accessed July 24, 2019. 13. Stassinos GL, Klein-Schwartz W. Bupropion "abuse" reported to US poison centers. J Addict Med 2016;10:357–62.
https://doi.org/10.1016/j.jemermed.2019.12.020
Clinical Communications: Adult NEW-ONSET SEIZURE IN PATIENT MEDICATED WITH BUPROPION FOR SMOKING CESSATION: A CASE REPORT Donna Saffaei, MS,* Shannon Lovett, MD,† and Megan A. Rech, PHARMD, MS†‡ *Stritch School of Medicine, Loyola University, Chicago, Illinois, †Department of Emergency Medicine, Loyola University Medical Center, Chicago, Illinois, and ‡Department of Pharmacy, Loyola University Medical Center, Maywood, Illinois Reprint Address: Donna Saffaei, MS, Stritch School of Medicine, Loyola University Chicago, Loyola University Medical Center, 2160 S 1st Avenue, Maywood, IL 60513
, Abstract—Background: Bupropion is a pharmacologic agent approved by the U.S. Food and Drug Administration as an antidepressant and to support smoking cessation. Because reduction of seizure threshold is a rare but serious side effect of bupropion, its use in patients with a known history of seizures is contraindicated. We report a patient without seizure risk factors who presented to the emergency department (ED) with new-onset seizures secondary to bupropion use. Case Report: A 66-year-old female presented to the ED by emergency medical services with altered mental status. She was determined to be postictal after a witnessed new-onset seizure 4 days after starting bupropion for smoking cessation. She had no personal or family history of seizure disorders, although her medication list raised suspicion that recent discontinuation of alprazolam may have contributed to a reduced seizure threshold. Why Should an Emergency Physician Be Aware of This?: New-onset seizures secondary to bupropion use are less likely in patients with no personal or family history of seizure disorders. Emergency medicine clinicians should be aware, however, of the seizure risk associated with bupropion regardless of personal risk factors. Discontinuation of bupropion should be considered if determined to be a contributor to seizures. Ó 2019 Elsevier Inc. All rights reserved.
INTRODUCTION Bupropion was introduced to the United States market in 1985 and is now available in more than 50 countries as an atypical antidepressant and aid for smoking cessation (1). Its mechanism of action involves the reuptake inhibition of norepinephrine and dopamine, as well as the noncompetitive antagonism of nicotinic acetylcholine receptors, resulting in the inhibition of nicotine’s stimulant effects (2). Bupropion and varenicline are the only two nicotine-free pharmaceuticals that are approved to aid in smoking cessation (3). An 8-week regimen of bupropion has demonstrated successful smoking abstinence for up to 12 months in 23.6–33.2% of patients (4). A meta-analysis in 2006 demonstrated the ability of bupropion to double the rate of cessation in a smoking population compared to placebo (5). Bupropion has a mild side effect profile compared to similar medications, consisting largely of gastrointestinal adverse effects. Generalized seizures are a rare but serious adverse effect that warrants the attention of emergency medicine providers. The risk of seizures is dosedependent and higher among patients with risk factors for seizures, including medical history or family history of seizures, bulimia, anorexia, alcohol intake, sleep deprivation, and history of head injury. Concomitant use of other medications that lower seizure threshold or withdrawal of specific drugs, such as alcohol or
, Keywords—bupropion; new-onset seizure; smoking cessation
RECEIVED: 17 October 2019; ACCEPTED: 16 December 2019 1
2
D. Saffaei et al.
benzodiazepines, are also contributing factors (6–8). Despite this risk, bupropion-related seizures appear to be underrepresented in emergency medicine literature. A study evaluating drug-related new-onset seizures in the emergency department (ED) during a 4-year period found that therapeutic-dose bupropion was the third leading cause, after cocaine intoxication and benzodiazepine withdrawal (7). The purpose of this case report is to document a case of new-onset seizure secondary to bupropion use in the setting of no personal or family history of seizures, and to promote awareness of bupropion as a possible cause of new-onset seizures.
was thought to have had a provoked seizure in the setting of bupropion use, and the neurology team was consulted for further recommendations. Neurology was in agreement with the diagnosis and did not feel any additional workup was indicated. The seizure was thought to be from bupropion use, potentially exacerbated by withdrawal from benzodiazepines. The patient and family were counseled on the risks associated with buproprion use and the importance of gradually weaning benzodiazepines to avoid withdrawal symptoms. The patient was discharged with seizure precautions and instructed to follow-up with her primary care provider to discuss her medications further.
CASE REPORT DISCUSSION A 66-year-old Caucasian female smoker with medical history of chronic back pain, hypothyroidism, and anxiety presented to the ED by emergency medical services (EMS) with altered mental status. She arrived awake and alert, but was agitated, restless, and confused. Limited history was available from EMS and limited medical records were available. The patient’s vitals on arrival were normal, with the exception of hypertension (154/104 mm Hg) and tachycardia (heart rate 107 beats/min). On examination, she was thin and appeared restless and confused. She had an abrasion over her nose and a small laceration to her tongue. She repeatedly moved to get off the cart but was cooperative when redirected. She was oriented to person and year but could not recall her medications. She had no focal neurologic deficits and the remainder of her examination was normal. A noncontrast computed tomography (CT) head was obtained. The patient was given 2 mg of intravenous lorazepam prior to CT, with some improvement in her agitation and restlessness. Family was contacted for additional history and reported witnessing an episode of seizure-like activity that lasted approximately 5 min, followed by confusion and lethargy. Her pharmacy was contacted for a medication list that included levothyroxine 137–150 mg alternating daily, alprazolam 1 mg three times daily, and bupropion XL 150 mg daily. CT head was unremarkable. Laboratory tests were within normal limits, with the exception of elevated lactate of 4.60 U/L and mild electrolyte abnormalities, including sodium 130 mEq/L, potassium 3.1 mEq/L, bicarbonate 12 mEq/L, glucose 208 mg/dL, and magnesium 1.5 mEq/L. Toxicology workup was negative other than benzodiazepines, which were administered on arrival. Clinically, the patient’s confusion improved back to baseline mental status and she was able to provide more history. She reported not taking her alprazolam the day of the event or the day prior and confirmed initiating bupropion 4 days prior for smoking cessation. The patient
This case describes a bupropion-induced seizure in an ED patient with no history of seizures. A medical history of seizures is a known risk factor for such an event (1). Our case serves to remind emergency medicine clinicians to look for medications as a precipitating factor inciting seizures. Additionally, when initiating bupropion while on medications like benzodiazepines, it is critical to counsel patients on the potential risk of seizures with concomitant withdrawal. One year after bupropion received approval from the U.S. Food and Drug Administration, it was removed from the market due to a significant incidence of epileptic seizures, but was later reintroduced at reduced recommended doses (1). Despite these measures, therapeutic bupropion use has been found to be the third leading cause, after cocaine intoxication and benzodiazepine withdrawal, of drug-related new-onset seizures (7). A retrospective study found a 75% increase in bupropion abuse between 2000 and 2012, with 33.5% of patients experiencing seizures (9). Additionally, 10,002 patients prescribed various antidepressants in a 10-year study demonstrated that bupropion had the most significant seizure risk (odds ratio 2.23; 95% confidence interval 1.58–3.16) (10). These findings support the need for further investigation into the confounding factors affecting bupropion use, as this case report depicts a patient experiencing a bupropion-induced seizure in the setting of no known risk factors. Bupropion should therefore be prescribed at lower doses with caution to possible drug interactions, such as benzodiazepines or alcohol, which could result in a decreased seizure threshold. The reported management of bupropion-induced seizures has varied in the literature, depending on co-ingestants, although benzodiazepines are indicated in any seizing patient. In the setting of life-threatening overdose, the use of intravenous lipid emulsion is recommended to reverse acute toxicity (11,12).
New-Onset Seizures Secondary to Bupropion Use
This case was confounded by withdrawal of alprazolam, which may have lowered seizure threshold. Seizures associated with alprazolam have only been reported in the context of alprazolam withdrawal (2). Current studies hypothesize that chronic activation of the inhibitory GABAA receptors results in increased sensitivity of the excitatory glutamatergic system, thereby increasing susceptibility to seizures (13). In this case report, the patient skipped doses of alprazolam within 48 h preceding seizures, which likely lowered her seizure threshold and contributed to her presentation. While this case report is limited in that it consists of a single patient, it has important implications for emergency medicine clinicians, as this patient was on a low dose of bupropion (one-third of the recommended daily maximum) and had no risk factors for seizure disorders. This highlights the need to closely monitor patients taking bupropion, and to advise patients of other medications or conditions that may lower seizure threshold. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS? Bupropion is an effective antidepressant and aid for smoking cessation. However, a rare yet serious adverse effect is lowering seizure threshold. This case report demonstrates that bupropion at a low therapeutic dose can still potentially induce new-onset seizures in patients lacking a history of seizures. Patients should be advised of additional conditions that may contribute to a lowered seizure threshold when initiating bupropion. While there are many possible etiologies for acute seizures, emergency medicine clinicians should consider medications that lower the seizure threshold.
3
REFERENCES 1. Fava M, Rush AJ, Thase ME, et al. 15 years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL. Prim Care Companion J Clin Psychiatry 2005;7(3): 106–13. 2. Vicente Ferreira Naves P, Calderaro M, Caboclo LO. De novo myoclonic status epilepticus after benzodiazepine withdrawal. Clin Neuropharmacol 2018;41(4):142–4. 3. Baker CL, Ferrufino CP, Bruno M, Kowal S. Estimated budget impact of adopting the affordable care act’s required smoking cessation coverage on United States healthcare payers. Adv Ther 2017; 34:156–70. 4. Swan GE, McAfee T, Curry SJ, et al. Effectiveness of bupropion sustained release for smoking cessation in a health care setting. Arch Intern Med 2003;163:2337–44. 5. Wu P, Wilson K, Dimoulas P, Mills EJ. Effectiveness of smoking cessation therapies: a systematic review and meta-analysis. BMC Public Health 2006;6:300. 6. Mishra DK, Sardesai U, Rastogi P, Rhamghulam. Seizure secondary to bupropion extended release preparation: a report. Asian J Psychiatry 2017;30:86–7. 7. Pesola GR, Avasarala J. Bupropion seizure proportion among newonset generalized seizures and drug related seizures presenting to an emergency department. J Emerg Med 2002;22:235–9. 8. Tran AX, Ho TT, Varghese-Gupta S. Role of CYP2B6 pharmacogenomics in bupropion-mediated smoking cessation. J Clin Pharm Ther 2019;44:174–9. 9. Dunner DL, Zisook S, Billow AA, Batey SR, Johnston JA, Ascher JA. A prospective safety surveillance study for bupropion sustained-release in the treatment of depression. J Clin Psychiatry 1998;59:366–73. 10. Wu CS, Liu HY, Tsai HJ, Liu SK. Seizure risk associated with antidepressant treatment among patients with depressive disorders: a population-based case-crossover study. J Clin Psychiatry 2017;78: e1226–32. 11. Cave G, Harvey M. Intravenous lipid emulsion as antidote beyond local anesthetic toxicity: a systematic review. Acad Emerg Med 2009;16:815–24. 12. Baylis J. IV lipid emulsion for drug toxicity in the ED. In: CanadiEM, ed. Medical Concepts. 2017. Available at: canadiem.org/iv-lipidemulsion-for-drug-toxicity-in-the-ed/. Accessed July 24, 2019. 13. Stassinos GL, Klein-Schwartz W. Bupropion "abuse" reported to US poison centers. J Addict Med 2016;10:357–62.