A Case Report of Seizure Induced by Bupropion Nasal Insufflation

Sir: Bupropion hydrochloride (HCl) is an aminoketone antidepressant currently approved by the U.S. Food and Drug Administration (FDA) for depression and smoking cessation. Off-label uses include treatment of attention-deficit/hyperactivity disorder, chronic fatigue, and cocaine dependence and adjunctive treatment for Parkinson's disease. Bupropion is available in 3 formulations: immediate-release (IR), sustained-release (SR), and extended-release (XL).

Bupropion-induced seizures have been described in safety surveillance studies and case reports. As with other antidepressants and psychotropic medications, bupropion appears to lower the seizure threshold in a dose-dependent fashion. The seizure incidence in patients taking ≤ 450 mg per day of bupropion IR is 0.4%, while the incidence in those taking 600 to 900 mg per day is 2.8%.^1,2 This elevated risk of seizure led to a lowering of the maximum dose and the development of sustained- and extended-release products. The seizure rate for the sustained-release formulation decreased to 0.1% at doses of up to 300 mg per day.² An emergency medicine study revealed that bupropion was the third leading cause of new-onset seizures at 1.4%, behind cocaine and benzodiazepine withdrawal.³ Overdose literature indicates that 68% to 77% of bupropion-induced seizures occur within 4 hours of ingestion.^1,4

While bupropion-induced seizures are well described, data reflecting the consequences of bupropion nasal insufflation are limited. A MEDLINE search using the keywords bupropion and insufflation only revealed 2 letters reporting bupropion nasal insufflation in 2 adolescents, with 1 case resulting in seizure.^5,6 Neither of the 2 letters hypothesized about the mechanism for seizure production. This is the second reported case describing bupropion nasal insufflation–induced seizure.

Case report. Mr. A, a 50-year-old homeless white man with a history of multiple emergency department (ED) admissions was brought into the ED in March 2005 by para-medics secondary to seizures from a standing position witnessed by 2 bystanders. Each seizure lasted 30 to 60 seconds with a brief postictal period and no incontinence. Bystander descriptions of the seizures were unavailable. During the intake history, Mr. A admitted to the nasal insufflation of bupropion SR tablets, but was unable to quantify the amount. The patient admitted to a history of bupropion nasal insufflation occasionally resulting in seizures over the past 3 years. He denied a long-standing seizure disorder or treatment with anticonvulsants. He claimed that this route of administration gives him a chemical euphoria, which he described as a “cocaine high.” He did not complain of any auditory or visual hallucinations and exhibited no signs of intoxication.

Mr. A's medical history was significant for substance abuse, questionable schizoaffective disorder, and prior seizures secondary to bupropion nasal insufflation. He denied a family history of seizure disorder or substance abuse. The patient admitted to smoking, but denied any current alcohol or illicit drug use. The patient reported being incarcerated 3 years ago. He reported no medication allergies and that he was prescribed bupropion SR 150 mg orally twice daily and olanzapine 10 mg orally daily. He stated that he receives his medications from various free clinics and EDs in San Diego, Calif. The patient denied the use of any over-the-counter or herbal medications. He was deemed a reliable historian based on his alertness and ability to provide a thorough intake history.

Upon presentation to the ED, Mr. A was stable, alert, and oriented. Results of the physical examination were normal except for a small hematoma and abrasion over the right eye, with no focal neurologic deficits. Tachycardia with a heart rate of 112 was noted, but results of the cardiac examination were otherwise normal. The complete blood count and metabolic panel were within normal limits. His blood alcohol level was negative. A urine toxicology screen was collected but not completed. Previous urine toxicology screens over the past 6 months were negative. A plasma bupropion level was not evaluated during this admission. Brain computed tomography scan results were nonsignificant. The ED treatment course consisted of lorazepam 2 mg intravenously and observation for approximately 6 hours. Mr. A displayed no further seizure activity or mental status changes and was deemed stable and safe for discharge. He was counseled to avoid future nasal insufflation of bupropion SR tablets and to follow up with outpatient psychiatric services.

Bupropion HCl is structurally similar to phenyl-ethylamines, which include such compounds as meth-amphetamine, amphetamine, methylenedioxy-metham-phetamine (MDMA, “Ecstasy”), and diethylpropion.⁷ In addition, the 3-dimensional structure of bupropion resembles that of cocaine. Bupropion is a weak catecholamine reuptake inhibitor that affects predominantly dopamine, norepinephrine, and serotonin.^8,9 While the exact mechanism of action is unclear, animal studies suggest that bupropion enhances dopaminergic and noradrenergic activity.^8,9

The stimulant effects of bupropion have been studied because it has structural similarities to amphetamine and there is evidence indicating that bupropion produces stimulant effects in animals.¹⁰ A study by Griffith et al.¹¹ compared oral bupropion with oral amphetamine to determine its abuse potential. The physiologic effects of oral bupropion were not significantly different than placebo for all subjective and objective measures testing stimulant effects. The authors concluded that the pharmacologic profile of oral bupropion was not similar to that produced by amphetamine. They also concluded that it is unlikely for oral bupropion to produce amphetamine-like abuse patterns. Despite limited information, the increasing illicit use of intranasal bupropion, gabapentin, quetiapine, trihexyphenidyl, and tricyclic antidepressants has been recognized in prison populations (Del Paggio¹² and Deborah Lomeli, Pharm.D.; Atascadero State Hospital, Atascadero, Calif.; personal communication, August 2005). Information disseminated on the Internet suggests that this practice may be growing among individuals experimenting with illicit drugs and other psychotropics.¹³

For intranasal bupropion to result in seizures, significantly elevated levels of bupropion in the body would be required. While no data are available to determine the rate and extent of nasal absorption of bupropion, it is known that various drugs are efficacious after intranasal administration, including cocaine, epinephrine, fentanyl, and meth-amphetamine. The absorption of these drugs is dependent on their physical and chemical properties. The nasopharynx has a large, highly vascularized surface area for drug absorption. Drug entry occurs through systemic absorption from nasal mucosa, direct entry into the brain, and/or neuronal transport along the olfactory bulb.¹⁴ Since bupropion is a small, lipophilic drug that is readily and extensively absorbed into the body,^15,16 it is likely that systemic absorption will occur after nasal insufflation. Since bupropion is structurally similar to methamphet-amine, the deposition of intranasal bupropion may be similar to that of intranasal methamphetamine. The route of administration can dramatically affect the amount of drug present in the body. One study found the intranasal bioavailability of meth-amphetamine to be 79% and the oral bioavailability to be 67%.^17,18 This 12% increase in bioavailability into the systemic circulation may explain why the onset of action is faster and peak effects are more pronounced with insufflation. The oral bioavailability of bupropion is approximately 5%,¹⁹ and consequently it is reasonable that an increase in bioavailability will occur after intranasal administration. Even a modest increase in bioavailability would result in a significant elevation of peak concentrations and a shortened time of onset than with oral administration.

The pharmacokinetics of bupropion have only been described after oral administration, but the alteration in bupropion disposition after nasal insufflation can be predicted based on the knowledge that bupropion is a high-extraction, hepatically eliminated drug. The venous equilibrium model describing hepatic clearance dictates that the clearance of bupropion is a perfusion rate-limited elimination, meaning that bupropion is cleared from the blood as quickly as it is delivered to the liver. Since the intrinsic clearance of bupropion is dependent on hepatic blood flow, assuming this is not changing significantly, a decrease in the effective extraction ratio after nasal insufflation would explain elevated drug levels. The extraction ratio is the percent decrease in the concentration of the drug as it is removed from the blood by the liver. After oral administration, the entire dose of bupropion would be directly delivered to the liver from the gastrointestinal tract with approximately 95% of the dose being metabolized, primarily by cytochrome P450 2B6, before being distributed throughout the rest of the body. With nasal insufflation, the bupropion dose would be delivered to the entire body before circulating through the liver, leaving a higher proportion of intact drug, resulting in an elevated peak plasma concentration (C_max) and increased area under the curve (AUC).

A single-dose pharmacokinetic study revealed that bupro-pion IR had a C_max of approximately 190 ng/mL, twice that of bupropion SR at 90 ng/mL, and that the AUC and half-life were similar for both formulations.² While the therapeutic range of bupropion has not been confirmed, pharmacokinetic studies suggest that the trough range may be between 10 to 100 ng/mL.^20–22 In a case series evaluating plasma bupropion levels in patients who developed seizures, the mean plasma level 6 hours postseizure was 170 ng/mL.²³ Although safety surveillance and toxicology studies suggest that elevated and rapidly increasing plasma bupropion levels increase the risk of seizure, plasma levels have not correlated well with either the therapeutic effect or the incidence of seizures.^21–23 After nasal insufflation, plasma bupropion levels may increase faster and be higher than those seen with oral administration of bupropion IR and could explain the production of seizures.

While there are several factors that support production of seizures by bupropion nasal insufflation, there are limitations within this case. The patient claimed to be prescribed and properly taking olanzapine concurrently, which could reduce the seizure threshold. The incidence of seizures with olanzapine is 0.9%. Moreover, the patient had a history of alcohol abuse, which could increase his risk of seizures. On physical examination, a slight tachycardia was present, which is a common sign in bupropion overdose or mild alcohol withdrawal. Another limitation is that a toxicology screen was not completed to rule out any illicit drug use. Also, the patient could not state the number of tablets insufflated. Finally, since serum bupropion levels have not correlated well with therapeutic effects or toxicity, a bupropion drug level was not obtained to help confirm bupropion intoxication.

Bupropion is FDA-approved for the treatment of depression and nicotine dependence. The incidence of seizure with orally administered bupropion has been described in safety surveillance and toxicology literature. However, there is a paucity of literature discussing the role of bupropion nasal insufflation in the production of seizures. This case describes a patient who developed seizures after the nasal insufflation of bupropion SR tablets.