Hrev_master Abstract Bupropion intranasal misuse potential should be considered in the suspect of sympathomimetic syndrome for illicit drug or medi- cation intoxication. A 31-year-old man was admitted for intranasal misuse of 30 crushed tablets of bupropion with adrenergic mild pre- sentation. Lorazepam infusion was started with complete clinical resolution. Further forensic investigations detected a bupropion serum and urine concentration levels at 18 hours from intake of 1905.26 ng/mL and 2001.57 ng/mL, respectively. This case of intranasal bupropion misuse shared only some features with oral overdose, despite a plasma concentration five times higher than the lowest toxic level. Nasal bupropion snorting in chronic users could have lower toxicity compared to other snorted stimulants but symp- tomatic treatment remains the gold standard for preventing compli- cations. Bupropion misuse might rapidly become a concerning issue and monitoring by healthcare professionals is needed. Introduction Despite being an under-recognized phenomenon, prescription and Over The Counter (OTC) medication misuse (a practice known with the term “pharming”) is rapidly becoming an issue of world-wide concern.1 Bupropion is an atypical antidepressant with medical indica- tion for major or seasonal depressive disorder and smoking cessa- tion,2 in addition to off-label uses for Attention Deficit Hyperactivity Disorder (ADHD), obesity, binge-eating disorder and some Substance Use Disorder (SUD) (e.g. cocaine and methamphetamine).3 Bupropion acts by blocking dopamine, nore- pinephrine and to a lesser extent serotonin reuptake. It also acts as an antagonist on many nicotine receptors.4 Its chemical structure is similar to cathinone, a natural stimulant extracted from Catha edulis, and therefore it is comprised within the pharmacological class of substituted cathinones along with other synthetic com- pounds (e.g. amphetamines and ‘bath salts’).5 Bupropion has a nar- row therapeutic window, leading to severe cases of overdose with possible fatal complication such as seizures6 and heart failure.7 Despite the belief of bupropion having a lesser addictive potential compared to cocaine or amphetamines,5 issues about its non-medical use have been raised for years1 especially among young adults8 and inmates in correctional facilities.9 Its recreation- al snorting misuse has been reported since 2002,10 whereas over- dose ingestion is more associated with suicidal attempts.11 Intravenous (IV) bupropion abuse has also been reported12 some- times leading to serious complications.13 We hereby present a case of nasal sniffing of a huge amount of bupropion crushed tablets, requiring benzodiazepine (BZD) infu- sion without the development of any major complication. Case Report In April 2021, a 31-year-old man was referred to the Emergency Department 2 hours after sniffing 30 crushed bupropi- on tablets “for playful purpose”. His medical history was positive for ADHD treated with psy- Emergency Care Journal 2021; volume 17:10037 Correspondence: Simone Sartori, Medical Toxicology Unit and Poison Control Centre, Viale San Luca Vecchio, Careggi University Hospital, Florence, Italy. Tel.: +39.055.7946244 E-mail: simone.sartori@unifi.it Key words: Bupropion; abuse; sniffing; intoxication; case report. Contribution: All Authors equally contributed in the development of this paper. SS, VB, LP, ES and MGDM collected data. SS and FG initiated the idea. SS performed a literature search and wrote the paper. VB helped with writing the paper. CL, FG and MG reviewed the manu- script. MG acts as the guarantor of the paper. Conflict of interest: The authors declare no conflict of interests. Availability of data and materials: All data underlying the findings are fully available from the corresponding author upon reasonable request. Ethics approval and consent to participate: No ethical committee approval was required for this case report by the Department, because this article does not contain any clinical studies with human participants or animals. Consent for publication: Not applicable. The evaluation of the case was performed using anonymized patient data, therefore without the need for patient consent. Received for publication: 13 August 2021. Revision received: 4 December 2021. Accepted for publication: 6 December 2021. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2021 Licensee PAGEPress, Italy Emergency Care Journal 2021; 17:10037 doi:10.4081/ecj.2021.10037 [Emergency Care Journal 2021; 17:10037] [page 45] Acute intoxication following massive bupropion sniffing: A case report Simone Sartori,1 Valentina Brilli,1 Cecilia Lanzi,2 Luca Pratticò,3 Elisabetta Sarcoli,3 Maria Grazia Di Milia,4 Francesco Gambassi,2 Guido Mannaioni1,2 1Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Florence, Florence; 2Medical Toxicology Unit and Poison Control Centre, Careggi University Hospital, Florence; 3Emergency Department, Azienda USL Toscana sud est, Grosseto; 4Forensic Toxicology Unit, Medical Toxicology Unit and Poison Control Centre, Careggi University Hospital, Florence, Italy Non -co mmerc ial us e o nly chotherapy and bupropion (unknown formulation dosage) besides a previously diagnosed cocaine use disorder. Mental confusion, hypertension, deep tendon hyperreflexia and dry mouth were present at medical examination while electro- cardiogram (ECG) at arrival showed sinus tachycardia with a 484 msec corrected QT interval (QTc) prolongation (Figure 1). No QRS complex alteration was present. The above-mentioned find- ings were compatible with the suspected intoxication. A toxicology consultation was requested and Poison Control Centre (PCC) suggested cardiac monitoring in addition to IV rehy- dration. Given the risk of hyper-activation status, possible seizures and serotonin syndrome due to the hypothetical high amount of absorbed bupropion, lorazepam (4 mg IV) was administered. Subsequent electroencephalogram (EEG) and CT-scan ruled out any evidence of neurologic impairment (epileptic patterns, parenchymal lesions and blood extravasation) due to acute bupro- pion intoxication. A toxicological urine screening was performed with resulting positivity only for BZD, whereas only mild leuko- cytosis was detected at blood test (15.23 x103/uL with normal range 3.5-9.5). Clinical signs and symptoms of intoxication normalized after 27 hours of observation without any complication. The patient decided to self-discharge after a psychiatric consultation, being therefore referred to his psychotherapist. To certify the reported intake of bupropion, blood and urine samples were taken 18 hours after the event in order to perform a second-level investigation with gas chromatography-mass spectrometry (GC-MS). Bupropion serum and urine concentration levels were 1905.26 and 2001.57 ng/mL, respectively (Figure 2). Urine toxicological screening and clinical monitoring of vital signs throughout hospitalization are summarized in Table 1. Discussion This case of intranasal bupropion misuse shared only some of the most common clinical features of a classical bupropion inges- tion overdose (considering comparable amounts of medication).14 Therapeutic daily doses for bupropion are usually up to 300 mg/day15 reaching peak concentration after 1.5 hours and 3-5 hours for immediate or modified-release formulations, respectively.16 Half-life is about 21 hours in chronic users and it can be even longer for the presence of active metabolites.14 Therapeutic win- dow is considered between 5 to 100 ng/mL.17 Although our patient’s bupropion dose formulation was unknown, only 150 mg and 300 mg modified/sustained formulations are available on the Case Report Figure 1. Sinus tachycardia with 125 beats per minute heart rate and nonspecific alterations of ventricular repolarization.QTc prolongation (484 msec). Figure 2. Bupropion serum and urine concentration levels at 18- hours from the event. Table 1. Patients vitals and laboratory screening during hospitalization. Vitals Day 1 12:42 pm Day 1 01:41 pm Day 1 02:24 pm Day 1 02:26 pm Day 1 09:46 pmDay 2 10:06 am Day 2 14:41 pm HR (bpm) 140 88 120 95 90 85 RR 20 16 16 BP (sys mmHg) 158 130 133 133 122 120 130 BP (dia mmHg) 116 60 72 72 82 70 79 BT (C°) 36 36 36.9 36 36 36.7 Pain (VAS) 1 0 GCS 15 15 15 15 15 SpO2 (% AA) 97 97 99 98 98 96 Semi-quantitative Day 2 09:54 am Amphetamine Benzodiazepines+ Cannabinoids Cocaine Methadone Opioids screening (urine) [page 46] [Emergency Care Journal 2021; 17:10037] Non -co mmerc ial us e o nly Italian market, making the possible total intranasal intake ranging from 4,5 g to 9 g. Second-level forensic investigation assessed an 18-hour blood bupropion level of 1905,26 ng/ml, estimating this way an approximate 6 g intake consistent with the number of tablets stated by our patient (anecdotal computation given the dif- ferent oral versus nasal route of administration). Considering that decontamination would not be effective after intranasal misuse, this case suggests that this administration route might have less or slower absorption compared to an almost 100% absorption by enteral route4, differently from what happens with other typical snorted stimulants (e.g. cocaine) that have faster intranasal intoxication in contrast to its ingestion.18 Furthermore, neurologic complications are usually more likely above 450 mg dosing.6 This case may imply that chronic abusers may not be as sensitive to average toxic levels as naïve or therapeutic use patients, as was also reported on a case of 2.1 g snorting without seizures occurrence.19 Another interesting aspect that could be con- sidered is the different amount of active metabolites after nasal overdose compared to ingestion, due to lesser intestinal/hepatic metabolism.20 This could possibly explain a milder clinical presen- tation despite high dosages. In spite of the known bupropion cross reactivity for amphetamines,21 only iatrogenic BZD were found in the patient’s initial urine screening, requiring further investigations as to con- firm the reported source of intoxication. High levels of the original compound were indeed assessed even after 18 hours from misuse. This stresses the idea that expectancy for urinary cross reactivity at standard screenings can underestimate the real incidence of bupro- pion abusers and it should be taken with a grain of salt. As previously reported by other authors,22 leukocytosis can be found in case of oral bupropion overdose. Our case, despite the dif- ferent route of exposition, was consistent with this aspect. Eventually, in this case report we would like to underline the chance that bupropion nasal exposure toxicokinetic may differ from classical enteral intoxication. Still, symptomatic treatment of mild presentations with BZD remains the gold standard for pre- venting complications such as seizures and life-threatening arrhythmias. Because of its “cathinone-like” properties, bupropion results among the most frequent antidepressants prone to pharming and this highlights the need for a more vigilant monitoring by health- care professionals both in prescribing and selling medications, especially as long as specific categories are involved (e.g. unfamil- iar patients or past SUD patients) and urine screenings may not always detect the misused substance. Prompt PCC consultation enables health providers to effectively manage intoxications deriv- ing from unordinary administration routes for medication misuse. References 1. Chiappini S, Schifano F. What about “Pharming”? Issues regarding the misuse of prescription and over-the-counter drugs. Brain Sci 2020;10:736. 2. Huecker MR, Smiley A, Saadabadi A. Bupropion. StatPearls 2021. 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