Nopaine no gain: Recreational ethylphenidate toxicity

To the Editor:

Availability of novel psychoactive substances (NPS), or ‘legal highs’, has increased markedly over recent years, with an average of 1–2 new NPSs reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) every week in 2013/2014.¹

Ethylphenidate (ethyl 2-phenyl-2-(piperidin-2-yl)acetate) is a psychostimulant NPS that inhibits reuptake of both dopamine and noradrenaline.² It is an analogue of methylphenidate that was first reported to the EMCDDA in 2011 from the UK.³ It is often sold under the street name ‘Nopaine’. We present a series of three cases of acute ethylphenidate toxicity, including one with analytical confirmation.

The first case was a previously well 21-year-old male brought to the Emergency Department (ED) by ambulance with anxiety, paranoia, agitation and visual disturbances. He also described left-sided, retrosternal chest pain lasting for ‘seconds’ associated with palpitations and ‘tingling’ in both hands. He reported using 500 mg of ethylphenidate in incremental doses over several hours on the evening of presentation, predominantly by nasal insufflation but also by smoking, and had also consumed seven cans of beer; he had purchased the ethylphenidate from a UK-based internet supplier. His symptoms developed 3 h after using ethylphenidate, for which he had self-medicated with 3 mg of etizolam, purchased from the same internet supplier. On arrival to the ED 17 h after the first ethylphenidate use, he was restless with tachycardia (heart rate: 114 bpm), hypertension (blood pressure: 184/98 mmHg) and dilated (4 mm) pupils; there was no hypertonia or clonus and he was afebrile (37.1°C). Electrocardiogram demonstrated sinus tachycardia with normal corrected QT interval. Venous blood gas, full blood count and renal profile were normal; creatine kinase was 290 I U/L (normal range: 0–229 IU/L). He was treated with 15 mg of oral diazepam in divided doses and admitted for observation; his symptoms resolved and he was discharged 10 h after presentation to the ED.

Paired serum and urine samples were collected with informed consent 20 h after ethylphenidate and etizolam use. Analysis by high-resolution liquid chromatography–mass spectrometry (LC–MS) identified ethylphenidate (0.24 microg/mL in blood and 0.98 microg/mL in urine). Methylphenidate and ritalinic acid were not detected in blood; low concentrations of methylphenidate (0.059 microg/mL) and ritalinic acid (0.098 microg/mL) were detected in urine, consistent with in vivo de-ethylation of ethylphenidate to methylphenidate and its subsequent metabolism to ritalinic acid. Diazepam and etizolam were the only other substances detected, in trace amounts.

The second case was a 37-year-old female brought to the ED by ambulance following intravenous injection of 1 g of ethylphenidate. She was feeling drowsy, had palpitations and felt feverish. Assessment in the ED demonstrated tachycardia (heart rate: 143 bpm), hypertension (blood pressure: 186/96 mmHg) and fever (38.4°C). ECG was normal apart from sinus tachycardia. Lactate was 2.7 mmol/L without acidaemia, and full blood count, renal and liver profiles were normal apart from a blood urea nitrogen concentration of 7.9 (normal range: 3.3–6.7) mmol/L [22.1 (normal range: 9.2–18.8) mg/dL]. She received a single dose of 5 mg of oral diazepam. Four hours after admission, her heart rate, blood pressure and temperature had returned to normal and she was asymptomatic and discharged.

The third case was a 23-year-old male who presented himself to the ED with palpitations and anxiety, after using 2 g of ethylphenidate over 3 days by nasal insufflation. On examination, his heart rate was 80 bpm, blood pressure was 148/100 mmHg and temperature was 36.8°C. He had a mild bilateral intention tremor, but neurological examination was otherwise unremarkable. ECG, full blood count and renal profile were normal, but creatine kinase level was elevated at 579 IU/L. He received 11 mg of diazepam in three divided doses and was discharged after resolution of his symptoms – 3 h after presentation.

No published reports of confirmed acute recreational ethylphenidate toxicity exist in the medical literature to date. These cases suggest that ethylphenidate is associated with stimulant-like features similar to other amphetamine-type stimulants. Recreational ethylphenidate use has been described on internet drug forums since 2010,⁴ causing a range of unwanted effects, including chest pain, palpitations, agitation, nasal pain and irritation, bruxism, and abdominal and testicular pain. Structurally similar to methylphenidate, which has been used as both a recreational drug and a study aid, ethylphenidate has far greater dopaminergic selectivity compared with methylphenidate, which may increase its dependence potential.

Although ethylphenidate is controlled in Austria, Germany and Sweden, it remains uncontrolled in the UK and elsewhere. These cases demonstrate that the use of ethylphenidate can be associated with acute stimulant drug toxicity, and alongside the user reports on internet drug forums of adverse effects coupled with its detection in two deaths,⁵ these cases demonstrate the potential for ethylphenidate to cause significant harm. Consideration should therefore be made to more widespread control of this NPS to reduce potential harm related to its use.

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.