Abstract
Introduction
The use of non-prescription slimming products has become increasingly popular. 1 Contrary to the general belief that these products are relatively harmless, consumption can be risky when adulteration of these products with undeclared substances including prescription drugs is not uncommon. 2 From 2004 to 2009, 81 non-prescription slimming products causing clinical poisoning in 66 patients were analysed in the laboratory of the authors. In 67 (82.7%) of these products, sibutramine or its structurally related unlicensed drug analogues (N-desmethylsibutramine and N-bisdesmethylsibutramine) were found. 3 Products containing sibutramine were originally prescription medicines in Hong Kong but were withdrawn from the market in November 2010. However, sibutramine can still be readily obtained from the Internet and may be marketed as a non-prescription slimming product.
Owing to the public’s misconception that sibutramine-containing non-prescription slimming products are relatively harmless, together with their easy accessibility, incidents involving their overdose are to be expected. Sibutramine is a centrally acting weight reduction agent that works as a selective serotonin and noradrenaline reuptake inhibitor in central neurons with subsequent activation of several receptors, including 5HT2A/2C. 4 Serotonin syndrome, a potentially life-threatening condition caused by excessive serotonin stimulation of the central nervous system, is a potential complication of sibutramine overdose. 5 A few case reports of serotonin syndrome associated with sibutramine have been published in the literature. 6,7 However, the serum concentration of sibutramine at the time of presentation in patients with serotonin syndrome following an overdose has not been reported before.
We report a case of serotonin syndrome after an intentional overdose of a non-prescription slimming product bought through the Internet. The product was later found to contain multiple medications including sibutramine. We also performed quantitative analysis of the patient’s serum collected at presentation to determine the toxic serum concentration in acute poisoning.
Case report
A 21-year-old woman was brought to the Accident and Emergency Department of Pamela Youde Nethersole Eastern Hospital, Hong Kong, China, for somnolence after an intentional overdose of a non-prescription slimming product purchased from the Internet. According to her suicide note, she had taken around 120 tablets. The exact time of ingestion was not known, but it was very likely within 6 hours according to her companion. Further history from her companion revealed that the patient had been taking that product intermittently for 4 years for weight reduction and she was successful in losing around 36 kg. Two different drug items (capsules in green–light green and in beige colour) were identified in the product but no labelling or information on the exact ingredients or recommended dosage were provided. The patient was not taking any other medication and she had been enjoying good health all along.
On arrival, she was comatose with a Glasgow Coma Scale (GCS) of 8 (E4M3V1). Her blood pressure was 148/102 mmHg, pulse rate 133 beats per minute (bpm), respiratory rate 16 per min and tympanic temperature 36.1°C. Both her pupils were 3 mm in diameter and reactive to light. Neurological examination showed generalised increase in tone with hyper-reflexia and spontaneous clonus more prominent in the lower limbs. Electrocardiogram showed sinus tachycardia (135 bpm) with a normal QRS interval (70 ms) and corrected QT interval (QTc) (424 ms). Blood tests including a complete blood picture, urea and electrolytes, liver function test, random glucose level and arterial blood gas were all unremarkable. The level of creatinine kinase was elevated to 329 IU/L (reference range 24–180 IU/L). Paracetamol, salicylate and ethanol were all undetectable in patient’s serum using enzymatic/colorimetric method (tests performed by the Abbott Architect c16000 System with Abbott reagents).
Although the causative agent was not certain at the time of presentation, the presence of spontaneous clonus raised the suspicion of serotonin syndrome. The patient was managed with supplemental oxygen and intravenous fluid. Her GCS improved to 12 (E4M6V2) soon after arrival. She was admitted to the intensive care unit (ICU) for close monitoring. A thyroid function test ordered after admission revealed slightly raised free T4 (19.4 pmol/L, reference range 9.5–18.1 pmol/L) and free T3 level (6.0 pmol/L, reference range 3.0–5.7 pmol/L) but a normal thyroid-stimulating hormone (TSH) level (2.74 mIU/L, reference range 0.35–3.8 mIU/L). Clinically, the patient had no palpable goitre and there was no evidence of Graves’ disease. The levels of both free T4 and free T3 returned to normal on the next day.
The patient’s blood and urine collected upon presentation, together with the slimming product were sent to the Hospital Authority Toxicology Reference Laboratory for analysis. Sibutramine, phenolphthalein and caffeine were identified by high-performance liquid chromatography coupled to a diode-array detector (Agilent 1100 series HPLC-DAD) in the green–light green capsule found in the package. In addition, 3,5-diiodo-L-thyronine (T2), 3,3′,5-triiodo-L-thyronine (T3), L-thyroxine (T4), 3,3′,5′-triiodo-L-thyronine (rT3), 3,5-diiodo-L-tyrosine (DIT) and 3-iodo-L-tyrosine (MIT) were detected by liquid chromatography-tandem mass spectrometry ([LC-MS/MS]; Applied Biosystems 4000 Q Trap [Foster City, CA, USA] ) in the same drug item, which confirmed the presence of animal thyroid tissue and explained the transient abnormalities of the patient’s thyroid function. No common drug, herb or thyroid hormone was found in the beige capsule using the aforementioned techniques. Quantitative analysis of the amount of sibutramine, caffeine and phenolphthalein in the slimming products was not performed because no more capsules were available.
Sibutramine and its metabolites and phenolphthalein were detected in the patient’s urine. No other common serotonergic medications or abusive drugs were detected in the urine general toxicology screen. The patient’s serum collected at presentation was analysed quantitatively for sibutramine. In brief, the serum sample (0.2 mL) was subjected to solid-phase extraction using Oasis HLB cartridges (60 mg, 3 mL). Imipramine was used as internal standard. The eluate was evaporated to dryness, reconstituted in mobile phase and analysed on Applied Biosystems 3200 Q Trap tandem mass spectrometer. Calibration was performed by spiking drug-free serum with 5–200 ng/mL of sibutramine. The serum concentration of sibutramine at presentation was found to be 112 ng/mL. Sibutramine was not quantitated in the patient’s urine. As to caffeine and phenolphthalein, they were not quantitated in either biological specimens because they were unlikely to be the cause of serotonin syndrome.
The patient developed a low grade fever with persistent sinus tachycardia after ICU admission. She was given a maintenance dose of intravenous fluid replacement (0.9% normal saline and 5% dextrose solution) with close haemodynamic and fluid status monitoring. She regained full consciousness 3 hours after admission and her clonus subsided 12 hours later. Both her body temperature and pulse rate returned to normal 16 hours after admission. She was transferred to the emergency medicine ward 25 hours after admission. During psychiatric assessment she admitted she had taken around 120 tablets of the slimming product as stated in her suicide note and denied co-ingestion. She remained stable and was discharged against medical advice 37 hours post-admission. Upon follow-up, 1 month and 1½ months later, she remained totally asymptomatic. Subsequent thyroid function tests were unremarkable.
Discussion
Serotonin syndrome is a predictable consequence of excessive serotonergic agonism of the central nervous system (CNS) and peripheral serotonergic receptors that results from therapeutic drug use, intentional self-poisoning or inadvertent interaction between serotonergic drugs. 5 Our patients presented with CNS depression, sinus tachycardia, generalised increase in tone, hyper-reflexia and spontaneous clonus more prominent in the lower limbs, together with a history of overdose of a sibutramine-containing slimming product. These clinical features and drug history justified our diagnosis of serotonin syndrome, based on both the Sternbach’s criteria 8 and the Hunter Serotonin Toxicity Criteria. 9 The authors believe that sibutramine was the major culprit in causing serotonin syndrome in our patient, based on the temporal relationship, plausible biological explanation, lack of alternative explanations and resolution of the condition after withdrawal of the offending agent.
So far reports of serotonin syndrome after sibutramine overdose have been rather limited. In a retrospective review of the California Poison Control System database over a 10-year period, where 94% of the cases had unintentional overdose (doses ranging from 2.5 to 75 mg), no serotonin syndrome was reported. 10 Riedl and Faure reported a case of serotonin syndrome in a 58-year-old man associated with comedication of fluoxetine and sibutramine in their therapeutic doses, in which the symptoms resolved after cessation of sibutramine and dose reduction of fluoxetine. 6 Bucaretchi et al. reported a case of serotonin syndrome following an accidental overdose of sibutramine in a 4-year-old child. The maximum estimated dose was 23 mg/kg and the case demonstrated that sibutramine overdose alone could result in serotonin syndrome. 7
The serum concentrations of sibutramine and its active metabolites, M1 (mono-desmethyl sibutramine) and M2 (di-desmethyl sibutramine), were quantified sequentially in the case reported by Bucaretchi et al., but the samples were collected from 25 to 147 hours postingestion. 7 The serum concentration of sibutramine at the time of presentation was not known. Moreover, to the knowledge of authors, the therapeutic serum concentrations of sibutramine have not been published previously. Despite this, the serum concentration of sibutramine in the present case (112 ng/mL) far exceeded the reported peak serum concentration (C max) of sibutramine after a single oral dose of 15 mg (the maximum daily recommended dose), which was 2.98 ± 1.63 ng/mL and 7.63 ± 3.71 ng/mL under fasting and fed condition, respectively. 11 The peak serum concentration was not known in our case, due to an uncertain time of ingestion and lack of sequential quantitative assay. Serum concentrations of the active metabolites M1 and M2 were also not known because the assay is not currently available in the authors’ centre.
Conclusion
This case illustrated the emerging health threat posed by the sale of non-prescription slimming products through the Internet. Although rarely reported, sibutramine overdose can result in serotonin syndrome, as in overdoses of other serotonergic agents. Early recognition, timely supportive treatment and laboratory support are essential to ensure a good clinical outcome.
Footnotes
Acknowledgements
The authors would like to express their gratitude to Dr Wai Man Ho for making the initial diagnosis.
The authors declared no conflicts of interest.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.