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'Ecstasy' and MH
- Andrew P Hall, John A. Henry (27 November 2006)
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'Ecstasy' (MDMA) and malignant hyperthermia
- Mark U. Gerbershagen, Frank Wappler (15 November 2006)
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Andrew P Hall , John A. Henry
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Response from Hall & Henry to letter (from Mark U. Gerbershagen & Frank Wappler) commenting on: Hall A P, Henry J A. Acute toxic effects of ‘Ecstasy’ (MDMA) and related compounds: overview of pathophysiology and clinical management. BJA 2006; 96: 678-85. ‘Ecstasy’ & MH Editor- We thank Gerbershagen & Wappler for their interest in our paper.1 It is agreed that a possible link between 'Ecstasy' (3,4- methylenedioxymethamphetamine, MDMA) and malignant hyperthermia (MH) is worthy of attention. This issue was discussed in our manuscript; however, article size constraints limited its coverage. There is clearly an overlap in clinical features of MDMA- induced hyperthermia, severe heat stroke, neuroleptic malignant syndrome, serotonergic syndrome and MH that cannot be ignored. However, it may be that these pathological entities simply share a final common pathway associated with the consequences of extreme hyperthermia. With regards to the question of whether MDMA is a MH trigger, the work of Denborough and Hopkinson was discussed 2. They looked for a direct effect of MDMA on muscle biopsy specimens that had been taken for investigation of possible MH and found some augmentation of the halothane- and caffeine-induced contraction in vitro. The data was far from conclusive. Furthermore, this work has been criticized for using concentrations of MDMA up to 2000 times greater than that found in the plasma of Ecstasy-related fatalities.3 As far as we are aware, there have been no reports in the literature regarding MDMA-precipitated hyperthermic reactions in known MH-sensitive individuals. Though MH is in itself rare, the extremely widespread use of MDMA might be expected to have included some such subjects. Additionally, there have been no reports of any clear familial sensitivity to the drug, unlike susceptibility to MH where a strong family history is often evident. The common unifying feature of the sporadic MDMA-related fatal hyperthermic reactions has been noted to relate more to the circumstances of drug use than to any genetic or metabolic characteristic of the individual concerned.4 We would agree with Gerbershagen & Wappler that there is still much work to be done in establishing the possible susceptibility to MDMA- induced hyperthermia in MH-sensitive individuals. A.P. Hall & J.A. Henry E-mail: andrew.p.hall@uhl-tr.nhs.uk 1. Hall A P, Henry J A. Acute toxic effects of ‘Ecstasy’ (MDMA) and related compounds: overview of pathophysiology and clinical management. Br J Anaesth 2006; 96: 678-85 2. Denborough MA, Hopkinson KC. Dantrolene and ‘Ecstasy’. Med J Aust 1997; 166: 165-6 3. Hall AP. Dantrolene and ‘Ecstasy’. Med J Aust 1997; 167: 506 4. Henry JA. Ecstasy and the dance of death. Br Med J 1992; 305: 5-6 Conflict of Interest:None declared |
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Mark U. Gerbershagen Department of Anaesthesiology, Hospital Cologne-Merheim, University Witten-Herdecke, Germany, Frank Wappler
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Mark U. Gerbershagen, Frank Wappler mark.gerbershagen@uni-wh.de We read with great interest the review by Hall and Henry2 published in the 6/2006 issue of the British Journal of Anaesthesia, yet in our opinion a closer look on 'ecstasy' (3,4-methylenedioxymethamphetamine, MDMA) and malignant hyperthermia (MH) would have been welcome. Indeed overlaps in the pathophysiology of MDMA-induced hyperthermia and MH as well as severe heat stroke, neuroleptic malignant syndrome and serotonergic syndrome are tempting to speculate. Yet the some main questions concering MH were not adressed: 1) Is MDMA a MH trigger? 2) Is the MDMA-abuse in MH susceptible patients associated with higher morbidity compared to MH negative patients? Currently, there seems to be little common sense in the definition of a MH trigger. On the one hand there is a narrow definition which entitles a substance as MH trigger when it is able to release Ca2+ from the sarcoplasmic reticulum via activation of the ryanodine 1 receptor or the dihydropyridine receptor4,6. On the other hand a MH trigger is defined as a substance that is capable of inducing a MH crisis in a genetically determined individual in a clinically relevant dosage without any relevant co-factors1. Our study group was able to demonstrate that cumulative doses (0.5 – 12 mg/kg) of MDMA induced a hypermetabolic state in MH susceptible as well as in MH negative swine. However, after administration of 12 mg/kg MDMA the metabolic alterations were more severe in MHS compared to MHN swine, and all MHS swine fulfilled the predefined criteria of MH. Klingler et al. did not find an effect of MDMA on isolated sarcoplasmic reticulum vesicles4. However, by monitoring Ca2+ transients in myotubes and patch clamp measurements in human embryonic kidney cells they found an activation of the nicotinic acetylcholine receptor by MDMA. The authors concluded that the neuromuscular junction is a target of MDMA. This is comparable to the site of action of succinylcholine, one of the classic MH triggers. However, yet there is no case reported of a MH crisis after succinylcholine injection by itself without the following administration of a volatile anaesthetic3, which would by definition exclude succinylcholine as a MH trigger. Summarizing, the MH trigger potency of MDMA is not yet clarified. Nonetheless, in our opinion the indication to especially advise MHS- patients against the abuse of MDMA remains. Albeit, MDMA might just present as a MH triggering co-factor at the receptor interaction on the skeletal muscle level, the actual risk in combination with central serotoninergic, dopaminergic, cholinergic, histaminergic and adrenergic effects5 is not yet clarified. Furthermore, MDMA-abusers are usually exposed to further MH co-factors such as caffeine (supplementation of ecstasy pills with caffeine, caffeine containing 'energy drinks'), external heat (exposure to heat at 'raves') and impaired thermoregulation (excessive exertion and inadequate fluid replacement)2,4. At least, additive effects should receive consideration. Considering the above mentioned issues, it is obvious that the pharmacological properties of MDMA have to be defined more precisely, especially in patients susceptible to malignant hyperthermia. References 1. Fiege M, Wappler F, Weisshorn R et al. Induction of malignant hyperthermia in susceptible swine by 3,4-methylenedioxymethamphetamine („ecstasy“). Anesthesiology 2003; 99: 1132-6 2. Hall A P, Henry J A. Acute toxic effects of ‚Ecstasy’ (MDMA) and related compounds: overview of pathophysiology and clinical management. Br J Anaesth 2006; 6: 678-85 3. Klingler W, Lehmann-Horn F, Jurkat-Rott K. Complications of anaesthesia in neuromuscular disorders. Neuromuscul Disord 2005; 15: 195-206 4. Klingler W, Heffron J J A, Jurkat-Rott K, et al. 3,4- Methylenedioxymethamphetamine (Ecstasy) activates skeletal muscle nicotinic acetylcholine receptors. JPET 2005; 314: 1267-73 5. Mechan A O, Esteban B, O`Shea E, Elliot J M, Colado M I, Green M R. The pharmacology of the acute hyperthermic response that follows administration of 3,4-methylenedioxymethamphetamine (MDMA, ‚ecstasy’) to rats. Br J Pharmacol 2002; 135: 170-80 6. Rusyniak D E, Banks M L, Mills E M, Sprague J E. Dantrolene use in 3,4- methylenedioxymethamphetamine („Ecstasy“)-mediated hyperthermia. Anesthesiology 2004; 101: 263 Conflict of Interest:None declared |
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