We read with great interest the study by Fiege et al.  1published in the November 2003 issue of Anesthesiology. Although we applaud the authors’ attempt to shed some light on the controversial use of dantrolene in 3,4-methylenedioxymethamphetamine (MDMA)–mediated hyperthermia, several flaws in the design and interpretation of their results cast doubts on their conclusions.

Our strongest criticism of this study is in the authors’ use of a combination therapy (dantrolene, sodium bicarbonate, and hyperventilation) to determine the role of dantrolene in MDMA-mediated hyperthermia. The positive results attributed to dantrolene in figure 2 of this study, a reduction in partial pressure of carbon dioxide and an increase in pH, can be explained by the use of sodium bicarbonate and hyperventilation alone without any contribution from dantrolene. More notably, we believe that the failure to show a reduction in core body temperature (their fig. 2C) with their treatment supports the idea that dantrolene has no role in MDMA-mediated hyperthermia. Because malignant hyperthermia–normal swine were similarly affected (although slightly less so), we are curious why the authors did not study their treatment regimen in these animals. Because malignant hyperthermia–normal animals were not genetically susceptible, dantrolene would not have been expected to be beneficial and could have differentiated the effects of dantrolene from the other treatments given.

Also, questions arise with the authors’ sole reliance on clinical criteria in their definition of malignant hyperthermia. Based on their criteria for malignant hyperthermia, any agent that uncouples oxidative phosphorylation, irrespective of its effects on calcium dihydropyridine and ryanodine receptors (RyR), would meet the criteria for mediating malignant hyperthermia. Although we agree that the study by Fiege et al.  1suggests an exaggerated hyperthermic response to MDMA in malignant hyperthermia–susceptible swine, the significant alterations in the partial pressure of carbon dioxide, pH, and temperature seen in the malignant hyperthermia–normal swine suggests that the effect is largely not mediated through RyR complexes.

Finally, in the design of their study, Fiege et al. ,1chose to use sequential dosing of 0.5 mg/kg MDMA every 20 min until a cumulative dose of 12 mg/kg was achieved. MDMA-induced hyperthermia is well established in both humans2and rodents3and has been shown to occur after a single dose or intermittent “binge” doses in numerous animal species,4which typically patterns human consumption. Therefore, we question the validity of extrapolating results from the authors’ swine model to that of human ingestions.

Because MDMA-mediated hyperthermia largely resembles malignant hyperthermia, a pharmacogenetic syndrome triggered by anesthetic agents that manifests itself in skeletal muscle of individuals bearing missense mutations in the gene coding for the RyR,5it has become tempting to speculate and even assume that the molecular underpinnings of anesthesia- and MDMA-induced hyperthermic syndromes are the same.6Although largely unscientific, this assumption has translated into clinical medicine, where patients admitted to the emergency room with MDMA-induced hyperthermia are often given dantrolene, an RyR antagonist, along with other cooling and supportive therapies. Whereas dantrolene is effective in reducing anesthesia-induced hyperthermia,7it seems to be only marginally if at all effective in reducing MDMA-generated hyperthermia.8–10Similar to what Fiege et al.  1observed in swine, we observed that dantrolene pretreatment does not prevent or significantly reduce MDMA-induced hyperthermia in rats (fig. 1). The inability of dantrolene to block MDMA-induced hyperthermia suggests that this is not a true “malignant” hyperthermia and that other mechanisms are evoked after MDMA exposure.

Fig. 1. Effects of dantrolene (2.5 mg/kg, intraperitoneal) 30 min before 3,4-methylenedioxymethamphetamine (MDMA; 40 mg/kg, subcutaneous) on rat rectal temperatures. Data are presented as mean ± SEM (n = 6). * Significantly different from saline and dantrolene-only groups (  P < 0.001). 

Fig. 1. Effects of dantrolene (2.5 mg/kg, intraperitoneal) 30 min before 3,4-methylenedioxymethamphetamine (MDMA; 40 mg/kg, subcutaneous) on rat rectal temperatures. Data are presented as mean ± SEM (n = 6). * Significantly different from saline and dantrolene-only groups (  P < 0.001). 

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Controlled trials have not been performed to determine whether the few purported clinical successes using dantrolene to control MDMA-induced hyperthermia are due to dantrolene alone versus  all other supportive, first-line cooling therapies. The inability of dantrolene to block the thermogenic effects of MDMA in both our study and that of Fiege et al.  1suggests that RyR-mediated calcium cycling is not the mediator of the thermogenic effects of MDMA. The authors’ recommendation to use dantrolene in all cases of MDMA-induced hyperthermia is not supported by their data or other current scientific literature and may result in overreliance on a drug that may not benefit critically ill patients with MDMA-induced hyperthermia.

* Ohio Northern University, Ada, Ohio. j-sprague@onu.edu

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