Dextrorphan

To the Editor:

We noted with interest the article in CHEST by Einarson et al (February 2001)[1] focusing on the teratogenicity of dextromethorphan. The merit of the authors is to point out a low or absent teratogenic potential of dextromethorphan. However, apart from the investigation of its teratogenic effects, the substance might have other serious side effects that have to be considered.

The nitrogen-bound-methyl-dextro-aspartate (NMDA) receptor plays an important role in the developing mammalian brain with respect to the establishment of synaptic connections and learning processes. Antagonists of the NMDA receptor potentially disrupt these processes; this has been clearly shown[2] in animal models but not yet in man.

Further observations[3] refer to the fact that NMDA-receptor blocking agents enhance apoptotic neurodegeneration in the developing brain. This was shown[4] for different NMDA-receptor antagonists including alcohol.

From the standpoint of pediatric neurology, we are in fact very interested in the field of NMDA blockade with regard to the treatment of severe epilepsy or to neuroprotection. The underlying pathophysiology comprises overstimulation of the NMDA receptor by excitatory amino acids like glycine or glutamate. In certain epileptic disorders, dextromethorphan medication is established as an anticonvulsant.[5] In nonketotic hyperglycinemia, for instance, an inborn metabolic dysfunction, in molybdenum cofactor deficiency, and in early infantile epileptic encephalopathy (Ohtahara syndrome), it can be helpful.[6-8] Furthermore, dextromethorphan was used for neuroprotection in children undergoing cardiac surgery[9] or suffering from bacterial meningitis.[10] The above findings[2-4] led, however, to the withdrawal of further clinical studies.

Theoretically, all mechanisms involved in antagonizing the NMDA receptor might threaten the developing brain of fetuses as well, similar to the neuronal damage of fetuses exposed to alcohol. To our knowledge, no neurodevelopmental data exist on offspring of mothers who received dextromethorphan during their pregnancies. We therefore feel that dextromethorphan should be administered with the utmost caution during pregnancy for safety reasons. Further studies are needed to clarify this issue.

Correspondence to: Otfried Debus, MD, University Children's Hospital Muenster, Department of Pediatrics, Albert-Schweitzer-Str. 33, D-48129 Muenster, Germany; e-mail: debuso@unimuenster. de

REFERENCES

[1] Einarson A, Lyszkiewicz D, Koren G. The safety of dextromethorphan in pregnancy: results of a controlled study. Chest 2001; 119:466-469

[2] Lipton SA, Kater SB. Neurotransmitter regulation of neuronal outgrowth, plasticity and survival. Trends Neurosci 1989; 12:265-270

[3] Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999; 283:70-74

[4] Ikonomidou C, Bittigau P, Ishimaru M, et al. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000; 287:1056-1060

[5] Rogawski MA. The NMDA receptor, NMDA antagonists and epilepsy therapy: a status report. Drugs 1992; 44:279-292

[6] Schmitt B, Steinmann B, Gitzelmann R, et al. Nonketotic hyperglycinemia: clinical and electrophysiologic effects of dextromethorphan, an antagonist of the NMDA receptor. Neurology 1993; 43:421-424

[7] Kurlemann G, Debus O, Schuierer G. Dextrometorphan in molybdenum cofactor deficiency. Eur J Pediatr 1996; 155: 422-423

[8] Debus O, Schellscheidt, Strater R, et al. Erfolgreicher Einsatz von Dextrometorphan beim Ohtahara-Syndrom [abstract]. Monatsschrift Kinderheilkd 1999; 147:898A

[9] Schmitt B, Bauersfeld U, Fanconi S, et al. The effect of the N-methyl-D-aspartate receptor antagonist dextromethorphan on perioperative brain injury in children undergoing cardiac surgery with cardiopulmonary bypass: results of a pilot study. Neuropediatrics 1997; 28:191-197

[10] Schmitt B, Wohlrab G, Steinlin M, et al. Treatment with the N-methyl-D-aspartate receptor antagonist dextromethorphan in severe bacterial meningitis: preliminary results. Eur J Pediatr 1998; 157:863-868

To the Editor:

We wish to thank Dr. Debus and colleagues for their letter asking us to consider the role of dextromethorphan as an N-methyl-D-aspartate (NMDA)-receptor antagonist in the developing fetal brain. We agree that the NMDA receptor plays an important role in the developing mammalian brain, and that NMDA-receptor antagonists can potentially disrupt these processes. However, these adverse effects on the brain are probably dose related.

Over-the-counter antitussives generally contain either 15 mg or 30 mg of dextromethorphan per dose, and in any 24-h period, the dose is not to exceed 60 mg. As pointed out, several studies have established dextromethorphan as an anticonvulsant due to its ability to block NMDA receptors. However, these anticonvulsant effects are only achieved if high doses are administered, generally 160 to 200 mg/d in both adults and children.[1-4] Although these doses were shown to exhibit anticonvulsant properties, one of the potential problems of using dextromethorphan as an anticonvulsive agent is the occurrence of adverse neurobehavioral effects that have been attributed to extensive NMDA-receptor blockade in the brain.[5] Dextromethorphan is a weak blocker of NMDA receptors. In animal models[6] showing apoptotic neurodegeneration, much more potent NMDA-receptor antagonists were used, such as dizocilpine ([+] MK-801). Such potent agents cause behaviors and discriminative stimulus effects that are nearly indistinguishable from those produced by the psychotomimetic phencyclidine and ketamine. In humans, clinical trials with MK-801 were withdrawn due to the high incidence of adverse effects such as somnolence, ataxia, and mood changes.[5]

In our study, patients were never exposed to [is greater than] 60 mg/d of dextromethorphan. Furthermore, when administered orally, dextromethorphan has low bioavailability due to its extensive first-pass elimination by the cytochrome P450 2D6 enzyme, further reducing dextromethorphan plasma concentrations,[7] Generally, patients who ingest dextromethorphan as a cough suppressant do not experience adverse effects due to the low dose used; therefore, such low doses are not sufficient to significantly block NMDA receptors.

Regarding the fetus, fetal expression of NMDA receptors peaks during weeks 20 to 22 of gestation, a period that marks the beginning of the brain growth spurt.[6,8] As the outcome of this study was not postnatal neurodevelopment, merely the occurrence of birth defects, assessing long-term neurodevelopment would be important in children exposed in the second and third trimester, particularly among women who are taking more than the recommended dosage of cough suppressants, or are using cough syrups recreationally (not for the prescribed indication).

While we agree that more studies are needed, it is important not to extrapolate animal data or studies with doses that are several orders of magnitude higher than the standard human dose to the human experience. The predictive value of in vivo fetal animal data is poor at best.

Correspondence to: Adrienne Einarson, RN, Hospital For Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8; e-mail: einarson@sickkids.on.ca

REFERENCES

[1] Kimiskidis VK, Mirtsou-Fidani V, Papaioannidou PG, et al. A phase I clinical trial of dextromethorphan in intractable partial epilepsy. Methods Find Exp Clin Pharmacol 1999; 10:673-678

[2] Kazis A, Kimiskidis V, Niopas I. Pharmacokinetics of dextromethorphan and dextrorphan in epileptic patients. Acta Neurol Scand 1996; 93:94-98

[3] Hamosh A, Maher JF, Bellus GA, et al. Long-term use of high-dose benzoate and dextromethorphan for the treatment of nonketotic hyperglycinemia. J Pediatr 1998; 132:709-713

[4] Schmitt B, Netzer R, Fanconi S, et al. Drug refractory epilepsy in brain damage: effect of dextromethorphan on EEG in four patients. J Neurol Neurosurg Psychiatr 1994; 57:333-339

[5] Rogawski MA, Porter RJ. Antiepileptic drugs: pharmaoclogical mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 1990; 42:223-285

[6] Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain, Science 1999; 283:70-73

[7] Zhang Y, Britto MR, Valderhaug KL, et al. Dextromethorphan: enhancing its systemic availability by way of low-dose quinidine-mediated inhibition of cytochrome P4502D6. Clin Pharmacol Ther 1992; 51:647-655

[8] Lee H, Choi BH. Density and distribution of excitatory amino acid receptors in the developing human fetal brain: a quantitative autoradiographic study. Exp Neurol 1992; 118:284-290

COPYRIGHT 2001 American College of Chest Physicians
COPYRIGHT 2001 Gale Group