Article, Neurology

Is there sufficient evidence to suggest cyclobenzaprine might be implicated in causing serotonin toxicity?

Correspondence

Is there sufficient evidence to suggest cyclobenzaprine might be implicated in causing serotonin toxicity?

To the Editor,

Day and Jeanmonod [1] overinterpret a single case report that contains low reliability evidence and suggest that a patient exhibited serotonin toxicity (ST), and that this justifies a caution about cyclobenzaprine. They perpetuate misunderstandings about ST by misinterpreting some of the material they cite, and some additions to their literature review are required.

The current best evidence indicates that their case is not “typical for the Serotonin syndrome” because ST is characterized by excitation, not drowsiness, and by hyperre- flexia and clonus [2-6]. Those key symptoms are usually severe and generalized well before “rigidity” ever develops, and that occurs almost exclusively in severe cases of mixed monoamine oxidase inhibitor (MAOI)/Selective serotonin reuptake inhibitor (SSRI) ingestions and, rarely, if at all, with SSRI overdoses. The above references illustrate that the usual picture is somewhat different and that ST is a specific and well-delineated toxidrome. The word protean, repeated from Boyer et al is, perhaps, not a good description, to that these authors add “and nonspecific”. I suspect Boyer meant to convey the notion that some prominent signs, like confusion, hyperthermia, diaphoresis, mydriasis, and the like, are nonspecific and occur in other conditions and intoxications, as opposed to the highly characteristic, indeed pathognomonic, ones (in context) of clonus and hyperre- flexia. Serotonin toxicity is not “rare” (a point made specifically by Boyer): SSRIs induce ST in about 15% of overdoses; hundreds of cases are documented in the Hunter Area toxicology service series of articles on this subject [3,7]). These above publications add usefully to the topic and illustrate the problems of achieving adequate citations in case reports with brief reviews that limit their value [8]. They appear unclear about “horizontal nystagmus,” later referring to ocular clonus (in which the speed of oscillation is the same both ways, unlike true nystagmus). What drugs were actually ingested is not supported by clear evidence, or blood levels, and no pill counts, and the like, are mentioned. It would be helpful to know the site and method of the single temperature reading provided and the values of the other measurements taken, because these can be surprisingly inaccurate [9].

A reinterpretation of some other references they cite is

required. Their table of serotonergic drugs, which is not referenced or attributed, is introduced with the very inaccurate comment “any combination could precipitate the syndrome.” The table has errors and omissions (see Table 2 in reference [2]): among others, bupropion, amitriptyline, carbamazepine, levodopa, codeine, methylphenidate, which have no serotonergic potency for precipitating ST, and they omit MAOIs entirely, and clomipramine, fluvoxamine, sibutramine, and various serotonergic opioids (despite having cited the most recent review about ST and opioids, by Gillman).

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To posit the involvement of cyclobenzaprine is rather speculative because there is no evidence it has any SSRI potency. Although there is a paucity of neuropharmacologic data, it seems to be structurally more closely related to cyproheptadine rather than the triCyclic antidepressants, especially when its 3-dimensional structure is viewed [10]. Its actions, like cyproheptadine’s, appear to be those of a sedative (H1 antagonist) antimuscarinic 5-HT2A antagonist [11,12]. Ironically, the cyproheptadine they gave their patient may have worsened the symptoms by adding to the sedative and antimuscarinic effects. They do not discuss either the apparent failure of cyproheptadine to ameliorate the symptoms (which suggests it was not ST), or that in more than 400 cyclobenzaprine overdoses, no serotonergic features were described (in the reference they cite, [11]). The picture was, as in this case, more a sedative/ antimuscarinic toxidrome. The severity and duration of diaphoresis are not specified, and, although that argues against an antimuscarinic toxidrome, that can be manifested centrally after the peripheral effects have worn off.

This article is not good evidence for the proposition that cyclobenzaprine causes ST. It is regrettable that out-of-patent drugs such as this tend not to have their profiles assayed (see http://pdsp.med.unc.edu/pdsp.php), but it seems unlikely that cyclobenzaprine is an SSRI. Clinicians need to familiarize themselves with other materials, especially the references below, to make well-informed decisions concern- ing ST.

P. Ken Gillman PO Box 86 Bucasia, Queensland 4750, Australia E-mail address: [email protected]

doi:10.1016/j.ajem.2009.03.001

References

  1. Day LT, and Jeanmonod RK, Serotonin syndrome in a patient taking Lexapro and Flexeril: a case report. Am. J. Emerg. Med., 2008;26(9): 1069. e1-e3.
  2. Gillman PK. A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biol Psychiatry 2006;59: 1046-51.
  3. Whyte IM. Serotonin toxicity (syndrome). In: Dart RC, editor. Medical toxicology. Baltimore: Lippincott Williams and Wilkins; 2004. p. 103-6.
  4. Isbister GK, Bowe SJ, Dawson A, Whyte IM. Relative toxicity of Selective serotonin reuptake inhibitors in overdose. J Toxicol Clin Toxicol 2004;42(3):277-85.
  5. Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust 2007;187(6):361-5.
  6. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;

    352(11):1112-20.

    Dunkley EJC, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. Hunter serotonin toxicity criteria: a simple and accurate diagnostic decision rule for serotonin toxicity. Q J Med 2003;96:635-42.

  7. Gillman PK. Extracting value from case reports: lessons from serotonin toxicity (serotonin syndrome). Anaesthesia 2006;61:419-22.

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    Hooper VD, Andrews JO. Accuracy of noninvasive core temperature measurement in acutely ill adults: the state of the science. Biol Res Nurs 2006;8(1):24-34.

  8. Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, et al. DrugBank: a comprehensive resource for in silico drug dis- covery and exploration. Nucleic Acids Res 2006;34(Database issue): D668-72.
  9. Spiller HA, Winter ML, Mann KV, Borys DJ, Muir S, Krenzelok EP. Five-year multicenter retrospective review of cyclobenzaprine toxicity. JA Emerg Med 1995;13(6):781-5.
  10. Honda M, Nishida T, Ono H. Tricyclic analogs cyclobenzaprine, amitriptyline and cyproheptadine inhibit the spinal reflex transmission through 5-HT(2) receptors. Eur J Pharmacol 2003;458(1-2):91-9.

    Author response to “Is there sufficient evidence to suggest cyclobenzaprine causes serotonin toxicity?”

    To the Editor,

    This is an interesting article by Dr Gillman. He certainly raises many salient points, and his authority on the subject is not in question. However, Dr Gillman’s interest seems to be more toward a detailed review of both serotonin syndrome and the pharmacokinetics of cyclobenzaprine. It does not address the consideration which was at the core of our article, namely, that there are substances both known and unknown that have both overt and covert serotonin agonism. In doing so, his article, although valuable and in many aspects correct, misses the proverbial clinical forest for the academic trees. This was an observational case report only and was not meant to present the breadth and intricacies of the serotonin toxidrome, or the pharmacology of cyclobenzaprine.

    Although we appreciate his detailed response, we published this as a case report only. We were not seeking to publish a detailed toxicologic review of serotonin syndrome. This can be found elsewhere in a more expansive, detailed, and erudite format. Much of the issue with our article seems to be directed at its lack of detail, a necessity foisted on us by the dictated brevity of a case report and not by a deficit in our understanding of the condition. For instance, the table of drugs, synthesized from several sources, lists the most common drugs within the current

    pharmacologic milieu, and not infrequently used drugs, such as MAOIs, which are rarely if ever prescribed these days. As emergency physicians, we look for the common instead of the uncommon and focused on this in our review.

    The author also takes issue with the description of our patient’s clinical symptoms and the accuracy of our diagnosis. We are sure the author is aware that serotonin syndrome may present with coma, and we consider it unnecessary to defend the clinical diagnosis made real-time by the providers treating the patient. As with so much of medicine, serotonin syndrome is a clinical diagnosis.

    All medical literature is open to interpretation and speculation. We diagnosed and successfully treated an abnormal instance of the serotonin syndrome and found the literature lacking when it came to certain details of the case, prompting first literature research and then the writing of an article. As with all case reports of conditions not previously discussed in the literature, the intent was to stimulate discussion. This will hopefully prompt a more comprehen- sive examination of the pharmacokinetics of cyclobenzapr- ine, a frequently prescribed medication with poisoning side effects not previously quantified within the known toxico- logic spectra. We stand behind our interpretation of the current medical literature as it pertains to serotonin syndrome and urge vigilance in diagnosing the condition in certain patient populations. We continue to assert that our case report contributes an interesting and heretofore not discussed facet to the said literature.

    Luke T. Day MD

    LT, MC, USN

    Department of Emergency Medicine

    Naval Medical Center San Diego, CA, USA

    Rebecca K. Jeanmonod MD

    Department of Emergency Medicine

    Albany Medical Center Albany, NY, USA

    E-mail address: [email protected] doi:10.1016/j.ajem.2009.03.002