Evidence has emerged that Metaxalone (Skelaxin) may be a weak monoamine oxidase inhibitor (MAOI) which when used in large doses may be sufficiently potent to induce serotonin toxicity (ST) (aka Serotonin Syndrome), but only if combined with serotonin reuptake inhibitors (SRIs). Metaxalone was introduced just over 50 years ago and is used widely for the treatment of musculoskeletal pain.
It was approved in the days when comprehensive pharmacological data concerning drugs was neither easy to obtain, and not expected, prior to regulatory approval. However, modern theoretical computational (in silico) techniques allow a degree of useful prediction of the likely receptor and enzyme targets of drugs (this is now being undertaken with Metaxalone- done, see below). This, combined with the fact that it is an ‘oxazolidinone’, structurally and pharmacologically related to oxazolidinone antibiotics (e.g. linezolid), which can exhibit both MAOI potency and the clinical effect of inducing ST, suggests the wisdom of vigilance concerning this possibility.
Several recent case reports have described what is probably severe ST in patients who have received metaxalone in combination with an SRI. The fact that such reports have only recently emerged may reflect the increasing knowledge and understanding of ST. This has been highlighted recently by various misleading warnings emanating from several drug regulatory agencies concerning ST with such agents as triptans and antiemetic drugs like ondansetron. The rationale surrounding why it is logical to dismiss ondansetron (and triptans) as a suspect, but suggest Metaxalone is ‘guilty’, contains further lessons in understanding pharmacology, toxicology and serotonin toxicity (1-3).
New Data on Metaxalone
*** Update Feb 2015. Another report of severe ST with OD of metaxalone + SSRI has just come in- see below.
Perhaps we should not be too surprised that an understanding of serotonin toxicity (ST)mechanisms is continuing to provide useful elucidation of the probable mode of action of various drugs (2). The utility of such an understanding has been clearly illustrated by the story of methylene blue, dealt with extensively both on my website and in my peer reviewed publications (3). More recently its utility has been exemplified in the rebuttal of the warnings issued about triptans and ST (3-5) and about ondansetron and ST (6).
The above review (3) explained how an understanding of the potencies and mechanisms of ST, and their important interactions, leads to precise and reliable predictions. Almost the only possible explanation of severe ST involving usual therapeutic doses of drugs is the classic and potentially fatal interaction of an MAOI with an SRI. A few days ago (15/11) Dr Pete Bentham alerted me to recent case reports suggesting severe ST involving metaxalone (7, 8).
The fact that metaxalone has been used for such a long time (more than 50 yrs) with no apparent reports of ST would at first seem to make ST unlikely: after all one might suppose it surely would have occurred and been reported somewhere? Maybe it has been and no-one has yet unearthed the reports? (which seems to be the case, see below) I am attempting to ascertain this, which is not as easy as one might think. Such considerations notwithstanding, it does suggest that it is a rather weak MAOI, probably reversible, like moclobemide. Therefore, it is only when it is ingested in large doses and in combination with a serotonin reuptake inhibitor (SRI) that severe ST is exhibited. That is precisely the same picture that we do indeed see with the reversible MAO-A selective drug moclobemide (9, 10). Some people tried using combinations of moclobemide and SSRIs, but it proved to be a rather delicate and brave balancing act which could (and did) easily go seriously amiss (11, 12): there were deaths, some published, some only reported to me privately. Most people stopped doing it fairly quickly (see note on ST and moclobemide accessible in the menu on the left-hand side of this page). I summed it up with this comment: “The above data indicate clearly that such combinations represent a predictably risky strategy. Moclobemide, if combined with any SRI, produces a significant risk of severe ST and also the possibility of fatalities even with ‘therapeutic’ doses.” (12).
I recap on this story because there are parallels and lessons between moclobemide, linezolid and metaxalone whereby small increases in dosage (or increases in blood levels due to pharmaco-kinetic interactions) may rapidly lead to catastrophic and fatal toxicity. In short, combing such drugs with SRIs is a pharmacological balancing act of such delicacy as to be practicably unattainable in real-life clinical practice.
The current evidence about metaxalone provides a warning signal that is sufficiently strong that it mandates further investigation. One arm of this investigation should be the effort to ascertain whether other cases of toxicity with this drug involve typical ST manifestations and whether these have only occurred in the presence of (S)SRIs (which is what is predicted). So far that would appear to be the case. Another step is to establish a more precisely the likelihood of it being a significant MAO inhibitor. This can be done with computer modelling techniques, and there is good reason for pursuing this because many similar compounds have been studied in the search for antibiotics (13) and one of them, that has now been on the market for some time, linezolid, definitely has significant MAOI activity at high, but sometimes clinically achieved, blood levels. The other main possibility is to actually assay its MAO activity in vitro using similar techniques to those we (Ramsay et al) used for MB (14). Its ability to modify the tyramine pressor response would also give additional information as would testing in a rat model of ST e.g. see (15). However, that is all time and money. It would be worth doing if there is someone out there with the time (and money).
This is an actively progressing area and some researchers who read this may well be able to make contributions. Should this be the case such persons are welcome to contact me with any questions or suggestions.
After all, it would be rather surprising if there were not a few cases of severe or fatal ST from metaxalone SRI overdoses out there somewhere.
Update: Progress to 28/11/2014
These initial cases (7, 8) were brought to my attention by Dr Pete Bentham. My research since then has revealed further previously reported, by unrecognised, cases where metaxalone appears to be implicated in ST (16, 17).
There are also one or two post-mortem toxicology reports of suicides or deaths that that involve metaxalone & SRIs. In these cases there is usually no information indicating symptoms before death, so establishing that such cases represent ST is impossible. Nevertheless these do constitute another suspicious signal (18-20).
The Huska case (16) falls into that minuscule group of case reports in the last decade about ST which are actually useful. It contains elements which immediately make one think it is likely to be severe ST involving an MAOI and an SRI. Their patient presented to the emergency department complaining of feverishness and shaking. Her temperature was normal on presentation. Rapidly, over the period of assessment in ED her temperature rose to 39 and she exhibited severe tremulousness, shivering and muscle rigidity. With appropriate treatment her clinical condition improved quickly and markedly within 24 hours. This is very much the classic picture of ST with dramatic and rapid onset dominated by neuromuscular symptoms and resolving rapidly following cessation of medication (and in this case the use of cyproheptadine). It is instructive to compare this case with the cyclobenzaprine cases (see below) and those put forward by the FDA and used to justify the idea with ST occurs with ondansetron: those cases, quite apart from not meeting formal diagnostic criteria, just do not look like ST.
The other cases described are all ‘probable’ or ‘definite’ ST and involved an SRI, except for one of the cases reported by Bosak. The investigation of this case involved steps to ascertain what drugs had been taken as part of the overdose, but as is so often the case, sources of information were limited and of uncertain reliability. Although drug screening showed no other known ‘serotonergic’ drugs it remains entirely possible the patient had ingested a serotonergic drug prior to the overdose.
These cases provide a strong indication that metaxalone is probably MAOI. The detailed reasoning that justifies this statement is contained in the other extensive information about ST, both in my peer-reviewed papers, and on this website. In short, it is the same picture as we see with moclobemide. Overdoses of moclobemide alone do not cause serotonergic symptoms or ST, but when it is mixed with even small doses of SRIs serious cases of ST are frequent and fatal cases are well-documented. Thus, we would expect no signs of ST with metaxolone by itself, but we would expect it if large doses of metaxalone are combined with therapeutic doses of an SRI.
That is precisely what the above cases appear to illustrate.
Since my initial comment posted just over a week ago colleagues that I have contacted about this have responded promptly and calculations using theoretical modelling on computers (in silica, as they say) have predicted that the drug is indeed a weak monoamine oxidase inhibitor. We have Prof Yelecki in Turkey to thank for this (see acknowledgements the below). The computed value is 4.3 µmol for the inhibition of MAO-A and 3.5 µmol for MAO-B: this puts it in the same ballpark as moclobemide and linezolid. Other variables such as metabolism and the degree of brain penetrance mean that prediction of the potency in the human brain is not presently possible with any great accuracy. Nevertheless, there is a strong indication that this drug probably has clinically relevant MAOI activity in high doses.
It is precisely because accurate estimation of the potency of drug effects at the relevant receptors in the human brain is so difficult to ascertain that the occurrence or absence of ST with drug combinations is a useful tool for revealing whether the concentrations are actually reaching clinically relevant levels and altering central serotonin neuro-transmission.
More and higher quality data from toxicology databases of overdoses in humans would therefore be of great value, because it would establish the frequency and severity of ST with different doses and combinations of drugs. Unfortunately, despite recommendations made nearly 20 years ago (21), such data is not routinely collected. If there are any poisons centres in the USA that have suitable data that could be re-analysed then looking at such data might well elucidate some of these important questions.
It is also worth noting in passing that one of the other drugs used in the same context as metaxalone is cyclobenzaprine. This drug has also been implicated in possible cases of ST, although there do not appear to be any clear cases of severe toxicity like the ones above with metaxalone (22-24). Previous discussion on this question prompted a similar chain of events to be set in motion as is related above. Dr Oprea and colleagues performed both in vitro & In silica modelling which demonstrated that cyclobenzaprine is a weak SRI, comparable to amitriptyline (25, 26). It is used in rather lower doses, 5 – 10 mg three times daily, than AMI 75 – 150 mg (to which it is closely structurally related) so one wonders about its toxicity and effect on HERG etc.
I will discuss these useful and interesting results about cyclobenzaprine in a separate commentary when I have time. In this immediate context the current data on cyclobenzaprine serves to illustrate this interesting and important point about the drug interactions that precipitate ST. If cyclobenzaprine is a significant SRI in humans then we would expect it to cause serotonin-mediated symptoms, or even ST, when it is taken in overdose (which, like amitriptyline, it does not seem to do), but we would not expect it to cause major ST when combined with other (S)SRIs. This is because both drugs are working by the same mechanism of action and our current understanding indicates clearly that this does not lead to any greater elevation of serotonin than would be expected by simply increasing the dose of one or other of the SRI drugs. However, if cyclobenzaprine were to be mixed with an MAOI then the story would be dramatically different and severe life-threatening ST would be likely. Because MAOIs are not used very frequently the result is that cases of ST emerging with cyclobenzaprine would be expected to be rather less common than cases with metaxalone (other things being equal). This is because a lot of people in the general community are taking (S)SRI drugs (like 5-10%) so you do not have to have a very big series of metaxalone overdoses before it becomes inevitable that a proportion of them will have ingested both drugs.
The subtle twist appears to be that metaxalone is just sufficiently weak as an MAOI that in general circumstances it does not cause problems when combined with SRIs. Perhaps it is only in patients who ingest large doses, or develop particularly high blood levels, for the usual reasons, that unusually high blood levels then constitute the risk of ST with SRIs and thus it has managed to stay under the radar. In this way it most closely resembles linezolid which definitely increases serotonin-mediated side effects, but rarely provokes severe toxicity (27-30).
Latest Case Reports
Serotonin syndrome following metaxalone overdose and therapeutic use of a selective serotonin reuptake inhibitor
The following colleagues have generously assisted with data, interpretation and advice:
Prof. Dr. Kemal Yelekci, Kadir Has University Faculty of Engineering and Natural Sciences Department of Bioinformatics and Genetics (Head) Cibali Campus TR-34083 Fatih Istanbul TURKIYE
Rona Ramsay, Centre for Biomolecular Sciences, University of St Andrews, Fife, Scotland, UK
Tudor Oprea, Division of Biocomputing, Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
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2. Gillman, PK, A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biol Psychiatry, 2006. 59(11): p. 1046-51.
3. Gillman, PK, CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. J Psychopharmacol (Oxf), 2011. 25(3): p. 429-3.
4. Evans, RW, Tepper, SJ, Shapiro, RE, Sun-Edelstein, C, et al., The FDA alert on serotonin syndrome with use of triptans combined with selective serotonin reuptake inhibitors or selective serotonin-norepinephrine reuptake inhibitors: American Headache Society position paper. Headache, 2010. 50(6): p. 1089-99.
5. Tepper, S, Allen, C, Sanders, D, Greene, A, et al., Coprescription of triptans with potentially interacting medications: a cohort study involving 240,268 patients. Headache, 2003. 43(1): p. 44-8.
6. Rojas-Fernandes, C, Can 5-HT3 antagonists really contribute to serotonin toxicity? A call for clarity and pharmacological law and order. Drugs – Real World Outcomes, 2014: p. 10.1007/s40801-014-0004-3.
7. Bosak, AR and Skolnik, AB, Serotonin Syndrome Associated with Metaxalone Overdose. J Med Toxicol, 2014: p. [Epub ahead of print] 10.1007/s13181-014-0404-5. http://www.ncbi.nlm.nih.gov/pubmed/24805103.
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10. Isbister, GK, Hackett, LP, Dawson, AH, Whyte, IM, et al., Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity. Brit J of Clin Pharmacol, 2003. 56: p. 441-450.
11. Gillman, PK, Serotonin syndrome: clomipramine too soon after moclobemide. Int Clin Psychopharmacolog, 1997. 12: p. 339-342.
12. Gillman, PK, Moclobemide and the risk of serotonin toxicity (or serotonin syndrome). CNS Drug Rev, 2004. 10: p. 83-85.
13. Ramsay, RR and Gravestock, MB, Monoamine oxidases: to inhibit or not to inhibit. Mini Rev Med Chem, 2003. 3(2): p. 129-36.
14. Ramsay, RR, Dunford, C, and Gillman, PK, Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. Br J Pharmacol, 2007. 152(6): p. 946-51.
15. Shioda, K, Nisijima, K, Yoshino, T, and Kato, S, Mirtazapine abolishes hyperthermia in an animal model of serotonin syndrome. Neurosci. Lett., 2010.
16. Huska, MT, Catalano, G, and Catalano, MC, Serotonin syndrome associated with the use of escitalopram. CNS Spectr, 2007. 12(4): p. 270-274 http://www.cnsspectrums.com/aspx/articledetail.aspx?articleid=1038.
17. Rivera, A, Gaudino, W, and Weiss, L, Serotonin syndrome in a patient taking tramadol and nefazodone concomitantly: A case report. Arch. Phys. Med. Rehabil., 2003. 84(9): p. E23.
18. Moore, KA, Levine, B, and Fowler, D, A fatality involving metaxalone. Forensic Sci Int, 2005. 149(2-3): p. 249-51.
19. Poklis, JL, Ropero-Miller, JD, Garside, D, and Winecker, RE, Metaxalone (Skelaxin)-related death. J. Anal. Toxicol., 2004. 28(6): p. 537-41.
20. Gruszecki, AC, Kloda, S, Simmons, GT, Daly, TM, et al., Polydrug fatality involving metaxalone. J. Forensic Sci., 2003. 48(2): p. 432-4.
21. Gillman, PK, Serotonin Syndrome: History and Risk. Fundam. Clin. Pharmacol., 1998. 12(5): p. 482-491.
22. Day, LT and Jeanmonod, RK, Serotonin syndrome in a patient taking Lexapro and Flexeril: a case report. Am. J. Emerg. Med., 2008. 26(9): p. 1069 e1-3.
23. Keegan, MT, Brown, DR, and Rabinstein, AA, Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs. Anesth. Analg., 2006. 103(6): p. 1466-8.
24. Gillman, PK, Is there sufficient evidence to suggest cyclobenzaprine might be implicated in causing serotonin toxicity? Am. J. Emerg. Med., 2009. 27(4): p. 509-510.
25. Gregori-Puigjane, E, Setola, V, Hert, J, Crews, BA, et al., Identifying mechanism-of-action targets for drugs and probes. Proc Natl Acad Sci USA, 2012.
26. Mestres, J, Seifert, SA, and Oprea, TI, Linking pharmacology to clinical reports: cyclobenzaprine and its possible association with serotonin syndrome. Clin Pharmacol Ther, 2011. 90(5): p. 662-5.
27. Lawrence, KR, Adra, M, and Gillman, PK, Serotonin Toxicity Associated with the Use of Linezolid: A Review of Postmarketing Data. Clin Infect Dis, 2006. 42: p. 1578-83.
28. Kulkarni, RR and Kulkarni, PR, Linezolid-induced near-fatal serotonin syndrome during escitalopram therapy: case report and review of literature. Indian J Psychol Med, 2013. 35(4): p. 413-6.
29. Lodise, TP, Patel, N, Rivera, A, Tristani, L, et al., Comparative evaluation of serotonin toxicity among veterans affairs patients receiving linezolid and vancomycin. Antimicrob Agents Chemother, 2013. 57(12): p. 5901-11.
30. Butterfield, JM, Lawrence, KR, Reisman, A, Huang, DB, et al., Comparison of serotonin toxicity with concomitant use of either linezolid or comparators and serotonergic agents: an analysis of Phase III and IV randomized clinical trial data. J. Antimicrob. Chemother., 2012. 67(2): p. 494-502.
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