Abstract

Evidence has emerged that Metaxalone (Skelaxin) is 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 it is combined with a serotonin reuptake inhibitor (SRI).  Metaxalone was introduced over 50 years ago and is used widely for the treatment of musculoskeletal pain.

It was approved in the days when less extensive pharmacological data concerning drugs existed.  Now, theoretical computational (in silico) techniques allow a degree of useful prediction of the likely receptor and enzyme targets of drugs (this has shown metaxalone to be a weak MAOI (see below).  This, combined with the fact that it is an ‘oxazolidinone’ (5-(3,5-dimethylphenoxymethyl)-2-oxazolidinone), structurally and pharmacologically related to antibiotics like linezolid, which do exhibit both MAOI potency and the clinical effect of inducing ST [1, 2] suggests the wisdom of vigilance concerning the probability of ST with high-dose metaxalone.

As of Dec 2015, several 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, at least partly, reflect the increasing knowledge and understanding of ST.  The importance of such understanding has been highlighted recently by various incorrect and misleading warnings emanating from several drug regulatory agencies (WHO, FDA etc.) concerning ST.  These misleading warnings include triptans and antiemetic drugs like ondansetron.  The explication of why it is logical to dismiss ondansetron (and triptans) as suspects, but conclude that Metaxalone is ‘guilty’, contains valuable lessons in understanding pharmacology, toxicology and serotonin toxicity [3-5].  The same applies to methylthionimium (methylene blue).  These lessons have, evidently, not yet gained general recognition despite all the computers in use, nor have the proper interaction warnings been incorporated into clinical management protocols.

Background

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 [4].  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 [5].  More recently its utility has been exemplified in the rebuttal of the warnings issued about triptans and ST [5-7] and about ondansetron and ST [8].

The above review [5] 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.

This chain of events was started in Nov 2014 when Dr Pete Bentham alerted me to recent case reports suggesting severe ST involving metaxalone [9, 10].  After investigation I posted a warning in 2014, based on the supposition that it was a weak MAOI.

The fact that metaxalone has been used for such a long time (more than 50 years) with no apparent reports of ST would at first seem to make ST unlikely: after all, one might suppose it would have occurred and been reported somewhere?  Maybe it has been, and no-one has yet unearthed the reports?  (which maybe the case, see below).  I have attempted to ascertain this, with limited success, it is not as easy as one might think.  Such considerations notwithstanding, this suggest that it is a weak MAOI, probably reversible, like moclobemide.  Therefore, it is only when it is ingested in large doses and in combination with an SRI that ST is precipitated.

That is precisely the same picture that we do indeed see with the reversible MAO-A selective drug moclobemide [11, 12].  Some people tried using combinations of moclobemide and SSRIs, but it proved to be a delicate and brave balancing act which could (and did) easily go seriously amiss [13, 14]: there were deaths, some published, some only reported to me privately.  Most people stopped doing it.  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 drug exhibiting significant SRI potency, produces a risk of severe ST and also the possibility of fatalities even with ‘therapeutic’ doses.’ [14].

I recap on this story because there are close parallels and lessons between moclobemide, linezolid and metaxalone, whereby small increases in dosage (or increases in blood levels due to pharmaco-kinetic interactions) may lead to fatal toxic interactions.

The current evidence about metaxalone provides a warning signal that is sufficiently strong that it mandates further investigation [which, as of 2019, has now been done, see below].  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 I would confidently predict).  Thus far that would appear to be the case.  It would be surprising if there were not a few cases of severe or fatal ST from metaxalone overdoses in subjects on SRIs out there somewhere.

Update: Case Reports

These initial cases [9, 10] 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 [15, 16].  There is a further report this year, 2015, of 2 cases of probable ST involving ODs of metaxalone and therapeutic doses of an SRI [17], exactly as I predicted in my original warning.

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, establishing that such cases represent ST is not usually possible.  The reports by, Bishop-Freeman [18] which had 3 fatal cases involving SRIs with ODs of metaxalone, and also [19-21] constitute a strong warning signal.

The Huska and Martini cases [15, 17] fall into that minuscule group of case reports about ST in the last decade which are useful.  They both contain elements which immediately make one think it is likely to be severe ST involving an MAOI and an SRI.  The patients presented acutely complaining of feverishness and shaking, temperatures rose rapidly, and they exhibited severe tremulousness, shivering, hyperreflexia, clonus (ocular and ankle) and muscle rigidity.

This is the classic picture of ST with dramatic and rapid onset dominated by neuro-muscular symptoms and resolving rapidly following cessation of medication (and the use of cyproheptadine).  It is instructive to compare these cases with the cyclobenzaprine cases (see below) and the poor cases put forward by the FDA and used to justify the idea of ST with ondansetron: those cases, apart from not meeting formal diagnostic criteria, do not look like ST, especially because the progression of symptoms and signs over time does not fit.

The other metaxalone cases described are ‘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 often the case, sources of information were limited and of uncertain reliability.  Although drug screening showed no other known SRI drugs it remains entirely possible the patient had ingested an SRI prior to the overdose.

These cases provide a strong indication that metaxalone is an 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 as the picture 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 metaxalone by itself, but we would expect it if large doses of metaxalone are combined with therapeutic doses of an SRI.

That is indeed precisely what the above cases illustrate.

New Data on Metaxalone

As of August 2019 new data became available from Hodgman and colleagues [22] showing that with the concentration of metaxalone reported after ODs (range from 31 to 61 mcg/ml (140–276 mM)) [9, 17, 23] there is approximately 75% inhibition of MAO-A.

That is concordant with another avenue of investigation I initiated several years ago with Professor Yelecki in Turkey, which had already established the likelihood of it being a significant MAO inhibitor.  This was done with computer modelling techniques.  I contacted him in 2014 and calculations using theoretical modelling on computers (in silico modelling) indicated that the drug was indeed a monoamine oxidase inhibitor (see acknowledgements below).  Prof Yelecki’s 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.

These data are a strong indication that this drug 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 difficult to ascertain, that the occurrence or absence of ST with drug combinations is a useful tool for revealing whether the concentrations are reaching clinically relevant levels and altering central serotonin neuro-transmission.

The other method is to assay its MAO activity in vitro using similar techniques to those we (Ramsay et al.) used for MB [24].  Also, 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 [25].  However, that takes time and money.  It would be worth doing if there is someone out there with the time and money.

More and higher quality data from toxicology databases of overdoses in humans would therefore be of 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 [26], such data is not routinely collected.

A Note About Cyclobenzaprine

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 [27-29].  Earlier discussion on this question prompted a similar chain of events to be set in motion as is related above.  In silico modelling by Tudor Oprea’s group has suggested that cyclobenzaprine is a weak SRI, comparable to amitriptyline [30, 31], and is therefore unlikely to be a cause of ST.

In this immediate context the current data on cyclobenzaprine serves to illustrate this interesting and important point about the drug interactions the precipitate ST.  If cyclobenzaprine is a significant SRI in humans then we would expect it to cause serotonergic 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 shows 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 used infrequently the result is that cases of ST emerging with cyclobenzaprine would be expected to be 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%), therefore, you do not have to have a large series of metaxalone overdoses before it becomes inevitable that a proportion of them will have ingested both drugs.

Conclusion

The subtle twist appears to be that metaxalone is sufficiently weak as an MAOI that in general circumstances it does not cause problems when combined with SRIs.  Only in patients who ingest large, supra-therapeutic doses, or develop particularly high blood levels, is there a risk of ST with SRIs.  And thus, metaxalone has managed to stay under the radar for half a century.  It most closely resembles linezolid which, likewise, rarely provokes severe toxicity [32-35].

Acknowledgements

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