Methylene Blue toxicity with serotonin reuptake inhibitors (SRIs). PsychoTropical Research - Dr Ken Gillman, Serotonin Syndrome, Mirtazapine, Dual Action Drugs. Serotonin toxicity, serotonin syndrome: 2008 update, overview and analysis.

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Serotonin toxicity, serotonin syndrome

Drug safety interaction warning.

Methylthioninium chloride (Methylene Blue) is a potent MAOI and causes potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors.

N.B. This article is a work in progress, and the web version is not always the most up to date revision.

The most up to date version of this article in Word.doc format can be downloaded for printing here.

The most up to date version of this article in Adobe.pdf format can be downloaded for printing here.

Introduction

My web site introduces me thus: ‘I am Dr Ken Gillman, an internationally acknowledged authority on serotonin toxicity (ST), sometimes called serotonin syndrome (SS), and also an expert on other sorts of drug interactions, side effects and adverse effects’. Hence my interest in, and recognition of, this problem of serotonin toxicity with Methylthioninium chloride (methylene blue).

Since my initial ‘alert’ (1) and web site posting in 2006 about serotonin toxicity from combinations of Methylthioninium (Methylene Blue) + (selective) serotonin reuptake inhibitor interactions ((S)SRIs), further serious cases, and one fatality (possibly from ST) have been reported/recognised. First, two retrospective series Kartha (2) & Sweet (3), and another cases report, Shanmugam (4). In my 2006 paper (1) I stated ‘Further corroboration and quantification of Methylene Blue’s potency [as an MAOI] is in progress to establish the degree of effect in the doses used in surgery.’ (Hereafter I shall use the term serotonin toxicity (ST)).

That in vitro study I initiated, courtesy of Rona Ramsay in St Andrews, has yielded data unequivocally demonstrating that Methylene Blue is a potent inhibitor of monoamine oxidase A (MAO-A) (5). This clarifies why it precipitates serious and potentially fatal serotonin toxicity if combined with (S)SRIs (1, 6), just as moclobemide and the old monoamine oxidase inhibitors (MAOIs) do. SSRIs include all ‘Prozac’ like drugs (SSRIs) as well as other drugs that act as SRIs like the tricyclic antidepressant (TCA) clomipramine, tramadol, meperidine (aka pethidine), sibutramine, venlafaxine, duloxetine, chlorpheniramine etc. See (7) Table 2 , or my web site, for an authorative list. NB many published lists contain multiple errors and mis-information (that includes the official MHRA warning).

Mixtures of MAOIs (in this instance Methylthioninium [aka methylene blue]) combined with SRIs (of any sort, specific or non-specific) are the only likely cause of serious (i.e. potentially fatal) serotonin toxicity. Such mixtures produce a high risk of toxicity and should be studiously avoided.

This new finding of potent MAO inhibition by Methylthioninium is important because it is used intra-venously in surgery for thyroid operations, for methaemaglobinuria and for resistant hypotension in septic shock and cardiac surgery (8-11).

If Methylthioninium is judged to be indicated SRIs must be ceased, prior to treatment/procedure/surgery. Other types of serotonergic drugs are not implicated in significant toxicity e.g. tryptans, mirtazapine, bupropion, lithium, tricyclic antidepressants etc. See (7).

The MHRA warning

The MHRA in UK have issued a warning, instigated indirectly by me, around September 2007, but appear to have been unaware of the Ramsay paper or my input. Their warning is not as clear as it might be and does not explain the implicated drugs, the mechanism or the risks. It also contains significant errors, omissions and mis-information (e.g. it incorrectly refers to mirtazapine and bupropion as serotonergic drugs). These detract from its usefulness and introduce an element of confusion that is likely to lead clinicians to make misconceived and faulty decisions that will have negative consequences (e.g. it suggests avoiding Methylthioninium with drugs that have ‘serotonergic’ activity, whereas it is only SRIs that pose a danger). The MHRA warning does not contain the key word serotonin syndrome (or serotonin toxicity), nor refer to our paper demonstrating methylene blue is an MAOI. Other agencies have yet to act. Hence this internet post is for those who are smart and use google. For those that do not, I suggest they may be directed here.

Warning!

The MHRA warning contains significant errors, omissions and mis-information. These detract from its usefulness and introduce an element of confusion that will lead clinicians to make misconceived and faulty decisions that could have negative consequences.

Any information may be sent to:
Pharmacovigilance Signal Management Group,
Vigilance and Risk Management,
MHRA
Market Towers,
1 Nine Elms Lane,
London SW8 5NQ
pharmacovigilance@mhra.gsi.gov.uk

The story

In 2005 David Bogod, the editor of the journal Anaesthesia, invited me to write an editorial concerning case reports and serotonin toxicity (6). Anaesthesia had already published an interesting case report by Martindale et al of ‘Neurological sequelae following methylene blue injection for parathyroidectomy’, although it had not then been recognised as a possible example of ST (12). One of my routine google searches for SS/ST led me to an unpublished report on the internet (still available as of June 2008) by Rosenbaum (13), who, most astutely in my opinion, suggested the symptoms and signs observed in that patient might be serotonin toxicity (ST) resulting from an interaction between methylene blue and a serotonin reuptake inhibitor (SSRI). Rosenbaum noted the similarities to the Martindale report: medical.mhaus.org

I immediately corresponded with Rosenbaum, in order to encourage him to publish his case in a peer reviewed Journal (he never got round to it, but it is still up on the web site), and to let him know that in my opinion he was correct, and furthermore that this strongly suggested (because of the severity of symptoms) that methylene blue must be a monoamine-oxidase inhibitor. I searched for information concerning methylene blue and MAOI activity, with some success, and submitted a comment to Bogod concerning this (1), particularly because the case illustrated the problems and potential of case reports, the subject of my previous Anaesthesia editorial. As they were preparing to go to press with my letter the editor contacted me to say they had received another report that he thought I might wish to comment on. Indeed, it seemed very likely that this was indeed another case of ST (14). All subsequently discovered/recognised reports, as of June 2008, are listed below.

The key issue to grasp is that severe degrees of ST, involving therapeutic doses of (S)SRIs, only occur following combination with MAOIs (7), but not with other serotonergic drugs (with other mechanisms of action (cf MHRA warning)). These few cases therefore indicated (one could almost say ‘proved’) that methylene blue must posses significant potency as an MAOI.

A search of the existing standard texts (Goodman and Gilman, Rang and Dale, British National Formulary, Martindale etc) revealed no information or suggestion that Methylene Blue is an MAOI: however other older, and some recent literature did support a degree of MAOI inhibition (15-17), but one of uncertain potency and relevance in relation to humans. I therefore sought the assistance of Rona Ramsay at St Andrews, an expert in the field of assessing MAOI potency, who took on the task of assaying MAO inhibition by methylene blue. The rest, as they say, is history.

SRIs have been in use for more than three decades. Clomipramine has been in use since 1966- France, 1968- UK, well before fluoxetine, 1986-USA, 1988- UK. It would be astonishing if substantial numbers of patients taking them had not been operated on with procedures that utilize the infusion of methylene blue. Since (we now know) that it is a potent MAOI one would expect a large number of reports of toxicity; there are few. This is similar to the situation with pethidine and imipramine (18, 19). In my opinion the most parsimonious explanation is that ST has occurred and not been recognised, or the relevance of the reactions seen has not been appreciated: cf. pethidine, imipramine, linezolid (20). The fact that most of the cases now uncovered have been reported as ‘encephalopathy’ re-enforces my point. This is congruous with the well documented history of failure to recognise serotonin toxicity when it occurred frequently between 1955 and 1982 without recognition (21), usually caused by MAOIs + imipramine or clomipramine or pethidine. It would be interesting to know if, in retrospect, experienced practitioners recognise that they have indeed seen ST symptoms (particularly clonus, hyperreflexia, pyrexia and agitation/confusion) in such cases (see Kartha (2) below).

Currently known cases: methylene blue and serotonin toxicity

Currently known cases relevant to methylene blue and serotonin toxicity, serotonin toxicity are listed here (2, 4, 12-14, 22-27). Note: Patel (28) has been opined by Ng (29) to be ST but does not meet any criteria to justify that assignation.

If you are aware of any others that might be relevant please let me know via email or ‘contact me’ through this site.

It is especially noteworthy that two cases series have now appeared, in Nov 2006 Kartha (2) and in March 2007 Sweet (3). Other recent case series exist, e.g. Han’s series of 473 patients (9) that make no mention of ‘encephalopathy’ or ST. It might be useful to re-examine such series.

Kartha reported 12 cases of ‘toxic metabolic encephalopathy’ (which I am sure are serotonin toxicity) from a retrospective analysis of 193 patients operated on for parathyroidectomy using methylene blue: one patient died (possibly of serotonin toxicity). All 12 with ‘toxic metabolic encephalopathy’ were on SSRIs pre-operatively. I.e. Of the total of 28 patients who were on SSRIs (in the series of 193) 12/28 had ‘toxic metabolic encephalopathy’. It is almost certain that had these patients all been fully assessed for the key symptoms of serotonin toxicity the % exhibiting significant serotonin toxicity symptoms would have been in excess of 50%. This paper was published just after my August 2006 review so I was unable to take its valuable data into account (and have only just ‘found’ it, 6/2008).

Sweet & Standiford report on a series of 132 cases, 17 had SSRIs pre-op. None of those who had no prior use of SSRIs got symptoms, 5/17 who did take SSRIs pre-op did get symptoms (30%). They considered the possible explanation of serotonin toxicity but did not favour it because of the symptom profile. In my opinion the main reason for the different and varying symptom profile is treatment: i.e. these subjects were coming out of anaethesia which is an effective treatment for serotonin toxicity. The rate at which various drugs are cleared, especially relaxants, probably plays a key role in suppressing hyperreflexia etc. I would observe also that it is certain that a proportion of the patients on SSRIs were either on sub-therapeutic doses of SSRI or were non-compliant; so the real denominator in the fractions needs to be adjusted lower, in my opinion by at least 30%, i.e. ~12/20 not 12/28). The nominator is also certain to be too low (missed cases), so the real % experiencing a reaction is probably between 50 & 75%.

Both these series (totalling 325 patients) support my supposition that almost all these cases had previously been going unrecognised/unreported. From my detailed knowledge of the history of serotonin toxicity that is exactly what I would predict. To restate it simply: Doctors do not see what they are not looking for.

Also, as Rosenbaum points out (personal communication) symptoms that obscure ST, such as shivering, are very common on emergence from anaesthesia.

This is an important point to appreciate because it seems that a major stumbling block for many people who do not have a good understanding of serotonin toxicity (and the spectrum concept) is the comparative rarity of (reported) cases relative to the presumed large number of cases where Methylthioninium chloride (methylene blue) and SSRIs must have been used together (e.g. see (30)).

The author Ng (29) has more recently summarised some more of the cases published up till late 2007, but also missed most of them: viz Kartha & Sweet (the date of publication of his paper, ‘revision accepted October 23 2007, was just after our Ramsay Gillman MAOI paper Aug 2007), and added, post hoc, his opinion that they represent serotonin toxicity. But he appears to insufficiently appreciate, or recognise, the previous work (31), or the full implications of the fact methylene blue is definitely an MAOI, on the risk of toxicity. Hence his contribution, although useful in commenting on one or two more references, is misleading. He seems not to have recognised (or acknowledged) that serotonergic mechanisms, specifically serotonin toxicity, had previously been concluded to be the explanation by other authors, because in his introduction he states: ‘to consider this diagnosis [serotonin syndrome] in previ¬ous, unexplained reports of adverse reactions amongst patients undergoing parathyroidectomy using methylene blue.’ However, they were not ‘unexplained’ at all, so his contribution is not original either. In my 2006 paper Gillman (1) which I sent to Ng (along with other references to help him prepare his report), I had stated that because these cases so obviously were serotonin toxicity that ‘Further corroboration and quantification of Methylene Blue’s potency is in progress to establish the degree of effect in the doses used in surgery.’ The Patel (28) case, reported by Ng as serotonin syndrome (see also his comment (30)) is not reported to have involved use of SSRIs, but also the symptoms are entirely different, epileptic seizures, with no other symptoms or signs suggesting serotonin toxicity. Note epileptic seizures are definitely not seen in serotonin toxicity, although severe clonus may be seen as epileptic by less experienced clinicians. So, the Patel case is irrelevant, and Ng’s comment ‘Our review suggests that this combination may be responsible for the majority of reported cases, but one case (28) had methylene blue alone causing delirium (30)’, is not only factually incorrect (the patient exhibited ‘epilepsy’ not delirium) but also mis-conceived. It is impossible, in this context, to avoid repeating my comment about poor case reports which is elaborated in detail in my editorial ‘Extracting value from case reports: lessons from Serotonin toxicity (serotonin syndrome)’(6). Poorly informed comment based on faulty case reports bedevils the whole issue and causes much confusion. ‘Plus ça change, plus c'est la même chose’, as Alphonse said (32).

Several other commentators had previously speculated about serotonergic mechanisms, even if they did not quite make all the connections and appreciate the implication that Methylthioninium chloride (methylene blue) must be an MAOI. Since we have touched on the area of precedence, acknowledging prior contributions and learning from history, it is most appropriate to give due credit to Clare Stanford (22)(the 1st author is her sister), they came tantalisingly close to getting it right: A decade later I can now, with Clare’s help, complete the circle!

When I checked the fine details of all the various accumulated references (to update my web posting- viz this doc, in June 2008) my attention was drawn to the correspondence relating to Bach (24) from Siebert (33), Howard (34) and Palmer (23) that highlighted the apparent anomaly of the earliest potentially related report from (Clare & sister) Stanford in 1999 (22), which, although very similar, did not report the use of Methylthioninium chloride (methylene blue).

That Stanford report is so important, interesting and educative that I abridge the abstract below:

‘… postoperative delirium … during recovery from anaesthesia. Features agitation, confusion, uncontrolled limb movements, abnormal ocular function (KG-probably horizontal ocular oscillations- not nystagmus), hypertension, pyrexia, brisk reflexes, ankle clonus and raised creatine kinase. … had been taking paroxetine. … had many features in common with problems associated with, the serotonin syndrome and the malignant neuroleptic syndrome. We offer several alternative explanations for this event, all of which rest on disruption of serotonergic and/or dopaminergic transmission.’ NB The bolded features are typical/pathognomonic of serotonin toxicity. This degree of severity could only result from MAOI + SSRI: ergo, the patient must have received an MAOI, somehow.

But, the report neither mentions Methylthioninium chloride (methylene blue) nor what the operation was for! That is why other commentators (Bach (24), Siebert (33), Howard (34) and Palmer (23)) ‘wrote it off’ as different. I hope readers will by this stage be sufficiently well informed about serotonin toxicity to guess the remainder of the story.

Yes, I emailed Clare to ask her to provide more information and check for omissions in her report: yes the operation was a parathyroidectomy. Yes, Methylthioninium chloride (methylene blue) was used. So hers was the 1st report thus far identified, even if she did not realize it for ten years.

All this illustrates the predictive power of the spectrum concept of serotonin toxicity, as detailed in my most recent review (35). To fully and properly understand the situation a brief review of serotonin toxicity is required.

Serotonin toxicity, Serotonin syndrome: summary

Serotonin toxicity (ST) is an iatrogenic drug-induced toxidrome displaying the characteristics of a synaptic serotonin concentration-related phenomenon. The term ST is preferable because serotonin syndrome (SS) insinuates an idiosyncratic reaction like malignant hyperthermia (MH) or neuroleptic malignant syndrome (NMS). ST is important because potentially fatal combinations of therapeutic drugs are sometimes inadvertently combined. Also, many texts contain incomplete and erroneous information concerning which drugs are capable of precipitating ST, and its mechanism, symptoms and treatment. Such texts include the British National Formulary, Australian Medicines Handbook, and even ‘Goodman and Gilman’ and Rang & Dale, and now the MHRA.

The generally poor understanding of serotonin toxicity has been highlighted, more recently, by the availability of several drugs, not used as antidepressants, that posses the property of monoamine oxidase inhibition. It was the accidental discovery of the mood elevating properties of iproniazid, in the trials for tuberculosis around 1955, that led to the discovery of the monoamine oxidase inhibiting properties of those drugs, and to the development of the original MAOI antidepressants. The first patient to die as a result of serotonin toxicity was a doctor, in the original trials of iproniazid, who was given pethidine (36) i.e. a combination of MAOI + SRI. So it’s a long story, a saga even!

In 50 years the wheel has now gone full circle, in that the latest new drug causing this problem is again an anti-microbial, linezolid, that also has significant activity as an MAOI. Thus history repeats itself, and we demonstrate how slowly and painfully we learn from history, and how quickly we forget its lessons (37). Students of the history of medicine may, by this time, be exhibiting wry smiles as they recollect the original work, going back to the nineteenth century, following the discovery of inorganic dyes from petroleum, and how Paul Erhlich studied their antimicrobial properties. These eventually resulted in the discovery of the tricyclic psychotropics, including antihistamines, and the tricyclic antidepressants, and the Neuroleptics (all based on the Methylene Blue nucleus).

The evidence relating to serotonin toxicity from Professor Whyte's research group (HATS) series of 2,222 serotonergic overdoses has been published in a seminal series of papers (38-45). Other recommended papers concerning serotonin toxicity are: (20, 21, 46-57).

The clinical features of serotonin toxicity

The typical clinical features of ST in humans, are (i) neuromuscular hyperactivity: tremor, clonus, myoclonus and hyperreflexia, and, in the advanced stage, pyramidal rigidity; (ii) autonomic hyperactivity: diaphoresis, fever, tachycardia, tachypnoea and mydriasis; and (iii) altered mental status: agitation, excitement, with confusion in the advanced stage only. Descriptions of the clinical presentation may be found elsewhere (38, 50). Whyte concludes …‘only clonus (inducible, spontaneous or ocular), agitation, diaphoresis, tremor and hyperreflexia were needed for accurate prediction of ST as diagnosed by a clinical toxicologist.’ If, in the presence of a potent serotonergic agent, the single sign of spontaneous clonus is present, then ST may be reliably diagnosed.

The spectrum concept explains ST as a progression of serotonergic effects mediated by the degree of elevation of intra-synaptic serotonin. These range from serotonin-related side effects (at therapeutic doses) through to toxicity, and culminate in death with MAOI / SRI combinations. The three important mechanisms are serotonin reuptake inhibition (SRI), MAO inhibition and pre-synaptic release. The only therapeutic drugs implicated in severe reactions are: over-dose of MAOIs-alone, combinations of MAOIs with either SRIs, or the only clinically available serotonin releaser, amphetamine (methylphenidate is not a risk (7, 58)).

The data suggests that about 50 per cent of patients who have ingested the weak ‘RIMA’ moclobemide, in combination with SRIs, will exhibit at least moderately severe ST (cf. Kartha). SSRIs alone do not result in severe ST or pyrexia in excess of 38.5c (46) which indicates they have a ceiling effect.

Understanding ST as a form of poisoning reveals the importance of knowing the degree to which different drugs are capable of elevating brain serotonin, indeed the relative frequency and severity of ST with different drugs (and combinations) is useful in refining hypotheses about the potency and actions of those drugs (7).

Death can result from a single dose of an SRI when errors are made in a patient already on an MAOI, as two recent deaths illustrate. The Otte case (imipramine 225 mg), in a European teaching hospital (59), and also Cassens (60). Neither were treated with 5-HT2A antagonists. It is entirely predictable the same thing will happen when linezolid or Methylene Blue achieve substantial MAO inhibition, which they do, in a dose dependent manner.

Since paralysis and anaesthesia constitute effective treatment of severe serotonin toxicity exhibiting hyperpyrexia, the clinical picture on emergence from anaesthesia will be modified, Further reviews like Kartha’s, of series of patients, may help clarify the way in which the symptoms differ (from the usual presentation in the absence of anaesthesia). Post-operatively, previously suppressed serotonin toxicity will ‘emerge’ as the effects of anaesthesia wear off.

The good news is Methylthioninium chloride (methylene blue) is safe, it is only the interaction with SRIs which needs to be avoided.

It would be neat if someone could actually measure the degree of platelet MAO inhibition that various doses of Methylthioninium chloride (methylene blue) produces in patients.

Conclusions

  1. Methylthioninium chloride (methylene blue) is safe.
  2. Mixing it with SRIs causes serotonin toxicity: so cease SRIs, with appropriate washout periods, beforehand.
  3. Make sure you know the following drugs which are in fact significant serotonin reuptake inhibitors from (7), table 2. Paroxetine, sertraline, fluoxetine, fluvoxamine, citalopram. Venlafaxine, milnacipran, duloxetine, sibutramine, Clomipramine, imipramine. Tramadol, meperidine (pethidine), dextromethorphan, dextropropoxyphene pentazocine (fentanil is unlikely to be significantly serotonergic in usual doses), Chlorpheniramine, brompheniramine.
  4. Remember patients may forget to mention drugs recently ceased. Because fluoxetine has an elimination half-life of up to 7+ days it may be present in significant amounts more than one month after cessation.
  5. Be aware of the signs and symptoms of serotonin toxicity and how to treat it and be aware that post-anaesthetic cases present with modified signs and symptoms.
  6. The ‘corrected’ % of patients experiencing a reaction (see above) may be as high as 50% - 75%.
  7. The question of interactions between opioid analgesics (pethidine, tramadol, fentanyl etc) and MAOIs is dealt with in another of my reviews (20).
  8. The MHRA warning is in need of revision.
  9. Other agencies (including professional associations and colleges) need to get organised in a timely fashion and issue guidance.

References

1. Gillman, PK, Methylene Blue implicated in potentially fatal serotonin toxicity. Anaesthesia, 2006. 61: p. 1013-1014.
2. Kartha, SS, Chacko, CE, Bumpous, JM, Fleming, M, Lentsch, EJ, and Flynn, MB, Toxic metabolic encephalopathy after parathyroidectomy with methylene blue localization. Otolaryngol Head Neck Surg, 2006. 135(5): p. 765-8.
3. Sweet, G and Standiford, SB, Methylene-blue-associated encephalopathy. J Am Coll Surg, 2007. 204(3): p. 454-8.
4. Shanmugam, G, Kent, B, Kirby, S, and Baskett, R, Serotonin syndrome following cardiac surgery. Interact Cardiovasc Thorac Surg, 2008.
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