MAOIs and anaesthesia

by | Last updated Dec 2, 2019 | Published on Apr 24, 2019 | Anti-Depressants, MAOIs

Myth: One cannot give an anaesthetic without ceasing MAOIs first.

Summary

The issue in anaesthesia and post-operative care, in patients taking MAOI treatment, is the avoidance of drugs that act as SRIs, particularly opioid analgesics, a few of which have some mild SRI potency; viz. meperidine (pethidine), tramadol, tapentadol, methadone, dextromethorphan, dextropropoxyphene, and pentazocine (other opioids are safe).  If high and repeated doses are used severe ST is possible.

Also, and this is a ‘googly’ (or ‘curveball’ for baseball aficionados) especially for operating theatre situations, methylene blue (aka methylthioninium) is used (including intravenously) in various circumstances in the belief that it is ‘only a dye’; whereas it is active as an MAOI in usually administered dosages [1].  It inevitably interacts with pre-operatively administered SRIs — if they are present at therapeutically relevant concentrations — to precipitate serious, and sometimes fatal, serotonin toxicity (ST) [2-5].

Drugs that have clinically significant action as SRIs can precipitate severe ST in a patient treated with either a non-selective MAOI or MAO-A inhibitor.  Other opioids [bar the above-mentioned] are safe (because they have no SRI potency); that includes; codeine, oxycodone, hydrocodone, buprenorphine, morphine, remifentanil, alfentanil, sufentanil, and fentanyl.  These do not act as SRIs and there is no scientific evidence that they are causal, or contributory, in either serious or life-threatening ST —  i.e. ST resulting in potentially-lethal degrees of hyperthermia, and severe truncal rigidity; see [6].

It is important to understand that those opioids that do have weak SRI potency cannot precipitate severe ST when combined with other serotonin reuptake inhibitors, only when they are combined with MAOIs.

MAOI + SRI – potential severe ST. 

SRI + SRI – no problem.

See here for more detailed information.

One or two useful recent reviews are summarised and commented on, because they contain material that adds usefully to what I have discussed previously [7-10].

A storm in a teacup

The eminent clinical toxicologist, Professor Isbister, has explicated the opinion of the world-leading ‘Clinical Toxicology Research Group’ (from the University of Newcastle) in a recent discussion about CNS toxidromes and antidotes, ‘Therapeutics in clinical toxicology: in the absence of strong evidence how do we choose between antidotes, supportive care and masterful inactivity’ [11].

He reminds us that classifying each patient’s complex of symptoms and signs is far less important [because specific antidotes are rarely indicated] and can often result in the use of multiple inappropriate antagonists, causing further adverse effects.  A proper knowledge of the pharmacology of the implicated drugs, and Bayesian reasoning, is the foundation for analysis and (in)action (‘masterly inactivity’); i.e. drug cessation and supportive care is usually the best course of action, not specific antagonists.

Baldo & Rose’s excellent recent review [9] ‘The anaesthetist, opioid analgesic drugs, and serotonin toxicity: a mechanistic and clinical review’ contains much of academic value, including a thorough documentation and analysis of the many more recent case reports and the most complete references on basic research about the in vitro SRI potencies of opioids.  He concludes that:

‘Anaesthetists must maintain a heightened awareness of its [ST] possible occurrence and a readiness to engage in early treatment to avoid poor outcomes’.

This may be supplemented by adding, assuming there is an informed awareness that there could be a problem, that in the majority of cases (which involve SRI + SRI, not SRI + MAOI) there is little possibility of a serious or fatal outcome (from ST) as a result of a combination of drugs that only have serotonin reuptake inhibition (or other ‘non-MAOI’ serotonin-related activity) — therefore, Isbister’s counsel not to engage in overly aggressive intervention may be noted.

It is only combinations of MAOI/SRI that have the potential to cause serious and fatal ST — even then specific antidotes (5-HT2A antagonists) should be used cautiously.

While such symptoms and signs might not be induced by the addition of the opioid, that does not mean they are not mediated by serotonin and they may, on occasion, be significant enough to call toxicity.  There are many patients who have features of serotonin excess — that might not reach a degree of severity to justify labelling them as toxicity — solely from therapeutic doses of their SRIs.  Putting them in a stressful situation (an illness or condition requiring opioids for example) may be enough to make it manifest as ‘toxicity’.  Such cases reported as an opioid interaction resulting in ST, where mechanistically an interaction seems unlikely or impossible, may therefore reflect association rather than causation.

For instance; case reports of rapidly progressive life-threatening complications, e.g. seizures or coma, after low-to-moderate doses of fentanyl in the presence of an SSRI cannot be attributed to ST.  On the other hand, non-specific mild-to moderate symptoms or signs such as agitation, tremor, sweating, and (mild) clonus, have been described in patients on SSRIs receiving opioids that we know have no SRI potency — such symptoms are not necessarily serotonin-mediated, and do not really represent ‘toxicity’.  They might be contributed to by an indirect effect of decreased GABA-mediated inhibition of 5-HT release [12].

No other drugs used in anaesthesia have clinically significant SRI properties and therefore there are no other serotonin-related problems or ST. 

Clinical doses of ketamine for used for induction of anaesthesia, maintenance of analgesia, or treatment of depression, do not result in serotonin re-uptake inhibition (SRI).  Peak concentrations of ketamine when used for induction of anaesthesia may result in inhibition of norepinephrine reuptake and might theoretically result in exaggerated hypertension when used in the presence of MAO-A or non-selective MAO-AB inhibition; but this has not been reported.

Dexmedetomidine is not a problem; it decreases 5-HT release [13] and has been used to treat serotonin or serotonin+dopamine+adrenergic (i.e. methamphetamine) toxicity.

Ondansetron doses used for prophylaxis or treatment of PONV have not been associated with ST.  Indeed, because they are serotonin antagonists (not agonists), there is no pharmacological reason to suppose that they would be capable of that, despite warnings that have been issued by various ‘agencies’ including the FDA and the UK MHRA.  These warnings have been criticised and rebutted because they are based solely on poor quality and second-hand case reports which do not describe definite symptoms or signs of ST; more importantly, their pharmacological properties make that inherently implausible [14-20].

It should also be noted that it is important that surgeons and anaesthetists be aware of giving drugs that have ‘off-target’ action as MAOIs — examples at the moment are methylene blue (MB), used in various procedures (see other commentaries for details, and [1, 4, 21]), and high-dose linezolid for infections (NB see metaxalone, Skelaxin, below and separate commentary on metaxalone).  A proportion of the population take antidepressant drugs that act by serotonin reuptake inhibition (SSRIs and SNRIs), which will interact with MAOIs to precipitate ST.  Both MB and linezolid do have MAOI activity at high dosage/blood levels, and can thus precipitate serious or even fatal ST in those already on an SRI [4, 5, 22, 23].

As discussed below, extraordinary as it may seem, even now most comments and guidelines do not include this information about MB.

History and background

The idea that an anaesthetic cannot be given without first ceasing MAOIs is another of the deeply embedded and ill-founded concerns that one encounters about MAOIs.  The idea stems from a time when the interactions and toxicities of these drugs were not properly understood and information for doctors has not been revised and updated with our current understanding in subsequent texts, partly because of the disinterest in MAOI drugs; but also because of poor scholarship, poor pharmacological knowledge and poor refereeing of papers (see below).

This misconception about MAOIs and anaesthesia is of potentially fatal consequence, because poorly informed surgeons (some of whom act is if ‘pharmacology’ was a foreign-language word) may tell patients due for elective surgery to cease treatment, probably without consultation with the prescribing doctor, or being aware of their history, or the possibility of rapid relapse and suicide.  I have had experience of suicides from relapse of depression as a direct result of such ill-advised cessation of treatment — see [the farmers story].  Hence, my disparaging view of those surgeons (and anaesthetists) who are too ignorant and arrogant to ask for advice.

In ‘uncomplicated’ anaesthesia, apart from avoiding any use of narcotic analgesics with SRI potency, there are no major problems or interactions.  The preponderance of informed opinion has agreed with that view for some time [24-31]; however, some reviews and guidelines still contain erroneous information and advice (see below).

Major operations

For ‘major’ operations that might require treatment to raise or lower blood pressure there are some minor adjustments of dosage and agents that may be required, but there are no major obstacles or risks.

For instance, the hypotensive effect of MAOIs may potentiate blood pressure decreases with general anaesthesia or neuraxial anaesthesia.  A retrospective cohort study demonstrated less intraoperative hypotension in 26 patients on tranylcypromine, and no difference in the incidence of tachycardia, hypertension or bradycardia [29].

On the other hand, if vasopressor agents are required then directly acting alpha agonists may have their effects slightly potentiated — initial doses of  norepinephrine (noradrenaline), epinephrine (adrenaline) and phenylephrine may need to be lower when used in patients taking MAOIs [32].  These initial lower doses may then be rapidly titrated as needed without significant difficulty or inconvenience.

Particular care may be required where large amounts of ‘topical’ phenylephrine are used to control bleeding vascular beds (e.g. in ENT surgery), oxymetazoline may be preferred [33].

What were formerly referred to as ‘indirectly acting’ agents (ISAs, now commonly referred to by the preferred term ‘releasers’), like ephedrine, are the agents that are best avoided because they produce more pronounced and less predictable or controllable elevations of blood pressure.

Adrenaline (epinephrine) and noradrenaline (norepinephrine) are direct post-synaptic agonists and therefore do not cause any problematic interaction with MAOIs.  Equivocation about that has been evinced repeatedly over the years in most standard texts, yet the lack of any major interaction was established at the dawn of modern pharmacology by researchers whose names, Gaddum and Brodie, among others, are prominent in history [34-36].  That work has been forgotten.  It is TCAs that have a more pronounced interaction with adrenaline.  Ironically, I cannot recall anyone getting too worried about that.

In dental anaesthesia, if it is preferred to avoid adrenaline, then felypressin can be used instead.

A typical misleading case report

Pay-to-publish journals specialising in case reports have produced a veritable tsunami of nonsense which does not look like abating any time soon.  Many such reports are being published without any meaningful refereeing whatsoever.  The FDA ‘FAERS’ system is worse because it includes self-reports from the public (these are included in Baldo & Rose’s review and he cautiously expresses reservations about these).

Science is going has gone to the dogs.

For instance; a case report of an adult on HAART for HIV taking escitalopram and up to 40 mg of oral ondansetron daily [37] describes paroxysmal myoclonus (NB clonus, not myoclonus, is diagnostic of ST) that abated with a change in HAART with reduced nausea, and reduction, then discontinuation, of ondansetron.  This may have been associated with increased serotonergic neurotransmission related to a pharmaco-kinetic interaction that would elevate escitalopram blood levels, and thus increase its SEs.

No other symptoms of ST were present, so this is not ST and this report is unhelpful: it is jumping on the bandwagon of reporting supposed ST when it is in fact describing a well-known side-effect that has been recognised for over half a century.  It is absurd to describe it as toxicity.

Myoclonus is not the same as clonus***, and myoclonus is not a diagnostic feature of ST, although it is seen quite commonly (~10% of cases), but not in isolation [personal communication: data courtesy of Prof Whyte from their database, Nov 2019].  It is seen in therapeutic doses as an idiosyncratic, seemingly serotonin-mediated, SE with many SRIs, often occurring hypnagogically, and was recognised with clomipramine about 50 years ago (e.g. [38, 39]). 

*** the essential difference is that myoclonus is irregular, biphasic, and usually involves groups of muscles, not single muscles.  Clonus is mono-phasic, regular, and involves one set of opposing muscles (like the calf or biceps) [40]. Pathological clonus manifests with 10-12 beats, rather than just 2 or 3,

One suspects many of these poor case reports have not observed true pathological clonus, few reports have details, like the essential details of how many beats of clonus, whether it was present in the calf, greater in the lower than the upper limbs (as is typical in ST).

Recent demythologizing data

MAOIs and enzyme inhibition

More recent and reliable data on the effect of MAOIs on metabolic enzymes emanates from the research group of Prof Glen Baker (DSc) whose members have done much work in this area.  In a more recent paper, they state [41], of MAOIs:

None of these inhibitory effects are considered clinically significant at usual therapeutic doses. However, in certain situations such as high dose tranylcypromine therapy, or in poor metabolizers of CYP2C19 substrates, clinically significant interactions might occur, particularly when tranylcypromine is co-administered with drugs with a narrow therapeutic index.

Essentially, this is because none of the ‘irreversible’ MAOIs act as anything other than weak competitive inhibitors that only have significant action in the micromolar range, which is much higher than the concentrations achieved therapeutically.  Since tranylcypromine only has a half-life of about two hours that makes it improbable that it would maintain concentrations able to cause such interactions for long enough to make even a minor difference to the metabolism of other drugs.

The reversible drug Moclobemide (RIMA) is a weak inhibitor of 2D6 and 2C19 which might have some minor consequences [42, 43].

Much of the misunderstanding that has been promulgated in the literature originates from this old paper by Clark [44], which, it should be noted, predates the more sophisticated understanding of cytochrome P-450-based drug interactions.  It only suggested inhibition at concentrations way beyond the concentration achieved therapeutically.

SRI potency of opioids updated

Being so frequently obliged to make negative comments about publications in the ‘ST space’ it is good to be able to recommend the review by Baldo & Rose in the Br. J of Anaesthesia [9] which is a thorough and up-to-date review of many significant and recent references [7, 45-49].  It is the best and most recent source of references and data relating to SRI potency of opioids.

Provenance

I strongly recommend to readers to note that the experience and expertise of the people making case reports is of great relevance when interpreting them.  The above references are a good example of this, one of them being form Prof Isbister, who is a distinguished clinical toxicologist and has extensive experience in treating drug toxicity, particularly ST, (a long-time colleague of Prof Whyte at the Clinical Toxicology Research Group, University of Newcastle).  It would be prudent to take a great deal notice of what is said by all these authors, from this world-renowned research unit.

On the other hand, the Walczyk reference reporting ST with tapentadol is form a group of pharmacists — none of the four authors are doctors, never mind clinical toxicologists.  A pharmacist cannot make a report like this, which depends on experienced interpretation of complex clinical signs in a case of toxicity.  I hope readers give such reports the scant attention and credibility they deserve.

If you had a high-performance sports car would you take any notice of what a bicycle repair man said about what might be wrong with it?  It is classic Bayesian reasoning.  Ignore it at your peril.

Professor Isbister commented on Walczyk’s report, dismissing the notion it represented ST, and I quote from their response:

In all cases, the treatment must focus on removal (or reduction) of the implicated agent.  Classifying each patient’s complex of symptoms and signs is far less important and can often result in the use of multiple inappropriate antagonists, causing further adverse effects.  Supportive treatment is

far more important than the use of specific antagonists.  … Cases such as this one reported by Walczyk et al are best looked at through the lens of Bayesian analysis as to the most likely cause of the symptoms, with ideally an emphasis on supportive care of the overdose.

Guidelines and other pontifications: Ultracrepidarian issues

If anyone’s feathers are ruffled by my use of the word ‘pontification’, then they might pause for thought, and read on.

Since I initially posted this commentary one or two noteworthy publications have appeared including De Hert et al.; ‘Pre-operative evaluation of adults undergoing elective noncardiac surgery: Updated guideline from the European Society of Anaesthesiology’ [50].  I note that there is an amusing incongruity in a publication by the first author (De Hert), who later co-authored a paper concerning the unreliability of guidelines (Pitfalls of clinical practice guidelines in the era of broken science: Let’s raise the standards), with which I heartily agree [51].

Management of Psychiatric Medications During Perianesthesia Period’ by Trigo-Blanco & Oprea is another recent breath of fresh air and contains generally accurate information about MAOIs [52], although a citation they rely on [53] is less satisfactory and has some misinformation.

The authors of the De Hert et al. ‘Guideline’, have got themselves into a bit of a tangle and been ‘hoist by their own petard’.  They state:

We recommend stopping irreversible MAOI at least 2 weeks prior to anaesthesia.  In order to avoid relapse of underlying disease, medication should be changed to reversible MAOI [54]*.

*This reference [54] is Castanheira and Mercado.

First; patients are likely to have been exposed to a ‘reversible MAOI’ unsuccessfully prior to being put on an irreversible MAOI, making that suggestion superfluous (moclobemide is the only reversible MAOI on the market, and only in a few places — it was never approved for use in the USA).  Furthermore, most psychopharmacology specialists regard moclobemide as being substantially less effective.  They also mention ‘third generation MAOIs’ without indicating what that term means, if they know — indeed, the meaning is certain to be opaque to everyone, since this expression is not in in common currency.  To my knowledge, as an MAOI expert, it has only ever been used once in the literature by [55].  Ultracrepidarian (opining about things beyond one’s expertise).

Furthermore, De Hert et al. misrepresent the paper by Castanheira et al. [54] which states:

‘Thus, for patients undergoing elective surgery without major psychiatric risk to stopping therapy, it would be prudent to withhold MAO inhibitors; but, for patients undergoing urgent surgery or who are psychiatrically unstable without them, it appears that MAO inhibitors can cautiously be continued, along with care to avoid or minimize sympathomimetics, anticholinergics and meperidine’.

Castanheira et al. give no indication whatsoever of what an ‘MAOI-safe technique’ might be (it is not a defined or recognised concept); they provide no original data, but simply (mis)cite yet another paper (which itself self-cites another paper by the same senior author).  Such citation practices do not constitute scientific evidence (or any evidence at all) to support their contention.  Ultracrepidarian.

***Note that Mercado is the ‘senior author’ of the Castanheira et al. paper and is a general physician with no publications relevant to this subject, nor any apparent expertise in psychopharmacology.  Mercado’s text contains various errors, is and is well out of date, being now 15 years since publication — not the most felicitous of references to have used.

In support of their pontifications the Castanheira paper states ‘others agree’ (which hardly constitutes a scientific position or argument) and cites Mercado [56] , which is a self-citation.  It is very reassuring to know that Dr Mercado agrees with herself.

Mercado is opining in a vague and poorly informed manner.  Ultracrepidarian.

In stating ‘Thus, for patients undergoing elective surgery without major psychiatric risk to stopping therapy’ there is no recognition of the fact that it is unlikely that patients would be continuing such MAOI therapy, unless there was a significant risk of relapse on cessation.  These are not the kind of drugs that are taken for trivial reasons.  They provide no references or explanation for their view and evince no understanding of the pharmacological interactions that are relevant.  Ultracrepidarian.

Mercado also cites Michaels [57] in support, that paper is horribly misinformed (it classifies TCP as a reversible MAOI — a serious and consequential error of fact) and is way out of date; Mercado cites also El-Ganzouri [24] which is again 30 years out of date, but at least it does contain a little relevant original data.  Ultracrepidarian.

In summary: they have selected inappropriate references to start with, then they have misinterpreted them — just how inept can one get?

A recent review of anaesthesia for ECT by Zafirova does not recommend cessation MAOI treatment, although it is yet another example of a review by authors who obviously do not understand ST [58].  It is enough to make one weep in despair because it is full of misconceptions and inappropriate references [59].

Yet more errors are evident in a somewhat more recent citation; ‘Antidepressants and antipsychotics: anaesthetic implications’ [60], where Rasool says:

‘MAOIs decrease the dose requirement of thiopentone*.’ Phenelzine decreases plasma cholinesterase concentration and prolongs the action of suxamethonium.

*That is incorrect, and obviously is not true of all ‘MAOIs’, even if it could be true of one of them, even though the evidence they produce is weak and unreliable.  Either way, it’s a trivial non-problematic effect (see below).

It is poor academic practice to make general statements, as above, about the pharmacological properties of a group of drugs.  Such statements are almost inevitably going to be wrong, especially since many classes of drugs are defined as such via non-pharmacological properties.

Incidentally

Incidentally, not one of these guidelines or pontifications even mention methylene blue (which may be used intra-operatively — e.g. in thyroid surgery).  Considering how long the knowledge of MB’s MAOI potency has been in the academic space [1, 3] that reflects poor academic knowledge and thoroughness.  This is a serious error since these interactions (MB/SRI) have undoubtedly caused deaths.  Anyone who thinks my criticism of guidelines and similar documents is harsh might like to remember this example.  I am in good (and distinguished) company in my cynical opinions, as was drawn to my attention by Prof Whyte who quoted John Ioannidis [61] from his recent editorial discussing the removal of Peter Gøtzsche from the Cochrane group, under unsatisfactory and controversial circumstances:

“Despite valiant efforts to make them more evidence-based, guidelines, recommendations and exercise of policy power unfortunately remain among the least evidence-based activities, impregnable strongholds of expert-based insolence and eminence-based innumeracy [61].”

Impregnable strongholds of expert-based insolence and eminence-based innumeracy’ — it is refreshing to see someone so distinguished expressing clear and forthright opinions about such matters without equivocation and the usual pandering to propriety.

There are 1001 perceptive and acerbic quotes about committees, which may be applicable.

As Cecil Northcote Parkinson [his most well-known quote is ‘work expands to fill the time available’] said, ‘Deliberative bodies become decreasingly effective after they pass five to eight members’.  Most guidelines committees have well in excess of that number of members!  But perhaps we should allow Robert Copeland the last word, ‘To get something done a committee should consist of no more than three people, two of whom are absent.’

None of the above papers define what they mean when they use terms like first and second generation MAOIs, neither do they even mention selegiline or rasagiline or any of the other new irreversible selective drugs that are being used for Parkinson’s disease.  While vigilance is always indicated, use of MAO-B inhibitors like rasagiline (Azilect) and selegiline (Eldepryl, Zelapar) does not require avoidance of medications with SRI properties or norepinephrine releasers (e.g. ephedrine).  Patients who are using these medications at the recommended doses for the treatment of Parkinson’s disease should therefore not discontinue them peri-operatively.

It hardly needs saying that the authors of these documents evince a limited understanding of ST.  They come nowhere near explaining the pharmacology or rationale of these interactions, which is necessary if doctors are to learn and be enabled to practice logical and sensible medical pharmacology.

Will no-one protect us from the self-appointed experts who sit on these committees?  It is high time such people were held to account for the guidelines and pontifications that they pretentiously and portentously promulgate.

Myth and misinformation cost lives

These examples help readers to understand that the epithet of caveat lector must constantly be borne in mind, because myth, misinformation, and ultracrepidarianism cost lives.  We are deep into the territory in of unsubstantiated rumour and myth, carelessly repeated ad nauseam.

These patterns of iterations of misquotation and misunderstanding by authors who all seem to be wanting in their understanding of pharmacology are now tediously and embarrassingly common in modern academic writing.  No one seems to check their references, and worse still, nor do the referees.

I have lectured before about how the standards in the medical scientific literature have reached an all-time low.

In summary: we have a lamentable and dispiriting procession of poor scholarship, misunderstanding, misinformation, misinterpretation, mistakes, and misattribution.  It reflects little credit on academia and much of it represents the blind leading the blind, leading the blind.  Blindly.

Acknowledgements

I acknowledge advice, assistance, amendments, and corrections, during the drafting of this commentary by; Professor Rosenbaum and Prof Whyte

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