MAOIs and anaesthesia

by | Last updated Sep 13, 2019 | Published on Apr 24, 2019 | Anti-Depressants, MAOIs

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

In brief

The issue in most anaesthesia, and post-operative periods, is the avoidance of drugs, particularly analgesics, that act as SRIs, viz. meperidine (pethidine), tramadol, tapentadol, dextromephorphan, dextropropoxyphene, and pentazocine.  Such drugs, that have action as SRIs, can precipitate serotonin toxicity.  Other opioids like codeine, oxycodone, morphine, and fentanyl, are safe (see [1].  See here for more detailed information.

No other drugs used in routine anaesthesia have SRI properties and therefore there are no other problems.

It really is that simple for most anaesthetic procedures.

But it may also be noted that it is important that surgeons and anaesthetists be aware of giving drugs that act as MAOIs — examples at the moment are methylene blue (MB), used in various procedures (see other commentaries for details) and high-dose intravenous linezolid for infections.  This is because a significant proportion of the population take antidepressant drugs that act by serotonin reuptake inhibition (SSRIs and SNRIs), which will interact with MAOIs.  Both MB and linezolid can have MAOI activity at high dosage levels or high blood levels, and can thus precipitate serious or even fatal serotonin toxicity in those already on an SRI [2-5].

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

History

The idea that an anaesthetic cannot be given without first ceasing MAOIs is yet 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 has not been revised and updated in most texts since that time (see below), partly because of the low usage of, and disinterest in, MAOI drugs and partly because of pure ignorance of pharmacology.

Sadly, this misconception is not inconsequential, 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 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 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 published opinion is, fortunately, lining up behind that view [6-13], even though some guidelines still contain significantly erroneous information and advice (see below).

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.  For instance, the hypotensive effect of MAOIs may mean that intra-operative hypotensive measures may be potentiated, and accordingly doses of such drugs may need to be lower.  On the other hand, if vasopressor agents are required then directly acting alpha agonists may have their effects slightly potentiated, that means norepinephrine, epinephrine and phenylephrine doses may need to be slightly lower when used in patients taking MAOIs.

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

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

Guidelines and other pontifications

Since I initially posted the above one or two noteworthy publications have appeared including; ‘Pre-operative evaluation of adults undergoing elective noncardiac surgery: Updated guideline from the European Society of Anaesthesiology [14].  There is an element of incongruity in another contemporaneous publication by one of these authors concerning the unreliability of guidelines, with which I heartily agree [15].

If anyone’s feathers are ruffled by my use of the term pontificate, then they should pause for thought.

I would suggest that to some extent these authors (De Hert et al.) have 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 [16].

First; patients are likely to have been exposed to that drug unsuccessfully prior to being put on an irreversible MAOI, making that suggestion superfluous (i.e. moclobemide, the only one that is on the market now, at least in some places — it was never approved for use in the USA).  Also, most specialists would regard moclobemide as being substantially less effective anyway.  Furthermore, they commit the error of citing a paper that has no original data itself, but simply (mis)cites another paper (which itself cites another paper) and therefore does not constitute good or scientific evidence to support the contention they make.  They (mis)cite Castanheira, who says;

For patients currently taking monoamine oxidase inhibitors (MAOI) and scheduled for surgery, if MAOI-safe technique anaesthesia is used, MAOI should be continued until the day of surgery, inclusively. 
If MAOI-safe technique* anaesthesia cannot be used, MAOI should be discontinued 2 weeks before surgery.  After surgery, MAOI should be restarted with oral intake.

*They give that no definition of, or reference to, what they consider an ‘MAOI-safe technique’ might be. 

Routine anaesthesia is safe.

In support of their pontifications Castanheira states ‘others agree’ and cites Mercado [17].  Mercado:

‘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’.

However, Mercado is just opining, somewhat thoughtlessly in my view.  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 on such MAOI therapy, unless there was a significant risk of relapse on cessation.  They provide no references or explanation for their view and evince no understanding of the pharmacological interactions that are relevant.

Thus, we have the blind leading the blind, leading the blind.  Blindly.

These are iterations of misquotation and misunderstanding (by authors who all seem to be deficient in their understanding of pharmacology) — this is embarrassingly common in modern academic writing when no one seems to check their references properly (nor do the referees, as I have said on previous occasions).

Yet more errors are evident in; ‘Antidepressants and antipsychotics: anaesthetic implications’ [18], where Rasool says:

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

*First, 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 a cardinal sin to make general statements, as above, about the pharmacological properties of a group of drugs.  Such statements are inevitably going to be wrong, especially since many classes of drugs are defined as such via non-pharmacological properties.

As the above examples illustrate, we are deep into the territory in of unsubstantiated rumour and myth, carelessly repeated ad nauseam.  I give these examples in order to help readers understand that the epithet of caveat lector must constantly be borne in mind.   Trust no one.

Recent data

More recent and reliable data on the effect of MAOIs on metabolic enzymes emanates from Prof Glenn Baker’s research group whose members have done more work in this area than everyone else put together.  In a more recent paper, they state [19], 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 coadministered 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 even less likely that it would maintain concentrations sufficient 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 [20, 21].

I suspect much of the misunderstanding that has been promulgated in the literature originates from this old paper by Clark, which, it may be noted, predates the more sophisticated understanding of cytochrome P-450-based drug interactions [22].  It only suggested inhibition at concentrations way beyond the concentration achieved therapeutically.

A recent review of anaesthesia for ECT does not recommend cessation MAOI treatment, although it is yet another example of a review by authors who obviously do not understand serotonin toxicity [23].  The review by Zafirova is enough to make one weep in despair because it is full of misconceptions and inappropriate references [24], if the refereeing system was functioning properly it would never have seen the light of day.

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 that knowledge has been in the academic space [25, 26] that reflects poor academic knowledge and thoroughness.  This is a serious error since these interactions (MB/SRI) have undoubtedly caused a number of deaths.  Anyone who thinks my criticism of guidelines and similar documents is harsh might like to remember this example.  There are 1001 good and witty quotes about committees, many of which are undoubtedly applicable to many of these bodies.

None of the above 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.

It hardly needs saying that the authors of these documents evince a poor understanding of serotonin toxicity.  They come nowhere near explaining the pharmacology or rationale of these interactions, which is absolutely necessary if doctors are to learn and be enabled to practice logical and sensible medical pharmacology [4].

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.

References

 

  1. Gillman, P.K., Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. British Journal of Anaesthesia, 2005. 95(4): p. 434-441.
  2. Chapin, J.W., et al., Serotonin Toxicity after Administration of Methylene Blue for Vasoplegia. Anesthesiology, 2011. A1203 October 18: p. http://www.asaabstracts.com/strands/asaabstracts/abstract.htm;jsessionid=CF56798584D09F70CF58376698762F4F?year=2011&index=2&absnum=4403.
  3. Gillman, P.K., Methylene Blue: A Risk for Serotonin Toxicity. Australian and New Zealand College of Anaesthetists Bulletin, 2008. 17: p. 36.
  4. Gillman, P.K., CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of Psychopharmacology, 2011. 25(3): p. 429-3.
  5. Schwiebert, C., C. Irving, and P.K. Gillman, Small doses of methylene blue, previously considered safe, can precipitate serotonin toxicity. Anaesthesia, 2009. 64: p. 924-924.
  6. el-Ganzouri, A.R., et al., Monoamine oxidase inhibitors: should they be discontinued preoperatively? Anesthesia and Analgesia, 1985. 64(6): p. 592-6.
  7. Remick, R.A., P. Jewesson, and R.W. Ford, Monoamine Oxidase Inhibitors in General Anesthesia: A Reevaluation. Convulsive Therapy, 1987. 3(3): p. 196-203.
  8. Ebrahim, Z.Y., et al., Monoamine oxidase inhibitors and elective surgery. Cleve Clin J Med, 1993. 60(2): p. 129-30.
  9. Cameron, A.G., Monoamine oxidase inhibitors and general anaesthesia. Anaesthesia and Intensive Care, 1986. 14(2): p. 210.
  10. Noorily, S.H., C.B. Hantler, and E.Y. Sako, Monoamine oxidase inhibitors and cardiac anesthesia revisited. Southern Medical Journal, 1997. 90(8): p. 836-8.
  11. van Haelst, I.M., et al., Antidepressive treatment with monoamine oxidase inhibitors and the occurrence of intraoperative hemodynamic events: a retrospective observational cohort study. J Clin Psychiatry, 2012. 73(8): p. 1103-1109.
  12. Krings-Ernst, I., S. Ulrich, and M. Adli, Antidepressant treatment with MAO-inhibitors during general and regional anesthesia: a review and case report of spinal anesthesia for lower extremity surgery without discontinuation of tranylcypromine. Int J Clin Pharmacol Ther, 2013. 51(10): p. 763-70.
  13. Wells, D.G. and A.R. Bjorksten, Monoamine oxidase inhibitors revisited. Canadian Journal of Anaesthesia, 1989. 36(1): p. 64-74.
  14. De Hert, S., et al., Pre-operative evaluation of adults undergoing elective noncardiac surgery: Updated guideline from the European Society of Anaesthesiology. Eur J Anaesthesiol, 2018. 35(6): p. 407-465.
  15. Afshari, A. and S. De Hert, Pitfalls of clinical practice guidelines in the era of broken science: Let’s raise the standards. Eur J Anaesthesiol, 2018. 35: p. 903–906.
  16. Castanheira, L., P. Fresco, and A.F. Macedo, Guidelines for the management of chronic medication in the perioperative period: systematic review and formal consensus. J Clin Pharm Ther, 2011. 36(4): p. 446-67.
  17. Mercado, D.L. and B.G. Petty, Perioperative medication management. Med Clin North Am, 2003. 87(1): p. 41-57.
  18. Rasool, F., R. Ghafoor, and D. Lambert, Antidepressants and antipsychotics: anaesthetic implications. Anaesthesia & Intensive Care Medicine, 2011. 12(4): p. 166-169.
  19. Salsali, M., A. Holt, and G.B. Baker, Inhibitory effects of the monoamine oxidase inhibitor tranylcypromine on the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP2D6. Cell Mol Neurobiol, 2004. 24(1): p. 63-76.
  20. Gram, L.F., et al., Moclobemide, a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6, and CYP1A2: a panel study. Clinical Pharmacology and Therapeutics, 1995. 57(6): p. 670-7.
  21. de Leon, J., M.T. Susce, and E. Murray-Carmichael, The AmpliChip CYP450 genotyping test: Integrating a new clinical tool. Mol Diagn Ther, 2006. 10(3): p. 135-51.
  22. Clark, B., J. Thompson, and G. Widdrington, Analysis of the inhibition of pethidine N‐demethylation by monoamine oxidase inhibitors and some other drugs with special reference to drug interactions in man. British journal of pharmacology, 1972. 44(1): p. 89-99.
  23. Bryson, E.O., et al., Individualized Anesthetic Management for Patients Undergoing Electroconvulsive Therapy: A Review of Current Practice. Anesth Analg, 2017. 124(6): p. 1943-1956.
  24. Zafirova, Z., K.G. Vázquez-Narváez, and D. Borunda, Preoperative Management of Medications. Anesthesiology clinics, 2018. 36(4): p. 663-675.
  25. Gillman, P.K., Methylene Blue implicated in potentially fatal serotonin toxicity. Anaesthesia, 2006. 61: p. 1013-1014.
  26. Ramsay, R.R., C. Dunford, and P.K. Gillman, 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.

 

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