Issues for surgery
Risk of withdrawal symptoms and risk of relapse if omitted (see Further Information).
Risk of serotonin syndrome if continued, or if any doses taken in previous 2 weeks (see Interactions with common anaesthetic agents and Interactions with other common medicines used in the perioperative period).
Risk of hypertensive crisis if continued, or if any doses taken in previous 2 weeks (see Interactions with common anaesthetic agents and Interactions with other common medicines used in the perioperative period).
Advice in the perioperative period
Elective surgery
Plan elective surgery with anaesthetist and patient’s psychiatrist at earliest opportunity. The patient should be involved in these discussions.
If continuing MAOI
MAOI-safe anaesthesia should be used. Avoid:
- cocaine
- indirect-acting sympathomimetics (e.g. ephedrine, metaraminol)
- ketamine
- pethidine
- suxamethonium
Consider premedication with benzodiazepines to reduce stress as stress may lead to sympathetic stimulation.
If stopping MAOI
The manufacturers advise stopping irreversible MAOIs two weeks before elective surgery as it takes 2-3 weeks for enzyme levels to return to normal. However, there is little documentary evidence that withdrawal before anaesthesia is necessary and it has been suggested stopping is unreasonable as safe anaesthetic agents are available. Stopping an MAOI before elective surgery should be done gradually, with regular review of the patient and only on the recommendation of the patient’s psychiatrist because the risk of withdrawal and relapse must be considered.
Emergency surgery
Inform anaesthetist if patient received any doses of irreversible MAOI in last 2 weeks.
MAOI-safe anaesthesia will need to be used. Avoid:
- cocaine
- indirect-acting sympathomimetics (e.g. ephedrine, metaraminol)
- ketamine
- pethidine
- suxamethonium
Consider premedication with benzodiazepines to reduce stress as stress may lead to sympathetic stimulation.
Post-operative advice
If discontinued pre-operatively restart as soon as possible after the operation once there is no longer a risk of interactions. If switched to an alternative antidepressant pre-operatively follow management plan from patient’s psychiatrist.
If continued pre-operatively be alert to potential interactions (see Interactions with common anaesthetic agents and Interactions with other common medicines used in the perioperative period).
If a long nil by mouth (NBM) period is anticipated, or if there are concerns with enteral absorption, advice on alternative preparations/routes should be sought from a psychiatrist.
Interactions with common anaesthetic agents
Anaesthesia
General and regional anaesthesia can be given safely to patients taking MAOIs provided there is proper monitoring, adequate preparation and prompt recognition (and treatment) of anticipated and predictable reactions. Certain drugs should be avoided or used with extreme caution.
Inhalational anaesthetics (e.g. isoflurane and nitrous oxide) are all safe in the presence of MAOIs (although there is a theoretical risk of hepatic damage with halothane, which is no longer used in the UK). Intravenous induction agents (thiopental, propofol, etomidate and ketamine) have also been used without problem in patients taking MAOIs. However, ketamine should ideally be avoided due to potential sympathetic stimulation, although no interactions have been reported. A dose reduction may be necessary for barbiturates due to reduced hepatic metabolism.
Hypotension may occur following spinal anaesthesia in patients taking phenelzine or tranylcypromine due to an additive hypotensive effect.
Sympathomimetics
Vasopressors
Indirectly-acting sympathomimetics can lead to potentially fatal hypertensive crisis in patients taking irreversible MAOIs; therefore indirectly-acting sympathomimetics are absolutely contraindicated in patients who are taking or have taken MAOIs within the previous 2 weeks.
Directly-acting sympathomimetics (e.g. adrenaline / epinephrine, isoprenaline, noradrenaline / norepinephrine and phenylephrine) can be used safely in patients taking MAOIs, however, caution is advised as the effect is likely to be intensified and prolonged due to receptor hypersensitivity in those patients who have a hypotensive response to MAOIs. Doses should be carefully titrated. The manufacturers of dopamine recommend that the initial dose is reduced to one tenth of the normal dose and great care is taken. The response to parenteral phenylephrine is approximately doubled, and whilst the UK manufacturer contraindicates concurrent use, the US manufacturer does not.
Hypotension should initially be treated with fluids and then with cautious doses of directly-acting sympathomimetics titrated carefully against clinical response.
Local anaesthetics
Caution is advised with use of local anaesthetics and isocarboxazid or tranylcypromine as there may be potentiation of their effect. Concomitant use of local anaesthesia containing sympathomimetic vasoconstrictors with phenelzine or tranylcypromine is not recommended. In addition, as MAOIs probably augment the pressor effect of cocaine, concomitant use of cocaine is not recommended in patients who are taking phenelzine or tranylcypromine.
Opioids
CNS excitation (serotonin syndrome)
Some opioids act as weak serotonin reuptake inhibitors (SRIs) and can precipitate serotonin syndrome in conjunction with MAOIs.
- Pethidine – concurrent use of pethidine and an MAOI has resulted in serious and potentially fatal reactions, including central excitation, muscle rigidity, hyperpyrexia, circulatory collapse, respiratory depression and coma. Concurrent use is contra-indicated.
- Fentanyl – possibly increased risk of serotonergic effects when MAOIs given with fentanyl. There are conflicting reports in the literature with some case reports of serotonin toxicity, including fatalities, and others of uneventful use.
- Fentanyl congeners (alfentanil, remifentanil and sufentanil) are expected to be safer as they have short half-lives and are quickly reversible. Case reports describe safe use of alfentanil in patients taking phenelzine and tranylcypromine, remifentanil in patients taking phenelzine and sufentanil in patients taking tranylcypromine.
- Tramadol – it is suggested that tramadol causes release of serotonin as well as being an SRI. Case reports, including a fatality, have been reported. Concurrent use is not recommended. Furthermore, there is potential increased risk of seizures if tramadol is given to patients taking MAOIs.
CNS depression (opioid toxicity)
Patients taking MAOIs are at risk of opioid toxicity. MAOI inhibition of cytochrome P450 results in accumulation of opioids leading to respiratory depression, hypotension and coma. The reaction is mainly associated with morphine however serious adverse effects are predicted to occur with other opioids.
Recommendations
Dextromethorphan, methadone, pethidine, tramadol, fentanyl and tapentadol should be avoided in patients who are currently taking MAOIs or have taken any doses of MAOIs in the previous 14 days.
Morphine, codeine, oxycodone and buprenorphine are not thought to be inhibitors of serotonin reuptake so are preferred opioids for patients taking MAOIs, however caution is advised9. Morphine appears to be the strong opioid of choice – start with a low dose (a third to a half the normal dose) and titrate to clinical response. Monitor the patient carefully for any signs of adverse effects, particularly blood pressure and signs and symptoms of CNS and respiratory depression.
Neuromuscular Blocking Drugs (NMBDs)
Phenelzine prolongs the effects of suxamethonium by decreasing plasma cholinesterase concentrations.
Pancuronium should be avoided due to the release of stored noradrenaline. Atracurium appears to be a suitable alternative.
Interactions with other common medicines used in the perioperative period
CNS excitation (serotonin syndrome)
For a discussion of opioids see Interactions with common anaesthetic agents.
There is also an increased risk of developing serotonin syndrome when MAOIs are used concurrently with the following:
- granisetron
- ondansetron
- linezolid
- methylthioninium chloride (methylene blue)
Monitor patients for symptoms of serotonin syndrome such as fever, tremors, diarrhoea, and agitation. Concurrent treatment should be stopped if serotonin syndrome occurs.
Nefopam
Nefopam has sympathomimetic activity and may precipitate hypertensive crisis; the concurrent use of nefopam and an MAOI is contraindicated.
Further information
Withdrawal
MAOIs are associated with withdrawal symptoms on cessation of therapy. Withdrawal effects may occur within 5 days of stopping treatment and are usually mild and self-limiting but in cases may be severe. Symptoms include agitation, irritability, ataxia, movement disorders, insomnia, drowsiness, vivid dreams, cognitive impairment, and slowed speech. Withdrawal symptoms occasionally experienced when discontinuing MAOIs include hallucinations and paranoid delusions.
If possible MAOIs should be withdrawn slowly over at least 4 weeks. The risk of withdrawal is increased if MAOIs are stopped suddenly after regular administration for more than 8 weeks.
Relapse
In addition to the withdrawal effects stopping MAOIs prematurely is associated with a significant risk of relapse. In one study nearly 40% of patients switched from phenelzine to a placebo relapsed within four weeks, with half of those relapsing within two weeks.
Switching to moclobemide
It has been suggested that patients on irreversible MAOIs could switch to moclobemide, a reversible MAOI, two weeks pre-operatively allowing treatment to continue until the day before surgery. Some sources advise that irreversible MAOIs should be tapered then stopped for 2 weeks before starting moclobemide. However, other sources indicate a gap is not needed providing MAOI dietary restrictions are maintained for 10-14 days after switching. Such switches should only be instigated by the patient’s psychiatrist.
Dietary restrictions
Potentially life-threatening hypertensive crisis can develop in those taking MAOIs who eat tyramine-rich food (e.g. mature cheese, salami, pickled herring, Bovril®, Oxo®, Marmite® or any similar meat or yeast extract or fermented soya bean extract, and some beers, lagers or wines) or foods containing dopa (such as broad bean pods). Patients should avoid tyramine or dopa-rich food or drinks whilst taking irreversible MAOIs (and for 2 to 3 weeks after stopping irreversible MAOIs).
References
Luck JF, Wildsmith JAW & Christmas DMB. Monoamine Oxidase Inhibitors and Anaesthesia. The Royal College of Anaesthetists. 2003; Bulletin 21:1029-1034
Summary of Product Characteristics – Nardil ® (phenelzine) Tablets. Kyowa Kirin Limited. Accessed via www.medicines.org.uk 11/06/2019 [date of revision of the text February 2017]
Summary of Product Characteristics – Isocarboxazid Tablets 10mg. Alliance Pharmaceuticals. Accessed via www.medicines.org.uk 11/06/2019 [date of revision of the text February 2019]
Summary of Product Characteristics – Tranylcypromine 10mg Tablets. ADVANZ Pharma. Accessed via www.medicines.org.uk 11/06/2019 [date of revision of the text July 2017]
Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 11th June 2019]
Phenelzine. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. Electronic version. Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com. [Accessed 20th June 2019]
Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 11th June 2019]
Summary of Product Characteristics – Dopamine 40 mg/ml Concentrate for solution for infusion. Consilient Health Ltd. Accessed via www.medicines.org.uk 19/06/2019 [date of revision of the text October 2016]
Specialist Pharmacy Service. What is the risk of interaction between opioids and monoamine oxidase inhibitors (MAOIs)? (2017). Available at: www.sps.nhs.uk [Accessed on 22nd June 2019]
Taylor D, Barnes T, Young A. The Maudsley Prescribing Guidelines in Psychiatry. 13th ed. Chichester: Wiley-Blackwell; 2018.
Summary of Product Characteristics – Manerix® (moclobemide) 300mg. Mylan. Accessed via www.medicines.org.uk 19/06/2019 [date of revision of the text February 2018]
Bazire S. Psychotropic Drug Directory 2016. The Professionals’ Pocket Handbook and Aide Memoire. Dorsington: Lloyd-Reinhold Publications Limited. 2016.