What is the risk of interaction between opioids and monoamine oxidase inhibitors (maois)?

Medicines Q&As

What is the risk of interaction between opioids and monoamine oxidase inhibitors (MAOIs)?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals

Before using this Q&A, read the disclaimer at https://www.sps.nhs.uk/articles/about-ukmi-medicines-qas/

Date prepared: June 2017

Background

The interaction between MAOIs and opioids can take on either of two distinctive forms (1-4):

• 
  CNS excitation - serotonin syndrome
  
• 
  CNS depression - opioid toxicity
  

The BNF advises that the use of opioids in a patient who has taken an MAOI in the last two weeks should be avoided if possible and only undertaken with caution and appropriate monitoring, due to possible CNS depression or excitation (4). Many summaries of product characteristics for both opioids and MAOIs advise avoidance of, or caution with, the combination. However, not all opioid analgesics have been reported to cause problems and safe use of some combinations has been described.

Serotonin Syndrome

Serotonin syndrome can be described as a drug-induced excess of serotonergic activity at central receptors (3). The characteristic symptoms fall into 3 main areas, although features from each group may not be seen in all patients (4,5):

1. 
   Neuromuscular hyperactivity; tremor, clonus, myoclonus, hyper-reflexia and (in the advanced stage) rigidity.
   
2. 
   Autonomic hyperactivity; diaphoresis, fever, tachycardia and tachypnoea.
   
3. 
   Altered mental status; agitation, excitement and (in the advanced stage) confusion.
   

Clinical features can range from mild and transient to severe and life-threatening (3,4,6). Fatalities have occurred (1). The onset of serotonin syndrome is often within minutes of altering a drug regimen, although there have also been some delayed reactions. The occurrence and severity do not appear to be dose related, but are due to the extent and duration of the rise in intrasynaptic serotonin (3). Controversially, other sources have claimed there is a dose-effect relationship to the reaction (5). Current thinking favours the spectrum concept of ‘serotonin toxicity’ as a continuum of serotonergic effects (7). For a review of serotonin syndrome see UKMi Q&A What is serotonin syndrome and which medicines cause it? (7).

Drugs Associated with Serotonin Syndrome

There is a risk of serotonin syndrome when serotonergic drugs are combined. Serotonergic classes of drugs include MAOIs, tricyclic antidepressants, selective serotonin re-uptake inhibitors (SSRIs), opioids (including the structurally related over-the-counter cough suppressants dextromethorphan and pholcodine), 5-HT₁-receptor agonists (“triptans”), weight reduction agents, some anti-emetics, drugs of abuse and herbal products (6).
MAOIs that are irreversible or non-selective or that inhibit MAO subtype A, are strongly associated with severe cases of serotonin syndrome (6). The selective inhibitor of monoamine oxidase type B, selegiline, may also pose problems at high doses as its selectivity starts to diminish (3). In addition to medicines deliberately used for their inhibition of MAO, a number of other drugs have MAOI activity, including linezolid, tedizolid (4) and methylthioninium chloride (“methylene blue”) (8).
There is evidence that some opioid analgesics act as serotonin re-uptake inhibitors: fentanyl (and congeners), pethidine, tramadol, methadone, and dextromethorphan (1,5). Additionally, it has been suggested that tramadol releases serotonin (9). Morphine, codeine, oxycodone and buprenorphine are not thought to be inhibitors of serotonin reuptake (1,5).

Opioid Toxicity

Some reactions involving MAOIs and opioid analgesics present as cases of opioid toxicity (respiratory depression, hypotension, coma) instead of serotonin syndrome (1,3). Opioid toxicity is caused by CYP450 inhibition by the MAOI leading to accumulation of opioid (3). This reaction is primarily associated with morphine, but serious adverse effects are predicted to occur with the concurrent use of other opioids (such as buprenorphine, codeine, diamorphine, dihydrocodeine, dipipanone, hydromorphone, meptazinol, methadone and oxycodone) and the MAOIs, although there do not appear to be any published reports of an interaction (1).

Answer

There are few systematic studies of interactions between an MAOI and an opioid. These are not recent and measure different outcomes from those now included in the definition of serotonin syndrome (3,5,6). Because of the lack of study data and the difficulty in defining and diagnosing serotonin syndrome, it is difficult to draw any definite conclusions (1,2). Almost all information is based on numerous case reports –see the table on page 4 for a summary.
A study comparing intramuscular injections of water, pethidine and morphine found no significant difference between rises in blood pressure in patients receiving phenelzine or isocarboxazid (or other MAOIs that are no longer available) (2). This study was not powered and the low number of patients (n=15) was the reason given by the authors for the lack of a significant difference (2). Gillman points out that due to a lack of understanding and a definition of serotonin syndrome, the parameters assessed were inappropriate and the results of this study do not reflect the clinical importance of the pethidine interaction seen in case reports (5).
Opioids that should usually be avoided in combination with a MAOI

Given the widespread availability of several suitable alternative drugs, the combination of the following drugs with an MAOI (or reversible MAOI) should usually be avoided, including in the 14 day period following the discontinuation of an irreversible MAOI:

Pethidine (1,3,5,6,10-15)

The interaction between pethidine and MAOIs is based on several case reports (1). The reaction may be idiosyncratic and the severity is unpredictable, but it is potentially fatal. Dose-dependence has not been verified. The use of test doses has been suggested, but seems unnecessary given the availability of alternatives to both pethidine and MAOIs. A literature review of the interaction between linezolid and a range of serotonergic drugs (including pethidine) suggests a serotonin syndrome incidence of 0.24-4% and a variable onset time of the interaction (<1 to 20 days) after co-administration (10). Due to the lack of evidence and potential harm, the combination should be avoided (1,3).

Dextromethorphan (1,3,5,6,11-15)

Fatalities have occurred in patients taking dextromethorphan with phenelzine; the related cough suppressant, pholcodine, is predicted to interact similarly (1).

Tramadol (1,3,5,8,9,13,15)

Case reports, including a fatality, have been reported with tramadol and MAOIs (1). Animal studies have shown increased deaths with concurrent administration of tramadol and MAOIs (8). Seizure potential should be borne in mind if given together as this combination may increase the risk of seizures (1,8).

Methadone (5,13,16-18)

Methadone is a weak serotonin reuptake inhibitor which has been implicated in serotonin toxicity when given alongside an MAOI (5,13). Some sources state concurrent use of MAOIs as an absolute contraindication for methadone (16). However, published reports of interactions between MAOIs and methadone are lacking (1,17) and concurrent use has been reported without mishap (3,18).

.

Fentanyl (1,5,9,12-15,18)

Fentanyl is known to be serotonergic (15). There is conflicting information in the literature regarding the risk of an interaction with MAOIs. Some reviewers have stated that it is safe when co-administered with MAOIs (12-14,18) and there are reports of the uneventful use of this combination (see table). However, there have been case reports of serotonin toxicity including fatalities with this combination (1,9,15). If concomitant use is unavoidable, strict monitoring for serotonin syndrome is necessary (15).

Tapentadol (3)

Although there are currently no case reports, it may be prudent to avoid the combination of tapentadol and a MAOI, as this opioid also inhibits the reuptake of noradrenaline (3).

Opioids that may be used cautiously in combination with a MAOI

Morphine, codeine, oxycodone and buprenorphine have been described as the preferred opioids for use in patients taking MAOIs, because they are not thought to be inhibitors of serotonin reuptake (1, 5,13). Some sources suggest morphine is the strong opioid of choice in patients receiving MAOIs and requiring emergency or elective surgery (3,18,19). Case reports describe the uneventful use of alfentanil and remifentanil in patients taking MAOIs (1,3). These fentanyl congeners have short half-lives and may be expected to be safer because they are quickly reversible (5).
However, any opioid should be used with caution in patients taking an MAOI, making use of test doses and frequent titration of small doses against pain. The patient should be closely monitored for signs and symptoms of CNS and respiratory depression (3,12,17). One author suggests initiating opioids at a third or half the normal dose (17).
When assessing the risk of combining an opioid with an MAOI, it is important to consider any other serotonergic drugs the patient is taking. One literature review suggested that use of a variety of opioids (e.g. fentanyl, morphine and hydromorphone) plus any antidepressant with serotonergic activity, might be a risk factor for the development of serotonin syndrome. Co-administration of linezolid (an antimicrobial) increases the risk (20). The authors therefore suggest that opioid use with linezolid should be minimised (20).

Summary

• 
  The use of most MAOIs with opioids is contraindicated or cautioned by manufacturers. There is conflicting information in the literature about the degree of risk of an interaction.
  
• 
  Some opioid analgesics are associated with a risk of serotonin syndrome in combination with MAOIs due to their serotonergic properties. Other combinations may result in opioid toxicity due to CYP450 enzyme inhibition by the MAOI.
  
• 
  Any trials conducted in this field are not recent and measured different outcomes from those now included in the definition of serotonin syndrome. This means almost all information is based on case reports.
  
• 
  Given the widespread availability of several suitable alternative drugs, the combination of dextromethorphan, methadone, pethidine, tramadol, fentanyl or tapentadol with an MAOI should usually be avoided, including in the 14 day period following the withdrawal of an irreversible MAOI.
  
• 
  Morphine, codeine, oxycodone and buprenorphine are alternative opioids for patients receiving MAOIs, though starting at a low dose and titrating cautiously against clinical response is advised. Blood pressure and the signs and symptoms of CNS and respiratory depression should be monitored closely.
  

The table below represents a summary of evidence for the use of various MAOI and opioid combinations:

Buprenorphine

Codeine

Dextromethorphan^i

Dextropropoxyphene

Diamorphine

Dipipanone

Dihydrocodeine

Fentanyl^e

Alfentanil^f

Remifentanil^f

Hydromorphone

Meptazinol

Methadone

Morphine^b

Oxycodone

Papaveretum

Pentazocine

Pethidine^a,c,j

Pholcodine

Tapentadol

Tramadol^g,h

Isocarboxazid

O1

O1

S3

OS1

O1

O1

O1

OS2

OS1

OS1

O1

O1

OS1

O2

O1

O1

O1

S2 O1

S1

OS1

OS1

^a,d,h,iLinezolid

O1

O1

S3,2

OS1

O1

O1

O1

OS1

OS1

OS1

O1

O1

OS1

O1

O1

O1

O1

S3 O1

S1

OS1

O1 S3

^eMethylthioninium chloride (methylene blue)

O1

O1

S1

OS1

O1

O1

O1

O1 S3

OS1

OS1

O1

O1

OS1

O1

O1

O1

O1

OS1

S1

OS1

OS1

^dMoclobemide

O1

O1

S3

OS1

O1

O1

O1

OS1

OS1

OS1

O1

O1

OS1

O1

O1

O1

O1

S3 O1

S1

OS1

O1 S3

^b,jPhenelzine

O1

O1

S3

S3 O3

O1

O1

O1

OS2 S3

OS2

OS2

O1

O1

OS1

O3,2 S3,2

O1

O1

O1

S3,2 O1

S1

OS1

O1 S3

^cRasagiline MAOI-B

O1

O1

S1

OS1

O1

O1

O1

OS1

OS1

OS1

O1

O1

OS1

O1

O1

O1

O1

OS1

S1

OS1

OS1

^cSelegeline MAOI-B

O1

O1

S1

OS1

O1

O1

O1

OS1

OS1

OS1

O1

O1

OS1

O1

O1

O1

O1

O1 S3

S1

OS1

OS1

^dTedizolid

O1

O1

S1

OS1

O1

O1

O1

OS1

OS1

OS1

O1

O1

OS1

O1

O1

O1

O1

OS1

S1

OS1

OS1

^e,jTranylcypromine

O1

O1

S1

OS1

O1

O1

O1

OS2 S3

OS2

OS1

O1

O1

O2 S1

O3,2

O1

O1

O1

S3,2 O1

S1

OS1

OS1

O Combination may result in opioid toxicity 3 Case reports of harm

S Combination may result in serotonin syndrome 2 Case reports of safe use

OS Combination may result in either/both 1 No case reports identified

Specific Advice

^a Serotonin syndrome has been reported with this combination (1,21). Unless there are facilities available for close observation and monitoring for blood pressure, linezolid should not be administered to patients on pethidine (1).
^b Various sources recommend using morphine as an alternative to pethidine in patients receiving MAOIs. Hypotensive reactions have been seen but are of a different character to the severe reaction seen with pethidine and appear to be rare (1). It is advised to start with a low initial dose of morphine and titrate to clinical response (3,12,17). A case of serotonergic adverse effects has been reported in a patient given phenelzine and morphine (22).
^c Although selective for MAO type B, selegiline and rasagiline lose their selectivity when used at increasing doses, posing the risk of serotonin syndrome. A case of fluctuating stupor and agitation, with muscle rigidity, sweating and a raised temperature has been reported when pethidine was used with selegiline (1). Rasagiline is expected to interact similarly (1). Some manufacturers contra-indicate the use of selegiline with pethidine or other opioids (23).

^d As moclobemide is a reversible MAOI, it is unlikely to interact 24 hours after it has been stopped (1). Linezolid and tedizolid are also reversible MAOIs (4).
^e Fentanyl has been described as a weak serotonin reuptake inhibitor (22). Whilst fentanyl has been given to patients taking MAOIs without problems (1,3) cases have been reported of serotonergic type reactions associated with concurrent use (1,5,9). A death associated with fentanyl in a patient taking tranylcypromine has been cited in a review paper as evidence of a fatal serotonin syndrome reaction induced by fentanyl use (5). However, the authors of the original case report stated that there was insufficient evidence to make any definitive conclusion concerning the safety of fentanyl in patients taking MAOIs (5,24). Another case report links serotonin syndrome to the concurrent use of fentanyl and methylthioninium (methylene blue) (25). While causality is not confirmed, this report highlights the importance of being aware of the potential for reactions even when low doses of drugs, used routinely in the perioperative setting, are given. Advice from manufacturers reflects this conflicting information. Some contraindicate the use of fentanyl within two weeks of taking an MAOI (26) while others suggest use of fentanyl alongside MAOIs should be cautious and state that serotonin syndrome may occur within the recommended dose (27). This combination should only be used if there is no suitable alternative and patients should be closely monitored (24).

^f As alfentanil and remifentanil have shorter half-lives than fentanyl, they would be expected to be safer (5).
^g Tramadol has serotonergic effects and manufacturers contraindicate concurrent use with MAOIs (28). Whilst the clinical evidence for an interaction is limited, Stockley recommends close monitoring for serotonin syndrome if used together (1).
^h A review of postmarketing data identified a case of suspected serotonin syndrome in a patient receiving linezolid, tramadol and paroxetine, all of which are known to inhibit serotonin re-uptake (29). If the combination of linezolid and tramadol is clinically necessary, the patient should be monitored for signs of serotonin syndrome (4).
ⁱ Two fatal case reports of hyperpyrexia and coma (similar to serotonin syndrome) with the combination of dextromethorphan and phenelzine. Three other serious reactions reported with the combination of dextromethorphan and either phenelzine and isocarboxazid (1). However, some of these cases were complicated by overdose and the use of multiple interacting drugs (1). There is no pharmacokinetic interaction between dextromethorphan and linezolid, but there is one case report of concurrent use resulting in serotonin syndrome (1).
^j Severe, toxic reactions including loss of consciousness and death have been reported following a single dose of pethidine in patients taking tranylcypromine or phenelzine respectively (1,30).
Limitations

• 
  Opioid analgesics and MAOIs are defined as per the BNF latest edition
  
• 
  In addition, methylthioninium chloride (methylene blue) included as an MAOI
  
• 
  In addition, dextromethorphan and pholcodine included as opioids
  

References

1. Preston CL, editor. Stockley’s Drug Interactions. London: Pharmaceutical Press. Electronic version accessed via www.medicinescomplete.com on 12/04/2017.

2. Evans-Prosser CDG. The use of pethidine and morphine in the presence of monoamine oxidase inhibitors. Br J Anaesth 1968; 40: 279-82.

3. Brayfield A, editor. Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Accessed via www.medicinescomplete.com on 12/04/2017.

4. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. Accessed via http://www.medicinescomplete.com on 12/04/2017.

5. Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth 2005; 95: 434-41.

6. Boyer EW, Shannon M. Current Concepts: The Serotonin Syndrome. N Engl J Med 2005; 352: 1112-1120.

7. McKie J. What is serotonin syndrome and which medicines cause it? Accessed via https://www.sps.nhs.uk/articles/what-is-serotonin-syndrome-and-which-medicines-cause-it-2/ on 26/04/2017.

8. McEvoy GK, editor. AHFS Drug Information. Accessed via www.medicinescomplete.com on 26/4/2017.

9. Barann M, Stamer UM, Lyutenska M. Effects of opioids on human serotonin transporters. Arch Pharmacol (2015) 388:43-49.

10. Ramsey TD, Lau TTY, Ensom, MHH. Serotonergic and adrenergic drug interactions associated with linezolid: a critical review and practical management approach. Ann. Pharmacother. 2013; 47:543-559.

11. Lecrubier Y. Risk-benefit assessment of newer versus older monoamine oxidase (MAO) inhibitors. Drug Safety 1994,10:292-300.

12. Rossiter A, Souney PF. Interaction between MAOIs and opioids: pharmacologic and clinical considerations. Hosp Formul 1993, 28: 692-698.

13. Lum CT, Stahl SM. Opportunities for reversible inhibitors of monoamine oxidase-A (RIMAs) in the treatment of depression. CNS Spectrums 2012; 17:107-120.

14. Rapaport MH. Dietary restrictions and drug interactions with monoamine oxidase inhibitors: the state of the art. J Clin Psychiatry 2007, 68(suppl 8):42-46.

15. Drugdex Drug Evaluations for linezolid Micromedex® 2.0 (healthcare series): (Last modified: 27/01/2015) Accessed via http://www.micromedexsolutions.com/home/dispatch on 21/06/2017.

16. Nicholson AB. Methadone for cancer pain (review). Cochrane Database Syst Rev. 2007; 17(4):CD003971.

17. Bazire S. Psychotropic Drug Directory 2016. Lloyd-Reinhold Publications Limited.

18. Stack CG, Rogers P, Linter SPK. Monoamine oxidase inhibitors and anaesthesia. Br J Anaesth1988, 60:222-227.

19. Pedavelly S, Fugate JE, Rabinstein AA. Serotonin syndrome in the intensive care unit: Clinical presentations and precipitating medications. Neurocrit Care 2014; 21:108-113.

20. Huang V, Gortney, JS. Risk of serotonin syndrome with concomitant administration of linezolid and serotonin agonists. Pharmacother. 2006; 26:1784-1793.

21. Das PK, Warkentin DI, Hewko R, et al. Serotonin syndrome after concomitant treatment with linezolid and meperidine. Clin Infect Dis 2008; 46: 264-5.

22. Mateo-Carrasco H., Muñoz-Aguilera E. M., García-Torrecillas J. M.et al. Serotonin syndrome probably triggered by a morphine–phenelzine interaction. Pharmacotherapy (2015) 35: e102–e105. doi:10.1002/phar.1581

23. Summary of Product Characteristics. Zelapar. Cephalon UK. Last revised Aug 2015. Accessed via www.medicines.org.uk/emc on 22/06/2017.

24. Noble W.H, Baker, A. MAO inhibitors and coronary artery surgery: a patient death. Can J Anaesth (1992) 39: 1061. doi:10.1007/BF03008376

25. Adler AR, Charnin JA, Quraishi SA. Serotonin Syndrome: The potential for a severe reaction between common perioperative medications and selective serotonin reuptake inhibitors. A&A Case Reports. 2015;5:156-9. doi: 10.1213/XAA.0000000000000217

26. Summary of Product Characteristics. Actiq 200mcg Lozenges. Teva Pharma. Last revised May 2017. Accessed via www.medicines.org.uk/emc on 22/06/2017.

27. Summary of Product Characteristics. Abstral. Kyowa Kirin Ltd. Last revised May 2016. Accessed via www.medicines.org.uk/emc on 22/06/2017.

28. Summary of Product Characteristics. Zydol 50mg Capsules. Grunenthal Ltd. Last revised July 2016. Accessed via www.medicines.org.uk/emc on 22/06/2017.

29. Lawrence KR, Adra M, Gillman PK. Serotonin toxicity associated with the use of linezolid: a review of postmarketing data. Clin Infect Dis. 2006; 42:1578-83.

30. Summary of Product Characteristics. Nardil Tablets. Kyowa Kirin Limited. Last revised Feb 2017. Accessed via www.medicines.org.uk/emc on 23/06/2017.

Quality Assurance

Prepared by

Jill Forrest, South West Medicines Information, University Hospitals Bristol NHS Foundation Trust. (Based on earlier work by Matthew Jones).

Date Prepared

June 2017

Checked by
Julia Kuczynska, South West Medicines Information, University Hospitals Bristol NHS Foundation Trust

Date of check

6th July 2017

Search strategy

• 
  Embase: ((exp “MONOAMINE OXIDASE INHIBITOR”/ OR TEDIZOLID/ OR LINEZOLID/ OR “METHYLENE BLUE”/) + (exp”OPIATE AGONIST”/ OR OPIATE/ OR exp “FENTANYL DERIVATIVE”/ OR PENTAZOCINE/ OR PHOLCODINE/)) [Limit to Publication Year 2015-2017]
  
• 
  Embase: ((exp “MONOAMINE OXIDASE INHIBITOR”/ OR TEDIZOLID/ OR LINEZOLID/ OR “METHYLENE BLUE”/) + exp “NARCOTIC AGENT”/) [Limit to Publication Year DT 2015-2017]
  
• 
  Medline: ((exp “MONOAMINE OXIDASE INHIBITORS”/ OR “METHYLENE BLUE”/ OR LINEZOLID/ OR (tedizolid).ti,ab OR (rasagiline).ti,ab) + (exp “ANALGESICS, OPIOID”/ OR DEXTROMETHORPHAN/ OR (dipipanone).ti,ab OR (dihydrocodeine).ti,ab OR (pholcodine).ti,ab OR (tapentadol).ti,ab)) [Limit to Publication Year 2015-2017]
  
• 
  Medline: "(exp NARCOTICS/ AND (exp "MONOAMINE OXIDASE INHIBITORS"/ OR "METHYLENE BLUE"/ OR LINEZOLID/ OR (tedizolid).ti,ab OR (rasagiline).ti,ab)) [Limit to Publication Year DT 2015-2017]"
  
• 
  Medline: ((“SEROTONIN SYNDROME”/ AND exp “DRUG INTERACTIONS”/) AND exp “MONOAMINE OXIDASE INHIBITORS”/) [Limit to Publication Year DT 2015-2017]
  
• 
  Medline: *”SEROTONIN SYNDROME”/ [Limit to Publication Year DT 2014-2017]
  
• 
  PubMed: (("monoamine oxidase inhibitors"[Pharmacological Action] OR "monoamine oxidase inhibitors"[MeSH Terms] OR ("monoamine"[All Fields] AND "oxidase"[All Fields] AND "inhibitors"[All Fields]) OR "monoamine oxidase inhibitors"[All Fields]) AND ("analgesics, opioid"[Pharmacological Action] OR "analgesics, opioid"[MeSH Terms] OR ("analgesics"[All Fields] AND "opioid"[All Fields]) OR "opioid analgesics"[All Fields] OR "opioids"[All Fields])) AND ("2012/04/07"[PDat] : "2017/04/05"[PDat])
  
• 
  Internet Search: NICE Evidence Search via www.evidence.nhs.uk (opioid “monoamine oxidase inhibitors”)
  
• 
  In-house database/resources
  

Available through Specialist Pharmacy Service at

www.sps.nhs.uk