What Is the Risk of Interaction Between Opioids and Monoamine Oxidase Inhibitors (Maois)?

Q&A 192.5

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

Date prepared: 1st April 2015

Background

The interaction between MAOIs and opioids can take on either of two distinctive forms (1,2,3,4):

CNS excitation - serotonin syndrome

CNS depression - opioid toxicity

The BNF advises that the use of opioids in a patient who has taken a 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 of the opioid analgesics have been reported to cause problems and safe use of some combinations has been reported.

Serotonin Syndrome

The serotonin syndrome can be described as a drug-induced excess ofserotonergic activity at central receptors(3). It is characterized by a triad of symptoms(5):

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

The severity of serotonin syndrome is highly variable(3). Reactions can be mild and transient, presenting as mild tachycardia. However, reactions may also result in severe hypertension and tachycardia that abruptly deteriorates into frank shock(6). Fatalities have occurred (1).

The onset of serotonin syndrome is often within minutes of altering a drugregimen, 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).For a review of serotonin syndrome see UKMi Q&A 219 What is serotonin syndrome and which medicines cause it?

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 (4) and methylthioninium chloride (“methylene blue”) (7).

There is evidence that some opioid analgesics act as serotonin re-uptake inhibitors:fentanyl (and congeners), pethidine, tramadol, methadone, dextromethorphan and (dextro)propoxyphene (5). Morphine, codeine, oxycodone and buprenorphine are not thought to be inhibitors of serotonin reuptake (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 inhibitionby 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 numerous case reports of interactions between an MAOI and an opioid – see the table on page 4 for a summary. However, there are few systematic studies.

A blinded randomised placebo controlled trial comparing intramuscular injections of water, pethidine and morphine found no significant difference between rises in blood pressure in patients receiving phenelzine orisocarboxazid (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 in the study were inappropriate (5). The results of this study do not reflect the clinical importance of reports of the pethidine interaction (5).

There is a difficulty in defining and diagnosing serotonin syndromeandthe current definition appears to have been used only within the last 20 years (3,5,6).The above study and other sources of information do not use a standardised definition of serotonin syndrome reaction. As a consequence,it is difficult to draw any definite conclusions (1,2).

The interaction between pethidine and MAOIs is based on case reports;dose-dependence has not been verified.The reaction may be idiosyncratic and the severity is unpredictable, but it is potentially fatal.Due to the lack of evidence and potential harm, the combination should be avoided. The use of test doses has been suggested, but seems unnecessary given the availability of alternatives to both pethidine and MAOIs

Based on a literature review of the interaction between linezolid and a range of serotonergic drugs (including pethidine), Ramsey et al. suggest a serotonin syndrome incidence of 0.24-4% of patients taking such a combination of medicines (8). Onset time of the interaction is also variable, ranging from less than 1 to 20 days after the co-administration of linezolid and a serotonergic drug (8).

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

• Dextromethorphan (including the combination with reversible MAOIs) (1,3,9-12)
• Pethidine (including the combination with reversible MAOIs) (1,3,8-10,11,13)
• Methadone (11,14,15)
• Tramadol (3,11)

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

Morphine, fentanyl, codeine, oxycodone and buprenorphine have been described as suitable for use in patients taking MAOIs (10,11). One review suggested that morphine is the strong opioid of choice in patients receiving MAOIs and requiring emergency or elective surgery (16). However, any opioid should be used with caution in patients taking a MAOI, making use of test doses and frequent titration of small doses against pain whilst closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression(10,11,16,17). One author suggests initiating opioids at a third or half the normal dose (17).

Note that fentanyl is known to be serotonergic (16), but whilst there have been case reports of serotonin syndrome when used with a MAOI, there are also reports of the safe use of this combination (see table).

When assessing the risk of combining an opioid with a MAOI, it is also 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) might be a risk factor for the development of serotonin syndrome following co-administration of linezolid and one of a variety of antidepressants (18). The authors suggest that opioid use with linezolid should be minimised (18).

Summary

• The use of most MAOIs with opioids is contraindicated or cautioned by manymanufacturers. There are significant variations between UK and US literature.
• Some opioid analgesics are associated with a risk of serotonin syndrome in combination with MAOIs due 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 either dextromethorphan, methadone, pethidine, tramadol or tapentadol with a MAOI should usually be avoided, including in the 14 day period following the withdrawal 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.

1

Available throughNICE Evidence Search at

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

Buprenorphine / Codeine / Dextromethorphani / Dextropropoxyphene / Diamorphine / Dipipanone / Dihydrocodeine / Fentanyle / Alfentanilf / Remifentanilf / Hydromorphone / Meptazinol / Methadone / Morphineb / Oxycodone / Papaveretum / Pentazocine / Pethidinea,j / Pholcodine / Tapentadol / Tramadolg,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
Methylthioninium chloride / O1 / O1 / S1 / OS1 / O1 / O1 / O1 / OS1 / 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
jPhenelzine / O1 / O1 / S3 / S3
O3 / O1 / O1 / O1 / OS2
S3 / OS2 / OS2 / O1 / O1 / OS1 / O3,2 / 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
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 toxicity3Case reports of harm

SCombination may result in serotonin syndrome2 Case reports of safe use

OS Combination may result in either/both1 No case reports identified

1

Available throughNICE Evidence Search at

Specific Advice

aSerotonin syndrome has been reported with this combination (1,19).Unless there are facilities available for close observation and monitoring for blood pressure, linezolid should not be administered to patients on pethidine (1,20).

bVarious sources recommend using morphine as an alternative to pethidine in patients receiving MAOIs.It is advised to start with a low initial dose and titrate to clinical response (3).

cAlthough selective for MAO type B, selegiline and rasagiline lose their selectivity when used at increasing doses, posing the risk of serotonin syndrome. In clinical practice, low doses of selegiline are used to treat Parkinson’s disease(21).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 consider other opioids may interact similarly (1).

dAs moclobemide is a reversible MAOI, it is unlikely to interact 24 hours after it has been stopped (1). Linezolid is also a reversible MAOI (4,20).

e Fentanyl and its congeners (e.g. alfentanil andremifentanil) have been described as being inhibitors of serotonin re-uptake. Fentanyl is also described in a review as possibly being associated with a fatal serotonin toxicity reaction (5). However, the evidence for this appears rather weak. The author of the review concluded that a fatal serotonin syndrome reaction occurred due to the use of fentanyl in one case report. However, the authors of the original case report concluded that there was insufficient evidence to make the same conclusion (5,22). The authors of another report quoted in the review did not conclude that serotonin syndrome had occurred. The review does not contraindicate use if there is no appropriate alternative(5). The manufacturers of Sublimaze (fentanyl citrate injection) contraindicate the use of fentanyl within two weeks of taking a MAOI. If serotonin syndrome is suspected, rapid discontinuation of fentanyl should be considered (23).

f As alfentanil and remifentanil have shorter half-lives than fentanyl, they would be expected to be safer(5).

g UK manufacturers contraindicate tramadol and MAOIs, but the US manufacturer advises great caution. In practice, this probably means monitoring closely for signs of serotonin syndrome (1).

h Suspected serotonin syndrome occurred in a patient receiving linezolid, tramadol and paroxetine, all of which are known to inhibit serotonin re-uptake. If the combination of linezolid and tramadol is clinically necessary, the patient should be monitored for signs of serotonin syndrome (16).

i Two fatal case reports of hyperpyrexia and coma (similar to serotonin syndrome) with the combination of dextromethorphan and phenelzine (1). 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 Death has been reported following a single dose of pethidine in patients taking tranylcypromine or phenelzine (24,25)

Limitations

Opioid analgesics and MAOIs are defined as per the BNF 68thedition

In addition, methylthionium chloride (methylene blue) included as a MAOI

In addition, dextromethorphan and pholcodine included as opioids

References

1. Preston CL, editor. Stockley’s Drug Interactions. London: Pharmaceutical Press. Electronic versionaccessed via 04/03/2015

2. Evans-Prosser CDG. The use of pethidine and morphine in the presence of monoamine oxidase inhibitors. Br J Anaesth1968; 40: 279-82

3. Brayfield A, editor. Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Accessed via 04/03/2015

4. Khanderia S, editor. British National Formulary 68th edition. London: BMJ Publishing Group Ltd, RPS Publishing,2014.

5. Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth2005; 95: 434-41

6. Boyer EW, Shannon M. Current Concepts: The Serotonin Syndrome. N Engl J Med2005; 352: 1112-1120

7. McEvoy GK, editor. AHFS Drug Information. Accessed via 1/4/2015.

8. 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.

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

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

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

12. 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.

13. Berlin I, Lecrubier Y. Food and drug interactions with monoamine oxidase inhibitors – how safe are the newer agents? CNS Drugs 1996, 5:403-413.

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

15. Royal College of General Practitioners. Guidance for the use of substitute prescribing in the treatment of opioid dependence in primary care. 2011, 1st edition.

16. Drugdex Drug Evaluations for linezolid. Micromedex® 2.0 (healthcare series): (Last modified: 27/01/2015) Accessed: 25/02/2015

17. Bazire, S. Psychotropic Drug Directory 2014. Dorsington: Lloyd-Reinhold Communications.

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

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

20. Summary of Product Characteristics - Zyvox 600mg Film-Coated Tablets(date text last revised September 2014 Pharmacia Limited. Accessed via

21. McDonald WM, Richard IH, DeLong MR. Prevalence, etiology and treatment of depression in Parkinson’s Disease. Biol Psychiatry 2003; 54:363-375

22. Noble WH, Baker A. MAO inhibitors and coronary artery surgery: a patient death. Can J Anaesth1992; 39: 1061-66

23. Summary of Product Characteristics – Sublimaze (date text last revised 6th June 2013) Jansen Cilag Ltd. Accessed via on 21/10/2014

24. Summary of Product Characteristics – Tranylcypromine 10mg Tablets (date text last revised 21st March 2014. Amdipharm Mercury Company Limited. Accessed via 25/2/2015.

25. Summary of Product Characteristics – Nardil Tablets (date text last revised 14th March 2014. Archimedes Pharma UK Limited. Accessed via 25/2/2015.

Quality Assurance

Prepared by

Matthew Jones, South West Medicines Information, University Hospitals Bristol NHS Foundation Trust. (Based on earlier work by Gill Lewis,Jenny Haylor and Richard Leung).

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

Date of check

15th April 2015

Search strategy

• Embase: (exp LINEZOLID/it OR exp MONOAMINE OXIDASE INHIBITOR/it) + exp NARCOTIC ANALGESIC AGENT/it [Limit to: Publication Year 2012-2014]Embase: (exp LINEZOLID/it OR exp *MONOAMINE OXIDASE INHIBITOR/it OR exp *METHYLENE BLUE/it) + (exp *NARCOTIC ANALGESIC AGENT/it OR exp *PAPAVERINE/it OR exp *PAPAVERINE DERIVATIVE/)

• Embase: (exp DEXTROMETHORPHAN/it OR exp DEXTROMETHORPHAN HYDROBROMIDE/it OR exp DEXTROMETHORPHAN HYDROBROMIDE PLUS AMMONIUM CHLORIDE/ OR exp DEXTROMETHORPHAN HYDROBROMIDE PLUS BROMPHENIRAMINE MALEATE PLUS PHENYLPROPANOLAMINE HYDROCHLORIDE/ OR exp DEXTROMETHORPHAN HYDROBROMIDE PLUS GUAIFENESIN/ OR exp DEXTROMETHORPHAN HYDROBROMIDE PLUS GUAIFENESIN PLUS PSEUDOEPHEDRINE/ OR exp PHOLCODINE/it) + (exp LINEZOLID/it OR exp MONOAMINE OXIDASE INHIBITOR/it OR exp METHYLENE BLUE/it)

• Medline: exp MONOAMINE OXIDASE INHIBITORS/ + exp DRUG INTERACTIONS/ + exp OPIATE ALKALOIDS/ [Limit to: Publication Year 2012-2014]
• Medline: exp MONOAMINE OXIDASE INHIBITORS/ + exp DRUG INTERACTIONS/ + exp NARCOTICS/ [Limit to: Publication Year 2012-2014]
• Medline: (exp MONOAMINE OXIDASE INHIBITORS/ OR linezolid.af OR rasagiline.af OR exp METHYLENE BLUE/) + exp DRUG INTERACTIONS/ + (exp OPIATE ALKALOIDS/ OR exp NARCOTICS/ OR dipipanone.af OR dihydrocodeine.af OR remifentanil.af OR tapentadol.af)
• Medline: pholcodine.af + (exp MONOAMINE OXIDASE INHIBITORS/ OR linezolid.af OR rasagiline.af OR exp METHYLENE BLUE/)
• In-house database/resources

• Internet search:NICE Evidence Search via (opioid “monoamine oxidase inhibitors)

1

Available throughNICE Evidence Search at