Interaction between opioids and monoamine oxidase inhibitors (MAOIs)
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 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):
- Neuromuscular hyperactivity; tremor, clonus, myoclonus, hyper-reflexia and (in the advanced stage) rigidity.
- Autonomic hyperactivity; diaphoresis, fever, tachycardia and tachypnoea.
- 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).
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).
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).
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:
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).
Fatalities have occurred in patients taking dextromethorphan with phenelzine; the related cough suppressant, pholcodine, is predicted to interact similarly (1).
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 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 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).
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).
- 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.