Published: 1 September 2022


Opioids and serotonergic medicines: some combinations may increase the risk of serotonin syndrome

Prescriber Update 43(3): 32–34
September 2022

Key messages

  • There is a risk of developing serotonin syndrome with concomitant use of opioids and serotonergic medicine(s). The risk varies depending on the medicine combination.
  • Pethidine, dextromethorphan and tramadol are high-risk opioids for serotonin syndrome when used with serotonergic antidepressants.
  • When prescribing opioids with serotonergic medicines, consider the risk of a drug-drug interaction leading to serotonin syndrome.

The Medicines Adverse Reaction Committee (MARC) recently reviewed the risk of serotonin syndrome with concomitant use of opioids and serotonergic medicines.

Medsafe is working with sponsors of opioid and serotonergic medicines to update the data sheets with information on this interaction (see MARC’s remarks in this edition of Prescriber Update).

Serotonin syndrome is a rare but potentially life-threatening condition

Serotonin toxicity/syndrome is a drug-induced condition caused by an excess of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) in the synapses of the brain.1

Signs and symptoms of serotonin syndrome range from mild to life-threatening and may include diarrhoea, diaphoresis (excessive sweating), agitation, tremor, hypertension, hyperthermia, tachycardia, hyperreflexia (twitching) and clonus (involuntary muscle movements).2

Serotonin syndrome usually follows from a combination of two or more serotonergic medicines.1 These include most antidepressants, such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs).1

The serotonergic potential of opioids is increasingly recognised. When prescribing opioids with serotonergic medicines, consider the possibility of a drug-drug interaction leading to serotonin syndrome.3

If serotonin syndrome is suspected, and depending on the severity of the symptoms, consider discontinuing at least one of the serotonergic medicines. Initiate supportive care.2

The risk of developing serotonin syndrome varies between different opioid and serotonergic medicine combinations

Table 1 outlines the risk stratification and management of the drug-drug interaction between different opioids and antidepressant medicines.4

Pethidine, tramadol and dextromethorphan (a common ingredient in cough medicines) are opioids with a high risk of causing serotonin syndrome when used with serotonergic antidepressants.4 Concomitant use of these medicines with MAOIs is contraindicated due to this interaction.4 Individuals who misuse or abuse cough medicines containing dextromethorphan are at a greater risk of developing serotonin syndrome.5

Methadone and fentanyl also have serotonergic properties and are considered medium risk for inducing serotonin syndrome.4 An interaction may occur with these opioids in combination with antidepressant medicines (see Table 1).4 This interaction is more likely to occur with higher doses of methadone used in opioid substitution therapy and higher doses of fentanyl used in anaesthesia or post-operative recovery.3

Morphine, codeine, buprenorphine and oxycodone are not expected to interact with antidepressant medicines to cause serotonin syndrome.4 Dihydrocodeine (not included in Table 1) is likely to act similarly to these low risk opioids.3,6

There is potential for serotonin syndrome to develop in individuals taking antidepressants with other opioid narcotics, such as methylenedioxymethamphetamine (MDMA or ‘ecstasy’).6 Herbal products, such as St John’s wort, may also increase 5-HT levels and potentially interact with serotonergic opioids.1

Table 1: The risk of serotonergic toxicity with combinations of antidepressants and opioids

Opioids Antidepressants
Low-intermediate risk
SSRIs, SNRIs, TCAs, St John’s wort, lithium
High risk
MAOIs (or previous history of serotonin toxicity)
Low risk Morphine, codeine,* buprenorphine, oxycodone Should be safe Possible rare interaction. Use with caution
Medium risk Fentanyl, methadone Possible rare interaction. Use with caution Increased risk of serotonin syndrome
High risk Tramadol,* pethidine, dextromethorphan Increased risk of serotonin syndrome Contraindicated

* risk of decreased analgesic effect
SSRI selective serotonin reuptake inhibitor
SNRI serotonin noradrenaline reuptake inhibitor
TCA tricyclic antidepressant
MAOI monoamine oxidase inhibitor

Source: Perananthan V and Buckley NA. 2021. Opioids and antidepressants: which combinations to avoid. Australian Prescriber 44(2): 41–4. DOI: (accessed 17 June 2022). © NPS MedicineWise. Reproduced with permission. Visit Licensed under CC BY-NC-ND 4.0.

Note: Oxymorphone, hydromorphone, tapentadol are not currently available in New Zealand.

Some opioids act as serotonin reuptake inhibitors in vitro

The serotonin transporter (SERT) maintains serotonin (5-HT) plasma concentrations and is important for the rapid reuptake of serotonin into presynaptic nerve terminals.6 Medicines that inhibit SERT may increase the plasma, synaptic cleft and postsynaptic serotonin concentrations, that, in turn, activate the postsynaptic 5-HT receptors.6 Excessive activation of 5-HT receptors may lead to serotonin syndrome.

In vitro studies have investigated the potential mechanisms by which some opioids directly or indirectly increase serotonin levels.6 Dextromethorphan, methadone, pethidine and tramadol inhibit SERT in vitro.7 Fentanyl does not inhibit SERT in vitro but, unlike other opioids, shows affinity for both the 5-HT1A and 5-HT2A receptors.7 As cases of serotonin syndrome have been reported with fentanyl, there may be some SERT-independent effects on the 5-HT system in vivo.7 Codeine, morphine, buprenorphine, oxycodone and dihydrocodeine do not inhibit SERT and do not have affinity for 5-HT receptors.7

Further research is needed to confirm the clinical implications of these in vitro findings.6,7


  1. Foong AL, Grindrod KA, Patel T, et al. 2018. Demystifying serotonin syndrome (or serotonin toxicity). Canadian Family Physician 64(10): 720–7. URL: (accessed 17 June 2022).
  2. Boyer EW and Shannon M. 2005. The serotonin syndrome. New England Journal of Medicine 352(11): 1112–20. DOI: 10.1056/NEJMra041867 (accessed 18 July 2022).
  3. Baldo BA. 2018. Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects. Archives of Toxicology 92(8): 2457–73. DOI: 10.1007/s00204-018-2244-6 (accessed 17 June 2022).
  4. Perananthan V and Buckley NA. 2021. Opioids and antidepressants: which combinations to avoid. Australian Prescriber 44(2): 41–4. DOI: (accessed 17 June 2022).
  5. Pharmacy Retailing (NZ) t/a Healthcare Logistics. 2021. Bisolvon Dry New Zealand Datasheet 20 December 2021. URL: (accessed 17 June 2022).
  6. Baldo BA and Rose MA. 2020. The anaesthetist, opioid analgesic drugs, and serotonin toxicity: a mechanistic and clinical review. British Journal of Anaesthesia 124(1): 44–62. DOI: 10.1016/j.bja.2019.08.010 (accessed 17 June 2022).
  7. Rickli A, Liakoni E, Hoener MC, et al. 2018. Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome. British Journal of Pharmacology 175(3): 532–43. DOI: 10.1111/bph.14105 (accessed 18 July 2022).
Hide menus
Show menus
0 1 2 4 5 6 7 9 [ /