VOLUME 44 : NUMBER 2 : APRIL 2021 ARTICLE Opioids and antidepressants: which combinations to avoid Varan Perananthan SUMMARY Clinical pharmacology and toxicology advanced Some opioids such as tramadol, pethidine, dextromethorphan and tapentadol increase trainee1,2 serotonergic activity. Fentanyl and methadone also do this but to a lesser extent. Nicholas Buckley Consultant clinical These opioids may increase the risk of serotonin toxicity when combined with antidepressants. pharmacologist and Some selective serotonin reuptake inhibitors block the metabolism of opioids. This may reduce the toxicologist1 concentrations and analgesic effect of some opioids such as codeine and tramadol, and increase Professor of Clinical 2 the concentrations and risk of adverse effects of other opioids such as methadone. Pharmacology 1 Fluoxetine and irreversible monoamine oxidase inhibitors – tranylcypromine and phenelzine – Edith Collins Centre, Drug Health Services, Royal have prolonged actions and may interact for weeks after they have been discontinued. Prince Alfred Hospital, Sydney Introduction • autonomic hyperactivity – fevers, tachycardia, 2 School of Medical diaphoresis, tachypnoea Sciences, Biomedical Opioid dispensing increased fourfold in Australia Informatics and Digital from 1990 to 2014 and prescribing of antidepressants • altered mental state. Health, University of Sydney doubled from 2000 to 2016. The prescribing of Serotonin toxicity generally only occurs when both classes in combination is therefore increasingly serotonergic opioids are given with another Keywords 1,2 common. While many combinations have minimal risk, serotonergic drug such as an antidepressant, antidepressants, drug some may increase the risk of serotonergic effects and even at therapeutic doses (see Box).3 The highest interactions, monoamine other toxicity, or reduce analgesic efficacy. The simplest risk opioid drugs are tramadol, pethidine and oxidase inhibitors, opioids, preventive strategy is to generally avoid prescribing dextromethorphan.7 The highest risk serotonergic serotonin toxicity opioids associated with higher risks of interaction. drugs are the irreversible monoamine oxidase inhibitor (MAOI) antidepressants, tranylcypromine Aust Prescr 2021;44:41–4 Opioids and serotonergic activity and phenelzine.8 The risk and precautions with https://doi.org/10.18773/ The analgesic effect of opioids is mediated through three different combinations are summarised in the austprescr.2021.004 major opioid receptors – mu, delta and kappa. However, Table.3,6,7,9 The highest risk for serotonin toxicity by many opioids have actions on other targets, for example far is with irreversible MAOIs and pethidine, tramadol blocking serotonin and noradrenaline reuptake or dextromethorphan. and N-methyl-aspartate (NMDA) receptors.3 This is There have been occasional case reports of mostly a phenomenon with synthetic opioids. These serotonin toxicity with low-risk opioid and additional actions may be beneficial or harmful and antidepressant combinations, such as oxycodone occur peripherally and in the central nervous system.3 and buprenorphine/naloxone (Suboxone) with Serotonin in the neuronal synapse is tightly regulated other serotonergic medicines.10-13 Many of these via multiple mechanisms – a key one involves the reports have very obvious alternative medical serotonin transporter. Some opioids inhibit the explanations for all the signs of the alleged severe serotonin transporter which increases concentrations serotonin toxicity.14 However, it also seems likely that of serotonin in the synaptic cleft and therefore moderate serotonin toxicity may occasionally be postsynaptic serotonin signalling.4,5 precipitated by any opioid in susceptible individuals taking an antidepressant, perhaps due to indirect Toxicity effects of opioids on serotonin release. A high Serotonin toxicity or syndrome results from excessive index of suspicion is therefore needed.8 Similarly, serotonin and its severity depends on the amount of antidepressants such as agomelatine, mianserin and 6 excess serotonin. The three main groups of features are: reboxetine have a very low risk of serotonin syndrome • neuromuscular hyperactivity – clonus, myoclonus, but caution still might be warranted in combination tremor, hyperreflexia, rigidity with very high-risk serotonergic drugs.3,5,7 © 2021 NPS MedicineWise Full text free online at nps.org.au/australian-prescriber 41 VOLUME 44 : NUMBER 2 : APRIL 2021 ARTICLE Opioids and antidepressants: which combinations to avoid Box Drugs likely to increase the risk of serotonin toxicity Inhibition of opioid metabolism when combined with serotonergic opioids3 The two most commonly used ‘weak opioids’ codeine and tramadol require cytochrome P450 (CYP) 2D6 Monoamine oxidase inhibitors for conversion to an active opioid agonist. They • irreversible inhibitors (phenelzine, tranylcypromine) consequently have less abuse potential which • reversible inhibitors of monoamine oxidase (moclobemide) allows less restrictive scheduling in most countries. However, many antidepressants are CYP2D6 inhibitors • non-antidepressant monoamine oxidase inhibitors (linezolid, methylene blue, lamotrigine) (fluoxetine, paroxetine, and to a lesser extent Serotonin-releasing drugs duloxetine, fluvoxamine, sertraline, desvenlafaxine and • appetite suppressants (fenfluramine, sibutramine) escitalopram). This means combinations of codeine • amphetamines (methamphetamine, methylphenidate, phentermine) or tramadol with these antidepressants may lead to • synthetic stimulants (MDMA, cathinones) reduced analgesia.15 Serotonin reuptake inhibitors Conversely, inhibition of metabolism of other opioids • selective serotonin reuptake inhibitors (via a variety of enzymes) may lead to increased risks • serotonin noradrenaline reuptake inhibitors of opioid adverse effects. The combinations that are particularly of concern are specific to individual drugs • tricyclic antidepressants (clomipramine, imipramine) such as tramadol, tapentadol, fentanyl and methadone. • serotonin modulators (vortioxetine) Miscellaneous Tramadol • lithium While tramadol’s main metabolite is an opioid agonist, • St John’s wort it is remarkably similar in structure to venlafaxine, • tryptophan with similar inhibitory effects on noradrenaline and 16,17 • buspirone serotonin reuptake. The combination of tramadol with an antidepressant is by far the most common • triptans serotonergic drug–drug interaction.18,19 As tramadol inhibits serotonin and noradrenaline MDMA 3,4-methylenedioxymethamphetamine reuptake, combinations with selective serotonin reuptake inhibitors (SSRIs) or serotonin noradrenaline reuptake inhibitors (SNRIs) are likely to have additional adverse effects without added benefits. Inhibition Table The risk of serotonergic toxicity with combinations of CYP2D6 by common antidepressants such as 3,6,7,9 of antidepressants and opioids paroxetine and fluoxetine20 not only reduces conversion of tramadol to an opioid agonist, it also results Antidepressants in higher concentrations of tramadol. Thus, these Low–intermediate risk High risk antidepressants both directly and indirectly increase SSRIs, SNRIs, TCAs, MAOIs (or previous history the serotonergic and other adverse effects of tramadol, Opioids St John’s wort, lithium of serotonin toxicity) while potentially reducing analgesic efficacy.16,21 Low risk Should be safe Possible rare interaction. Seizures are a key adverse effect of tramadol and Use with caution Morphine, codeine,* can occur in overdose.22 Tramadol is also commonly buprenorphine, implicated in new onset seizures with therapeutic oxymorphone, use.23 This risk is further heightened when it is hydromorphone, oxycodone co-administered with SSRIs, tricyclic antidepressants, venlafaxine and bupropion.21,24-26 Medium risk Possible rare interaction. Increased risk of serotonin Fentanyl, tapentadol, Use with caution syndrome Tapentadol methadone Tapentadol has different pharmacology to tramadol. High risk Increased risk of serotonin Contraindicated It is an opioid agonist without active metabolites Tramadol,* pethidine, syndrome and a noradrenaline reuptake inhibitor with only dextromethorphan weak effects on serotonin reuptake.27 MAOI use is contraindicated with tapentadol and there have been * risk of decreased analgesic effect many reports to regulatory agencies of serotonin SSRI selective serotonin reuptake inhibitor toxicity with this combination.7 MAOIs were also SNRI serotonin noradrenaline reuptake inhibitor 9 TCA tricyclic antidepressant excluded from most tapentadol trials. Currently, it is MAOI monoamine oxidase inhibitor unclear if tapentadol has a greater risk of serotonin toxicity than other opioids. 42 Full text free online at nps.org.au/australian-prescriber VOLUME 44 : NUMBER 2 : APRIL 2021 ARTICLE Fentanyl Other drug interactions Fentanyl is a high-potency opioid agonist with no Sedating antidepressants such as tricyclics, tetracylics effect on serotonin reuptake and low affinity (relative (mirtazepine and mianserin) and agomelatine to opioid receptor affinity) for postsynaptic serotonin in combination with opioids can exacerbate 5 receptors (5-HT1A and 5-HT2A). Co-administration drowsiness which can increase the risk of falls and with an SSRI has been reported to cause an agitated respiratory depression.30 28 delirium consistent with serotonin toxicity. However, Serotonergic drug interactions are not confined in a retrospective analysis of 4583 people who to antidepressants and opioids. For example, very