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British Journal of Anaesthesia
BJA

The anaesthetist, opioid analgesic drugs, and serotonin toxicity: a mechanistic and clinical review

  • Author Footnotes
    † The author is retired. Listed are the author's affiliations before his retirement.
    Brian A. Baldo
    Correspondence
    Corresponding author.
    Footnotes
    † The author is retired. Listed are the author's affiliations before his retirement.
    Affiliations
    Molecular Immunology Unit, Kolling Institute of Medical Research, Royal North Shore Hospital of Sydney, NSW, Australia

    Department of Medicine, University of Sydney, Sydney, NSW, Australia
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  • Michael A. Rose
    Affiliations
    Department of Anaesthesia, Royal North Shore Hospital of Sydney, Sydney, NSW, Australia

    Northern Clinical School, University of Sydney, Sydney, NSW, Australia
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  • Author Footnotes
    † The author is retired. Listed are the author's affiliations before his retirement.
Open ArchivePublished:October 22, 2019DOI:https://doi.org/10.1016/j.bja.2019.08.010

      Summary

      Most cases of serotonin toxicity are provoked by therapeutic doses of a combination of two or more serotonergic drugs, defined as drugs affecting the serotonin neurotransmitter system. Common serotonergic drugs include many antidepressants, antipsychotics, and opioid analgesics, particularly fentanyl, tramadol, meperidine (pethidine), and methadone, but rarely morphine and other related phenanthrenes. Symptoms of serotonin toxicity are attributable to an effect on monoaminergic transmission caused by an increased synaptic concentration of serotonin. The serotonin transporter (SERT) maintains low serotonin concentrations and is important for the reuptake of the neurotransmitter into the presynaptic nerve terminals. Some opioids inhibit the reuptake of serotonin by inhibiting SERT, thus increasing the plasma and synaptic cleft serotonin concentrations that activate the serotonin receptors. Opioids that are good inhibitors of SERT (tramadol, dextromethorphan, methadone, and meperidine) are most frequently associated with serotonin toxicity. Tramadol also has a direct serotonin-releasing action. Fentanyl produces an efflux of serotonin, and binds to 5-hydroxytryptamine (5-HT)1A and 5-HT2A receptors, whilst methadone, meperidine, and more weakly tapentadol, bind to 5-HT2A but not 5-HT1A receptors. The perioperative period is a time where opioids and other serotonergic drugs are frequently administered in rapid succession, sometimes to patients with other serotonergic drugs in their system. This makes the perioperative period a relatively risky time for serotonin toxicity to occur. The intraoperative recognition of serotonin toxicity is challenging as it can mimic other serious syndromes, such as malignant hyperthermia, sepsis, thyroid storm, and neuroleptic malignant syndrome. Anaesthetists must maintain a heightened awareness of its possible occurrence and a readiness to engage in early treatment to avoid poor outcomes.

      Keywords

      Serotonin toxicity (ST), often referred to as serotonin syndrome, is an iatrogenic drug-induced toxidrome
      • Gillman P.K.
      A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action.
      • Gillman P.K.
      Extracting value from case reports: lessons from serotonin toxicity.
      associated with raised intra-synaptic concentrations of serotonin (5-hydroxytryptamine [5-HT]) in the CNS.
      • Oates J.A.
      • Sjoerdsma A.
      Neurologic effects of tryptophan in patients receiving a monoamine oxidase inhibitor.
      Symptoms of toxicity caused by drugs that induce an increase in serotonin become apparent within hours of ingestion or administration. The list of clinical features, ranging from mild to severe, is often viewed as a triad of changes in neuromuscular hyperactivity (clonus, hyperreflexia, myoclonus, and rigidity in advanced stages of toxicity), autonomic nervous system hyperactivity (hyperthermia, tachycardia, diaphoresis, and mydriasis), and changes in mental status (agitation, excitement, restlessness, and confusion in advanced stages).
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      The serotonin syndrome.
      • Dunkley E.J.
      • Isbister G.K.
      • Sibbritt D.
      • Dawson A.H.
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      The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.
      • Gillman P.K.
      • Whyte I.M.
      Serotonin syndrome.
      • Whyte I.M.
      Serotonin syndrome (toxicity).
      • Boyer E.W.
      • Shannon M.
      The serotonin syndrome.
      • Isbister G.K.
      • Buckley N.A.
      The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment.
      Mild toxicity generally does not greatly inconvenience the patient; moderate toxicity causes significant distress requiring treatment, whilst severe cases may be life threatening.
      • Gillman P.K.
      A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action.
      • Dunkley E.J.
      • Isbister G.K.
      • Sibbritt D.
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      • Whyte I.M.
      The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.
      • Boyer E.W.
      • Shannon M.
      The serotonin syndrome.
      • Isbister G.K.
      • Buckley N.A.
      • Whyte I.M.
      Serotonin toxicity: a practical approach to diagnosis and treatment.
      • Otte W.
      • Birkenhager T.K.
      • van der Broek W.W.
      Fatal interaction between tranylcypromine and imipramine.
      In the perioperative setting, most cases of ST and, in particular, severe cases, are provoked by therapeutic doses of a combination of two or more serotonergic drugs, but single high doses of some drugs, such as tramadol and 3,4-methylenedioxymethamphetamine (MDMA or ‘ecstasy’), may induce ST.
      • Isbister G.K.
      • Buckley N.A.
      The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment.
      • Isbister G.K.
      • Buckley N.A.
      • Whyte I.M.
      Serotonin toxicity: a practical approach to diagnosis and treatment.
      Moderate toxicity may rarely occur with an overdose or an increased dosage of a single drug.
      Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs) that inhibit the uptake of both neurotransmitters, serotonin releasers, monoamine oxidase inhibitors (MAOIs) that inhibit serotonin metabolism, serotonin precursors, serotonin receptor agonists, and opioid analgesic drugs (OADs). It is easy to foresee that a patient requiring urgent surgery and already taking one of the aforementioned antidepressants or having MDMA in their system might be exposed in rapid fashion to OADs, or perhaps the not widely recognised serotonergic agents and MAOI linezolid,
      • Lawrence K.R.
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      • Gillman P.K.
      Serotonin toxicity associated with the use of linezolid: a review of postmarketing data.
      an antibiotic, or the thiazine dye methylene blue

      Gillman PK. Methylene blue and serotonin toxicity syndrome. Available from: https://psychotropical.info/methylene-blue-serotonin-toxicity-syndrome/(accessed 2 November 2018).

      • Francescangeli J.
      • Vaida S.
      • Bonavia A.S.
      Perioperative diagnosis and treatment of serotonin syndrome following administration of methylene blue.
      used for sentinel lymph node localisation. Although a number of different criteria have been advanced for the diagnosis of ST, the so-called Hunter Serotonin Toxicity Criteria, validated by the Hunter Area Toxicology Service, Newcastle, Australia,
      • Dunkley E.J.
      • Isbister G.K.
      • Sibbritt D.
      • Dawson A.H.
      • Whyte I.M.
      The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.
      has generally become the preferred and most widely applied diagnostic approach.
      Here, we review what is currently known of mechanisms, some still speculative, thought to underlie opioid-induced ST and provide a clinical perspective for risk assessment, identification of ST intraoperatively, differential diagnosis, and treatment of the condition.

      Early reports of opioid analgesic drugs in serotonin toxicity

      Although not fully understood at the time, reactions to the phenylpiperidine meperidine (pethidine) given with a MAOI provided early examples of what would now be interpreted as ST. Mitchell
      • Mitchell R.S.
      Fatal toxic encephalitis occurring during iproniazid therapy in pulmonary tuberculosis.
      reported 63 yr ago a case of a patient on the MAOI iproniazid (then used to treat tuberculosis), who experienced severe symptoms of cyanosis, diaphoresis, rapid pulse, ankle clonus, and exaggerated reflexes after being given meperidine 100 mg. Three subsequent early reports described alarming toxic reactions to the same two drugs mentioning ‘frightening and dramatic’ reactions. A collective list of observed reactions includes flushing, diaphoresis, pyrexia, rapid HR, extreme agitation, uncontrollable hyperactivity, extensor plantar reflexes, absence of deep reflexes, dilated and unreactive pupils, vertical deviation of eyeballs, and unrousable coma.
      • Papp C.
      • Benaim S.
      Toxic effects of iproniazid in a patient with angina.
      • Shee J.C.
      Dangerous potentiation of pethidine by iproniazid, and its treatment.
      • Clement A.J.
      • Benazon D.
      Reactions to other drugs in patients taking monoamine-oxidase inhibitors.
      Further early evidence of the possibility of dangerous toxic reactions after the administration of meperidine to patients taking a MAOI is recorded in three reports, including two deaths, on four patients taking phenelzine or tranylcypromine.
      • Palmer H.
      Potentiation of pethidine.
      • Pells-Cocks D.
      • Passmore-Rowe A.H.
      Dangers of monoamine oxidase inhibitors.
      • Reid N.C.R.W.
      • Jones D.
      Pethidine and phenelzine.
      • Taylor D.C.
      Alarming reaction to pethidine in patients on phenelzine.
      • Denton P.H.
      • Borrelli V.M.
      • Edwards N.V.
      Dangers of monoamine oxidase inhibitors.
      Both of these MAOIs are structurally similar to amphetamine. The toxic effect of administering meperidine and the sympathomimetics amphetamine and methylamphetamine in the presence of a MAOI was also shown in mice pretreated with phenelzine. Although given only one-fifth of a toxic dose of the pressor amines and meperidine, the animals died from acute poisoning. The observed toxic effects in the mice given meperidine were said to resemble cases of meperidine poisoning in humans.
      • Brownlee G.
      • Williams G.W.
      Potentiation of amphetamine and pethidine by monoamineoxidase inhibitors.
      Apart from meperidine, there are few early reports of adverse responses dealing with other OADs administered to patients taking a MAOI.
      • Spencer G.T.
      • Smith S.E.
      Dangers of monoamine oxidase inhibitors.
      • Rivers N.
      • Horner B.
      Possible lethal reaction between nardil and dextromethorphan.
      The symptoms evoked in the aforementioned cases involving meperidine and a MAOI suggest central stimulation likely resulting from the MAOI-induced elevation of serotonin in the CNS. Early experiments with rabbits and mice
      • Nymark M.
      • Møller Nielsen I.
      Reactions due to the combination of monoamineoxidase inhibitors with thymoleptics, pethidine or methylamphetamine.
      • Rogers K.J.
      • Thornton J.A.
      The interaction between monoamine oxidase inhibitors and narcotic analgesics in mice.
      • Rogers K.J.
      Role of brain monoamines in the interaction between pethidine and tranylcypromine.
      showed that prior administration of a MAOI markedly increased the acute toxicity of meperidine, and this increase was caused by an increased central concentration of serotonin rather than a decrease in the metabolism of meperidine.
      • Rogers K.J.
      • Thornton J.A.
      The interaction between monoamine oxidase inhibitors and narcotic analgesics in mice.
      There is as yet little or no compelling evidence of such toxicity with most other OADs, particularly the phenanthrenes (Fig. 1).
      Fig 1
      Fig 1Structures of naturally occurring, semi-synthetic, and synthetic opioid analgesic drugs commonly used in anaesthesia and for pain management. (a) Structure of morphine and closely related rigid structures of the commonly used phenanthrene opioids, including dextromethorphan, which, like the parent phenanthrene structure, lacks the 4–5 oxygen bridge present in morphine and the other opioids included in the table. *Buprenorphine has a 1-hydroxyl-1,2,2-trimethylpropyl substituent at C-7. Endo-ethano bridge between C-6 and C-14. (b) Structure of the synthetic opioid meperidine, a phenylpiperidine that shares a phenylpropylamine structure with morphine. (c) Structure of the phenylheptylamine methadone. Although it lacks a piperidine ring, methadone retains a phenylpropylamine substituent. Methadone has a single chiral centre, and therefore, occurs as two stereoisomers: the R- and S-enantiomers. The drug is used commercially and clinically as the racemic mixture of the R-enantiomer R-(–)methadone (levomethadone) and the S-enantiomer S-(+)-methadone (dextromethadone). The R-enantiomer is the active form of the opioid showing μ-opioid receptor selectivity; the S-enantiomer has almost no opioid activity at normal therapeutic doses. (d) Structures of the anilidopiperidine fentanyl and its congeners alfentanil, remifentanil, and sufentanil. Structural and conformational similarities to morphine are retained by the presence of a 4-anilidophenylpropylamine substituent.
      Blood platelets and neurones show close similarities in the uptake and storage of serotonin and in the inhibition of uptake by various drugs.
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      • Ahtee L.
      • Solatunturi E.
      Blood platelet as a model for monoaminergic neurons.
      • Pletscher A.
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      • Wong D.T.
      Serotonin uptake and serotonin uptake inhibition.
      In 1969, Carlsson and Lindqvist
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      • Lindqvist M.
      Central and peripheral monoaminergic membrane-pump blockade by some addictive analgesics and antihistamines.
      showed that methadone and meperidine prevented the uptake of serotonin by mice neurones. Whereas morphine proved inactive, methadone and pentazocine were potent inhibitors, and meperidine moderately inhibited the uptake of serotonin by blood platelets and isolated rat brain nerve terminals (synaptosomes).
      • Ahtee L.
      • Saarnivaara L.
      The effect of narcotic analgesics on the uptake of 5-hydroxytryptamine and (–)-metaraminol by blood platelets.
      • Ciofalo F.R.
      Methadone inhibition of 3H-5-hydroxytryptamine uptake by synaptosomes.
      In the light of what we now know of the signs, symptoms, and drug involvements associated with ST, the aforementioned case reports are likely to have been early examples of the toxicity caused by an effect on serotonergic transmission caused by increased concentrations of serotonin.

      Effects of opioids on serotonin reuptake and receptors

      The serotonin transporter (SERT), found in both platelets and neurones, maintains and ensures low 5-HT plasma concentrations, and is important for the rapid reuptake of the neurotransmitter into presynaptic nerve terminals.
      • Schloss P.
      • Williams D.C.
      The serotonin transporter: a primary target for antidepressant drugs.
      Drugs that inhibit the SERT, for example, SSRIs, may therefore increase the plasma, synaptic cleft, and postsynaptic serotonin concentrations that, in turn, activate the 5-HT receptors. Figure 2 summarises the drug-induced events associated with raised intra-synaptic concentrations of serotonin, inhibition of its reuptake promoted by different serotonergic drugs, activation of 5-HT receptors, and serotonin metabolism by MAO within the presynaptic neurone.
      Fig 2
      Fig 2Diagrammatic representation of drug-induced events associated with raised intra-synaptic concentrations of serotonin (5-hydroxytryptamine [5-HT]) and inhibition of reuptake of 5-HT by different serotonergic drugs, mainly certain opioids; selective serotonin reuptake inhibitors (SSRIs); and serotonin–norepinephrine reuptake inhibitors (SNRIs), including tricyclic antidepressants (TCAs), 3,4-methylenedioxymethamphetamine (MDMA or ‘ecstasy’), and cocaine. Serotonin, derived from 5-hydroxytryptophan (5-HTP) in the presynaptic neurone, is packaged into synaptic vesicles by vesicular monoamine transporter 2 (VMAT2) and released by Ca2+-dependent exocytosis into the synapse where it diffuses to its receptors on postsynaptic neurones. Reuptake of the neurotransmitter into presynaptic nerve terminals is effected by the serotonin transporter (SERT), which ensures and maintains low 5-HT plasma concentrations and is important for the rapid reuptake of the 5-HT into presynaptic nerve terminals. Opioids, in particular, tramadol, dextromethorphan, meperidine, methadone, tapentadol (but generally not morphine and other phenanthrenes), and other serotonergic agents inhibit the reuptake of serotonin by inhibiting SERT, thus increasing plasma and synaptic cleft serotonin concentrations available to bind and activate the postsynaptic 5-HT receptors. In presynaptic neurones, serotonin is metabolised by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid (5-HIAA). Diverse monoamine oxidase inhibitors (MAOIs) (some antidepressants, the antibiotic linezolid, and the thiazine dye methylene blue) that inhibit serotonin metabolism have been implicated in serotonin toxicity.
      A number of investigations, mainly using isolated rat synaptic nerve terminals, but some with human tissue, showed that some OADs interact directly with the SERT.
      • Larsen J.J.
      • Hyttel J.
      5-HT-uptake inhibition potentiates antinociception induced by morphine, pethidine, methadone and ketobemidone in rats.
      • Driessen B.
      • Reimann W.
      Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro.
      • Raffa R.B.
      • Friderichs E.
      • Reimann W.
      • et al.
      Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol.
      • Codd E.E.
      • Shank R.P.
      • Schupsky J.J.
      • Raffa R.B.
      Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception.
      • Giusti P.
      • Buriani A.
      • Cima L.
      • Lipartiti M.
      Effect of acute and chronic tramadol on [3H]-5-HT uptake in rat cortical synaptosomes.
      • Gobbi M.
      • Mennini T.
      Release studies with rat brain cortical synaptosomes indicate that tramadol is a 5-hydroxytryptamine uptake blocker and not a 5-hydroxytryptamine releaser.
      • Tzschentke T.M.
      • Christoph T.
      • Kogel B.
      • et al.
      (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel μ-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties.
      • Raffa R.B.
      • Buschmann H.
      • Christoph T.
      • et al.
      Mechanistic and functional differentiation of tapentadol and tramadol.
      Like meperidine, tramadol is a weak serotonin reuptake inhibitor.
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      Codd and colleagues,
      • Codd E.E.
      • Shank R.P.
      • Schupsky J.J.
      • Raffa R.B.
      Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception.
      showed that racemic tramadol and its enantiomers (Fig. 3), (S)-(+)-methadone, (R)-(-)-methadone, and the phenanthrenes dextromethorphan (Fig. 1a) and levomethorphan inhibited the rat synaptosomal uptake of serotonin (Table 1). However, unlike the methorphans, phenanthrene opioids, such as morphine, codeine, hydrocodone, and oxycodone with an oxygen bridge between C4 and C5 (Fig. 1a), showed no inhibitory activity. Of the opioids tested, (R)-(–)-methadone was the most potent inhibitor of 5-HT uptake (Ki=0.014 μM), being 71 times more active than its S-enantiomer (Ki=0.99 μM). For tramadol enantiomers, (+)-tramadol (Ki=0.53 μM) was 4.4 times as active as (–)-tramadol (Ki=2.35 μM) and 1.9 times as potent an inhibitor as the racemate (Ki=0.99 μM). Unpublished rat brain homogenate studies by Codd and colleagues
      • Codd E.E.
      • Shank R.P.
      • Schupsky J.J.
      • Raffa R.B.
      Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception.
      of (+)-O-desmethyltramadol- and (–)-O-desmethyltramadol-induced inhibition of 5-HT uptake produced Ki values of 2.98 and 17.7 μM, respectively.
      • Raffa R.B.
      • Buschmann H.
      • Christoph T.
      • et al.
      Mechanistic and functional differentiation of tapentadol and tramadol.
      In an earlier investigation into the uptake and release of serotonin,
      • Driessen B.
      • Reimann W.
      Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro.
      tramadol inhibited the uptake of [3H]5-HT into rat cortex synaptosomes with an IC50 of 3.1 μM. The IC50 for (+)-tramadol was 2.1 μM, about four times more potent than the (–)-enantiomer (8.6 μM), whilst O-desmethyltramadol was about one-tenth as potent (24.2 μM). Both of the methorphans proved to be more active than (S)-(+)-methadone, and the tramadol compounds with dextromethorphan (Ki=0.023 μM) were 1.6 times as potent an inhibitor as its levo-isomeric form (Table 1). In vitro studies such as these provide a valuable screen of the potential for OADs to cause ST.
      Fig 3
      Fig 3Tramadol, (2-dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol, has two chiral centres in the cyclohexane ring, and can therefore exist in four different stereoisomeric forms: (1R,2R), (1S,2S), (1R,2S), and (1S,2R). The drug used commercially as the hydrochloride is a racemic mixture of the (1R,2R) and (1S,2S) enantiomers, designated as the (+)- and (–)-enantiomers shown here. These structures have the hydroxyl group and the dimethylaminomethyl group in the cis configuration and the methoxyphenyl group and dimethylaminomethyl group in the trans configuration. Tramadol shares a phenylpropylamine structure with morphine and its analogues and with the synthetics, and methadone. Tapentadol, 3-[(1R,2R)-3-dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrochloride, has two chiral centres: the 3-ethyl and 2-methyl groups, and exists as four enantiomers: (R,R), (S,S), (S,R), and (R,S). For the different stereoisomers, the ethyl and aminopropyl groups adopt different orientations in relation to the phenol ring. The drug used commercially is the single (R,R) stereoisomer. Like tramadol, tapentadol shares a phenylpropylamine structure with morphine, its analogues and the synthetic opioids.
      Table 1Inhibition of serotonin (5-HT) uptake, SERT binding, and receptor binding by opioid analgesic drugs. *Results from Codd and colleagues.
      • Codd E.E.
      • Shank R.P.
      • Schupsky J.J.
      • Raffa R.B.
      Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception.
      Earlier uptake inhibition studies by Driessen and Reimann
      • Driessen B.
      • Reimann W.
      Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro.
      produced IC50 concentrations of (±)-tramadol 3.1 μM, (+)-tramadol 2.1 μM, (–)-tramadol 8.6 μM, O-desmethyltramadol 24.2 μM. Results from Rickli and colleagues.
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      Results from Raffa and colleagues
      • Raffa R.B.
      • Friderichs E.
      • Reimann W.
      • et al.
      Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol.
      • Raffa R.B.
      • Buschmann H.
      • Christoph T.
      • et al.
      Mechanistic and functional differentiation of tapentadol and tramadol.
      and Tzschentke and colleagues.
      • Tzschentke T.M.
      • Christoph T.
      • Kogel B.
      • et al.
      (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel μ-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties.
      (+)-Tramadol and (+)-methadone inhibited 5-HT uptake with Ki values of 0.76 and 0.27 nM, respectively (Giusti and colleagues
      • Giusti P.
      • Buriani A.
      • Cima L.
      • Lipartiti M.
      Effect of acute and chronic tramadol on [3H]-5-HT uptake in rat cortical synaptosomes.
      ). h, human; r, rat; SERT, serotonin transporter; 5-HT, 5-hydroxytryptamine.
      OpioidrSynaptosomal uptake inhibition of 5-HT* (Ki [μM])hSERT inhibition in vitro (IC50 [μM])Receptor binding (Ki [affinity] [μM])hSERT binding affinity (Ki [μM])
      5-HT1A5-HT2A
      Dextromethorphan0.0230.068InactiveInactive
      Levomethorphan0.036
      (±)-Tramadol0.993.3InactiveInactive1.19
      (+)-Tramadol0.530.87
      (–)-Tramadol2.35
      O-desmethyl-tramadol24InactiveInactive
      (±)-Methadone0.23Inactive0.61
      (S)(+)-Methadone0.995.6Inactive0.52
      (R)(–)-Methadone0.0140.28Inactive0.72
      Tapentadol2.373.3Inactive6.35.28
      Meperidine1.6Inactive3.6
      Fentanyl1542.11.3
      Further evidence that some OADs inhibit serotonin uptake was obtained by Barann and colleagues,
      • Barann M.
      • Stamer U.M.
      • Lyutenska M.
      • Stuber F.
      • Bonisch H.
      • Urban B.
      Effects of opioids on human serotonin transporters.
      who used cultured human kidney (HEK-293) cells stably transfected with human SERT (wild type, Family 6, Member 4) and human platelets ex vivo in investigations of the effect of opioids on human SERT. With the aim of determining whether opioids and ketamine inhibit human SERT and increase concentrations of serotonin in plasma, the effects of morphine, hydromorphone, meperidine, tramadol, fentanyl, alfentanil, ketamine, and citalopram (as a specific SERT inhibitor) on the uptake of serotonin by transfected cells and platelets were examined. Tramadol (IC50 of 0.93 μM), meperidine (IC50 of 20.9 μM), and ketamine (IC50 of 230 μM) suppressed the uptake of serotonin by transfected HEK-293 cells, inhibiting SERT in a dose-dependent manner; morphine, hydromorphone, fentanyl, and alfentanil were inactive in the concentration range 10–30 μM. In experiments examining the inhibition of platelet SERT, tramadol, meperidine, and a high dose of ketamine inhibited the uptake into human platelets causing a significant concentration-dependent increase in the free concentration of serotonin in human plasma. Again, morphine, hydromorphone, fentanyl, and alfentanil did not affect the free plasma serotonin concentrations.
      • Barann M.
      • Stamer U.M.
      • Lyutenska M.
      • Stuber F.
      • Bonisch H.
      • Urban B.
      Effects of opioids on human serotonin transporters.
      These results confirmed the conclusion from earlier studies showing that meperidine and tramadol inhibit human SERT, and (+) and (–) tramadol inhibit SERT at concentrations equivalent to a bolus tramadol concentration of ∼10 μM, whereas the enantiomers of the drug's active metabolite, O-desmethyltramadol, were only weak inhibitors.
      • Barann M.
      • Stamer U.M.
      • Lyutenska M.
      • Stuber F.
      • Bonisch H.
      • Urban B.
      Effects of opioids on human serotonin transporters.
      • Barann M.
      • Urban B.
      • Stamer U.
      • Dorner Z.
      • Bonisch H.
      • Bruss M.
      Effects of tramadol and O-demethyl-tramadol on human 5-HT reuptake carriers and human 5-HT3A receptors: a possible mechanism for tramadol-induced early emesis.
      In a recent study of opioid-induced inhibition of human SERT, Rickli and colleagues
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      also used SERT-transfected human kidney cells to determine the OADs that inhibit SERT at concentrations of drugs close to observed plasma and estimated brain concentrations. Inhibitors, in descending order of potency, were dextromethorphan (IC50 of 0.068), racemic and R-(–)-methadone, meperidine, and racemic tramadol and tapentadol (both IC50 of 3.3 μM). S-(+)-methadone (IC50 of 5.6 μM) and O-desmethyltramadol (IC50 of 24 μM) were moderate-to-weak inhibitors, and fentanyl was a very weak inhibitor (IC50 of 154 μM) (Table 1). Morphine, monoacetylmorphine, heroin, hydromorphone, oxymorphone, codeine, dihydrocodeine, hydrocodone, oxycodone, and buprenorphine were non-inhibitors of human SERT. Of the opioids tested, and their binding affinities to serotonin 5-HT1A and 5-HT2A receptors, only fentanyl interacted with the 5-HT1A receptor and racemic methadone, its enantiomers, fentanyl, and meperidine showed 5-HT2A receptor activity in the low micromolar range. Tapentadol, used as the (1R,2R) stereoisomer (Fig. 3), showed moderate interaction with the 5-HT2A receptor, but dextromethorphan, tramadol, and O-desmethyltramadol proved inactive
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      (Table 1). Other binding studies undertaken with human SERT produced Ki values of 1.19 μM for racemic tramadol, 0.87 μM for (+)-tramadol, and 5.28 μM for tapentadol (Table 1).
      • Raffa R.B.
      • Friderichs E.
      • Reimann W.
      • et al.
      Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol.
      • Tzschentke T.M.
      • Christoph T.
      • Kogel B.
      • et al.
      (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel μ-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties.
      • Raffa R.B.
      • Buschmann H.
      • Christoph T.
      • et al.
      Mechanistic and functional differentiation of tapentadol and tramadol.
      These opioid–serotonin receptor-binding results were preceded by the findings of Martin and colleagues,
      • Martin D.C.
      • Introna R.P.
      • Aronstam R.S.
      Fentanyl and sufentanil inhibit agonist binding to 5-HT1A receptors in membranes from the rat brain.
      who showed that fentanyl, sufentanil, alfentanil (Fig. 1d), and meperidine disrupted the receptor binding in rat brain membrane and that the former two anilidopiperidines interacted directly with the 5-HT1A receptor.

      Role of opioid analgesic drugs in serotonin toxicity for the anaesthetist

      Although evidence for some severe cases of ST, including fatalities, induced by meperidine with MAOIs is strong
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      (see preceding discussion), it has been claimed that tapentadol is not a significant cause, methadone is an ‘unlikely’ cause, and the involvement of fentanyl and its congeners in ST is uncertain.
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      For the phenanthrene opioids morphine, codeine, oxycodone, and buprenorphine, there is also an absence of convincing clinical reports of ST when these opioids are administered with MAOIs.
      • Codd E.E.
      • Shank R.P.
      • Schupsky J.J.
      • Raffa R.B.
      Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception.
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      Given the range of serotonergic medicines now widely prescribed and being introduced,
      • Taciak P.P.
      • Lysenko N.
      • Mazurek A.P.
      Drugs which influence serotonin transporter and serotonergic receptors: pharmacological and clinical properties in the treatment of depression.
      the expansion in the number of clinical reports of the apparent involvement of OADs in ST,
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      results from studies of animal models,
      • Isbister G.K.
      • Buckley N.A.
      The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment.
      • Nymark M.
      • Møller Nielsen I.
      Reactions due to the combination of monoamineoxidase inhibitors with thymoleptics, pethidine or methylamphetamine.
      • Rogers K.J.
      Role of brain monoamines in the interaction between pethidine and tranylcypromine.
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      and mechanistic studies of regulation of serotonergic neurotransmission,
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      • Barann M.
      • Stamer U.M.
      • Lyutenska M.
      • Stuber F.
      • Bonisch H.
      • Urban B.
      Effects of opioids on human serotonin transporters.
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      opioids may be the most important drug associated with ST in anaesthesia.
      • Davis J.J.
      • Buck N.S.
      • Swenson J.D.
      • Johnson K.B.
      • Greis P.E.
      Serotonin syndrome manifesting as patient movement during total intravenous anesthesia with propofol and remifentanil.
      Individual implicated OADs will be examined with emphasis on patients who are at most risk and relevance of the findings to the practising anaesthetist.

       Fentanyl

      For the anaesthetist, the anilidopiperidine fentanyl is perhaps the OAD of prime interest, being used to produce balanced anaesthesia and widely given for procedural sedation with a low-dose i.v. hypnotic, usually a benzodiazepine. Fentanyl may be used to induce and contribute to the maintenance of anaesthesia in critically ill and cardiac patients. This potent, relatively inexpensive, rapidly, but relatively short-acting synthetic OAD shows minimal cardiovascular effects and does not induce histamine release, making it the most commonly used opioid for intraoperative analgesia and, in the form of transdermal patches, for chronic pain in and outside the hospital setting.
      In relation to ST, and given its effectiveness and heavy usage, fentanyl, more than any other agent, opioid or not, is of most interest to anaesthetists. Of 1641 Individual Case Safety Reports (ICSRs) in the WHO global VigiBase™ database

      VigiBase. Available from: https://www.who-umc.org/vigibase/vigibase/(accessed 29 December 2018).

      involving the association of opioids and ST, alone or with other drugs, fentanyl, after tramadol, was the second most frequently reported OAD with 363 ICSRs (Fig. 4; see also Rickli and colleagues
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      ). Of 147 ICSRs, in which an OAD was the only suspected cause of ST, fentanyl was the third most reported drug with 19 cases.

      VigiBase. Available from: https://www.who-umc.org/vigibase/vigibase/(accessed 29 December 2018).

      In the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database from January 1969 to June 2013, 28 cases of ST were associated with fentanyl, making it the most commonly FDA-implicated opioid associated with the toxicity. In five of these cases, fentanyl was administered with at least one other opioid; four cases with oxycodone; and one case with each of morphine, hydromorphone, and hydrocodone.
      • US Food and Drug Administration
      Drug safety communications: FDA warns about several safety issues with opioid pain medicines; requires label changes.
      Fig 4
      Fig 4Numbers of Individual Case Safety Reports (ICSRs) of serotonin toxicity in the WHO global VigiBase database identifying individual opioids as the only suspected cause or the only suspected cause amongst other administered drugs. Reproduced from Rickli and colleagues, Br J Pharmacol 2018;175:532-43, an open-access article distributed under the terms of the Creative Commons Attribution License.
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      Individual published reports of the apparent involvement of fentanyl in cases diagnosed as ST are listed in Table 2. Serotonergic drugs most commonly co-administered with fentanyl are known inhibitors of serotonin uptake. The list comprises the SSRIs citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; the SNRIs duloxetine and venlafaxine; the antidepressants trazodone and amfebutamone (bupropion); the OADs methadone and meperidine; and the drug of abuse MDMA.
      • Davis J.J.
      • Buck N.S.
      • Swenson J.D.
      • Johnson K.B.
      • Greis P.E.
      Serotonin syndrome manifesting as patient movement during total intravenous anesthesia with propofol and remifentanil.
      • Ailawadhi S.
      • Sung K.W.
      • Carlson L.A.
      • Baer M.R.
      Serotonin syndrome caused by interaction between citalopram and fentanyl.
      • Ozkardesler S.
      • Gurpinar T.
      • Akan M.
      • et al.
      A possible perianesthetic serotonin syndrome related to intrathecal fentanyl.
      • Rang S.T.
      • Field J.
      • Irving C.
      Serotonin toxicity caused by an interaction between fentanyl and paroxetine.
      • Kirschner R.
      • Donovan J.W.
      Serotonin syndrome precipitated by fentanyl during procedural sedation.
      • Alkhatib A.A.
      • Peterson K.A.
      • Tuteja A.K.
      Serotonin syndrome as a complication of fentanyl sedation during esophagogastroduodenoscopy.
      • Altman C.S.
      • Jahangiri M.F.
      Serotonin syndrome in the perioperative period.
      • Reich M.
      • Lefebvre-Kuntz D.
      Serotoninergic antidepressants and opiate analgesics: a sometimes-painful association. A case report.
      • Rastogi R.
      • Swarm R.A.
      • Patel T.A.
      Case scenario: opioid association with serotonin syndrome: implications to the practitioners.
      • Gollapudy S.
      • Kumar V.
      • Dhamee M.S.
      A case of serotonin syndrome precipitated by fentanyl and ondansetron in a patient receiving paroxetine, duloxetine, and bupropion.
      • Adler A.R.
      • Charnin J.A.
      • Quraishi S.A.
      Serotonin syndrome: the potential for a severe reaction between common perioperative medications and selective serotonin reuptake inhibitors.
      • Gaffney R.R.
      • Schreibman I.R.
      Serotonin syndrome in a patient on trazodone and duloxetine who received fentanyl following a percutaneous liver biopsy.
      • Atkinson T.J.
      • Fudin J.
      • Pham T.C.
      • et al.
      Combined fentanyl and methadone induced serotonin syndrome is called into question.
      • Hillman A.D.
      • Witenko C.J.
      • Sultan S.M.
      • Gala G.
      Serotonin syndrome caused by fentanyl and methadone in a burn injury.
      • Lee C.
      • Kim E.-J.
      • Joe S.
      • Ban J.S.
      • Lee J.-H.
      • An J.-H.
      A case of postoperative serotonin syndrome following the administration of fentanyl, palonosetron, and meperidine—a case report.
      • Shah N.D.
      • Jain A.B.
      Serotonin syndrome presenting as pulmonary edema.
      • Smischney N.J.
      • Pollard E.M.
      • Nookala A.U.
      • Olatoye O.O.
      Serotonin syndrome in the perioperative setting.
      Note that MDMA is also a serotonin releaser. Co-administered serotonergic drugs representative of other mechanisms underlying ST include the MAOIs methylene blue and linezolid; serotonin receptor activators dihydroergotamine, lithium, metoclopramide, and meperidine; and inhibitors/substrates for CYP450 enzymes CYP2D6 (inhibitors fluoxetine and sertraline, and substrate oxycodone), CYP3A4 (substrates methadone, oxycodone, and venlafaxine), and CYP2C19 (substrate citalopram) (Table 2).
      Table 2Reports of serotonin toxicity in patients given fentanyl and other serotonergic drugs. MDMA, 3,4-methylenedioxymethamphetamine. *Fentanyl administered as a topical patch. All symptoms developed within 24 h of application of fentanyl patch. Last dose taken the day before hospitalisation. Taken 2–3 weeks earlier. §Fentanyl administered intraoperatively and after operation. ||Symptoms not noted until the first postoperative day, suggested to be masked by morphine and midazolam given during and after surgery. #A serotonin receptor blocker. **Hydromorphone also given during surgery. ††Diagnosis completed only after reversal of neuromuscular block. ‡‡Fentanyl administered as a nasal spray. ¶¶Increased replacement frequency of fentanyl patch suggested to be the determining factor in precipitating serotonin toxicity. §§Fentanyl given at induction; remifentanil given during maintenance of anaesthesia. ||||Clonus and nystagmus manifested, and most obvious, after fentanyl. ##Polypharmacy made it difficult to identify the culprit drugs. ***Authors' diagnostic conclusion has been called into question.
      • Atkinson T.J.
      • Fudin J.
      • Pham T.C.
      • et al.
      Combined fentanyl and methadone induced serotonin syndrome is called into question.
      †††A 5-HT3 antagonist. The drug shows a prolonged therapeutic effect, persisting for >40 h. ‡‡‡Patient difficult to wean from ventilator. Successfully treated with cyproheptadine and lorazepam. ¶¶¶Meperidine given after operation for shivering intensified the myoclonic jerks.
      Patient age (yr); M/FSerotonergic drugs administered in addition to fentanylSymptomsReferences
      65

      F
      Citalopram*Confusion, agitation, combativeness, upper extremity tremors, hyperreflexia, myoclonic jerks, increased HR, and unsteady gaitAilawadhi and colleagues (2007)
      • Ailawadhi S.
      • Sung K.W.
      • Carlson L.A.
      • Baer M.R.
      Serotonin syndrome caused by interaction between citalopram and fentanyl.
      25

      M
      Ergot alkaloids, MDMA, ephedrine, and marijuanaAgitation, shivering, rigidity of the upper extremities, increased HR, visual and auditory hallucinations, temperature 39°C, flushing, and muscle rigidityOzkardesler and colleagues (2008)
      • Ozkardesler S.
      • Gurpinar T.
      • Akan M.
      • et al.
      A possible perianesthetic serotonin syndrome related to intrathecal fentanyl.
      60

      F
      Paroxetine§Agitation, vagueness, hyperreflexia, inducible clonus, and hypertensionRang and colleagues (2008)
      • Rang S.T.
      • Field J.
      • Irving C.
      Serotonin toxicity caused by an interaction between fentanyl and paroxetine.
      46

      F
      SertralineReduced SpO2, restless, shivering, confused, agitated, increased HR, hyperflexia, lower extremity rigidity, ankle clonus, combative, and diaphoresisKirschner and Donovan (2010)
      • Kirschner R.
      • Donovan J.W.
      Serotonin syndrome precipitated by fentanyl during procedural sedation.
      59

      F
      Trazodone, escitalopram, and oxycodoneAgitation, hyperreflexia, clonus, and diaphoresis||Kirschner and Donovan (2010)
      • Kirschner R.
      • Donovan J.W.
      Serotonin syndrome precipitated by fentanyl during procedural sedation.
      39

      F
      SertralineRigidity in extremities, diaphoresis, fever, and roving eye movementsAlkhatib and colleagues (2010)
      • Alkhatib A.A.
      • Peterson K.A.
      • Tuteja A.K.
      Serotonin syndrome as a complication of fentanyl sedation during esophagogastroduodenoscopy.
      44

      F
      Duloxetine, lithium, quetiapine,# and ondansetron**Extremities rigid, unresponsive to verbal and tactile stimulation, upper extremity clonus, and nystagmus††Altman and Jahangiri (2010)
      • Altman C.S.
      • Jahangiri M.F.
      Serotonin syndrome in the perioperative period.
      66

      M
      Escitalopram and oxycodone‡‡Diaphoresis, night sweating, tremor, visual disorder with mydriasis, and diarrhoeaReich and Lefebvre-Kuntz (2010)
      • Reich M.
      • Lefebvre-Kuntz D.
      Serotoninergic antidepressants and opiate analgesics: a sometimes-painful association. A case report.
      58

      M
      Citalopram, mirtazapine, and oxycodone*Anxiety, fever, sweating, confusion, agitation, tremor, and insomnia¶¶Rastogi and colleagues (2011)
      • Rastogi R.
      • Swarm R.A.
      • Patel T.A.
      Case scenario: opioid association with serotonin syndrome: implications to the practitioners.
      68

      F
      Ondansetron, paroxetine, duloxetine, amfebutamone, oxycodone, and hydromorphoneAgitation, confusion, non-responsive to commands, increased temperature, and apnoeicGollapudy and colleagues (2012)
      • Gollapudy S.
      • Kumar V.
      • Dhamee M.S.
      A case of serotonin syndrome precipitated by fentanyl and ondansetron in a patient receiving paroxetine, duloxetine, and bupropion.
      23

      M
      Fluoxetine§§Bilateral clonus at ankle, horizontal nystagmus, and diaphoresis||||Davis and colleagues (2013)
      • Davis J.J.
      • Buck N.S.
      • Swenson J.D.
      • Johnson K.B.
      • Greis P.E.
      Serotonin syndrome manifesting as patient movement during total intravenous anesthesia with propofol and remifentanil.
      20s

      M
      Fluoxetine, ondansetron, metoclopramide, methylene blue, and metronidazole##Hypertension, tachycardia, febrile, agitation, confusion, hyperreflexia, rigidity, and nystagmusAdler and colleagues (2015)
      • Adler A.R.
      • Charnin J.A.
      • Quraishi S.A.
      Serotonin syndrome: the potential for a severe reaction between common perioperative medications and selective serotonin reuptake inhibitors.
      59

      F
      Duloxetine and trazodoneHypertension, agitation, diaphoresis, flushing, bowel sounds, rigidity in extremities, and impaired speechGaffney and Schreibman (2015)
      • Gaffney R.R.
      • Schreibman I.R.
      Serotonin syndrome in a patient on trazodone and duloxetine who received fentanyl following a percutaneous liver biopsy.
      36

      M
      MethadoneIncreased temperature, BP, and HR; tremor; myoclonus; agitation; hyperreflexia; and diaphoresis***Hillman and colleagues (2015)
      • Hillman A.D.
      • Witenko C.J.
      • Sultan S.M.
      • Gala G.
      Serotonin syndrome caused by fentanyl and methadone in a burn injury.
      51

      M
      Palonosetron††† and meperidineIncreased temperature, BP, and HR; shivering; confused; agitation; drowsy; and diaphoresisLee and colleagues (2015)
      • Lee C.
      • Kim E.-J.
      • Joe S.
      • Ban J.S.
      • Lee J.-H.
      • An J.-H.
      A case of postoperative serotonin syndrome following the administration of fentanyl, palonosetron, and meperidine—a case report.
      58

      M
      Fluoxetine, fluvoxamine, sertraline, and linezolidAgitation, increased BP, diaphoresis, involuntary jerks, altered mental status, and pulmonary oedema‡‡‡Shah and Jain (2016)
      • Shah N.D.
      • Jain A.B.
      Serotonin syndrome presenting as pulmonary edema.
      70

      M
      VenlafaxineMyoclonic jerks in extremities,¶¶¶ hypertonia, rigidity, diaphoresis, shaking, and shiveringSmischney and colleagues (2018)
      • Smischney N.J.
      • Pollard E.M.
      • Nookala A.U.
      • Olatoye O.O.
      Serotonin syndrome in the perioperative setting.
      In what was described as an ‘unusual reaction’, a postoperative death occurred after cardiac surgery on a patient taking the MAOI tranylcypromine and undergoing high-dose fentanyl–midazolam induction.
      • Noble W.H.
      • Baker A.
      MAO inhibitors and coronary artery surgery: a patient death.
      Symptoms preceding death included hypertension, hyperthermia, severe shivering, and later hypotension, leading the authors to disagree with the previous opinion that, unlike meperidine, patients on MAOIs can be given fentanyl safely.
      • Stack C.G.
      • Rogers P.
      • Linter S.P.
      Monoamine oxidase inhibitors and anaesthesia. A review.
      • Wells D.G.
      • Bjorksten A.R.
      Monoamine oxidase inhibitors revisited.
      Although a MAOI-mediated increase in cerebral concentration of serotonin was mentioned, ST was not suggested as a possible explanation for the observed symptoms and death. Gillman
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      has stated that the reaction was ‘probably a result of serotonin toxicity’. The question of the safety of fentanyl and other OADs when administered in combination with MAOIs, principally in relation to cardiac surgery, has been considered in a number of published commentaries and case reports over the years. Although some wariness of fentanyl's safety has been expressed and under-diagnosis and -reporting were suspected especially when used with large doses with a MAOI,
      • Insler S.R.
      • Kraenzler E.J.
      • Licina M.G.
      • Savage R.M.
      • Starr N.J.
      Cardiac surgery in a patient taking monoamine oxidase inhibitors: an adverse fentanyl reaction.
      the ongoing regular, widespread, and apparent safe use of the drug has, unsurprisingly, led to a large majority of communications expressing confidence in its safety and continued usage.
      • Stack C.G.
      • Rogers P.
      • Linter S.P.
      Monoamine oxidase inhibitors and anaesthesia. A review.
      • Michaels I.
      • Serrins M.
      • Shier N.Q.
      • Barash P.G.
      Anesthesia for cardiac surgery in patients receiving monoamine oxidase inhibitors.
      • el-Ganzouri A.R.
      • Ivankovich A.D.
      • Braverman B.
      • McCarthy R.
      Monoamine oxidase inhibitors: should they be discontinued preoperatively?.
      • Baele P.
      • Kestens-Servaye Y.
      • Goenen M.
      MAOI and cardiac surgery.
      • Noorily S.H.
      • Hantler C.B.
      • Sako E.Y.
      Monoamine oxidase inhibitors and cardiac anesthesia revisited.
      • Krishnan G.
      • Singh R.P.
      • Agrawal M.
      • Agrawal R.
      Anesthesia for a patient on monoamine oxidase inhibitors.
      Gillman
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      has observed that fentanyl together with a MAOI has probably been used and unreported many times with no problems, and the risk would seem to be so low that one could not suggest that its use is contraindicated in the absence of a suitable alternative. Fentanyl's congeners alfentanil, sufentanil, and remifentanil have shorter half-lives and might be selected to minimise the possibility of an adverse reaction in patients on MAOI therapy, although there is no direct evidence. Remifentanil, with no evidence so far that it reacts adversely with a MAOI and with a short elimination half-life of 5–8 min, was selected and used safely in major surgery as part of a balanced anaesthetic technique in a patient treated with phenelzine.
      • Ure D.S.
      • Gillies M.A.
      • James K.S.
      Safe use of remifentanil in a patient treated with the monoamine oxidase inhibitor phenelzine.
      Gillman
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      and Kirschner and Donovan
      • Kirschner R.
      • Donovan J.W.
      Serotonin syndrome precipitated by fentanyl during procedural sedation.
      have drawn attention to an atypical case of low-dose fentanyl-induced muscle rigidity during recovery from anaesthesia in an adult patient on venlafaxine, who was also given a single dose of meperidine before the procedure.
      • Roy S.
      • Fortier L.P.
      Fentanyl-induced rigidity during emergence from general anesthesia potentiated by venlafexine.
      Although a diagnosis of ST was not considered, symptoms including hyperreflexia and ankle clonus, prompted speculation that chest wall rigidity in some other patients taking serotonergic drugs
      • Streisand J.B.
      • Bailey P.L.
      • LeMaire L.
      • et al.
      Fentanyl-induced rigidity and unconsciousness in human volunteers. Incidence, duration, and plasma concentrations.
      • Stuerenburg H.J.
      • Claassen J.
      • Eggers C.
      • Hansen H.C.
      Acute adverse reaction to fentanyl in a 55 year old man.
      may be a manifestation of ST. The finding that pretreatment with the serotonin antagonist ketanserin attenuated alfentanil-mediated muscle rigidity in the rat appears to add some credibility to the speculation.
      • Kirschner R.
      • Donovan J.W.
      Serotonin syndrome precipitated by fentanyl during procedural sedation.
      • Weinger M.B.
      • Cline E.J.
      • Smith N.T.
      • Koob G.F.
      Ketanserin pretreatment reverses alfentanil-induced muscle rigidty.
      In light of a claimed recent increase in case reports of ST associated with opioids, particularly fentanyl, a retrospective analysis of a database of 112 045 patients taking serotonergic agents over a 2 yr period (2012–3) was undertaken at the Massachusetts General Hospital.
      • Koury K.M.
      • Tsui B.
      • Gulur P.
      Incidence of serotonin syndrome in patients treated with fentanyl on serotonergic agents.
      Patients receiving fentanyl whilst on another serotonergic agent numbered 4538 (4%), and of these, 23 were documented with some symptoms of ST. Application of the Hunter diagnostic approach for ST revealed only four patients (0.09%) who met the criteria: three were on fentanyl patches and one was given i.v. fentanyl in the hospital. In comparison, the incidence of ST in patients who did not receive fentanyl whilst on a serotonergic agent was 0.005%.
      It is claimed that ST is becoming a more frequent diagnosis in the ICU in patients with unexplained encephalopathy or a toxidrome, but also in patients after receiving serotonergic medications in intensive care.
      • Pedavally S.
      • Fugate J.E.
      • Rabinstein A.A.
      Serotonin syndrome in the intensive care unit: clinical presentations and precipitating medications.
      In 33 cases of ST (who met the Hunter Serotonin Toxicity Criteria), 13 patients developed ST after hospitalisation and, although SSRIs and SNRIs were the most common medications in the patients before hospitalisation, opioids and anti-emetics were the most commonly administered serotonergic agents in the hospital. Of the OADs implicated, fentanyl, tramadol, or methadone was administered to one of the 33 patients (3%) before admission. After admission, 21 patients (64%) were given an OAD, 19 (58%) received fentanyl, three (9%) received tramadol, and two (6%) received meperidine. No cases related to the use of MAOIs were found.
      As an inhibitor of human SERT, fentanyl can, at best, be said to show only weak activity (IC50 of 154 μM) (Table 1), but it shows affinity for the serotonin 5-HT1A and 5-HT2A receptors in the low micromolar range
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      • Martin D.C.
      • Introna R.P.
      • Aronstam R.S.
      Fentanyl and sufentanil inhibit agonist binding to 5-HT1A receptors in membranes from the rat brain.
      (Table 1). Following the early finding that fentanyl and sufentanil have affinity for the rat 5-HT1A receptor,
      • Martin D.C.
      • Introna R.P.
      • Aronstam R.S.
      Fentanyl and sufentanil inhibit agonist binding to 5-HT1A receptors in membranes from the rat brain.
      Tao and colleagues
      • Tao R.
      • Karnik M.
      • Ma Z.
      • Auerbach S.B.
      Effect of fentanyl on 5-HT efflux involves both opioid and 5-HT1A receptors.
      showed that systemic administration of fentanyl produced a relatively short-lasting (2–3 h) efflux of serotonin in the rat dorsal raphe nucleus (DRN). Prior injection of naltrexone blocked the increase in serotonin, indicating that opioid receptors are involved. In contrast, direct infusion of fentanyl into the DRN led to a decrease in serotonin unaffected by naltrexone, but selective 5-HT1A receptor antagonists blocked the decrease, allowing an increase in serotonin in response to local infusion or systemic administration of fentanyl.
      • Tao R.
      • Karnik M.
      • Ma Z.
      • Auerbach S.B.
      Effect of fentanyl on 5-HT efflux involves both opioid and 5-HT1A receptors.
      These results show that fentanyl both stimulates opioid receptors and is a serotonin 5-HT1A receptor agonist, and indicated that direct activation of 5-HT1A receptors at high concentrations inhibited serotonin efflux.

       Tramadol

      Tramadol, which shows no immediately obvious structural similarity to morphine, is used medicinally as a racemic mixture, the (+)-enantiomer (1R,2R) and the (–)-enantiomer (1S,2S) (Fig. 3). The (+)-enantiomer is four to five times as potent as (–)-tramadol in inhibiting serotonin uptake
      • Driessen B.
      • Reimann W.
      Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro.
      • Codd E.E.
      • Shank R.P.
      • Schupsky J.J.
      • Raffa R.B.
      Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception.
      (Table 1). Although important opioid adverse effects, such as respiratory depression and drug dependence, are lesser problems with tramadol than other OADs, a large body of clinical publications reflects its involvement in the induction of physical and psychological dependence, seizures, and drug-related intoxications and fatalities.
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      • The WHO Expert Committee
      Tramadol update review report: Expert committee on drug dependence (ECDD) 36th meeting agenda item 6.1, Geneva.
      A number of studies have shown that tramadol in the low micromolar range inhibits serotonin uptake by rat cortical synaptosomes
      • Driessen B.
      • Reimann W.
      Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro.
      • Raffa R.B.
      • Friderichs E.
      • Reimann W.
      • et al.
      Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol.
      • Codd E.E.
      • Shank R.P.
      • Schupsky J.J.
      • Raffa R.B.
      Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception.
      • Giusti P.
      • Buriani A.
      • Cima L.
      • Lipartiti M.
      Effect of acute and chronic tramadol on [3H]-5-HT uptake in rat cortical synaptosomes.
      • Gobbi M.
      • Mennini T.
      Release studies with rat brain cortical synaptosomes indicate that tramadol is a 5-hydroxytryptamine uptake blocker and not a 5-hydroxytryptamine releaser.
      • Frink M.C.
      • Hennies H.H.
      • Englberger W.
      • Haurand M.
      • Wilffert B.
      Influence of tramadol on neurotransmitter systems of the rat brain.
      and by human SERT
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      • Barann M.
      • Stamer U.M.
      • Lyutenska M.
      • Stuber F.
      • Bonisch H.
      • Urban B.
      Effects of opioids on human serotonin transporters.
      • Barann M.
      • Urban B.
      • Stamer U.
      • Dorner Z.
      • Bonisch H.
      • Bruss M.
      Effects of tramadol and O-demethyl-tramadol on human 5-HT reuptake carriers and human 5-HT3A receptors: a possible mechanism for tramadol-induced early emesis.
      (Table 1). This effect on serotonin transport underlies tramadol's potential involvement in ST. There is also some evidence that racemic and (+)-tramadol act as serotonin releasers.
      • Bamigbade T.A.
      • Davidson C.
      • Langford R.M.
      • Stamford J.A.
      Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus.
      Even when given alone, especially in high- or overdose, tramadol has been implicated in a small number of cases of ST.
      • Garrett P.M.
      Tramadol overdose and serotonin syndrome manifesting as acute right heart dysfunction.
      • Marechal C.
      • Honorat R.
      • Claudet I.
      Serotonin syndrome induced by tramadol intoxication in an 8-month-old infant.
      • Pothiawala S.
      • Ponampalam R.
      Tramadol overdose: a case report.
      It has also been suggested that much of the toxicity seen in cases of tramadol overdose is attributable to its monoamine uptake inhibition effect causing mild ST,
      • Spiller H.A.
      • Gorman S.E.
      • Villalobos D.
      • et al.
      Prospective multicenter evaluation of tramadol exposure.
      but in an assessment of 71 cases of tramadol overdose, Ryan and Isbister
      • Ryan N.M.
      • Isbister G.K.
      Tramadol overdose causes seizures and respiratory depression but serotonin toxicity appears unlikely.
      found no cases that met the Hunter Serotonin Toxicity Criteria
      • Dunkley E.J.
      • Isbister G.K.
      • Sibbritt D.
      • Dawson A.H.
      • Whyte I.M.
      The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.
      and concluded that tramadol overdose is unlikely to cause ST. However, the potential risk of tramadol causing ST is increased when it is administered with other serotonin reuptake inhibitors, drugs that increase the synthesis and release of serotonin, inhibitors of serotonin metabolism, serotonin precursors, and other OADs. The list of serotonergic drugs co-administered with tramadol in case reports of its apparent involvement in ST is extensive and includes fluoxetine, citalopram, sertraline, escitalopram, paroxetine, venlafaxine, amfebutamone, trazodone, oxycodone, morphine, hydrocodone, and dextromethorphan.
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      Of the 1641 ICSRs in the WHO VigiBase database involving an opioid alone or with another drug(s), tramadol, with 647 reports, topped the list. In cases where an opioid was the only suspected cause, tramadol again contributed the highest number of cases with 62 of 147 reports
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      (Fig. 4). Of all the non-psychotropic medications associated with ST, case reports, clinical and laboratory studies, and pharmacovigilance data show that tramadol is the most commonly implicated drug.
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      • Chassot M.
      • Munz T.
      • Livio F.
      • Buclin T.
      [Serotonin syndrome: review and case series from the Swiss pharmacovigilance system].
      • Abadie D.
      • Rousseau V.
      • Logerot S.
      • Cottin J.
      • Montastruc J.L.
      • Montastruc F.
      Serotonin syndrome: analysis of cases registered in the French pharmacovigilance database.
      • Beakley B.D.
      • Kaye A.M.
      • Kaye A.D.
      Tramadol, pharmacology, side effects, and serotonin syndrome: a review.
      A contributing factor to this may be co-prescribing of antidepressants, a possibility suggested by a retrospective cohort analysis showing that 1061 of 4774 (22.2%) individuals were given a prescription for an antidepressant within 30 days of their first prescription for tramadol.
      • Shatin D.
      • Gardner J.S.
      • Stergachis A.
      • Blough D.
      • Graham D.
      Impact of mailed warning to prescribers on the co-prescription of tramadol and antidepressants.

       Tapentadol

      Tapentadol, like tramadol, shows no immediately obvious structural similarity to morphine, but unlike tramadol, tapentadol is administered as a single enantiomer (–)-(1R,2R) (Fig. 3). It is a μ-opioid receptor agonist, a norepinephrine reuptake inhibitor, and weak serotonin uptake blocker in the rat (Ki=2.37 μM), about 2.4 times less potent in this respect than racemic tramadol and 4.5 times less potent than (+)-tramadol (Table 1).
      • Codd E.E.
      • Shank R.P.
      • Schupsky J.J.
      • Raffa R.B.
      Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception.
      • Raffa R.B.
      • Buschmann H.
      • Christoph T.
      • et al.
      Mechanistic and functional differentiation of tapentadol and tramadol.
      In studies on human SERT, binding affinities for tapentadol, racemic tramadol, and (+)-tramadol were 5.28, 1.19, and 0.87 μM, respectively, showing tapentadol to be 4.4 and six times less potent than the racemic and (+)-enantiomeric forms of tramadol, respectively (Table 1). In vitro human SERT inhibition and 5-HT receptor-binding experiments undertaken by Rickli and colleagues
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      observed that inhibition was weak and equal (IC50 of 3.3 μM) for tapentadol and racemic tramadol, and, although both drugs did not bind to 5-HT1A receptors, tapentadol showed weak affinity for the 5-HT2A receptor, whereas tramadol was inactive (Table 1).
      The minimal-to-weak serotonin reuptake inhibitor activity in vitro and the lack of convincing clinical evidence of tapentadol have suggested to some that it is an unlikely cause of ST.
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      However, adverse drug events involving tapentadol for the period September 2013 to March 2017 reported to the Australian Therapeutic Goods Administration included 16 cases of ST, of which 14 (87.5%) involved co-administration of another serotonergic medication.
      • Abeyaratne C.
      • Lalic S.
      • Bell J.S.
      • Ilomäki J.
      Spontaneously reported adverse drug events related to tapentadol and oxycodone/naloxone in Australia.
      Post-marketing surveillance and a small number of case reports suggest rare reactions to the drug alone and when given concomitantly with other serotonergic medications,
      • US Food and Drug Administration
      Drug safety communications: FDA warns about several safety issues with opioid pain medicines; requires label changes.

      NUCYNTA ER (tapentadol). Highlights of prescribing information 2016. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/200533s014lbl.pdf (accessed 29 October 2018).

      • Mancano M.A.
      ISMP adverse drug reactions. Serotonin syndrome with concomitant use of tapentadol and venlafaxine.
      • Franco D.M.
      • Ali Z.
      • Levine B.
      • Middleberg R.A.
      • Fowler D.R.
      Case report of a fatal intoxication by Nucynta.
      • Walczyk H.
      • Liu C.H.
      • Alafris A.
      • Cohen H.
      Probable tapentadol-associated serotonin syndrome after overdose.
      but Gressler and colleagues
      • Gressler L.E.
      • Hammond D.A.
      • Painter J.T.
      Serotonin syndrome in tapentadol literature: systematic review of original research.
      and others
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      • Mullins M.E.
      • Dribben W.H.
      Comment on tapentadol and serotonin syndrome.
      • Russo M.
      • Santarelli D.
      • Isbister G.
      Comment on “probable tapentadol-associated serotonin syndrome after overdose”.
      have questioned the claimed association of tapentadol and ST.
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      Even so, figures from the WHO VigiBase database rank tapentadol third on the list of ST ICSRs associated with an opioid alone or with another drug(s) (115 out of 1641 cases; 7%), and second when the opioid was the only suspected cause (42 out of 147 cases; 28.6%) (Fig. 4). Both of these percentages seem surprisingly high. Without all of the details of the individual VigiBase ICSRs, it is difficult to reconcile the WHO data for tapentadol with the current general conclusion that tapentadol is not a significant cause of ST reached from an overall consideration of the rare published individual case reports. However, a recent in vivo microdialysis study in rat brain and spinal cord designed to examine the effects of tapentadol on monoamines revealed a significant increase in serotonin in the dorsal horn, thought to be caused by the activation of opioid receptors in brain regions with serotonergic projections to the dorsal horn.
      • Benade V.
      • Nirogi R.
      • Bhyrapuneni G.
      • et al.
      Mechanistic evaluation of tapentadol in reducing the pain perception using in-vivo brain and spinal cord microdialysis in rats.
      Hence, in addition to tapentadol's weak SERT inhibitory activity, a tapentadol-induced increase in serotonin concentrations combined with other serotonergic medications, such as SSRIs or SNRIs, might explain its apparently rare involvement in ST.
      • Mancano M.A.
      ISMP adverse drug reactions. Serotonin syndrome with concomitant use of tapentadol and venlafaxine.

       Meperidine

      The phenylpiperidine meperidine (Fig. 1b) has a relatively long history of involvement in ST. Early observations outlined previously of dangerous toxic reactions in patients and mice generated by the combination of meperidine and an MAOI, and supported by the demonstration that p-chlorophenylalanine, an inhibitor of serotonin synthesis, prevented the toxic interaction between meperidine and phenelzine in rabbits,
      • Mattila M.J.
      • Jounela A.J.
      Effect of p-chlorophenylalanine on the interaction between phenelzine and pethidine in conscious rabbits.
      led to the tentative conclusion of toxicity induced by an increase in concentration of serotonin in the CNS. Further confirmation of this conclusion was provided by inhibition of human SERT-transfected kidney cells by meperidine at low molar concentrations
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      • Barann M.
      • Stamer U.M.
      • Lyutenska M.
      • Stuber F.
      • Bonisch H.
      • Urban B.
      Effects of opioids on human serotonin transporters.
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      (Table 1). Receptor/ligand-binding experiments have also shown that meperidine binds the human 5-HT2A receptor at therapeutic drug plasma concentrations
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      (Table 1), thus possibly inducing direct receptor activation in addition to enhanced receptor activation after SERT inhibition.
      Given the known association of meperidine with ST, the large number of serotonergic drug administrations, the potential for inadequate and inaccurate medical histories, and the availability of other analgesics, the routine use of meperidine in emergency departments has been questioned. A finding that 26 of 262 (10%) emergency department patients given meperidine were also taking other serotonergic agents was proffered in support of this view.
      • Weiner A.L.
      Meperidine as a potential cause of serotonin syndrome in the emergency department.
      Perhaps at least partly because of reduced usage, the number of recorded cases of meperidine-induced ST over the past few decades has been small. Serotonergic drugs associated with meperidine in published case reports include fluoxetine, clomipramine, and citalopram, whilst meperidine alone was responsible in one patient.
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      The WHO VigiBase database shows 66 (4%) ICSRs where there was an association of meperidine with ST when this opioid was used alone or with another drug(s) (Fig. 4).

       Methadone

      The phenylheptylamine methadone (Fig. 1c) is a racemic mixture of the R-enantiomer R-(–)methadone (levomethadone) and the S-enantiomer S-(+)-methadone (dextromethadone). The racemic mixture is the form commonly used clinically. The R-enantiomer is the active form of the opioid showing μ-opioid receptor selectivity; the S-enantiomer has almost no opioid activity at normal therapeutic doses. Levomethadone, administered in some countries as an antitussive and for pain and opioid maintenance therapy, is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor
      • Ebert B.
      • Andersen S.
      • Krogsgaard-Larsen P.
      Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord.
      (like its enantiomer) and a potent non-competitive antagonist of the α3β4 neuronal nicotinic acetylcholine receptor. Importantly, methadone, which is slowly metabolised (half-life: 15–60 h; mean: ∼22 h) by CYP450 isoenzymes, particularly CYP2B6 but also CYP3A4 and CYP2D6, shows a wide variation in metabolism between individuals.
      Methadone therapy and ST have been associated in a few cases when co-administered with SSRI (sertraline)
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      • Martín-Lázaro J.
      • Hayde-West J.
      • Chatzimichael S.
      • Kirwin S.
      A dangerous triad: sertraline, mirtazapine and methadone.
      and also with fentanyl, although this claim has been questioned.
      • Atkinson T.J.
      • Fudin J.
      • Pham T.C.
      • et al.
      Combined fentanyl and methadone induced serotonin syndrome is called into question.
      • Hillman A.D.
      • Witenko C.J.
      • Sultan S.M.
      • Gala G.
      Serotonin syndrome caused by fentanyl and methadone in a burn injury.
      Methadone metabolism may explain some other toxicities observed when the drug was given with the quinolone antibacterial ciprofloxacin, a potent inhibitor of the CYP450 isoenzyme system.
      • Herrlin K.
      • Segerdahl M.
      • Gustafsson L.L.
      • Kalso E.
      Methadone, ciprofloxacin, and adverse drug reactions.
      • Nair M.K.
      • Patel K.
      • Starer P.J.
      Ciprofloxacin-induced torsades de pointes in a methadone-dependent patient.
      • Lee J.
      • Franz L.
      • Goforth H.W.
      Serotonin syndrome in a chronic-pain patient receiving concurrent methadone, ciprofloxacin, and venlafaxine.
      • Samoy L.
      • Shalansky K.F.
      Interaction between methadone and ciprofloxacin.
      For the period January 1969 to June 2013, the FAERS database reported five cases of methadone-associated ST.
      • US Food and Drug Administration
      Drug safety communications: FDA warns about several safety issues with opioid pain medicines; requires label changes.
      The WHO VigiBase database records 93 (5.7%) ICSRs of the association of methadone with ST when the opioid was used alone or with another drug(s) (Fig. 4).
      Studies on inhibition of serotonin uptake in rat synaptosomes revealed that (R)-(–)-methadone, but not its S-enantiomer, is a potent inhibitor of serotonin uptake
      • Codd E.E.
      • Shank R.P.
      • Schupsky J.J.
      • Raffa R.B.
      Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception.
      and, as an inhibitor of human SERT, R-(–)-methadone proved 20 times as potent as S-(+)-methadone (IC50 of 0.28 vs 5.6 μM; Table 1).
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      In addition to the potent SERT inhibitory activity of racemic methadone and its enantiomers, each of the compounds showed strong affinity for the human 5-HT2A receptor, although the rank order of potency for receptor binding, (S)(+)-methadone > (±)-methadone > (R)(–)-methadone, did not match the corresponding SERT inhibitory activities, namely, (±)-methadone and (R)(–)-methadone >> (S)(+)-methadone (Table 1).
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.

       Oxycodone

      Oxycodone, a semi-synthetic OAD and selective agonist for the μ-opioid receptor, has half the affinity of morphine and methadone for the receptor. With a methoxy group at position C3, a keto group at C6, and a 17-methyl constituent on the phenanthrene nucleus (Fig. 1a) for good analgesic action, oxycodone is widely used, including after surgery, for pain relief. O-demethylation of oxycodone via CYP2D6 forms the active metabolite oxymorphone, which has a higher binding affinity than oxycodone for the μ-opioid receptor. Apart from the experiments of Codd and colleagues,
      • Codd E.E.
      • Shank R.P.
      • Schupsky J.J.
      • Raffa R.B.
      Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception.
      who found that oxycodone, like other phenanthrene opioids with an oxygen bridge between C4 and C5 (Fig. 1a), did not inhibit rat synaptosomal reuptake of serotonin, there appears to be no other SERT and receptor-binding studies for this opioid.
      Reports of ST associated with oxycodone include cases of co-administration of the OAD with the SSRIs sertraline, fluvoxamine, citalopram, and escitalopram.
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      • Gnanadesigan N.
      • Espinoza R.T.
      • Smith R.
      • Israel M.
      • Reuben D.B.
      Interaction of serotonergic antidepressants and opioid analgesics: is serotonin syndrome going undetected?.
      The FAERS database for the period January 1969 to June 2013 mentioned seven apparent cases of ST involved with oxycodone, including four associated with fentanyl administration.
      • US Food and Drug Administration
      Drug safety communications: FDA warns about several safety issues with opioid pain medicines; requires label changes.
      The WHO VigiBase database records 101 (6.2%) ICSRs of the association of oxycodone with ST when the opioid was used alone or with another drug(s) (Fig. 4).

       Dextromethorphan

      The morphinan dextromethorphan (Fig. 1a) is an NMDA receptor antagonist with low affinity for the μ-, δ-, and κ-opioid receptors. It shows no significant affinity for the serotonin 5-HT1A and 5-HT2A receptors, but is a potent inhibitor of mouse and human SERT and serotonin uptake (Table 1). Dextromethorphan, used as an antitussive, acts centrally and is converted to a 10-fold more potent active metabolite dextrorphan by CYP2D6 metabolism. Adverse effects associated with dextromethorphan
      • Bem J.L.
      • Peck R.
      Dextromethorphan. An overview of safety issues.
      include usage abuse, attempted suicide, poisoning, and NMDA receptor-mediated hallucinogenic states induced by the parent drug and dextrorphan after recreational use of the parent drug in excessive dosage.
      Amongst the toxicities associated with dextromethorphan is ST from the opioid being sourced over the counter and used alone, often in supra-therapeutic doses, or co-administered with other serotonergic agents. Co-administered serotonergic drugs implicated include methadone and the SSRIs fluoxetine, citalopram, sertraline, paroxetine, and escitalopram.
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      Attention has been drawn to the likely involvement of chlorpheniramine, unsuspected at the time, in some cases of ST thought to be provoked by dextromethorphan alone. It has been pointed out that chlorpheniramine is a strong serotonin reuptake inhibitor and a 5-HT1A receptor agonist. Because this is not widely known, the association of this antihistamine with ST could go unrecognised.
      • Karamanakos P.N.
      • Pappas P.
      • Marselos M.
      Involvement of the brain serotonergic system in the locomotor stimulant effects of chlorpheniramine in Wistar rats: implication of postsynaptic 5-HT1A receptors.
      • Karamanakos P.N.
      • Panteli E.S.
      Comment on “dextromethorphan-induced serotonin syndrome”.

       Other opioids

      Cases of ST associated with other opioids, in particular morphine, hydromorphone, oxymorphone, codeine, hydrocodone, dihydrocodeine, and buprenorphine (Fig. 1a), are acknowledged by the WHO VigiBase database (Fig. 4), but individual published case reports are rare and hard to find, and the relatively high numbers of cases for some of these opioids shown in Figure 4 are surprising, especially for morphine. A likely case of ST involving morphine was reported in a 57-yr-old patient with symptoms, including restlessness, hallucinations, confusion, sweating, nausea, high blood pressure, and clonus in the lower extremities.
      • Mateo-Carrasco H.
      • Munoz-Aguilera E.M.
      • Garcia-Torrecillas J.M.
      • Abu Al-Robb H.
      Serotonin syndrome probably triggered by a morphine-phenelzine interaction.
      Progressive resolution of symptoms occurred over 48 h after discontinuation of phenelzine, which was part of the patient's routine medications. ST has been reported after the co-administration of hydrocodone and escitalopram,
      • Gnanadesigan N.
      • Espinoza R.T.
      • Smith R.
      • Israel M.
      • Reuben D.B.
      Interaction of serotonergic antidepressants and opioid analgesics: is serotonin syndrome going undetected?.
      and a case of ST involving hydromorphone was recently diagnosed in an adult patient taking duloxetine and oxycodone. Symptoms included extreme restlessness, combativeness, anxiety and agitation, diaphoresis, hyperreflexia, myoclonus in the lower extremities, bilateral upturned toes, and muscle rigidity.
      • Wang S.J.
      Hydromorphone precipitating serotonin syndrome.
      The numbers of published cases of ST for the same 14 opioids shown in Figure 4 identified by Rickli and colleagues
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      searching the MEDLINE PubMed database accord more closely with the numbers of reports in the accessible published literature. Inclusion of all relevant publications up to August 2016 yielded 99 patient cases from 114 administrations, and revealed the most frequently reported opioids to be fentanyl (45 cases), tramadol (26), oxycodone (13), and dextromethorphan (12). Surprisingly, the non-serotonergic opioid morphine accounted for four cases compared with meperidine (five), methadone (three), hydromorphone and hydrocodone (two each), tapentadol and buprenorphine (one each), and codeine (no cases). In all but two cases, other drugs (mostly SSRIs) and the opioid were involved.
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      Although the FDA mentioned the anilidopiperidines alfentanil, sufentanil, and remifentanil in the FAERS database,
      • US Food and Drug Administration
      Drug safety communications: FDA warns about several safety issues with opioid pain medicines; requires label changes.
      except for the latter, there appears to be few if any published reports of ST involving these congeners of fentanyl.
      • Davis J.J.
      • Buck N.S.
      • Swenson J.D.
      • Johnson K.B.
      • Greis P.E.
      Serotonin syndrome manifesting as patient movement during total intravenous anesthesia with propofol and remifentanil.
      • Ibarra A.J.
      • Meng L.
      Serotonin syndrome in the post-anesthesia care unit after remifentanil infusion and ondansetron: a case report and literature review.

      Risk assessment and planning of anaesthesia

      It is essential that the anaesthetist obtains a complete and accurate medical history of patients taking serotonergic medications, identifies patients scheduled for certain procedures (such as methylene blue marker dye investigations), and notes the interval since the last dose in those who discontinued a serotonergic drug. The long half-life of some serotonergic agents, such as SSRIs, can lead to an extended period of risk before exposure to an OAD (Table 3). Cases illustrating this include meperidine-induced ST in a patient who discontinued fluoxetine therapy 2 weeks before the reaction,
      • Tissot T.A.
      Probable meperidine-induced serotonin syndrome in a patient with a history of fluoxetine use.
      and signs and symptoms of ST in a patient 1 min after receiving meperidine 30 mg i.v. (Five years earlier, the patient had experienced a life-threatening episode whilst taking clomipramine.
      • Guo S.-L.
      • Wu T.-J.
      • Liu C.-C.
      • Ng C.-C.
      • Chien C.-C.
      • Sun H.-L.
      Meperidine-induced serotonin syndrome in a susceptible patient.
      ) The 2 week half-life of fluoxetine's active metabolite norfluoxetine (Table 3) is the probable explanation for the former case.
      • Coplan J.D.
      • Gorman J.M.
      Detectable levels of fluoxetine metabolites after discontinuation: an unexpected serotonin syndrome.
      Table 3Approximate half-lives or duration of inhibition of commonly used serotonergic antidepressants. MAOI, monoamine oxidase inhibitor; SARI, serotonin antagonist and reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
      AntidepressantMetabolic half-life/duration of physiological effects
      SSRIs
      • Marken P.A.
      • Munro J.S.
      Selecting a selective serotonin reuptake inhibitor: clinically important distinguishing features.
       Fluoxetine4–6 days (7–15 days for active metabolite)
       Fluvoxamine15–26 h
       Sertraline26 h
       Citalopram33 h
       Paroxetine21 h
      SNRIs
      • Sansone R.A.
      • Sansone L.A.
      Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison.
       Venlafaxine5 h
       Venlafaxine XR11 h
       Desvenlafaxine11 h
       Desvenlafaxine XR13–14 h
      Tricyclic antidepressants
       Amitriptyline
      • Gupta S.K.
      • Shah J.C.
      • Hwang S.S.
      Pharmacokinetic and pharmacodynamic characterization of OROS and immediate-release amitriptyline.
      10–28 h (16–80 h for active metabolite)
       Amoxapine
      • Rudorfer M.V.
      • Potter W.Z.
      Metabolism of tricyclic antidepressants.
      10 h (30 h for active metabolite)
       Clomipramine
      • Rudorfer M.V.
      • Potter W.Z.
      Metabolism of tricyclic antidepressants.
      24 h (65.5 h for active metabolite)
       Desipramine
      • Ramey K.
      • Ma J.D.
      • Best B.M.
      • Atayee R.S.
      • Morello C.M.
      Variability in metabolism of imipramine and desipramine using urinary excretion data.
      7–60 h
       Doxepin
      • Negrusz A.
      • Moore C.M.
      • Perry J.L.
      Detection of doxepin and its major metabolite desmethyldoxepin in hair following drug therapy.
      16.8 h (51.3 h for active metabolite)
       Imipramine
      • Ramey K.
      • Ma J.D.
      • Best B.M.
      • Atayee R.S.
      • Morello C.M.
      Variability in metabolism of imipramine and desipramine using urinary excretion data.
      8–16 h
       Nortriptyline
      • Rudorfer M.V.
      • Potter W.Z.
      Metabolism of tricyclic antidepressants.
      28 h
       Protriptyline
      • Saef M.A.
      • Saadabadi A.
      Protriptyline. [Updated 2019 Jan 17]. StatPearls [Internet].
      74 h
       Trimipramine
      • Abernethy D.R.
      • Greenblatt D.J.
      • Shader R.I.
      Trimipramine kinetics and absolute bioavailability: use of gas-liquid chromatography with nitrogen-phosphorus detection.
      24 h (longer for active metabolite)
      MAOIs
       Phenelzine
      • Cooper A.J.
      Tyramine and irreversible monoamine oxidase inhibitors in clinical practice.
      Physiological effects (MAOI) for 2–3 weeks
       Selegiline
      • Mahmood I.
      Clinical pharmacokinetics and pharmacodynamics of selegiline. An update.
      Physiological effects (MAOI) for almost 2 weeks
       Isocarboxazid
      • Cooper A.J.
      Tyramine and irreversible monoamine oxidase inhibitors in clinical practice.
      Physiological effects (MAOI) for 2–3 weeks
       Tranylcypromine
      • Cooper A.J.
      Tyramine and irreversible monoamine oxidase inhibitors in clinical practice.
      Physiological effects (MAOI) for 2–3 weeks
       Moclobemide
      • Bonnet U.
      Moclobemide: therapeutic use and clinical studies.
      Physiological effects (MAOI) for 16–24 h
      SARIs
       Trazodone
      • Bryant S.G.
      • Ereshefsky L.
      Antidepressant properties of trazodone.
      10–12 h
      The relative risk of a patient experiencing ST in the perioperative period is influenced by a combination of factors that includes a history of taking a serotonergic drug(s) and the perioperative administration of additional serotonergic drugs, including OADs. Clearly, individual vulnerability must also be a factor as the same combination of drugs can cause ST in one patient, but not another. Although there appears to be little or no progress in the development of tests to aid in the prediction and diagnosis of ST, studies of genetic polymorphisms, such as in SERT and CYP2D6 (e.g. in methadone metabolism), show some promise of identifying patients more likely to be sensitive to ST. Currently, other than a prior history of ST, a carefully gathered patient history identifying all serotonergic medicines (MAOIs including linezolid and methylene blue, SSRIs, SNRIs, TCAs, OADs, the herb St John's wort, chlorpheniramine, the antidepressant trazodone, and the over-the-counter cold treatment dextromethorphan and lithium) and tailoring analgesic and anti-emetic regimens to avoid risky combinations of drugs is of key importance in minimising the risk of perioperative ST. A summary of important drugs and considerations is presented in Fig. 5. In particular, patients at a significantly higher risk should be identified, namely, those with a history of ST, those on MAOIs (such as the antidepressants phenelzine, tranylcypromine, moclobemide, the antibiotic linezolid, and methylene blue), or patients undergoing treatment for MDMA toxicity. In these patients, OADs most implicated in ST should be avoided, namely, meperidine and tramadol. With MAOIs, methadone, tapentadol, fentanyl, and oxycodone appear to be of low-to-intermediate risk.
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      They should be used with vigilance whilst the possibility of a rare potential interaction should be kept in mind when fentanyl congeners (remifentanil, alfentanil, and sufentanil), morphine, hydromorphone, oxymorphone, codeine, hydrocodone, dihydrocodeine, or buprenorphine are used in patients on an MAOI (Fig. 5). This is also the case for methadone, tapentadol, fentanyl, and oxycodone when used with patients at medium risk of ST, such as those on SSRIs (fluoxetine, citalopram, sertraline, paroxetine, and escitalopram), SNRIs (venlafaxine, desvenlafaxine, and duloxetine), and certain TCAs (clomipramine and imipramine). Meperidine and tramadol should be used with vigilance in these patients, whilst remifentanil, alfentanil, sufentanil, morphine, hydromorphone, oxymorphone, codeine, hydrocodone, dihydrocodeine, and buprenorphine have a very low risk of ST (Fig. 5). Anaesthesia is sometimes conducted in emergency situations where a patient's medication history is unknown. This can increase the risk of ST if multiple analgesics, including OADs, are used in a short time frame.
      Fig 5
      Fig 5Stratification of risk of serotonin toxicity by patient and OAD risks. *Evidence so far points to low-to-intermediate risk for methadone
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      • US Food and Drug Administration
      Drug safety communications: FDA warns about several safety issues with opioid pain medicines; requires label changes.
      • Martín-Lázaro J.
      • Hayde-West J.
      • Chatzimichael S.
      • Kirwin S.
      A dangerous triad: sertraline, mirtazapine and methadone.
      and tapentadol.
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      • US Food and Drug Administration
      Drug safety communications: FDA warns about several safety issues with opioid pain medicines; requires label changes.
      • Abeyaratne C.
      • Lalic S.
      • Bell J.S.
      • Ilomäki J.
      Spontaneously reported adverse drug events related to tapentadol and oxycodone/naloxone in Australia.
      • Mancano M.A.
      ISMP adverse drug reactions. Serotonin syndrome with concomitant use of tapentadol and venlafaxine.
      • Gressler L.E.
      • Hammond D.A.
      • Painter J.T.
      Serotonin syndrome in tapentadol literature: systematic review of original research.
      ST said to be ‘unlikely’ when used with MAOIs.
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      Genetic polymorphisms of CYP450 isoenzymes influence the inter-individual variability in methadone metabolism. Tramadol, meperidine, methadone, fentanyl, and dextromethorphan have been ‘implicated in multiple reports’ of ST.
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      MAOI, monoamine oxidase inhibitor; MDMA, 3,4-methylenedioxymethamphetamine; OAD, opioid analgesic drug; SNRI, serotonin–norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; ST, serotonin toxicity; TCA, tricyclic antidepressant.

      Identification of serotonin toxicity in the perioperative period

      The key features of ST are the triad of changes in neuromuscular hyperactivity, autonomic nervous system hyperactivity, and changes in mental status, as described previously.
      • Gillman P.K.
      A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action.
      • Sternbach H.
      The serotonin syndrome.
      • Dunkley E.J.
      • Isbister G.K.
      • Sibbritt D.
      • Dawson A.H.
      • Whyte I.M.
      The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.
      • Gillman P.K.
      • Whyte I.M.
      Serotonin syndrome.
      • Whyte I.M.
      Serotonin syndrome (toxicity).
      • Boyer E.W.
      • Shannon M.
      The serotonin syndrome.
      • Isbister G.K.
      • Buckley N.A.
      The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment.
      Depending on the stage and type of anaesthesia used, many of these symptoms and signs may be absent. In particular, neuromuscular paralysis may eliminate signs of neuromuscular hyperactivity, tachycardia can be precipitated by surgery or either precipitated or masked by drugs, diaphoresis may not be obvious under drapes, mydriasis may be difficult to assess because of the effects on the iris by narcotics and anticholinergics (e.g. atropine and glycopyrrolate), and mental state may be impossible to assess because of anaesthesia. Certainly, there is a better chance of accurate identification of ST in all but its severest form in regional anaesthetic techniques and the PACU.
      Whilst many of the symptoms and signs are common to multiple other disorders, including sepsis, hyperthyroidism, neuroleptic malignant syndrome (NMS), meningoencephalitis, anticholinergic syndromes, and sympathomimetic toxicity, the most important differential diagnosis for the anaesthetist is malignant hyperthermia (MH). MH is an anaesthetic emergency that may become rapidly fatal, even despite accurate diagnosis and treatment. Its hallmarks are an increase in end-tidal carbon dioxide (ETCO2) (with tachypnoea in a spontaneously breathing patient), hyperthermia, tachycardia, and muscular rigidity.
      • Gupta P.K.
      • Hopkins P.M.
      Diagnosis and management of malignant hyperthermia.
      Importantly, the autonomic instability, hyperthermia, and neuromuscular rigidity are common to both, and severe cases of ST may closely resemble MH clinically.
      • Isbister G.K.
      • Whyte I.M.
      Serotonin toxicity and malignant hyperthermia: role of 5-HT2 receptors.
      An increase in ETCO2 may also be seen in ST; however, it is usually less dramatic than in MH and a later feature. Early clues to suggest the presence of MH are a rapidly escalating respiratory acidosis from hypercarbia that usually precedes the hyperthermia and does not respond to increases in ventilation (generated by the patient if spontaneously breathing or the anaesthetist if mechanically ventilated), development of arrhythmias, rapid development of a metabolic acidosis with hyperkalaemia and hypercalcaemia, and onset of progressive hyperthermia. The muscular rigidity in MH does not have the neuromuscular excitation characteristics seen in ST (clonus and hyperreflexia).
      • Isbister G.K.
      • Buckley N.A.
      • Whyte I.M.
      Serotonin toxicity: a practical approach to diagnosis and treatment.
      This may help differentiate the two syndromes in non-paralysed patients. Of course, MH can be ruled out in cases where a triggering agent (volatile anaesthetic or succinylcholine) has not been administered. Timing may also provide a clue; ST can occur at any time during a patient's care (often occurring rapidly after the administration of a serotonergic drug),
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      whereas MH is unusual if the hyperthermia occurs after the patient has been discharged from PACU.
      • Gupta P.K.
      • Hopkins P.M.
      Diagnosis and management of malignant hyperthermia.
      Muscular rigidity seen with ST will abate with neuromuscular paralysis, but will continue unabated in MH. The cornerstone of pharmacological treatment in MH is dantrolene. Dantrolene has been suggested as both a possible treatment for ST; however, it is not generally recommended for the treatment of ST as it has also been implicated in ST development.
      • Boyer E.W.
      • Shannon M.
      The serotonin syndrome.
      With significant concern that a reaction is MH, dantrolene administration should not be delayed as it is potentially life-saving.
      Thyroid storm, sepsis, and NMS can also cause diagnostic confusion with ST perioperatively. Both sepsis and thyroid storm can mimic the autonomic instability and hyperpyrexia of ST, but not the neuromuscular excitation and rigidity. NMS can mimic the fever, autonomic instability, and muscular rigidity of ST; however, the onset is usually slower (1–3 days), there is an absence of neuromuscular excitability (clonus and hyperreflexia), and instead features bradykinesia and lead pipe rigidity of muscles. Extrapyramidal features are also present.
      • Isbister G.K.
      • Buckley N.A.
      The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment.

      Treatment

      The urgency for treatment of ST depends on the severity of the syndrome. Mild cases (characterised by hyperreflexia and tremor, but no fever) can usually be treated with supportive care, observation and monitoring, discontinuation of any serotonergic drugs, and treatment with benzodiazepines.
      • Volpi-Abadie J.
      • Kaye A.M.
      • Kaye A.D.
      Serotonin syndrome.
      Patients with clinically significant ST should be monitored for signs of increasing toxicity for at least 6 h.
      • Isbister G.K.
      • Buckley N.A.
      The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment.
      Patients with progressive cognitive changes, fever autonomic instability, or significant neuromuscular excitability require management in intensive care. Hypertension and tachycardia can be controlled with propranolol, in part because of its actions as a 5HT1A antagonist.
      • Jones D.
      • Story D.A.
      Serotonin syndrome and the anaesthetist.
      It is important for the anaesthetist to understand that the presence of rapidly rising temperature (38.5˚C), hypertonia, and rigidity indicates a life-threatening emergency, and has been labelled ‘serotonin storm’ or ‘serotonin crisis’
      • Isbister G.K.
      • Buckley N.A.
      The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment.
      to reflect its gravity. Rigidity classically affects the lower limbs, and then truncal muscles,
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      impairing ventilation. Hyperthermia in this setting results from muscular contraction. Multi-organ failure (including renal failure) from hyperthermia, rhabdomyolysis, and disseminated intravascular coagulation can occur if not aggressively treated.
      • Isbister G.K.
      • Buckley N.A.
      • Whyte I.M.
      Serotonin toxicity: a practical approach to diagnosis and treatment.
      Cases of acute cardiomyopathy have also been reported.
      • Sasaki H.
      • Yumoto K.
      • Nanao T.
      • et al.
      Cardiogenic shock due to Takotsubo cardiomyopathy associated with serotonin syndrome.
      • Levine M.
      • Truitt C.A.
      • O’Connor A.D.
      Cardiotoxicity and serotonin syndrome complicating a milnacipran overdose.
      • Mehta N.K.
      • Aurigemma G.
      • Rafeq Z.
      • Starobin O.
      Reverse Takotsubo cardiomyopathy: after an episode of serotonin syndrome.
      • Jang S.H.
      • Nam J.H.
      • Lee J.
      • Chang M.C.
      Takotsubo cardiomyopathy associated with serotonin syndrome in a patient with stroke: a case report.
      If aggressive use of benzodiazepines and cooling fail to cause significant improvement within 5–10 min, or if benzodiazepines significantly impair consciousness, these patients must be paralysed, ventilated, and actively cooled to stop further progression of ST. Invasive cardiovascular monitoring and support, i.v. fluids, and correction of electrolyte abnormalities are necessary. Specific serotonin antagonists, such as cyproheptadine (only oral, useful for milder cases only) or chlorpromazine i.v., can be used,
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      although caution should be used with the latter as orthostatic hypotension can result. This may not be as relevant in many cases of ST where hypertension is problematic, but should be borne in mind.

      Conclusions

      The evolutionarily conserved SERT has a central role in regulating the serotonergic system by regulating the availability of serotonin to its receptors. SERT terminates the action of serotonin as a neurotransmitter, and recycles it from the synaptic cleft back to the presynaptic terminal (Fig. 2). Results of in vitro studies suggest that OADs that are good inhibitors of SERT, namely, dextromethorphan, tramadol, methadone, meperidine, and tapentadol, are the opioids most frequently associated with ST. This conclusion, however, is not always clear-cut as seen from a consideration of findings with tramadol where inhibition results are only in the low micromolar range compared with, for example, dextromethorphan (Table 1). Nevertheless, doses of both (+)-tramadol and (–)-tramadol i.v., high enough to produce plasma concentrations to block serotonin uptake by inhibiting SERT, have been used in a perioperative setting.
      • Barann M.
      • Stamer U.M.
      • Lyutenska M.
      • Stuber F.
      • Bonisch H.
      • Urban B.
      Effects of opioids on human serotonin transporters.
      • Barann M.
      • Urban B.
      • Stamer U.
      • Dorner Z.
      • Bonisch H.
      • Bruss M.
      Effects of tramadol and O-demethyl-tramadol on human 5-HT reuptake carriers and human 5-HT3A receptors: a possible mechanism for tramadol-induced early emesis.
      Therefore, when tramadol is given with serotonin reuptake inhibitors, such as SSRIs, SNRIs, or TCAs that produce an elevation in serotonin concentrations, the cumulative effect of the co-administered drugs may lead to an additional elevation of serotonin and ST. In addition, reuptake inhibition potency may not provide a complete explanation for the elevation of serotonin concentrations. Racemic tramadol and its (+)-enantiomer blocked the reuptake of serotonin in rat brain (see earlier), but also increased serotonin efflux. Driessen and Reimann
      • Driessen B.
      • Reimann W.
      Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro.
      and Reimann and Schneider
      • Reimann W.
      • Schneider F.
      Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine.
      showed that tramadol facilitated the outflow of serotonin from rat cortex slices with the (+)-enantiomer proving more potent than the racemate, the (–)-enantiomer, or O-desmethyltramadol. Interestingly, Bamigbade and colleagues
      • Bamigbade T.A.
      • Davidson C.
      • Langford R.M.
      • Stamford J.A.
      Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus.
      found that serotonin efflux preceded serotonin uptake, suggesting that uptake block did not cause the efflux, and tramadol may therefore have a direct serotonin-releasing action. However, using rat synaptosomes rather than cortex slices, Gobbi and Mennini
      • Gobbi M.
      • Mennini T.
      Release studies with rat brain cortical synaptosomes indicate that tramadol is a 5-hydroxytryptamine uptake blocker and not a 5-hydroxytryptamine releaser.
      found that, although tramadol inhibited
      • Oates J.A.
      • Sjoerdsma A.
      Neurologic effects of tryptophan in patients receiving a monoamine oxidase inhibitor.
      [H]5-HT reuptake, it showed no releasing effect up to 30 mM.
      Although it seems unlikely that normal approved doses of meperidine (e.g. 50–100 mg) would induce ST by inhibiting SERT and increasing serotonin concentrations, high, and probably unlikely, plasma concentrations of meperidine after bolus i.v. doses
      • Barann M.
      • Stamer U.M.
      • Lyutenska M.
      • Stuber F.
      • Bonisch H.
      • Urban B.
      Effects of opioids on human serotonin transporters.
      • Koska 3rd, A.J.
      • Kramer W.G.
      • Romagnoli A.
      • Keats A.S.
      • Sabawala P.B.
      Pharmacokinetics of high-dose meperidine in surgical patients.
      • Paech M.J.
      • Moore J.S.
      • Evans S.F.
      Meperidine for patient-controlled analgesia after Cesarean section. Intravenous versus epidural administration.
      might do so if co-administered with another serotonergic drug.
      Even though the apparent lack of convincing clinical evidence for involvement of tapentadol in ST in the few relevant clinical reports
      • Baldo B.A.
      Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.
      • Walczyk H.
      • Liu C.H.
      • Alafris A.
      • Cohen H.
      Probable tapentadol-associated serotonin syndrome after overdose.
      does not accord with incidences reported in records, such as the WHO VigiBase database (see above and Fig. 4), the increase in spinal serotonin concentrations induced in non-anaesthetised rats by the opioid,
      • Benade V.
      • Nirogi R.
      • Bhyrapuneni G.
      • et al.
      Mechanistic evaluation of tapentadol in reducing the pain perception using in-vivo brain and spinal cord microdialysis in rats.
      together with its weak SERT inhibitory activity and co-administration with other serotonergic medications, might explain any involvement it may have in provoking cases of ST. A contrary finding of decreased serotonin release in the dorsal horn of anaesthetised rats
      • Tzschentke T.M.
      • Folgering J.H.
      • Flik G.
      • De Vry J.
      Tapentadol increases levels of noradrenaline in the rat spinal cord as measured by in vivo microdialysis.
      has been countered by the suggestion that spinal serotonin modulation is dependent on locomotor activity,
      • Gerin C.
      • Teilhac J.R.
      • Smith K.
      • Privat A.
      Motor activity induces release of serotonin in the dorsal horn of the rat lumbar spinal cord.
      and anaesthesia might have reduced serotonergic neuronal activity.
      • Tao R.
      • Auerbach S.B.
      Anesthetics block morphine-induced increases in serotonin release in rat CNS.
      Another difficulty of an apparent direct relationship between SERT inhibition and ST is the finding that fentanyl and oxycodone, reported in a number of case studies and ranking at or near the top of databases showing the most frequently reported opioids associated with ST, do not interact with SERT to inhibit serotonin reuptake. This suggests the possibility of SERT-independent effects on the serotonergic system in vivo. There seems to be little information available for oxycodone, but fentanyl binds to 5-HT1A and 5-HT2A receptors (Table 1) as does methadone, and, more weakly, tapentadol,
      • Rickli A.
      • Liakoni E.
      • Hoener M.C.
      • Liechti M.E.
      Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.
      and this direct activation of receptors may be at least part of the mechanism by which these OADs, rarely alone and more usually with other serotonergic agents, provoke ST in certain vulnerable patients. In particular, fentanyl acts as an agonist at the 5-HT1A receptor and produces an efflux of serotonin in the DRN after systemic administration. Tao and colleagues
      • Tao R.
      • Karnik M.
      • Ma Z.
      • Auerbach S.B.
      Effect of fentanyl on 5-HT efflux involves both opioid and 5-HT1A receptors.
      suggested that these effects may contribute to the lethality of fentanyl in overdose.
      A satisfying explanation of the mechanism(s) explaining the rare reports of ST induced by morphine and chemically related phenanthrene opioids codeine, oxymorphone, hydromorphone, and buprenorphine, generally considered to be non-serotonergic agents, has yet to be advanced, and this remains a puzzling question, especially as the chemically related oxycodone shows a higher incidence of involvement in ST. Findings by Tao and Auerbach
      • Tao R.
      • Auerbach S.B.
      GABAergic and glutamatergic afferents in the dorsal raphe nucleus mediate morphine-induced increases in serotonin efflux in the rat central nervous system.
      suggest that morphine stimulates the release of serotonin by a disinhibitory mechanism. It is proposed that, in the rat DRN, μ-opioid receptor-binding opioids reduce gamma-aminobutyric-acid (GABA)-mediated postsynaptic currents in 5-HT neurones,
      • Jolas T.
      • Aghajanian G.K.
      Opioids suppress spontaneous and NMDA-induced inhibitory postsynaptic currents in the dorsal raphe nucleus of the rat in vitro.
      and this inhibition of GABAergic afferents leads to an increase in serotonin efflux.
      Continuing progress in elucidating mechanisms underlying ST is an important aim, along with studies to predict at-risk patients, a better understanding of the relative potential and potencies of different OADs to provoke ST, and the development of reliable tests to facilitate diagnosis when the clinical signs and symptoms do not lead to a confident conclusion. Results in a mouse model for ST suggest that some SERT polymorphisms may reduce SERT by more than 50% and lead to increased vulnerability,
      • Fox M.A.
      • Jensen C.L.
      • Murphy D.L.
      Tramadol and another atypical opioid meperidine have exaggerated serotonin syndrome behavioural effects, but decreased analgesic effects, in genetically deficient serotonin transporter (SERT) mice.
      and human studies of CYP2D6 polymorphisms show that patients who are poor drug metabolisers are at greater risk of overdose, whilst rapid metabolisers may experience treatment failure because of inadequate therapeutic concentrations of drugs. Genetic polymorphisms have been shown to influence the phenotype of drug responses to OADs, antidepressants, and antipsychotics,
      • Kirchheiner J.
      • Sasse J.
      • Meineke I.
      • Roots I.
      • Brockmoller J.
      Trimipramine pharmacokinetics after intravenous and oral administration in carriers of CYP2D6 genotypes predicting poor, extensive and ultrahigh activity.
      • Kirchheiner J.
      • Nickchen K.
      • Bauer M.
      • et al.
      Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response.
      • Zanger U.M.
      • Raimundo S.
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      • Wilkinson G.R.
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      and CYP2B6 to methadone
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      metabolism suggest that extension of such polymorphism approaches may lead to the genetic identification of patients likely to be susceptible to ST and perhaps even the likely severity of the resultant toxic response. Combinations of polymorphisms might help to identify genotypes associated with good and poor responders, and those susceptible to drug reactions.
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      In conclusion, the wide range of adverse effects of OADs ranging from mild to life-threatening
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      Adverse effects of systemic opioid analgesics.
      and resulting from specific binding of OADs to opioid receptors (e.g. central depression, sedation, addiction, and constipation),
      • Freye E.
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      histamine release, and hypersensitivities
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      • Pham N.H.
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      • Baldo B.A.
      • Pham N.H.
      are well known and studied, but this cannot yet be said of the involvement of OADs in ST where the serotonergic effects of some of the drugs have only more recently been emphasised.
      • US Food and Drug Administration
      Drug safety communications: FDA warns about several safety issues with opioid pain medicines; requires label changes.
      The heavy and increasing usage of both OADs in and outside the hospital setting and psychiatric medicines in all types of patient populations
      • Sonnenberg C.M.
      • Deeg D.J.
      • Comijs H.C.
      • van Tilburg W.
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      Serotonin syndrome.
      points to an increased possibility of ST in some opioid-treated patients, an outcome suggested in the recently issued 2016 FDA Drug Safety Communication warning
      • US Food and Drug Administration
      Drug safety communications: FDA warns about several safety issues with opioid pain medicines; requires label changes.
      for ‘the entire class of opioid pain medicines’. The high prevalence of depression and pain indicates that co-administration of OADs and antidepressants will continue, if not increase. Despite an increased awareness of the potential for reactions, there is still concern that cases of ST are going undetected.
      • Gnanadesigan N.
      • Espinoza R.T.
      • Smith R.
      • Israel M.
      • Reuben D.B.
      Interaction of serotonergic antidepressants and opioid analgesics: is serotonin syndrome going undetected?.
      • Mackay F.J.
      • Dunn N.R.
      • Mann R.D.
      Antidepressants and the serotonin syndrome in general practice.

      Authors' contributions

      Study conception: BAB
      Concept revision: BAB, MAR
      Literature review: BAB, MAR
      Mechanistic detail: BAB
      Clinical detail: MAR
      Drafting paper: BAB, MAR
      Revising paper: BAB, MAR
      Both authors approved the final draft and agree to be accountable for all aspects of the work.

      Acknowledgements

      The authors thank Nghia H. Pham for technical help in the preparation of figures.

      Declaration of interest

      The authors declare that they have no conflict of interest.

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