Combined Fentanyl and Methadone Induced Serotonin Syndrome is Called Into Question

Atkinson, Timothy; Fudin, Jeffrey; Pham, Thien C.; Hillman, Ashley; Witenko, Corey; Sultan, Said; Gala, Gary J.

doi:10.1002/phar.1601

Cited by 3 publications

(2 citation statements)

References 15 publications

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“…***Authors' diagnostic conclusion has been called into question. 67 As an inhibitor of human SERT, fentanyl can, at best, be said to show only weak activity (IC 50 of 154 mM) (Table 1), but it shows affinity for the serotonin 5-HT 1A and 5-HT 2A receptors in the low micromolar range 46,49 (Table 1). Following the early finding that fentanyl and sufentanil have affinity for the rat 5-HT 1A receptor, 49 Tao and colleagues 88 showed that systemic administration of fentanyl produced a relatively short-lasting (2e3 h) efflux of serotonin in the rat dorsal raphe nucleus (DRN).…”

Section: Opioidmentioning

confidence: 99%

“…Methadone therapy and ST have been associated in a few cases when co-administered with SSRI (sertraline) 50,113 and also with fentanyl, although this claim has been questioned. 67,68 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. 114e117 For the period January 1969 to June 2013, the FAERS database reported five cases of methadone-associated ST. 55 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.…”

Section: Methadonementioning

confidence: 99%

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

Baldo

Rose

2020

British Journal of Anaesthesia

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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 5hydroxytryptamine (5-HT) 1A and 5-HT 2A receptors, whilst methadone, meperidine, and more weakly tapentadol, bind to 5-HT 2A but not 5-HT 1A 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.

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Section: Opioidmentioning

confidence: 99%

Section: Methadonementioning

confidence: 99%

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

Baldo

Rose

2020

British Journal of Anaesthesia

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Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects

Baldo

2018

Arch Toxicol

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Drugs may cause serotonin toxicity by a number of different mechanisms including inhibition of serotonin uptake and metabolism, increased serotonin synthesis and release, activation of serotonin receptors, and inhibition of cytochrome P450 oxidases. Some drug interactions involving opioids can increase intrasynaptic levels of serotonin, and opioid analgesic drugs are now recognized as being involved in some cases of serotonin toxicity especially if administered in conjunction with other serotonergic medications including monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants. In March 2016, the FDA issued a Drug Safety Communication concerning the association of the entire class of opioid pain medicines with serotonin toxicity. Reports of the involvement of individual opioids particularly tramadol, tapentadol, meperidine, methadone, oxycodone, fentanyl, and dextromethorphan are reviewed. While relevance to human serotonin toxicity of animal models, including many studies on rat brain synaptosomes, is questionable, important insights have recently been forthcoming from research utilizing 5-HT receptors, serotonin transporter (SERT), and knockout mice. In studies with human SERT-transfected human HEK293 cells, the synthetic opioids tramadol, meperidine, methadone, tapentadol, and dextromethorphan inhibited SERT, but fentanyl and a number of phenanthrenes including morphine and hydromorphone did not. Receptor ligand-binding assays revealed interaction of fentanyl with 5-HT receptors and interaction of meperidine, methadone, and fentanyl with 5-HT receptors. Although the opioids most often associated with serotonin toxicity in humans inhibit human SERT in vitro, fentanyl and oxycodone are not inhibitory even though their clinical involvement has been reported. This suggests some SERT-independent effects on the serotonin system in vivo. Heightened clinician awareness of the possibility of serotonin toxicity among patients taking opioids and serotonergic antidepressants is called for.

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A 5-year single-centre retrospective study of potential drug interactions in burns inpatients with psychiatric comorbidities

Al-Khalil

Sack

Elson

et al. 2020

Burns

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Combined Fentanyl and Methadone Induced Serotonin Syndrome is Called Into Question

Cited by 3 publications

References 15 publications

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

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

Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects

A 5-year single-centre retrospective study of potential drug interactions in burns inpatients with psychiatric comorbidities

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