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

Abstract

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.

Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats

“…Tramadol is commercially available as a racemate; while (+)-tramadol provides for serotonin (5-HT) reuptake inhibition, (−)-tramadol accounts for noradrenaline (NA) uptake inhibition [ 1 , 2 , 11 , 19 , 32 , 34 , 35 , 36 , 37 ]. It undergoes extensive hepatic metabolism, mainly through O- and N-demethylation and conjugation reactions, yielding at least 14 phase I and 12 phase II metabolites [ 1 , 2 , 11 , 35 , 37 , 38 , 39 ].…”

“…Although tramadol and tapentadol are claimed to have better safety profiles than their opioid peers, several adverse events have been reported, including nausea, vomiting, dizziness, seizures, dyspnea, respiratory depression [ 1 , 2 , 14 , 47 , 48 , 49 , 50 , 51 ], and even fatal cases [ 10 , 42 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ]. In the VigiBase™ World Health Organization (WHO) Global Database of Individual Case Safety Reports concerning 5-HT toxicity, tramadol ranks 1st and tapentadol ranks 3rd (with 647 and 115 cases out of 1641, respectively) as the only suspected cause or amongst other drugs, and 1st and 2nd (with 62 and 42 cases out of 147, respectively) as the only suspected cause [ 34 , 69 ]. In addition, in spite of their theoretically lower potential for abuse and dependence, cases of misuse, dependence and addiction have been reported [ 1 , 2 , 10 , 11 , 14 , 60 , 70 ].…”

Serotonin Syndrome Developing Immediately after the Initiation of Low-Dose Methadone Therapy: A Case Report

“…Methadone has an inhibitory effect on SERT [2,3]. Methadone administration is categorized as an intermediate risk factor for SS according to a study by Baldo and Rose [2].…”

“…Methadone has an inhibitory effect on SERT [2,3]. Methadone administration is categorized as an intermediate risk factor for SS according to a study by Baldo and Rose [2]. In addition, a Drug Safety Communication released by the FDA in 2016 covering cases of opioidrelated SS in the FDA Adverse Event Reporting System database from 1969 through 2013 included 5 cases secondary to methadone and 7 cases secondary to oxycodone [4].…”

“…Serotonin syndrome (SS) is an adverse event triggered by the use of molecules such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors and causes some symptoms such as excessive perspiration, clonus, and tremors due to excessive serotonin in the central nervous system [1]. In recent years, opioids including methadone have been reported to have an inhibitory effect on the serotonin transporter (SERT), a factor that plays an important role in the reuptake of serotonin in the nerve endings [2,3]. In 2016, the United States Food and Drug Administration (FDA) released a Drug Safety Communication to warn the medical community of the SS risk that is secondary to opioid use [4].…”