A Case of Serotonin Syndrome and Mutism associated with Methadone

Abstract

A patient was seen on the palliative care service at our institution who developed serotonin syndrome and mutism associated with methadone use. Serotonin syndrome is often described as a clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities, but not all of these findings are consistently present in all patients with the disorder. The incidence of the serotonin syndrome is thought to mirror the increasing number of proserotonergic agents being used in clinical practice. In 2002, the Toxic Exposure Surveillance System, which receives case descriptions from office-based practices, inpatient settings, and emergency departments, reported 26,733 incidences of exposure to selective serotonin-reuptake inhibitors (SSRIs) that caused significant toxic effects in 7349 persons and resulted in 93 deaths. Serotonin syndrome is not an idiopathic drug reaction; it is a predictable consequence of excess serotonergic agonism of central nervous system (CNS) receptors and peripheral serotonergic receptors. The myriad of symptoms with which serotonin syndrome may present is compounded by the fact that more than 85% of physicians are unaware of serotonin syndrome as a clinical diagnosis. Other SSRIs such as fluoxetine and fluvoxamine have been shown to increase methadone plasma concentrations in dependent patients. Although the exact mechanism is unknown, there are several pathways via which a significant interaction could occur. This would include the effects methadone has on N-methyl-D-aspartate (NMDA) in addition to the impact of methadone on the cytochrome P450 enzyme system. The mainstay of treatment of serotonin syndrome is withdrawal of the offending agent and supportive care. These actions resulted in resolution of our patient's symptoms. Serotonin syndrome is becoming more common, and with the utilization of polypharmacy on many palliative care services should be considered as unifying differential diagnosis in the appropriate setting.

Deaths involving serotonergic drugs

“…It must be noted that symptoms experienced in Case 6 and others involving serotonergic drugs may not have been necessarily caused by ST, however where a number of symptoms associated with ST occur together, these are more likely to reflect this form of toxicity, particularly when serotonin-active drugs are present. Such drugs include the SSRIs, SNRIs, MDMA, some TCAs and opioids, and other miscellaneous drugs capable of increasing serotonin, such as lithium and carbamazepine [9,11,13,20,28,[33][34][35][36][37][38]. ST has also been implicated in some cases of drug monotherapy [39][40][41] and rare cases involving the use of MDMA alone.…”

“…There were 4 cases of methadone combined with venlafaxine. While reports of ST associated with this combination are uncommon, the methadone-induced increase of serotonin synthesis in laboratory animals [18], and the mounting research supporting methadone's ability to increase serotonin in humans [13], suggests that combination with any pro-serotonergic agent may cause toxicity, particularly in genetically susceptible individuals. However, fatal ADRs involving opioids are usually attributed to their non-serotonergic mechanisms and thus the involvement of opioids in causing ST is speculative.…”

“…ST is associated with a range of over-the-counter and prescription medications, herbal products and drugs of abuse, including in particular tramadol, ecstasy (MDMA) and a multitude of antidepressants [9][10][11][12][13][14][15][16][17][18][19]. The sudden withdrawal of pharmaceuticals and absence of appropriate washout periods following drug discontinuation can also cause ST [8,20].…”

Uso de metadona en el anciano con dolor oncológico: una revisión sistemática

“…Se ha hipotetizado que la metadona no podría generar reacciones neurotóxicas debido a la falta de metabolitos activos; sin embargo, en la literatura hay casos que describen la aparición de mioclonus 38,69 , movimientos coréicos 70 , síndrome serotoninérgico y mutismo 71 .…”

Deaths involving contraindicated and inappropriate combinations of serotonergic drugs

“…Identified drugs were subsequently confirmed using quantitative gas chromatography-mass spectrometry with List compiled using drug interaction and severity data from Drugdex® Evaluations in the Micromedex® Internet database [8]. Drugs with an asterisk (e.g., pethidine*) are combinations where an adverse drug reaction has been reported involving this combination; however, it did not feature on the Micromedex® list [16][17][18][57][58][59][60][61]. The mechanisms of interactions are explained within the Micromedex® database *Not from Micromedex a Only includes combinations observed in this study lower limits of quantitation at the low end of their respective blood concentrations when used therapeutically.…”