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

Abstract

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.

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

“…Although evidence for some severe cases of ST, including fatalities, induced by meperidine with MAOIs is strong 45,50 (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. 45 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.…”

“…45 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. 40,45 Given the range of serotonergic medicines now widely prescribed and being introduced, 51,52 the expansion in the number of clinical reports of the apparent involvement of OADs in ST, 50 results from studies of animal models, 9,27,29,50 and mechanistic studies of regulation of serotonergic neurotransmission, 46,47,50 opioids may be the most important drug associated with ST in anaesthesia. 53 Individual implicated OADs will be examined with emphasis on patients who are at most risk and relevance of the findings to the practising anaesthetist.…”

“…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 drugrelated intoxications and fatalities. 50,89 A number of studies have shown that tramadol in the low micromolar range inhibits serotonin uptake by rat cortical synaptosomes 38e42,90 and by human SERT 46e48 (Table 1). This effect on serotonin transport underlies tramadol's potential involvement in ST.…”

“…The list of serotonergic drugs coadministered 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. 50 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 46 (Fig.…”

“…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. 45 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. 101 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, 55,102e105 but Gressler and colleagues 106 and others 45,107,108 have questioned the claimed association of tapentadol and ST. 50 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).…”