**13. Serotonin syndrome**

Serotonin syndrome (SS) is a potentially fatal syndrome due to increased synthesis, decreased metabolism, increased release, and reuptake inhibition of serotonin or direct agonism at the serotonin receptors [5,53]. This syndrome is often due to complex interactions between the consumed medications. Three key clinical features of this syndrome include:


The exact rate of SS is unclear but is generally not expected to occur in more than 5% of the hospitalized patients [5,44,53,96-98]. The (+) enantiomer of tramadol inhibits re-absorption of serotonin [99]. Usually, SS happens after tramadol overdose or its concurrent use with other medications especially antidepressants; however, it may happen even after a single therapeutic dose of tramadol [5,98,100].

Patients who consume mono amine oxidase (MAO) inhibitors are at the risk of development of SS [66,101]. SS has been reported after concurrent use of tramadol with serotonin reuptake inhibitors (SSRIs), venlafaxine, atypical antipsychotics, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, moclobemide, clomipramine, mirtazapine, and tricyclic antidepres‐ sants [5,7,53,97,102].

In patients who develop lethargy, hypotension, hypoxia, agitation, tachycardia, hypertension, confusion, hyperthermia, or hyper-reflexia, diagnosis of SS should be borne in mind [7,101,103]. Treatment is conservative and includes cessation of the culpable medication as well as administration of the antiserotonergics (ciproheptadine, metisergide, propranolol, and chlorpromazine). Clinical manifestations recover within 24 hours except in those who have consumed medications with longer half-lives [5,53,97]. Up to 42% of the patients may need ICU admission [48,53]. Pretreatment with chlordiazepoxide may prevent tramadol-induced SS [48].
