**14. Drug interactions**

**Authors Publication**

Elkalioubie et al.

[148]

**year**

110 Toxicology Studies - Cells, Drugs and Environment

**13. Serotonin syndrome**

impaired coordination).

auditory hallucinations).

diarrhea, vomiting).

dose of tramadol [5,98,100].

sants [5,7,53,97,102].

2011 Case

**Table 2.** Studies on patients with tramadol poisoning

**Number of patients**

report

**Sex Co-**

**administration or comorbidity**

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

**1.** Neuromuscular hyperactivity (tremor, clonus, myoclonus, hyper-reflexia, stiffness,

**2.** Autonomic hyperactivity (profuse sweating, fever, tachycardia, tachypnea, chills, nausea,

**3.** Mental status changes (agitation, confusion, restlessness, hypomania and/or visual or

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

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‐

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

consumed medications. Three key clinical features of this syndrome include:

female \_ \_ Hypoglycemia

**Mortality Findings Dosage or**

hypothermia, renal and liver failure, cardiac arrest, coagulopathy

**concentration**

4500 mg

Opioids metabolized by CYP450 (including tramadol) may induce many drug-drug interac‐ tions [104]. In an Australian study, unwanted drug interactions were evaluated in 46859 patients who consumed antidepressants. In 8.1% of the patients who had experienced such complications, the most common consumed medication was tramadol (3.6%). As previously clarified, tramadol is similar to venlafaxine in structure and is believed to have antidepressant effects. Venlafaxine can even cause false positive results for tramadol in urine tests [5]. Coadministration of tramadol and antidepressants especially TCAs, SSRIs, venlafaxine, bupro‐ pion, and phenothiazines should be performed cautiously because of the increased risk of seizure [6,25,72]. Hallucinations and SS have been reported after co-administration of tramadol and SSRIs [87]. Concurrent administration of tramadol and NSAIDs can result in gastrointes‐ tinal hemorrhages due to severe platelet inhibition [105]. Fatal toxicities have been reported after tramadol-TCA overdoses [106]. It has been shown that tramadol-related mortality is more common after co-ingestion of benzodiazepines [8,26]. Co-administration of tramadol and CNS depressants, TCAs, and MAO inhibitors are therefore contraindicated [23]. Tramadol can also interact with antitumor medications. For instance, tramadol decreases the efficacy of cisplatin by affecting gap junctions [107]. In a case report, combination of paroxetine, dosulepin, and tramadol caused hallucination which improved after cessation of the medications [108].
