4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for tramadol are summarized in Table 4. Only those drug-drug interactions identified as clinical significance severe or those considered life-threatening which have not yet been classified will be reviewed:

Table 3. Tramadol Drug-Drug Interactions³

Target Drug	Interacting Drug	Interaction	Recommendation	Clinical Significance Level
tramadol	barbiturates	adjunctive use may result in respiratory depression, hypotension, profound sedation and potentially death due to additive CNS depression; potential as well for decreasing tramadol levels as barbiturates induce CYP3A4 and tramadol is CYP3A4 substrate	avoid use, if possible; if combined administration necessary, observe for respiratory depression and loss of tramadol analgesic effects	major (CP)
tramadol	carbamazepine (CBZ)	potential for reduced analgesic effect due to CBZ-associated CYP3A4 enzyme induction; potential for additive CNS depressant effects, increased seizure risk with concurrent therapy	reserve concomitant use of tramadol and CBZ for patients in whom alternative treatment options are inadequate	major (CP)
tramadol	CYP inducers (e.g., phenytoin, rifampin)	potential for reduced tramadol analgesic efficacy as tramadol metabolized by CYP3A4, CYP2D6	monitor for reduced analgesic effects; adjust dosages as necessary	moderate (CP)
tramadol	CYP2D6 inhibitors (e.g., fluoxetine propafenone,  ritonavir)	potential for enhanced tramadol pharmacologic/ adverse effects as tramadol metabolized by CYP2D6	monitor for enhanced analgesic effects, increased adverse effects (including seizures); adjust dosages as necessary	moderate (CP)
tramadol	CYP3A4 inhibitors (e.g., amiodarone, erythromycin,  ritonavir)	potential for enhanced tramadol pharmacologic/ adverse effects as tramadol metabolized by CYP3A4	monitor for enhanced analgesic effects, increased adverse effects (including seizures); adjust dosages as necessary	moderate (CP)
tramadol	MAOIs+/MAOI-like compounds (e.g., phenelzine, selegiline, rasagiline, linezolid)	potential for additive effects on serotonin and norepinephrine reuptake inhibition; increased risk for respiratory depression, coma, and serotonin syndrome (e.g., nausea, vomiting, hypertension, hyperthermia, cardiovascular collapse)	concurrent administration or prescribing within 14 days of MAOI discontinuation contraindicated	severe, major (CP)
tramadol	neuroleptics (e.g., thioridazine, risperidone)	increased seizure risk (mechanism unknown), and potential for increased CNS, respiratory depression	avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together	major (CP)
tramadol	opioid analgesics	increased seizure risk	avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together	major (CP)
tramadol	serotonergic drugs (e.g., SSRIs/ SNRIs, milnacipran)	increased risk of respiratory depression, hypotension, sedation, and death	Limit the use of opioid analgesics with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response	moderate, major (CP)
tramadol	TCAs^ (e.g., imipramine, cyclobenzaprine)	increased seizure risk (TCAs lower seizure threshold), increased risk of serotonin syndrome (e.g., nausea/vomiting, hypertension, hyperthermia, cardiovascular collapse) as both compounds inhibit serotonin/norepinephrine reuptake	avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together	major (CP)
tramadol	warfarin	rare reports of increased prothrombin time with increased bleeding risk; mechanism unknown	closely monitor for INR changes, bleeding; adjust doses as necessary	moderate (CP)

Legend:

• * CP = Clinical Pharmacology
• +MAOI = monoamine oxidase inhibitor
• ^TCA = tricyclic antidepressant