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 level 1 or those considered life-threatening which have not yet been classified will be reviewed2-6.
| 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 (DrugReax) 2-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 | concurrent use not recommended | major (DrugReax) 2-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 (DrugReax) 3-moderate (CP) |
| tramadol | CYP2D6 inhibitors (e.g., amiodarone, 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 (DrugReax) 3-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 (DrugReax) 3-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 seizures, hypertensive reactions, serotonin syndrome (e.g., nausea, vomiting, hypertension, hyperthermia, cardiovascular collapse) | concurrent administration or prescribing within 14 days of MAOI discontinuation contraindicated | contraindicated, major (DrugReax) 1-severe, 2-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 (DrugReax) 2-major (CP) |
| tramadol | opioid analgesics | increased seizure risk | avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together | 2-major (CP) |
| tramadol | serotonergic drugs (e.g., SSRIs/ SNRIs, milnacipran) | increased seizure risk, increased risk of serotonin syndrome (e.g., nausea/vomiting, hypertension, hyperthermia, cardiovascular collapse) due to additive increases in serotonin concentrations | avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together | major (DrugReax) 2-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 (DrugReax) 3-moderate (CP) |
| tramadol | warfarin | increased prothrombin time with increased bleeding risk; mechanism unknown | closely monitor for INR changes, bleeding; adjust doses as necessary | moderate (DrugReax) 2-major (CP) |
Legend:
- * CP = Clinical Pharmacology
- +MAOI = monoamine oxidase inhibitor
- ^TCA = tricyclic antidepressant