ULTRAM
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ULTRAM (ULTRAM).
Tramadol is a centrally acting synthetic opioid analgesic that binds to μ-opioid receptors and inhibits norepinephrine and serotonin reuptake.
| Metabolism | Primarily metabolized by CYP2B6 and CYP3A4 to O-desmethyltramadol (active, M1) and by CYP2D6 to N-desmethyltramadol; undergoes glucuronidation and sulfation. |
| Excretion | Renal: ~90% (tramadol and metabolites; conjugated metabolites are major), Fecal: ~10% |
| Half-life | Tramadol: ~6 hours; M1 metabolite (O-desmethyltramadol): ~7 hours; prolonged in renal/hepatic impairment |
| Protein binding | 20% bound to albumin; low protein binding |
| Volume of Distribution | 2.6-3.1 L/kg; indicates extensive tissue distribution |
| Bioavailability | Oral: ~75% (due to first-pass metabolism); IM: 100%; IV: 100% |
| Onset of Action | Oral immediate-release: 30-60 minutes; IV: 5-10 minutes; IM: 30-45 minutes |
| Duration of Action | Oral immediate-release: 4-6 hours; Extended-release: 12-24 hours; IV/IM: 3-6 hours |
| Action Class | Opioids |
| Brand Substitutes | Bestodol 100 Injection, Tricare Injection, Tramot 100mg Injection, Supridol 100mg Injection, Tramazac Injection |
50-100 mg orally every 4-6 hours as needed for pain; maximum 400 mg/day (for extended-release: 100 mg once daily, titrated up to 300 mg once daily).
| Dosage form | TABLET |
| Renal impairment | CrCl 30-59 mL/min: extend dosing interval to 12 hours; maximum 200 mg/day. CrCl <30 mL/min: extend interval to 12 hours; maximum 100 mg/day. Hemodialysis: administer dose post-dialysis, maximum 100 mg/day. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: reduce dose to 50 mg every 12 hours; maximum 100 mg/day. Child-Pugh Class C: not recommended. |
| Pediatric use | Not recommended for children <17 years. For ages 17 and older, same as adult dosing. |
| Geriatric use | Age >65 years: caution, reduce initial dose to 25 mg every 6 hours as needed; maximum 300 mg/day. Avoid extended-release formulations. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ULTRAM (ULTRAM).
| Breastfeeding | Tramadol and its active metabolite M1 are excreted in breast milk. Milk-to-plasma ratio: approximately 1.2-2.7 for tramadol, 1.6-2.9 for M1. Relative infant dose estimated at 2-3% of maternal weight-adjusted dose. Use with caution; monitor infant for drowsiness, respiratory depression, and constipation. Avoid in women who are ultra-rapid metabolizers of CYP2D6. |
| Teratogenic Risk | Tramadol crosses the placenta. First trimester: Limited data, but associated with neural tube defects and cardiac malformations in some studies (risk <2x baseline). Second/third trimester: Chronic use may cause fetal opioid dependence and neonatal abstinence syndrome. Avoid in third trimester near term due to risk of respiratory depression in neonate. |
■ FDA Black Box Warning
["Risk of addiction, abuse, and misuse; can lead to overdose and death.","Life-threatening respiratory depression; monitor closely, especially during initiation or dose escalation.","Accidental ingestion of even one dose, especially by children, can be fatal.","Concomitant use with CNS depressants (e.g., benzodiazepines, alcohol) may result in profound sedation, respiratory depression, coma, and death.","Concomitant use with CYP3A4 inhibitors (e.g., macrolide antibiotics, azole antifungals) may increase tramadol exposure and risk of adverse effects.","Neonatal opioid withdrawal syndrome with prolonged use during pregnancy.","Risk of serotonin syndrome with concurrent serotonergic drugs.","Cytochrome P450 2D6 poor metabolizers: reduced efficacy; ultra-rapid metabolizers: increased risk of toxicity."]
| Serious Effects |
["Hypersensitivity to tramadol or any component","Significant respiratory depression","Acute or severe bronchial asthma in an unmonitored setting or without resuscitative equipment","Known or suspected gastrointestinal obstruction, including paralytic ileus","Concurrent use of MAOIs or within 14 days of discontinuation","Use in children <12 years of age","Use in adolescents <18 years of age following tonsillectomy and/or adenoidectomy"]
| Precautions | ["Addiction, abuse, and misuse","Life-threatening respiratory depression","Accidental ingestion","Neonatal opioid withdrawal syndrome","Interactions with CNS depressants","Serotonin syndrome risk","Seizure risk (especially in patients with seizure disorders, head injury, or concomitant use of SSRIs/SNRIs/tricyclics)","Adrenal insufficiency","Severe hypotension","Use in elderly: increased risk of respiratory depression and falls","Use in renal or hepatic impairment: dose adjustment needed"] |
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| Fetal Monitoring | Maternal: Monitor for sedation, respiratory depression, constipation, and opioid dependence. Assess for serotonin syndrome if used with other serotonergic agents. Fetal/neonatal: Monitor fetal growth with ultrasound if prolonged use. At birth, observe neonate for signs of opioid withdrawal (NAS) and respiratory depression for at least 48 hours. |
| Fertility Effects | Tramadol may impair male fertility by reducing sperm motility and testosterone levels, likely reversible. In females, animal studies show no significant effect on fertility, but human data limited. Consider effects in patients planning to conceive. |