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 |
| Molecular Weight | 263.38 |
| 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 | Use only if potential benefit justifies risk; studies show increased risk of respiratory malformations with first-trimester exposure. |
| 2nd trimester | Use with caution; may cause fetal dependence and withdrawal; avoid prolonged use. |
| 3rd trimester | Avoid near term; risk of neonatal respiratory depression and withdrawal syndrome. |
Clinical note
Comprehensive clinical and safety monograph for ULTRAM (ULTRAM).
| Placental transfer | Tramadol and its active metabolite readily cross the placenta; fetal concentrations are similar to maternal levels. |
| Breastfeeding | Tramadol enters breast milk in small amounts; maximum relative infant dose ~2-3%. In mothers with CYP2D6 ultra-rapid metabolism, higher levels of active metabolite (O-desmethyltramadol) may cause infant sedation and respiratory depression. Breastfeeding is generally not recommended, especially in rapid metabolizers or with high maternal doses. |
■ 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 of the formulationAcute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids, or psychotropic drugsSevere respiratory depressionSignificant respiratory depression, especially in unmonitored settingsAcute or severe bronchial asthmaParalytic ileusConcurrent use of MAO inhibitors (or within 14 days of discontinuation)Use of linezolid (MAOI) or methylene blueSevere hepatic impairment (Child-Pugh class C)
| 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 |
Loading safety data…
| Lactation Rating | L4 (Possibly Hazardous) |
| 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. |
| 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. |
| Food/Dietary | Grapefruit and grapefruit juice may inhibit CYP3A4, potentially increasing tramadol levels; avoid concurrent use. Alcohol consumption is contraindicated due to increased risk of CNS depression and seizures. High-fat meals may delay absorption but not overall efficacy. Maintain adequate hydration to prevent constipation. |
| Clinical Pearls | Tramadol (Ultram) is a prodrug requiring CYP2D6 metabolism for analgesic effect; poor metabolizers may have reduced efficacy. Risk of serotonin syndrome when combined with SSRIs, SNRIs, MAOIs, or triptans. Seizure threshold is lowered, especially in patients with epilepsy, head injury, or on other proconvulsants. Avoid in patients with a history of opioid addiction due to mu-opioid agonist activity. Onset of action is ~1 hour; peak effect at 2-3 hours. Dose adjustment needed in renal impairment (CrCl <30 mL/min) and severe hepatic impairment. |
| Patient Advice | Do not take more than prescribed; overdose can cause life-threatening respiratory depression. · Do not drink alcohol while taking this medication; it can increase dizziness and risk of seizures. · Avoid driving or operating heavy machinery until you know how this drug affects you. · Tell your doctor about all other medications you take, especially antidepressants, MAOIs, or migraine drugs, as serious interactions can occur. · Do not suddenly stop taking this drug without medical advice; withdrawal symptoms may occur. · Store this medication securely away from children and others; accidental use can be fatal. · If you have a history of seizures or head injury, use with caution; this drug can lower seizure threshold. · Seek emergency care if you experience slow or shallow breathing, confusion, or difficulty waking up. |