Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Tramadol is a centrally acting synthetic opioid analgesic that binds to μ-opioid receptors and inhibits the reuptake of norepinephrine and serotonin, modulating pain transmission.
| Metabolism | Hepatic via CYP2D6 and CYP3A4 to active metabolite O-desmethyltramadol (M1) and other inactive metabolites; undergoes conjugation. |
| Excretion | Primarily renal (90%): ~30% as unchanged drug, ~60% as metabolites. Biliary/fecal: ~10%. |
| Half-life | Terminal elimination half-life: approximately 6.3 hours (range 5-9 hours) for tramadol; active metabolite M1 has half-life ~7-9 hours. Clinically, dosing interval is typically every 4-6 hours. |
| Protein binding | Approximately 20% bound to plasma proteins (primarily albumin). |
| Volume of Distribution | Approximately 2.6-3.0 L/kg (306-350 L for a 70 kg adult), indicating extensive tissue distribution. |
| Bioavailability | Oral: approximately 70-75% (high first-pass metabolism). Rectal: similar to oral. Intramuscular: 100% (relative to IV). |
| Onset of Action | Oral immediate-release: 30-60 minutes. Intravenous: within 5 minutes. Intramuscular: 15-30 minutes. Rectal: 30-60 minutes. |
| Duration of Action | Analgesic effect lasts 4-6 hours with immediate-release formulations; extended-release formulations provide 12-24 hours of effect. |
| Molecular Weight | 263.38 |
| Action Class | Opioids |
| Brand Substitutes | Tranzex 50mg Capsule, Termeg 50mg Capsule, Tramatas 50mg Capsule, Tramadex 50mg Capsule, Dolodol 50mg Capsule |
50-100 mg orally every 4-6 hours as needed for pain; maximum 400 mg/day. For moderate to severe pain, 50-100 mg IV or IM every 4-6 hours; maximum 600 mg/day.
| Renal impairment | CrCl 30-59 mL/min: extend dosing interval to every 12 hours. CrCl <30 mL/min: extend interval to every 12 hours and consider max dose 200 mg/day. Hemodialysis: administer dose after dialysis, with same interval adjustments. |
| Liver impairment | Child-Pugh Class A (mild): 50 mg every 12 hours. Child-Pugh Class B (moderate): 50 mg every 12 hours. Child-Pugh Class C (severe): not recommended. |
| Pediatric use | Age ≥16 years: same as adult dosing. Age 12-15 years: 50-100 mg orally every 4-6 hours; max 400 mg/day. For children <12 years: not recommended. |
| Geriatric use | Initiate at 25 mg orally every 6 hours as needed; titrate cautiously to 50 mg every 6 hours; max 300 mg/day. Consider creatinine clearance for dose adjustments. |
| 1st trimester | Tramadol is not recommended in the first trimester due to lack of well-controlled studies and potential risk of neural tube defects. |
| 2nd trimester | Use with caution; may be considered if benefits outweigh risks, but avoid prolonged use. |
| 3rd trimester | Avoid in third trimester due to risk of neonatal respiratory depression, withdrawal, and persistent pulmonary hypertension of the newborn (PPHN). |
Clinical note
Avoid in pregnancy. Tramadol is a synthetic opioid and norepinephrine-serotonin reuptake inhibitor. Associated with Neonatal Opioid Withdrawal Syndrome (NOWS) and neonatal seizures when used near delivery. Contraindicated during breastfeeding (FDA 2017, same warning as codeine). No established teratogenicity at therapeutic doses but risk-benefit strongly favors alternatives.
| Placental transfer | Tramadol crosses the placenta; fetal concentrations are approximately 50-80% of maternal serum levels. Active metabolite M1 also crosses. |
| Breastfeeding |
■ FDA Black Box Warning
Risk of addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; risks from concomitant use with benzodiazepines or other CNS depressants; interactions with drugs affecting CYP450 isoenzymes; risk of serotonin syndrome; risk of seizures; risk of suicide in patients with depression.
| Serious Effects |
Acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids, or psychotropic drugsPrevious hypersensitivity to tramadol or any opioidMAO inhibitor use within 14 daysUncontrolled epilepsySevere respiratory depressionSevere hepatic impairment
| Precautions | Respiratory depression; seizures; serotonin syndrome; suicide risk; adrenal insufficiency; severe hypotension; use in renal/hepatic impairment; anaphylaxis; use with MAOIs; use in pregnancy (neonatal withdrawal); use in breastfeeding. |
| Food/Dietary | No significant food interactions. Grapefruit juice does not substantially affect tramadol metabolism. Avoid alcohol entirely due to additive CNS depression and increased risk of hepatotoxicity. St. John's Wort may reduce tramadol efficacy by inducing CYP3A4 and CYP2D6. High-fat meals may delay absorption but do not significantly affect overall exposure; take extended-release tablets consistently with or without food. |
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| Tramadol and its active metabolite M1 are excreted into breast milk. In mothers with normal CYP2D6 activity, the relative infant dose is low (2-3%). However, in ultra-rapid metabolizers, higher levels may cause neonatal sedation, respiratory depression, or withdrawal. Caution is advised; monitor infant for drowsiness, poor feeding, or breathing difficulties. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Limited human data; animal studies show no clear teratogenicity at therapeutic doses but increased risk of neural tube defects at high doses. Second and third trimesters: Risk of neonatal respiratory depression, withdrawal syndrome, and reduced fetal growth with chronic use. Avoid or use lowest effective dose. |
| Fetal Monitoring | Maternal: Pain scores, respiratory rate, sedation level, signs of serotonin syndrome (especially with other serotonergic drugs). Fetal/neonatal: Fetal heart rate monitoring if near term; observe neonate for respiratory depression, withdrawal signs (tremors, irritability, poor feeding) for 48-72 hours after delivery. |
| Fertility Effects | Tramadol may impair female fertility by increasing prolactin levels and disrupting ovulation. In males, high doses may reduce sperm motility and count. Effects are reversible upon discontinuation. |
| Clinical Pearls | Tramadol is a prodrug requiring CYP2D6 metabolism to its active metabolite M1 for analgesic effect. Poor metabolizers (7-10% of population) may experience reduced efficacy. Caution with serotonergic drugs due to risk of serotonin syndrome. Seizure risk increased in patients with epilepsy, history of seizures, or concomitant use of SSRIs, SNRIs, tricyclic antidepressants, or other drugs that lower seizure threshold. Dose adjustment needed in renal impairment (CrCl <30 mL/min: extended interval or avoid) and hepatic cirrhosis (reduce dose or extend interval). Avoid use in patients with severe hepatic impairment. Not recommended for children <12 years, or <18 years for tonsillectomy/adenoidectomy. Maximum single dose: 100 mg; maximum daily dose: 400 mg (300 mg in patients >75 years). Onset of action: 30-60 minutes; peak effect: 2-3 hours; duration: 4-6 hours. |
| Patient Advice | Take exactly as prescribed; do not increase dose or frequency without consulting your doctor. · Do not crush or chew extended-release tablets; swallow whole. · Avoid alcohol and other CNS depressants (e.g., benzodiazepines, sedatives) as they increase risk of severe drowsiness, respiratory depression, and overdose. · Tramadol may cause dizziness or drowsiness; avoid driving or operating machinery until you know how it affects you. · Do not stop abruptly; withdrawal symptoms (anxiety, sweating, insomnia, pain) may occur. Taper under medical supervision. · Report symptoms of serotonin syndrome (agitation, hallucinations, rapid heart rate, fever, muscle stiffness, twitching, nausea, diarrhea) immediately. · Seek emergency help if you experience slow/shallow breathing, severe drowsiness, or difficulty waking up. · Dispose of unused tramadol properly via drug take-back programs to prevent accidental ingestion or misuse. · Inform your doctor of all medications you take, especially antidepressants, antipsychotics, and pain relievers. · Pregnancy: avoid during labor; prolonged use may cause neonatal withdrawal syndrome. Breastfeeding: not recommended. · Grapefruit juice has not been shown to interact significantly, but avoid excessive intake. |