TRAMADOL HYDROCHLORIDE
Clinical safety rating: avoid
CNS depressants including alcohol and benzodiazepines increase sedation risk MAOIs and other serotonergic drugs can cause serotonin syndrome.
Tramadol hydrochloride is a centrally acting opioid analgesic that binds to μ-opioid receptors and inhibits the reuptake of norepinephrine and serotonin, modulating pain transmission in the central nervous system.
| Metabolism | Extensively metabolized via O- and N-demethylation in the liver primarily by cytochrome P450 2D6 (CYP2D6) and CYP3A4, producing active metabolite O-desmethyltramadol (M1). |
| Excretion | Primarily renal (90% total clearance, 30% as unchanged drug, 60% as metabolites); fecal (~10%); biliary minor. |
| Half-life | 5-6 hours (parent drug); 7-9 hours (M1 active metabolite). In renal impairment, half-life prolonged up to 11 hours (parent) and 17 hours (M1). |
| Protein binding | ~20% bound to albumin. Low binding reduces drug interactions. |
| Volume of Distribution | 2-3 L/kg (306 L total). Indicates extensive tissue distribution, including CNS penetration. |
| Bioavailability | Oral: 70-75% (first-pass metabolism); IM: 100%; rectal: ~78% relative to oral; IV: 100%. |
| Onset of Action | Oral immediate-release: ~30-60 min; IV: ~5-10 min; IM: ~10-20 min; rectal: ~30-60 min. |
| Duration of Action | Oral immediate-release: 4-6 hours; extended-release: 12-24 hours. Pain control duration correlates with M1 levels; accumulation possible with repeated dosing due to active metabolite. |
| Molecular Weight | 299.84 |
| Action Class | Opioids |
| Brand Substitutes | Tramore Injection, Tramacad 50mg Injection, Tranzex 50mg Injection, Contramal 50 Injection, Tramazac HP 50mg Injection |
50-100 mg orally every 4-6 hours as needed for pain, not to exceed 400 mg/day (100 mg for immediate-release).
| Dosage form | TABLET |
| Renal impairment | For CrCl < 30 mL/min: increase dosing interval to 12 hours; maximum dose 200 mg/day. For CrCl < 10 mL/min: not recommended. |
| Liver impairment | Child-Pugh Class B: reduce dose by 50% and extend interval to 12 hours. Child-Pugh Class C: not recommended. |
| Pediatric use | 1-2 mg/kg/dose every 4-6 hours, not to exceed 8 mg/kg/day or 400 mg/day (whichever less). Not recommended for children < 12 years for post-operative pain. |
| Geriatric use | Elderly (>75 years): use lowest effective dose, maximum 300 mg/day; extend dosing interval to 6-8 hours due to decreased clearance. |
| 1st trimester | Limited data; associated with rare congenital malformations in some studies but no clear pattern; use only if benefit outweighs risk. |
| 2nd trimester | No specific increase in major malformations reported; use caution due to potential maternal dependence and neonatal withdrawal. |
| 3rd trimester | Risk of neonatal opioid withdrawal syndrome (NOWS) and respiratory depression with chronic use; avoid in late pregnancy unless necessary. |
Clinical note
CNS depressants including alcohol and benzodiazepines increase sedation risk MAOIs and other serotonergic drugs can cause serotonin syndrome.
| FDA category | Positive |
| Placental transfer | Tramadol crosses the placenta and distributes into fetal tissues. The fetal-to-maternal plasma concentration ratio is approximately 0.8, indicating significant transfer. |
■ FDA Black Box Warning
WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 2D6 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; SEROTONIN SYNDROME; HEPATIC TOXICITY
| Serious Effects |
Hypersensitivity to tramadol or any component of the formulationAcute or severe bronchial asthma, hypercapnia, or respiratory depression in unmonitored settings or absence of resuscitative equipmentUse of MAO inhibitors (MAOIs) or within 14 days of stopping MAOIsConcurrent use of linezolid or methylene blueKnown or suspected gastrointestinal obstruction, including paralytic ileusSignificant respiratory depressionAcute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids, or psychotropic drugs
| Precautions | Risk of serotonin syndrome when used with serotonergic drugs; risk of seizures in patients with epilepsy or those taking medications that lower seizure threshold; anaphylactic reactions; opioid-induced hyperalgesia; adrenal insufficiency; complex regional pain syndrome; withdrawal symptoms upon discontinuation. |
| Food/Dietary |
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| Breastfeeding |
| Tramadol and its active metabolite O-desmethyltramadol are excreted in breast milk in low concentrations. However, there is a risk of infant sedation and withdrawal symptoms. Use with caution, especially in mothers who are ultra-rapid metabolizers of CYP2D6, as this can lead to higher levels of the active metabolite. The American Academy of Pediatrics considers tramadol to be usually compatible with breastfeeding, but monitor infant for drowsiness and feeding difficulties. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Tramadol hydrochloride is FDA Pregnancy Category C. First trimester: Limited human data; animal studies show increased skeletal variations and delayed ossification at maternally toxic doses. Second and third trimesters: Risk of neonatal respiratory depression, serotonin syndrome, and withdrawal if used near term. Avoid prolonged use or high doses. |
| Fetal Monitoring | Monitor maternal respiratory rate, sedation level, and signs of serotonin syndrome (agitation, hyperthermia, clonus). Assess fetal heart rate and uterine tone during labor. Monitor neonate for respiratory depression, withdrawal (irritability, poor feeding), and serotonin syndrome if exposed in utero, especially near term. |
| Fertility Effects | Tramadol may impair fertility in males and females based on animal studies. In humans, elevated prolactin levels can occur, potentially causing menstrual irregularities and decreased libido. Clinical significance is uncertain; use with caution in patients attempting conception. |
| Avoid alcohol consumption; may enhance CNS depression and increase risk of hepatotoxicity. Grapefruit juice may inhibit CYP2D6 and alter tramadol metabolism; limit intake. High-fat meals may delay absorption of immediate-release formulations but not significantly affect overall exposure. |
| Clinical Pearls | Tramadol is a prodrug requiring CYP2D6 metabolism to its active M1 metabolite for opioid analgesia; efficacy varies with CYP2D6 phenotype. Avoid concurrent use with MAOIs due to serotonin syndrome risk; use cautiously with SSRIs/SNRIs as additive serotonergic effects may occur. Tramadol lowers seizure threshold; avoid in patients with epilepsy or those taking other seizure threshold-lowering drugs. Renal impairment (CrCl < 30 mL/min) requires extended dosing interval (q12h). Do not exceed 400 mg/day (300 mg in elderly >75 years). Onset of analgesia is ~1 hour; peak effect at 2-3 hours. |
| Patient Advice | Take exactly as prescribed; do not increase dose or frequency without consulting your doctor. · May cause dizziness or drowsiness; avoid driving or operating machinery until you know how this medication affects you. · Risk of serotonin syndrome if combined with other serotonergic drugs (e.g., antidepressants, migraine medications); seek immediate medical attention if symptoms like agitation, hallucinations, rapid heart rate, or fever occur. · Do not crush, chew, or dissolve extended-release tablets; swallow whole. · Avoid alcohol and sedatives (e.g., benzodiazepines) as they increase risk of respiratory depression and oversedation. · Do not stop abruptly; withdrawal symptoms may occur. Taper under medical supervision. · Store at room temperature, away from moisture and heat, and out of reach of children. · Report any history of seizures, head injury, or substance abuse to your doctor. |