TRAMADOL HYDROCHLORIDE

Clinical safety rating: avoid

CNS depressants including alcohol and benzodiazepines increase sedation risk MAOIs and other serotonergic drugs can cause serotonin syndrome.

How it works

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.

What the body does with it

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.

Classification & Brands

Action Class	Opioids
Brand Substitutes	Tramore Injection, Tramacad 50mg Injection, Tranzex 50mg Injection, Contramal 50 Injection, Tramazac HP 50mg Injection

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

CNS depressants including alcohol and benzodiazepines increase sedation risk MAOIs and other serotonergic drugs can cause serotonin syndrome.

FDA category	Positive
Breastfeeding	Tramadol and its active metabolite O-desmethyltramadol (M1) are excreted into breast milk. Milk-to-plasma ratio is approximately 2.2 for tramadol and 2.9 for M1. Relative infant dose is estimated at 2.88% of maternal weight-adjusted dose. Although generally considered compatible, monitor infant for sedation, respiratory depression, and withdrawal symptoms. Use lowest effective dose for shortest duration.
Teratogenic Risk

Warnings & precautions

■ 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

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to tramadol; acute or severe bronchial asthma; significant respiratory depression; gastrointestinal obstruction (including paralytic ileus); concurrent use of MAOIs or within 14 days of MAOI discontinuation; ethanol intoxication; severe hepatic impairment; use in children <12 years for postoperative tonsillectomy/adenoidectomy; known CYP2D6 ultra-rapid metabolizers.

Clinical Precautions

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.

Clinical Tips & Counseling

Drug interactions

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TRAMADOL HYDROCHLORIDE

Clinical safety rating: avoid

CNS depressants including alcohol and benzodiazepines increase sedation risk MAOIs and other serotonergic drugs can cause serotonin syndrome.

How it works

What the body does with it

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.

Classification & Brands

Action Class	Opioids
Brand Substitutes	Tramore Injection, Tramacad 50mg Injection, Tranzex 50mg Injection, Contramal 50 Injection, Tramazac HP 50mg Injection

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

CNS depressants including alcohol and benzodiazepines increase sedation risk MAOIs and other serotonergic drugs can cause serotonin syndrome.

FDA category	Positive
Breastfeeding	Tramadol and its active metabolite O-desmethyltramadol (M1) are excreted into breast milk. Milk-to-plasma ratio is approximately 2.2 for tramadol and 2.9 for M1. Relative infant dose is estimated at 2.88% of maternal weight-adjusted dose. Although generally considered compatible, monitor infant for sedation, respiratory depression, and withdrawal symptoms. Use lowest effective dose for shortest duration.
Teratogenic Risk