Trade Names:
Trade Names:
Trade Names:
Binds to certain opioid receptors and inhibits reuptake of norepinephrine and serotonin; exact mechanism of action unknown.
Mean absolute bioavailability of tramadol is 75%. High-fat meals increased T max 3 h and decreased C max and AUC 28% and 16%, respectively (ER). T max is 2 to 3 h (immediate-release) and 12 to 15 h for (ER). Steady-state plasma concentrations of both tramadol and the metabolite are achieved within 2 days (immediate-release) and within 4 days (ER).
Tramadol is 20% protein bound and is independent of concentrations up to 10 mcg/mL. Vd is approximately 2.7 L/kg. Tramadol follows linear kinetics.
There is no evidence of self-induction. Production of M1 (metabolite) is dependent on CYP-450 2D6. The O-demethylated metabolite is M1. Tramadol is extensively metabolized after administration. The major metabolic pathway is N- and O-demethylation, and glucuronidation or sulfation in liver.
30% of a dose is excreted unchanged in urine; 60% is excreted as metabolites. The t ? is 6.3 h for tramadol immediate-release and 7.4 h for the metabolite. The t ? is 7.9 h for tramadol ER and 8.8 h for the metabolite.
The onset of action is 1 h (immediate-release).
Time to peak effect is 2 to 3 h (immediate-release) and 12 to 15 h (ER).
In patients with renal function impairment, there is a decreased rate and extent of excretion of tramadol and M1. In patients with CrCl less than 30 mL/min, dose adjustment is recommended.
Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis. In cirrhotic patients, dose adjustment is recommended.
In patients older than 75 yr of age, dose adjustment is recommended.
Absolute bioavailability, AUC, and C max are higher in women than in men. The clinical importance of these differences in unknown.
Relief of moderate to moderately severe pain (immediate-release); relief of moderate to moderately severe chronic pain for patients who require around-the-clock treatment for an extended period of time (ER).
Premature ejaculation; restless leg syndrome.
Acute intoxication with alcohol, hypnotics, centrally acting analgesics, narcotics, opioids, or psychotropic agents; hypersensitivity.
Dosage and Administration Immediate-Release Tablets
PO Start with 25 mg/day in the morning and titrate in 25 mg increments as separate doses every 3 days to reach Сто mg/day (25 mg 4 times daily). Thereafter, increase the dose by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg 4 times daily). After titration, administer 50 to Сто mg every 4 to 6 h as needed for pain relief (max, Четыресто mg/day).
PO Start with low end of dosing (max, 300 mg/day in patients 75 yr of age and older).
Renal Function Impairment (CrCl less than 30 mL/min)
PO Increase the dosing interval to 12 h (max, 200 mg/day).
PO Patients not currently on tramadol immediate-release: Start with Сто mg once daily and titrate as needed in Сто mg increments every 5 days to relief of pain, depending upon tolerability (max, 300 mg/day). Patients currently on tramadol immediate-release: Calculate the tramadol immediate-release dose and start a total dose of tramadol ER rounded down to the next lowest Сто mg increment. Subsequently, individualize the dose as needed. Because of limitations in flexibility of the tramadol ER dosage form, some patients maintained on tramadol immediate-release may not be able to convert to tramadol ER (max, 300 mg/day).
PO Use with caution, starting at the low end of the dosing range.
Renal Function Impairment?(CrCl less than 30 mL/min)
Do not administer.
Severe Hepatic Function Impairment (Child-Pugh class C)
Do not administer.
Store at 59° to 86°F in a tightly closed container.
Drug Interactions Alpha-2 adrenergic blockers, lithium, St. John's wort
Increased the risk of serotonin syndrome.
Amitriptyline, erythromycin, ketoconazole, linezolid, MAOIs, selective 5-HT 1 receptor agonists (eg, sumatriptan), SSRIs (eg, fluoxetine), tricyclic antidepressants
Increased risk of serotonin syndrome and increased risk of seizures.
May reduce serum tramadol levels, leading to decreased efficacy.
CNS depressants (eg, alcohol, anesthetics, narcotics, phenothiazines, sedative-hypnotics, tranquilizers)
Risk of CNS and respiratory depression may be increased.
Cyclobenzaprine, drugs that reduce the seizure threshold, neuroleptics, other opioids
Risk of seizures may be increased.
Digoxin toxicity has been reported.
Tramadol plasma levels may be increased; however, the clinical importance of this interaction is not known.
Anticoagulant effect of warfarin may be increased.
None well documented.
Postural hypotension (5%); vasodilation (less than 5% to 1%).
Dizziness/vertigo (33%); headache (32%); somnolence (25%); stimulation (14%); asthenia (12%); insomnia (11%); anxiety, confusion, coordination disturbance, depression, euphoria, hypoesthesia, lethargy, malaise, miosis, nervousness, paresthesia, pyrexia, restlessness, sleep disorder, tremor, weakness (less than 5% to 1%).
Flushing (16%); pruritus (12%); sweating (9%); dermatitis, skin rash (less than 5% to 1%).
Blurred vision, nasal congestion, nasopharyngitis, rhinorrhea, sneezing, sore throat, visual disturbance (less than 5% to 1%).
Constipation (46%); nausea (40%); vomiting (17%); dyspepsia (13%); diarrhea, dry mouth (10%); anorexia (6%); abdominal pain, flatulence, viral gastroenteritis (less than 5% to 1%).
Menopausal symptoms, urinary frequency, urinary retention, urinary tract infection (less than 5% to 1%).
Increased blood CPK (less than 5% to 1%).
Decreased appetite, decreased weight (less than 5% to 1%).
Arthralgia, back pain, hypertonia, limb pain, neck pain, rigors (less than 5% to 1%).
Bronchitis, cough, dyspnea, sinus congestion, sinusitis, upper respiratory tract infection (less than 5% to 1%).
Influenza, influenza-like symptoms (2%); chest pain, fall, feeling hot, fever, pain, (less than 5% to 1%).
Category C .
Excreted in breast milk.
Immediate-release: Safety and efficacy not established in children younger than 16 yr of age. ER: Safety and efficacy not established in children younger than 18 yr of age.
Use with caution, usually starting at the low end of the dosage range, because of the greater frequency of hepatic, renal, or cardiac function impairment, and concomitant diseases or other drug therapy. In patients older than 75 yr of age, daily doses in excess of 300 mg are not recommended.
Serious and, rarely, fatal anaphylactoid reactions may occur.
Dosage adjustments may be required.
Dosage adjustments may be required in patients with cirrhosis.
Tramadol may complicate the assessment of acute abdominal conditions.
Use with caution and in reduced dosage when administering to patients receiving CNS depressants or SSRIs.
May induce psychic and physical dependence of the morphine type. Do not use in opioid-dependent patients.
Use with caution in patients with increased intracranial pressure or head trauma.
Use with great caution in patients taking MAOIs.
Not recommended for patients who are opioid-dependent; use caution when administering to patients who have recently received substantial amounts of opioids.
Use with caution.
Potentially life-threatening serotonin syndrome may develop, particularly when combined with serotinergic agents (eg, SSRIs, SNRIs, triptans).
Seizures may occur within the recommended dosage range. In addition, the risk of convulsions may be increased in patients with epilepsy, history of seizures, or risk of seizures (eg, head trauma).
Do not use in patients who are suicidal or addiction prone (ER only).
If tramadol is discontinued abruptly, withdrawal symptoms may occur.
Bradycardia, cardiac arrest, coma, constricted pupils, death, hypotension, lethargy, respiratory depression, seizure, skeletal or muscle flaccidity.
Copyright © 2009 Wolters Kluwer Health.
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