Ultracet; Acetaminophen; Tramadol
Ultracet®
37.5 mg tramadol hydrochloride/325 mg acetaminophen tablets
Classification:Analgesics
NOTE: This monograph discusses the use of the acetaminophen; tramadol combination product for the management of pain. Clinicians may wish to consult the individual drug monographs for more information about each agent.
Description: Acetaminophen; tramadol is used orally for short-term (<= 5 days) management of acute pain. Acetaminophen is a non-narcotic analgesic and tramadol is a centrally acting analgesic with a unique, dual mechanism of action. Some studies have evaluated acetaminophen; tramadol for the treatment of chronic pain, such as osteoarthritis and low-back pain. In a 4-week study, pain relief scrores between acetaminophen; tramadol and acetaminophen; codeine were similar.[3346] The primary advantage of Ultracet® appears to be a quicker onset of action than Ultram® and greater pain relief than either acetaminophen or tramadol given alone. However, in oral surgical patients the analgesia produced by acetaminophen; tramadol was comparable to ibuprofen. Ultracet® was approved by the FDA August 15, 2001.
Mechanism of Action: Acetaminophen; tramadol produces analgesia via two different mechanisms of action leading to a synergistic analgesic effect.
Acetaminophen: Acetaminophen acts within the CNS to increase the pain threshold by inhibiting central cyclooxygenase, an enzyme involved in prostaglandin (PG) synthesis. Acetaminophen inhibits both isoforms of central cyclooxygenase, COX-1 and COX-2. Acetaminophen does not inhibit PG synthesis in peripheral tissues, which is the reason for its lack of peripheral anti-inflammatory effects.
Tramadol: Tramadol appears to have two complementary mechanisms of pain relief, specifically binding of the parent drug and M1 metabolite to ß-opioid receptors and reuptake inhibition of serotonin and norepinephrine. The affinity of the parent drug for ß-opioid receptors is much less than the M1 metabolite, with the M1 metabolite being 6 times more potent in analgesic effects and 200 times more potent in ß-binding activity.
The reuptake inhibition of serotonin and norepinephrine may lead to reduced spinal cord pain transmission. The stereochemistry of tramadol influences the affinity of these compounds to various receptors. The (+) enantiomer has higher affinity for the ß-receptor and preferentially inhibits serotonin uptake and enhances serotonin release. The (-) enantiomer preferentially inhibits norepinephrine reuptake by stimulating alpha2-adrenergic receptors.[897] The racemate of the trans isomer of tramadol is more potent than either enantiomer alone. The inhibitory reuptake effects of tramadol on norepinephrine and serotonin are 100 - 1000 times less than imipramine.
Pharmacokinetics: Acetaminophen; tramadol combination product is administered orally.
Acetaminophen: Acetaminophen is rapidly and almost completely absorbed from the GI tract. Peak plasma concentrations of acetaminophen from the combination product occur in one hour. Absorption, which occurs primarily from the small intestine, may be decreased if taken with a high-carbohydrate meal. Protein binding is minimal. Acetaminophen is metabolized in the liver via glucuronidation and sulfate conjugation and is excreted in the urine as glutathione and sulfate conjugates. However about 10 - 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes (CYP) 2E1 and 1A2 and then glucuronidation to cysteine and mercapturic acid conjugates. In cases of glucuronide depletion, such as acetaminophen overdose, a hepatotoxic metabolite is formed. The mean half-life of acetaminophen as part of the combination product is 2.5 hours. The pharmacokinetics of acetaminophen are not altered when combined with tramadol.
Tramadol: Racemic tramadol and the M1 metabolite reach peak plasma concentrations at 2 and 3 hours, respectively, following oral administration. Absolute bioavailability of tramadol from the combination product has not been determined, but bioavailability of tramadol as a single product is roughly 75%. When acetaminophen; tramadol was administered with food, the time to peak concentrations was delayed, but the extent of absorption and final peak concentrations were not affected. For oral surgical patients, the onset of analgesia for the combination product occurred in less than one hour, more quickly than individual tramadol. Minimal protein binding occurs (roughly 20%). Tramadol crosses the placenta and about 0.1% is distributed into breast milk. Tramadol undergoes significant first-pass metabolism. The major metabolic pathways appear to be N- and O- demethylation, glucuronidation and sulfation. Extensive hepatic metabolism occurs via isoenzymes CYP2D6 and CYP3A4. The formation of the active metabolite M1 (O-desmethyltramadol) is dependent upon the 2D6 enzyme and therefore inhibition of this enzyme can affect therapeutic response. The elimination mean half-life of the racemic tramadol and M1 metabolite is 5 and 7 hours, respectively. Multiple dosing lengthens the half-life of racemic tramadol to 7 - 9 hours. About 90% of a dose is excreted in the urine (30% as unchanged drug and 60% as metabolites) and 10% is excreted in the feces.
Special Populations: In clinical trials, tramadol clearance was 20% higher in females versus males; the clinical significance of this effect is not known. Approximately 7% of the general population are termed “poor metabolizers” of tramadol due to reduced activity of the CYP2D6 isoenzymes. Phase 1 pharmacokinetic studies have shown “poor metabolizers” have 20% higher concentrations of tramadol and 40% lower concentrations of the active M1 metabolite. The addition of drugs that inhibit CYP2D6 to these patients’ regimens could further alter tramadol concentrations; the clinical significance of these actions is not known.
The pharmacokinetics of acetaminophen; tramadol have not been studied in patients with renal or hepatic impairment. In patients with a creatinine clearance < 80 ml/min, the half-life of tramadol increases 1.5 - 2 times as compared to patients with normal renal function. Less than 7% of tramadol and M1 are removed by dialysis during a 4 hour session. In patients with cirrhosis or significant liver dysfunction, the half life of tramadol and M1 increases 2 - 3 times as compared to normal. The half-life of acetaminophen also increases with hepatic impairment. The use of acetaminophen; tramadol is not recommended in hepatic dysfunction.
References
897. Raffa RB, Friderichs E, Reimann W, et al. Complimentary and synergistic antinociceptive interaction between the enantiomers of tramadol. J Pharmacol Exp Ther 1993;267:331 - 40.
3346. Mullican WS, Lacy JR, TRAMAP-ANAG-006 Study Group. Tramadol/acetaminophen combination tablets and codeine/acetaminophen combination capsules for the management of chronic pain: a comparative trial. Clin Ther 2001;23:1429 - 45.
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