Analgesics, Opioids in combination with non-opioid analgesics. ATC Code:
Pharmacology: Pharmacodynamics: Pharmacodynamic effects:
Tramadol is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.
Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to μ-opioid binding receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound (see Pharmacology: Pharmacokinetics under Actions).
Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol.
Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids.
Acetaminophen: Acetaminophen is a non-opiate, non-salicylate analgesic.
Single Dose Studies for Treatment of Acute Pain: In pivotal single-dose studies in acute pain, two tablets of ULTRACET administered to patients with pain following oral surgical procedures provided greater relief than placebo or either of the individual components given at the same dose. The onset of pain relief after ULTRACET was faster than tramadol alone. Onset of analgesia occurred in less than one hour. The duration of pain relief after ULTRACET was longer than acetaminophen alone. Analgesia was generally comparable to that of the comparator, ibuprofen.
Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. The pharmacokinetics of plasma tramadol and acetaminophen following oral administration of one ULTRACET tablet are shown in table as follows. Tramadol has a slower absorption and longer half-life when compared to acetaminophen. (See table.)
Click on icon to see table/diagram/image
A single dose pharmacokinetic study of ULTRACET in volunteers showed no drug interactions between tramadol and acetaminophen. Upon multiple oral dosing to steady state, however, the bioavailability of tramadol and metabolite m1 was lower for the combination tablets compared to tramadol administered alone. The decrease in AUC was 14% for (+)-tramadol, 10.4% for (-)-tramadol, 11.9% for (+)-m1 and 24.2% for (-)-m1. The cause of this reduced bioavailability is not clear. Following single or multiple dose administration of Ultracet, no significant change in acetaminophen pharmacokinetics was observed when compared to acetaminophen given alone.
The absorption bioavailability of tramadol from ULTRACET tablets has not been determined. Tramadol hydrochloride has a mean absolute bioavailability of approximately 75% following administration of a single 100 mg oral dose of ULTRACET tablets. The mean peak plasma concentration of racemic tramadol and M1 after administration of two ULTRACET tablets occurs approximately two and three hours, respectively, post-dose.
Peak plasma concentrations of acetaminophen occur within one hour and are not affected by co-administration with tramadol. Oral absorption of acetaminophen following administration of ULTRACET occurs primarily in the small intestine.
When ULTRACET was administered with food, the time to peak plasma concentration was delayed for approximately 35 minutes for tramadol and almost one hour for acetaminophen. However, peak plasma concentration or the extent of absorption of either tramadol or acetaminophen were not affected. The clinical significance of this difference is unknown.
The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 μg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. Acetaminophen appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg. A relative small portion (~20%) of acetaminophen is bound to plasma protein.
Following oral administration, tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites.
Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The major metabolic pathways appears to be N
- and O
-demethylation and glucoronidation or sulfation in the liver. Metabolite M1 (O
-desmethyltramadol) is pharmacologically active in animal models. Formation of M1 on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see Precautions and Interactions).
Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P450. These individuals are "poor metabolizers" of debrisoquine, dextromethorphan, tricyclic antidepressants, among other drugs. Based on population PK analysis of Phase 1 studies in healthy subjects, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers", while M1 concentrations were 40% lower. In vitro drug interaction studies in human liver microsomes indicates that inhibitors of CYP2D6 such as Fluoxetine and its metabolite norfluoxetine, amitriptylline and quinidine inhibit the metabolism of tramadol to various degrees. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown.
Concomitant use of SEROTONIN re-uptake INHIBITORS and MAO INHIBITORS may enhance the risk of adverse events, including seizure (see Warnings) and serotonin syndrome.
Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: conjugation with glucuronide; conjugation with sulfate; and oxidation via cytochrome P450 enzyme pathway, P450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP2A2 and CYP3A4 as additional pathways.
In adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser extent, with sulfate. These glucuronide-, sulfate-, and glutathione-derived metabolites lack biologic activity. In premature infants, newborns, and young infants, the sulfate conjugate predominates.
Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The plasma elimination half-lives of racemic tramadol and M1 are approximately 5-6 and 7 hours, respectively, after administration of ULTRACET. The apparent plasma elimination half-life of racemic tramadol increased to 7-9 hours upon multiple dosing of Ultracet. The half-life of acetaminophen is about 2 to 3 hours in adults. It is somewhat shorter in children and somewhat longer in neonates and in cirrhotic patients. Acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Less than 9% of acetaminophen is excreted unchanged in the urine.
Renal: The pharmacokinetics of ULTRACET in patients with renal impairment have not been studied. Based on studies using tramadol alone, excretion of tramadol and metabolite M1 is reduced in patients with creatinine clearance of less than 30 mL/min, adjustment of dosing regimen in this patient population is recommended. (See Dosage & Administration.) The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose based on studies using tramadol alone.
Hepatic: The pharmacokinetics and tolerability of ULTRACET in patients with impaired hepatic function has not been studied. Since tramadol and acetaminophen are both extensively metabolized by the liver, the use of ULTRACET in patients with hepatic impairment is not recommended (see Dosage & Administration and Precautions).
Geriatric: A population pharmacokinetic analysis of data obtained from a clinical trial in patients with chronic pain treated with ULTRACET which included 55 patients between 65 and 75 years of age and 19 patients over 75 years of age, showed no significant changes in pharmacokinetics of tramadol and acetaminophen in elderly patients with normal renal and hepatic function (see Geriatric Use under Precautions).
Gender: Tramadol clearance was 20% higher in female subjects compared to males on four phase I studies of ULTRACET in 50 male and 34 female healthy subjects. The clinical significance of this difference is unknown.
Pediatric: Pharmacokinetics of ULTRACET tablets have not been studied in pediatric patients below 16 years of age.