Ultracet Mechanism of Action

Pharmacology: Mechanism of Action: Tramadol: 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 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 Pharmacokinetics as follows).
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 opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left ventricular function or cardiac index. Orthostatic hypotension has been observed.
Paracetamol: Paracetamol is a non-opiate, non-salicylate analgesic.
Tramadol/Paracetamol Combination: When evaluated in a standard animal model, the combination of tramadol and paracetamol exhibited a synergistic effect. That is, when tramadol and paracetamol were administered together, significantly less of each drug was needed to produce a given analgesic effect than would be expected if their effects were merely additive. Tramadol reaches peak activity in 2 to 3 hours with a prolonged analgesic effect, so that its combination with paracetamol, a rapid-onset, short-acting analgesic agent, provides substantial benefit to patients over either component alone.
Pharmacodynamics: Central Nervous System: Tramadol produces respiratory depression by direct action on brain stem respiratory centres. The respiratory depression involves both a reduction in the responsiveness of the brain stem centres to increases in CO₂ tension and to electrical stimulation.
Tramadol depresses the cough reflex by direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia.
Tramadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of oxycodone overdose.
Gastrointestinal Tract and Other Smooth Muscle: Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.
Endocrine System: Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes.
Immune System: In vitro and animal studies indicate that opioids have a variety of effects on immune functions, depending on the context in which they are used. The clinical significance of these findings is unknown.
Cardiac Electrophysiology: In a randomized, double-blind, 4-way crossover, placebo- and positive-controlled, multiple dose ECG assessment study in healthy subjects (N=62), the following tramadol treatments were tested: A) 100 mg every 6 h on days 1-3 (400 mg/day), with a single 100 mg dose on day 4 and B) 150 mg every 6 h (600 mg/day) on days 1-3, with a single 150 mg dose on day 4. The maximum dose for ULTRACET is 8 tablets per day or 300 mg of tramadol/day. In both treatment arms, the maximum difference from placebo in the mean change from baseline QTcF interval occurred at the 8 h time point: 5.5 ms (90% CI 3.2, 7.8) in the 400 mg/day treatment arm and 6.5 ms (90% CI 4.1, 8.8) in the 600 mg/day mg treatment arm. Both treatment groups were within the 10 ms threshold for QT prolongation (see Cardiovascular under Precautions; Other Clinically Significant Adverse Experiences Previously Reported in Clinical Trials or Post-marketing Reports with Tramadol under Adverse Reactions; Overview: QTc Interval-Prolonging Drugs under Interactions; Recommended Dose and Dosage Adjustment under Dosage & Administration; Overdosage). (See figure.)

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Concentration - Efficacy Relationships: The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent opioid agonists. The minimum effective analgesic concentration of tramadol for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance.
Concentration - Adverse Reaction Relationship: There is a relationship between increasing tramadol plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions (see Dosage & Administration).
Pharmacokinetics: Tramadol: 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 paracetamol following oral administration of one tablet are shown in Table 1. Tramadol has a slower absorption and longer half-life when compared to paracetamol. (See Table 1.)

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A single-dose pharmacokinetic study of ULTRACET in volunteers showed no drug interactions between tramadol and paracetamol. 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 paracetamol pharmacokinetics was observed when compared to paracetamol given alone.
Absorption: The absolute 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 tramadol HCl tablets. The mean peak plasma concentration of racemic tramadol and M1 after administration of two ULTRACET tablets occurs at approximately two and three hours, respectively, post-dose.
Peak plasma concentrations of paracetamol occur within one hour and are not affected by co-administration with tramadol. Oral absorption of paracetamol following administration of ULTRACET occurs primarily in the small intestine.
Food Effects: 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 paracetamol. However, peak plasma concentration and the extent of absorption of either tramadol or paracetamol were not affected. The clinical significance of this difference is unknown.
Distribution: 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.
Paracetamol appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg. A relatively small portion (~ 20%) of paracetamol is bound to plasma protein.
Metabolism: 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 appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. Metabolite M1 (O-desmethyltramadol) is pharmacologically active in animal models.
Patients who are CYP2D6 ultra-rapid metabolizers convert tramadol to its active metabolite (M1) more rapidly and completely than other patients.
Conversely, some patients are CYP2D6 poor metabolizers of tramadol, or other drugs (e.g., debrisoquine, dextromethorphan, and tricyclic antidepressants) (see Special Populations and Conditions: Race as follows).
Based on a population PK analysis of Phase I studies in healthy subjects, concentrations of tramadol were approximately 20% higher in "CYP2D6 poor metabolizers" versus "extensive CYP2D6 metabolizers", while M1 concentrations were 40% lower. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline 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 reuptake inhibitors and MAO inhibitors may enhance the risk of adverse events, including seizure and serotonin syndrome (see Precautions).
Paracetamol: Paracetamol is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: a. Conjugation with glucuronide.
b. Conjugation with sulfate.
c. Oxidation via the cytochrome, 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 CYP1A2 and CYP3A4 additional pathways.
In adults, the majority of paracetamol 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.
Excretion: 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 paracetamol is about 2 to 3 hours in adults. It is somewhat shorter in children and somewhat longer in neonates and in cirrhotic patients. Paracetamol is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Less than 9% of paracetamol is excreted unchanged in the urine.
Special Populations and Conditions: Pediatrics: Individuals under 18 years of age should not take ULTRACET tablets.
The pharmacokinetics of ULTRACET tablets have not been studied in pediatric patients below 18 years of age.
Geriatrics: 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 paracetamol in elderly patients with normal renal and hepatic function.
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.
Race: Some patients are CYP2D6 ultra-rapid metabolizers of tramadol due to a specific genotype. These individuals convert tramadol into its active metabolite, M1, more rapidly and completely than other people leading to higher-than-expected serum M1 levels. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese, Japanese and Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups (see Respiratory under Precautions; Labour, Delivery and Nursing Women under Use in Pregnancy & Lactation).
In contrast, some patients exhibit the CYP2D6 poor metabolizer phenotype and do not convert tramadol to the active M1 metabolite sufficiently to benefit from the analgesic effect of the drug (see Overview under Interactions). The prevalence of this CYP2D6 phenotype is about 5-10 percent in Caucasians and 1 percent of Asians.
Hepatic Impairment: The pharmacokinetics and tolerability of ULTRACET in patients with impaired hepatic function has not been studied. Since tramadol and paracetamol are both extensively metabolized by the liver, the use of ULTRACET in patients with hepatic impairment is not recommended (see Contraindications; Hepatic under Precautions).
Renal Impairment: 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. 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. ULTRACET is contraindicated in patients with severe renal impairment (see Contraindications; Renal under Precautions).