Tramapan Mechanism of Action

Pharmacotherapeutic group: Analgesics, Opioids in combination with non-opioid analgesics, ATC code: N02AJ13.
Pharmacology: Pharmacodynamics: Tramadol is a centrally acting opioid analgesic. It is a non-selective pure agonist at opioid receptors with a higher affinity for the μ receptor. In addition, 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.
Tramadol has an antitussive effect. In contrast to morphine, analgesic doses of tramadol over a wide range have no respiratory depressant effect. Also gastrointestinal motility is not affected. Effects on the cardiovascular system tend to be slight. The potency of tramadol is reported to be 10%-17% that of morphine. Paracetamol is another centrally acting analgesic. Although the exact site and mechanism of its analgesic action is not clearly defined, paracetamol appears to produce analgesia by elevation of the pain threshold. The potential mechanism may involve inhibition of the nitric oxide pathway mediated by a variety of neurotransmitter receptor including N-methyl-D-aspartate and Substance P.
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.
Pharmacokinetics: General: Tramadol is administered as a racemate and both the [+] and [-] forms of both tramadol and its M1 metabolite are detected in the circulation. Although tramadol is rapidly absorbed after administration, it has a slower absorption (and longer half-life), when compared to paracetamol.
After a single oral dose of one Tramadol/Paracetamol combination tablet (37.5 mg/325 mg) peak plasma concentrations of 64.3/55.5 ng/ml [(+)-Tramadol/(-)-Tramadol] and 4.2 μg/ml (Paracetamol) are reached after 1.8h [(+)-Tramadol/(-)-Tramadol] and 0.9h (Paracetamol), respectively. Mean elimination half lives t1/2 are 5.1/4.7 h [(+)-Tramadol/(-)-Tramadol] and 2.5 h (Paracetamol).
Single and multiple oral dose pharmacokinetic studies of TRAMAPAN in volunteers showed no significant drug interactions between tramadol and paracetamol.
Absorption: Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a single 100mg oral dose is approximately 75%. With multiple dosing, bioavailability increases to approximately 90%.
Oral absorption of paracetamol following administration of TRAMAPAN is rapid and almost complete and occurs primarily in the small intestine. Peak plasma concentrations of paracetamol occur within 1 hour and are not affected by co-administration with tramadol.
Food Effects: When TRAMAPAN 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 or the extent of absorption of either tramadol or paracetamol were not affected. The clinical significance of this difference is unknown.
Metabolism: Plasma concentration profiles for tramadol and its M1 metabolite measured following dosing of TRAMAPAN in volunteers showed no significant change compared to dosing with tramadol alone. Tramadol is extensively metabolized after oral administration. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as may convert tramadol to its active metabolite (M1) more rapidly and completely than other patients (see CYP2D6 Ultra-rapid metabolism of tramadol under Precautions). The prevalence of this CYP2D6 genotype varies by population and has been reported in literature to range from 1% to 10% in African Americans, Caucasian Americans, Asians and Europeans (including specific studies in Greeks, Hungarians and Northern Europeans) to as high as 29% in African/Ethiopians.
Paracetamol is primarily metabolized in the liver by first-order kinetics and involves as principal separate pathways: conjugation with glucuronide; conjugation with sulfate; and oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway.
Elimination: Tramadol and its metabolites are eliminated primarily by the kidney. 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.
Toxicology: Non-clinical Information: Preclinical Safety Data: Tramadol/Paracetamol Combination: There are no animal or laboratory studies on the combination product (tramadol and paracetamol) to evaluate carcinogenesis, mutagenesis, or impairment of fertility.
No drug-related teratogenic effects were observed in the progeny of rats treated orally with the combination of tramadol and paracetamol. The tramadol/paracetamol combination product was shown to be embryotoxic and fetotoxic in rats at a maternally toxic dose (50/434 mg/kg tramadol/paracetamol) 8.3 times the maximum human dose but was not teratogenic at this dose level. Embryo and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs. Lower and less severe maternally toxic dosages (10/87 and 25/217 mg/kg tramadol/paracetamol) did not produce embryo or fetal toxicity.
Carcinogenicity/Mutagenicity: A slight but statistically significant increase in two common murine tumors, pulmonary and hepatic, were observed in a mouse carcinogenicity study with tramadol, particularly in aged mice (dosing orally up to 30 mg/kg for approximately two years, although the study was not done with the Maximum Tolerated Dose). This finding is not believed to suggest risk in humans. No such finding occurred in a rat carcinogenicity study.
Various animal bioassays on a weight-of-evidence basis have demonstrated no evidence of carcinogenic potential for paracetamol.
Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters.
Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.
Paracetamol has been found to have no mutagenic potential using the Ames Salmonella - Microsomal Activation Test, the Basic test on Drosophila germ cells, and the Micronucleus test on mouse bone marrow.
Impairment of Fertility/Effect on Reproduction: No effects on fertility were observed for tramadol at oral dose levels up to 50mg/kg in male rats and 75mg/kg in female rats.
Tramadol was evaluated in peri- and post-natal studies in rats. Progeny of rats receiving oral (gavage) dose levels of 50 mg/kg or greater had decreased weights, and pup survival was decreased early in lactation at 80mg/kg (6 to 10 times the maximum human dose). No toxicity was observed for progeny of rats receiving 8, 10, 20, 25 and 40 mg/kg. Maternal toxicity was observed at all dose levels of tramadol in this duty, but the effects on progeny were evident only at higher dose levels where maternal toxicity was more severe.
There was no effect on pregnancy or offspring when paracetamol alone was given at dose levels of 600 mg/kg/day in the diet of male rats for 60 days prior to mating and to female rats from 14 days before mating to the end of pregnancy. An oral dose of 600mg/kg/day produced no teratogenicity or embryotoxicity when given from days 6 through 15 of pregnancy. When paracetamol was given from day 16 of pregnancy through a 3-week lactation period, no deleterious effect was noted on pregnancy rate or on percent of live births, but a decrease in body weight gain and survival rate was noted among offspring of drug-treated females. In another study, paracetamol 250mg/kg/day did not affect fetal length or weight, incidence of resorptions, or placental weight.