Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2022 Publisher: Seqirus (NZ) Ltd, PO Box 62 590, Greenlane, Auckland 1546, New Zealand, Telephone: 0800 502 757
Pharmacotherapeutic group: other opioids
ATC Code: N02AX02
Tramadol is a centrally-acting synthetic analgesic of the aminocyclohexanol group with opioid-like effects. It is not derived from natural sources, nor is it chemically related to opiates. Although pre-clinical testing has not completely explained the mode of action, at least two complementary mechanisms appear applicable: binding to µ-opioid receptors and inhibition of re-uptake of noradrenaline and serotonin. The opioid-like activity of tramadol derives from low affinity binding of the parent compound to µ-opioid receptors and higher affinity binding of the principal active metabolite, O-desmethyltramadol, denoted M1, to µopioid 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. The contribution to human analgesia of tramadol relative to M1 is unknown.
Both animal and human studies have shown that antinociception induced by tramadol is only partially antagonised by the opiate antagonist naloxone. In addition, tramadol has been shown to inhibit re-uptake of noradrenaline and serotonin in vitro, as have some other opioid analgesics. These latter mechanisms may contribute independently to the overall analgesic profile of tramadol.
The analgesic effect is dose-dependent, but the relationship between serum concentrations and analgesic effect varies considerably between individuals. In one study, the median serum concentration of tramadol required for effective post-operative analgesia was 300 ng/mL, with individual values ranging from 20 to 990 ng/mL.
Apart from analgesia, tramadol may produce other symptoms similar to that of opioids including: dizziness, somnolence, nausea, constipation, sweating and pruritus. However, tramadol causes significantly less respiratory depression than morphine. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no clinically significant effect on heart rate, left ventricular function or cardiac index. Orthostatic changes in blood pressure have been observed.
Tramadol is administered as a mixture of two stereoisomers; the following information refers to the combined concentration of both isomers. Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.
Tramadol is rapidly and almost completely absorbed after oral administration of 50 mg capsules following a mean absorption delay (t0) of approximately thirty minutes. The absorption half-life (t½) is 23 ± 11 minutes. After oral administration of two 50 mg capsules, the mean absolute bioavailability (fabs) is 68-72%, and the peak serum level (Cmax) is reached two hours (range one to three) after administration. The mean peak plasma concentration (Cmax) is approximately 280 ng/mL after oral administration of two capsules. At this time, the mean serum concentration after intravenous injection is 1.46 times higher, amounting to approximately 410 ng/mL.
Oral administration of tramadol with food does not significantly affect its rate or extent of absorption. Therefore tramadol can be administered without regard to food.
After repeated oral administration of 50 mg and 100 mg tramadol capsules at six hourly intervals, steady state is reached 30 to 36 hours after the first administration and the bioavailability is greater than 90%. The plasma concentrations at steady state exceeded by 52% and 36% those extrapolated from the single dose administration studies with 50 mg and 100 mg capsules, respectively. This can be explained by first pass metabolic saturation.
After intramuscular injection of 50mg tramadol, the bioavailability is approximately 100%, and the peak serum level is attained after 45 minutes (range 15 to 90).
After oral administration of Tramal SR, more than 90% of tramadol is absorbed. After a single dose, the mean absolute bioavailability is approximately 70%, irrespective of the concomitant intake of food. Oral bioavailability increases to 90% after repeated administration. The difference between absorbed and bioavailable tramadol is due to firstpass metabolism (maximum of 30%). The administration of Tramal SR every 12 hours and Tramal (immediate release) every 6 hours at the same daily dose, resulted in similar peak and trough serum tramadol concentrations and total tramadol exposure for the two preparations.
Serum tramadol concentrations in young males treated with Tramal SR (mean ± sd):
| Single Dose | Steady State | |||
|---|---|---|---|---|
| 100 mg | 200 mg | 100 mg q12 h | 200 mg q12 h | |
| Peak (ng/mL) | 142 ± 40 | 260 ± 113 | 293 ± 113 | 579 ± 149 |
| Time to peak (h) | 4.9 ± 0.8 | 4.8 ± 0.8 | 3.5 ± 1 | 3.9 ± 1.1 |
| Trough (ng/mL) | - | - | 156 ± 87 | 265 ± 67 |
Tramadol is rapidly distributed in the body, with a volume of distribution of 2-3 L/kg in young adults. The volume of distribution is reduced by about 25% in those aged over 75 years. Plasma protein binding is about 20% and is independent of concentration up to 10 µg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. Tramadol crosses the placental and blood-brain barriers. Very small amounts of tramadol and M1 are found in breast milk (0.1% and 0.02% respectively of the administered dose).
Tramadol is extensively metabolised after oral administration. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. Only O-desmethyltramadol (M1) is pharmacologically active. Production of M1 is dependent on the CYP2D6 isoenzyme of cytochrome P450. Patients who metabolise drugs poorly via CYP2D6 may obtain reduced benefit from tramadol, due to reduced formation of M1. N-demethylation is catalysed by the CYP3A4 isoenzyme of cytochrome P450. The inhibition of one or both types of the isoenzymes CYP3A4 and CYP2D6 involved in the biotransformation of tramadol may affect the plasma concentration of tramadol or its active metabolite.
Tramadol and its metabolites are excreted mainly by the kidneys, with a cumulative renal excretion (tramadol and metabolites) of approximately 95%. In young adults approximately 15=19% of an administered dose of tramadol is excreted in the urine as unmetabolised drug. In the elderly, this increases to about 35%. Biliary excretion is of little importance. In young adults, the half-life of tramadol is 5-7 h and the half-life of M1 is 6-8 h. Total clearance is approximately 430-610 mL/min.
Elimination of tramadol and M1 is impaired in patients with hepatic or renal impairment (see section 4.4 Special warnings and precautions for use). In patients with hepatic impairment, the mean half-life of tramadol was found to be 13 h (range up to 19 h), and the mean half-life of M1 was 19 h (range up to 36 h). In patients with renal impairment including subjects with considerably decreased CLCr [<5mL/min] the mean half-life of tramadol was 11 h (range up to 20 h), and the mean half-life of M1 was 17 h (range up to 43 h).
In the elderly (age over 75 years), the volume of distribution of tramadol is decreased by 25% and clearance is decreased by 40%. As a result, tramadol Cmax and total exposure are increased by 30% and 50%, respectively, but the half-life of tramadol is only slightly prolonged (by 15%).
Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the presence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamster cells, and bone marrow micronucleus tests in mice and Chinese hamster cells. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus tests in rat cells. Overall, the weight of evidence from these tests indicates tramadol does not possess a genotoxic risk to humans.
A slight, but statistically significant increase in two common murine tumours (pulmonary and hepatic) was observed in a mouse carcinogenicity study, particularly in aged mice dosed orally up to 30 mg/kg for approximately two years. Although the study was not conducted using the Maximum Tolerated Dose, or at exposure levels expected in clinical use, this finding is not believed to suggest risk in humans. No such findings occurred in a rat carcinogenicity study.
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