Source: Health Products and Food Branch (CA) Revision Year: 2020
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.
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. The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in the ZYTRAM XL clinical studies.
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. 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.
Tramadol is a centrally acting analgesic but is atypical in having at least two complementary mechanisms of action. It is a non-selective pure agonist at mu, delta- and kappa-opioid receptors, with greater affinity for the mu receptor. Other mechanisms that contribute to its analgesic effect are inhibition of neuronal re-uptake of norepinephrine and serotonin, which are thought to result in activation of inhibitory pain pathways in the dorsal horn of the spinal cord. As a result, tramadol-induced analgesia is only partially antagonized by the opioid antagonist naloxone. It is also antagonized by α2 adrenoceptor antagonists.
The opioid activity of tramadol is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite (M1) to the mu-opioid receptor. The affinity of tramadol for the mu receptor is 10 times less than codeine, 200 times less than O desmethyl tramadol, and 6,000 times less than morphine. The affinity of tramadol for delta and kappa opioid receptors is 20-25 times less than to mu receptors. The (+) enantiomer has 20 times greater affinity for the mu-opioid receptor than the (-) enantiomer.
Tramadol inhibits the neuronal re-uptake of serotonin and also increases its release through a pre-synaptic mechanism. The ( + ) enantiomer is more potent than the ( - ) enantiomer in inhibiting serotonin reuptake. Conversely, the ( - ) enantiomer is more potent than the (+) enantiomer in inhibiting norepinephrine reuptake, and also increases norepinephrine release through stimulation of a pre-synaptic autoreceptor.
Both enantiomers have anti-nociceptive effects in animals and analgesic effects in humans, and the interaction between the two enantiomers is synergistic. However, for adverse effects, the interaction is less than additive (rotarod performance), additive (colonic motility) or antagonistic (cardiovascular and respiratory endpoints). Effects on gastrointestinal motility and respiration are less than with morphine, consistent with clinical observations of less constipation and respiratory depression at recommended doses.
The administration of naloxone only partially antagonizes tramadol’s antinociceptive and analgesic effects in animals and man, indicating a contribution from non-opioid analgesic mechanisms. In animals and man the effect of tramadol is attenuated by the α2 adrenoceptor antagonist, yohimbine, and in animals, the serotonin antagonist ritanserin reduces the antinociceptive effect of tramadol. This indicates the potential for a contribution to the analgesic effect of tramadol through modulation of monaminergic inhibitory pain pathways in the dorsal horn of the spinal cord, in addition to an opioidergic effect.
Tramadol may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes, hyperhidrosis and/or orthostatic hypotension.
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 ZYTRAM XL is 300 mg/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 WARNINGS AND PRECAUTIONS, Cardiovascular; ADVERSE REACTIONS, Post-Marketing Reports with Tramadol; DRUG INTERACTIONS, QTc Interval-Prolonging Drugs; DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment; OVERDOSAGE).
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.
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.
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.
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.
Absorption: Following oral administration of a single dose, tramadol is almost completely absorbed and the absolute bioavailability is approximately 70%. The elimination half-life of tramadol is around 6 hours, although this is extended to around 16 hours as a result of prolonged absorption from the ZYTRAM XL tablets.
Following administration of one ZYTRAM XL tablet 200 mg in the fasting state, the mean peak plasma concentration (Cmax) was 34% (dose adjusted) that of a 100 mg dose of tramadol given as an oral solution. This was associated with a more prolonged tmax (median 6 hours; range 4-8 hours) compared with the oral solution (median 1.5 hours; range 0.75-4 hours). The extent of absorption of tramadol from the ZYTRAM XL tablet 200 mg was equivalent to that of the immediate release tramadol solution 100 mg, after dose adjustment. In the presence of food, the bioavailability and controlled release properties of ZYTRAM XL tablets are maintained, with no evidence of dose-dumping.
In a single dose study, the dose-adjusted bioavailability of the 200 mg, 300 mg and 400 mg tablets were equivalent, confirming a linear pharmacokinetic response (in relation to both tramadol and O-desmethyltramadol) over this range of strengths.
In a steady state study, the dose adjusted bioavailability of the 150 mg and 200 mg tablets administered once-daily were equivalent. The bioavailability of all strengths of ZYTRAM XL is therefore, dose-proportional. A steady-state study also confirmed that the ZYTRAM XL tablet 150 mg provided an equivalent peak concentration and extent of absorption of tramadol as an immediate release capsule 50 mg administered 8-hourly.
Tramadol has a great affinity for tissues (Vd = 203 ± 40 L) and the plasma protein binding is approximately 20%.
Tramadol is extensively metabolized after oral administration. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. Only one metabolite (mono-O-desmethyltramadol – denoted M1) is pharmacologically active. Production of M1 is dependent on the CYP2D6 isoenzyme of cytochrome P450.
Tramadol and its metabolites are almost completely excreted with the urine. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites.
The elimination half-life of tramadol is around 6 hours, although this is extended to around 12 to 16 hours following prolonged absorption from the controlled release tablet.
The safety and efficacy of ZYTRAM XL has not been studied in the pediatric population. Individuals under 18 years of age should not take ZYTRAM XL.
Healthy elderly subjects aged 65 to 75 years have plasma tramadol concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. In subjects over 75 years maximum serum concentrations are slightly elevated (208 vs. 162 ng/mL) and the elimination half-life is slightly prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients older than 75 years (see DOSAGE AND ADMINISTRATION).
The absolute bioavailability of tramadol was 73% in males and 79% in females. The plasma clearance was 6.4 mL/min/kg in males and 5.7 mL/min/kg in females following a 100 mg IV dose of tramadol. Following a single oral dose, and after adjusting for body weight, females had a 12% higher peak tramadol concentration and a 35% higher area under the concentrationtime curve compared to males. This difference may not be of any clinical significance.
Not applicable.
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 WARNINGS AND PRECAUTIONS, Respiratory and Special Populations, Nursing Women).
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 DRUG INTERACTIONS, Overview). The prevalence of this CYP2D6 phenotype is about 5%-10% in Caucasians and 1% of Asians.
Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in a larger area under the serum-concentration time curve for tramadol and longer tramadol and M1 elimination half-lives (13 hours for tramadol and 19 hours for M1). ZYTRAM XL is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) (see CONTRAINDICATIONS).
Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite M1. ZYTRAM XL is contraindicated in patients with creatinine clearances of less than 30 mL/min (see CONTRAINDICATIONS). The total amount of tramadol and M1 removed during a dialysis period is less than 7% of the administered dose.
After a single oral administration in mice, rats, guinea pigs, rabbits and dogs, the LD50 of tramadol was 228-850 mg/kg; after s.c. injection in mice, rats and guinea pigs the LD50 range was 200-286 mg/kg; after i.m. injection in rabbits and dogs, the LD50 was 75-225 mg/kg; and after i.v. injection in mice, rabbits and dogs, the LD50 was 45-68 mg/kg.
Clinical, hematological, clinical chemistry and histological investigations revealed no drugrelated changes following repeated oral and parenteral administration for 6 and 26 weeks to rats and dogs, as well as oral administration for 12 months to dogs. Only with doses far above those used in therapy, changes in general behaviour and CNS effects, such as weight loss (probably due to reduced food intake), decreased grooming activity, restlessness, salivation and convulsions were observed.
No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats. Tramadol has been shown to be embryotoxic (delayed ossification) and fetotoxic in mice, rats and rabbits at maternally toxic doses 3 to 15 times the maximum human dose or higher (120 mg/kg in mice, 25 mg/kg or higher in rats and 75 mg/kg or higher in rabbits) but was not teratogenic at those dose levels. No harm to the fetus due to tramadol was observed at doses that were not maternally toxic.
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