Tramadol
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Mechanism of action
Tramadol hydrochloride tablets contains tramadol, an opioid agonist and inhibitor of norepinephrine and serotonin re-uptake. Although the mode of action is not completely understood, the analgesic effect of tramadol is believed to be due to both binding to μ-opioid receptors and weak inhibition of re-uptake 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 opioid 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
Clinical Pharmacology (12.2)]
.
Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.
Pharmacodynamics
Effects on the Central Nervous System
Tramadol produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.
Tramadol administration may produce a constellation of symptoms including nausea and vomiting, dizziness, and somnolence.
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 origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
Effects on the 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 biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED).
Effects on the Cardiovascular System
Tramadol produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of peripheral vasodilation may include pruritus, flushing, red eyes, sweating and/or orthostatic hypotension.
The effect of oral tramadol on the QTcF interval was evaluated in a double-blind, randomized, four-way crossover, placebo- and positive- (moxifloxacin) controlled study in 68 adult male and female healthy subjects. At a 600 mg/day dose (1.5-fold the maximum immediate-release daily dose), the study demonstrated no significant effect on the QTcF interval.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon
[see
Warnings and Precautions (5.13);
Adverse Reactions (6)]
.
Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date
[see
Adverse Reactions (6)]
.
Effects on the Immune System
Opioids have been shown to have a variety of effects on components of the immune system in
in vitroand animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
Concentration–Efficacy Relationships
The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with 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
[see
Dosage and Administration (2)]
.
Concentration–Adverse Reaction Relationships
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 and Administration (2)]
.
Pharmacokinetics
Absorption
The analgesic activity of tramadol hydrochloride tablet is due to both parent drug and the M1 metabolite
[see
Clinical Pharmacology (12.1,
12.2)]
. Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.
Absorption
The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. In general, both enantiomers of tramadol and M1 follow a parallel time course in the body following single and multiple doses although small differences (~ 10%) exist in the absolute amount of each enantiomer present.
Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with four times per day dosing. There is no evidence of self-induction (see Figure 1 and Table 3 below).
Figure 1: Mean Tramadol and M1 Plasma Concentration Profiles after a Single 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol Hydrochloride given four times per day.
Table 3: Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite
Population/Dosage
Regimen
a
Parent Drug/
Metabolite
Peak Conc.(ng/mL)
Time to Peak
(hrs)
Clearance/F
b
(mL/min/Kg)
t
1/2(hrs)
Healthy Adults,
Tramadol
592 (30)
2.3 (61)
5.90 (25)
c
6.7 (15)
100 mg qid, MD p.o.
M1
110 (29)
2.4 (46)
7.0 (14)
Healthy Adults,
Tramadol
308 (25)
1.6 (63)
8.50 (31)
c
5.6 (20)
100 mg SD p.o.
M1
55.0 (36)
3.0 (51)
6.7 (16)
Geriatric, (> 75 yrs)
Tramadol
208 (31)
d
2.1 (19)
d
6.89 (25)
c
7.0 (23)
d
50 mg SD p.o.
M1
Hepatic Impaired,
Tramadol
217 (11)
1.9 (16)
4.23 (56)
c
13.3 (11)
50 mg SD p.o.
M1
19.4 (12)
9.8 (20)
18.5 (15)
Renal Impaired,
Tramadol
c
c
4.23 (54)
c
10.6 (31)
CLcr10-30 mL/min
M1
c
c
11.5 (40)
100 mg SD i.v.
Renal Impaired,
Tramadol
c
c
3.73 (17)
c
11.0 (29)
CLcr < 5 mL/min
M1
c
c
16.9 (18)
100 mg SD i.v.
aSD = Single dose, MD = Multiple dose, p.o.= Oral administration, i.v.= Intravenous administration, q.i.d. = Four times daily
bF represents the oral bioavailability of tramadol
cNot applicable
dNot measured
Food Effects
Oral administration of tramadol hydrochloride tablets with food does not significantly affect its rate or extent of absorption, therefore, tramadol hydrochloride tablets can be administered without regard to food.
Distribution
The volume of distribution of tramadol was 2.6 and 2.9 liters/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 mcg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
Elimination
Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The mean (%CV) apparent total clearance of tramadol after a single 100 mg oral dose is 8.50 (31) mL/min/kg. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing.
Metabolism
Tramadol is extensively metabolized after oral administration 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 remainder is excreted either as unidentified or as unextractable metabolites. The major metabolic pathways appear to be
N- and
O-demethylation and glucuronidation or sulfation in the liver. One metabolite (
O-desmethyltramadol, denoted M1) is pharmacologically active in animal models. …
External links
Source: DailyMed — Tramadol ↗
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