Pharmacodynamics Ultram is a centrally acting synthetic analgesic compound that is not derived from natural sources nor is it chemically related to opiates. Although its mode of action is not completely understood from animal tests, at least two complementary mechanisms appear applicable; binding to µ-opioid receptors and inhibition of reuptake of norepinephrine and serotonin. Ultram opioid activity derives from low affinity binding of the parent compound to µ-opioid receptors and higher affinity binding of the M1 metabolite. 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.
Tramadol-induced antinociception is only partially antagonized by the opiate naloxone in several animal tests. In addition, tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These latter mechanisms may contribute independently to the overall analgesic profile of Ultram. Onset of analgesia in humans is evident within one hour after administration and reaches a peak in approximately two to three hours. peak plasma concentrations are reached about two hours after administration, which correlates closely with the time to peak pain relief.
Apart from analgesia, Ultram administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of an opioid. 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, Ultram has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic changes in blood pressure have been observed.
Pharmacokinetics Absorption: Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. Oral administration of Ultram with food does not significantly affect its rate or extent of absorption. Therefore, Ultram can be administered without regard to food. The mean peak (± SD) plasma concentration of racemic tramadol is 308 ± 78 ng/ml and occurs at approximately two hours after a single 100 mg oral dose in healthy subjects. At this dose the mean peak plasma concentration of the active mono-O-desmethyl metabolite, racemic M1 is 55 ± 20 ng/ml and occurs approximately three hours post-dose. The separate [+]- and [-]-enantiomers of tramadol generally follow a parallel time course in plasma after a single 100 mg oral dose of Ultram. Following 100 mg oral administration of tramadol the maximum plasma concentrations of the [-]-enantiomer of tramadol are somewhat lower than those of the [+]-enantiomer (148 ± 33 vs. 168 ± 36 ng/ml respectively). The [-]-M1 enantiomer is present at slightly higher plasma concentrations than the [+]-M1 enantiomer (35 ± 10 vs. 26 ± 13 ng/ml respectively). At steady state following a 100 mg q.i.d. regimen of tramadol, 3 out of 18 subjects formed relatively low amounts of [+]-M1, while their [-]-M1 formation remained similar to that of other subjects. This is believed not to be clinically significant.
Plasma concentrations of racemic tramadol are predictable over a 50 mg to 100 mg single-dose range. This is also true under multiple-dose conditions. Steady state is achieved after two days of dosing Ultram by a 100 mg q.i.d. regimen (maximum plasma concentration was 592 ± 177 ng/ml). The plasma half-life of tramadol following a single and multiple dosing was 6 and 7 hours, respectively. This increase in half-life upon multiple dosing is not considered to be clinically significant or to warrant dosage adjustment for chronic use.
Mean plasma racemic tramadol and racemic M1 concentration-versus-time profiles following a single 100 mg oral dose of Ultram and following twenty-nine 100 mg doses four times daily.
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 µg/ml. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. Although not confirmed in humans, tramadol has been shown in rats to cross the blood-brain barrier.
Metabolism: 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 metabolites. The remainder is excreted either as unidentified or an unextractable metabolites. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. Only the one metabolite (mono-O-desmethyltramadol denoted M1) is pharmacologically active. Production of M1 is dependent on the CYP2D6 isoenzyme of cytochrome P-450.
Elimination: 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.
Special Populations: Renal: Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite M1. In patients with creatinine clearances of less than 30/ml/min adjustment of the dosing regimen is recommended (see DOSAGE AND ADMINISTRATION). The total amount of tramadol and M1 removed during a dialysis period is less than 7% of the administrator dose.
Hepatic: Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver resulting in a larger area under the serum-concentration-versus-time to curve tramadol and longer tramadol and M1 elimination half-lives (13 hrs. for tramadol and 19 hrs. for M1). In cirrhotic patients adjustment of the dosing regimen is recommended (see DOSAGE AND ADMINISTRATION).
Age: 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).
Gender: 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 concentration-time curve compared to males. This difference may not be of any clinical significance.
Clinical Studies: Ultram (tramadol hydrochloride) has been given in single oral doses of 50, 75, 100, 150 and 200 mg to patients with pain following surgical procedures (orthopedic, gynecological, cesarean section) and pain following oral surgery (extraction of impacted molars).
In single-dose models of pain following oral surgery, pain relief was demonstrated in some patients at doses of 50 mg and 75 mg. A dose of 100 mg Ultram tended to provide analgesia superior to codeine sulfate 60 mg, but it was not effective as the combination of aspirin 650 mg with codeine phosphate 60 mg. In single-dose models of pain following surgical procedures, 150 mg provided analgesia generally comparable to the combination of acetaminophen 650 mg with propoxyphene napsylate 100 mg, with a tendency toward later peak effect.
Ultram (tramadol hydrochloride) has been studied in three long-term controlled trials involving a total of 820 patients with 530 patients receiving Ultram. Patients with chronic conditions such as low back pain, cancer, neuropathic pain and orthopedic and joint conditions entered a double-blind phase of one to three months. Average daily doses of approximately 250 mg of Ultram in divided doses produced analgesia comparable with five doses of acetaminophen 300 mg with codeine phosphate 30 mg (Tylenol® with Codeine #3) daily five doses of aspirin 325 mg with codeine phosphate 30 mg daily and with two to three doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg (Tylox®) daily. Following the double-blind period, some patients took Ultram in an open period for up to two years.
