ULTRAM (Page 2 of 12)

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and 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 potent 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).

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).


The analgesic activity of ULTRAM is due to both parent drug and the M1 metabolite (see CLINICAL PHARMACOLOGY; Pharmacodynamics). 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.


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 1 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 HCl given four times per day.

Figure 1
(click image for full-size original)
Table 1 Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite
Population/Dosage Regimen *Parent Drug/MetabolitePeak Conc. (ng/mL) Time to Peak (hrs)Clearance/F (mL/min/Kg) t 1/2 (hrs)
SD = Single dose, MD = Multiple dose, p.o.= Oral administration, i.v.= Intravenous administration, q.i.d. = Four times daily
F represents the oral bioavailability of tramadol
Not applicable
Not measured
Healthy Adults, 100 mg qid, MD p.o.Tramadol M1 592 (30) 110 (29) 2.3 (61) 2.4 (46) 5.90 (25) 6.7 (15) 7.0 (14)
Healthy Adults, 100 mg SD p.o.Tramadol M1 308 (25) 55.0 (36) 1.6 (63) 3.0 (51) 8.50 (31) 5.6 (20) 6.7 (16)
Geriatric, (>75 yrs) 50 mg SD p.o.Tramadol M1 208 (31) §2.1 (19) §6.89 (25) 7.0 (23) §
Hepatic Impaired, 50 mg SD p.o.Tramadol M1 217 (11) 19.4 (12) 1.9 (16) 9.8 (20) 4.23 (56) 13.3 (11) 18.5 (15)
Renal Impaired, CL cr 10–30 mL/min 100 mg SD i.v. Tramadol M1 4.23 (54) 10.6 (31) 11.5 (40)
Renal Impaired, CL cr <5 mL/min 100 mg SD i.v. Tramadol M1 3.73 (17) 11.0 (29) 16.9 (18)

Food Effects

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 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.

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