Mechanism Of Action
ULTRAM® 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 (see Pharmacokinetics).
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 ULTRAM®. Analgesia in humans begins approximately within one hour after
administration and reaches a peak in approximately two to three hours.
Apart from analgesia, ULTRAM® administration may produce
a constellation of symptoms (including dizziness, somnolence, nausea, constipation,
sweating and pruritus) similar to that of opioids. 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 hypotension has been observed.
The analgesic activity of ULTRAM® is due to both parent
drug and the M1 metabolite (see Mechanism of Action). Tramadol is
administered as a racemate and both the [-] and [+] forms of both tramadol and
M1 are detected in the circulation. Tramadol is well absorbed orally with an
absolute bioavailability of 75%. Tramadol has a volume of distribution of
approximately 2.7 L/kg and is only 20% bound to plasma proteins. Tramadol is
extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4,
as well as by conjugation of parent and metabolites. One metabolite, M1, is
pharmacologically active in animal models. The formation of M1 is dependent
upon CYP2D6 and as such is subject to inhibition, which may affect the
therapeutic response (see DRUG INTERACTIONS). Tramadol and its
metabolites are excreted primarily in the urine with observed plasma half-lives
of 6.3 and 7.4 hours for tramadol and M1, respectively. Linear pharmacokinetics
have been observed following multiple doses of 50 and 100 mg to steady-state.
Racemic tramadol is rapidly and almost completely
absorbed after oral administration. 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 q.i.d. dosing. There is no evidence of
self-induction (see Figure 1.1 and Table 1.4 below).
Figure 1.1: 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 q.i.d.
Table 1.4: Mean (%CV) Pharmacokinetic Parameters for
Racemic Tramadol and M1 Metabolite
|Population/ Dosage Regimena
||Parent Drug/ Metabolite
|Time to Peak (hrs)
100 mg q.i.d., MD p.o.
|Healthy Adults, 100 mg SD p.o.
|Geriatric, ( > 75 yrs) 50 mg SD p.o.
|Hepatic Impaired, 50 mg SD p.o
|Renal Impaired, CLcr10-30 mL/min 100 mg SD i.v.
|Renal Impaired, CLcr < 5 mL/min 100 mg SD i.v.
|a SD = Single dose, MD = Multiple dose, p.o.=
Oral administration, i.v.= Intravenous administration, q.i.d. = Four times
b F represents the oral bioavailability of tramadol
c Not applicable
d Not measured
The volume of distribution of tramadol was 2.6 and 2.9
L/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
Following oral administration, tramadol is extensively
metabolized 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 major metabolic pathways appear to be N- and O- demethylation
and glucuronidation or sulfation in the liver. Metabolite M1
(O-desmethyltramadol) is pharmacologically active in animal models. Formation
of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may
affect the therapeutic response (see DRUG INTERACTIONS).
Approximately 7% of the population has reduced activity
of the CYP2D6 isoenzyme of cytochrome P450. These individuals are “poor
metabolizers” of debrisoquine, dextromethorphan, and tricyclic antidepressants,
among other drugs. Based on a population PK analysis of Phase I studies in
healthy subjects, concentrations of tramadol were approximately 20% higher in
“poor metabolizers” versus “extensive metabolizers”, while M1 concentrations
were 40% lower. In vitro drug interaction studies in human liver microsomes
indicate that inhibitors of CYP2D6 such as fluoxetine and its metabolite
norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol
to various degrees. The full pharmacological impact of these alterations in
terms of either efficacy or safety is unknown. Concomitant use of serotonin
reuptake inhibitors and MAO inhibitors may enhance the risk of adverse events,
including seizure (see WARNINGS AND PRECAUTIONS) and serotonin syndrome.
Tramadol is eliminated primarily through metabolism by
the liver and the metabolites are eliminated primarily by the kidneys. 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
Special Populations and Conditions
Pharmacokinetics of ULTRAM® tablets have not been studied
in pediatric patients below 18 years of 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 elevated (208 vs. 162 ng/mL) and the
elimination half-life is 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 i.v. 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. The clinical
significance of this difference is unknown.
Metabolism of tramadol and M1 is reduced in patients with
advanced cirrhosis of the liver, resulting in both a larger area under the
concentration time curve for 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 WARNINGS AND
PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Excretion of tramadol and metabolite M1 is reduced in
patients with creatinine clearance of less than 30 mL/min, adjustment of dosing
regimen in this patient population is recommended. The total amount of tramadol
and M1 removed during a 4-hour dialysis period is less than 7% of the
administered dose (see WARNINGS AND PRECAUTIONS and DOSAGE AND
ULTRAM® was evaluated in single-dose trials (dental and
surgery), multiple-dose, [short-term trials (dental and surgery), long-term
trials (chronic malignant and non-malignant pain), and trials evaluating the
impact of dose titration on tolerability]. Clinical trials in non-malignant
pain included patients with osteoarthritis, low back pain, diabetic neuropathy
and fibromyalgia. These trials included a randomized, double-blind, parallel
group design, and in each of the single-dose and short-term multiple-dose
trials tramadol was compared to a standard reference analgesic (either codeine,
ASA/codeine or APAP/propoxyphene), placebo or to both. The active controls were
included to establish model sensitivity. The efficacy of tramadol in these
trials was established based on Total Pain Relief (TOTPAR), Sum of Pain
Intensity Difference (SPID) and time to remedication.
Collectively, a total of 2549 patients with dental pain,
1940 patients with surgical pain, 170 patients with chronic malignant pain, 119
patients with sub-acute low back pain, and 2046 patients with chronic non-malignant
pain were enrolled into the 28 efficacy trials. Of the 6824 total patients
enrolled into these trials, 4075 were randomized to a tramadol treatment arm.
Acute Pain, Single- and Multiple-Dose Studies
ULTRAM® has been given in single oral doses of 50, 75 and
100 mg to patients with pain following surgical procedures and pain following
oral surgery (extraction of impacted molars).
Results of these trials demonstrated statistically
superior pain relief for tramadol compared to placebo. Data from these key
trials provide information regarding the optimal analgesic dosage range of
In single-dose dental trials, tramadol was superior to
placebo at doses of 100 mg or greater (p ≤ 0.05).
In addition, tramadol at doses of 100mg or greater were equivalent to or
statistically superior to the reference analgesics for Total Pain Relief
(TOTPAR) and Sum of Pain Intensity Difference (SPID) across the entire
evaluation interval. The results of the multiple-dose short-term trials in
acute pain also provide evidence for efficacy of tramadol in the management of
Tramadol has been studied in three long-term controlled
trials involving a total of 820 patients, with 530 patients receiving tramadol.
Patients with a variety of chronic painful conditions were studied in
double-blind trials of one to three months duration.
Two titration trials, TPS DOS and CAPSS-047, provide
information regarding appropriate dose titration during chronic use of
tramadol. These trials show that a longer titration period can significantly
reduce the incidence of adverse events, and the frequency of withdrawal due to
adverse events, leading to improved tolerability and overall benefit-risk
profile. Efficacy evaluations in these studies suggest that slowing the rate of
titration improves tolerability and does not negatively impact on drug
In a randomized, blinded clinical study with 129 to 132
patients per group, a 10-day titration to a daily ULTRAM® dose of 200 mg (50 mg
q.i.d.), attained in 50 mg increments every 3 days, was found to result in
fewer discontinuations due to dizziness or vertigo than titration over only 4
days or no titration. In a second study with 54 to 59 patients per group,
patients who had nausea or vomiting when titrated over 4 days were randomized
to re-initiate ULTRAM® therapy using slower titration rates.
A 16-day titration schedule, starting with 25 mg qAM and
using additional doses in 25 mg increments every third day to 100 mg/day (25 mg
q.i.d.), followed by 50 mg increments in the total daily dose every third day
to 200 mg/day (50 mg q.i.d.), resulted in fewer discontinuations due to any
cause than did a 10-day titration schedule. See Figure 2.1.
Figure 2.1: Protocol CAPSS-047 – Time to
Discontinuation Due to Nausea/Vomiting
Tramadol HCl, 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)
cyclohexanol HCl, is a centrally acting synthetic analgesic compound. It is
thought to produce its analgesic effect through at least two complementary
mechanisms of action: agonist activity at the μ-opioid receptor and weak
inhibition of neuronal monoamine reuptake. These dual activities are observed
in studies conducted in vitro as well as in nonclinical animal models of
antinociception. In studies conducted in vitro, tramadol inhibited binding to
native rat μ-opioid receptor at approximately the same concentration at
which it blocked the reuptake of norepinephrine and serotonin. The K1 values
for μ-opioid receptor affinity and monoamine reuptake inhibitory
activities are 2.1 and ~ 1 μM, respectively. Tramadol affinities for
recombinant human opioid receptors (K1 = 17 μM) were slightly weaker than
those observed at the rat receptors. Apart from analgesia, tramadol may produce
a constellation of symptoms similar to that of an opioid.
Tramadol is an efficacious analgesic in a wide variety of
standard analgesic models of acute, tonic, chronic, or neuropathic pain. In
some of these studies, specific antagonists were used to probe the mechanism of
tramadol's antinociceptive action. In contrast to the full blockade of morphine
antinociception by naloxone, the antinociceptive action of tramadol in most
tests is only partially blocked by naloxone. Furthermore, although the
antinociception of morphine is unaffected by the alpha2-adrenergic antagonist
yohimbine or the serotonergic antagonist ritanserin, each of these antagonists
reduces tramadol's antinociception. These pharmacologic studies suggest the
contribution of both opioid and monoamine mechanisms to tramadol
In drug interaction studies carried out with tramadol, a
substantial increase in toxicity was found after pretreatment with an MAO
inhibitor, tranylcypromine. The antinociceptive effect of the compound was
reduced by concomitant administration of barbiturates and atropine, and was
virtually eliminated by tranylcypromine. Physostigmine potentiated the
antinociceptive effect of a sub-maximal dose of tramadol. Other potential drug
interactions based on enzyme induction or displacement from protein binding were
thought to be unlikely with tramadol as no inductive effect on liver enzymes
has been found for this agent and the protein binding is too low to induce
relevant interference with the binding of other compounds.
Tramadol was rapidly absorbed after oral administration
in the mouse, rat, and dog. In dogs, the mean absolute bioavailability of a
single 20 mg/kg oral dose of tramadol (Avicel formulation in gelatin capsules)
was 81.8%, with maximum plasma concentrations achieved in about one hour.
Distribution of radioactivity into tissues was rapid following the intravenous
administration of 14C-labelled tramadol to rats, with the highest concentration
of radioactivity found in the liver. Radioactivity levels in the brain were
comparable to plasma levels for the first 2 hours post-injection, demonstrating
that the drug crosses the blood brain barrier. Concentrations in the kidneys,
lungs, spleen, and pancreas were also higher than the serum concentration.
The major metabolic pathway was qualitatively similar for
all species studied, including mouse, rat, hamster, guinea pig, rabbit, and
man, and involved both Phase I (N- and O-demethylation and 4-hydroxylation;
eight metabolites) and Phase II (glucuronidation or sulfation; thirteen
metabolites) reactions. The primary metabolite mono-O-desmethyltramadol (M1)
has antinociceptive activity. In biochemical studies, (±)
mono-O-desmethyltramadol and its enantiomers each had greater affinity for
opioid receptors and were less potent inhibitors of monoamine uptake than were
the corresponding parent compounds.
Excretion was primarily by the renal route in the animal
species studied. After oral administration, fecal excretion was approximately
13% in rats and dogs, and 80% of 14C-labelled tramadol doses were excreted in
the urine within 72 to 216 hours of dosing. Amounts of unchanged tramadol
excreted in the urine were higher in man (approximately 30% of the dose) than
in animals (approximately 1%).
Tramadol is a mild inducer of ethoxycoumarin deethylase
activity in the mouse and dog.
The acute toxicity of tramadol hydrochloride has been
examined in the rat. The results of the study are summarized in the following
Table 2.1: Acute Toxicity Studies Summary
||No./Sex/ Group Duration
||Dosage Levels (mg/kg)
|Rat Crl:COBS® (WI) BR Age: 7 to 8 wk B.W. Range: 161 to 220 g
||5M or 8M single dose
|1% aqueous HPMC
||Tramadol: 150 APAP: 300 Tramadol/APAP: 150/300 Vehicle Control: 1% aqueous HPMC (9 mL/kg)
||No treatment-related mortality, clinical observations, or effects on body weight.
|APAP = acetaminophen; B.W. = body weight; HPMC =
hydroxypropylmethylcellulose; M = male; F = female; mo = month; p.o. = oral; wk
= week; ↑ = increased; ↓= decreased
Multi-dose toxicity studies were conducted in rats and
dogs. The following table summarizes the results of the two pivotal multi-dose
Table 2.2: Multi-dose Toxicity Studies–Protocol
|Rat Crl:CD® BR, VAF/Plus®
||10/3 mo/p.o. (gavage)
||1) Vehicle Control: 0.5% Methocel (10 mL/kg/day)
||Mortality, clinical observations, B.W., food consumption, ophthalmological examination, drug metabolism, hematology, coagulation, clinical chemistry, urinalysis, organ weights, gross pathology, histopathology
||Vehicle Control: Four M deaths (attributed to dosing errors); alopecia in both sexes
7.5/65: Alopecia in both sexes; ↑liver weights in males
22.5/195: One M death (cause of death not determined); alopecia in both sexes; ↑ liver weights in males; slightly ↑urine volume in females
|45/390: Alopecia, ↑ salivation, slightly higher urine volume in both sexes; mild treatment related increases in K+ concentration, slightly ↓ RBC, ↑ MCV, MCH, ↑ liver weights, slightly ↓ ALT and AST activity and ↑ ALP in females
|3) Tramadol: 45
|4) APAP: 390
||45: Alopecia, ↑ salivation, in both sexes; slightly ↓ ALT and AST activity and ↑ ALP in females.
|390: ↑ salivation, slightly higher urine volume in both sexes; ↑ liver weights in males; slightly ↓ RBC, ↑ MCV, MCH in males; alopecia, mild treatment related increases in K+ concentration, slightly ↓ ALT and AST activity and ↑ ALP in females.Additional findings: (1) higher kidney weights in males dosed with APAP or tramadol/APAP; (2) lower adrenal gland weights in males dosed with tramadol and/or APAP.
|ALP = alkaline phosphatase; ALT = alanine
aminotransferase; APAP = acetaminophen; AST = aspartate aminotransferase; K =
potassium; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; mo
= month; p.o. = oral; RBC = red blood cell; wk = week; ↑ = increased; ↓
Table 2.2: Multi-dose Toxicity Studies - Protocol
||No./Group/ Duration/ Route
||1) Vehicle Control: 0.5% Methocel (1 mL/kg/b.i.d.)
||Mortality, clinical observations, B.W., estimated food consumption, electrocardiographic/ ophthalmological/ physical examination, drug absorption, hematology. Coagulation, clinical chemistry, urinalysis, gross pathology, microscopic histopathology, organ weights.
p.o. (gavage) daily dose divided between two dosing sessions approx.5.5 h apart
|22.5/195: One male dog was sacrificed moribund on Day 32. ↓ activity, discoloured/food emesis, decreased/absent feces, discoloured urine, urine stained coat, jaundice, occult blood in urine, ↓ B.W. early in study related to ↓ food consumption, slightly to moderately ↓ RBC, Hb, and Hct counts, ↑ MCV, reticulocyte and platelet counts, slightly to moderately ↑ ALT, ALP, GGT, and urine bilirubin values, changes in liver, kidney, bone marrow, spleen, (males) and thymus (males) in both sexes; fine tremor, edema in males; hunched posture, emaciation, ataxia, pallor, ↑ total bilirubin, in females
22.5: ↓ B.W. early in study related to ↓ food consumption in both sexes.
|195: ↓ B.W. early in study related to ↓ food consumption, slightly to moderately ↓ RBC, Hb, and Hct counts, ↑ MCV, reticulocyte and platelet counts, ↑ urine bilirubin, changes in liver, kidney, bone marrow, spleen (males), and thymus (males) in both sexes; slightly ↑ ALP, GGT, and total bilirubin values in females
|2) Tramadol/ APAP: 7.5/65
|3) Tramadol: 22.5
|4) APAP: 195
|a Continuation of 4 week dog study results
ALP = alkaline phosphatase; ALT = alanine aminotransferase; APAP =
acetaminophen; AST = aspartate aminotransferase; K = potassium; MCH = mean
corpuscular hemoglobin; MCV = mean corpuscular volume; mo = month; p.o. = oral;
RBC = red blood cell; wk = week; ↑ = increased; ↓ = decreased; Hb
= Hemoglobin; Hct = Hematocrit; GGT = γ-glutamyl transferase
A slight, but statistically significant, increase in two
common murine tumors, pulmonary and hepatic, was observed in a mouse
carcinogenicity study, particularly in aged mice. Mice were dosed orally up to
30 mg/kg (90 mg/m² or 0.36 times the maximum daily human dosage of 246 mg/m²)
for approximately two years, although the study was not done with the Maximum
Tolerated Dose. This finding is not believed to suggest risk in humans. No such
finding occurred in a rat carcinogenicity study (dosing orally up to 30 mg/kg,
180 mg/m², or 0.73 times the maximum daily human dosage).
Tramadol was not mutagenic in the following assays: Ames
Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse
lymphoma assay (in the absence of metabolic activation), dominant lethal
mutation tests in mice, chromosome aberration test in Chinese hamsters, and
bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenic
results occurred in the presence of metabolic activation in the mouse lymphoma
assay and micronucleus test in rats. Overall, the weight of evidence from these
tests indicates that tramadol does not pose a genotoxic risk to humans.
No effects on fertility were observed for tramadol at
oral dose levels up to 50 mg/kg (300 mg/m²) in male rats and 75 mg/kg (450
mg/m²) in female rats. These dosages are 1.2 and 1.8 times the maximum daily
human dosage of 246 mg/m², respectively.
Tramadol has been shown to be embryotoxic and fetotoxic
in mice, (120 mg/kg or 360 mg/m²), rats ( ≥ 25
mg/kg or 150 mg/m²) and rabbits ( ≥ 75
mg/kg or 900 mg/m²) at maternally toxic dosages, but was not teratogenic at
these dose levels. These dosages on a mg/m² basis are 1.4, ≥ 0.6, and ≥ 3.6 times the maximum daily
human dosage (246 mg/m²) for mouse, rat and rabbit, respectively.
No drug-related teratogenic effects were observed in
progeny of mice (up to 140 mg/kg or 420 mg/m²), rats (up to 80 mg/kg or 480
mg/m²) or rabbits (up to 300 mg/kg or 3600 mg/m²) treated with tramadol by
various routes. Embryo and fetal toxicity consisted primarily of decreased
fetal weights, skeletal ossification and increased supernumerary ribs at
maternally toxic dose levels. Transient delays in developmental or behavioral
parameters were also seen in pups from rat dams allowed to deliver. Embryo and
fetal lethality were reported only in one rabbit study at 300 mg/kg (3600
mg/m²), a dose that would cause extreme maternal toxicity in the rabbit. The
dosages listed for mouse, rat and rabbit are 1.7, 1.9 and 14.6 times the
maximum daily human dosage (246 mg/m²), respectively.
Tramadol was evaluated in peri- and post-natal studies in
rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (300
mg/m² or 1.2 times the maximum daily human tramadol dosage) or greater had
decreased weights, and pup survival was decreased early in lactation at 80
mg/kg (480 mg/m² or 1.9 and higher the maximum daily human dose).
Table 2.3: Reproductive Study – Summary
|Rat Crl:CD® BR, VAF/Plus® 28/group
||p.o. (gavage) Gestation Days 6 through 17
||1) Vehicle Control: 0.5% Methocel (10 mL/kg/day)
2) Tramadol/APAP: 10/87 25/217 50/434
3) Tramadol: 50
|Maternal B.W.; food consumption, clinical signs, and post-mortem exam; number of corpora lutea, implantations, fetuses, resorptions, and pre- and postimplantation loss; fetal weight; fetal alterations
10/87: ↓ B.W. gain during treatment; ↑ B.W. gain during postdose period; ↓ food consumption during treatment
25/217: ↑ alopecia during and after treatment; B.W. loss at treatment initiation; ↓ B.W. gain during treatment; ↑ B.W. gain during postdose period; ↓ food consumption during treatment
50/434: ↑ alopecia during and after treatment; B.W. loss at treatment initiation; ↓ B.W. gain during treatment; ↑ B.W. gain during postdose period; ↓ food consumption during treatment; ↓ fetal B.W.; ↑ supernumerary ribs (attributed to maternal stress, not drug treatment)
50: ↑ alopecia during and after treatment; B.W. loss at treatment initiation; ↓ B.W. gain during treatment; ↑ B.W. gain during postdose period; ↓ food consumption during treatment
|APAP = acetaminophen; B.W. = body weight; NOAEL =
no-observed-adverse-effect level; p.o. = oral; ↑ = increased; ↓ =
The physical dependence liability potential associated
with the chronic use of tramadol has been evaluated in a number of animal studies,
including investigations in the mouse, rat, and monkey. A slight degree of
antinociceptive tolerance to tramadol evolved in the mouse studies, but there
was little or no indication of the development of physical dependence. No
evidence of dependence was observed in the rat study. However, in dogs addicted
to morphine, withdrawal symptoms were relieved by tramadol. In primate studies,
which evaluated the physical dependence and reinforcement properties of
tramadol, the physical dependence of the drug was deemed to be low.
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