AJVR, Vol 70, No. 8, August 2009 945
Tramadol hydrochloride is an analgesic that has become
popular in veterinary medicine, although it has been li-
censed for use in humans in the United States since 1994.
The drug is inexpensive, has a low potential for abuse, and
is not controlled by the Drug Enforcement Administration,
making it appealing for use in animals; however, only the oral
formulation is available in the United States.
The analgesic effectiveness of tramadol results
from a complex interaction between opiate, A-adren-
ergic, and serotonergic receptor systems.1 Tramadol
provides analgesia by increasing release and decreasing
reuptake of serotonin and norepinephrine in the spinal
cord.3,4 The parent drug and one of its metabolites, M1
(O-desmethyltramadol), have opioid M-receptor agonist
effects,1 although the importance of these effects may
Effect of intravenous administration of tramadol
hydrochloride on the minimum alveolar
concentration of isoﬂurane in rabbits
Christine M. Egger, DVM, MVSc; Marcy J. Souza, DVM, MPH; Cheryl B. Greenacre, DVM;
Sherry K. Cox, PhD; Barton W. Rohrbach, VMD, MPH
Objective—To evaluate the effect of IV administration of tramadol hydrochloride on the
minimum alveolar concentration of isoﬂurane (ISOMAC) that prevented purposeful
movement of rabbits in response to a noxious stimulus.
Animals—Six 6- to 12-month-old female New Zealand White rabbits.
Procedures—Anesthesia was induced and maintained with isoﬂurane in oxygen. A base-
line ISOMAC was determined by clamping a pedal digit with sponge forceps until gross
purposeful movement was detected or a period of 60 seconds elapsed. Subsequently,
tramadol (4.4 mg/kg) was administered IV and the posttreatment ISOMAC (ISOMACT) was
Results—Mean ± SD ISOMAC and ISOMACT values were 2.33 ± 0.13% and 2.12 ± 0.17%,
respectively. The ISOMAC value decreased by 9 ± 4% after tramadol was administered.
Plasma tramadol and its major metabolite (M1) concentrations at the time of ISOMACT
determination varied widely (ranges, 181 to 636 ng/mL and 32 to 61 ng/mL, respectively).
Intervals to determination of ISOMACT and plasma tramadol and M1 concentrations were
not correlated with percentage change in the ISOMAC. Heart rate decreased signiﬁcantly
immediately after tramadol administration but by 10 minutes afterward was not different
from the pretreatment value. Systolic arterial blood pressure decreased to approximately
60 mm Hg for approximately 5 minutes in 3 rabbits after tramadol administration. No ad-
verse effects were detected.
Conclusions and Clinical Relevance—As administered, tramadol had a signiﬁcant but
clinically unimportant effect on the ISOMAC in rabbits. Higher doses of tramadol may
provide clinically important reductions but may result in a greater degree of cardiovascular
depression. (Am J Vet Res 2009;70:945–949)
vary among animal species. When tramadol is adminis-
tered to humans, there is a lower incidence of adverse
effects such as respiratory depression or constipation,
compared with the incidence of adverse effects with
other M-receptor agonist opioids.1,2,5
Tramadol is reportedly an effective postoperative
analgesic for abdominal and orthopedic surgery in dogs
and intercostal thoracotomy in cats.6–9 In horses, epi-
dural administration of tramadol provides long-term
analgesia with no adverse effects.10 Results of several
studies11–13 in rats suggest the drug is also an effective
analgesic in that species.
Received July 31, 2008.
Accepted October 29, 2008.
From the Departments of Small Animal Clinical Sciences (Egger,
Greenacre) and Comparative Medicine (Souza, Cox, Rohrbach),
College of Veterinary Medicine, University of Tennessee, Knoxville,
Supported by the Companion Animal Health Fund, College of Veteri-
nary Medicine, University of Tennessee and Carolyn Bond.
Presented in abstract form at the American College of Veterinary
Anesthesiologists Annual Meeting, Phoenix, September 2008.
Address correspondence to Dr. Egger.
ETISO End-tidal concentration of isoﬂurane
HPLC High-performance liquid chromatography
ISOMAC Minimum alveolar concentration of
ISOMACT Minimum alveolar concentration of iso-
ﬂurane after administration of tramadol
MAC Minimum alveolar concentration
PETCO2 End-tidal partial pressure of carbon
SAP Systolic arterial blood pressure
08-07-0248r.indd 945 7/22/2009 1:41:35 PM
946 AJVR, Vol 70, No. 8, August 2009
The MAC is deﬁned as the anesthetic concentra-
tion at which 50% of anesthetized subjects will respond
with gross purposeful movement to a noxious stimulus.
It is a measure of the potency of a volatile anesthetic
and can be used to compare the efﬁcacy of analgesic
and anesthetic drugs.14,15 In dogs16 and rats,17 admin-
istration of tramadol signiﬁcantly reduces the MAC
of isoﬂurane. Whereas SC administration of tramadol
does not appear to increase the pressure and thermal
thresholds in awake cats,18 oral administration reduces
the MAC of sevoﬂurane in the same species.19
To the authors’ knowledge, the analgesic or MAC-re-
ducing effects of tramadol in rabbits have not been report-
ed. The purpose of the study reported here was to evalu-
ate the effects of IV administration of tramadol on the
ISOMAC in rabbits. Speciﬁcally, it was hypothesized that
administration of tramadol would decrease the ISOMAC.
Materials and Methods
Animals—Six female New Zealand White rab-
bits (Oryctolagus cuniculus), aged 6 to 12 months and
weighing 4.0 to 4.6 kg, were included in the study. Rab-
bits were judged to be healthy on the basis of medi-
cal history, results of physical examination and plasma
biochemical analysis, serum total protein concentra-
tion, and Hct. Rabbits were housed together in pens
in a temperature-controlled environment (20°C) with
managed lighting (12 hours light and 12 hours dark).
All were fed a pelleted diet and timothy hay daily and
fresh greens 3 to 4 times/wk. Although access to wa-
ter was unrestricted at all times, food was withheld for
12 hours prior to anesthesia. The study protocol was
approved by the University of Tennessee Institutional
Animal Care and Use Committee.
Anesthesia and monitoring—Anesthesia was in-
duced with 4% isoﬂurane in 100% oxygen (2 L/min),
delivered via mask from a pediatric circle anesthetic sys-
tem. After rabbits were endotracheally intubated with a
cuffed 4-mm endotracheal tube, anesthesia was main-
tained with isoﬂurane in 100% oxygen (2 L/min) by
use of a small animal anesthesia machine.a Rabbits were
positioned in right lateral recumbency and ventilated
to prevent hypercarbia. The ETISO and PETCO2 were
monitored continually with an infrared sidestream gas
analyzer.b Gas samples were collected from the Y-piece
at a ﬂow rate of 50 mL/min. A 24-standard wire gauge
(1.5-cm) catheterc was placed in a cephalic or saphenous
vein for infusion of a balanced, isotonic crystalloid solu-
tiond (3 mL/kg/h). Body temperature was measured with
an esophageal thermometer,b and a circulating water heat-
ing blanket was used to maintain esophageal temperature
within the reference range (37.0° to 39.0°C). Systolic arte-
rial blood pressure was measured by placing a Doppler
transducer on the shaved palmar surface of a forelimb
over the common digital branch of the radial artery to
detect blood ﬂow and then placing a blood pressure cuff
(width, 40% to 50% of limb circumference) halfway be-
tween the elbow and the carpus, with the limb positioned
with the elbow and carpal joints in extension. Heart rate
and ECGb readings were monitored continuously. Arterial
hemoglobin saturation was also monitored continuously
with a pulse oximeter.b
MAC determination—Approximately 45 minutes
after induction of anesthesia, with the ETISO held
constant at 2.0% for at least 20 minutes, the baseline
ISOMAC was determined by use of a bracketing tech-
nique for rabbits.20 The noxious stimulus consisted of
clamping a pedal digit with 24-cm sponge forceps,f with
protective plastic tubing on each forceps jaw. The for-
ceps was closed to the ﬁrst notch until gross purpose-
ful movement (deﬁned as gross movement of the head
or extremities) was detected or a period of 60 seconds
elapsed, whichever happened ﬁrst. Coughing, straining,
stiffening, and chewing were not considered purposeful
movement. When purposeful movement was detected,
the ETISO was increased by 0.1%; otherwise, it was de-
creased by 0.1%, and the stimulus was reapplied after a
20-minute equilibration period. The order in which the
limbs and digits were clamped was randomized.
The ISOMAC was deﬁned as the mean of the ETISO
values at which movement was and was not detected.
The ISOMAC determination was performed in dupli-
cate, and the mean value was taken as the ISOMAC;
however, when the difference between the 2 ISOMAC
values was > 10%, a third ISOMAC was determined and
averaged with the ﬁrst 2 to attain the ISOMAC.
A 5% tramadol hydrochloride solution was pre-
pared from tramadol hydrochloride powderg according
to a reported method.21 Potency was conﬁrmed with
reversed-phase HPLC, as described elsewhere.22 After
the ISOMAC was determined, tramadol (4.4 mg/kg)
made up to a total volume of 1 mL with saline (0.9%
NaCl) solution was administered IV over 60 seconds.
Determination of ISOMACT began 20 minutes after ad-
ministration of tramadol, with the ETISO held constant
at ISOMAC for at least 20 minutes. The ISOMACT was
determined as for the ISOMAC. After the ISOMACT was
determined, rabbits were allowed to recover from anesthe-
sia. Interval from termination of isoﬂurane anesthesia to
extubation (minutes) was recorded for each rabbit.
Drug analysis—For determination of plasma tra-
madol and M1 concentrations, a blood sample (approx
4 mL) was collected from a jugular vein immediately af-
ter the ISOMACT was determined. Blood samples were
placed in lithium heparin tubes, and plasma was har-
vested and stored at –80°C before analysis.
Measurement of plasma tramadol and M1 concen-
trations was performed by means of reversed-phase
HPLC with ﬂuorescence detection as described else-
where.22 Intra-assay variability ranged from 0.3% to
11.2% for M1 and 0.2% to 3.9% for tramadol. Inter-
assay variability ranged from 2.8% to 8.4% for M1 and
1.9% to 9.5% for tramadol.
Statistical analysis—All analyses were performed
with commercial software.h Percentage change in
MAC was calculated by use of the following equation:
(ISOMACT – ISOMAC)/ISOMAC X 100. Values for in-
terval to ISOMAC determination, ISOMAC, interval to
ISOMACT determination, ISOMACT, percentage change
in ISOMAC, tramadol concentration, and M1 concen-
tration are reported as mean ± SD. A paired t test was
used to evaluate the percentage difference between the
ISOMAC and ISOMACT. A mixed-model repeated-mea-
sures ANOVA was used to test for signiﬁcant changes in
08-07-0248r.indd 946 7/22/2009 1:41:35 PM
AJVR, Vol 70, No. 8, August 2009 947
heart rate, blood pressure, and esophageal temperature
over time. The variable rabbit was included in the model
as a random effect. Results of the ANOVA are reported
as the least-squares mean ± SEM. Interval to extuba-
tion is reported as mean ± SD. Correlations for interval
to ISOMACT determination, tramadol concentration,
and M1 concentration with percentage change in the
ISOMAC were analyzed by calculation of the Pearson
product-moment correlation. Values of P < 0.05 were
considered signiﬁcant for all analyses.
All 6 rabbits completed the experiment to evaluate
the effect of tramadol administration on the ISOMAC.
No adverse effects of anesthesia or tramadol adminis-
tration were detected in rabbits at any time.
Mean ± SD values for the ISOMAC and ISOMACT
were 2.33 ± 0.13% and 2.12 ± 0.17%, respectively.
The ISOMAC decreased signiﬁcantly by 9 ± 4% after
administration of tramadol (P = 0.004). The inter-
val from induction of anesthesia to determination of
the ISOMAC was 99 ± 15 minutes, and the interval
from determination of the ISOMAC to determination
of the ISOMACT was 65 ± 6 minutes. The overall in-
terval to ISOMACT determination ranged from 208
to 250 minutes.
The mean plasma tramadol concentration at the
time of ISOMACT determination was 346 ± 152 ng/mL
(range, 181 to 636 ng/mL), and that for plasma M1
concentration was 41 ± 12 ng/mL (range, 32 to 61 ng/
mL). Intervals to determination of ISOMACT, plasma
tramadol concentration, and plasma M1 concentration
were not correlated with the percentage change in the
ISOMAC (r = 0.16 [P = 0.76], r = 0.19 [P = 0.72], and
r = 0.56 [P = 0.23], respectively).
Statistical analyses revealed that heart rate decreased
signiﬁcantly (P = 0.002) immediately after tramadol ad-
ministration but was not signiﬁcantly different from the
pretreatment value by 10 minutes after administration
(Table 1). The SAP decreased to approximately 60 mm
Hg for approximately 5 minutes in 3 rabbits after tra-
madol administration, but the overall change in value
was not signiﬁcant. Esophageal temperature did not
change after tramadol administration. The PETCO2 was
30 to 32 mm Hg and hemoglobin saturation was > 96%
at all times. Mean ± SD interval to extubation was 6.7 ±
3.5 minutes (range, 3 to 13 minutes) after discontinua-
tion of isoﬂurane.
The HPLC analysis revealed that the potency of the
tramadol solution was 98%. Mean percentage recover-
ies from plasma samples were 93% and 84% for M1 and
The baseline ISOMAC (2.33 ± 0.13%) in the study
reported here was slightly higher than the value (2.05
± 0.18%) reported for New Zealand White rabbits in
a study23 in which a tail-clamping technique was used
as the noxious stimulus for MAC determination. Other
studies involving New Zealand White rabbits in which
the digit-clamping technique was used as the noxious
stimulus revealed ISOMAC values of 2.08 ± 0.02%20
and 2.49 ± 0.07%.24 Interindividual and intraindividual
variations in MAC values are typically < 20% and 10%,
respectively14,; however, the MAC of an inhalation an-
esthetic can differ substantially among animals of the
same species and even among strains of the same spe-
cies.20,25 Variation within our study was minimized by
having 1 observer of purposeful movement (CME) and
maintaining esophageal temperature, hemoglobin satu-
ration, PETCO2, and arterial blood pressure within ranges
that do not affect the MAC.14,26 The rabbits were slightly
hypocarbic during MAC determination, but this degree
of hypocarbia does not affect the MAC. The transient
hypotension (SAP, approx 60 mm Hg) that was evident
in 3 rabbits immediately after tramadol administration
was unlikely to have affected the MAC. Within a spe-
cies, the variability of the MAC is not inﬂuenced by
duration of anesthesia, an SAP > 50 mm Hg, or PaCO2
values between 10 and 90 mm Hg.14,26
In the rabbits of the study reported here, IV admin-
istration of tramadol at a dose of 4.4 mg/kg resulted in
mean plasma tramadol and M1 concentrations of 346
ng/mL and 41 ng/mL, respectively, and a reduction in
ISOMAC of 9%, compared with the value before tra-
madol administration. This ISOMAC reduction was not
correlated with plasma tramadol or M1 concentrations.
In rats, IV administration of tramadol (10 mg/kg) sig-
niﬁcantly reduces the MAC of isoﬂurane by 16%,17 and
in cats, oral administration of tramadol (8.6 to 11.6
mg/kg) reduces the MAC of sevoﬂurane by 40%.19 The
studies17,19 in rats and cats involved the tail-clamping tech-
nique as the noxious stimulus, but plasma tramadol and
M1 concentrations were not reported. In another study16
involving dogs, when tramadol was administered via a
constant rate IV infusion of 1.3 mg/kg/h or 2.6 mg/kg/h,
the resulting plasma concentrations of tramadol (2,201
± 1,552 ng/mL and 4,446 ± 3,875 ng/mL, respectively)
and M1 (57 ± 18 ng/mL and 86 ± 20 ng/mL, respectively)
caused a reduction in ISOMAC of 26% to 36% when a nox-
ious electrical stimulus was used, although this change was
not correlated with plasma tramadol or M1 concentration.
In the present study, the variability in plasma tramadol and
M1 concentrations at the time of ISOMACT determina-
tion and lack of correlation with percentage reduction in
ISOMAC could have been attributable to the effects of an-
esthesia on drug distribution, clearance, and elimination;
individual and species variability in pharmacokinetic and
pharmacodynamic responses to tramadol; and variability
in the interval to ISOMACT determination in the rabbits.
Administration of a constant rate infusion of tramadol fol-
lowing the bolus injection may have reduced some of this
Before Immediately 10 minutes
Variable tramadol after tramadol after tramadol
Heart rate (beats/min) 224 10 188 10* 196 10
SAP (mm Hg) 93 8 87 10 83 10
Esophageal 38 1 38 1 38 1
*Value is signiﬁcantly (P = 0.004) different from value obtained
before tramadol was administered.
Table 1—Least-squares mean ± SEM values of physiologic vari-
ables in 6 laboratory rabbits before and after IV administration of
tramadol hydrochloride (4.4 mg/kg).
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948 AJVR, Vol 70, No. 8, August 2009
Few studies have been conducted to investigate
the MAC-reducing effects of analgesics in rabbits. In 1
study27 in which the effects of diclofenac and ketopro-
fen in rabbits were evaluated, the MAC of halothane
increased after drug administration. In another study,24
administration of butorphanol alone or with meloxi-
cam signiﬁcantly reduced the ISOMAC in rabbits by
7.6% to 12.4%.24 The MAC-reducing effects of tramadol
could be attributable to activation of opioid, serotoner-
gic, or A-adrenergic receptors by the parent drug or any
of its metabolites. Activation of opioid, serotonergic,
and noradrenergic receptors reportedly mediates anal-
gesia in humans,1 dogs,20,28 and rats.29–31 Interestingly, in
a model of peripheral neuropathy in rats,11 the analge-
sic effects of tramadol appeared to change from opioid
receptor mediated to A-adrenergic receptor mediated
over time. Opioid receptor activation is an important
mechanism for the reduction in MAC achieved with
tramadol in rats and cats because naloxone blocks its
MAC-reducing effect in those species.17,19 The M1 me-
tabolite reportedly has a considerable analgesic effect in
humans attributable to its action at opioid receptors,2
but there are several tramadol metabolites that could be
responsible for its ISOMAC-lowering effects.31,32 Mea-
surement of the reduction in ISOMAC achieved with
tramadol after treatment with opioid, A-adrenergic, or
serotonin receptor antagonists would help to determine
the mechanism of the ISOMAC reduction in rabbits.
Although pharmacokinetic characteristics and
antinociceptive properties of tramadol have now been
reported for cats and dogs,6–9,18,19,21,33 minimum effec-
tive doses for analgesia have not been determined. The
pharmacokinetic and pharmacodynamic characteristics
of tramadol when administered IV have not been evalu-
ated in rabbits, and the dose used in the present study
was chosen on the basis of a published dose of tramadol
that appears safe in awake dogs.21 Although there were
clinically unimportant decreases in the ISOMAC in our
study, there were signiﬁcant decreases in heart rate and,
although transient, a signiﬁcant decrease in SAP in 3 of
6 rabbits after tramadol was administered over 1 min-
ute, indicating that higher doses of tramadol may cause
more signiﬁcant cardiovascular depression. Slower IV
administration of tramadol, over 5 minutes rather than
over 1 minute, might have reduced the adverse cardio-
vascular effects detected in the rabbits. Besides provid-
ing preemptive analgesia, preoperative administration
of analgesics often has a MAC-sparing effect, allowing
lower concentrations of volatile anesthetic to be used
to achieve surgical anesthesia, resulting in an improve-
ment in cardiopulmonary variables. Even a modest de-
crease in the ISOMAC can result in improved cardiac
output and tissue perfusion.34–36
a. North American Drager, Telford, Pa.
b. Patient monitor, model 1100, Criticare Systems Inc, Waukesha,
c. Monoject veterinary IV catheter, Tyco/Healthcare-Kendall, Mans-
d. Normosol-R, Abbott Laboratories, North Chicago, Ill.
e. Model 811, Parks Medical Electronics Inc, Beaverton, Ore.
f. Robbins Instruments Inc, Chatham, NJ.
g. Spectrum Chemical Manufacturing, New Brunswick, NJ.
h. SAS, version 9.1, SAS Institute Inc, Cary, NC.
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