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Effect of intravenous administration of tramadol hydrochloride on the minimum alveolar concentration of isoflurane in rabbits



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 baseline 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 (ISOMAC(T)) was measured. Results: Mean +/- SD ISOMAC and ISOMAC(T) 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 ISOMAC(T) determination varied widely (ranges, 181 to 636 ng/mL and 32 to 61 ng/mL, respectively). Intervals to determination of ISOMAC(T) 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 adverse 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.
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,
TN 37996.
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
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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
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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
tramadol, respectively.
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
temperature (°C)
*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,
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d. Normosol-R, Abbott Laboratories, North Chicago, Ill.
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g. Spectrum Chemical Manufacturing, New Brunswick, NJ.
h. SAS, version 9.1, SAS Institute Inc, Cary, NC.
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... In preclinical studies, a low dose of tramadol induced a slight increase in arterial blood pressure and heart rate in anaesthetized rabbits [61], dogs [62] and rats [63], possibly due to enhancement of the release of NE and/or 5-HT, which may result in peripheral vasoconstriction and/or heart stimulation [63]. While, at high doses, tramadol caused myocardial depression and hypotension in anaesthetized rabbits [64], dogs [65] and rats [66], possibly due to mu opioid receptor activation [66] and vascular relaxation as a result of nitric oxide production, and exerted a direct effect on smooth muscle [67]. These depressive effects are typically reported in human overdoses. ...
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1-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho, meta and para. Each of these has structural similarities with the analgesic tramadol and the dissociative anesthetic phencyclidine. In light of these structural analogies, and based on the fact that both tramadol and phencyclidine are substances that cause toxic effects in humans, the aim of this study was to investigate the in vitro and in vivo pharmacodynamic profile of these molecules, and to compare them with those caused by tramadol and phencyclidine. In vitro studies demonstrated that tramadol, ortho, meta and para were inactive at mu, kappa and delta opioid receptors. Systemic administration of the three stereoisomers impairs sensorimotor responses, modulates spontaneous motor activity, induces modest analgesia, and alters thermoregulation and cardiorespiratory responses in the mouse in some cases, with a similar profile to that of tramadol and phencyclidine. Naloxone partially prevents only the visual sensorimotor impairments caused by three stereoisomers, without preventing other effects. The present data show that 1-cyclohexyl-x-methoxybenzene derivatives cause pharmaco-toxicological effects by activating both opioid and non-opioid mechanisms and suggest that their use could potentially lead to abuse and bodily harm.
... However, a recent study showed that a dose of 11 mg kg e1 did not reach the human therapeutic plasma concentration and a higher dose might be necessary to provide analgesia in this species (Souza et al. 2008). In a study on six female NZW rabbits, 4.4 mg kg e1 tramadol administered IV while under anaesthesia using isoflurane vaporized in 100% oxygen caused a decrease in the heart rate and arterial blood pressure with a minimal change in the minimum alveolar concentration of isoflurane (Egger et al. 2009). ...
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Objective: To provide an overview of pain and analgesia in rabbits with the aim of developing a more accurate understanding of these topics. To illustrate and discuss the areas that have advanced in recent years and those that still require further research. Databases used: Three key subject resources were used: Web of Science, Medline and CAB Abstracts. Search terms were rabbits, lagomorphs, laboratory animals, pet, pain, surgical procedures, ovariohysterectomy, orchiectomy, castration, analgesia, opioids, and non-steroidal anti-inflammatory drugs. References from books and articles relevant to the topics were also included. Conclusions: Rabbit medicine has improved over the last 20 years, but the literature suggests that pain management in this species is still inadequate and veterinary professionals believe their knowledge of pain and analgesia in this species is limited. Assessment and quantification of pain in rabbits can be challenging in a clinical environment not only because, as a prey species, rabbits tend to hide signs of pain but also because there are no validated methods to assess pain, except the Rabbit Grimace Scale, which is based on only one rabbit breed. Current consensus is that perioperative multimodal analgesia is the best practice. However, it is not widely used in rabbits. In rabbits, analgesia protocols and dosages reported in the literature are often poorly researched and do not result in complete pain amelioration with the return of normal. The present literature on rabbit pain and analgesia presents gaps either due to unexplored areas or insufficient findings. Further research should focus on these areas with the aim of improving the welfare of rabbits within a veterinary clinic.
... 60 In the rabbit, plasma concentrations of tramadol were low after oral administration 61 and doses recommended for analgesic use (4.4 mg/kg intravenous [IV]) had minimal effects on isoflurane mac. 62 Until clinical efficacy is demonstrated in rabbits, it should be used only when other agents are considered unsuitable. ...
Managing pain effectively in any species is challenging, but small mammals present particular problems. Methods of pain assessment are still under development in these species, so the efficacy of analgesic therapy cannot be evaluated fully. Methods of assessing abdominal pain are established; however, applying these can be challenging. Alternative methods, using assessment of facial expression, may be more applicable to a range of painful procedures and across species. Multimodal and preventive analgesic strategies are most likely to be effective. Although data on analgesic dose rates are limited, sufficient information is available to enable analgesia to be provided safely.
... In our animal model we used rabbits, because they have been used in many pharmacologic and pharmacokinetic studies of tramadol [16,23,24]. Moreover, the pharmacokinetics, especially biotransformation of tramadol, is identical in men and rabbits [25]. ...
Background: The combined use of tramadol with selective serotonin and norepinephrine reuptake inhibitors e.g. venlafaxine may be associated with serotonin syndrome. No previous studies exist examining the influence of a weak CYP2D6 inhibitor venlafaxine on the pharmacokinetics of tramadol. Therefore, the aim of this study was to determine the effect of a single and chronic administration of venlafaxine on the pharmacokinetics of tramadol using a rabbit model. Methods: Adult New Zealand white rabbits of both sexes (n=21) were used. Animals received 100mg of tramadol per os (one slow release tablet) and 75mg of venlafaxine (one prolonged release capsule), and were divided into four groups: control group - a single dose of tramadol alone, 1day group - a single dose of tramadol and venlafaxine, 7 and 14days groups - seven and fourteen days administration of venlafaxine once daily plus a single dose of tramadol on the last day of the study. Results: Venlafaxine administration over a period of 7 and 14days resulted in faster elimination of tramadol compared to the control group: significantly higher values of k el, and lower values of t1/2kel and MRT for the 7 and 14days group were observed. Although no differences in bioavailability of tramadol were obtained. Conclusion: Using a rabbit model, there is no evidence that the combined administration of tramadol and venlafaxine may increase the plasma exposure of tramadol and therefore increase the risk of serotonin syndrome.
... Ketamine-butorphanol combination has been tried and the combination prized for its good visceral analgesia for which ketamine alone is weak (Sawyer et al., 1993;Lamont et al., 2000). However, the routine use of butorphanol is limited in most countries due to strict regulation and high cost (Ajadi et al., 2009;Egger et al., 2009). ...
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Objective: The aim of the present study is to explore the combination of dexmedetomidine (DXM) and tramadol (TMD) on sedative effect in patients with pregnancy-induced hypertension (PIH). Methods: A total of 356 patients with pregnancy-induced hypertension (PIH) were randomly divided into three groups: DXM, TMD and DXM + TMD groups. These patients were treated with different doses of DXM, TMD or combination of DXM and TMD by a patient-controlled intravenous injection device. The scores of static pain and dynamic pain, sedation degree, and adverse reaction were recorded. The plasma levels of inflammatory mediators IL-10 and C-reactive protein (CRP), and the serum level of p-p38-MAPK were evaluated. Results: It was found that administration with DXM 1.0 µg/kg/h + TMD 700 mg and DXM 2.0 µg/kg/h + TMD 600 mg result in stronger sedative effect than single administration with DXM or TMD. The mean arterial pressure (MAP) and heart rate (HR) of patients with PIH were decreased with the combinational treatment of DXM and TMD. Interestingly, the PIH patients injected with DXM 1.0 µg/kg/h + TMD 700 mg and DXM 2.0 µg/kg/h + TMD 600 mg showed stronger sedative effect. In addition, the plasma level of level of IL-10 was increased and CRP decreased. The serum level of p-p38/MAPK was decreased. Conclusion: Taken together, our study indicates that combination of DXM and TMD effectively lowers blood pressure and reduces inflammation through increasing the level of IL-10, reducing CRP and inhibiting p-p38/MAPK in patients with PIH. This study suggests that the combination of DXM and TMD could be an anesthetic choice in the management of PIH.
Objective To evaluate the efficacy and cardiopulmonary effects of ketamine–midazolam for chemical restraint, isoflurane anesthesia and tramadol or methadone as preventive analgesia in spotted pacas subjected to laparoscopy. Study design Prospective placebo-controlled blinded trial. Animals A total of eight captive female Cuniculus paca weighing 9.3 ± 0.9 kg. Methods Animals were anesthetized on three occasions with 15 day intervals. Manually restrained animals were administered midazolam (0.5 mg kg–1) and ketamine (25 mg kg–1) intramuscularly. Anesthesia was induced and maintained with isoflurane 30 minutes later. Tramadol (5 mg kg–1), methadone (0.5 mg kg–1) or saline (0.05 mL kg–1) were administered intramuscularly 15 minutes prior to laparoscopy. Heart rate (HR), respiratory rate, mean arterial pressure (MAP), peripheral oxygen saturation (SpO2), end-tidal CO2 partial pressure (Pe′CO2), end-tidal concentration of isoflurane (Fe′Iso), pH, PaO2, PaCO2, bicarbonate (HCO3⁻), anion gap (AG) and base excess (BE) were monitored after chemical restraint, anesthesia induction and at different laparoscopy stages. Postoperative pain was assessed by visual analog scale (VAS) for 24 hours. Variables were compared using anova or Friedman test (p < 0.05). Results Chemical restraint was effective in 92% of animals. Isoflurane anesthesia was effective; however, HR, MAP, pH and AG decreased, whereas Pe′CO2, PaO2, PaCO2, HCO3⁻ and BE increased. MAP was stable with tramadol and methadone treatments; HR, Fe′Iso and postoperative VAS decreased. VAS was lower for a longer time with methadone treatment; SpO2 and AG decreased, whereas Pe′CO2, PaCO2 and HCO3⁻ increased. Conclusions and clinical relevance Ketamine–midazolam provided satisfactory restraint. Isoflurane anesthesia for laparoscopy was effective but resulted in hypotension and respiratory acidosis. Tramadol and methadone reduced isoflurane requirements, provided postoperative analgesia and caused hypercapnia, with methadone causing severe respiratory depression. Thus, the anesthetic protocol is adequate for laparoscopy in Cuniculus paca; however, methadone should be avoided.
The efficacy and safety of anesthetic techniques in wildlife have increased greatly, but complications still exist. Some of these complications are predictable but others, such as hyperthermia, acidosis, and capture myopathy may result from the capture event. With anesthesia of domestic animals, it is often possible to titrate induction drugs to minimize adverse effects, but during anesthesia of wildlife, drugs are often delivered at the higher end of the dose range in an attempt to induce anesthesia rapidly. Opioids are administered during the perianesthetic period to provide sedation and preemptive analgesia prior to induction, and are part of balanced anesthesia, reducing minimal anesthetic concentration of the inhalant anesthetic. Both hydromorphone and oxymorphone 0.1‐0.3 mg/kg IM have been used by the authors in lagomorphs as primary analgesics for treatment of moderate to severe pain, but they are also useful for preemptive analgesia and postoperative pain.
In this chapter, the scientific literature regarding the alleviation of pain in small mammals, including pets and laboratory animals, is summarized. Alleviating pain in small mammals is an integral part of patient care. Essential to this end is the treatment of concurrent disease, attention to hydration status, minimization of stress, and provision of other types of supportive care. Because of advancements in laboratory animal medicine, some detailed scientific information is available regarding the effects of analgesics in small mammals. Most information is derived from studies in the rat, including pharmacokinetic (PK) and pharmacodynamic (PD) studies and standard pain models. More species-specific analgesia studies, better pain models, and better methods of assessing pain are needed for clinicians to provide species appropriate drugs, doses, and dosing intervals. Given the information currently available, the best approach is to individualize treatment and continually reassess the patient.
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Dez cães foram submetidos à substituição experimental do ligamento cruzado cranial e receberam tramadol (1mg/kg) pela via epidural lombo-sacra como técnica analgésica trans e pós-operatória. Avaliaram-se as funções cardiovascular e respiratória, o consumo de halotano e a analgesia pós-operatória. Observou-se estabilidade hemodinâmica e respiratória, analgesia adequada durante e após a cirurgia, bem como a possibilidade de redução no consumo de anestésico inalatório. Conclui-se que o tramadol epidural é efetivo como adjuvante anestésico em cães submetidos à substituição do ligamento cruzado cranial.
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A toracotomia é um procedimento cirúrgico que produz estímulo doloroso intenso. O objetivo deste estudo foi avaliar o efeito cardiovascular da associação tramadol, butorfanol e atropina na medicação pré-anestésica de gatos anestesiados com propofol e halotano. Doze animais, SRD, machos ou fêmeas, com peso médio de 2,7 ± 0,62kg receberam como medicação pré-anestésica (MPA), a associação de tramadol (2,0mg kg-1), butorfanol (0,4mg kg-1) e atropina (0,044mg kg-1), via intramuscular. Trinta minutos após MPA, a indução foi realizada com propofol (5,0mg kg-1) por via intravenosa. A manutenção anestésica foi obtida com halotano e oxigênio 100% sob ventilação artificial manual. Os gatos foram submetidos à toracotomia intercostal para implante de um segmento autólogo de pericárdio no diafragma. As variáveis avaliadas foram: freqüência cardíaca (bpm), saturação de oxigênio da hemoglobina (%), pressão arterial sistólica (mmHg) e vaporização de halotano (%). As variáveis foram mensuradas 20 minutos após a MPA (TMPA), 10 minutos após indução e a cada 10 minutos até o final do procedimento cirúrgico (T10 a T100).Os dados obtidos foram analisados estatisticamente através de ANOVA e teste de Bonferroni (p
It has been suggested previously that tramadol increases central nervous system activity and 'lightens' anaesthesia with volatile agents. We assessed the effects of tramadol on the minimum alveolar concentration (MAC) of isoflurane in 56 Wistar rats, instrumented chronically with an arterial and central venous catheter. The MAC of isoflurane was determined using the tail clamp method under three conditions: (1) after injection of saline (control); (2) after administration of tramadol 10 mg kg(-1) i.v.; and (3) after administration of morphine 1 mg kg(-1) i.v. The studies were repeated after treatment with the antagonists naloxone or yohimbine, Tramadol and morphine both reduced the MAC of isoflurane from mean 1.38 (SEM 0.05)% to 1.22 (0.06)% and 1.17 (0.06)%, respectively (P<0.05). Concomitant administration of yohimbine did not abolish this reduction in MAC. In contrast, after pretreatment with naloxone, tramadol (1.47 (0.04)%) or morphine (1.38 (0.07)%) did not cause a reduction in the MAC of isoflurane compared with controls (1.39 (0.06)%). We conclude that tramadol and morphine reduced the MAC of isoflurane to a small but significant extent For both drugs, this effect was related to their action at opioid receptors.
Tramadol is a synthetic, centrally acting analgesic agent with 2 distinct, synergistic mechanisms of action, acting as both a weak opioid agonist and an inhibitor of monoamine neurotransmitter reuptake. The 2 enantiomers of racemic tramadol function in a complementary manner to enhance the analgesic efficacy and improve the tolerability profile of tramadol. In several comparative, well designed studies, oral and parenteral tramadol effectively relieved moderate to severe postoperative pain associated with surgery. Its overall analgesic efficacy was similar to that of morphine or alfentanil and superior to that of pentazocine. Tramadol provided effective analgesia in children and in adults for both inpatient and day surgery. Tramadol was generally well tolerated in clinical trials. The most common adverse events (incidence of 1.6 to 6.1%) were nausea, dizziness, drowsiness, sweating, vomiting and dry mouth. Importantly, unlike other opioids, tramadol has no clinically relevant effects on respiratory or cardiovascular parameters at recommended doses in adults or children. Tramadol also has a low potential for abuse or dependence. Conclusions: The efficacy of tramadol for the management of moderate to severe postoperative pain has been demonstrated in both inpatients and day surgery patients. Most importantly, unlike other opioids, tramadol has no clinically relevant effects on respiratory or cardiovascular parameters. Tramadol may prove particularly useful in patients with poor cardiopulmonary function, including the elderly, the obese and smokers, in patients with impaired hepatic or renal function, and in patients in whom nonsteroidal anti-inflammatory drugs are not recommended or need to be used with caution. Parenteral or oral tramadol has proved to be an effective and well tolerated analgesic agent in the perioperative setting. Pharmacodynamic Profile Tramadol is a synthetic, centrally acting analgesic agent with 2 distinct, synergistic mechanisms of action. It is both a weak opioid agonist with selectivity for the μ-receptor and a weak inhibitor of the reuptake of noradrenaline (norepi-nephrine) and serotonin (5-hydroxytryptamine; 5-HT). This dual mechanism of action may be attributed to the 2 enantiomers of racemic tramadol. The (+)-enantiomer has a higher affinity for the μ-receptor and is a more effective inhibitor of 5-HT reuptake, whereas the (−)-enantiomer is a more effective inhibitor of noradrenaline reuptake and increases its release by autoreceptor activation. In healthy volunteers, oral tramadol 100mg provided superior analgesia compared with placebo. The peak analgesic effect occurred 1 to 4 hours after drug administration, with analgesia persisting for 3 to 6 hours. Tramadol is extensively metabolised in the liver, with the O-desmethyl (M1) metabolite of tramadol having an ≈200-fold higher affinity for opioid receptors than the parent drug. The O-desmethylation of tramadol is dependent on the cytochrome P450 enzyme CYP2D6 sparteine-oxygenase (deficient in ≈8% of Caucasians). Studies in healthy volunteers deficient in this enzyme (poor tramadol metabolisers) provided evidence for the possible contribution of the M1 metabolite to the analgesic effects of tramadol, with reduced analgesia in poor metabolisers compared with extensive metabolisers. The two enantiomers of tramadol act synergistically to provide analgesia. In both clinical and animal studies, the (+)-enantiomer provided similar analgesia to that of racemic tramadol and superior analgesia compared with the (−)-enantiomer. However, racemic tramadol showed an improved tolerability profile compared with the (+)-enantiomer in these studies. Several comparative, double-blind studies, in both adults and children, indicated that unlike other opioids (such as morphine, pethidine, oxycodone and nalbuphine) postoperative tramadol was not associated with clinically relevant respiratory depression. In addition, although one study demonstrated a statistically significant increase in both systolic and diastolic blood pressure, these were not considered clinically relevant. There were also no clinically relevant effects on heart rate with tramadol and it reduced shivering in postoperative patients. Pharmacokinetic Profile Tramadol is rapidly absorbed following single or multiple oral 100mg doses in adult volunteers. The mean absolute bioavailability of tramadol was ≈68% and increased to >90% with multiple doses and with intramuscular administration. Food intake had no clinically relevant effects on its bioavailability. In healthy adult volunteers administered a lOOmg single oral dose of tramadol, the maximum plasma concentration (Cmax) was 308 μg/L at 1.6 hours and with a single intramuscular dose was 193 μg/L attained at 0.75 hours. Cmax for the M1 metabolite after a single oral 100mg dose was 55 μg/L and was reached in ≈3 hours. Tramadol has a high tissue affinity, with an apparent volume of distribution after parenteral administration of ≈260L. Tramadol undergoes extensive first-pass metabolism in the liver, with ≈10 to 30% of an oral dose excreted unmetabolised in healthy volunteers. Both tramadol and its metabolites are primarily excreted via the kidneys (90%). The terminal elimination half-life (t½β) value for tramadol after a single oral (100mg) or parenteral (50mg) dose was ≈5.5 hours. t½β values for the M1 metabolite following oral single or multiple 100mg doses were 6.69 and 6.98 hours, respectively. t½β is increased ≈2-fold in patients with renal or hepatic impairment. Concomitant administration with carbamazepine, an inducer of hepatic enzymes, reduced the t½β of tramadol by ≈50%. Clinical Efficacy The analgesic efficacy of intravenous, intramuscular and oral tramadol has been established in several randomised, double-blind, parallel-group, comparative studies in adult patients with moderate to severe acute postoperative pain, and in a limited number of studies in paediatric patients. Parenteral or oral tramadol effectively relieved moderate to severe postoperative pain associated with several types of surgery (including abdominal, orthopaedic and cardiac surgery), reducing pain intensity by 46.8 to 57.6% within 4 to 6 hours (assessed using a 100mm or 100-point visual analogue scale). There is also a dose-dependent reduction in the severity and prevalence of postoperative shivering with tramadol treatment. The overall analgesic efficacy with tramadol was comparable to that achieved using equianalgesic doses of parenteral morphine or alfentanil. Intramuscular tramadol also provided similar efficacy compared with intramuscular ketorolac in postoperative patients. Concomitant use of intravenous tramadol 50 or 100mg with dipyrone 25 or 50mg (a nonsteroidal anti-inflammatory drug; NSAID) using patient controlled analgesia provided better analgesia than intravenous piritramide 0.75 or 1.5mg (an opioid agent). A continuous infusion of tramadol 10 mg/h with concomitant oral propacetamol 2g 4 times daily achieved superior analgesic efficacy compared with tramadol monotherapy. In children, intramuscular tramadol 2 mg/kg as required provided analgesia similar to that of intramuscular pethidine 1 mg/kg or nalbuphine 0.1 mg/kg following lower abdominal surgery. Furthermore, a single caudal injection of tramadol 2 mg/kg provided similar analgesia 3 to 12 hours postoperatively to that of caudal bupivacaine 2 mg/kg (a local anaesthetic) or tramadol 2 mg/kg with concomitant bupivacaine 2 mg/kg, although at the 3-hour time point bupivacaine provided superior analgesia. Tramadol provided effective postoperative pain relief in patients after day surgery (including groin and gynaecological surgery). The majority of these studies involved complex treatment regimens, with the concomitant administration (pre-, intra-and/or postoperatively) of several other analgesic agents (both opioids and NSAIDs). In a large multicentre study, perioperative intravenous and oral tramadol 100mg provided superior analgesic efficacy for the first 24 hours compared with a combination of intraoperative fentanyl 100μg and postoperative oral codeine 16mg/paracetamol 1000mg. Tramadol 100mg (administered intra-and post-operatively) also provided similar analgesic efficacy compared with naproxen sodium 500mg in 91 patients. Furthermore, intravenous tramadol 1.5 mg/kg, administered at the induction of anaesthesia, provided superior pain relief compared with intravenous ketorolac 10mg in 60 patients after laparoscopic surgery. Results from early studies investigating the intraoperative use of tramadol were controversial, with reports of increased recall of intraoperative events following its use. However, several recent studies using volatile or intravenous anaesthetic techniques, in both inpatients and day surgery patients, have not shown any clinically significant lightening of anaesthesia depth sufficient to cause accidental awareness while undergoing surgery. Tolerability In general, tramadol was well tolerated in clinical trials. The most common adverse events with single or multiple dose oral or parenteral administration of tramadol were nausea (6.1% of patients), dizziness (4.6), drowsiness (2.4), tiredness (2.3), sweating (1.9), vomiting (1.7) and dry mouth (1.6). Adverse events occurred in ≈15% of patients. Unlike other opioids, notably morphine, tramadol did not cause clinically relevant respiratory depression at recommended therapeutic doses. The incidence of seizures in patients receiving tramadol is estimated to be <1%. The risk of dependence or abuse with tramadol is low (0.7 to 1.5 cases of abuse per 100 000 individuals). The most common symptoms associated with an overdose were lethargy (30% of patients), nausea (14%), tachycardia (13%), agitation (10%), seizures (8%), coma (5%), hypertension (5%) and respiratory depression (2%). Naloxone treatment reversed sedation and apnoea in 50% of patients. No serious cardiotoxicity was observed with tramadol overdose. Dosage and Administration Tramadol is recommended for the management of acute or chronic moderate to severe pain. In adults and adolescents, the usual dosage is 50 to 100mg every 4 to 6 hours as required, with a maximum dosage of 400 mg/day. It may be administered orally or parenterally, although only an oral formulation is available in the US. Dosage adjustments may be required in patients with renal or hepatic impairment and in those >75 years of age. Recommendations for the use of tramadol in paediatric patients may vary between individual countries. For example, tramadol is not recommended for use in children <12 years of age in the UK or in those <16 years of age in the US, whereas in Germany some formulations are approved for use in children aged ≥1 year. Tramadol is not recommended in patients receiving monoamine oxidase inhibitors and is contraindicated in cases of acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs. The risk of seizure with tramadol administration may be enhanced in patients receiving monoamine oxidase inhibitors, neuroleptics, other drugs that reduce the seizure threshold, patients with epilepsy or patients otherwise at risk of seizure. Tramadol should be used with caution in patients with increased intracranial pressure and when treating patients with respiratory depression or if concomitant central nervous system depressant agents are being administered. When used with concomitant carbamazepine, dosages of tramadol may require adjustment.
Intercostal thoracotomy is a very painful procedure that deserves proper prevention and treatment. In this study we aimed to investigate the cardiovascular effect of the association of tramadol, butorphanol and atropine in the premedication of cats anesthetised with propofol and halothane. Twelve cats of mixed breed, female and male, with mean body weight of 2.7 ± 0.62kg were premedicated with 2.0mg kg-1 tramadol and 0.4mg kg-1 butorphanol and 0.044mg kg-1 atropine combined in the same syringe intramuscularly administered. After 30 minutes of premedication, anesthetic induction was obtained with 5.0mg kg-1 propofol intravenously. Anesthetic maintenance was done with halothane and 100% oxygen with manual artificial ventilation. All cats were submitted to lateral intercostal thoracotomy for an autogenic pericardium graft implantation in the diaphragm. Variables studied were heart rate (bpm), hemoglobin oxygen saturation (%), systolic arterial pressure (mmHg), and halothane vaporization (%). Time for data collection were 20 minutes after premedication (TMPA), 10 minutes after induction and every 10 minutes up to the end of the surgical procedure (T10 to T100). Data were analyzed with ANOVA and Bonferroni's test (p<0.05). Results demonstrated statistically significant reduction in arterial systolic pressure and heart rate, however, kept within the physiologic variation parameter to felines. Hemoglobin oxygen saturation was close to 100% in all times. Halothane vaporization decreased significantly from T30 to T100, staying for most of the surgical time below the minim alveolar concentration for cats. In conclusion the assotiation tramadol (2.0mg kg-1), butorphanol (0.4mg kg-1) and atropine (0.044mg kg-1) in the premedication of cats anesthetised with propofol (5.0mg kg-1) and halothane, intramuscularly, produces minimal changes cardiovasculares, don't produce sedation and promote analgesia satisfactory for lateral intercostal thoracotomy.
Non-steroidal anti-inflammatory drugs obviously act also on the central nervous system. We, therefore, studied the effect of diclofenac 3 mg/kg and ketoprofen 4 mg/kg on the minimum alveolar concentration (MAC) of halothane in 10 New Zealand White rabbits. After determination of halothane MAC, total doses of NSAIDs were administered intravenously as three subdoses: 12.5%, 37.5% and 50% of the total dose. Depth of anaesthesia did not increase significantly after the first two doses with either drug. With ketoprofen, halothane MAC increased after subdose 3 from 1.52 (SD 0.42) vol% to 1.9 (SD 0.36) vol% (p
To evaluate the effect of tramadol on sevoflurane minimum alveolar concentration (MAC(SEVO)) in dogs. It was hypothesized that tramadol would dose-dependently decrease MAC(SEVO). Randomized crossover experimental study. Six healthy, adult female mixed-breed dogs (24.2 +/- 2.6 kg). Each dog was studied on two occasions with a 7-day washout period. Anesthesia was induced using sevoflurane delivered via a mask. Baseline MAC (MAC(B)) was determined starting 45 minutes after tracheal intubation. A noxious stimulus (50 V, 50 Hz, 10 ms) was applied subcutaneously over the mid-humeral area. If purposeful movement occurred, the end-tidal sevoflurane was increased by 0.1%; otherwise, it was decreased by 0.1%, and the stimulus was re-applied after a 20-minute equilibration. After MAC(B) determination, dogs randomly received a tramadol loading dose of either 1.5 mg kg(-1) followed by a continuous rate infusion (CRI) of 1.3 mg kg(-1 )hour(-1) (T1) or 3 mg kg(-1) followed by a 2.6 mg kg(-1 )hour(-1) CRI (T2). Post-treatment MAC determination (MAC(T)) began 45 minutes after starting the CRI. Data were analyzed using a mixed model anova to determine the effect of treatment on percentage change in baseline MAC(SEVO) (p < 0.05). The MAC(B) values were 1.80 +/- 0.3 and 1.75 +/- 0.2 for T1 and T2, respectively, and did not differ significantly. MAC(T) decreased by 26 +/- 8% for T1 and 36 +/- 12% for T2. However, there was no statistically significant difference in the decrease between the two treatments. Tramadol significantly reduced MAC(SEVO) but this was not dose dependent at the doses studied.
To determine the pharmacokinetics of an orally administered dose of tramadol in domestic rabbits (Oryctolagus cuniculus). 6 healthy adult sexually intact female New Zealand White rabbits. Physical examinations and plasma biochemical analyses were performed to ensure rabbits were healthy prior to the experiment. Rabbits were anesthetized with isoflurane, and IV catheters were placed in a medial saphenous or jugular vein for collection of blood samples. One blood sample was collected before treatment with tramadol. Rabbits were allowed to recover from anesthesia a minimum of 1 hour before treatment. Then, tramadol (11 mg/kg, PO) was administered once, and blood samples were collected at various time points up to 360 minutes after administration. Blood samples were analyzed with high-performance liquid chromatography to determine plasma concentrations of tramadol and its major metabolite (O-desmethyltramadol). No adverse effects were detected after oral administration of tramadol to rabbits. Mean +/- SD half-life of tramadol after administration was 145.4 +/- 81.0 minutes; mean +/- SD maximum plasma concentration was 135.3 +/- 89.1 ng/mL. Although the dose of tramadol required to provide analgesia in rabbits is unknown, the dose administered in the study reported here did not reach a plasma concentration of tramadol or O-desmethyltramadol that would provide sufficient analgesia in humans for clinically acceptable periods. Many factors may influence absorption of orally administered tramadol in rabbits.