530
Med. Weter. 2014, 70 (9)
Praca oryginalna
Original paper
PK/PD evaluations of the novel atypical opioid
tapentadol in red-eared slider turtles*)
MARIO GIORGI, VIRGINIA DE VITO, HELEN OWEN*,
MARIA PIERA DEMONTIS**, MARIA VITTORIA VARONI**
Department of Veterinary Sciences, University of Pisa, Via Livornese (lato monte) 1, San Piero a Grado, Pisa, Italy
*School of Veterinary Sciences, University of Queensland, Gatton, Brisbane, Australia
**Department of Dipartimento di Medicina Veterinaria, Università di Sassari, Sassari, Italy
Received 27.05.2014
Accepted 20.06.2014
Giorgi M., De Vito V., Owen H., Demontis M. P., Varoni M. V.
PK/PD evaluations of the novel atypical opioid tapentadol in red-eared slider turtles
Summary
The aim of this study was to evaluate the pharmacokinetics and pharmacodynamics of tapentadol (TAP) in
red-eared slider turtles after a single intramuscular injection of 5 mg/kg. Turtles (n = 9) were randomly assigned
to two treatment groups, according to an open, single-dose, single-treatment, unpaired, two-period crossover
design. Group A (n = 5) received a single IM dose of TAP (5 mg/mL) at 5 mg/kg. Group B (n = 4) received a single
IM injection of saline (equivalent to the opioid in volume). After a one-month wash-out period, the groups were
rotated, and the experiment was repeated. TAP plasma concentrations were evaluated by a validated HPLC-FL
method, while an infrared thermal stimulus was applied to the plantar surface of the turtles’ hind limbs to
evaluate the thermal withdrawal latency (TWL). TAP plasma concentrations were detectable between 1 and
24 h (2141 – 42 ng/mL, respectively). The TAP-treated group showed a dramatic increase in TWL one hour
after drug administration (15.31 ± 4.73 s). Subsequently, TWL decreased with time. Significant differences
between the treatment and control groups were apparent up to 10 h following treatment. A linear relationship
(r2 = 0.98) between the TAP plasma concentration and effect was found. Given these qualities, TAP appears to
be an attractive option for antinociception in turtles because of its rapid onset and acceptable duration of effect.
Keywords: opioids, pharmacokinetics, tapentadol, thermal withdrawal latency, turtles
Veterinary medicine faces the unique challenge of
having to treat many animal species, including mammals, birds, reptiles and fish. The main challenge for
veterinarians is not just to select a drug, but also to
determine, a rational dosing regimen for the selected
agent. Determining this is a long and complicated
endeavour because of differences in the expression of
enzymes, receptors and signal transduction molecules
between species (9). Both inter- and intra-species
differences in drug response can be accounted for as
either being due to variations in drug pharmacokinetics
(PK) or drug pharmacodynamics (PD), the magnitude
of which varies from drug to drug (26). Hence, PK/
PD studies are critical when a drug is applied to a new
animal species.
Nowadays we are far more cognisant of pain in
animals. Animal species that one decade ago were
considered wild animals are now pets, and their owners
*) This study was equally supported by a grant from the University of Pisa
(ex 60%) and the University of Sassari. No external funding supported the preparation of manuscript.
expect an adequate level of care to be provided. This
change in attitude has resulted in a push for the development of more effective and innovative veterinary
therapies (14, 16, 18). With the increasing popularity of
herpetoculture, there is more information on associated
diseases, and treatment options are being investigated,
starting with the classes of drugs that have proven
efficacy in other species. This research has emphasized the inaccuracies that result when the effects and
consequences of drugs for the species of interest are
predicted by extrapolation from other species that are
markedly different in their physiology (21).
Opioids are considered the most effective drugs
for controlling pain in mammals (4). Veterinary clinicians have a number of options: the classical µ-opioid
receptor (MOR) agonists (eg, morphine), the partial
MOR agonists (eg, buprenorphine), the mixed opioid
κ-receptor agonists MOR-antagonists (eg, butorphanol), and the atypical opioids (eg, tramadol).
In reptiles, opioid drug administration has yielded
unexpected results with respect to analgesia. Butor-
Med. Weter. 2014, 70 (9)
phanol does not change thermal withdrawal latencies
(TWL) in red-eared slider turtles (30) and bearded
dragons (28) or thermal thresholds in green iguanas
(6). Buprenorphine did not alter responses to a noxious
electrical stimulus administered to green iguanas (19),
and did not provide an analgesic effect in red-eared
slider turtles exposed to a noxious thermal stimulus
(23). Morphine increased TWL in turtles (30) and
bearded dragons (28) at doses ranging between 1.5
and 20 mg/kg, but was ineffective at doses up to 40
mg/kg in corn snakes (28). In contrast, the atypical
opioid tramadol, whose use in mammals has been
widely questioned (10, 15, 17), has proven to be effective (10 mg/kg SC) for at least 48 hours following
administration in turtles (1). Tramadol produces MOR
activation (6000 times lower than morphine), as well
as the inhibition of serotonin (5HT) and noradrenalin
(NA) reuptake. It has been shown that the analgesic
efficacy of tramadol is mediated by the M1 metabolite
(200-300 times more potent on MOR activation than
the parental compound) (25).
Tapentadol (TAP) is a novel atypical opioid drug labelled for human use. Because of its unique mechanism
of action, it has been proposed as the first representative of a new pharmacological class of centrally acting
analgesics: the MOR agonist, NA reuptake inhibitors
(8). Interestingly, even though its MOR affinity is 50
times lower than that of morphine, it is only 2-3 times
lower after systemic administration. This finding, consistent across different pain relief evaluation models,
may be due to a better brain penetration of TAP, but it
also suggests that the NA reuptake-inhibitory property
contributes to a more potent analgesia that would be
expected solely from its MOR agonism (34). Given the
moderate affinity of TAP at the MOR and the opioidsparing effect of TAP’s NRI component, it seems logical that TAP would produce fewer opioid-related side
effects than classical MOR agonists, such as morphine.
Hence, the aim of this study is to assess the PK/PD of
TAP in red-eared slider turtles after a single intramuscular injection of TAP.
Material and methods
Material. TAP hydrochloride was supplied as a pure
powder (> 99.8% purity; Bepharm). M1, the metabolite of
tramadol, was used as an internal standard and supplied as
pure powder (> 99.8% purity; LCG Promochem). Additionally, high-performance liquid chromatography (HPLC)
grade acetonitrile (ACN), dichloromethane (CH2Cl2) and
diethyl ether (Et2O) were used in the assays (Scharlau).
Acetic acid and sodium tetraborate decahydrate (BDH)
were of analytical grade. HPLC grade water was obtained
by distilling deionised water produced by a Milli-Q Millipore water system (EDM Millipore). All the other reagents
and materials were of analytical grade and supplied from
commercial sources.
Animals and experimental design. Nine turtles (Trachemys scripta elegant) of undetermined sex, with body
weights ranging from 0.8 to 1.5 kg (mean 1.1 kg), sup-
531
plied by a local park, were used for the study. Turtles were
acclimated for a 2-week period prior to the study. Turtles
were judged to be in good health on the basis of physical
examination at the time of acquisition and at the start of
the study, and through daily observation of behaviour and
appetite. These observations were made by specialized veterinary personnel. Turtles were divided into groups A or B,
and each group was placed in a separate 300 L plastic pool,
with a water depth of 20 cm, water temperature of 27°C,
and custom-built mechanical and biological filtration. A dry
basking area was heated to 30°C with an infrared lamp. The
ambient temperature in the room varied from 25 to 26°C
(electronic temperature sensors assured constant temperature in the water and the basking area). Turtles were fed
a floating pelleted diet three times a week. Animal care
and handling were performed according to the provision of
the EC council Directive 86/609 EEC and also according
to Institutional Animal Care and Use directives issued by
the Animal Welfare Committee of the University of Pisa,
which approved the study protocol.
Turtles were randomly assigned to two treatment groups,
by means of slips of paper marked with the numbers 1-9,
selected blind from a box. An open, single-dose, singletreatment, unpaired, two-period crossover design was used.
Each turtle in group A (n = 5) received a single IM dose of
TAP at 5 mg/kg (5 mg/mL). This dose was selected on the
basis of previous information describing the effectiveness
of TAP in rabbits (13). Group B (n = 4) received a single IM
injection of saline (equivalent to TAP solution in volume).
The injectable TAP solutions were prepared by dissolving
pure TAP hydrochloride powder in saline to produce a 5 mg/
mL solution, which was then passed through a 0.45 µm filter
under sterile conditions. A one-month wash-out period was
observed to ensure a complete metabolism and excretion
of TAP. After this period, the groups were rotated, and the
experiment was repeated (second period). By the end of
the study, each turtle had received both the saline and TAP
treatments. Blood samples (1 mL) were collected from the
dorsal cervical, subcarapacial venipuncture site at 0, 1, 2,
4, 6, 10, and 24 h after TAP administration and placed in
collection tubes containing lithium heparin. Specimens were
centrifuged at 1,000 g within 30 min of collection, and the
harvested plasma was stored at –70°C and used within 15
days of collection.
Thermal analgesia experiments. Just before each blood
collection, analgesia experiments were conducted by applying infrared thermal stimuli to the plantar surface of the
turtles’ hind limbs with a plantar analgesia device (Hargreaves’s instrument, model 37370, Ugo Basile) according
to previously described methods (1, 28, 30) with slight
modifications. Turtles were gently dried with a smooth
cloth and individually placed in clear, plastic boxes (300,
200, 150 mm, W, L, H, respectively, with a 1 mm thickness) on a clear acrylic surface. The room temperature was
set at 25-26°C. An infrared radiation source was activated
(70°C) directly below the surface on which the turtle rested
the plantar surface of either hind limb. Hind limb TWLs
were measured by a motion-sensitive timer, which stopped
automatically when the hind limb was removed from the
noxious stimulus. The increasing temperature caused the
turtle to withdraw the limb, and the time to withdrawal was
532
Med. Weter. 2014, 70 (9)
Ttest – Tcon
%MPR =
× 100%
Tcut – Tcon
where Ttest represents TWL value after injection of TAP,
Tcon is TWL value after injection of saline (control) and
Tcut is the cut-off time (22.5 s).
High performance liquid chromatography (HPLC).
Based on a previously published HPLC technique (12), the
analytical method was re-validated for turtle plasma samples. The intra- and inter-day repeatability was measured as
a coefficient of variation and was lower than 10.2%, whereas
accuracy, measured as closeness to the concentration added
on the same replicates, was lower than 5.9%. The limits of
detection (LOD) and quantification (LOQ) were 0.5 ng/mL
and 2 ng/mL, respectively. The chromatographic separation assay was performed with a SunFire C18 analytical
column (150 × 4.6 mm inner diameter, 5 µm particle size,
Water), maintained at 25°C. The mobile phase consisted of
ACN (A): 0.2% acetic acid (B) at a flow rate of 1 mL/min.
Excitation and emission wavelengths were set at 273 and
298 nm, respectively. The linear gradient elution system
was performed as follows: 5-95% B (0-20 min), 95-5% B
(20-25 min) and 5% B isocratically (25-32 min).
Preparation of plasma samples. Briefly, 50 µL of IS solution (0.5 µg/mL) and 0.2 mL 2 mM borate buffer, adjusted
to pH 9.3, were added to a 1.5 mL polypropylene snap cap
tube (Sarsedt) containing 0.5 mL of plasma. After vortexmixing, 0.4 mL of extraction solvent (Et2O : CH2Cl2 7 : 3
v/v) was added. The tube was then placed in a vortex for
30 s, shaken for 5 min, and then centrifuged for 10 min at
15,625 g. The organic layer (0.3 mL) was then transferred
into a clean 1.5 mL polypropylene snap cap conical tube,
placed in a vortex and then shaken with 0.2 mL of backextraction solvent (0.05 M HCl : ACN 1 : 1 v/v) for 5 min,
before being centrifuged for 10 min at 15,625 g. The aqueous phase (50 µL) was injected into the HPLC system.
Pharmacokinetic evaluation. The pharmacokinetic calculations were carried out by WinNonLin v 5.3 (Pharsight).
The maximum concentration (Cmax) of TAP in plasma and
the time required to reach Cmax (Tmax) were predicted from
the data. The terminal rate constant (λ) was determined
from the slope of the terminal phase of the plasma concentration curve that included a minimum of three points. The
half-life of the terminal phase (T1/2 λz) was calculated with
T1/2 = 0.693⁄λ. The area under the concentration vs. time
curve (AUC0-∞) was calculated using the linear trapezoidal
rule. Changes in the plasma concentration of TAP were
evaluated by the standard non-compartmental analysis, and
the relative pharmacokinetic parameters were determined
using standard non-compartmental equations (7).
Statistical analysis. The Kolmogorov-Smirnov test was
applied to verify data distribution. Pharmacodynamic data
were evaluated by Student’s t test to determine statistically
significant differences. The TAP plasma concentrations and
the pharmacokinetic and pharmacodynamic parameters are
presented as means ± standard error mean. All analyses
were performed by GraphPad InStat (GraphPad Software).
In all experiments, differences were considered significant
if P < 0.05.
Results and discussion
One hour after the TAP IM administration, some signs
of sedation were noticed in the animals. The turtles did
not appear to be responsive to external stimuli (eg, drying process) and had flaccid limbs and necks compared
to the control animals. This effect was transient and
was almost completely absent at 2 h following drug
administration. Unfortunately, the respiratory rate was
not evaluated because of the lack of a breathing chamber
described earlier (30).
Tab. 1. Pharmacokinetic parameters after IM injection of
TAP at 5 mg/kg in turtles (n = 9)
Pharmacokinetic
parameters
Unit
Mean ± SE
λz
1/h
0.29 ± 0.19
T1/2λz
h
5.22 ± 2.98
Tmax
h
1.42 ± 0.39
Cmax
ng/mL
1899 ± 242_
AUCo-∞
h ng/mL
8987 ± 4879
VZ/F
L/kg
4.65 ± 1.34
CL/F
L/min/kg
0.92 ± 0.66
MRT
h
5.74 ± 1.39
Explanations: λz – first-order rate constant; T1/2λz – half-life of
the terminal portion of the curve; Tmax – time at the maximum
drug concentration; Cmax – maximum drug plasma concentration;
AUC0−∞ – area under the curve from 0 to infinity; VZ/F – apparent
volume of distribution; Cl/F – apparent total body clearance;
MRT – mean residence time
Plasma concentration (ng/mL)
automatically measured. A maximum exposure duration of
22.5 s (cut-off time) was allowed to prevent tissue damage.
At each time point, the TWL was measured in both hind
limbs. When the difference between the two TWL values
was > 2 s, a third measurement was obtained. The observer
in the analgesia experiments was blinded to treatments received. TWLs were measured before drug administration
(baseline) and at the time of blood collection.
The thermal antinociceptive effect was expressed as
percentage of Maximum Possible Response (% MPR) (20),
which was calculated as:
2000
1500
1000
500
Human MEC 148 ng/mL
†
0
0
10
20
Time (h)
Fig. 1. Mean plasma concentrations of TAP (± SE) vs. time
curve after IM administration in turtles (n = 9). The dashed
line shows the Minimal Effective Concentration (MEC) of
TAP reported for humans (148 ng/mL). † Data obtained in
seven turtles
Med. Weter. 2014, 70 (9)
533
Pharmacokinetics (PK). The average TAP plasma
concentration vs. time curve after IM administration
of 5 mg/kg in turtles is presented in Fig. 1. The absolute plasma concentrations of TAP were in the range
of 42-2141 ng/mL and detectable up to 24 h, except
in two subjects. The corresponding pharmacokinetic
parameters are shown in Table 1. The theoretical peak
plasma drug concentration (Cmax) of 1899 ± 242 ng/mL
was observed at 1.42 ± 0.39 h (Tmax) after injection. TAP
was eliminated slowly in turtles with a long terminal
half-life of 5.22 ± 2.98 h, and it showed a large volume
of distribution (VZ/F) of 4.65 ± 1.34 L/kg.
Pharmacodynamics (PD). Differences in TWL in
the control group animals (n = 9) were statistically insignificant at any point tested. Hence, to establish the
TWL base line, all the saline solution data were grouped
for each time point. The T0 was 4.9 ± 0.50 s with average values of the whole base line ranging from 4.90 to
5.56 s (Fig. 2A).
The animals given TAP showed a drastic increase in
TWL one hour after drug administration (15.31 ± 4.73
s). Subsequently, TWL decreased in proportion to time
with significant differences from the saline group still
20
Plasma concentration (ng/mL)
A)
15
10
5
2000
60
1500
40
1000
20
500
0
0
0
0
0
10
20
B)
Antinociception (% MPR)
B)
Antinociception (% MPR)
Time (h)
80
60
40
20
0
1
2
4
6
Time (h)
8
10
24
Fig. 2. (A) Mean (± SE) TWL vs. time curve in turtles (n = 9)
after IM saline (open square) and IM TAP (open circle) administration (5 mg/kg); (B) mean (± SE)% MPR after IM
administration of TAP (5 mg/kg). * Significantly different
(P < 0.05) from saline value (control)
20
80
60
40
20
0
0
0
10
Time (h)
Antinociception (% MPR)
Thermal withdrawal latency (s)
A)
apparent up to 10 h. The average TWL value in the TAP
group after 24 h was 5.01 ± 0.73 s, which is still greater
than that of baseline, but not significantly so (P = 0.18).
Mean MPR started at 1.31 ± 1.98% (T0), increased
to a maximum of 59.01 ± 15.30% at 1 h and decreased
to a minimum of 1.00 ± 1.51% at 24 h (Fig. 2B). The
MPR difference between the TAP and saline groups was
still significant at 10 h.
PK/PD evaluation. The pharmacokinetic/pharmacodynamic correlations are reported in Fig. 3A, B. The
mean TAP plasma concentration and% MPR vs. time
curves were very similar (Fig. 3a). The average plasma
concentration associated with a maximum% MPR of
59.01 ± 15.30% was 1899 ± 242 ng/mL. The mean
plasma concentration at each time point ranged between
52.34 ng/mL (24 h) and 1619 ng/mL (1 h), associated
with% MPR of 1.00 and 59.01%, respectively. A linear
relationship (r2 = 0.98) between TAP plasma concentration and% MPR was found (Fig. 3B).
If it is difficult to recognize whether an animal feels
pain, it is even more challenging to determine objectively whether pain medication is effective in exotic
animals. In general, to determine the efficacy of drugs in
500
1000
1500
Plasma concentration (ng/mL)
2000
Fig. 3. (A) Mean (± SE) experimental plasma concentrations
(open circles) of TAP and mean (± SE)% MPR (open squares)
vs. time curves in turtles (n = 9) after IM TAP administration
(5 mg/kg); (B) mean (± SE) experimental plasma concentrations (open circles) vs. mean (± SE)% MPR curve. The
dotted line is the computed correlation line (experimental
plasma concentrations vs.% MPR). Numbers in the circles
represent time order
534
any species, it is important to determine the pharmacokinetic and pharmacodynamic properties of the drug in
that species (32). Knowing pharmacokinetic values for
a specific analgesic is often insufficient to determine appropriate doses and dosing frequencies, because plasma
levels of drugs do not always correlate with analgesia.
Plasma concentrations can provide guidance for dosing frequencies, but that does not always hold true,
because the effect of analgesics (eg. NSAID) may be
much longer than what would be expected from plasma
levels. The pharmacokinetics of analgesics also vary
considerably across all species that have been studied,
so extrapolating clinical doses and dosing intervals from
one species to another is not appropriate (9).
There is great potential for the use of TAP in veterinary species (8). Its PK profiles have already been tested
in dogs (11), cats (22) and goats (Prof. E. Lavy, unpublished data), and its PK/PD profile has been assessed in
rabbits (13). Although TAP is an atypical opioid, like
tramadol, it might theoretically be free of some disadvantages of tramadol reported in mammals, because
[1] TAP exists only as a single enantiomer (including
both mechanisms of action in the same molecule);
[2] only the parent compound is involved in its pharmacological activity (ie, no metabolic activation is necessary); [3] time-dependent changes in the dynamics of
opioid and monoaminergic analgesia occur in parallel;
[4] there is no CYP450 induction/inhibition that could
negatively affect analgesia; [5] TAP is likely to produce
less side effects compared with classical opioids such
as morphine because of its lower MOR affinity (34).
However, reptiles seem to react to opioids differently
than mammals, and therefore a PK/PD study in turtles
is essential to understand the effectiveness of this drug.
Several nociceptive tests have been established for
use in vertebrates, but only a few are available for
reptiles. In the present study, the TWL was evaluated
using a noxious heat radiant model with an automatic
motion sensor device. This method is easy, fast and
non-invasive compared with other methods, and turtles
can escape the stimuli immediately by moving their
hind limb. Owing to these advantages, many nociceptive tests in turtles (13, 29, 30) have been carried out
by this method. The TWL evaluated by Hargreaves’s
device has proven to be a sound and reproducible measure of complex nociceptive behaviour (3), and it has
been extensively used for pain assessment in reptiles
(6, 19, 28-30).
In an earlier pilot trial conducted on another group
of turtles (to set up the experimental method), it was
observed that the amount of water residue on the turtles’
limbs could affect TWL measurement. This was in line
with a previous study characterizing the variables in
TWL measurement (3). To eliminate this factor, the
turtles’ hind limbs were completely and consistently
dried just before blood collection, and after each animal
had been examined, the box surface had to be dried.
This procedure was essential to reduce variability in
the study.
Med. Weter. 2014, 70 (9)
In the present study, a different temperature (70°
rather than 50°C) was set for the beam source compared to previous studies (13, 29, 30). This change was
needed because the PK/PD design was contingent on
the blood collection and TWL measurement occurring
together. If the 50°C setting had been used, the result
could have taken several minutes, making the PK/PD
protocol assumption invalid.
After the IM injection of TAP, plasma drug concentrations were detectable for up to 24 h. This persistence
was longer than that reported in cats (8 h) and goats
(6 h) despite the same dose and route being used (Prof,
E. Lavy et al., unpublished data) (22). TAP in turtles
showed slower absorption (Tmax = 1.42 h) than in cats
(Tmax = 0.25 h) (22) and goats (Tmax = 0.17 h; Lavy et
al., unpublished data). Furthermore, TAP in turtles had
a half-life almost double that reported in cats (T1/2 λz
4.04 h vs 2.28 h) (22). TAP is metabolized predominantly by glucuronidation in humans (31), as 83% of
an oral dose of TAP is converted into and excreted as an
inactive glucuronated metabolite. Compared to mammals, turtles have a lower liver metabolic capacity and
a slower metabolic rate (2, 24). These differences may
have contributed to the long terminal half-life value of
TAP found in turtles.
In a previous study, morphine (6.5 mg/kg SC) produced analgesic effect between 2 and 24 h in turtles (30).
Tramadol (10 mg/kg SC) produced a long-lasting analgesic effect between 6 and 48 h (1). According to Sladky
et al. (29), thermal antinociception of opioids in turtles
appeared to be attributable mainly to MOR activation
with a relatively minor contribution of delta-opioid
receptor activation. It was assumed that the analgesic
effect continued from 2 to 8 h after the administration
of an experimental MOR agonist ((D-Ala2, N-Me-Phe4,
Gly5-ol)-enkephalin acetate salt) by SC at a dose of 6.6
mg/kg (29). When TAP (5 mg/kg IM) was administered
to turtles, the analgesic effect occurred within 1 h and
lasted for 10 h after administration. Compared with
other studies, TAP produced a thermal antinociception
effect more rapidly than morphine and tramadol in
turtles, despite a lower dose. It is likely that the onset
of the analgesic effect of TAP depends on the different
administration route used (IM vs. SC). Classical MOR
agonists (eg morphine) cause a long-lasting respiratory
depression in turtles (30) because of their strong MOR
activation. The present study did not evaluate the respiratory rate. It is expected, however, that TAP would
cause less respiratory depression, because of its lower
MOR affinity compared to morphine and M1 (34).
The TAP plasma concentration and effect vs. time
curves have shown to be in phase (Fig. 3A). Indeed,
when antinociception effect is plotted against plasma
concentration, the plasma concentration and effect form
a linear correlation (r2 = 0.98) (Fig. 3B). This varies
from an earlier study reporting PK/PD of buprenorphine
in cats (27). The linear relationship between the TAP
plasma concentration and effect might be accounted
for by the rapid blood-brain equilibration and its high
Med. Weter. 2014, 70 (9)
MOR affinity (33). This is consistent with the high
lipophilicity of TAP (5).
In humans, the Minimal Effective Concentration
(MEC) of TAP is reported to be 0.67 µmol/L, equivalent
to 148 ng/mL (33). The TAP plasma concentration in
turtles exceeded this threshold from 1 to 10 h (Fig. 1),
and during this time the thermal antinociceptive effect
was noted. However, the extrapolation of the MEC value
from humans to animals should be done with caution
(18) and verified by larger sample size animal studies.
Compared to other animal species, turtles were slow
in absorbing and eliminating TAP after IM injection.
The thermal antinociceptive effect occurred within 1 h,
reached its peak at 1 h, lasted for at least 10 h and was
plasma-concentration dependent. TAP appears to be an
attractive option for antinociception in turtles because
of the rapid onset and acceptable duration of its effect.
However, before adopting it for use in reptile clinical
practice, it is necessary to consider systemic pharmacokinetics and biophase distribution characteristics, as
well as to make a sound assessment of the drug’s safety.
Conflict of interest statement. None of the authors
has any financial or personal relationships that could
inappropriately influence or bias the content of the
paper.
References
1. Baker B. B., Sladky K. K., Johnson S. M.: Evaluation of the analgesic effects
of oral and subcutaneous tramadol administration in red-eared slider turtles.
JAVMA 2011, 238, 220-227.
2. Berner N. J.: Oxygen consumption by mitochondria from an endotherm and
an ectotherm. Comp. Biochem. Physiol. Part B 1999, 124, 25-31.
3. Dirig D. M., Salami A., Rathbun M. L., Ozaki G. T., Yaksh T. L.: Characterization
of variables defining hindpaw withdrawal latency evoked by radiant thermal
stimuli. J. Neurosci. Meth. 1997, 76, 183-191.
4. Duke-Novakovski T.: Opioids, [in:] Egger C. M., Love L., Doherty T. (ed):
Pain Management in Veterinary Practice, First Ed. Wiley-Blackwell, Ames,
IA, USA 2013, pp. 41-68.
5. Fejős I., He Y., Völgyi G., Kazsoki A., Sun J., Chen W., Sohajda T., Szente L.,
Jiang X., Béni S.: Tapentadol enantiomers: Synthesis, physico-chemical characterization and cyclodextrin interactions. J. Pharm. Biomed. Anal. 2013, 88,
594-601.
6. Fleming G. J., Robertson S. A.: Assessments of thermal antinociceptive effects
of butorphanol and human observer effect on quantitative evaluation of analgesia in green iguanas (Iguana iguana). Am. J. Vet. Res. 2012, 73, 1507-1511.
7. Gabrielsson J., Weiner D. (ed): Pharmacokinetic and Pharmacodynamic Data
Analysis: Concepts and Applications, Fourth Ed. Swedish Pharmaceutical
Press, Stockholm, Sweden 2002, pp. 141-151.
8. Giorgi M.: Tramadol vs tapentadol: A new horizon in pain treatment? Am J.
Anim. Vet. Sci. 2012, 7, 7-11.
9. Giorgi M.: Veterinary pharmacology: Is it still pharmacology’s cinderella?
Clin. Exp. Pharmacol. 2012, 2, 103.
10. Giorgi M., Del Carlo S., Saccomanni G., Łebkowska-Wieruszewska B.,
Turini V., Kowalski C.: Biopharmaceutical profile of tramadol in the dog. Vet.
Res. Commun. 2009, Suppl. 1, 189-192.
11. Giorgi M., Meizler A., Mills P. C.: Pharmacokinetics of the novel atypical
opioid tapentadol following oral and intravenous administration in dogs. Vet. J.
2012, 194, 309-313.
12. Giorgi M., Meizler A., Mills P. C.: Quantification of tapentadol in canine plasma
by HPLC with spectrofluorimetric detection: Development and validation of
a new methodology. J. Pharm. Biomed. Anal. 2012, 67-68, 148-153.
13. Giorgi M., Mills P. C., Tayari H., Rota S., Breghi G., Briganti A.: Plasma
Concentrations of Tapentadol and Clinical Evaluations of a Combination of
Tapentadol Plus Sevoflurane for Surgical Anaesthesia and Analgesia in Rabbits
(Oryctolagus cuniculus) Undergoing Orchiectomy. Isr. J. Vet. Med. 2013, 68,
141-148.
View publication stats
535
14. Giorgi M., Owen H.: Flupirtine: a human drug with potential for use in the
veterinary field. Am. J. Anim. Vet. Sci. 2012, 7, 213-217.
15. Giorgi M., Saccomanni G., Del Carlo S., Andreoni V.: Pharmacokinetic of
tramadol and its major metabolites after intravenous and intramuscular injections in alpacas (Vicugna pacos). J. Camel Pract. Res. 2010, 17, 123-126.
16. Giorgi M., Saccomanni G., Del Carlo S., Manera C., Lavy E.: Pharmacokinetics
of intravenous and intramuscular parecoxib in healthy Beagles. Vet. J. 2012b,
193, 246-250.
17. Giorgi M., Soldani G., Manera C., Ferrarini P., Sgorbini M., Saccomanni G.:
Pharmacokinetics of Tramadol and its Metabolites M1, M2 and M5 in Horses
Following Intravenous, Immediate Release (Fasted/Fed) and Sustained Release
Single Dose Administration. J. Equine Vet. Sci. 2007, 27, 481-488.
18. Giorgi M., Yun H.: Pharmacokinetics of mirtazapine and its main metabolites
in Beagle dogs: a pilot study. Vet. J. 2012, 192, 239-241.
19. Greenacre C. B., Schumacher J. P., Talke G.: Comparative antinociception of
morphine, butorphanol, and buprenorphine versus saline in the green iguana,
Iguana iguana, using electrostimulation. J. Herpetol. Med. Surg. 2006, 16,
88-92.
20. Harris L. S., Pierson A. K.: Some narcotic antagonists in the benzomorphan
series. J. Pharmacol. Exp. Ther. 1964, 143, 141-148.
21. Hunter R. (red): Zoological pharmacology, [in:] Riviere J. E., Papich M. G.
(ed): Veterinary pharmacology and therapeutics, Ninth Ed. Wiley-Blackwell,
Ames, IA, USA 2009, pp. 1343-1352.
22. Lee H. K., Łebkowska-Wieruszewska B., Kim T. W., Kowaski C. J., Giorgi M.:
Pharmacokinetics of the novel atypical opioid tapentadol after intravenous,
intramuscular and subcutaneous administration in cats. Vet. J. 2013, 198,
620-624.
23. Mans C., Lahner L. L., Baker B. B., Johnson S. M., Sladky K. K.: Antinociceptive efficacy of buprenorphine and hydromorphone in red-eared slider
turtles (Trachemys scripta elegans). J. Zoo Wildlife Med. 2012, 43, 662-665.
24. Penick D. N., Spotila J. R., O’Connor M. P., Steyermark A. C., George R. H.,
Salice C. J., Paladino F. V.: Thermal independence of muscle tissue metabolism
in the leatherback turtle, Dermochelys coriacea. Comp. Biochem. Physiol. Part
A 1998, 120, 399-403.
25. Raffa R. B., Friderichs E., Reimann W., Shank R. P., Codd E. E., Vaught J. L.:
Opioid and nonopioid components independently contribute to the mechanism
of action of tramadol, an ‘atypical’ opioid analgesic. J. Pharmacol. Exp. Ther.
1992, 260, 275-285.
26. Riviere J. E., Martin-Jimenez T., Sundlof S. F., Craigmill A. L.: Interspecies
allometric analysis of the comparative pharmacokinetics of 44 drugs across
veterinary and laboratory animal species. J. Pharmacol. Exp. Ther. 1997, 20,
453-463.
27. Robertson S. A., Lascelles B. D. X., Taylor P. M., Sear J. W.: PK-PD modeling
of buprenorphine in cats: intravenous and oral transmucosal administration.
J. Vet. Pharmacol. Therap. 2005, 28, 453-460.
28. Sladky K. K., Kinney M. E., Johnson S. M.: Analgesic efficacy of butorphanol
and morphine in bearded dragons and corn snakes. JAVMA 2008, 233, 267-273.
29. Sladky K. K., Kinney M. E., Johnson S. M.: Effects of opioid receptor activation on thermal antinociception in red-eared slider turtles (Trachemys scripta).
Am. J. Vet. Res. 2009, 70, 1072-1078.
30. Sladky K. K., Miletic V., Paul-Murphy J., Kinney M. E., Dallwig R. K., Johnson
S. M.: Analgesic efficacy and respiratory effects of butorphanol and morphine
in turtles. JAVMA 2007, 230, 1356-1362.
31. Terlinden R., Ossig J., Fliegert F., Gohler K.: Pharmakokinetics, excretion, and
metabolism of tapentadol HCl, a novel centrally acting analgesic, in healthy
subjects. J. Pain 2006, 7, 26-26.
32. Toutain P. L., Lees P.: Integration and modelling of pharmacokinetic and
pharmacodynamic data to optimize dosage regimens in veterinary medicine.
J. Vet. Pharmacol. Ther. 2004, 27, 467-477.
33. Tzschentke T. M., Christoph T., Kögel B., Schiene K., Hennies H. H.,
Englberger W., Haurand M., Jahnel U., Cremers T. I., Friderichs E.:
(-)-(1R,2R)-3- (3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): A novel mu-opioid receptor agonist/norepinephrine
reuptake inhibitor with broad-spectrum analgesic properties. J. Pharmacol.
Exp. Ther. 2007, 323, 265-276.
34. Tzschentke T.xM., De Vry J., Terlinden R., Hennies H.xH., Lange C.,
Strassburger W., Haurand M., Kolb J., Schneider J., Buschmann H.: Tapentadol
HCl, analgesic, mu-opioid receptor agonist, noradrenaline reuptake inhibitor.
Drugs Future 2006, 31, 1053-1061.
Corresponding author: Dr. Mario Giorgi, Department of Veterinary
Sciences, University of Pisa, Via Livornese (lato monte) 1, San Piero a Grado
56122, Pisa, Italy; e-mail: mgiorgi@vet.unipi.it