Influence of Surgery on the Pharmacokinetics of Tramadol Following Intravenous Administration in Dogs
Surgery and anesthesia causes fluctuations in hemodynamics which can lead to
subtherapeutic drug levels and usually therapeutic failure, making postsurgical
pain management difficult. The influence of surgery and anesthesia on the pharmacokinetics
of intravenous tramadol in dogs was investigated. Tramadol (3 mg kg-1)
was administered during premedication to female dogs (n = 6) undergoing ovariohysterectomy
(Group 1) and to another non-surgery group (n = 6) of female dogs (Group 2)
and the pharmacokinetics were compared between the groups. The outcome of this
study showed that surgery and anesthesia affected the pharmacokinetics of tramadol,
as indicated by a two-fold increase in the elimination half-life (1.10±0.18
h in Group 1 compared to 0.49±0.07 h in Group 2) and a three-fold increase
in the area under the curve (770.21±117.76 ng.h mL-1 for Group
1 compared to 117.61±85.16 ng.h mL-1 for Group 2). Clearance
was also significantly lower (3.98±0.56 mL min-1 kg-1)
in Group 1 than in Group 2 (21.06±9.34 mL kg-1). Serum levels
of both interleukin-6 and β-endorphin were increased at 6 and 9 h in the
surgery group which further indicates that the rapid metabolism and clearance
of tramadol in dogs are correlated with postsurgical pain. Therefore, re-administration
of tramadol at 3 h is necessary for pain control. This suggests that surgery
has a significant effect on the pharmacokinetics of tramadol in dogs.
Received: October 06, 2012;
Accepted: February 06, 2013;
Published: February 26, 2013
Control of post surgical pain is becoming increasingly important in small animal
practice (Taylor, 2003). Pain recognition in humans
is subjective and pain in animals can be challenging to identify because many
species have evolved to mask signs of illness and distress (De
Sousa et al., 2008). Many nonsteroidal anti-inflammatory drugs (NSAIDs)
are effective in managing post-surgical pain in dogs (Abu-Seida,
2012); however, their use is limited due to the development of unwanted
side effects (Riviere and Papich, 2001). The use of
opioids as a substitute for the use of NSAIDs for the management of postsurgical
pain is well established in small animal practice (Waterman
and Kalthum, 1989).
Tramadol is an analgesic with a dual mechanism of action. It binds to the μ1-opioid
receptor (Kukanich and Papich, 2004; Guedes
et al., 2005) and inhibits the monoaminergic pathway, which includes
the Noradrenaline (NA) and serotonin (5HT) reuptake pathways (Kubota
et al., 2008; McMillan et al., 2008).
For this reason, tramadol is also referred to as an atypical opioid
and is partially inhibited by the opioid receptor antagonist naloxone (McMillan
et al., 2008). Tramadol is widely used preoperatively for post-surgical
pain control in humans (Wang et al., 2005) and
has also been used recently in dogs (Kubota et al.,
2008; Almeida et al., 2010). However, tramadol
is reported to have a relatively short half-life. Therefore, there is often
the need for re-administration, which may increase the incidence of collateral
effects (Kukanich and Papich, 2004).
As with any other stress, surgery causes fluctuations in hemodynamics, physiological
shifts, intense metabolic changes and protein catabolism, which often occur
within a few hours of the surgery. Although, it has been demonstrated that the
therapeutic concentration of tramadol must be attained within the plasma before
the beginning of surgery, it is not clear whether the therapeutic level can
be maintained throughout the whole surgical period. The potential for alterations
in the pharmacokinetics of drugs following surgery should be recognized. Surgery
involves a number of major stresses associated with pain, anxiety, cardiovascular
instability and possibly major intraoperative hemodynamic changes, especially
if there is major blood loss or cross-clamping of large vessels (Barker
et al., 1987). These stresses trigger the release of catecholamines,
corticosteroids and a range of hormones and cytokines (Kehlet,
1989). This can lead to subtherapeutic drug levels, especially when there
is massive blood loss and subsequent fluid replacement (Sue
et al., 1989; Markantonis et al., 2004)
and usually therapeutic failure, making postsurgical pain management difficult.
To date, there are only a few reports regarding the pharmacokinetics of tramadol
in dogs (Kukanich and Papich, 2004; McMillan
et al., 2008), particularly in terms of its pharmacokinetics following
surgery. Both surgery and anesthesia can influence the pharmacokinetics and
pharmacodynamics of drugs (Nimmo and Peacock, 1988;
Kennedy and Van Riji, 1998). Presently, the possible
effects of surgery and anesthesia on the pharmacokinetics of tramadol in dogs
have not been reported. The aim of this study was to evaluate the influence
of elective surgery on the pharmacokinetics of tramadol following intravenous
MATERIALS AND METHODS
The study started in the middle of 2011 and was completed within eight month. Female dogs (n = 12) between the ages of 1 and 3 years (1.95±0.65), weighing between 10.5 and 17.1 kg (13.12±1.95), were randomly selected. All dogs were judged to be healthy based on physical and clinical examinations prior to surgery. The dogs were individually housed in a kennel in a quiet and clean environment. All protocols and guidelines for the use, management and handling of animals in research were approved by the faculty of Veterinary Medicine, Universiti Putra Malaysia Animal Care and Utilization Committee (UPM/FPV/PS/22.214.171.1241/AUP-R86).
Experimental procedures: The dogs were randomly divided into two groups (n = 6). They were fasted for 12 h prior to surgery but had free access to water until two hours prior to sedation. A 20 gauge 1 1/4 inch sterile catheter was placed in a cephalic vein. Group 1 underwent an ovariohysterectomy (OHE) and received 3 mg kg-1 tramadol intravenously (i.v.) as premedication about 15 min before the commencement of the surgery. The premedication also consisted of 0.04 mg kg-1 atropine and 0.50 mg kg-1 xylazine. Group 2 received tramadol at a similar dosage without undergoing any surgery.
Induction and surgery: Each dog in group 1 was induced with ketamine HCl (NarketanR Vetoquinol SA, 70204 Lure, Cedex, France) at 10 mg kg-1 (i.v.) and the lungs were ventilated. After anesthesia, the ventral abdomen from the xiphoid to the pubis was clipped and aseptically prepared for OHE. An incision was made through the skin and subcutaneous tissue to expose the linea alba, just caudal to the umbilicus in the cranial third of the caudal abdomen. A stab incision was made into the abdominal cavity and extended cranially and caudally. The ovaries were identified, double ligated using 2-0 chromic catgut and transected in between. Both uterine horns were traced to the uterine body and ligated cranial to the cervix, then transected at the uterine body. Finally the abdominal wall was apposed in three layers (rectus fascia, subcutaneous tissue and skin).
Sample collection: Three milliliters of blood was taken at baseline and at 2.0, 5.0, 10.0, 15.0, 30.0 and 45.0 min and 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0 and 9.0 h post-administration of tramadol from each dog in both groups. Prior to drawing blood samples for pharmacokinetic analysis, blood (1 mL) was drawn from the jugular catheter and discarded. The catheters were flushed with 1 mL of sterile saline following each sampling. Samples were placed in a plain tube (Becton Dickinson, Franklin Lanes, New Jersey, USA), allowed to stand at room temperature for 30 min for clotting and were subsequently placed on ice. Samples were carefully labeled using a permanent marker. Blood samples were centrifuged at 1000 X g for 10 min. The separated sera were kept frozen at -80°C until analysis within six months.
To determine the levels of β-endorphins and interleukin-6 (IL-6), blood samples (2 mL) were collected at baseline and at 1.0, 2.0, 3.0, 6.0 and 9.0 h after tramadol administration. The blood samples were allowed to clot for 30 min before centrifugation for 15 min at 1000 X g. The separated sera were kept frozen at -80°C until analysis using commercially available Enzyme-linked Immunosorbent Assay (ELISA) kits (Cusabio Biotech Co., Ltd., Wuhan P.R. China) specific for canine β-endorphin and IL-6. A wavelength of 450 nm was selected for Optical Density (OD) measurements on an ELISA microplate reader (Bio-Rad model 680, Bio-Rad Laboratories Inc., Tokyo, Japan).
Extraction of tramadol using the solid phase extraction (SPE) method:
The extraction process was based on the method developed previously (Gan
et al., 2002).
Determination of serum tramadol concentrations by HPLC: The HPLC system consisted of a quaternary pump, degasser, automated sampler and UV detector that were set at 218 nm. The analytical column was Agilent Zobax reverse phase (RP-C18) (5 μm; 4.6x250 mm). The control of the HPLC system and data collection were achieved with an IBM-compatible computer equipped with Agilent LC ChemStation software (Agilent Technologies©, 32-bit version, Hewlett-Packard-Strasse 8 76337 Waldbronn, DE Germany).
Serum tramadol concentrations were detected by reverse phase HPLC with ultraviolet
(UV) detection based on the method described (Gan and Ismail,
2001) with some slight modifications. Briefly, the mobile phase was a mixture
of 70% phosphate buffer (0.01 M), 30% acetonitrile and 0.1% triethylamine (v/v)
and the final mixture was adjusted to pH 5.9. The phosphate buffer (KHPO4)
was prepared fresh daily by dissolving 1.36 g of KHPO4 (HPLC grade,
Fisher Scientific Loughborough, Leicestershire LE11 5RG UK) into 1000 mL of
ddH2O. The final mixture was filtered through a 0.45 μm cellulose
filter (Sartorius, Germany) under vacuum followed by sonication for 20 min to
remove any residual gas bubbles. A flow-rate of 0.75 mL min-1 was
used throughout. Each reconstituted sample was injected (25 μL) into the
column, which was heated to 40°C.
Pharmacokinetic analysis: Tramadols pharmacokinetic parameters were calculated using a pharmacokinetic computer software program (WinNonlin Version 5.3, Pharsight Corp., Mountain View CA, USA). The best fit model for compartmental analysis was determined by residual plots and Aikakes information criterion. An open two-compartment model with a central compartment best described the decline in the tramadol plasma concentration following i.v. administration. The total body clearance (Cl), volume of distribution (Vd), area under the plasma concentration curve (AUC), plasma distribution half-life (αT1/2), plasma clearance half-life (β T1/2), intercept of the distribution phase (A), intercept of the elimination phase (B), rate constant associated with distribution (alpha) and rate constant associated with elimination (beta) were derived.
Statistical analysis: Statistical analysis was performed using the SPSS
program (IBM® SPSS software Inc. version 16, New York, USA).
The results are expressed as the means±SD. The pharmacokinetic parameters
were compared using an independent t-test between two groups. A p-value of less
than 0.05 is considered to be statistically significant.
No adverse effects were observed after administration of tramadol HCl at 3 mg kg-1. All dogs appeared mildly sedated after administration and one dog exhibited nausea (salivating), which stopped after 5 min. A female dog from group 2 became very aggressive and was removed from the study. This dog was substituted with a randomly selected dog. The serum concentration over time was then plotted for both Groups 1 and 2 (Fig. 1).
The pharmacokinetics of tramadol are presented in Table 1.
The plasma concentration reflected in the mean AUC value was four times higher
in animals from Group 1 than that of Group 2, while the average Cl was approximately
five times lower in Group 1 than in Group 2 (21.06±9.34 mL min-1
kg-1). The mean serum β-endorphin levels were significantly
higher in Group 1 at 6 and 9 h than those of Group 2 (Fig. 2).
||Serum concentration of tramadol vs time
||Pharmacokinetic profile of tramadol
|λz: First-order rate constant, t½ λz: Half-life
of the terminal portion of the curve, MRT: Mean residence time, ClT:
Total body clearance, Vdss: Volume of distribution at steady state, AUC0-8:
Area under the curve from 0 to infinity, AUMC0-8: Area under
the first moment curve from 0 to infinity, C0: Concentration
at time 0, t½α: Distribution half-life, t½β: Elimination
half-life, α: Rate constant associated with distribution, β: rate
constant associated with elimination; A: Intercept for the distribution
phase, B: Intercept for the elimination phase, K10: Elimination rate from
compartment 1, K12: Rate of movement from compartment 1 to compartment 2,
K21: Rate of movement from compartment 2 to compartment 1, K10 t1/2:
Half-life of the elimination phase; V1: Volume of compartment 1, V2: Volume
of compartment 2, Group 1: Surgery group, Group 2: Non surgery group, aMeans
with superscript differ significantly at p<0.05 between groups
||Serum concentration of beta endorphins vs time. **Means with
superscript (asterisks) differ significantly at p<0.05 between groups
||Serum concentration of interleukin 6 vs time. **Means with
superscript (asterisks) differ significantly at p<0.05 between groups
Similarly, there was also a significant increase in mean serum IL-6 concentrations
in Group 1 at 6 h (Fig. 3), indicating that tramadol had similar
effects in controlling pain for both groups.
The present study was undertaken in light of the limited information available regarding tramadols pharmacokinetics in dogs. This study is the first to show that surgery significantly affects several pharmacokinetic parameters of tramadol when administered to dogs intravenously. The pharmacokinetic parameters that were significantly affected included the t1/2á, ClT, Vd(ss), AUC0-8 and C0.
In this study, it was found that a two-compartmental model best fit the plasma
tramadol concentrations when administered intravenously, as also reported by
Dayer et al. (1994), Kukanich
and Papich (2004) and McMillan et al. (2008).
However, even though Kukanich and Papich (2004) reported
that the metabolite concentrations are best represented by a non-compartmental
model, (McMillan et al., 2008) stated that the
plasma concentration of the active metabolite is too low to be reliably measured
in dogs, as is also the case in humans (Gan et al.,
2007). Similarly, it was found that the metabolite concentration was lower
than the detection limit of our machine and was therefore, not measured.
The liver tends to show increased activity in the post-surgical period (Kennedy
and Van Riji, 1998). It is reported that serum albumin increases post-surgically,
leading to changes in binding characteristics and subsequent decreases in albumin
concentrations (Kennedy and Van Riji, 1998). Although,
the protein binding of tramadol is relatively low (20%) Dayer
et al. (1994), this binding may lead to a decrease in the serum concentration
of tramadol post-surgically.
In this study, the plasma concentration of tramadol following i.v. administration
in non-surgery dogs declined very rapidly, with a t1/2 α between
0.006 and 0.12 h (mean 0.04±0.04 h) compared to between 0.06 and 0.22
h (mean 0.15±0.07 h) observed among the surgery group. A slightly higher
t1/2α (0.32 h) was reported by Kukanich
and Papich (2004) following i.v. administration of 4 mg kg-1
tramadol in beagle dogs. De Sousa et al. (2008)
reported a t1/2α of 0.18 h in dogs undergoing routine ovariohysterectomy
and a t1/2α of 0.12 hr following 2 mg kg-1 i.v. tramadol
administration to cats has also been reported (Cagnardi
et al., 2011).
The Vd(ss) following i.v. administration of tramadol to young healthy
volunteers was 203 L, indicating that tramadol has a high tissue affinity (Lee
et al., 1993). However, the Vd in dogs is lower than in humans. Furthermore,
during surgery, blood volume may be altered due to blood loss, venous pooling,
co-morbidity or shock, thus affecting the size of the compartments into which
the drug is delivered. In this study, the size of the second compartment (V2)
as well as the Vd(ss) significantly decreased in animals that underwent
surgery as opposed to the non-surgical group. The decrease in Vd may further
be compounded by alterations in cardiac function that occur postoperatively
(Moffat and Milne, 1983).
Reduction in cardiac output and hepatic blood flow caused by the anesthesia
and surgery slowed drug distribution from the central compartment to the immediate
peripheral tissues and subsequently impaired hepatic elimination of the drug
(Sue et al., 1989; Cagnardi
et al., 2011). This may explain why in our study, both the Vd(ss)
and Cl were significantly reduced in Group 1. A reduction in Vd tends to decrease
the time required for recovery after drug administration (Shafer
and Vavel, 1991). Cagnardi et al. (2011)
observed a significant decrease in tramadols Vd among cats undergoing
ovariohysterectomy compared with the distributional values reported by De
Sousa et al. (2008) in cats not undergoing surgery.
The decrease in Vd may lead to an increase in tramadol concentration, as reflected
in the AUC and C0 values, thus exposing the animals to toxicity,
especially in the initial stages. However, none of the animals from either group
showed any adverse effects from tramadol, perhaps due to the relatively low
dose used (3 mg kg-1). Choi et al. (2011)
administered tramadol to dogs at three different doses (1, 2 and 4 mg kg-1)
and reported no adverse effects seen in any of the animals except for those
receiving 4 mg kg-1, where the animals were reported to be sedated
at 15 min after administration. Kukanich and Papich (2004)
administered tramadol at a higher dose (4.4 mg kg-1) and observed
that some of the animals exhibited signs of nausea, including salivation and
increased swallowing. Furthermore, the initial tramadol concentrations varied
considerably (range 190-1350 g mL-1), indicating that there is high
inter-individual variability in plasma concentrations. This could be attributed
to using mixed-breed animals as opposed to using only purebred dogs, as did
Kukanich and Papich (2004).
The Cl of the drug from the body could be a reflection of the drugs elimination
half-life. However, this may vary because other pharmacokinetic parameters such
as Vd may be involved. Clearance, as opposed to the rate of Cl, is nevertheless
independent of such variables. The rate of clearance of tramadol from the plasma
is decreased among dogs undergoing surgery (3.98±0.56 ml/min kg-1)
in comparison with the non-surgery groups (21.06±9.34 ml/min kg-1).
This could be attributed to the longer t1/2 for Group 1. Similarly,
lower tramadol Cl were observed by Cagnardi et al.
(2011) in cats undergoing surgery under general anesthesia, contrary to
the values reported by Pypendop and Ilkiw (2008) in
experimental cats under normal laboratory conditions.
Blood loss due to surgery may alter kidney function and subsequently affect
renal elimination, hence slowing the Cl of the drug as reported by Sue
et al. (1989). Following oral administration of carbon 14-labelled
tramadol to humans, approximately 90% of the drug was excreted by the kidneys,
with the remaining 10% appearing in the feces (Lee et
al., 1993). It has also been reported that short operations are usually
followed by increased activity of hepatic drug metabolizing enzymes as a consequence
of enzyme induction (Kennedy and Van Riji, 1998). This
may contribute to the lower Cl values and the reduction in Cl which tend to
increase the time required for recovery from surgery (Shafer
and Vavel, 1991).
Liver hypoxia may also occur due to impaired hepatic blood flow, impaired oxygen
carrying capacity of the blood or impaired delivery of blood oxygen (Jones
et al., 1989). Phase I enzymes are susceptible to low oxygen tensions,
although some enzymes in the cyctochrome P450 (CYP) family are more tolerant
than others to hypoxia (Kennedy and Van Riji, 1998).
In humans, tramadol is metabolized by cytochrome P450 (CYP) 2D6 or CYP2D6, which
are highly polymorphic (Gan et al., 2002). However,
in animals, particularly in dogs, other genes may be involved. For example,
the CYP1A, 2C, 2D and 3A subfamilies have been reported to correlate with the
oxidative metabolism of many drugs in animal species (Shah
et al., 2007), with CYP1A showing high polymorphic activities in
dogs (Mise et al., 2008; Aretz
and Geyer, 2011). It has also been reported that increased levels of cytokines
can decrease the activity of CYP in humans (Young et
al., 1998). However, we did not measure cytokine levels in our study
to confirm this fact. The influence of the gene expression and cytokine levels
need to be investigated in future studies.
The lower Cl values of tramadol after surgery also resulted in a longer t½,
indicating that there is a higher chance of tramadol toxicity following surgery,
especially when higher tramadol doses are used. Reduced Cl after surgery, as
seen in this study, may also indicate the livers reduced capacity to biotransform
tramadol following surgery. It has been reported that the bodys response
to stress is usually hypermetabolism and the liver is the major site for this
activity (Kennedy and Van Riji, 1998). In addition
to secreting products such as albumin, the liver is also involved in the synthesis
of many products, including IL-6. In this study, IL-6 levels were significantly
elevated at six hours post-surgery. This is not surprising because it has been
reported that IL-6 is the major progenitor of the hepatic acute-phase response
to stress (Kennedy and Van Riji, 1998). Young
et al. (1998) reported that IL-6 levels increase from undetectable
levels preoperatively to 73.6±32.8 ng L-1 on the first day
after operation in humans.
In this study, β-endorphin levels were also significantly elevated at
six and nine hours post-surgery, perhaps because serum tramadol concentrations
were already decreased by this time and therefore the animals may have been
in pain. β-endorphin is an indicator of painful stimuli in humans, where
its concentrations were found to be elevated much longer in the presence of
pain stimuli as opposed to non-painful stimuli (Rasmussen
and Farr, 2009). De Riu et al. (1989) observed
that in severely injured dogs, serum β-endorphin levels were increased
over time and exceeded the levels in moderately traumatized dogs. These results
indicate a significant role for β-endorphin as an objective biomarker of
pain (Sommer and Kress, 2004; Rasmussen
and Farr, 2009) and as a modulator in acute traumatic conditions such as
surgery (Shahed and Shoskes, 2001). Therefore, tramadol
may need to be re-adiministered after three hours. It has also been reported
that circulating catecholamines tend to increase as part of the endocrine response
associated with surgery (Udelsman and Holbrook, 1994).
However, serum catecholamines are not measured in this study.
The results from this study provide pharmacokinetic information about tramadol for future consideration when this drug is required as an analgesic agent in dogs during surgery and anesthesia. The pharmacokinetic parameters for i.v. tramadol were significantly different in dogs undergoing surgery in comparison with non-surgery dogs.
This study was supported by a Research University Grant (1001/PPSP/815073), Universiti Sains Malaysia and Research University Grant 91465 University Putra Malaysia.
Almeida, R.M., A. Escobar and S. Maguilnik, 2010.
Comparison of analgesia provided by lidocaine, lidocaine-morphine or lidocaine-tramadol delivered epidurally in dogs following orchiectomy. Vet. Anesthesia Analgesia, 37: 542-549.CrossRef | PubMed | Direct Link |
Aretz, J.S. and J. Geyer, 2011.
Detection of the CYP1A2 1117C > T polymorphism in 14 dog breeds. J. Vet. Pharmacol. Ther., 34: 98-100.CrossRef |
Barker, S.J., D.M. Gamel and K.K. Tremper, 1987.
Cardiovascular effects of anesthesia and operation. Crit. Care Clin., 3: 251-268.PubMed | Direct Link |
Cagnardi, P., R. Villa, A. Zonca, M. Gallo and M. Beccaglia et al
Pharmacokinetics, intraoperative effect and postoperative analgesia of tramadol in cats. Res. Vet. Sci., 90: 503-509.CrossRef |
Choi, W., H.S. Jang, H.S. Yun, J.S. Park, Y.S. Kwon and K.H. Jang, 2011.
Effect of tramadol on medetomidine and ketamine anesthesia in dogs. Pak. Vet. J., 31: 99-104.Direct Link |
Dayer, P., L. Collart and J. Desmeules, 1994.
The pharmacology of tramadol. Drugs, 47: 3-7.PubMed | Direct Link |
De Riu, P., V. Petruzzi, G. Palmieri, C. Gentili and F. Melis et al
Beta-endorphin in experimental canine spinal ischemia. Stroke, 20: 253-258.CrossRef | Direct Link |
Gan, S.H. and R. Ismail, 2001.
Validation of a high-performance liquid chromatography method for tramadol and o-desmethyltramadol in human plasma using solid-phase extraction. J. Chromatogr. B: Biomed. Sci. Appl., 759: 325-335.CrossRef |
Gan, S.H., R. Ismail, W.A. Wan Adnan and W. Zulmi, 2007.
Impact of CYP2D6 genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics. Mol. Diagn. Ther., 11: 171-181.Direct Link |
Gan, S.H., R. Ismail, W.A. Wan Adnan and Z. Wan, 2002.
Method development and validation of a high-performance liquid chromatographic method for tramadol in human plasma using liquid-liquid extraction. J. Chromatogr. B, 772: 123-129.CrossRef |
Guedes, A.G.P., C.C. Natalini, E.P. Robinson, S.D.L. Alves and S.T. Oliveira, 2005.
Epidural administration of tramadol as an analgesic technique in dogs submitted to stifle surgery. Int. J. Applied Res. Vet. Med., 3: 351-359.Direct Link |
Jones, D.P., T.Y. Aw and X.Q. Shan, 1989.
Drug metabolism and toxicity during hypoxia. Drug Metab. Rev., 20: 247-260.CrossRef |
Kehlet, H., 1989.
The stress response to surgery: Release mechanisms and the modifying effect of pain relief. Acta Chir. Scand. Suppl., 550: 22-28.PubMed | Direct Link |
Kennedy, J.M. and A.M. Van Riji, 1998.
Effects of surgery on the pharmacokinetic parameters of drugs. Clin. Pharmacokinetics, 35: 293-312.Direct Link |
Kubota, R., T. Komiyama, Y. Miwa, T. Ide, H. Toyoda, F. Asanuma and Y. Yamada, 2008.
Pharmacokinetics and postoperative analgesia of epidural tramadol: A prospective, pilot study. Curr. Ther. Res., 69: 49-55.CrossRef |
Kukanich, B. and M.G. Papich, 2004.
Pharmacokinetics of tramadol and the metabolite O-desmethyl tramadol in dogs. J. Vet. Pharmacol. Ther., 27: 239-246.CrossRef |
Lee, C.R., D. McTavish and E.M. Sorkin, 1993.
Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in acute and chronic pain states. Drugs, 46: 313-340.PubMed |
Markantonis, S.L., G. Kostopanagiotou, D. Panidis, V. Smirniotis and D. Voros, 2004.
Effects of blood loss and fluid volume replacement on serum and tissue gentamicin concentrations during colorectal surgery. Clin. Ther., 26: 271-281.CrossRef |
McMillan, C.J., A. Livingston, C.R. Clark, P.M. Dowling, S.M. Taylor, T. Duke and R. Terlinden, 2008.
Pharmacokinetics of intravenous tramadol in dogs. Can. J. Vet. Res., 72: 325-331.PubMed |
Mise, M., T. Hashizume and S. Komuro, 2008.
Characterization of substrate specificity of dog CYP1A2 using CYP1A2-deficient and wild-type dog liver microsomes. Drug Metab. Dispos., 36: 1903-1908.CrossRef | Direct Link |
Moffat, J.A. and B. Milne, 1983.
Pharmacokinetics in anaesthesia. Can. J. Anesthesia, 30: 300-307.CrossRef |
Nimmo, W.S. and J.E. Peacock, 1988.
Effect of anaesthesia and surgery on pharmacokinetics and pharmacodvamics. Br. Med. Bull., 44: 286-301.Direct Link |
Pypendop, B.H. and J.E. Ilkiw, 2008.
Pharmacokinetics of tramadol and its metabolite O-desmethyl-tramadol, in cats. J. Vet. Pharmacol. Ther., 31: 52-59.CrossRef |
Rasmussen, N.A. and L.A. Farr, 2009.
Beta-endorphin response to an acute pain stimulus. J. Neurosci. Methods, 177: 285-288.CrossRef |
Riviere, J.E. and M.G. Papich, 2001.
Potential and problems of developing transdermal patches for veterinary applications. Adv. Drug Delivery Rev., 50: 175-203.CrossRef |
Shafer, S.L. and J.R. Vavel, 1991.
Pharmacokinetics, pharmacodynamics and rational opioid selection. Anesthesiology, 74: 53-63.Direct Link |
Shah, S.S., S. Sanda, N.L. Regmi, K. Sasaki and M. Shimoda, 2007.
Characterization of cytochrome P450-mediated drug metabolism in cats. J. Vet. Pharmacol. Ther., 30: 422-428.CrossRef |
Shahed, A.R. and D.A. Shoskes, 2001.
Correlation of β-endorphin and prostaglandin e2 levels in prostatic fluid of patients prostatitis with diagnosis and with chronic treatment response. J. Urol., 166: 1738-1741.CrossRef |
Sommer, C. and M. Kress, 2004.
Recent findings on how proinflammatory cytokines cause pain: Peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci. Lett., 361: 184-187.CrossRef |
De Sousa, A.B., A.C.D. dos Santos, J.C. Florio and H.S. Spinosa, 2008.
Pharmacokinetics of tramadol administered by intravenous and intramuscular routes to female dogs submitted to ovariohysterectomy. Braz. J. Vet. Res. Anim. Sci., 45: 239-247.Direct Link |
Sue, D., T.A. Salazar, K. Turley and B.J. Guglielmo, 1989.
Effect of surgical blood loss and volume replacement on antibiotic pharmacokinetics. Ann. Thoracic Surg., 47: 857-859.CrossRef |
Taylor, P., 2003.
Pain management in dogs and cats-More causes and locations to contemplate. Vet. J., 165: 186-187.CrossRef |
Udelsman, R. and N.J. Holbrook, 1994.
Endocrine and molecular responses to surgical stress. Curr. Prob. Surg., 31: 662-720.CrossRef |
Wang, G., Y. Weng, Y. Ishiguro, H. Sakamoto and S. Morita, 2005.
The effect of tramadol on serum cytokine response in patients undergoing pulmonary lobectomy. J. Clin. Anesthesia, 17: 444-450.CrossRef |
Waterman, A. and W. Kalthum, 1989.
Pharmacokinetics of intramuscularly administered pethidine in dogs and the influence of anaesthesia and surgery. Vet. Rec., 124: 293-296.CrossRef |
Young, A.B., L.G. Ott, D. Beard, R.J. Dempsey, P.A. Tibbs and C.J. McClain, 1998.
The acute-phase response of the brain-injured patient. J. Neurosurg., 69: 375-380.CrossRef | Direct Link |
Abu-Seida, A.M., 2012.
Efficacy of diclofenac sodium, either alone or together with cefotaxime sodium, for control of postoperative pain, in dogs undergoing ovariohysterectomy. Asian J. Anim. Vet. Adv., 7: 180-186.CrossRef | Direct Link |