Pharmacokinetics and pharmacodynamics after oral administration of tapentadol hydrochloride in dogs

James Howard Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Turi K. Aarnes Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Jonathan Dyce Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Phillip Lerche Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Larry W. Wulf Department of Veterinary Diagnostic and Production Animal Medicine–Iowa State University Pharmacology Analytical Support Team, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.

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Johann F. Coetzee Department of Veterinary Diagnostic and Production Animal Medicine–Iowa State University Pharmacology Analytical Support Team, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.

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Jeffrey Lakritz Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Abstract

OBJECTIVE To evaluate pharmacokinetic and pharmacodynamic characteristics of 3 doses of tapentadol hydrochloride orally administered in dogs.

ANIMALS 6 healthy adult mixed-breed dogs.

PROCEDURES In a prospective, randomized crossover study, dogs were assigned to receive each of 3 doses of tapentadol (10, 20, and 30 mg/kg, PO); there was a 1-week washout period between subsequent administrations. Plasma concentrations and physiologic variables were measured for 24 hours. Samples were analyzed by use of high-performance liquid chromatography–tandem mass spectrometry.

RESULTS Tapentadol was rapidly absorbed after oral administration. Mean maximum plasma concentrations after 10, 20, and 30 mg/kg were 10.2, 19.7, and 31 ng/mL, respectively. Geometric mean plasma half-life of the terminal phase after tapentadol administration at 10, 20, and 30 mg/kg was 3.5 hours (range, 2.7 to 4.5 hours), 3.7 hours (range, 3.1 to 4.0 hours), and 3.7 hours (range, 2.8 to 6.5 hours), respectively. Tapentadol and its 3 quantified metabolites (tapentadol sulfate, tapentadol-O-glucuronide, and desmethyltapentadol) were detected in all dogs and constituted 0.16%, 2.8%, 97%, and 0.04% of the total area under the concentration-time curve (AUC), respectively. Plasma AUCs for tapentadol, tapentadol sulfate, and tapentadol-O-glucuronide increased in a dose-dependent manner. Desmethyltapentadol AUC did not increase in a linear manner at the 30-mg/kg dose. Sedation scores and heart and respiratory rates were not significantly affected by dose or time after administration.

CONCLUSIONS AND CLINICAL RELEVANCE Oral administration of tapentadol was tolerated well, and the drug was rapidly absorbed. Adverse events were not apparent in any dogs at any doses in this study.

Abstract

OBJECTIVE To evaluate pharmacokinetic and pharmacodynamic characteristics of 3 doses of tapentadol hydrochloride orally administered in dogs.

ANIMALS 6 healthy adult mixed-breed dogs.

PROCEDURES In a prospective, randomized crossover study, dogs were assigned to receive each of 3 doses of tapentadol (10, 20, and 30 mg/kg, PO); there was a 1-week washout period between subsequent administrations. Plasma concentrations and physiologic variables were measured for 24 hours. Samples were analyzed by use of high-performance liquid chromatography–tandem mass spectrometry.

RESULTS Tapentadol was rapidly absorbed after oral administration. Mean maximum plasma concentrations after 10, 20, and 30 mg/kg were 10.2, 19.7, and 31 ng/mL, respectively. Geometric mean plasma half-life of the terminal phase after tapentadol administration at 10, 20, and 30 mg/kg was 3.5 hours (range, 2.7 to 4.5 hours), 3.7 hours (range, 3.1 to 4.0 hours), and 3.7 hours (range, 2.8 to 6.5 hours), respectively. Tapentadol and its 3 quantified metabolites (tapentadol sulfate, tapentadol-O-glucuronide, and desmethyltapentadol) were detected in all dogs and constituted 0.16%, 2.8%, 97%, and 0.04% of the total area under the concentration-time curve (AUC), respectively. Plasma AUCs for tapentadol, tapentadol sulfate, and tapentadol-O-glucuronide increased in a dose-dependent manner. Desmethyltapentadol AUC did not increase in a linear manner at the 30-mg/kg dose. Sedation scores and heart and respiratory rates were not significantly affected by dose or time after administration.

CONCLUSIONS AND CLINICAL RELEVANCE Oral administration of tapentadol was tolerated well, and the drug was rapidly absorbed. Adverse events were not apparent in any dogs at any doses in this study.

Pain perception pathways are complex biological systems consisting of multifaceted peripheral nociceptors terminating at the CNS. Noxious stimuli are translated into action potentials, which are transmitted to the CNS as the genesis of each nociceptive pathway.1 This results in reflex activity or a cognitive perception of pain. The complex integration of the peripheral nervous system and CNS allows for a multimodal approach with pharmaceuticals that act at different levels of the nociceptive pathway.2

Complete multimodal analgesia can be difficult to achieve with oral medications alone regardless of the fact that multiple pathways of the peripheral nervous system and CNS can be targeted. Frequently, amelioration of clinical signs is the marker of clinically successful pain control.3 Opioids, NSAIDs, and local anesthetics are the 3 primary classifications of drugs used in the postoperative period for multimodal pain control.4 Of these first-line analgesics, opioids are the most effective for pain control in small animals.5 Other commonly prescribed therapeutics target N-methyl-d-aspartate receptors,6,7 γ-aminobutyric acid synthesis,4 voltage-dependent ion channels,7 and serotonin and norepinephrine reuptake pathways.8

Tapentadol is a μ-opioid receptor agonist with an additional mechanism of action as a monoamine (ie, norepinephrine) reuptake inhibitor.9 Norepinephrine reuptake potentiates chronic pain in humans and may also potentiate increases in 5-hydroxytryp tamine receptor activation, but similar mechanisms have not been established in dogs. The affinity of morphine for the μ-opioid receptor is 50 times that of tapentadol; however, evaluation of clinical pain in humans has revealed only a 2- to 3-fold decrease in potency for tapentadol because of the synergism of 2 distinct mechanisms of action (μ-opioid receptor agonist and norepinephrine reuptake inhibitor).10,11 Additionally, because of its lower affinity for the μ-opioid receptor and lack of known active metabolites, tapentadol has fewer adverse effects in humans than do other μ-opioid receptor agonists (eg, morphine) and orally administered μ-opioid receptor agonists, norepinephrine reuptake inhibitors, and 5-hydroyxtryptamine receptor activators (eg, tramadol).12 The dual mechanism of action of tapentadol results from a single biologically active molecule and a single enantiomer,13 rather than a racemic mixture of R and S isomers like tramadol.9 In contrast to tramadol, which derives its analgesic efficacy from active metabolites metabolized from the parent drug by cytochrome P450 monooxygenase and effects of those metabolites on norepinephrine reuptake, the analgesic effects of tapentadol are attributable to the effects of the parent drug at opioid receptors as well as through inhibition of norepinephrine reuptake.13 Despite its promising analgesic profile, standardized oral dosing regimens for tapentadol have not been evaluated in dogs.

The purpose of the study reported here was to evaluate the pharmacokinetics and effects of 3 doses of tapentadol on heart rate, respiratory rate, and sedation in healthy dogs. We hypothesized that clinically effective plasma concentrations of tapentadol associated with analgesia could be achieved within the dosing range used in this study.

Materials and Methods

Dogs

Six dogs (3 males and 3 females) with a mean ± SD age of 22.8 ± 2.1 months and mean body weight of 24.7 ± 2.5 kg were included in the study. Each dog was considered healthy on the basis of results of a physical examination, routine CBC, and serum biochemical analysis conducted before the start of the study. Animal husbandry and scientific protocols were approved by the Institutional Animal Care and Use Committee of The Ohio State University (No. 2015A00000036).

Experimental procedures

A single-observer, blinded, randomized crossover study was performed. Food was withheld from each dog for a minimum of 12 hours before tapentadol administration. At least 60 minutes before tapentadol administration, the hair on the lateral aspect of a hind limb was clipped, the skin was cleaned, and a single-lumen, 16-gauge over-the-wire sampling cathetera was aseptically placed in the saphenous vein for collection of venous blood samples. Catheters were filled with heparinized saline (0.9% NaCl) solution and capped.

Baseline sedation score, heart rate, and respiratory rate were recorded before oral administration of tapentadol. A sedation scoring scale of 0 to 3 was used to evaluate mental alertness (0 = no signs of sedation, 1 = signs of sedation but reacts to auditory stimulus, 2 = signs of sedation and no reaction to auditory stimulus but reacts to physical handling, and 3 = sedated and unresponsive to auditory stimulus and physical handling).14

Each dog was fed 85 g of a canned foodb that contained 1 of 3 doses of tapentadol hydrochloride tabletsc (10, 20, or 30 mg/kg). In humans, the AUC and Cmax of tapentadol increase 25% and 16%, respectively, following consumption of a high-fat, calorie-dense meal.15 Each dog received all 3 doses of tapentadol; there was a minimum washout period of 1 week between successive treatments.

Blood samples were collected at 0, 5, 15, 30, and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12, and 24 hours after administration of tapentadol. Time 0 was the time at which the tapentadol and food were administered and confirmed to have been consumed. At each time point, 5 mL of blood was collected from the catheter in the saphenous vein by use of a 3-syringe technique (5 mL of waste blood was withdrawn from the catheter before collection of the sample used for analysis). Waste blood was returned to the dog, and the catheter was flushed with 3 mL of heparinized saline solution. None of the dogs tolerated an Elizabethan collar; therefore, the sampling catheter was removed from the saphenous vein after collection of the blood sample at 12 hours, and the blood sample at 24 hours was collected from the same saphenous vein by use of a conventional venipuncture technique.

Blood samples were placed into evacuated heparinized plastic tubes and refrigerated (2°C). Each sample then was centrifuged at 2,000 × g for 20 minutes at 4°C; all samples were centrifuged within 1 hour after collection. Plasma supernatant was aspirated from the collection tubes and placed into duplicate micro-centrifuge tubes for storage. Plasma samples were frozen at −70°C until assayed by use of HPLC-MS-MS.

Tapentadol analytic standards

Certified reference standardsd of tapentadol, desmethyltapentadol, tapentadol sulfate, tapentadol-O-glucuronide, D3-tapentadol, and D3-tapentadol-O-glucuronide were obtained at concentrations of 1.0 mg/mL or 100 μg/mL. The D3-tapentadol and D3-tapentadol-O-glucuronide were used as internal standards at a concentration of 100 ng/mL in acetonitrile-0.1% formic acid. Solutions of tapentadol, desmethyltapentadol, tapentadol sulfate, and tapentadol-O-glucuronide were prepared at 4 concentrations (0.1, 1, 10, and 50 ng/μL) in 50% aqueous acetonitrile and used to create calibrators in 1.0 mL of canine plasma. Eleven calibrators were prepared (concentration range, 1 to 2,000 ng/mL). A second set of calibrators containing only tapentadol-O-glucuronide was also prepared in 100 μL of canine plasma (concentration range, 100 to 20,000 ng/mL). Three quality control samples were prepared in canine plasma for each set of calibrators. Aliquots of canine plasma (which contained no drugs) obtained from at least 3 dogs were tested for matrix effects and found to be suitable for use in the analysis; these plasma samples were used for preparation of the calibrators and quality control samples.

Sample preparation

An aliquot (100 μL) of plasma samples obtained from the experimental dogs, calibrators, and quality control samples was pipetted into 1.5-mL polypropylene centrifuge vials, and proteins were precipitated by the addition of 400 μL of the internal standard solution. Samples were capped and centrifuged at 5,400 × g for 20 minutes. Supernatant was decanted into glass cell culture tubes and dried by use of nitrogen gas at 50°C in a concentration evaporator.e Contents of each tube were reconstituted with 75 μL of 25% aqueous acetonitrile followed by 125 μL of deionized water. Samples then were transferred to autosampler vials fitted with glass inserts and centrifuged at 2,000 × g for 20 minutes before HPLC-MS-MS analysis.

HPLC-MS-MS analysis of plasma concentrations

Plasma concentrations of tapentadol, desmethyltapentadol, tapentadol sulfate, and tapentadol-O-glucuronide were quantified with HPLC-MS-MS by use of a method described elsewhere16 and an HPLC-triple-quadrupole mass spectrometerf operating in positive electrospray ionization mode. Samples were analyzed on a column (2.1 mm × 50 mm × 1.8 μm),g which was maintained at 45°C. Injection volume was 10 μL. The HPLC systemh consisted of a pump, autosampler, and column compartment. The mobile phase was 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B). The gradient started at 12.5% solvent B (flow rate, 0.335 mL/min), which was increased to 75% solvent B over 4 minutes and then returned to starting conditions by 5.5 minutes.

Three transition ions were selected for analysis of the parent drug (tapentadol) and metabolites (desmethyltapentadol, tapentadol sulfate, and tapentadol-O-glucuronide). The product ions for tapentadol, desmethyltapentadol, and D3-tapentadol were identical at an m/z of 77.1, 107.1, and 121.1, respectively. The product ions for tapentadol sulfate, tapentadol-O-glucuronide, and D3-tapentadol-O-glucuronide also included ions at an m/z of 107.1 and 121.1. The third product ion for these analytes was at an m/z of 222.1 for tapentadol sulfate and tapentadol-O-glucuronide and an m/z of 225.1 for D3-tapentadol-O-glucuronide.

Plasma blank samples, calibration spiked samples, quality control samples, and canine plasma samples were batch processed by use of a processing method developed for commercially available software.i The processing method automatically identified and integrated each analyte peak in each sample and calculated the calibration curve on the basis of a weighted (1/C) linear fit (C was the measured concentration of tapentadol or the tapentadol metabolites). Calibration curves had a high correlation coefficient (r2 > 0.995) across the concentration range. Quality control samples at concentrations of 15, 150, and 1,500 ng/mL for tapentadol, tapentadol sulfate, and desmethyltapentadol were within a tolerance of ± 15% of the nominal value, with most quality control samples within ± 5%. Quality control samples for tapentadol-O-glucuronide at concentrations of 1,250, 2,500, and 3,750 ng/mL were generally within ± 10% of the nominal value. The limit of quantification for tapentadol, tapentadol sulfate, and desmethyltapentadol was 1.0 ng/mL (limit of detection, < 0.1 ng/mL). The limit of quantification for tapentadol-O-glucuronide was 2.0 ng/mL (limit of detection, 0.2 ng/mL).

Pharmacokinetic and statistical analysis

Data for heart rate and respiratory rate were evaluated for normality by use of the Kolmogorov-Smirnov test; the data were not normally distributed, and results were reported as median and range. A Friedman test (with a Dunn posttest) was performed on data for heart rate, respiratory rate, and sedation score for each dose.

Pharmacokinetic values were determined by noncompartmental analysis.j Briefly, noncompartmental statistical moment analysis was conducted with the parent drug modeled with each of the 3 metabolites simultaneously. Parameters estimated after oral administration were λz (which incorporated at least 3 terminal data points of the concentration-time curve) and half-life of the terminal phase (which was calculated as ln 2/λz). Values for Cmax and Tmax were determined by direct examination of the plasma concentration for each analyte for each of the 3 doses. Similarly, Clast and time of Clast were determined directly from the concentration-time data for individual dogs. The AUC from time 0 to the last quantifiable data point and AUC0-∞ were calculated with the trapezoidal rule by use of log-linear data. The AUC0-∞ was calculated as Clastz for each dog, dose, and metabolite and the parent drug. The area under the moment curve for tapentadol was estimated by use of the logarithmic trapezoidal rule. Mean residence time was determined as area under the moment curve from time 0 extrapolated to infinity divided by AUC0-∞. The same procedures were performed for each metabolite. Total AUC for the parent drug and each metabolite was determined from the estimations of AUC0-∞ for each dog and each dose. Percentage of the total AUC0-∞ for the parent drug and each metabolite was then determined as each individual AUC divided by the total AUC (parent drug plus each of the metabolites), with results expressed as a percentage of the total.

Parameters were tested for normality by use of the Kolmogorov-Smirnov test. Normally distributed data were evaluated (for each dose) by use of a 1-way ANOVA. Data that were not normally distributed were evaluated by use of a 1-way ANOVA by ranks. Values were considered significant at P < 0.05.

Results

Pharmacodynamic analysis

Heart rate and respiratory rate did not change after administration of tapentadol at any dose (Table 1). Sedation scores did not change over time after oral administration of tapentadol at any dose.

Table 1—

Median (range) values for cardiopulmonary variables before and after oral administration of tapentadol at doses of 10, 20, and 30 mg/kg to 6 healthy dogs.

 Heart rate (beats/min)Respiratory rate (breaths/min)
Time10 mg/kg20 mg/kg30 mg/kg10 mg/kg20 mg/kg30 mg/kg
0 min80 (80–140)95 (80–110)90 (66–100)15 (12–70)12 (12–24)12 (12–70)
5 min90 (80–100)90 (80–110)100 (84–110)12 (12–24)12 (12–70)15 (12–18)
15 min90 (80–110)90 (80–120)90 (66–110)12 (12–18)12 (12–70)12 (12–18)
30 min90 (80–100)90 (80–110)90 (80–110)12 (12–18)12 (12–18)12 (12–18)
45 min85 (70–90)90 (80–120)90 (70–100)15 (12–18)12 (12–18)12 (NA)
1 h90 (70–110)90 (80–110)85 (70–110)12 (12–18)12 (12–18)12 (12–18)
1.5 h90 (70–110)90 (70–90)85 (70–100)12 (12–70)12 (NA)12 (12–18)
2 h90 (80–110)90 (70–90)90 (70–100)12 (12–18)12 (12–18)12 (12–18)
4 h80 (80–100)85 (70–90)90 (70–100)12 (12–18)12 (NA)12 (12–18)
6 h95 (60–120)80 (70–100)80 (70–90)12 (NA)12 (NA)12 (NA)
8 h80 (70–90)85 (70–90)85 (60–90)12 (12–18)12 (12–18)12 (NA)
12 h90 (70–110)80 (70–110)85 (70–100)12 (NA)12 (12–18)12 (NA)
24 h90 (70–140)100 (80–110)90 (70–90)12 (12–70)12 (12–18)12 (NA)

There was a 1-week washout period between successive administrations. Time 0 was the time at which tapentadol, administered in 85 g of food, was confirmed to have been consumed.

NA = Not applicable.

Pharmacokinetic analysis

Combinations of 50- and 100-mg tablets were used to approximate the targeted doses of 10, 20, and 30 mg/kg. Actual mean ± SD dose was 9.9 ± 0.14 mg/kg (range, 9.8 to 10.2 mg/kg), 19.9 ± 0.10 mg/kg (range, 19.7 to 20 mg/kg), and 30.0 ± 0.13 mg/kg (range, 29.9 to 30.2 mg/kg) for the 10-, 20-, and 30-mg/kg doses, respectively. Plasma concentrations over time for tapentadol, desmethyltapentadol, tapentadol sulfate, and tapentadol-O-glucuronide were determined for each of the 3 doses (Figure 1).

Figure 1—
Figure 1—

Mean ± SD plasma concentration of tapentadol (A), desmethyltapentadol (B), tapentadol sulfate (C), and tapentadol-O-glucuronide (D) after oral administration of tapentadol at doses of 10 (circles), 20 (squares), and 30 (triangles) mg/kg to 6 healthy dogs. There was a 1-week washout period between successive administrations. Notice that the scale on the y-axis differs among panels.

Citation: American Journal of Veterinary Research 79, 4; 10.2460/ajvr.79.4.367

Tapentadol appeared to be rapidly absorbed by dogs after oral administration of 10, 20, and 30 mg/kg, with a mean ± SD lag time of 0.6 ± 0.3 hours, 0.28 ± 0.27 hours, and 0.36 ± 0.32 hours after oral administration, respectively; these lag time values did not differ significantly (P = 0.331). Mean Tmax of tapentadol was 2.7 ± 0.9 hours and 2.4 ± 1.2 hours after doses of 10 and 20 mg/kg, whereas Tmax was 3.5 ± 1.2 hours after the 30-mg/kg dose (Table 2); these values did not differ significantly (P = 0.22). Mean Tmax of tapentadol after doses of 10, 20, and 30 mg/kg was 10.2 ± 1.8 ng/mL, 19.7 ± 5.5 ng/mL, and 31 ± 7.5 ng/mL, respectively; these values differed significantly (P < 0.001). Plasma concentrations of tapentadol decreased from Cmax; half-life of the terminal phase was approximately 3.5, 3.7, and 3.7 hours for the doses of 10, 20, and 30 mg/kg, respectively; these values did not differ significantly (P = 0.876). Mean plasma tapentadol AUC increased linearly with dose, from 62.6 ± 8.6 h•ng/mL at 10 mg/kg to 121 ± 22.5 h•ng/mL at 20 mg/kg to 225 ± 36 h•ng/mL at 30 mg/kg; these values differed significantly (P < 0.001). Mean of the last tapentadol concentration with a concentration greater than the LLOQ (> 1.0 ng/mL) after administration of a dose of 10, 20, and 30 mg/kg was 1.4 ± 0.3 ng/mL, 1.5 ± 0.4 ng/mL, and 3.0 ± 0.8 ng/mL, respectively, and was detected at 14, 24, and 24 hours, respectively. The Clast and time of Clast after a dose of 10 mg/kg were significantly (P < 0.001) different from those after a dose of 20 and 30 mg/kg. Of importance, Clast was detected at 24 hours after administration of the higher doses.

Table 2—

Mean ± SD results of noncompartmental analysis of plasma concentrations of tapentadol over time after oral administration of tapentadol at doses of 10, 20, or 30 mg/kg to 6 healthy dogs.

Parameter10 mg/kg20 mg/kg30 mg/kg
R20.95 ± 0.060.88 ± 0.160.85 ± 0.10
λz (1/h)*0.20 (0.16–0.26)0.19 (0.17–0.22)0.19 (0.11–0.25)
T1/2 λz (h)*3.5 (2.7–4.5)3.7 (3.1–4.0)3.7 (2.8–6.5)
Tlag (h)0.60 ± 0.300.28 ± 0.270.36 ± 0.32
Tmax (h)2.7 ± 0.92.4 ± 1.23.5 ± 1.2
Cmax (ng/mL)10.2 ± 1.819.7 ± 5.531.0 ± 7.5
Clast (ng/mL)1.4 ± 0.31.5 ± 0.43.0 ± 0.8
AUCTotal (h•ng/mL)62.6 ± 8.6121.0 ± 22.5225.0 ± 36.0
AUC0-∞ (h•ng/mL)65.5 ± 10.0144.0 ± 19.0274.5 ± 18.0
AUC%extrap (%)16.2 ± 3.316.0 ± 8.918.0 ± 10.0
AUMC0-∞ (h•h•ng/mL)548 ± 2611,830 ± 6564,143 ± 1,644

Values reported are geometric mean (range).

AUC%extrap = Percentage of the AUC that was extrapolated. AUCTotal = Total AUC for the parent drug plus each of the metabolites. AUMC0–∞ = Area under the moment curve from time 0 extrapolated to infinity; time 0 was the time at which tapentadol, administered in 85 g of food, was confirmed to have been consumed. t1/2 λz = Half-life of the terminal phase. Tlag = Lag time between administration and detection of tapentadol concentrations greater than the LLOQ.

At least 3 metabolites of tapentadol were detected in the plasma of dogs after all 3 doses. Desmethyltapentadol (a product of phase I metabolism) concentration was above the LLOQ after administration of a dose of 10 mg/kg for only a few data points. Therefore, it was not possible to calculate the value for λz or the half-life of desmethyltapentadol. After tapentadol was administered at doses of 20 and 30 mg/kg, plasma desmethyltapentadol concentrations were above the LLOQ for a mean ± SD of 10 ± 2.0 hours and 19 ± 7.3 hours, respectively (Table 3). The Cmax for tapentadol after doses of 10, 20, and 30 mg/kg was 266% to 443% the Cmax for desmethyltapentadol. The dose response (total AUC) for desmethyltapentadol increased in a linear manner up to the dose of 20 mg/kg; however, at the dose of 30 mg/kg, the AUC for desmethyltapentadol did not increase in a linear manner.

Table 3—

Mean ± SD results of noncompartmental analysis of plasma concentrations of desmethyltapentadol over time after oral administration of tapentadol at doses of 10, 20, or 30 mg/kg to 6 healthy dogs.

Parameter10 mg/kg20 mg/kg30 mg/kg
R20.70 ± 00.97 ± 0.040.91 ± 0.09
λz (1/h)*ND0.13 (0.07–0.19)0.11 (0.06–0.50)
t1/2 λz (h)*ND5.9 (3.6–9.8)6.2 (1.4–12.0)
Tlag (h)1.10 ± 0.600.87 ± 0.480.90 ± 0.40
Tmax (h)2.0 ± 1.02.3 ± 1.33.5 ± 1.2
Cmax (ng/mL)2.3 ± 1.17.4 ± 3.610.0 ± 7.7
Clast (ng/mL)1.4 ± 0.31.4 ± 0.51.3 ± 0.3
AUCTotal (h•ng/mL)4.5 ± 3.135.4 ± 18.759.8 ± 15.0
AUC0-∞ (h•ng/mL)5.9 ± 3.353.0 ± 20.073.0 ± 24.0
AUC%extrap (%)24.0 ± 025.0 ± 11.019.0 ± 7.0
AUMC0–∞ (h•h•ng/mL)18 ± 0515 ± 4001,014 ± 610

ND = Not determined.

See Table 2 for remainder of key.

Concentrations of products of phase II metabolism of tapentadol (sulfate and glucuronide conjugates) were higher than concentrations of the parent drug or desmethyltapentadol. Administration of a dose of 10, 20, and 30 mg/kg resulted in a Cmax of tapentadol sulfate that was at approximately the same time as the Cmax of the parent drug but at concentrations 19.5, 17, and 16.5 times the plasma concentrations of the parent drug, respectively (Table 4). Plasma tapentadol sulfate concentrations remained above the LLOQ for 24 hours after each of the 3 doses. In addition, administration resulted in linear responses for tapentadol sulfate concentrations on the basis of plots for dose versus Cmax (r2 = 0.996) or dose versus AUC0-∞ (r2 = 0.981). The Cmax of tapentadol sulfate was detected at 2 (10 and 20 mg/kg) and 4 (30 mg/kg) hours. Mean Cmax for tapentadol sulfate was 195, 336, and 511 ng/mL after administration of a dose of 10, 20, and 30 mg/kg, respectively.

Table 4—

Mean ± SD results of noncompartmental analysis of plasma concentrations of tapentadol sulfate over time after oral administration of tapentadol at doses of 10, 20, or 30 mg/kg to 6 healthy dogs.

Parameter10 mg/kg20 mg/kg30 mg/kg
R20.96 ± 0.060.97 ± 0.040.90 ± 0.10
λz (1/h)*0.09 (0.07–0.10)0.13 (0.07–0.19)0.08 (0.03–0.14)
t1/2 λz (h)*7.6 (4.7–12.0)8.0 (6.8–10.0)6.2 (1.4–12.0)
Tlag (h)0.40 ± 0.200.16 ± 0.050.30 ± 0.18
Tmax (h)2.7 ± 1.02.4 ± 1.23.5 ± 1.1
Cmax (ng/mL)195 ± 43336 ± 58511 ± 110
Clast (ng/mL)15 ± 829 ± 1452 ± 21
AUCTotal (h•ng/mL)1,355 ± 2692,390 ± 5583,950 ± 1012
AUC0-∞ (h•ng/mL)1,553 ± 3692,746 ± 7744,687 ± 1,006
AUC%extrap (%)12.0 ± 6.812.0 ± 4.017.0 ± 9.0
AUMC0–∞ (h•h•ng/mL)17,875 ± 8,34131,981 ± 15,37062,742 ± 16,701

See Table 2 for key.

Glucuronide conjugates of tapentadol were detected in plasma before the parent drug was detected. The Cmax of tapentadol-O-glucuronide was detected between 2.6 and 4 hours, but at concentrations 6- to 800-fold the Cmax for the parent drug (Table 5).

Table 5—

Mean ± SD results of noncompartmental analysis of plasma concentrations of tapentadol-O-glucuronide over time after oral administration of tapentadol at doses of 10, 20, or 30 mg/kg to 6 healthy dogs.

Parameter10 mg/kg20 mg/kg30 mg/kg
R20.95 ± 0.070.94 ± 0.090.90 ± 0.08
λz (1/h)*0.10 (0.08–0.15)0.13 (0.07–0.19)0.10 (0.06–0.15)
t1/2 λz (h)*6.6 (4.5–8.4)8.0 (6.8–10.0)7.0 (4.8–11.6)
Tlag (h)0.10 ± 0.070.01 ± 0.030.06 ± 0.07
Tmax (h)2.7 ± 1.02.6 ± 1.04.0 ± 1.2
Cmax (ng/mL)5,570 ± 41116,463 ± 4,64821,552 ± 1,453
Clast (ng/mL)271 ± 132496 ± 1581,180 ± 574
AUCTotal (h•ng/mL)34,654 ± 4,00182,037 ± 13,212144,804 ± 32,209
AUC0–∞ (h•ng/mL)37,539 ± 5,21487,141 ± 12,790157,352 ± 36,208
AUC%extrap (%)7.0 ± 4.06.0 ± 3.47.9 ± 3.2
AUMC0–∞ (h•h•ng/mL)337,523 ± 110,842679,944 ± 137,8631,513,853 ± 508,673

See Table 2 for key.

The Cmax of tapentadol after administration of doses of 10, 20, and 30 mg/kg was 5.2% to 6.0% and 0.12% to 0.18% the Cmax of tapentadol sulfate and tapentadol-O-glucuronide, respectively. Similar to the situation for tapentadol and tapentadol sulfate, the Cmax (r2 = 0.96) and AUC0-∞ (r2 = 0.99) for tapentadol-O-glucuronide increased by dose in a linear manner. The Cmax for tapentadol-O-glucuronide was detected at 2 (10 and 20 mg/kg) and 4 (30 mg/kg) hours. Mean Cmax of tapentadol-O-glucuronide was 5,570, 16,463, and 21,552 ng/mL after administration of doses of 10, 20, and 30 mg/kg, respectively.

Evaluation of the AUC for tapentadol and each of the 3 metabolites, compared with the total AUC for the parent drug and metabolites, confirmed that tapentadol rapidly underwent phase II metabolism to the sulfate and glucuronide conjugates in the dogs. Mean ± SD AUC0-∞ for tapentadol was 0.16 ± 0.02% of the total AUC, whereas mean AUC0-∞ was 0.04 ± 0.01% for desmethyltapentadol, 2.80 ± 0.51% for tapentadol sulfate, and 97 ± 0.51% for tapentadol-O-glucuronide.

Discussion

Tapentadol use in dogs is currently being evaluated to enable development and characterization of more efficacious and alternative modes of analgesia in canine patients. To our knowledge, the study reported here was the first in which oral administration of tapentadol in a randomized crossover design was used to evaluate pharmacokinetics and pharmacodynamics as well as to determine standardized dosing profiles for each dog. This allowed accurate pharmacokinetic and pharmacodynamic evaluation at specific time points. Doses in other studies ranged from 2 mg/kg12 to 15.7 mg/kg,17 with all dogs receiving approximately the same dose that had been used previously in humans.18

Information for rats and humans indicates that there is a substantial first-pass effect (mean reduction in absolute bioavailability of 92% and 68%, respectively) after oral administration.19 Most of the first-pass effect in dogs of the present study involved phase II conjugation to glucuronides or sulfates, and the lag time until detection of the sulfate (10 to 20 minutes) and glucuronide (0.6 to 6 minutes) conjugates suggested rapid first-pass formation of these metabolites in dogs. Although we did not specifically address the possibility that cytochrome P450 isoforms contributed directly to the metabolism of tapentadol in dogs, it would appear to have been limited in comparison with the phase II activity.

The metabolite profile seen in this study is similar to the profiles observed for humans.20 Furthermore, although genetic polymorphisms in UGT and sulfotransferase isoforms have been identified in humans, these polymorphisms are not the primary contributing factor for pharmacological inactivity. Rather, the production of inactive metabolites occurs primarily through phase II metabolism.20 It is likely in dogs that adverse reactions will be limited to patients with renal dysfunction or possibly severe hepatic disorders.

Tapentadol is metabolized mainly by O-glucuronidation mediated by UGT1A9 and UGT2B713 and sulfotransferases in the liver of humans.21 Tapentadol also undergoes oxidation and demethylation in humans; however, these are minimal routes of metabolism. In the dogs of the study reported here, it was apparent that tapentadol had many pharmacological similarities to results for humans. Tapentadol is rapidly absorbed with a Tmax of 1.25 hours in humans,19 whereas it was 2.4 to 3.5 hours for dogs of the present study. The elimination half-life is estimated to be 4 hours in humans19 and was 3.5 to 3.7 hours in dogs in the study reported here. Conjugated metabolites are almost completely eliminated through urinary excretion in humans.13 Conjugation of tapentadol to glucuronides comprises approximately 55% of the dose in humans,19 whereas it was estimated to be 97% of the total AUC in dogs of the present study. Similarly, sulfated tapentadol comprises approximately 15% of metabolites in humans,19 but it encompassed only 2.8% of the total drug in the dogs of the present study. Cytochrome P450 metabolism via cytochrome P450 2D6 and 2C9/19 comprises 15% of the metabolism in humans,19 whereas it was < 0.05% in the dogs of the study reported here. Although the metabolites derived from the parent compound comprised > 99.84% of the mean AUC0-∞ for the dogs of the present study, it has been found that these metabolites are not actively contributing to an analgesic mechanism of action in humans.22 The importance of this finding becomes evident when the mechanism of action of tapentadol is compared to that of similar analgesics, such as tramadol. Tramadol must undergo metabolism to form multiple active metabolites. These metabolites possess μ-opioid-like effects and also interact with serotonin receptors and are responsible for the adverse effects associated with tramadol. Most of the tapentadol metabolites in the present study were produced by phase II reactions that do not have inherent activity in humans. Therefore, these data suggested that tapentadol may be associated with fewer adverse effects in dogs.

The parent compound represented only 0.16% of the total concentration of drug in the pharmacokinetic analysis. The metabolites tapentadol-O-glucuronide, tapentadol sulfate, and desmethyltapentadol represented 97%, 2.8%, and 0.04% of the total concentration, respectively. Because plasma concentrations of desmethyltapentadol exceeded the LLOQ only between 1.5 and 4 hours after administration, it was considered a minor metabolite of the parent drug. Because the lag time for detection of desmethyltapentadol was 52 to 66 minutes after administration, it was possible that some of this metabolite was formed in the intestinal wall or at a later time in the liver.

The Cmax of tapentadol previously reported for dogs12 is approximately 13.5 times that detected in the study reported here. We hypothesize that this difference in Cmax may have been attributable to differences in HPLC-MS-MS detection of the tapentadol moiety. Although we could not verify this was the reason that the results for the present study conflicted with those previous results, it should be mentioned that the total plasma drug concentration of the parent compound and metabolites at each time point (as determined on the basis of the tapentadol moiety) were similar to plasma concentrations reported in the aforementioned study.12 Additionally, results for the study reported here had the same linearity (Cmax, AUC, and Tmax) when higher doses were administered, which is similar to results described for a comparable study23 of humans. Further studies are needed to elucidate the importance of these metabolites and their pharmacokinetic effects and clinical efficacy in dogs.

Tapentadol caused no changes in heart and respiratory rates in the dogs of the present study. In a previous study,12 tapentadol administration to dogs caused panting (particularly after IV administration), although this was not quantified. The limited number of adverse effects appeared to be desirable, but it should be mentioned that Clast increased linearly with increases in the dose. As such, quantitative determination of plasma concentrations with multiple daily doses is warranted to enable evaluation of potential adverse effects and determine ways in which to limit those effects. The Clast for the parent drug was detected at 24 hours for the 20- and 30-mg/kg doses. For the metabolites tapentadol sulfate and tapentadol-O-glucuronide, Clast was detected at 24 hours for all 3 doses. In addition, Clast for the metabolite desmethyltapentadol was detected at 24 hours for the 30-mg/kg dose but not the 10- or 20-mg/kg dose. Desmethyltapentadol contributed only 0.04% of the total amount of detectable drug, which may have been a contributing factor for its limited detection with the lower doses. Tapentadol-O-glucuronide was the major metabolite, contributing 97% of the total amount of detectable drug. An increase in Clast suggested that there may be drug accumulation with multiple daily doses. The contribution of multiple daily doses to potential adverse effects necessitates further studies. The efficacy of tapentadol in dogs with signs of pain should be investigated. The mean ± SD Cmax of tapentadol detected after doses of 10, 20, and 30 mg/kg was 10.2 ± 1.8 ng/mL, 19.7 ± 5.5 ng/mL, and 31 ± 7.5 ng/mL, respectively, which is consistent with minimal effective concentrations of 5 to 300 ng/mL.9,12

Sedation scores did not differ after administration of the 3 doses of tapentadol. It might be expected that higher doses would cause greater sedation. However, this was not observed in the study reported here. There were 2 reasons for the fact that the sedation scores did not differ significantly among the doses. First, this may have been attributable to variability in the individual temperament of each dog as well as variations in the surrounding environment. Each dog was a purpose-bred mixed-breed dog with minimal exposure to handling and socialization. Although the laboratory environment was strictly controlled, day-to-day variability from outside stimuli may have been a factor that affected the sedation scores. Second, pharmacological characteristics (eg, binding affinity for the μ-opioid receptor, 5-hydroxy-trypamine metabolism, norepinephrine uptake, and effects of active metabolites) attributable to sedation induced by other drugs were reduced or absent for tapentadol administration and its metabolism. This was further supported by the small percentage of the parent compound (mean ± SD of the total AUC, 0.16 ± 0.02%) responsible for the active effects in the body after administration that contributed to the lack of an increase in sedative effects with an increase in the dose. In previous studies12,24 of IV and oral administration of tapentadol to dogs, sedation was anecdotally noted. Additionally, the sedation scoring system used in the present study may not have been sufficiently sensitive to detect subtle differences in sedation.

Tapentadol has a dual mechanism of action, affinity for the μ-opioid receptor that is much less than that of morphine but which induces nearly equipotent analgesia as does morphine, lack of serotonergic activity, and potent action of the parent molecule. The therapeutic profile of tapentadol in dogs may offer advantages over commonly used but poorly efficacious drugs (eg, tramadol). Further investigation into the activity of the secondary metabolites in dogs is warranted. Data provided in the study reported here suggested that the disposition of tapentadol in dogs was extremely similar to that in humans. Rapid conjugation of the parent drug limited the availability of the active drug to the dogs. Further studies are warranted to investigate the usefulness of tapentadol in clinically affected dogs and to evaluate multiple daily dosing regimens with regard to plasma concentrations and adverse effects. Tapentadol has the potential to provide a useful alternative option for pain control in dogs, although studies are needed to determine its effects in dogs with acute and chronic pain.

Acknowledgments

Supported by a grant from the American College of Veterinary Surgeons Foundation and a grant from the Canine Research Funds of The Ohio State University.

The authors thank Linda Bednarski for technical assistance.

ABBREVIATIONS

AUC

Area under the concentration-time curve

AUC0–∞

Area under the concentration-time curve from time 0 extrapolated to infinity

Clast

Last observed quantifiable concentration

Cmax

Maximum plasma concentration

HPLC

High-performance liquid chromatography

HPLC-MS-MS

High-performance liquid chromatography–tandem mass spectrometry

λz

Elimination rate constant

LLOQ

Lower limit of quantification

Tmax

Time of the maximum plasma concentration

UGT

Uridine 5′-diphospho-glucuronosyltransferase

Footnotes

a.

Mila International Inc, Florence, Ky.

b.

Hill's a/d, Hill's Pet Nutrition Inc, Topeka, Kan.

c.

Nucynta, Janssen Pharmaceuticals, Titusville, NJ.

d.

Cerilliant, Round Rock, Tex.

e.

Turbovap, Biotage, Charlotte, NC.

f.

TSQ Vantage triple-stage quadrupole mass spectrometer, ThermoFisher Scientific, San Jose, Calif.

g.

Hypersil Gold column, ThermoFisher Scientific, San Jose, Calif.

h.

Agilent 1100, Agilent Technologies, Santa Clara, Calif.

i.

Xcalibur, ThermoFisher Scientific, San Jose, Calif.

j.

Phoenix WinNonlin, version 6.4, Pharsight Corp, St Louis, Mo.

References

  • 1. Giordano J. The neurobiology of nociceptive and anti-nociceptive systems. Pain Physician 2005;8:277290.

  • 2. Lamont LA. Multimodal pain management in veterinary medicine: the physiologic basis of pharmacologic therapies. Vet Clin North Am Small Anim Pract 2008;38:11731186.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3. Hansen BD. Assessment of pain in dogs: veterinary clinical studies. ILAR J 2003;44:197205.

  • 4. Chang CY, Challa CK, Shah J, et al. Gabapentin in acute postoperative pain management. Biomed Res Int 2014;2014:631756.

  • 5. Pascoe PJ. Opioid analgesics. Vet Clin North Am Small Anim Pract 2000;30:757772.

  • 6. Danysz W, Parsons CG, Kornhuber J, et al. Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents—preclinical studies. Neurosci Biobehav Rev 1997;21:455468.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Blanpied TA, Clarke RJ, Johnson JW. Amantadine inhibits NMDA receptors by accelerating channel closure during channel block. J Neurosci 2005;25:33123322.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. KuKanich B, Papich MG. Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs. J Vet Pharmacol Ther 2004;27:239246.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Tzschentke TM, Christoph T, Kögel B, et al. (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel μ-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther 2007;323:265276.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Tzschentke TM, de Vry J, Terlinden R, et al. Tapentadol hydrochloride: analgesic mu-opioid receptor agonist noradrenaline reuptake inhibitor. Drugs Future 2006;31:10531061.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. Schröder W, Tzschentke TM, Terlinden R, et al. Synergistic interaction between the two mechanisms of action of tapentadol in analgesia. J Pharmacol Exp Ther 2011;337:312320.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Giorgi M, Meizler A, Mills PC. Pharmacokinetics of the novel atypical opioid tapentadol following oral and intravenous administration in dogs. Vet J 2012;194:309313.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13. Vadivelu N, Timchenko A, Huang Y, et al. Tapentadol extended-release for treatment of chronic pain: a review. J Pain Res 2011;4:211218.

    • Search Google Scholar
    • Export Citation
  • 14. Vettorato E, Bacco S. A comparison of the sedative and analgesic properties of pethidine (meperidine) and butorphanol in dogs. J Small Anim Pract 2011;52:426432.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15. Fidman B, Nogid A. Role of tapentadol immediate release (Nucynta) in the management of moderate-to-severe pain. P T 2010;35:330357.

  • 16. Hillewaert V, Pusecker K, Sips L, et al. Determination of tapentadol and tapentadol-O-glucuronide in human serum samples by UPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2015;981–982:4047.

    • Search Google Scholar
    • Export Citation
  • 17. Giorgi M, Meizler A, Mills PC. Quantification of tapentadol in canine plasma by HPLC with spectrofluorimetric detection: development and validation of a new methodology. J Pharm Biomed Anal 2012;67–68:148153.

    • Search Google Scholar
    • Export Citation
  • 18. Pasero C. Tapentadol for multimodal pain management. J Perianesth Nurs 2011;26:343346.

  • 19. Ortho-McNeil-Janssen Pharmaceuticals Inc. Nucynta (tapentadol) immediate-release oral tablets. C-II US initial drug approval: 2008. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2010/022304s003lbl.pdf. Accessed Aug 15, 2016.

    • Search Google Scholar
    • Export Citation
  • 20. Barbosa J, Faria J, Queirós O, et al. Comparative metabolism of tramadol and tapentadol: a toxicological perspective. Drug Metab Rev 2016;48:577592.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21. Terlinden R, Ossig J, Fliegert F, et al. Absorption, metabolism, and excretion of 14C-labeled tapentadol HCl in healthy male subjects. Eur J Drug Metab Pharmacokinet 2007;32:163169.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22. Terlinden R, Kögel BY, Englberger W, et al. In vitro and in vivo characterization of tapentadol metabolites. Methods Find Exp Clin Pharmacol 2010;32:3138.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23. Göhler K, Brett M, Smit JW, et al. Comparative pharmacokinetics and bioavailability of tapentadol following oral administration of immediate- and prolonged-release formulations. Int J Clin Pharmacol Ther 2013;51:338348.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24. Kögel B, Terlinden R, Schneider J. Characterisation of tramadol, morphine and tapentadol in an acute pain model in Beagle dogs. Vet Anaesth Analg 2014;41:297304.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Figure 1—

    Mean ± SD plasma concentration of tapentadol (A), desmethyltapentadol (B), tapentadol sulfate (C), and tapentadol-O-glucuronide (D) after oral administration of tapentadol at doses of 10 (circles), 20 (squares), and 30 (triangles) mg/kg to 6 healthy dogs. There was a 1-week washout period between successive administrations. Notice that the scale on the y-axis differs among panels.

  • 1. Giordano J. The neurobiology of nociceptive and anti-nociceptive systems. Pain Physician 2005;8:277290.

  • 2. Lamont LA. Multimodal pain management in veterinary medicine: the physiologic basis of pharmacologic therapies. Vet Clin North Am Small Anim Pract 2008;38:11731186.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3. Hansen BD. Assessment of pain in dogs: veterinary clinical studies. ILAR J 2003;44:197205.

  • 4. Chang CY, Challa CK, Shah J, et al. Gabapentin in acute postoperative pain management. Biomed Res Int 2014;2014:631756.

  • 5. Pascoe PJ. Opioid analgesics. Vet Clin North Am Small Anim Pract 2000;30:757772.

  • 6. Danysz W, Parsons CG, Kornhuber J, et al. Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents—preclinical studies. Neurosci Biobehav Rev 1997;21:455468.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Blanpied TA, Clarke RJ, Johnson JW. Amantadine inhibits NMDA receptors by accelerating channel closure during channel block. J Neurosci 2005;25:33123322.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. KuKanich B, Papich MG. Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs. J Vet Pharmacol Ther 2004;27:239246.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Tzschentke TM, Christoph T, Kögel B, et al. (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel μ-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther 2007;323:265276.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Tzschentke TM, de Vry J, Terlinden R, et al. Tapentadol hydrochloride: analgesic mu-opioid receptor agonist noradrenaline reuptake inhibitor. Drugs Future 2006;31:10531061.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. Schröder W, Tzschentke TM, Terlinden R, et al. Synergistic interaction between the two mechanisms of action of tapentadol in analgesia. J Pharmacol Exp Ther 2011;337:312320.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Giorgi M, Meizler A, Mills PC. Pharmacokinetics of the novel atypical opioid tapentadol following oral and intravenous administration in dogs. Vet J 2012;194:309313.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13. Vadivelu N, Timchenko A, Huang Y, et al. Tapentadol extended-release for treatment of chronic pain: a review. J Pain Res 2011;4:211218.

    • Search Google Scholar
    • Export Citation
  • 14. Vettorato E, Bacco S. A comparison of the sedative and analgesic properties of pethidine (meperidine) and butorphanol in dogs. J Small Anim Pract 2011;52:426432.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15. Fidman B, Nogid A. Role of tapentadol immediate release (Nucynta) in the management of moderate-to-severe pain. P T 2010;35:330357.

  • 16. Hillewaert V, Pusecker K, Sips L, et al. Determination of tapentadol and tapentadol-O-glucuronide in human serum samples by UPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2015;981–982:4047.

    • Search Google Scholar
    • Export Citation
  • 17. Giorgi M, Meizler A, Mills PC. Quantification of tapentadol in canine plasma by HPLC with spectrofluorimetric detection: development and validation of a new methodology. J Pharm Biomed Anal 2012;67–68:148153.

    • Search Google Scholar
    • Export Citation
  • 18. Pasero C. Tapentadol for multimodal pain management. J Perianesth Nurs 2011;26:343346.

  • 19. Ortho-McNeil-Janssen Pharmaceuticals Inc. Nucynta (tapentadol) immediate-release oral tablets. C-II US initial drug approval: 2008. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2010/022304s003lbl.pdf. Accessed Aug 15, 2016.

    • Search Google Scholar
    • Export Citation
  • 20. Barbosa J, Faria J, Queirós O, et al. Comparative metabolism of tramadol and tapentadol: a toxicological perspective. Drug Metab Rev 2016;48:577592.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21. Terlinden R, Ossig J, Fliegert F, et al. Absorption, metabolism, and excretion of 14C-labeled tapentadol HCl in healthy male subjects. Eur J Drug Metab Pharmacokinet 2007;32:163169.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22. Terlinden R, Kögel BY, Englberger W, et al. In vitro and in vivo characterization of tapentadol metabolites. Methods Find Exp Clin Pharmacol 2010;32:3138.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23. Göhler K, Brett M, Smit JW, et al. Comparative pharmacokinetics and bioavailability of tapentadol following oral administration of immediate- and prolonged-release formulations. Int J Clin Pharmacol Ther 2013;51:338348.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24. Kögel B, Terlinden R, Schneider J. Characterisation of tramadol, morphine and tapentadol in an acute pain model in Beagle dogs. Vet Anaesth Analg 2014;41:297304.

    • Crossref
    • Search Google Scholar
    • Export Citation

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