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Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses
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Veterinary Anaesthesia and Analgesia xxxx, xxx, xxx
RESEARCH PAPER Q1
Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular
Q2 Q8
administration in horses
Q7
RA Reeda, HK Knychb, M Barlettaa, DM Sakaia, MM Rucha, CA Smytha & CA Ryana a
University of Georgia, College of Veterinary Medicine, Athens, GA, USA
b
K.L. Maddy Equine Analytical Chemistry Laboratory, University of CaliforniaeDavis, School of Veterinary Medicine,
Davis, CA, USA Correspondence: Rachel Reed, Large Animal Medicine Department, University of Georgia Veterinary Teaching Hospital, 2200 College Station Road, Athens, GA, 30602, USA. E-mail: [email protected]
Q3
Abstract Objective To compare the pharmacokinetics and pharmacodynamics of hydromorphone in horses after intravenous (IV) and intramuscular (IM) administration. Study design Randomized, masked, crossover design. Animals A total of six adult horses weighing (mean ± standard deviation [SD]) 447 ± 61 kg. Methods Horses were administered three treatments with a 7 day washout. Treatments were hydromorphone 0.04 mg kg⁻1 IV with saline placebo administered IM (H-IV), hydromorphone 0.04 mg kg⁻1 IM with saline placebo IV (HIM), or saline placebo IV and IM (P). Blood was collected for hydromorphone plasma concentration at multiple time points for 24 hours after treatments. Pharmacodynamic data were collected for 24 hours after treatments. Variables included thermal nociceptive threshold, heart rate (HR), respiratory frequency (fR), rectal temperature, and fecal weight. Data were analyzed using mixed-effects linear models. A p value of less than 0.05 was considered statistically significant. Results The mean ± SD hydromorphone terminal half-life (t1/2), clearance and volume of distribution of H-IV was 19 ± 8 minutes, 79 ± 12.9 mL minute⁻1 kg⁻1 and 1125 ± 309 mL kg⁻1. The t1/2 was 26.7 ± 9.25 minutes for H-IM. Area under the curve was 518 ± 87.5 and 1128 ± 810 minute ng mL⁻1 for H-IV and H-IM, respectively. The IM bioavailability was 217%. The overall thermal thresholds for both H-IV and H-IM were significantly greater than P (p < 0.0001 for both) and baseline (p ¼ 0.006). There was no difference in thermal threshold between H-IV and H-IM. No difference was found in physical examination parameters among groups or in comparison to baseline. Fecal weight was significantly less than P for H-IV and H-IM (p ¼ 0.02).
Conclusions IM hydromorphone has high bioavailability and provides a similar degree of antinociception as IV administration. Clinical relevance IM hydromorphone in horses provides a similar degree and duration of antinociception as IV administration. Keywords analgesia, equine, opioid, pharmacodynamics, pharmacokinetics, pharmacology.
Introduction Management of acute pain in veterinary species commonly employs the use of m-agonist opioids (Bennett & Steffey 2002). Hydromorphone is one such m-agonist opioid that is frequently used in management of pain in many species. Desirable qualities of this agent include a long duration of action in most species (4e6 hours) (Wegner et al. 2004; Machado et al. 2006; Natalini & Linardi 2006) and low potential for causing histamine release in dogs (Smith et al. 2001). The pharmacokinetics and pharmacodynamics of hydromorphone in horses after intravenous (IV) administration have been described (Reed et al. 2019). In that study, it was revealed that hydromorphone administration in nonpainful adult horses exhibits pharmacokinetics similar to that described in other species and affords a long-lasting antinociceptive effect (8e12 hours). The antinociceptive effect was accompanied by central nervous system (CNS) excitation and associated physiological effects including increased heart rate (HR), respiratory rate (GR) and rectal temperature. Similar opioid-induced effects have been described previously, with variable severity depending on the drug, dose, route of administration and individual characteristics of the horse (Clutton 2010). Several studies have revealed that the adverse effects after opioid
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Please cite this article as: Reed RA, Knych HK, Barletta M et al. Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.08.049
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IV versus IM hydromorphone in horses RA Reed et al.
administration in horses are less severe after intramuscular (IM) administration in comparison to IV administration. The opioids investigated include morphine (Figueiredo et al. 2012), dermorphin (Robinson et al. 2015), buprenorphine (Davis et al. 2012) and butorphanol (Sellon et al. 2009). The objectives of this study were to compare the pharmacokinetic profiles of hydromorphone after IM and IV administration, and to describe the associated pharmacodynamic variables including thermal threshold, HR, GR, rectal temperature, and fecal output. The authors hypothesized that hydromorphone administered IM would exhibit high bioavailability, longer terminal half-life (t1/2), with a large area under the curve (AUC) and that IV administration would result in a pharmacokinetic profile similar to that described previously (Reed et al. 2019). In addition, it was hypothesized that the analgesic effect of IM administration would be equivalent to that observed after IV administration, with less effect on physical variables, and fecal output. Materials and methods Animals This study was approved by the University of Georgia Institutional Animal Care and Use Committee. A total of six adult Quarter Horses including four females and two males, aged (mean ± standard deviation [SD]) 14 ± 5 years and weighing 447 ± 61 kg, were enrolled. Animals were determined to be healthy based on normal physical examination, complete blood count and biochemistry profile. Horses were randomly assigned to be administered each of three treatments using an online randomizer (www.randomizer.org, PA, USA) in a masked, prospective, Latin square design with a 7 day washout between each treatment. Horses were housed in a temperature-controlled facility throughout each study period. Individuals were acclimatized to the study environment for 12e18 hours prior to treatment administration. During the study period, horses were provided with 0.7 kg of senior feed (Seminole Feed, FL, USA) and 2e3 flakes of timothy hay twice daily with free access to water at all times. On the study day, a 14 gauge IV catheter (Mila International, Inc., KY, USA) was placed aseptically in each jugular vein, one for drug administration and one for blood sampling. On each study day horses were weighed, and a baseline physical examination was performed prior to treatment. Treatments were: 3 mL 0.9% saline IV and 3 mL 0.9% saline IM (P) 0.04 mg kg⁻1 hydromorphone IV and 3 mL 0.9% saline IM (H-IV) 3 mL 0.9% saline IV and 0.04 mg kg⁻1 hydromorphone IM (H-IM)
Each hydromorphone treatment (hydromorphone hydrochloride injection, 10 mg mL⁻1; TEVA Pharmaceuticals, Israel) 2
was diluted to a total volume of 3 mL with 0.9% saline (Baxter Healthcare Corporation, IL, USA) by an individual not involved in data collection to facilitate masking. Both IM and IV injections were administered simultaneously over 60 seconds. The IM injection was administered over the trapezius muscle of the neck using a 22 gauge 2.54 cm needle (BD Medical Technology, NJ, USA) after ruling out IV injection by aspiration. After completion of IV administration in the right jugular vein, the catheter was rapidly flushed and subsequently removed. Plasma concentration determination and pharmacokinetics Whole blood samples of 6 mL volume were obtained from the left jugular vein catheter for hydromorphone and hydromorphone 3-glucuoronide plasma concentration analysis at time points 0, 2, 5, 10, 15, 30, 45, 60, 120, 240, 360, 480, 720, and 1440 minutes after treatment and stored in lithium heparin blood collection tubes (Becton, Dickinson and Company, NJ, USA). The sampling catheter was removed after the 720 minute time point, and the final sample was collected via direct venipuncture of the left jugular vein. Whole blood was refrigerated and processed within 2 hours of collection by centrifuging at 1300 g for 10 minutes and plasma was collected, placed in storage cryovials (VWR International Radnor, PA, USA) and stored at e80 C until analysis. Hydromorphone and hydromorphone 3-glucuronide (H-3G) were quantified in plasma samples using previously published liquid chromatography tandem mass spectrometry (LC-MS/MS) methods (Reed et al. 2019). In brief, for hydromorphone quantification, a partial validation was performed using equine plasma as the matrix. For both analytes, calibrators and negative control samples were prepared fresh for each quantitative assay. In addition, quality control samples [drug free equine plasma fortified with analyte at three concentrations within the standard curve, high, medium and low (3 limit of quantification of the assay)] were included with each sample set as an additional check of accuracy. The response for hydromorphone and H-3-G were linear with a correlation coefficient of 0.99. Pharmacokinetic parameters for hydromorphone and H-3-G were obtained using commercially available software (Phoenix Winonlin Version 8.0; Pharsight, NJ, USA). For the parent compound, since clearance was nonlinear, noncompartmental analysis was performed on plasma hydromorphone concentrations for determination of pharmacokinetic parameters. The AUC was obtained by using the linear up log down trapezoidal rule then dividing the last plasma concentration by the terminal slope extrapolated to infinity. Determination of pharmacokinetic parameters for H-3-G was as described for the parent compound.
Published by Elsevier Ltd on behalf of Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia., xxx, xxx
Please cite this article as: Reed RA, Knych HK, Barletta M et al. Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.08.049
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IV versus IM hydromorphone in horses RA Reed et al.
Pharmacodynamic data collection
Data analysis
For the first 8 hours after treatment, horses were observed constantly for adverse effects of treatment. Physical examination variables including HR, GR and rectal temperature in addition to cutaneous thermal threshold were measured and recorded at baseline (prior to treatment), every 30 minutes for the first 8 hours after treatment, and again at 12 and 24 hours after treatment. Cutaneous thermal threshold was measured over the metacarpus. A coin toss was used to randomize the metacarpus used (right or left), and the area over the dorsal aspect was shaved prior to treatment on each study day. A Velcro strap was used to attach a thermal heating element over the metacarpus. A control unit (WTT2; TopCat Metrology, UK) affixed to the horses’ withers was controlled by a masked operator (RR). Upon activation, the thermal element heated at a rate of 0.8 C second⁻1 until the horse responded to the stimulus by stamping, pawing, lifting or nosing the stimulated limb. The temperature at which this avoidance behavior occurred was recorded as the threshold temperature for that time point. Baseline thermal threshold measurements were obtained in triplicate with a 10 minute interval between each stimulus. In order to avoid skin burns, the control unit terminated heating of the element once a temperature of 55 C was reached, and the thermal element was moved to an adjacent location after each measurement. The skin over which the thermal element was applied was inspected for evidence of tissue damage each time the thermal element was moved and again on the day after treatment. Fecal output was assessed via fecal count (number of defecations), and weight for the first 8 hours after treatment. Feces were collected and immediately weighed after passage. Total fecal weight throughout the 8 hours was used for statistical analysis. An attempt was made to measure step count for the first 8 hours after treatment using a pedometer (PedometersUSA, PA, USA) that was affixed to the metacarpus opposite of the thermal threshold element. A post hoc analysis (Bland & Altman 1986) of two horses was performed manually counting 250 steps and comparing to the pedometer count. As this device had a wide 95% limits of agreement (between e91% and 143%) with a bias of 26% with visually counted steps, the data collected were excluded from further analysis.
A two-tailed paired t test was used to compare the Cmax of H-3G between the H-IV and H-IM groups. Numerical data were tested for normality with the ShapiroeWilk test. Mixed-effects models were used to analyze the effects of time and treatment and the interaction time treatment (fixed effects) on HR, GR, rectal temperature and cutaneous thermal threshold. In these models, the variability of differences was adjusted with the GeissereGreenhouse correction and the horse, and the interactions horse time and horse treatment, were added as random effects. Tukey’s multiple comparisons test were used post hoc in the mixed-effects model. A generic F-test post hoc analysis was performed to compute power when required. One-way analysis of variance (ANOVA) followed by Tukey’s tests analyzed the fecal weight. Friedman followed by Dunn’s tests were used to compare the effect of treatments on fecal count. A survival analysis with log rank test and Bonferroni correction for multiple comparisons was performed to compare the duration of antinociceptive effects of hydromorphone. The antinociceptive effect was considered insignificant when the cutaneous thermal threshold did not increase by more than 5% from baseline for at least two consecutive readings. All analyses were performed using GraphPad Prism Version 8.1.2 (GraphPad Software, CA, USA).
Sample size calculation Sample size was estimated using previously recorded cutaneous thermal threshold AUC data (Reed et al. 2019). A priori calculation with power of 0.9 and alpha of 0.05, AUC (mean ± SD) of 5000 ± 2300, symmetry correlation matrix of 0.5, and difference between matched pairs, resulted in a sample size of 5 (Faul et al. 2009). We elected to enroll six animals to account for hypothetical larger variation in cutaneous thermal threshold and to allow for a balanced Latin square design.
Results Pharmacokinetics The precision and accuracy of the assay were determined by assaying quality control samples in replicates (n ¼ 6). Accuracy was reported as percent nominal concentration, and precision was reported as percent relative standard deviation. For hydromorphone, accuracy was 108%, 94% and 112% for 0.75, 15 and 120 ng mL⁻1, respectively. Precision was 9%, 9% and 4% for 0.75, 15 and 120 ng mL⁻1, respectively. For H-3-G, accuracy was 114%, 90% and 112% for 0.75, 15 and 120 ng mL⁻1, respectively. Precision was 5%, for 0.75, 15 and 120 ng mL⁻1. The technique was optimized to provide a limit of quantitation (LOQ) of 0.25 ng mL⁻1 and a limit of detection of approximately 0.1 ng mL⁻1 for both the parent drug and metabolite. Plasma concentration versus time for hydromorphone and H-3-G are presented in Figs. 1 and 2, respectively. There was a significant difference in AUC between H-IV and H-IM (p ¼ 0.0312) but no significant difference in terminal half-life or lambda. Pharmacokinetic parameters for hydromorphone after IV and IM administration are presented in Table 1. There was one horse that was an outlier, considered by visual inspection of concentration versus time plot, with IM administration
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Please cite this article as: Reed RA, Knych HK, Barletta M et al. Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.08.049
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IV versus IM hydromorphone in horses RA Reed et al.
Pharmacodynamics
Figure 1 Hydromorphone plasma concentration over time in horses (n ¼ 6) administered hydromorphone 0.04 mg kg⁻1 intravenously (triangles) and intramuscularly (circles). Each line represents a single individual.
achieving a maximum plasma concentration (Cmax) and AUCinf higher than the other five horses (Fig. 1). IM bioavailability of hydromorphone was 217% with inclusion of the outlier. Excluding the outlier data, IM bioavailability was 155%. Pharmacokinetic variables for H-3-G after IV and IM administration of hydromorphone are presented in Table 2. The Cmax achieved in H-IV (54.1 ± 5.84 ng mL⁻1) was significantly higher than the Cmax achieved in H-IM (23.5 ± 5.5 ng mL⁻1) (p ¼ 0.0001).
Figure 2 Hydromorphone 3-glucuronide plasma concentration over time in horses (n ¼ 6) administered hydromorphone 0.04 mg kg⁻1 intravenously (open triangles) and intramuscularly (open circles). Each line represents a single individual. 4
Ambient temperature ranged between 21.8 C and 29.3 C (mean ± SD, 25.2 ± 1.3 C). There was a significant effect of treatment (p ¼ 0.0068) and time (p < 0.0064) on thermal threshold (Fig. 3). For both treatments H-IV and H-IM, thermal threshold measurements were significantly greater than P throughout the initial 7 hours after treatment (p ¼ 0.0021 to 0.041). There was no significant difference in thermal threshold between treatments H-IV and H-IM (p ¼ 0.420). In comparison to baseline, thermal thresholds in H-IV and H-IM were significantly greater than baseline through 4 and 6.5 hours after treatment, respectively. Survival analysis is presented in Fig. 4. There was no significant effect of treatment on HR, GR, body temperature or fecal count. The HR values with the H-IV and H-IM treatments were higher than group P but not significantly (p ¼ 0.16). Fecal weight was significantly lower in treatments H-IV (p ¼ 0.011) and H-IM (p ¼ 0.016) in comparison to P; however, H-IV and H-IM were not significantly different from each other (Fig. 5). All individuals in H-IV experienced a short period of excitation lasting 1e2 hours after treatment. This effect was characterized by varying degrees of pacing, vocalizing, rearing and kicking. This behavior was not targeted at the personnel involved, and no individual was in danger at any time. In general, the horses would stand quietly when restrained with a lead rope for collection of physical examination variables. Discussion IV administration of hydromorphone was characterized by a rapid clearance, short terminal t1/2, and large apparent volume of distribution (VDSS) similar to those values reported previously in horses at the same dose after IV administration (Reed et al. 2019). These results were also akin to those found in other mammalian species administered similar dosages of IV hydromorphone (Wegner et al. 2004; Guedes et al. 2008; KuKanich et al. 2008; Kelly et al. 2014). IV hydromorphone exhibited a rapid clearance that exceeded average equine expected hepatic blood flow (25 mL kg⁻1 minute⁻1) (Boxenbaum 1980; Dyke et al. 1998). The clearance rate of 79 mL kg⁻1 minute⁻1 after IV administration of 0.04 mg kg⁻1 hydromorphone is very similar to the clearance rate of 74 mL kg⁻1 minute⁻1 found in a previous study using the same dose (Reed et al. 2019). In that study, the clearance rate exceeded hepatic blood flow. It was presumably caused by opioid-induced excitement, resulting in increased cardiac output (CO) and hepatic blood flow causing an increase in hepatic extraction. CO was not reported in that study; however, the authors did note a significant increase in HR in individuals administered higher dosages. They also reported a dose-dependent increase in total systemic clearance. Similar
Published by Elsevier Ltd on behalf of Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia., xxx, xxx
Please cite this article as: Reed RA, Knych HK, Barletta M et al. Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.08.049
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IV versus IM hydromorphone in horses RA Reed et al. Table 1 Mean ± standard deviation (SD) of pharmacokinetic parameters for hydromorphone after a single intravenous or intramuscular administration of 0.04 mg kg⁻1 of hydromorphone to six horses. All values in this table were generated using noncompartmental analysis Parameter
Intravenous (n ¼ 6)
Intramuscular (n ¼ 6)
C0 (ng mLe1) Cmax (ng mLe1) Tmax (minutes) Lambdaz (1 minutee1) Terminal t1/2 (minute)y AUCinf (minute ng mLe1)* CL (mL minutee1 kge1) MRT (minute) Vdss (mL kge1)
74.9 ± 20.1 e e 0.036 ± 0.017 19.4 ± 8.83 518 ± 87.5 79.0 ± 12.9 14.2 ± 2.65 1125 ± 309
e 20.0 ± 15.3 7.5 ± 4.2 0.025 ± 0.007 26.7 ± 9.25 1128 ± 810 e e e
C0, drug concentration at time 0; Cmax, maximum plasma concentration; Tmax, time of Cmax; lambdaz, slope of terminal portion of plasma concentration curve; AUCinf, area under the curve from time 0 to infinity; Cl, total systemic clearance; MRT, mean residence time; Vdss, volume of distribution at steady state. * Significant difference between groups. y Harmonic mean.
findings have been reported after administration of increasing doses of morphine in horses (Hamamoto-Hardman et al. 2019). The t1/2 reported here of 19.4 ± 8.8 minutes associated with IV administration is less than the 34.0 ± 8.8 minutes previously reported in horses administered the same dose of hydromorphone (Reed et al. 2019). This difference may be attributable to differences in study design and individual variation of horses enrolled in the study. Similarly, the t1/2 is less than that reported in dogs at a dose of 0.10 mg kg⁻1 (34 minutes) (KuKanich et al. 2008), and shorter than that reported previously in other mammalian species. These include cats administered 0.10 mg kg⁻1 (62.8 minutes) (Wegner et al. 2004), and macaques administered 0.075 mg kg⁻1 (142 minutes) (Kelly et al. 2014). The VDSS of IV hydromorphone reported here was 1125 mL kg⁻1, which is similar to that reported previously of 1460 mL
kg⁻1 after IV administration of the same dose (Reed et al. 2019). However, these values are less than those reported in other mammalian species including cats (Wegner et al. 2004), dogs (KuKanich et al. 2008) and macaques (Kelly et al. 2014). IM administration was associated with a long t1/2 and large AUC, affording a bioavailability in excess of 200%, higher than the bioavailability described in other species (Guzman et al. 2014; Kelly et al. 2014). A horse with much higher than expected Cmax and AUCinf was an outlier. This may have resulted from inadvertent IV injection of all or a portion of the treatment within a vessel present at the location of IM administration. Exclusion of this horse resulted in a calculated bioavailability of 155%, which is still higher than what has been found in other species. The authors have chosen to report both these calculated bioavailability values as the significance of the outlier is unclear. A study in macaques administered 0.075 mg kg⁻1 IV and IM revealed a median bioavailability of
Table 2 Mean ± standard deviation (SD) pharmacokinetic parameters for hydromorphone 3-glucuronide after a single intravenous or intramuscular administration of 0.04 mg kge1 of hydromorphone to six horses. All values in this table were generated using noncompartmental analysis Parameter
Intravenous (n ¼ 6)
Intramuscular (n ¼ 6)
Cmax (ng mLe1)* Tmax (minutes) Lambdaz (1 minutee1) Terminal t1/2 (minute)y AUCinf (minute ng mLe1) AUC % extrap
54.1 ± 5.84 11.7 ± 4.08 0.003 ± 0.001 210 ± 43 8776 ± 1505 4.84 ± 2.68
23.5 ± 5.5 47.5 ± 6.12 0.003 ± 0.001 257 ± 76.5 6991 ± 1513 5.11 ± 3.22
Cmax, maximum plasma concentration; Tmax, time of Cmax; lambdaz, slope of terminal portion of plasma concentration curve; AUCinf, area under the curve from time 0 to infinity; AUC % extrap, % of AUC extrapolated. * Significant difference between groups. y Harmonic mean.
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5
Please cite this article as: Reed RA, Knych HK, Barletta M et al. Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.08.049
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IV versus IM hydromorphone in horses RA Reed et al.
Figure 3 Mean ± standard deviation thermal thresholds ( C) at from 0 to 24 hours after administration of hydromorphone to horses (n ¼ 6). IV, hydromorphone intravenous treatment (triangles); IM, hydromorphone intramuscular treatment (circles); and saline (placebo) treatment (squares). *Different from placebo treatment (p < 0.0001).
92% (75e104%) (Kelly et al. 2014). Conversely, in birds the bioavailability was just 75% after IM administration of 0.6 mg kg⁻1 (Guzman et al. 2014). Although the hepatic extraction ratio of hydromorphone has not been established in horses, in humans it was found to be 0.51, classifying hydromorphone as a drug with an intermediate extraction ratio (Parab et al. 1988). Drugs with intermediate hepatic extraction ratios are
Figure 4 Survival analysis of time 0 to loss of antinociceptive effect. Time of event was considered when cutaneous thermal threshold was less than 5% higher than baseline for two consecutive readings. Survival curves comparison was performed with Log-rank test with Bonferroni post hoc adjustments. IV, hydromorphone intravenous treatment (triangles); IM, hydromorphone treatment (circles); and placebo treatment (squares). *Different from placebo treatment (p ¼ 0.047). yDifferent from placebo-saline treatment (p ¼ 0.0012). 6
subject to changes in extraction caused by both alterations in CO and hepatic enzyme activity (Wilkinson & Shand 1975). IV administration of opioid agonists to healthy nonpainful horses has been shown to cause a significant increase in CO (Muir et al. 1978). Although we did not measure CO in this study, it is possible that the high calculated IM bioavailability found here is a result of increased CO after IV administration, resulting in more rapid clearance. The increased clearance would result in a smaller AUC for the IV route of administration. This theory is further supported by the relatively rapid rise in metabolite concentrations (H-3-G) (Fig. 1), in association with a rapid decline in parent compound concentrations (Fig. 2). The active metabolite of hydromorphone, H-3-G, has been documented in many mammalian species and has been shown to have neuroexcitatory effects in rats (Cone et al. 1977; Lotsch 2005). The presence of this metabolite after IV administration has recently been documented in horses (Reed et al. 2019). H-3-G was immediately detected in the plasma in both H-IV and H-IM individuals. The Cmax achieved in H-IV (54.1 ± 5.84 ng mL⁻1) was similar to the Cmax reported previously after IV administration of the same dose (52.6 ± 7.75 ng mL⁻1) (Reed et al. 2019) and was significantly greater than the Cmax achieved in H-IM (23.5 ± 5.5 ng mL⁻1). The t1/2 reported here for both H-IV (210 ± 43 minutes) and H-IM (257 ± 76.5 minute) are similar to those reported previously (279 ± 65.6 minute) after IV administration of the same dose of hydromorphone to horses. The long t1/2 suggests some potential for accumulation of this metabolite with repeated dosing. However, the neuroexcitatory and antinociceptive effects of this metabolite in the horse are unknown. Therefore, the significance of accumulation of the metabolite is unclear. There is a need for further studies investigating the effect of the metabolite in the absence of the parent molecule to determine the clinical relevance of its presence and accumulation. In the current study, the plasma concentration of hydromorphone decreased below the LOQ several hours before the termination of effect on the thermal threshold. This effect has been previously documented in horses (Reed et al. 2019) and several possible explanations were cited. First, the minimum antinociceptive plasma concentration of hydromorphone may be below the LOQ for the assay. Second, it is possible that the H-3-G metabolite with its long t1/2 provides a prolonged antinociceptive effect, although this metabolite has not been investigated as a potential analgesic agent in horses. Lastly, this effect may be attributable to pharmacokinetic hysteresis. Hysteresis occurs when the effect of the drug persists as a result of drug concentration at the effect site lagging behind the plasma concentration, because receptor binding kinetics are slow, or owing to the presence of other effects (Louizos et al. 2014). This effect has been documented previously with several opioids (Groenendaal et al. 2008).
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Please cite this article as: Reed RA, Knych HK, Barletta M et al. Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.08.049
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IV versus IM hydromorphone in horses RA Reed et al.
Figure 5 Mean ± standard error of the mean fecal weight in horses (n ¼ 6) administered hydromorphone 0.04 mg kg⁻1 intravenously (IV), intramuscularly (IM) for 8 hours after administration or placebo e saline treatment. *Different from placebo treatment (p ¼ 0.0109). yDifferent from placebo treatment (p ¼ 0.016).
Thermal threshold was significantly elevated above baseline and P in both H-IV and H-IM for 7 hours after administration. This duration of effect is shorter than previously observed at the same dose, where thermal threshold was elevated for 12 hours after administration (Reed et al. 2019). This difference may be attributed to differences in testing environments and individual variation. Individual variation may also explain the placebo antinociceptive effect observed during the first 5 hours in three horses as the SD of thermal threshold at baseline was within 5% of the mean value obtained. An antinociceptive effect was still apparent, at 12 hours in two out of six horses after IV administration and four out of six horses after IM administration, respectively (Fig. 4). IV administration of hydromorphone causes an increase in HR, GR and body temperature (Reed et al. 2019). This effect is reported for other pure mu opioids administered IV (Muir et al. 1978; Figueiredo et al. 2012; Robinson et al. 2015). With
regard to morphine (Figueiredo et al. 2012) and dermorphin (Robinson et al. 2015), specifically, the effect on HR is greater after IV administration than IM administration. Although we report an increase in HR after hydromorphone administration, there was no statistically significant difference in HR among groups. Similarly, an increase in GR observed after IV administration of dermorphin (Robinson et al. 2015) and butorphanol (Sellon et al. 2009) was not observed after IM administration. However, we were unable to identify a statistically significant increase in GR for either IV or IM administration of hydromorphone in this study. In regard to both HR and GR, the inability to detect a statistically significant difference between treatments is likely attributable to an underpowered sample for these variables. A significant increase in body temperature was reported after IV administration of 0.08 mg kg⁻1 hydromorphone, but not after 0.04 mg kg⁻1 (Reed et al. 2019). The same lack of effect on rectal temperature with this lower dose of hydromorphone was observed in the study reported here. Individuals administered H-IV exhibited signs of excitation lasting approximately 1e2 hours after administration, although we were unable to quantify this effect objectively because of the inability to validate the pedometer used in the study. This behavioral response of nonpainful horses to IV administration of opioids has been previously reported with hydromorphone (Combie et al. 1979; Reed et al. 2019) and other opioids (Carregaro et al. 2007; Clutton 2010; Knych et al. 2014). For both dermorphin (Robinson et al. 2015) and buprenorphine (Davis et al. 2012), it has been noted that the severity of CNS excitation is greater after IV administration in comparison to IM administration. The exact mechanism of excitation is not well established, although it is thought to be associated with activation of dopaminergic pathways (Carregaro et al. 2007). However, the administration of dopamine antagonists failed to inhibit this response in horses administered alfentanil (Pascoe & Taylor 2003). It is also possible that this phenomenon is a result of the neuroexcitatory effects of H-3-G (Cone et al. 1977); however, it is impossible to determine from this study whether the effect was caused by the parent drug or the metabolite. At least one retrospective study has shown that this effect is not observed in horses that are painful at the time of administration (Mircica et al. 2003). The clinical experience of the authors supports this conclusion. Further studies are needed using a more accurate means of quantifying this CNS excitation in painful and nonpainful horses to establish the clinical relevance of this adverse effect. Agonism of kappa and mu opioid receptors in the myenteric plexus of the gastrointestinal tract results in decreased motility (Brock et al. 2012; Menozzi et al. 2012). This effect was confirmed by the decreased fecal weight in subjects administered H-IV and H-IM. Several studies have examined the effect
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Please cite this article as: Reed RA, Knych HK, Barletta M et al. Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.08.049
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of opioids on gastrointestinal motility in horses and have revealed conflicting results. A decrease in gastrointestinal motility has been observed in healthy, nonpainful, adult horses after administration of hydromorphone (Reed et al. 2019), morphine (Boscan et al. 2006; Sano et al. 2011; Figueiredo et al. 2012; Donselmann Im Sande et al. 2017), methadone (Donselmann Im Sande et al. 2017), buprenorphine (Levionnois et al. 2018) and butorphanol (Donselmann Im Sande et al. 2017). Nevertheless, administration of morphine to clinical patients undergoing general anesthesia has not been shown to negatively impact gastrointestinal motility in at least one prospective (Martin-Flores et al. 2014) and one retrospective (Andersen et al. 2006) clinical study. We were unable to objectively quantify the excitement characterized by increased physical activity exhibited by those individuals administered IV hydromorphone, which is a limitation of our study. Although we speculated that during this period of increased physical activity CO increased, this variable was not measured. It is important to note that although this presumed increase in CO may have resulted in an overestimation of IM bioavailability, administration by this route provided a long-lasting analgesic effect. In conclusion, hydromorphone is well absorbed IM and provides long-lasting analgesia as measured by increased thermal threshold after both IV and IM administration, confirming the authors’ hypotheses. IM administration is associated with an equivalent degree and duration of antinociceptive effect in comparison to IV administration. Both routes of administration cause a decrease in fecal output in nonpainful horses in the first 8 hours after administration, as measured by fecal weight. Based on the current study, clinical use of hydromorphone would be expected to provide analgesia lasting up to 8 hours after either IV or IM administration. Q5
Author’s contributions RR: Study design, data collection and management, manuscript preparation; HK: plasma concentration analysis, pharmacokinetic analysis, manuscript preparation; MB: study design, manuscript preparation; DS: data analysis, manuscript preparation; MR and CS: data collection and management, manuscript preparation; CR: study design, data collection and management.
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Conflicts of interest statement Authors declare no conflict of interest. References Andersen MS, Clark L, Dyson SJ et al. (2006) Risk factors for colic in horses after general anaesthesia for MRI or nonabdominal surgery: absence of evidence of effect from perianaesthetic morphine. Equine Vet J 38, 368e374. 8
Bennett RC, Steffey EP (2002) Use of opioids for pain and anesthetic management in horses. Vet Clin N Am Equine Pract 18, 47e60. Bland JM, Altman DG (1986) Statistical methods for assessing agreement between two methods of clinical measurement. Lancet (London, England) 1, 307e310. Boscan P, Van Hoogmoed LM, Farver TB et al. (2006) Evaluation of the effects of the opioid agonist morphine on gastrointestinal tract function in horses. Am J Vet Res 67, 992e997. Boxenbaum H (1980) Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance: extrapolation of data to benzodiazepines and phenytoin. J Pharmacokinet Biopharm 8, 165e176. Brock C, Olesen SS, Olesen AE et al. (2012) Opioid-induced bowel dysfunction: pathophysiology and management. Drugs 72, 1847e1865. Carregaro AB, Luna SP, Mataqueiro MI et al. (2007) Effects of buprenorphine on nociception and spontaneous locomotor activity in horses. Am J Vet Res 68, 246e250. Clutton RE (2010) Opioid analgesia in horses. Vet Clin N Am Equine Pract 26, 493e514. Combie J, Dougherty J, Nugent E, Tobin T (1979) The pharmacology of narcotic analgesics in the horse: IV. Dose and time response relationships for behavioral responses to morphine, meperidine, pentazocine, anileridine, methadone, and hydromorphone. J Equine Med Surg 3, 377e385. Cone EJ, Phelps BA, Gorodetzky CW (1977) Urinary excretion of hydromorphone and metabolites in humans, rats, dogs, guinea pigs, and rabbits. J Pharm Sci 66, 1709e1713. Davis JL, Messenger KM, LaFevers DH et al. (2012) Pharmacokinetics of intravenous and intramuscular buprenorphine in the horse. J Vet Pharmacol Ther 35, 52e58. Donselmann Im Sande P, Hopster K, Kastner S (2017) Effects of morphine, butorphanol and levomethadone in different doses on thermal nociceptive thresholds in horses. Tierarztl Prax Ausg D.Großtiere/Nutztiere 45, 98e106. Dyke TM, Hubbell JA, Sams RA et al. (1998) Hepatic blood flow in horses during the recuperative period from maximal exercise. Am J Vet Res 59, 1476e1480. Faul F, Erdfelder E, Buchner A et al. (2009) Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods 41, 1149e1160. Figueiredo JP, Muir WW, Sams R (2012) Cardiorespiratory, gastrointestinal, and analgesic effects of morphine sulfate in conscious healthy horses. Am J Vet Res 73, 799e808. Groenendaal D, Freijer J, Rosier A et al. (2008) Pharmacokinetic/ pharmacodynamic modelling of the EEG effects of opioids: the role of complex biophase distribution kinetics. Eur J Pharm Sci 34, 149e163. Guedes AG, Papich MG, Rude EP et al. (2008) Pharmacokinetics and physiological effects of intravenous hydromorphone in conscious dogs. J Vet Pharmacol Ther 31, 334e343. Guzman DS, KuKanich B, Drazenovich TL et al. (2014) Pharmacokinetics of hydromorphone hydrochloride after intravenous and intramuscular administration of a single dose to American kestrels (Falco sparverius). Am J Vet Res 75, 527e531.
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Muir WW, Skarda RT, Sheehan WC (1978) Cardiopulmonary effects of narcotic agonists and a partial agonist in horses. Am J Vet Res 39, 1632e1635. Natalini CC, Linardi RL (2006) Analgesic effects of epidural administration of hydromorphone in horses. Am J Vet Res 67, 11e15. Parab PV, Ritschel WA, Coyle DE et al. (1988) Pharmacokinetics of hydromorphone after intravenous, peroral and rectal administration to human subjects. Biopharm Drug Dispos 9, 187e199. Pascoe PJ, Taylor PM (2003) Effects of dopamine antagonists on alfentanil-induced locomotor activity in horses. Vet Anaesth Analg 30, 165e171. Reed R, Barletta M, Mitchell K et al. (2019) The pharmacokinetics and pharmacodynamics of intravenous hydromorphone in horses. Vet Anaesth Analg 46, 395e404. Robinson MA, Guan F, McDonnell S et al. (2015) Pharmacokinetics and pharmacodynamics of dermorphin in the horse. J Vet Pharmacol Ther 38, 321e329. Sano H, Martin-Flores M, Santos LC et al. (2011) Effects of epidural morphine on gastrointestinal transit in unmedicated horses. Vet Anaesth Analg 38, 121e126. Sellon DC, Papich MG, Palmer L et al. (2009) Pharmacokinetics of butorphanol in horses after intramuscular injection. J Vet Pharmacol Ther 32, 62e65. Smith LJ, Yu JK, Bjorling DE et al. (2001) Effects of hydromorphone or oxymorphone, with or without acepromazine, on preanesthetic sedation, physiologic values, and histamine release in dogs. J Am Vet Med Assoc 218, 1101e1105. Wegner K, Robertson SA, Kollias-Baker C et al. (2004) Pharmacokinetic and pharmacodynamic evaluation of intravenous hydromorphone in cats. J Vet Pharmacol Ther 27, 329e336. Wilkinson GR, Shand DG (1975) Commentary: a physiological approach to hepatic drug clearance. Clin Pharmacol Ther 18, 377e390. Received 21 June 2019; accepted 22 August 2019. Available online xxx
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RESEARCH PAPER Q1
Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular
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administration in horses
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RA Reeda, HK Knychb, M Barlettaa, DM Sakaia, MM Rucha, CA Smytha & CA Ryana a
University of Georgia, College of Veterinary Medicine, Athens, GA, USA
b
K.L. Maddy Equine Analytical Chemistry Laboratory, University of CaliforniaeDavis, School of Veterinary Medicine,
Davis, CA, USA Correspondence: Rachel Reed, Large Animal Medicine Department, University of Georgia Veterinary Teaching Hospital, 2200 College Station Road, Athens, GA, 30602, USA. E-mail: [email protected]
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Abstract Objective To compare the pharmacokinetics and pharmacodynamics of hydromorphone in horses after intravenous (IV) and intramuscular (IM) administration. Study design Randomized, masked, crossover design. Animals A total of six adult horses weighing (mean ± standard deviation [SD]) 447 ± 61 kg. Methods Horses were administered three treatments with a 7 day washout. Treatments were hydromorphone 0.04 mg kg⁻1 IV with saline placebo administered IM (H-IV), hydromorphone 0.04 mg kg⁻1 IM with saline placebo IV (HIM), or saline placebo IV and IM (P). Blood was collected for hydromorphone plasma concentration at multiple time points for 24 hours after treatments. Pharmacodynamic data were collected for 24 hours after treatments. Variables included thermal nociceptive threshold, heart rate (HR), respiratory frequency (fR), rectal temperature, and fecal weight. Data were analyzed using mixed-effects linear models. A p value of less than 0.05 was considered statistically significant. Results The mean ± SD hydromorphone terminal half-life (t1/2), clearance and volume of distribution of H-IV was 19 ± 8 minutes, 79 ± 12.9 mL minute⁻1 kg⁻1 and 1125 ± 309 mL kg⁻1. The t1/2 was 26.7 ± 9.25 minutes for H-IM. Area under the curve was 518 ± 87.5 and 1128 ± 810 minute ng mL⁻1 for H-IV and H-IM, respectively. The IM bioavailability was 217%. The overall thermal thresholds for both H-IV and H-IM were significantly greater than P (p < 0.0001 for both) and baseline (p ¼ 0.006). There was no difference in thermal threshold between H-IV and H-IM. No difference was found in physical examination parameters among groups or in comparison to baseline. Fecal weight was significantly less than P for H-IV and H-IM (p ¼ 0.02).
Conclusions IM hydromorphone has high bioavailability and provides a similar degree of antinociception as IV administration. Clinical relevance IM hydromorphone in horses provides a similar degree and duration of antinociception as IV administration. Keywords analgesia, equine, opioid, pharmacodynamics, pharmacokinetics, pharmacology.
Introduction Management of acute pain in veterinary species commonly employs the use of m-agonist opioids (Bennett & Steffey 2002). Hydromorphone is one such m-agonist opioid that is frequently used in management of pain in many species. Desirable qualities of this agent include a long duration of action in most species (4e6 hours) (Wegner et al. 2004; Machado et al. 2006; Natalini & Linardi 2006) and low potential for causing histamine release in dogs (Smith et al. 2001). The pharmacokinetics and pharmacodynamics of hydromorphone in horses after intravenous (IV) administration have been described (Reed et al. 2019). In that study, it was revealed that hydromorphone administration in nonpainful adult horses exhibits pharmacokinetics similar to that described in other species and affords a long-lasting antinociceptive effect (8e12 hours). The antinociceptive effect was accompanied by central nervous system (CNS) excitation and associated physiological effects including increased heart rate (HR), respiratory rate (GR) and rectal temperature. Similar opioid-induced effects have been described previously, with variable severity depending on the drug, dose, route of administration and individual characteristics of the horse (Clutton 2010). Several studies have revealed that the adverse effects after opioid
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Please cite this article as: Reed RA, Knych HK, Barletta M et al. Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.08.049
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administration in horses are less severe after intramuscular (IM) administration in comparison to IV administration. The opioids investigated include morphine (Figueiredo et al. 2012), dermorphin (Robinson et al. 2015), buprenorphine (Davis et al. 2012) and butorphanol (Sellon et al. 2009). The objectives of this study were to compare the pharmacokinetic profiles of hydromorphone after IM and IV administration, and to describe the associated pharmacodynamic variables including thermal threshold, HR, GR, rectal temperature, and fecal output. The authors hypothesized that hydromorphone administered IM would exhibit high bioavailability, longer terminal half-life (t1/2), with a large area under the curve (AUC) and that IV administration would result in a pharmacokinetic profile similar to that described previously (Reed et al. 2019). In addition, it was hypothesized that the analgesic effect of IM administration would be equivalent to that observed after IV administration, with less effect on physical variables, and fecal output. Materials and methods Animals This study was approved by the University of Georgia Institutional Animal Care and Use Committee. A total of six adult Quarter Horses including four females and two males, aged (mean ± standard deviation [SD]) 14 ± 5 years and weighing 447 ± 61 kg, were enrolled. Animals were determined to be healthy based on normal physical examination, complete blood count and biochemistry profile. Horses were randomly assigned to be administered each of three treatments using an online randomizer (www.randomizer.org, PA, USA) in a masked, prospective, Latin square design with a 7 day washout between each treatment. Horses were housed in a temperature-controlled facility throughout each study period. Individuals were acclimatized to the study environment for 12e18 hours prior to treatment administration. During the study period, horses were provided with 0.7 kg of senior feed (Seminole Feed, FL, USA) and 2e3 flakes of timothy hay twice daily with free access to water at all times. On the study day, a 14 gauge IV catheter (Mila International, Inc., KY, USA) was placed aseptically in each jugular vein, one for drug administration and one for blood sampling. On each study day horses were weighed, and a baseline physical examination was performed prior to treatment. Treatments were: 3 mL 0.9% saline IV and 3 mL 0.9% saline IM (P) 0.04 mg kg⁻1 hydromorphone IV and 3 mL 0.9% saline IM (H-IV) 3 mL 0.9% saline IV and 0.04 mg kg⁻1 hydromorphone IM (H-IM)
Each hydromorphone treatment (hydromorphone hydrochloride injection, 10 mg mL⁻1; TEVA Pharmaceuticals, Israel) 2
was diluted to a total volume of 3 mL with 0.9% saline (Baxter Healthcare Corporation, IL, USA) by an individual not involved in data collection to facilitate masking. Both IM and IV injections were administered simultaneously over 60 seconds. The IM injection was administered over the trapezius muscle of the neck using a 22 gauge 2.54 cm needle (BD Medical Technology, NJ, USA) after ruling out IV injection by aspiration. After completion of IV administration in the right jugular vein, the catheter was rapidly flushed and subsequently removed. Plasma concentration determination and pharmacokinetics Whole blood samples of 6 mL volume were obtained from the left jugular vein catheter for hydromorphone and hydromorphone 3-glucuoronide plasma concentration analysis at time points 0, 2, 5, 10, 15, 30, 45, 60, 120, 240, 360, 480, 720, and 1440 minutes after treatment and stored in lithium heparin blood collection tubes (Becton, Dickinson and Company, NJ, USA). The sampling catheter was removed after the 720 minute time point, and the final sample was collected via direct venipuncture of the left jugular vein. Whole blood was refrigerated and processed within 2 hours of collection by centrifuging at 1300 g for 10 minutes and plasma was collected, placed in storage cryovials (VWR International Radnor, PA, USA) and stored at e80 C until analysis. Hydromorphone and hydromorphone 3-glucuronide (H-3G) were quantified in plasma samples using previously published liquid chromatography tandem mass spectrometry (LC-MS/MS) methods (Reed et al. 2019). In brief, for hydromorphone quantification, a partial validation was performed using equine plasma as the matrix. For both analytes, calibrators and negative control samples were prepared fresh for each quantitative assay. In addition, quality control samples [drug free equine plasma fortified with analyte at three concentrations within the standard curve, high, medium and low (3 limit of quantification of the assay)] were included with each sample set as an additional check of accuracy. The response for hydromorphone and H-3-G were linear with a correlation coefficient of 0.99. Pharmacokinetic parameters for hydromorphone and H-3-G were obtained using commercially available software (Phoenix Winonlin Version 8.0; Pharsight, NJ, USA). For the parent compound, since clearance was nonlinear, noncompartmental analysis was performed on plasma hydromorphone concentrations for determination of pharmacokinetic parameters. The AUC was obtained by using the linear up log down trapezoidal rule then dividing the last plasma concentration by the terminal slope extrapolated to infinity. Determination of pharmacokinetic parameters for H-3-G was as described for the parent compound.
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Please cite this article as: Reed RA, Knych HK, Barletta M et al. Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.08.049
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Pharmacodynamic data collection
Data analysis
For the first 8 hours after treatment, horses were observed constantly for adverse effects of treatment. Physical examination variables including HR, GR and rectal temperature in addition to cutaneous thermal threshold were measured and recorded at baseline (prior to treatment), every 30 minutes for the first 8 hours after treatment, and again at 12 and 24 hours after treatment. Cutaneous thermal threshold was measured over the metacarpus. A coin toss was used to randomize the metacarpus used (right or left), and the area over the dorsal aspect was shaved prior to treatment on each study day. A Velcro strap was used to attach a thermal heating element over the metacarpus. A control unit (WTT2; TopCat Metrology, UK) affixed to the horses’ withers was controlled by a masked operator (RR). Upon activation, the thermal element heated at a rate of 0.8 C second⁻1 until the horse responded to the stimulus by stamping, pawing, lifting or nosing the stimulated limb. The temperature at which this avoidance behavior occurred was recorded as the threshold temperature for that time point. Baseline thermal threshold measurements were obtained in triplicate with a 10 minute interval between each stimulus. In order to avoid skin burns, the control unit terminated heating of the element once a temperature of 55 C was reached, and the thermal element was moved to an adjacent location after each measurement. The skin over which the thermal element was applied was inspected for evidence of tissue damage each time the thermal element was moved and again on the day after treatment. Fecal output was assessed via fecal count (number of defecations), and weight for the first 8 hours after treatment. Feces were collected and immediately weighed after passage. Total fecal weight throughout the 8 hours was used for statistical analysis. An attempt was made to measure step count for the first 8 hours after treatment using a pedometer (PedometersUSA, PA, USA) that was affixed to the metacarpus opposite of the thermal threshold element. A post hoc analysis (Bland & Altman 1986) of two horses was performed manually counting 250 steps and comparing to the pedometer count. As this device had a wide 95% limits of agreement (between e91% and 143%) with a bias of 26% with visually counted steps, the data collected were excluded from further analysis.
A two-tailed paired t test was used to compare the Cmax of H-3G between the H-IV and H-IM groups. Numerical data were tested for normality with the ShapiroeWilk test. Mixed-effects models were used to analyze the effects of time and treatment and the interaction time treatment (fixed effects) on HR, GR, rectal temperature and cutaneous thermal threshold. In these models, the variability of differences was adjusted with the GeissereGreenhouse correction and the horse, and the interactions horse time and horse treatment, were added as random effects. Tukey’s multiple comparisons test were used post hoc in the mixed-effects model. A generic F-test post hoc analysis was performed to compute power when required. One-way analysis of variance (ANOVA) followed by Tukey’s tests analyzed the fecal weight. Friedman followed by Dunn’s tests were used to compare the effect of treatments on fecal count. A survival analysis with log rank test and Bonferroni correction for multiple comparisons was performed to compare the duration of antinociceptive effects of hydromorphone. The antinociceptive effect was considered insignificant when the cutaneous thermal threshold did not increase by more than 5% from baseline for at least two consecutive readings. All analyses were performed using GraphPad Prism Version 8.1.2 (GraphPad Software, CA, USA).
Sample size calculation Sample size was estimated using previously recorded cutaneous thermal threshold AUC data (Reed et al. 2019). A priori calculation with power of 0.9 and alpha of 0.05, AUC (mean ± SD) of 5000 ± 2300, symmetry correlation matrix of 0.5, and difference between matched pairs, resulted in a sample size of 5 (Faul et al. 2009). We elected to enroll six animals to account for hypothetical larger variation in cutaneous thermal threshold and to allow for a balanced Latin square design.
Results Pharmacokinetics The precision and accuracy of the assay were determined by assaying quality control samples in replicates (n ¼ 6). Accuracy was reported as percent nominal concentration, and precision was reported as percent relative standard deviation. For hydromorphone, accuracy was 108%, 94% and 112% for 0.75, 15 and 120 ng mL⁻1, respectively. Precision was 9%, 9% and 4% for 0.75, 15 and 120 ng mL⁻1, respectively. For H-3-G, accuracy was 114%, 90% and 112% for 0.75, 15 and 120 ng mL⁻1, respectively. Precision was 5%, for 0.75, 15 and 120 ng mL⁻1. The technique was optimized to provide a limit of quantitation (LOQ) of 0.25 ng mL⁻1 and a limit of detection of approximately 0.1 ng mL⁻1 for both the parent drug and metabolite. Plasma concentration versus time for hydromorphone and H-3-G are presented in Figs. 1 and 2, respectively. There was a significant difference in AUC between H-IV and H-IM (p ¼ 0.0312) but no significant difference in terminal half-life or lambda. Pharmacokinetic parameters for hydromorphone after IV and IM administration are presented in Table 1. There was one horse that was an outlier, considered by visual inspection of concentration versus time plot, with IM administration
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IV versus IM hydromorphone in horses RA Reed et al.
Pharmacodynamics
Figure 1 Hydromorphone plasma concentration over time in horses (n ¼ 6) administered hydromorphone 0.04 mg kg⁻1 intravenously (triangles) and intramuscularly (circles). Each line represents a single individual.
achieving a maximum plasma concentration (Cmax) and AUCinf higher than the other five horses (Fig. 1). IM bioavailability of hydromorphone was 217% with inclusion of the outlier. Excluding the outlier data, IM bioavailability was 155%. Pharmacokinetic variables for H-3-G after IV and IM administration of hydromorphone are presented in Table 2. The Cmax achieved in H-IV (54.1 ± 5.84 ng mL⁻1) was significantly higher than the Cmax achieved in H-IM (23.5 ± 5.5 ng mL⁻1) (p ¼ 0.0001).
Figure 2 Hydromorphone 3-glucuronide plasma concentration over time in horses (n ¼ 6) administered hydromorphone 0.04 mg kg⁻1 intravenously (open triangles) and intramuscularly (open circles). Each line represents a single individual. 4
Ambient temperature ranged between 21.8 C and 29.3 C (mean ± SD, 25.2 ± 1.3 C). There was a significant effect of treatment (p ¼ 0.0068) and time (p < 0.0064) on thermal threshold (Fig. 3). For both treatments H-IV and H-IM, thermal threshold measurements were significantly greater than P throughout the initial 7 hours after treatment (p ¼ 0.0021 to 0.041). There was no significant difference in thermal threshold between treatments H-IV and H-IM (p ¼ 0.420). In comparison to baseline, thermal thresholds in H-IV and H-IM were significantly greater than baseline through 4 and 6.5 hours after treatment, respectively. Survival analysis is presented in Fig. 4. There was no significant effect of treatment on HR, GR, body temperature or fecal count. The HR values with the H-IV and H-IM treatments were higher than group P but not significantly (p ¼ 0.16). Fecal weight was significantly lower in treatments H-IV (p ¼ 0.011) and H-IM (p ¼ 0.016) in comparison to P; however, H-IV and H-IM were not significantly different from each other (Fig. 5). All individuals in H-IV experienced a short period of excitation lasting 1e2 hours after treatment. This effect was characterized by varying degrees of pacing, vocalizing, rearing and kicking. This behavior was not targeted at the personnel involved, and no individual was in danger at any time. In general, the horses would stand quietly when restrained with a lead rope for collection of physical examination variables. Discussion IV administration of hydromorphone was characterized by a rapid clearance, short terminal t1/2, and large apparent volume of distribution (VDSS) similar to those values reported previously in horses at the same dose after IV administration (Reed et al. 2019). These results were also akin to those found in other mammalian species administered similar dosages of IV hydromorphone (Wegner et al. 2004; Guedes et al. 2008; KuKanich et al. 2008; Kelly et al. 2014). IV hydromorphone exhibited a rapid clearance that exceeded average equine expected hepatic blood flow (25 mL kg⁻1 minute⁻1) (Boxenbaum 1980; Dyke et al. 1998). The clearance rate of 79 mL kg⁻1 minute⁻1 after IV administration of 0.04 mg kg⁻1 hydromorphone is very similar to the clearance rate of 74 mL kg⁻1 minute⁻1 found in a previous study using the same dose (Reed et al. 2019). In that study, the clearance rate exceeded hepatic blood flow. It was presumably caused by opioid-induced excitement, resulting in increased cardiac output (CO) and hepatic blood flow causing an increase in hepatic extraction. CO was not reported in that study; however, the authors did note a significant increase in HR in individuals administered higher dosages. They also reported a dose-dependent increase in total systemic clearance. Similar
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Please cite this article as: Reed RA, Knych HK, Barletta M et al. Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.08.049
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IV versus IM hydromorphone in horses RA Reed et al. Table 1 Mean ± standard deviation (SD) of pharmacokinetic parameters for hydromorphone after a single intravenous or intramuscular administration of 0.04 mg kg⁻1 of hydromorphone to six horses. All values in this table were generated using noncompartmental analysis Parameter
Intravenous (n ¼ 6)
Intramuscular (n ¼ 6)
C0 (ng mLe1) Cmax (ng mLe1) Tmax (minutes) Lambdaz (1 minutee1) Terminal t1/2 (minute)y AUCinf (minute ng mLe1)* CL (mL minutee1 kge1) MRT (minute) Vdss (mL kge1)
74.9 ± 20.1 e e 0.036 ± 0.017 19.4 ± 8.83 518 ± 87.5 79.0 ± 12.9 14.2 ± 2.65 1125 ± 309
e 20.0 ± 15.3 7.5 ± 4.2 0.025 ± 0.007 26.7 ± 9.25 1128 ± 810 e e e
C0, drug concentration at time 0; Cmax, maximum plasma concentration; Tmax, time of Cmax; lambdaz, slope of terminal portion of plasma concentration curve; AUCinf, area under the curve from time 0 to infinity; Cl, total systemic clearance; MRT, mean residence time; Vdss, volume of distribution at steady state. * Significant difference between groups. y Harmonic mean.
findings have been reported after administration of increasing doses of morphine in horses (Hamamoto-Hardman et al. 2019). The t1/2 reported here of 19.4 ± 8.8 minutes associated with IV administration is less than the 34.0 ± 8.8 minutes previously reported in horses administered the same dose of hydromorphone (Reed et al. 2019). This difference may be attributable to differences in study design and individual variation of horses enrolled in the study. Similarly, the t1/2 is less than that reported in dogs at a dose of 0.10 mg kg⁻1 (34 minutes) (KuKanich et al. 2008), and shorter than that reported previously in other mammalian species. These include cats administered 0.10 mg kg⁻1 (62.8 minutes) (Wegner et al. 2004), and macaques administered 0.075 mg kg⁻1 (142 minutes) (Kelly et al. 2014). The VDSS of IV hydromorphone reported here was 1125 mL kg⁻1, which is similar to that reported previously of 1460 mL
kg⁻1 after IV administration of the same dose (Reed et al. 2019). However, these values are less than those reported in other mammalian species including cats (Wegner et al. 2004), dogs (KuKanich et al. 2008) and macaques (Kelly et al. 2014). IM administration was associated with a long t1/2 and large AUC, affording a bioavailability in excess of 200%, higher than the bioavailability described in other species (Guzman et al. 2014; Kelly et al. 2014). A horse with much higher than expected Cmax and AUCinf was an outlier. This may have resulted from inadvertent IV injection of all or a portion of the treatment within a vessel present at the location of IM administration. Exclusion of this horse resulted in a calculated bioavailability of 155%, which is still higher than what has been found in other species. The authors have chosen to report both these calculated bioavailability values as the significance of the outlier is unclear. A study in macaques administered 0.075 mg kg⁻1 IV and IM revealed a median bioavailability of
Table 2 Mean ± standard deviation (SD) pharmacokinetic parameters for hydromorphone 3-glucuronide after a single intravenous or intramuscular administration of 0.04 mg kge1 of hydromorphone to six horses. All values in this table were generated using noncompartmental analysis Parameter
Intravenous (n ¼ 6)
Intramuscular (n ¼ 6)
Cmax (ng mLe1)* Tmax (minutes) Lambdaz (1 minutee1) Terminal t1/2 (minute)y AUCinf (minute ng mLe1) AUC % extrap
54.1 ± 5.84 11.7 ± 4.08 0.003 ± 0.001 210 ± 43 8776 ± 1505 4.84 ± 2.68
23.5 ± 5.5 47.5 ± 6.12 0.003 ± 0.001 257 ± 76.5 6991 ± 1513 5.11 ± 3.22
Cmax, maximum plasma concentration; Tmax, time of Cmax; lambdaz, slope of terminal portion of plasma concentration curve; AUCinf, area under the curve from time 0 to infinity; AUC % extrap, % of AUC extrapolated. * Significant difference between groups. y Harmonic mean.
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Please cite this article as: Reed RA, Knych HK, Barletta M et al. Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.08.049
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IV versus IM hydromorphone in horses RA Reed et al.
Figure 3 Mean ± standard deviation thermal thresholds ( C) at from 0 to 24 hours after administration of hydromorphone to horses (n ¼ 6). IV, hydromorphone intravenous treatment (triangles); IM, hydromorphone intramuscular treatment (circles); and saline (placebo) treatment (squares). *Different from placebo treatment (p < 0.0001).
92% (75e104%) (Kelly et al. 2014). Conversely, in birds the bioavailability was just 75% after IM administration of 0.6 mg kg⁻1 (Guzman et al. 2014). Although the hepatic extraction ratio of hydromorphone has not been established in horses, in humans it was found to be 0.51, classifying hydromorphone as a drug with an intermediate extraction ratio (Parab et al. 1988). Drugs with intermediate hepatic extraction ratios are
Figure 4 Survival analysis of time 0 to loss of antinociceptive effect. Time of event was considered when cutaneous thermal threshold was less than 5% higher than baseline for two consecutive readings. Survival curves comparison was performed with Log-rank test with Bonferroni post hoc adjustments. IV, hydromorphone intravenous treatment (triangles); IM, hydromorphone treatment (circles); and placebo treatment (squares). *Different from placebo treatment (p ¼ 0.047). yDifferent from placebo-saline treatment (p ¼ 0.0012). 6
subject to changes in extraction caused by both alterations in CO and hepatic enzyme activity (Wilkinson & Shand 1975). IV administration of opioid agonists to healthy nonpainful horses has been shown to cause a significant increase in CO (Muir et al. 1978). Although we did not measure CO in this study, it is possible that the high calculated IM bioavailability found here is a result of increased CO after IV administration, resulting in more rapid clearance. The increased clearance would result in a smaller AUC for the IV route of administration. This theory is further supported by the relatively rapid rise in metabolite concentrations (H-3-G) (Fig. 1), in association with a rapid decline in parent compound concentrations (Fig. 2). The active metabolite of hydromorphone, H-3-G, has been documented in many mammalian species and has been shown to have neuroexcitatory effects in rats (Cone et al. 1977; Lotsch 2005). The presence of this metabolite after IV administration has recently been documented in horses (Reed et al. 2019). H-3-G was immediately detected in the plasma in both H-IV and H-IM individuals. The Cmax achieved in H-IV (54.1 ± 5.84 ng mL⁻1) was similar to the Cmax reported previously after IV administration of the same dose (52.6 ± 7.75 ng mL⁻1) (Reed et al. 2019) and was significantly greater than the Cmax achieved in H-IM (23.5 ± 5.5 ng mL⁻1). The t1/2 reported here for both H-IV (210 ± 43 minutes) and H-IM (257 ± 76.5 minute) are similar to those reported previously (279 ± 65.6 minute) after IV administration of the same dose of hydromorphone to horses. The long t1/2 suggests some potential for accumulation of this metabolite with repeated dosing. However, the neuroexcitatory and antinociceptive effects of this metabolite in the horse are unknown. Therefore, the significance of accumulation of the metabolite is unclear. There is a need for further studies investigating the effect of the metabolite in the absence of the parent molecule to determine the clinical relevance of its presence and accumulation. In the current study, the plasma concentration of hydromorphone decreased below the LOQ several hours before the termination of effect on the thermal threshold. This effect has been previously documented in horses (Reed et al. 2019) and several possible explanations were cited. First, the minimum antinociceptive plasma concentration of hydromorphone may be below the LOQ for the assay. Second, it is possible that the H-3-G metabolite with its long t1/2 provides a prolonged antinociceptive effect, although this metabolite has not been investigated as a potential analgesic agent in horses. Lastly, this effect may be attributable to pharmacokinetic hysteresis. Hysteresis occurs when the effect of the drug persists as a result of drug concentration at the effect site lagging behind the plasma concentration, because receptor binding kinetics are slow, or owing to the presence of other effects (Louizos et al. 2014). This effect has been documented previously with several opioids (Groenendaal et al. 2008).
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Please cite this article as: Reed RA, Knych HK, Barletta M et al. Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.08.049
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IV versus IM hydromorphone in horses RA Reed et al.
Figure 5 Mean ± standard error of the mean fecal weight in horses (n ¼ 6) administered hydromorphone 0.04 mg kg⁻1 intravenously (IV), intramuscularly (IM) for 8 hours after administration or placebo e saline treatment. *Different from placebo treatment (p ¼ 0.0109). yDifferent from placebo treatment (p ¼ 0.016).
Thermal threshold was significantly elevated above baseline and P in both H-IV and H-IM for 7 hours after administration. This duration of effect is shorter than previously observed at the same dose, where thermal threshold was elevated for 12 hours after administration (Reed et al. 2019). This difference may be attributed to differences in testing environments and individual variation. Individual variation may also explain the placebo antinociceptive effect observed during the first 5 hours in three horses as the SD of thermal threshold at baseline was within 5% of the mean value obtained. An antinociceptive effect was still apparent, at 12 hours in two out of six horses after IV administration and four out of six horses after IM administration, respectively (Fig. 4). IV administration of hydromorphone causes an increase in HR, GR and body temperature (Reed et al. 2019). This effect is reported for other pure mu opioids administered IV (Muir et al. 1978; Figueiredo et al. 2012; Robinson et al. 2015). With
regard to morphine (Figueiredo et al. 2012) and dermorphin (Robinson et al. 2015), specifically, the effect on HR is greater after IV administration than IM administration. Although we report an increase in HR after hydromorphone administration, there was no statistically significant difference in HR among groups. Similarly, an increase in GR observed after IV administration of dermorphin (Robinson et al. 2015) and butorphanol (Sellon et al. 2009) was not observed after IM administration. However, we were unable to identify a statistically significant increase in GR for either IV or IM administration of hydromorphone in this study. In regard to both HR and GR, the inability to detect a statistically significant difference between treatments is likely attributable to an underpowered sample for these variables. A significant increase in body temperature was reported after IV administration of 0.08 mg kg⁻1 hydromorphone, but not after 0.04 mg kg⁻1 (Reed et al. 2019). The same lack of effect on rectal temperature with this lower dose of hydromorphone was observed in the study reported here. Individuals administered H-IV exhibited signs of excitation lasting approximately 1e2 hours after administration, although we were unable to quantify this effect objectively because of the inability to validate the pedometer used in the study. This behavioral response of nonpainful horses to IV administration of opioids has been previously reported with hydromorphone (Combie et al. 1979; Reed et al. 2019) and other opioids (Carregaro et al. 2007; Clutton 2010; Knych et al. 2014). For both dermorphin (Robinson et al. 2015) and buprenorphine (Davis et al. 2012), it has been noted that the severity of CNS excitation is greater after IV administration in comparison to IM administration. The exact mechanism of excitation is not well established, although it is thought to be associated with activation of dopaminergic pathways (Carregaro et al. 2007). However, the administration of dopamine antagonists failed to inhibit this response in horses administered alfentanil (Pascoe & Taylor 2003). It is also possible that this phenomenon is a result of the neuroexcitatory effects of H-3-G (Cone et al. 1977); however, it is impossible to determine from this study whether the effect was caused by the parent drug or the metabolite. At least one retrospective study has shown that this effect is not observed in horses that are painful at the time of administration (Mircica et al. 2003). The clinical experience of the authors supports this conclusion. Further studies are needed using a more accurate means of quantifying this CNS excitation in painful and nonpainful horses to establish the clinical relevance of this adverse effect. Agonism of kappa and mu opioid receptors in the myenteric plexus of the gastrointestinal tract results in decreased motility (Brock et al. 2012; Menozzi et al. 2012). This effect was confirmed by the decreased fecal weight in subjects administered H-IV and H-IM. Several studies have examined the effect
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Please cite this article as: Reed RA, Knych HK, Barletta M et al. Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.08.049
Q4
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IV versus IM hydromorphone in horses RA Reed et al.
of opioids on gastrointestinal motility in horses and have revealed conflicting results. A decrease in gastrointestinal motility has been observed in healthy, nonpainful, adult horses after administration of hydromorphone (Reed et al. 2019), morphine (Boscan et al. 2006; Sano et al. 2011; Figueiredo et al. 2012; Donselmann Im Sande et al. 2017), methadone (Donselmann Im Sande et al. 2017), buprenorphine (Levionnois et al. 2018) and butorphanol (Donselmann Im Sande et al. 2017). Nevertheless, administration of morphine to clinical patients undergoing general anesthesia has not been shown to negatively impact gastrointestinal motility in at least one prospective (Martin-Flores et al. 2014) and one retrospective (Andersen et al. 2006) clinical study. We were unable to objectively quantify the excitement characterized by increased physical activity exhibited by those individuals administered IV hydromorphone, which is a limitation of our study. Although we speculated that during this period of increased physical activity CO increased, this variable was not measured. It is important to note that although this presumed increase in CO may have resulted in an overestimation of IM bioavailability, administration by this route provided a long-lasting analgesic effect. In conclusion, hydromorphone is well absorbed IM and provides long-lasting analgesia as measured by increased thermal threshold after both IV and IM administration, confirming the authors’ hypotheses. IM administration is associated with an equivalent degree and duration of antinociceptive effect in comparison to IV administration. Both routes of administration cause a decrease in fecal output in nonpainful horses in the first 8 hours after administration, as measured by fecal weight. Based on the current study, clinical use of hydromorphone would be expected to provide analgesia lasting up to 8 hours after either IV or IM administration. Q5
Author’s contributions RR: Study design, data collection and management, manuscript preparation; HK: plasma concentration analysis, pharmacokinetic analysis, manuscript preparation; MB: study design, manuscript preparation; DS: data analysis, manuscript preparation; MR and CS: data collection and management, manuscript preparation; CR: study design, data collection and management.
Q6
Conflicts of interest statement Authors declare no conflict of interest. References Andersen MS, Clark L, Dyson SJ et al. (2006) Risk factors for colic in horses after general anaesthesia for MRI or nonabdominal surgery: absence of evidence of effect from perianaesthetic morphine. Equine Vet J 38, 368e374. 8
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Muir WW, Skarda RT, Sheehan WC (1978) Cardiopulmonary effects of narcotic agonists and a partial agonist in horses. Am J Vet Res 39, 1632e1635. Natalini CC, Linardi RL (2006) Analgesic effects of epidural administration of hydromorphone in horses. Am J Vet Res 67, 11e15. Parab PV, Ritschel WA, Coyle DE et al. (1988) Pharmacokinetics of hydromorphone after intravenous, peroral and rectal administration to human subjects. Biopharm Drug Dispos 9, 187e199. Pascoe PJ, Taylor PM (2003) Effects of dopamine antagonists on alfentanil-induced locomotor activity in horses. Vet Anaesth Analg 30, 165e171. Reed R, Barletta M, Mitchell K et al. (2019) The pharmacokinetics and pharmacodynamics of intravenous hydromorphone in horses. Vet Anaesth Analg 46, 395e404. Robinson MA, Guan F, McDonnell S et al. (2015) Pharmacokinetics and pharmacodynamics of dermorphin in the horse. J Vet Pharmacol Ther 38, 321e329. Sano H, Martin-Flores M, Santos LC et al. (2011) Effects of epidural morphine on gastrointestinal transit in unmedicated horses. Vet Anaesth Analg 38, 121e126. Sellon DC, Papich MG, Palmer L et al. (2009) Pharmacokinetics of butorphanol in horses after intramuscular injection. J Vet Pharmacol Ther 32, 62e65. Smith LJ, Yu JK, Bjorling DE et al. (2001) Effects of hydromorphone or oxymorphone, with or without acepromazine, on preanesthetic sedation, physiologic values, and histamine release in dogs. J Am Vet Med Assoc 218, 1101e1105. Wegner K, Robertson SA, Kollias-Baker C et al. (2004) Pharmacokinetic and pharmacodynamic evaluation of intravenous hydromorphone in cats. J Vet Pharmacol Ther 27, 329e336. Wilkinson GR, Shand DG (1975) Commentary: a physiological approach to hepatic drug clearance. Clin Pharmacol Ther 18, 377e390. Received 21 June 2019; accepted 22 August 2019. Available online xxx
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