Swine are the most widely used large-animal translational model in biomedical research.1 The anatomical and physiological similarities between swine and humans make them ideal for pharmaceutical and toxicology studies as well as surgical training. Although there have been significant refinements in the humane handling, anesthesia, and recovery monitoring of swine, precise dosing regimens for commonly used analgesics are currently lacking.1–4 To provide adequate animal welfare and pain management, the dose, frequency, and concentration of an analgesic must be appropriate.5 Swine should be provided safe, reliable, and efficacious pain management that is also largely free from adverse effects.
Buprenorphine is one of the most widely used opioid analgesics administered to both laboratory rodents and companion animals.6 As a semisynthetic partial μ-opioid agonist and δ- and κ-opioid antagonist with action in the brain, spinal cord, and peripheral tissues, buprenorphine suppresses both pain transmission and modulation.7,8 Buprenorphine is highly lipophilic and exhibits a ceiling effect with slow binding of the μ-opioid receptor, providing a long duration of action for analgesia—important qualities in effective and safe analgesia.9–11 Although dose-dependent respiratory depression and sedation are possible, many studies6,12–18 have established buprenorphine to be safe and effective in common laboratory animal species, including mice, rats, and nonhuman primates.
Despite the plethora of information regarding buprenorphine use in rodents, there is little information on adequate buprenorphine use in swine. The reported dose for buprenorphine HCl in swine is wide and ranges from 0.01 to 0.1 mg/kg, with a dosing frequency of twice or 3 times daily.3,4,8,19–27 The long-lasting buprenorphine formulations, sustained-release buprenorphine (SRB; Zoopharm/Wedgewood) and extended-release buprenorphine (Ethiqa XR; XRB), are superior to the conventional buprenorphine HCl formulations because their long-lasting formulations avoid repeat administrations—an important refinement for minimizing animal distress and pain. However, SRB pharmacokinetics in swine have only been described in 2 studies,21,28 with reported dose ranges from 0.12 to 0.24 mg/kg, SC, once daily, and therapeutic plasma concentrations of 0.1 ng/mL or more for at least 96 hours. To date, no studies have examined the pharmacokinetic profile of XRB in swine.
The goal of this study was to characterize the pharmacokinetics of XRB in swine. We hypothesized that after a single SC administration of XRB in adult Yorkshire swine, buprenorphine plasma concentrations would be at or above the therapeutic threshold of 0.1 ng/mL. Furthermore, we hypothesized that SC XRB administration would not result in major injection site reactions.
Methods
All animal handling and procedures were approved by the AAALAC International accredited University of Southern California IACUC. All animals were housed in accordance with the Guide for the Care and Use of Laboratory Animals, the Public Health Service Policy on the Humane Care and Use of Laboratory Animals, and the Animal Welfare Act and Regulations.15,29
Drug
Ethiqa XR is a commercially available XRB and is FDA indexed and approved for use in mice, rats, ferrets, and marmosets. Ethiqa XR is not approved for use in swine. Extended-release buprenorphine is a lipid-encapsulated, primarily consisting of cholesterol, low-viscosity buprenorphine suspension.30
Animals
Six approximately 3-month-old adult female Yorkshire domestic swine (Sus scrofa domestica) weighing, on average, 30 to 35 kg were obtained from Premier BioSource (formerly S&S Farms), a closed herd and Class A USDA-licensed facility. Although 6 animals were initially enrolled in the study, only 5 were used due to kinks in the catheters that prohibited blood collection of 1 animal. Animals were maintained under strict barrier conditions, monitored for pathogens quarterly, and regularly screened for parasites. According to the vendor-provided quarterly health monitoring reports, all animals were free from major swine bacterial, viral, and parasitic pathogens, including but not limited to porcine epidemic diarrhea virus, porcine reproductive and respiratory syndrome virus, Actinobacillus pleuropneumonia, transmissible gastroenteritis virus, Mycoplasma, Influenza A, parvovirus, leptospirosis, brucellosis, and pseudorabies.
Facility
Animals were fed pelleted feed (Laboratory Porcine Diet Grower 5084; Lab Diet) twice daily and food enrichments, such as fruit and vegetables, every other day. Environmental enrichment included scratch pads, manipulatable malleable toys, and hanging foraging balls and were available on a rotating basis. Water was provided ad libitum from an in-kennel automatic watering system. The animal room was maintained at 21 to 23 °C with 30% to 70% relative humidity and 100% recirculated air at 10 to 15 changes hourly. Fluorescent lighting was provided on a 12:12-hour light-dark cycle. Animals were housed in stainless steel bar–type open-top kennels with raised floors. Prior to enrollment in the study, animals were deemed healthy as determined by veterinary physical examination, comprehensive CBC, chemistry, and fecal examination. Animals were monitored daily throughout the study by the veterinarian and monitored after hours via a Wi-Fi–enabled live video monitoring system placed inside each animal's home kennel.
Acclimation
To facilitate low-stress sedations, recovery periods, and subsequent serial blood collections, the animals were acclimated to close contact with research staff via gentle touch and petting of the neck and ear region, high-value food rewards, and use of a Panepinto Sling.31,32 Acclimation to a Panepinto Sling (Panepinto & Associates, Masonville, CO) was accomplished through a previously described technique with multiple short (5- to 30-minute) daily training sessions and positive reinforcement for a minimum of 7 to 10 days before the start of study.33
Experimental design
All animals enrolled in this study were part of an IACUC approved protocol with the University of Southern California Keck School of Medicine Department of Surgery. Animals were cohoused in pairs prior to the start of the study and during the acclimation period. After catheterization and for the remainder of the study, animals were then singly housed in adjacent kennels while maintaining the ability to interact with each other through sniffing, vocalization, and sight through kennel bars. Animals were grouped in pairs, and each animal was randomly assigned to either a low-dose (0.2 mg/kg, SC, once) or high-dose (0.4 mg/kg, SC, once) administration of XRB. Animals assigned the low-dose cohorts received a single injection of XRB in the SC space behind 1 ear, and an equal volume of normal saline was administered in the SC space of the contralateral ear as a control. Due to the large, calculated volume of the high dose, animals assigned to the high-dose cohort received an evenly split dose (milliliters) administered in the SC space behind both the left and right ears. Catheters were placed under sedation (described below). After placement of the catheter, a time 0 blood sample was collected for baseline pharmacokinetic analysis, and animals were administered either the low or high dose of XRB. Blood was subsequently collected from animals at 0.25, 0.5. 1, 1.5, 2, 4, 8, 12, 24, 48, 72, and 96 hours postadministration. After the completion of the study, all animals were euthanized while under a surgical plane of anesthesia with an overdose of pentobarbital sodium and phenytoin sodium euthanasia solution IV at the conclusion of the separate terminal surgical training program procedure as mentioned above. Postmortem full-thickness skin and subcutis tissue samples were collected at drug and saline control injection sites and placed in 10% neutral-buffered formalin until paraffin embedding, slide preparation, and staining with H&E (slides prepared by IDEXX BioAnalytics). All tissues were incinerated as the final disposition at the conclusion of the study.
Catheter placement
Animals were fasted a minimum of 12 hours in preparation for sedation to perform jugular catheter placement and subsequent drug administration. Animals were sedated with a single IM injection of tiletamine HCl (Telazol) at 50 mg/mL and zolazepam HCl reconstituted with xylazine (100 mg/mL) to make a final concentration of 100 mg/mL at a dose administration at 2.2 to 4.4 mg/kg body weight. Animals were maintained on inhaled isoflurane mixed with oxygen and delivered by a precision vaporizer via face mask as needed to maintain anesthesia. A single triple-lumen indwelling jugular catheter (7 Fr X 30 cm; J1045B; JorVet) was placed percutaneously and aseptically using the previously described Seldinger technique, ultrasound guidance, and/or anatomical triangulation techniques in the right external jugular vein.34–36 At the time of jugular catheter placement, the luminal volume of the catheter was measured to be approximately 1 mL. Once placed, the jugular catheter was sutured to the skin and further secured with a sterile foam dressing. Cast padding, a stockinette/stretch tubular elastic dressing retention net, and bandage tape were used to make a comfortable “jacket” around the upper torso and neck. Before and after all timed blood draws, catheters were flushed and locked with heparinized saline to maintain patency.
Behavioral scoring
Given that opioids are analgesics that can synergistically act with other drugs to induce either hyperactivity and/or extreme sedation in other species, we monitored behavioral parameters for sedation and distress. A sedation and distress scoring guide (Table 1), adapted from Santos et al,37 was used to determine the degree of sedation and distress in each animal after the administration of low- or high-dose XRB.38 Scoring was assessed cageside at time 0 and 0.25, 0.5. 1, 1.5, 2, 4, 8, 12, 24, 48, 72, and 96 hours post administration of XRB. All animals were monitored multiple times daily by the veterinarian and remained healthy throughout the study. A second, separate veterinarian blinded to the treatment cohorts evaluated the overall welfare of each animal approximately 24 to 48 hours post drug administration. Veterinary examinations did not reveal any serious adverse effects.
Sedation and distress scoring system clinically evaluated in swine up to 96 hours after extended-release buprenorphine (XRB) administration.
| Sedation score | Behavior |
| 0 | No apparent sedation; pig is standing and able to walk. |
| 1 | Pig is quieter, standing, and reactive to manipulation. |
| 2 | Pig is drowsy, in sternal recumbency, and unable to walk. |
| 3 | Pig is asleep, in lateral recumbency, and nonreactive to manipulation. |
| Distress score | Behavior |
| 0 | No obvious distress. Pig is quiet and indifferent towards manipulation of the catheter and drug injection sites. |
| 1 | Mild distress. Pig is quiet with slight movement of ears, head, or tail during manipulation of the catheter and drug injection sites. |
| 2 | Moderate distress. Pig has slight vocalizations and slight body movement with attempts to escape manipulation of the catheter and drug injection sites. |
| 3 | Severe distress. Pig has vocalizations and significant body movement with significant attempts to escape manipulation of catheter and drug injection sites. |
Drug administration and blood collection
At the conclusion of jugular catheter placement and securement, XRB low dose (0.2 mg/kg) or high dose (0.4 mg/kg) was administered. Animals were allowed to recover from sedation in a Panepinto Sling for approximately 1 to 2 hours post drug administration. Animals were then slowly transitioned to either a rolling padded kennel for additional safe recovery or their home kennel depending on the level of recovery. Approximately 1 mL of the heparinized saline lock (previously measured) was collected via the jugular catheter injection port using an 18-gauge butterfly catheter attached to a 3-mL syringe to clear the catheter prior to blood sample collection. A new 18-gauge butterfly catheter attached to a new 3-mL syringe was then used to draw the experimental 1-to-2-mL blood sample and was immediately transferred to EDTA tubes at times 0.25, 0.5. 1, 1.5, 2, 4, 8, 12, 24, 48, 72, and 96 hours post administration of XRB. Blood samples were gently and repeatedly rolled in EDTA tubes and placed at 4 °C immediately after collection until centrifugation at 3,800 X g for 10 minutes at 4 °C. Plasma was then collected and subsequently stored at −80 °C until analysis approximately 1 month postcollection. Plasma was then shipped overnight on dry ice to the McWhorter School of Pharmacy, Pharmaceutical Sciences Research Institute in Samford University, Birmingham Alabama, for the measurement of plasma buprenorphine concentrations using HPLC-MS-MS. The presumed therapeutic plasma concentration of 0.1 ng/mL used in this study was based on the limited injectable buprenorphine pharmacokinetic data in both swine and extrapolations from human and nonhuman primate literature.8,28
Pharmacokinetic analysis
Buprenorphine standard spiking solutions were prepared in 50:50 deionized water:acetonitrile to give concentrations in plasma ranging from 0.2 to 200 ng/mL. The buprenorphine plasma samples and standards (100 μL) were fortified with internal standard (50 ng/mL terfenadine). Acetonitrile (1 mL) was added to precipitate the plasma proteins, and the mixture was vortexed and centrifuged. The organic layer was transferred to a clean test tube and evaporated to dryness under nitrogen in a water bath set at 50 °C. The samples were reconstituted in dilution solvent and analyzed by HPLC-MS-MS. Matrix-matched standards and quality control samples were prepared using blank control plasma. Chromatographic separation of buprenorphine and the internal standard from the extracted plasma matrix was achieved using a Shimadzu HPLC system (Shimadzu, Columbia, MD) consisting of 2 Shimadzu LC20-AD pumps, an SIL20-AC HT Autosampler, and a DGU-20A3 3-channel in-line degasser and controller with a 100 mm X 2-mm Luna C18 reverse phase column (Phenomenex) at ambient temperature. The mobile phase consisted of 5 mM ammonium acetate and acetonitrile, each fortified with 0.1% formic acid. The compounds were analyzed using a gradient elution profile in which mobile phase B was held at 30% for 1 minute, increased to 80% over 4 minutes, held at 80% for 0.5 minutes, and then returned to 30% and equilibrated for 2.5 minutes. Mass detection was accomplished with an 4000 QTRAP triple quadrupole ion trap mass spectrometer (Applied Biosystems) equipped with an electrospray ionization source operated at a potential of 5 kV at 450 °C operating in the multiple reaction monitoring mode. Data were collected and processed using Analyst, version 1.6.2 (Applied Biosystems). The following mass transitions of the compounds were monitored: buprenorphine (m/z, 468.4 to 396.1) and terfenadine (m/z, 472.4 to 436.2). Data were analyzed using a noncompartmental analysis.
Results
Pharmacokinetics
The pharmacokinetic data for animals treated with low-dose (0.2 mg/kg) or high-dose (0.4 mg/kg) XRB are reported in Figure 1 and Table 2. Average plasma buprenorphine levels for both the low- and high-dose cohorts reached therapeutic concentrations of 0.1 ng/mL starting 1.5 hours after XRB administration and were maintained above therapeutic concentrations throughout the 96-hour study period. In the low-dose cohort, the average half-life was 212.6 ± 107.1 hours, whereas the half-lives in the high-dose cohort were 63.8 and 48.9 hours, respectively. The earliest time point in which plasma concentration reached the therapeutic threshold was at 90 minutes in animal B (high dose), and the latest time point was at 8 hours in animal F (low dose). Both animals assigned to high-dose XRB reached therapeutic concentrations earlier than animals in the low-dose cohort—animal B at 1.5 hours and animal C at 2 hours. In contrast, low-dose animals reached the therapeutic concentration at 4 hours for animal A, 1.5 hours for animal E, and 8 hours for animal F. Extended-release buprenorphine was present in the plasma at the therapeutic concentration of 0.1 ng/mL or above at time points beginning at 8 hours and maintaining throughout the 96-hour time point for all animals in both cohorts. Although the time to peak concentration varied between individual animals within each dose cohort, the peak buprenorphine plasma concentration for the low-dose cohort was consistent, with an average of 0.36 ± 0.03 ng/mL. The peak buprenorphine plasma concentrations for the high-dose cohort varied, with animal B at 1.14 ng/mL and animal C at 0.73 ng/mL. With a mean area under the concentration-versus-time curve of 23.8 ± 1.9 and 48.1 h·ng/mL in the low- and high-dose XRB cohorts, respectively, the high-dose XRB cohort was double that of the low dose. In addition, the clearance of the drug varied between animals in both the low- and high-dose cohorts.
Swine treated with low-dose (0.2 mg/kg, SC) or high-dose (0.4 mg/kg, SC) extended-release buprenorphine (XRB) had circulating buprenorphine levels that were above the therapeutic effective threshold of 0.1 ng/mL (dashed line). Individual animal low-dose (A) and high-dose (B) circulating buprenorphine levels up to 96 hours postadministration. Averaged circulating buprenorphine levels (C) of low-dose (blue line) or high-dose (red line) XRB–treated pigs. Data for low-dose XRB (n = 3) are presented as mean ± SEM, and data for high-dose XRB (n = 2) are presented as mean only.
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.24.10.0313
Pharmacokinetic parameters of low- and high-dose XRB–treated pigs of averaged buprenorphine concentrations.
| Low dose (0.2 mg/kg, SC) | High dose (0.4 mg/kg, SC) | ||||||
|---|---|---|---|---|---|---|---|
| Individual pig | A | E | F | Average ± SE | B | C | Average |
| Half-life (h) | 169.2 | 415.9 | 52.6 | 212.6 ± 107.1 | 63.8 | 48.9 | 56.4 |
| Time to peak concentration (h) | 24 | 2 | 48 | 25 ± 13 | 4 | 48 | 26 |
| Peak concentration (ng/mL) | 0.35 | 0.42 | 0.32 | 0.36 ± 0.03 | 1.14 | 0.73 | 0.9 |
| AUC0–last (h·ng/mL) | 25.4 | 26.1 | 20.0 | 23.8 ± 1.9 | 47.3 | 48.8 | 48.1 |
| Clearance (mL/h/kg) | 2,381 | 769 | 6,077 | 3,076 ± 1,517 | 5,213 | 5,338,826 | 2,672,019 |
Values for low-dose XRB (n = 3) are reported as mean ± SEM, and values for high-dose XRB (n = 2) are reported as mean.
AUC0–last = Area under the concentration-versus-time curve from time 0 to the last measured concentration.
Sedation and distress scores
Although sedation and distress ethograms for adult swine have not been established, a sedation scoring system has been proposed in piglets by Di Giminiani et al38 For this study, we used an adapted form of Santos et al's37 sedation scoring system to determine the degree of sedation and distress in these catheterized adult swine (Table 1). Sedation scores (from 0 to 3, with 0 being no apparent sedation and 3 being asleep in lateral recumbency) peaked at the time of administration for both low- and high-dose XRB animals (Table 3). The last animal to reach an unsedated state (score of 0) was animal B at 24 hours (high dose). Sedation scores for both low- and high-dose cohorts did not correlate with time to maximum concentration or maximum serum concentration. The data indicate that distress scores (from 0 to 3, with 0 being no apparent distress and 3 being severe distress with vocalization and body movement) peak variably between animals and doses. Low-dose animals A and E have peak distress scores ranging from 1.0 to 1.5 at 0.5 hours to 2 hours, whereas animal F did not appear distressed at any point in the study. Among the high-dose animals, animal B had a distress score of 3 at 1.5 hours to 2 hours and did not appear normal until 24 hours after XRB administration, and animal C had peak distress scores at 1 hours to 1.5 hours. Interestingly, animal B's sedation and distress scores both appeared back to normal (score of 0) by 24 hours post high-dose XRB administration.
Sedation and distress scores in individual pigs up to 96 hours after low- or high-dose XRB administration.
| Low dose (0.2 mg/kg, SC) | High dose (0.4 mg/kg, SC) | |||||
|---|---|---|---|---|---|---|
| Individual pig | Time (h) | A | E | F | B | C |
| Sedation (0–3) | 0 | 3 | 3 | 3 | 3 | 3 |
| 0.25 | 3 | 2 | 3 | 2 | 3 | |
| 0.5 | 2 | 2 | 3 | 2 | 2 | |
| 1 | 1 | 2 | 2 | 2 | 2 | |
| 1.5 | 1 | 1.5 | 2 | 1.5 | 1.5 | |
| 2 | 0.5 | 1.5 | 2 | 1.5 | 1.5 | |
| 4 | 0 | 1 | 0.5 | 1 | 1 | |
| 8 | 0 | 0 | 0 | 1 | 0 | |
| 12 | 0 | 0 | 0 | 1 | 0 | |
| 24 | 0 | 0 | 0 | 0 | 0 | |
| 48 | 0 | 0 | 0 | 0 | 0 | |
| 72 | 0 | 0 | 0 | 0 | 0 | |
| 96 | 0 | 0 | 0 | 0 | 0 | |
| Distress (0–3) | 0 | 0 | 0 | 0 | 0 | 0 |
| 0.25 | 0 | 0 | 0 | 0 | 0 | |
| 0.5 | 1 | 0 | 0 | 2 | 0 | |
| 1 | 1 | 1.5 | 0 | 2 | 1.5 | |
| 1.5 | 1 | 1.5 | 0 | 3 | 1.5 | |
| 2 | 0 | 1.5 | 0 | 3 | 1 | |
| 4 | 0 | 0 | 0 | 1.5 | 1 | |
| 8 | 0 | 0 | 0 | 1 | 0 | |
| 12 | 0 | 0 | 0 | 1 | 0 | |
| 24 | 0 | 0 | 0 | 0 | 0 | |
| 48 | 0 | 0 | 0 | 0 | 0 | |
| 72 | 0 | 0 | 0 | 0 | 0 | |
| 96 | 0 | 0 | 0 | 0 | 0 | |
Histopathology
Gross skin lesions were not apparent during biopsy collection in either low- or high-dose XRB SC-injected sites. Saline-injected sites revealed no abnormal lesions grossly or histologically. Both low- and high-dose XRB biopsies revealed a thick white-to-cream-colored tissue reaction that extended down the subcutis; the high-dose XRB tissue reactions extended past the subcutis and into the musculature. Histologic evaluation of XRB injection sites revealed similar lesions in all animals regardless of dose (Figure 2; Table 4). The deep SC fat was characterized by varying degrees of granulomatous inflammation with patterns varying from dense macrophage infiltrates with frequent giant cell formation and numerous intralesional cholesterol clefts to large vacuoles lined by flattened epithelium and often rimmed by primarily macrophage infiltrates with varying numbers of accompanying neutrophilic infiltrates. Varying degrees of fibrosis were also detected amidst these vacuoles. The vacuolated pattern was usually at the periphery of the denser inflammation, and inflammation and vacuolation were often branching into adjacent superficial fatty tissue and deep musculature. Within the dense inflammation, single to multiple cores of mineralized necrotic debris rimmed by degenerating cells, including neutrophils, were observed in some swine, as were pockets of hemorrhage. A representative slide was evaluated under polarized light, and no birefringent material (eg, plant material) was detected.
Representative lesion observed in deep subcutaneous fat of pigs injected SC with XRB. Multiple areas of subcutaneous adipose tissue (asterisk). Regardless of dose, pigs acquired dense granulomatous inflammation with numerous intralesional cholesterol clefts bordered by large vacuoles lined by flattened epithelium and often rimmed by macrophage infiltrates. The inset shows a higher magnification of dense granulomatous infiltrates with cholesterol clefts (arrowheads) and giant cell formation. H&E stain; scale bar = 500 μm.
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.24.10.0313
Characteristic lesions found in H&E-stained skin biopsies from low- and high-dose XRB–treated pigs.
| Low dose (0.2 mg/kg, SC) | High dose (0.4 mg/kg, SC) | |
|---|---|---|
| Granulomatous inflammation | 3/3 | 2/2 |
| Cholesterol clefts/vacuoles | 3/3 | 2/2 |
| Fibrosis | 3/3 | 2/2 |
| Neutrophil infiltration | 3/3 | 2/2 |
| Hemorrhage | 2/3 | 2/2a |
| Mineralization of necrotic debris | 2/3 | 1/2 |
Values are reported as a proportion with a total of n = 3 for low-dose XRB–treated pigs and a total of n = 2 for high-dose XRB–treated pigs.
Hemorrhage from pig B was extensive.
Discussion
We characterized the pharmacokinetics of the injectable suspension of XRB in adult female Yorkshire swine. Furthermore, we described animal sedation and distress after XRB administration and assessed injection site reactions. This study is the first to reveal that XRB reaches the therapeutic buprenorphine plasma concentration of 0.1 ng/mL in adult swine at a low (0.2 mg/kg) and high (0.4 mg/kg) dose. All animals reached the therapeutic plasma threshold by 8 hours and maintained it to the end of the study at 96 hours. Animals had minimal lesions at the XRB SC injection site and a transient change in sedation and distress scores that returned to normal by 24 hours after administration. Together these results suggest that XRB in adult swine may provide sustained analgesia, and more research is warranted to assess both safety and efficacy.
Extended-release buprenorphine (Ethiqa XR) is currently the only pharmaceutical-grade, FDA-indexed XRB formulation that is approved for use in mice, rats, ferrets, and marmosets.39,40 In multiple strains of mice and rats, pharmacokinetic studies12,13,26,30,41–45 revealed that a single injection of XRB provides therapeutic plasma concentrations for 48 to 72 hours. Additionally, XRB has a superior safety profile and long-lasting analgesia effects of up to 72 hours in mice and rats after a single SC injection.16,26,46–50 Our results indicate that XRB provides longer therapeutic buprenorphine concentrations in swine, consistent with what is observed in other nonrodent species and swine breeds. In the cynomolgus macaque (Macaca fascicularis) and the common marmoset (Callithrix jacchus), therapeutic buprenorphine plasma levels lasted as long as 96 hours after XRB administration.51,52 Evaluation of another non–FDA-approved long-lasting buprenorphine, SRB, in diabetic Yucatan miniature swine revealed therapeutic plasma levels that surpassed 96 hours.21 Furthermore, our study revealed that XRB injection sites sustained minimal changes, including granulomatous inflammation and cholesterol clefts formation, lesions consistent with those reported in other species. These lesions are likely due to the medium-chain fatty acid triglyceride oil carrier.16,42,43,51,52 Therefore, XRB may provide long-lasting analgesia in swine, and more research is warranted for safety and efficacy studies in order to increase our options for analgesia.
Unfortunately, other currently available opioid-based pain management options in swine provide a highly variable and unreliable dose range, with fluctuations in therapeutic plasma concentrations and analgesic effectiveness.3,22,28,53–55 Although fentanyl patches are used, there is concern regarding the inaccurate dosage associated with patch location, variability among species and breeds, analgesic effectiveness, and potential adverse effects.3,22,53–55 Transdermal forms of buprenorphine have been evaluated in only a few studies. One study28 indicated that 30 µg/h patches in Yucatan minipigs had peak plasma buprenorphine concentrations between 0.37 and 0.75 ng/mL at 12 to 24 hours after application. Other studies53,54 found that 2 different transdermal patch doses (35 and 70 μg/h) failed to produce reliable serum buprenorphine concentrations; thus, transdermal patches are generally not recommended for use in swine. Furthermore, although the use of long-lasting injectable SRB in swine has been shown to reach therapeutic plasma concentrations, there are reservations with its safety, purity, and efficacy between batches since it has not undergone FDA approval.5 Studies43,51,52 comparing local injection reactions of SRB and XRB in multiple species revealed that XRB had less inflammatory changes. These findings encourage further research into the use of XRB formulations, such as XRB for non–food producing swine and studies to assess safety and efficacy.
Our primary goal was to characterize the pharmacokinetic parameters of XRB in adult, female, Yorkshire, non–food producing swine; however, we acknowledge a few limitations to our study. The therapeutic buprenorphine plasma concentration of at least 0.1 ng/mL used in this study has not been validated in swine and is extrapolated from other species.8,9,11,14–18,21,28,51,52,56 However, it is well known that pharmacokinetic studies cannot provide the full physiologic or biological effects on the animal. Studies55,57 have recommended not making estimations of adequate analgesia based on the level of drug in plasma until a standardized, validated, and humane methodology using a pain model or analgesiometric test is assessed. Furthermore, although we did not assess XRB efficacy in a painful swine model, we were able to clinically assess potential adverse effects using novel sedation and distress ethograms adapted from an adult swine sedation ethogram.37,38 Overall, the administration of postoperative analgesics should be based on multiple clinical factors, including reaction to incisional pain, abnormal posture, reluctance to lie down, or appetite-related changes.2
This study is the first to establish that a single SC administration of XRB in swine provides buprenorphine plasma concentrations above the therapeutic threshold of 0.1 ng/mL beginning at 8 hours and maintaining past 96 hours. Our results are consistent with our hypotheses and suggest that XRB is present in plasma at 0.1 ng/mL after a single SC administration and does not result in major injection site reactions. Additionally, there were minor changes in clinical signs of sedation and distress. These results support the use of multimodal analgesics to ensure adequate pain management and increase our options of long-lasting analgesics in swine within laboratory animal medicine, exotic medicine, mixed-animal practice, and practitioners in swine health management. In our opinion, this study and data is critically important from an animal welfare standpoint as our findings serve to potentially improve analgesia for a species that is lacking options for analgesia.
Acknowledgments
The authors would like to thank Tiffany Barajas and Angela Martinez from the University of Southern California Keck School of Medicine Department of Surgery for the animals enrolled in the study; Dr. Gregory Gorman at the McWhorter School of Pharmacy, Pharmaceutical Sciences Research Institute at Samford University, for pharmacokinetics analysis; and Emi Katayama, laboratory animal technologist within the American Association for Laboratory Animal Science (AALAS) Certification and Registry Board (CRB), and the “HMR Crew” for their exceptional animal care of animals A, B, C, D, E, and F.
Disclosures
Fidelis Animal Health Inc kindly provided the extended-release buprenorphine (Ethiqa XR) for this study.
No AI-assisted technologies were used in the composition of this manuscript.
Funding
Dr. Saenz was supported by a National Cancer Institute Cancer Metabolism Training Program Postdoctoral Fellowship (T32CA221709). This work was supported, in part, by intramural funding from the Department of Animal Resources at the University of Southern California and the Beckman Research Institute, City of Hope.
ORCID
L. M. Stevey-Rindenow https://orcid.org/0009-0009-7652-1260
M. Saenz https://orcid.org/0000-0003-3350-2675
C. Franklin https://orcid.org/0000-0002-9198-867X
P. Fueger https://orcid.org/0000-0003-0602-6458
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