Sustained-release Buprenorphine Research Articles

Evaluation and comparison of pharmacokinetic profiles and safety of two extended-release buprenorphine formulations in common marmosets (Callithrix jacchus)

While sustained-release buprenorphine (BSR) is used as a long-lasting opioid analgesic in common marmosets (Callithrix jacchus), there are no published studies on pharmaceutical-grade extended-release buprenorphine options such as Ethiqa XR (EXR) for this species. However, BSR is a compounded product and has been reported to cause injection site reactions in multiple species, including marmosets. Additionally, now with the availability of EXR, a pharmaceutical-grade veterinary product, the use of BSR in laboratory animals is not compliant with the Guide for the Care and Use of Laboratory Animals (Guide) unless scientifically justified and approved by the IACUC. We compared pharmacokinetic and safety profiles of BSR (0.15 mg/kg) and EXR (0.1–0.2 mg/kg) administered subcutaneously to adult marmosets. Blood was collected by venipuncture of the saphenous vein at multiple time points (0.25–72 h) and analyzed by liquid chromatography-tandem mass spectrometry (LC–MS/MS). EXR between 0.1 and 0.2 mg/kg resulted in a dose-dependent increase in Cmax (1.43–2.51 ng/mL) and were not statistically different from BSR (1.82 ng/mL). Tmax, lambdaz, and t1/2 were not statistically different between formulations. Mean plasma buprenorphine concentrations for BSR and EXR exceeded the therapeutic threshold (0.1 ng/mL) within 0.25 h and lasted for > 72 h. Mild sedation, but neither respiratory depression nor ataxia, was observed for both formulations. BSR injection sites had significantly higher histopathological scores compared to EXR. Video recordings for monitoring drug-induced behavioral changes showed increased animal activity levels after BSR and EXR versus saline controls. Norbuprenorphine, a buprenorphine metabolite associated with respiratory depression, was detected in the plasma after BSR and EXR administration as well as by in vitro liver microsome assays. In conclusion, we recommend using EXR over BSR as a long-lasting buprenorphine analgesic in marmosets because EXR is a pharmaceutical-grade formulation that is compliant with FDA guidelines and the Guide as well as exhibits comparable PK and safety profiles as BSR.

In-vitro and in-vivo evaluation of sustained-release buprenorphine using in-situ forming lipid-liquid crystal gels

AimsSustained-release systems reduce the incidence of drug side effects and the need for frequent drug consumption, thus increasing patient compliance with treatment. In this study, we aimed to produce sustained-release buprenorphine (BP) using lipid-liquid crystal gels. Main methodsThe three experimental groups in this study included: group I: lipid-liquid crystal formulation 5 (F5) containing BP, group II: BP-free F5, group III: BP solution in NMP, and group IV: control (no treatment). The formulations were injected subcutaneously into the rabbits' back neck. Key findingsThe results showed that the time required to reach the drug's maximum concentration (Tmax) was longer in group I than in group III. The maximum BP concentration (Cmax) and the constants of the drug removal rate and drug absorption rate (Ka) were significantly higher in group III compared to group I. The half-life (t1/2) of the drug in blood circulation was significantly longer in group I than in group III. Histopathological analysis revealed no histological abnormalities in the skin and heart in group I (BP-containing F5); however, mild hyperemia was observed in interstitial vessels in group III (BP-containing NMP). The kidney and liver tissues showed normal structure in the control group, as well as groups I and II. However, in the group receiving BP-containing NMP, significant congestion, tissue damage, necrosis, and fibrosis were observed in the kidney and liver. SignificanceThe results showed that the lipid-liquid crystal system can be used to design slow-release platforms for BP, minimizing the side effects associated with the use of its conventional forms.

Pharmacokinetics of Sustained-release and Extended-release Buprenorphine in Mice after Surgical Catheterization.

The Guide for the Care and Use of Laboratory Animals strongly encourages the use of pharmaceutical-grade chemicals and analgesics. Sustained-release buprenorphine (SRB) is administered extralabel to rodents to mitigate moderate to severe pain. An FDA-indexed buprenorphine formulation-extended-release buprenorphine (XRB)-has recently become available and is currently the only pharmaceutical-grade slow-release buprenorphine formulation approved for use in mice and rats. However, no studies have directly compared the pharmacokinetic parameters of SRB and XRB in surgically catheterized mice. To this end, we compared the plasma buprenorphine concentrations and pharmacokinetic parameters of SRB and XRB in mice after surgical catheterization. We hypothesized that mice treated before surgery with SRB or XRB would have circulating buprenorphine concentrations that exceeded the therapeutic threshold for as long as 72 h after surgery. Male and female C57Bl/6J mice were anesthetized, treated with a single dose of either SRB (1 mg/kg SC) or XRB (3.25 mg/kg SC), and underwent surgical catheterization. Arterial blood samples were collected at 6, 24, 48, and 72 h after administration. Weight loss after surgery (mean ± SEM) was similar between groups (SRB: males, 12% ± 2%; females, 8% ± 2%; XRB: males, 12% ± 1%; females, 8% ± 1%). Both SRB and XRB maintained circulating buprenorphine concentrations above the therapeutic level of 1.0 ng/mL for 72 h after administration. Plasma buprenorphine concentrations at 6, 24, and 48 h were significantly greater (3- to 4-fold) with XRB than SRB, commensurate with XRB's higher dose. These results support the use of either SRB or XRB for the alleviation of postoperative pain in mice. The availability of FDA-indexed XRB increases options for safe and effective pharmaceutical-grade analgesia in rodents.

Sterility of Sustained-release Buprenorphine.

Sustained-release formulations of controlled substances are commonly used to provide analgesia in research animals. These formulations represent refinements that offer the advantage of prolonged, multiday pain relief with a single injection, thereby decreasing handling stress in animals and saving time for scientists. Compounding pharmacies produce sustainedrelease buprenorphine for veterinary use (i. e., buprenorphine SR-LAB); one of these pharmacies has shortened the original 6-mo shelf-life to 28 d to comply with United States Pharmacopeia standards for ensuring sterility. This limitation risks increasing the waste of controlled substances, which require an expensive destruction process that is legally enforced in our state. To assess whether the sterility of buprenorphine SR-LAB is preserved for at least 6 mo in a general laboratory setting, we tested 5 bottles for the presence of endotoxin and bacterial and fungal contamination monthly for 6 mo. Overall, results of the study showed that the bottles remained sterile over the 6-mo duration as no endotoxin was detected and the bottles did not become contaminated with bacteria or fungi. In conclusion, when stored securely and used with aseptic handling techniques, buprenorphine SR-LAB can be maintained in a sterile state for 6 mo in a general laboratory setting.

Extended-release Buprenorphine, an FDAindexed Analgesic, Attenuates Mechanical Hypersensitivity in Rats (Rattus norvegicus).

A new extended-release buprenorphine (XR), an FDA-indexed analgesic, has recently become available to the laboratory animal community. However, the effectiveness and dosing of XR has not been extensively evaluated for rats. We investigated XR's effectiveness in attenuating postoperative hypersensitivity in a rat incisional pain model. We hypothesized that high dose of XR would attenuate mechanical and thermal hypersensitivity more effectively than the low dose of XR in this model. We performed 2 experiments. In experiment 1, male adult Sprague-Dawley rats (n = 31) were randomly assigned to 1 of the 4 treatment groups: 1) saline (saline, 0.9% NaCl, 5 mL/kg, SC, once); 2) sustained-release buprenorphine (Bup-SR; 1.2 mg/kg, SC, once), 3) low-dose extended-release buprenorphine (XR-Lo; 0.65 mg/kg, SC, once), and 4) high-dose extended-release buprenorphine (XR-Hi; 1.3 mg/kg, SC, once). After drug administration, a 1 cm skin incision was made on the plantar hind paw under anesthesia. Mechanical and thermal hypersensitivity were evaluated 1 d before surgery (D-1), 4 h after surgery (D0), and for 3 d after surgery (D1, D2, and D3). In experiment 2, plasma buprenorphine concentration (n = 39) was measured at D0, D1, D2, and D3. Clinical observations were recorded daily, and a gross necropsy was performed on D3. Mechanical and thermal hypersensitivity were measured for 3 d (D0-D3) in the saline group. Bup-SR, XR-Lo, and XR-Hi effectively attenuated mechanical hypersensitivity for D0-D3. Plasma buprenorphine concentrations remained above 1 ng/mL on D0 and D1 in all treatment groups. No abnormal clinical signs were noted, but injection site reactions were evident in the Bup-SR (71%), XR-Lo (75%), and XR-Hi (87%) groups. This study indicates that XR-Hi did not attenuate hypersensitivity more effectively than did XR-Lo in this model. XR 0.65 mg/kg is recommended to attenuate postoperative mechanical hypersensitivity for up to 72 h in rats in an incisional pain model.

Sustained release buprenorphine effectively attenuates postoperative hypersensitivity in an incisional pain model in neonatal rats (Rattus norvegicus)

Despite the need for safe and effective postoperative analgesia in neonates, research regarding pain management in neonatal rodents is relatively limited. Here, we investigate whether sustained release buprenorphine (Bup SR) effectively attenuates thermal hypersensitivity in a neonatal rat model of incisional pain. Male and female postnatal day 3 Sprague Dawley rat pups (n = 34) were randomly assigned to one of four treatment groups: 1) saline (control), 0.1 mL, once subcutaneously (SC); 2) buprenorphine HCl (Bup HCl), 0.05 mg/kg, once SC; 3) low dose Bup SR (low-SR), 0.5 mg/kg, once SC; 4) high dose Bup SR (high-SR), 1 mg/kg, once SC. Pups were anesthetized with sevoflurane and a 0.5-cm long skin incision was made over the left lateral thigh. The underlying muscle was dissected and closed using surgical glue. Thermal hypersensitivity testing was performed at 24 h prior to surgery and subsequently at 1, 4, 8, 24, and 48 h post-surgery using an infrared diode laser. Thermal hypersensitivity was attenuated at 1 h post-surgery in the Bup HCl group, while it was attenuated through the entire postoperative period in both low-SR and high-SR groups. This data suggests that a single dose of low-SR (0.5 mg/kg) or high-SR (1 mg/kg) effectively attenuates thermal hypersensitivity for at least 8 h in neonatal rat pups.

Erratum: A Comparison of Buprenorphine, Sustained-release Buprenorphine, and High- concentration Buprenorphine in Male New Zealand White Rabbits.

Erratum to article in Volume 59 Issue 5: https://www.ingentaconnect.com/contentone/aalas/jaalas/2020/00000059/00000005/art00012.

Pharmacokinetics of Buprenorphine and Sustained-release Buprenorphine in Common Marmosets (Callithrix jacchus).

Buprenorphine is an essential component of analgesic protocols in common marmosets (Callithrix jacchus). The use of buprenorphine HCl (BUP) and sustained-release buprenorphine (BSR) formulations has become commonplace in this species, but the pharmacokinetics have not been evaluated. Healthy adult (age, 2.4 to 6.8 y; 6 female and 6 male) common marmosets were enrolled in this study to determine the pharmacokinetic parameters, plasma concentration-time curves, and any apparent adverse effects of these compounds. Equal numbers of each sex were randomly assigned to receive BUP (0.02 mg/kg IM) or BSR (0.2 mg/kg SC), resulting in peak plasma concentrations (mean ± 1 SD) of 15.2 ± 8.1 and 2.8 ± 1.2 ng/mL, terminal phase t1/2 of 2.2 ± 1.0 and 32.6 ± 9.6 h, and AUC0-last of 16.1 ± 3.7 and 98.6 ± 42.7 ng × h/mL. The plasma concentrations of buprenorphine exceeded the proposed minimal therapeutic threshold (0.1 ng/mL) at 5 and 15 min after BUP and BSR administration, showing that both compounds are rapid-acting, and remained above that threshold through the final time points of 8 and 72 h. Extrapolation of the terminal elimination phase of the mean concentration-time curves was used to develop the clinical dosing frequencies of 6 to 8 h for BUP and 3.0 to 3.5 d for BSR. Some adverse effects were observed after the administration of BUP to common marmosets in this study, thus mandating judicious use in clinical practice. BSR provided a safe, long-acting option for analgesia and therefore can be used to refine analgesic protocols in this species.

Sustained-release buprenorphine induces acute opioid tolerance in the mouse

Sustained-release buprenorphine is widely used in mice with the intention of providing long-lasting analgesia. Statements about duration of therapeutic efficacy are based on persistence of serum buprenorphine levels over a minimum threshold, but behavioral data demonstrating sustained efficacy is not established. Additionally, chronic opioid exposure can induce tolerance and/or hyperalgesia; mice receiving sustained-release buprenorphine have not been evaluated for these effects. This study assessed clinical efficacy and duration of sustained-release buprenorphine in inflammatory, post-operative, and cancer pain; and screened for centrally-mediated opioid-induced hyperalgesia as well as opioid tolerance. At 1–2 mg/kg sustained-release buprenorphine, statistically significant analgesic efficacy occurred only at time points up to 2 h. These animals showed no changes in von Frey thresholds on the contralateral side, i.e. no centrally-mediated opioid hyperalgesia. To establish whether acute onset opioid tolerance resulted from a single sustained-release buprenorphine administration, we used the tail flick assay, exposing mice to sustained-release buprenorphine or saline on Day 1 and buprenorphine on Day 2. We measured duration and efficacy of 1 mg/kg buprenorphine after 1 mg/kg sustained-release buprenorphine, and also quantified a dose-response curve of buprenorphine (0.1–3 mg/kg) after 2 mg/kg sustained-release buprenorphine. Compared to control animals, mice previously exposed to sustained-release buprenorphine showed diminished analgesic response to buprenorphine; the resultant dose-response curve showed decreased efficacy. Pretreatment with naloxone, an opioid receptor antagonist, blocked sustained-release buprenorphine analgesic action. The short duration of antinociception following administration of sustained-release buprenorphine in mice is caused by the rapid development of tolerance.

Effects of Standard and Sustained-release Buprenorphine on the Minimum Alveolar Concentration of Isoflurane in C57BL/6 Mice.

Both standard and sustained-release injectable formulations of buprenorphine (Bup and BupSR, respectively) are used as preemptive analgesics, potentially affecting gas anesthetic requirements. This study tested the effects of Bup and BupSR on isoflurane requirements and confirmed that buprenorphine could reduce isoflurane requirements during a laparotomy in mice. We hypothesized that both Bup and BupSR would significantly decrease the required minimum alveolar concentration (MAC) of isoflurane. C57BL/6 mice received either isotonic crystalloid fluid (control), Bup (0.1 mg/kg), or BupSR (1.2 mg/kg) subcutaneously 10 min prior to the induction of anesthesia. Each anesthetized mouse was tested at 2 isoflurane concentrations. A 300-g noxious stimulus was applied at each isoflurane concentration, alternating between hindfeet. In addition, a subset of mice underwent terminal laparotomy or 60 min of anesthesia after injection with Bup, BupSR, or saline to ensure an appropriate surgical plane of anesthesia. Mice were maintained at the lowest isoflurane concentration that resulted in 100% of mice at a surgical plane from the aforementioned MAC experiments (control, 2.0%; Bup and BupSR, 1.7%). Analysis showed that both Bup and BupSR significantly decreased isoflurane requirements by 25.5% and 14.4%, respectively. The isoflurane MAC for the control injection was 1.80% ± 0.09%; whereas Bup and BupSR decreased MAC to 1.34% ± 0.08% and 1.54% ± 0.09%, respectively. Sex was not a significantly different between the injection groups during MAC determination. All of the mice that underwent surgery achieved a surgical plane of anesthesia on the prescribed regimen and recovered normally after discontinuation of isoflurane. Lastly, heart and respiratory rates did not differ between mice that underwent surgery and those that were anesthetized only. Bup and BupSR are MAC-sparing in male and female C57BL/6 mice and can be used for effective multimodal anesthesia.

Female Urine-induced Ultrasonic Vocalizations in Male C57BL/6J Mice as a Proxy Indicator for Postoperative Pain.

Objectively recognizing postoperative pain in mice is challenging, making it difficult to determine an appropriate postoperative analgesic regimen. Adult male mice produce ultrasonic vocalizations after exposure to adult female urine (FiUSV). To determine if FiUSV can be used as a indicator of postoperative pain, FiUSV produced by male C57BL/6J mice were assessed for 5 d before and after vasectomy or sham surgery with or without sustained-release buprenorphine. Postoperative pain was assessed by monitoring vocalization using an ultrasonic microphone and by evaluating orbital tightness, posture, and piloerection at postoperative time points. Before vasectomy or sham surgery, 25 of 38 male mice produced FiUSV on 4 of 5 d (143 ± 93 FiUSV). Vasectomized mice without postoperative analgesia produced significantly fewer FiUSV (59 ± 26 FiUSV) compared with baseline (212 ± 102 FiUSV) at 4 h postoperatively, but returned to baseline by 28 h. Vasectomized mice treated with buprenorphine and sham-surgery mice had no change in FiUSV from baseline at any time point after surgery. Activity was decreased compared with baseline in vasectomized mice, regardless of receiving postoperative analgesia or not, but only at the 4-h time point. There were no differences in behavior scores between vasectomized mice and sham-surgery mice at any time point. These results show that FiUSV can be used to detect postoperative pain in male C57BL/6J mice after vasectomy.

Effect of Feeding Hay on Nonesterified Fatty Acids in Appetite-Suppressed Pregnant New Zealand White Rabbits.

Pregnant rabbits are a common nonrodent model for reproductive safety evaluation in preclinical drug development. During reproductive toxicology studies, rabbits are prone to decreased food consumption and anorexia. When persistent or severe, this condition can lead to hepatic lipidosis and pregnancy toxemia, which may confound the interpretation of study results. Non-Esterified Fatty Acids (NEFAs) have been used in veterinary production medicine to evaluate the impact of diet on the energy balance of pregnant animals. In the current study, sustained-release buprenorphine was used to suppress the appetite of pregnant New Zealand white rabbits, mimicking the clinical presentation of animals in reproductive toxicology studies. Sequential NEFA evaluations during gestation, along with other clinical endpoints, such as the necessity and duration of veterinary intervention, were used to evaluate the effects of feeding hay and a pelleted diet as compared with a pelleted diet alone. Elevated NEFA levels were directly correlated to litter size, the number of viable fetuses and the number of days on veterinary consult due to severely decreased consumption of pelleted diet. Animals with hay as part of their diet did not require additional diet supplementation as determined by qualitative evaluation of hay intake and adequate fecal output. These data suggest that including hay as a portion of the standard diet benefits pregnant rabbits in laboratory or production settings.

Immunomodulation Associated with Sustained-release Buprenorphine in Female CD1 Mice Challenged with Ovalbumin.

Opioid analgesics have immunomodulatory properties, which often result in immunosuppression. Sustained-release buprenorphine (SR-Bup) has recently become available as an analgesic for pain management in mice, and little is known regarding potential effects of SR-Bup on the murine immune response. To this end, we immunized female CD1 mice with ovalbumin in complete Freud adjuvant and then treated them with either saline, SR-Bup, Bup-HCl, or SR-vehicle (SR-Veh) for 18 d. Splenocytes were isolated for culture and stimulation to assess cytokine responses, and blood was collected to determine serum antibody responses to ovalbumin. In all treatment groups, levels of IL10, TNFα, and IFNγ increased in ovalbumin-stimulated splenocytes compared with unstimulated splenocytes. Cytokine responses after stimulation did not differ between treatment groups except for IL10, which was significantly higher in SR-Bup-treated mice compared with those given saline or Bup-HCl. The antibody response was significantly increased after immunization but did not differ across treatment groups, except that the response to SR-Veh was lower. These results suggest that the immunomodulatory effects of prolonged treatment with SR-Bup on innate and adaptive immunity are negligible.

Colon constipation in horses after sustained-release buprenorphine administration

ObjectiveTo investigate the pharmacological profile and side effects of buprenorphine administered as a sustained-release formulation in horses. Study designPilot trial. AnimalsA total of four experimental horses, aged 18–27 years and weighing 508–578 kg. MethodsBuprenorphine (0.1 mg kg–1) was mixed as a freshly prepared sterile solution with a sustained-release drug carrier. It was administered by the subcutaneous (n = 2) or intramuscular (n = 2) route. During the experiment, the horses were closely monitored, equipped with a step counter and blood samples were collected for quantification of buprenorphine in plasma. ResultsAll four horses developed colon constipation requiring medical therapy, together with increased locomotor activity. One horse, requiring surgical treatment of colon constipation, was euthanized during recovery from anaesthesia for weakness and severe lower airway obstruction. The three other horses recovered fully within 5–7 days. Plasma buprenorphine concentrations were between 1 and 8 ng mL–1 for approximately 48 hours. No local reaction was observed at the injection sites. Conclusions and clinical relevanceAdministration of the sustained-release formulation of buprenorphine at a dose of 0.1 mg kg–1 resulted in plasma concentrations compatible with antinociceptive activity for at least 48 hours. The observed severe and undesirable effects of colon constipation and increased locomotor activity definitely preclude clinical use of sustained-release buprenorphine at this dose.

Evaluation of self-injurious behavior, thermal sensitivity, food intake, fecal output, and pica after injection of three buprenorphine formulations in rats (Rattus norvegicus).

OBJECTIVE To assess effects of buprenorphine hydrochloride (BH), sustained-release buprenorphine (SRB), and high-concentration buprenorphine (HCB) formulations in healthy rats. ANIMALS 8 Sprague-Dawley rats. PROCEDURES In a crossover-design study, rats received BH (0.05 mg/kg), SRB (1.2 mg/kg), HCB (0.30 mg/kg), or 5% dextrose solution (0.2 mL/kg), SC, once. Self-injurious behavior and thermal sensitivity (hind limb withdrawal latencies) were assessed prior to injection (time 0) and 1, 4, 8, 12, and 24 hours after injection. Food intake, kaolin intake, and fecal output were measured over 12-hour light and dark periods before and after each treatment. Values were compared among treatments and time points. RESULTS Self-injurious behavior was detected with all buprenorphine treatments; scores were greater at all time points during the 12 hours after HCB and 24 hours after SRB administration than at time 0. Percentage change in hind limb withdrawal latencies from time 0 was higher with BH and HCB 1 hour after injection than at other time points. Postinjection light-period food intake was higher (BH and HCB) and dark-period food intake was lower (BH, HCB, and SRB), compared with preinjection values for the same treatments. For SRB, postinjection light-period kaolin intake was greater than the preinjection value, and postinjection light- and dark-period kaolin intake was greater than that for other treatments. CONCLUSIONS AND CLINICAL RELEVANCE Hypoalgesic effects were briefly observed after administration of BH or HCB in healthy rats; adverse effects were detected in some rats with all buprenorphine formulations. Studies comparing effects of BH, SRB, and HCB in rats undergoing surgery or other noxious stimuli are indicated to determine clinical benefits in this species.

Evaluation of the Thermal Antinociceptive Effects of a Sustained-Release Buprenorphine Formulation After Intramuscular Administration to American kestrels ( Falco sparverius).

Previous studies have validated the clinical use of opioids with μ-receptor affinities for pain management in raptors. Buprenorphine has a longer duration of action and minimal adverse effects when compared with other opioids in American kestrels ( Falco sparverius). To evaluate the thermal antinociceptive effects, sedative effects, and duration of action of sustained-release buprenorphine given intramusculary in American kestrels, 12 adult kestrels (8 females and 4 males) were used in a randomized masked complete-crossover experimental design. Buprenorphine SR LAB (1.8 mg/kg) or a control solution were administered intramuscularly. Foot withdrawal response to a thermal stimulus was determined 1 hour before (baseline) and at 1.5, 6, 12, 24, 48, and 72 hours after treatment administration. Agitation-sedation scores were determined 3-5 minutes before each time point, and adverse effects were monitored at these times. Buprenorphine SR LAB significantly increased thermal thresholds at 6, 12, and 24 hours and resulted in mild sedation according to the mean sedation-agitation scores comparing the treatment and control groups. Depending on the severity and type of pain, adjunctive therapy, and individual response, Buprenorphine SR LAB administered at 1.8 mg/kg IM to American kestrels would require administration every 24 hours to manage pain. Further pharmacodynamic and clinical evaluations are warranted in kestrels and other Falconiformes, Accipitriformes, and Strigiformes to establish accurate dosing recommendations.

New FDA guidance on development of sustained-release buprenorphine for treatment of opioid dependence

New FDA guidance on development of sustained-release buprenorphine for treatment of opioid dependence

Pharmacokinetics and pharmacodynamics of buprenorphine and sustained-release buprenorphine after administration to adult alpacas

OBJECTIVE To determine pharmacokinetics and pharmacodynamics of buprenorphine after IV and SC administration and of sustained-release (SR) buprenorphine after SC administration to adult alpacas. ANIMALS 6 alpacas. PROCEDURES Buprenorphine (0.02 mg/kg, IV and SC) and SR buprenorphine (0.12 mg/kg, SC) were administered to each alpaca, with a 14-day washout period between administrations. Twenty-one venous blood samples were collected over 96 hours and used to determine plasma concentrations of buprenorphine. Pharmacokinetic parameters were calculated by use of noncompartmental analysis. Pharmacodynamic parameters were assessed via sedation, heart and respiratory rates, and thermal and mechanical antinociception indices. RESULTS Mean ± SD maximum concentration after IV and SC administration of buprenorphine were 11.60 ± 4.50 ng/mL and 1.95 ± 0.80 ng/mL, respectively. Mean clearance was 3.00 ± 0.33 L/h/kg, and steady-state volume of distribution after IV administration was 3.8 ± l.0 L/kg. Terminal elimination half-life was 1.0 ± 0.2 hours and 2.7 ± 2.8 hours after IV and SC administration, respectively. Mean residence time was 1.3 ± 0.3 hours and 3.6 ± 3.7 hours after IV and SC administration, respectively. Bioavailability was 64 ± 28%. Plasma concentrations after SC administration of SR buprenorphine were below the LLOQ in samples from 4 alpacas. There were no significant changes in pharmacodynamic parameters after buprenorphine administration. Alpacas exhibited mild behavioral changes after all treatments. CONCLUSIONS AND CLINICAL RELEVANCE Buprenorphine administration to healthy alpacas resulted in moderate bioavailability, rapid clearance, and a short half-life. Plasma concentrations were detectable in only 2 alpacas after SC administration of SR buprenorphine.

Safety and clinical effectiveness of a compounded sustained-release formulation of buprenorphine for postoperative analgesia in New Zealand White rabbits.

To determine the clinical effectiveness and safety of a compounded sustained-release formulation of buprenorphine, compared with effects of regular buprenorphine, for postoperative analgesia in rabbits. Blinded randomized controlled clinical trial. 24 purpose-bred adult male New Zealand White rabbits. Rabbits received titanium implants in each tibia as part of another study. Immediately prior to surgery, each rabbit received regular buprenorphine hydrochloride (0.02 mg/kg [0.009 mg/lb], SC, q 12 h for 3 days) or 1 dose of a compounded sustained-release formulation of buprenorphine (0.12 mg/kg [0.055 mg/lb], SC) followed by an equal volume of saline (0.9% NaCl) solution (SC, q 12 h for 3 days) after surgery. For 7 days after surgery, rabbits were evaluated for signs of pain by means of rabbit grimace and activity scoring and for adverse effects. No significant differences were identified between treatment groups in grimace and activity scores at any point. No major adverse effects were detected for either drug. However, 3 rabbits that received regular buprenorphine had pain scores suggestive of moderate to severe pain by the time dose administration was due (ie, within the 12-hour administration interval). No clinically important differences were detected in intraoperative anesthetic or postoperative recovery variables. Sustained-release buprenorphine administered SC at 0.12 mg/kg was at least as effective as regular buprenorphine in providing analgesia for rabbits following orthopedic surgery without any major adverse effects. This sustained-release formulation represents an important alternative for rabbit analgesia with potential to improve rabbit welfare over existing analgesic standards.

Effects of premedication with sustained-release buprenorphine hydrochloride and anesthetic induction with ketamine hydrochloride or propofol in combination with diazepam on intraocular pressure in healthy sheep.

To determine the effects of diazepam combined with ketamine hydrochloride or propofol for induction of anesthesia (IOA) following premedication with sustained-release buprenorphine hydrochloride (SRB) on intraocular pressure (IOP) in sheep. 20 healthy adult sheep. Diazepam with ketamine or propofol was given IV to each of 10 sheep after premedication with SRB (0.01 mg/kg, SC); after > 4 weeks, each sheep received the other induction combination with no premedication. For both eyes, IOPs were measured before premedication (if given), 10 minutes prior to (baseline) and immediately following administration of ketamine or propofol (time of IOA), after endotracheal intubation, and 5 minutes after IOA. Peak end-tidal P(CO2), globe position, and pupillary diameter were also analyzed. Data were not available for all sheep for all anesthetic episodes. Propofol-diazepam administration alone had no significant effect on IOP, whereas there was a significant decrease in IOP immediately following ketamine-diazepam administration alone. At 5 minutes after ketamine-diazepam administration, SRB-premedicated sheep had significantly higher IOP than unpremedicated sheep. Intraocular pressure was significantly higher at baseline, at intubation, and 5 minutes after IOA in SRB-premedicated sheep receiving propofol-diazepam, compared with unpremedicated sheep. Peak end-tidal P(CO2) at intubation was significantly higher in SRB-premedicated sheep. For sheep receiving either anesthetic treatment, IOPs did not differ significantly with or without SRB premedication. Globe position or pupillary diameter and IOP were not significantly related at any time point. Results suggested that both ketamine-diazepam and propofol-diazepam combinations were suitable for IOA without increasing IOP in sheep. The use of SRB should be avoided in sheep when increases in IOP are undesirable.