buprenorphine and carprofen

Rabbits are especially susceptible to adverse effects related to surgery, which can lead to inappetence and gastrointestinal (GI) stasis. However, these adverse effects may be related to discomfort from the procedure, anesthesia, the analgesics used, and the stress of restraint for analgesic administration. Opioid and NSAID analgesics which are frequently used in rabbits, can contribute to these adverse effects. This study compared the clinical GI side effects of buprenorphine and carprofen to saline controls in New Zealand White rabbits after a nonsurgical anesthetic event. Nine rabbits (3 females and 6 males, aged 8 to 20 mo) were randomly rotated through 5 treatment groups with a 7-d washout period between treatments: anesthesia control (no treatment), buprenorphine (0.05 mg/kg SC every 12 h for 72 h), carprofen (5 mg/kg SC every 24 h for 72 h), twice daily saline control (equivalent volume to buprenorphine SC every 12 h for 72 h), and once daily saline control (equivalent volume to carprofen SC every 24 h for 72 h). All rabbits were anesthetized 5 times and received initial treatments on the day of anesthesia. Generalized linear mixed models were used to assess food intake, water intake, and fecal output score for 7 days after anesthesia. Analysis showed that buprenorphine-treated rabbits had a significant 4-d decrease in food intake and a 3-d decrease in fecal output score compared with baseline. None of the other treatment groups showed any changes in food intake or fecal output score compared with baseline. These findings demonstrate that in the absence of pain, buprenorphine significantly depresses food intake in rabbits and that restraint and injections have minimal effect on food intake despite the possibility of increased stress.

Topics: Analgesics; Analgesics, Opioid; Animals; Appetite; Buprenorphine; Female; Male; Pain, Postoperative; Rabbits

Buprenorphine is a potent lipophilic opioid analgesic that is largely used in the multimodal treatment of acute pain. Simbadol (buprenorphine hydrochloride) is the first and only FDA-approved high-concentration formulation of buprenorphine for use in cats. The aim of this study was to evaluate the analgesic efficacy of carprofen in combination with one of two commercial formulations of buprenorphine (Simbadol and Vetergesic, 1.8 mg/mL and 0.3 mg/mL, respectively) in dogs undergoing ovariohysterectomy. Twenty-four dogs were included in a randomized, prospective, controlled, clinical trial. Patients were randomly divided into 2 groups as follows. Dogs were premedicated with acepromazine (0.02 mg/kg) and either 0.02 mg/kg of Vetergesic or Simbadol intramuscularly (Vetergesic group - VG; Simbadol group - SG, respectively; n = 12/group). General anesthesia was induced with propofol and maintained with isoflurane in 100% oxygen. Carprofen (4.4 mg/kg SC) was administered after induction of anesthesia. Heart rate, respiratory rate, blood pressure, pulse oximetry, pain scores using the Glasgow Composite Pain Scale Short Form (CMPS-SF), sedation scores using a dynamic interactive visual analogue scale and adverse events were evaluated before and after ovariohysterectomy by an observer who was unaware of treatment administration. If CMPS-SF scores were ≥ 5/20, dogs were administered rescue analgesia (morphine 0.5 mg/kg IM). Statistical analysis was performed using linear mixed models and Fisher's exact test (p < 0.05).. Pain and sedation scores and physiological parameters were not significantly different between treatments. Three dogs in VG (25%) and none in SG (0%) required rescue analgesia (p = 0.109). Adverse effects (i.e. vomiting and melena) were observed in two dogs in SG and were thought to be related to stress and/or nonsteroidal anti-inflammatory drug toxicity.. The administration of buprenorphine with carprofen preoperatively provided adequate postoperative analgesia for the majority of dogs undergoing OVH without serious adverse events. Prevalence of rescue analgesia was not significantly different between groups; however, it could be clinically relevant and explained by a type II error (i.e. small sample size). Future studies are necessary to determine if analgesic efficacy after Simbadol and Vetergesic is related to individual variability or pharmacokinetic differences.

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Carbazoles; Dogs; Drug Therapy, Combination; Female; Hysterectomy; Ovariectomy; Pain Measurement; Pain, Postoperative; Preanesthetic Medication; Prospective Studies

One hundred female cats undergoing routine ovariohysterectomy under midazolam-medetomidine-ketamine anaesthesia were included in a blinded, randomised, prospective clinical study to compare postoperative analgesia produced by four analgesic drug combinations given preoperatively (n = 25 per group). A secondary aim was to assess the effects in kittens and pregnant animals. Buprenorphine 180 µg/m(2) or butorphanol 6 mg/m(2) were given with either carprofen 4 mg/kg (groups BUPC and BUTC, respectively) or meloxicam 0.3 mg/kg (groups BUPM or BUTM, respectively). Medetomidine was not antagonised. A simple, descriptive scale (SDS; 0-4), a dynamic and interactive visual analogue scale (DIVAS; 0-100 mm) and mechanical nociceptive thresholds (MT; 2.5-mm diameter probe) were used to evaluate postoperative pain. All pain scores were low (DIVAS <10 mm, SDS <2 and MT >10 N) and there were no significant differences between the groups. It was concluded that all protocols provided adequate analgesia and when used with midazolam-medetomidine-ketamine are effective for routine feline ovariohysterectomy.

Topics: Analgesics, Opioid; Anesthesia, Obstetrical; Anesthetics, Combined; Animals; Behavior, Animal; Buprenorphine; Carbazoles; Cat Diseases; Cats; Double-Blind Method; Female; Humans; Hysterectomy; Meloxicam; Ovariectomy; Pain, Postoperative; Postoperative Care; Pregnancy; Premedication; Prenatal Exposure Delayed Effects; Prospective Studies; Thiazines; Thiazoles; Time Factors; Treatment Outcome

Multimodal analgesia is promoted as the best practice pain management for invasive animal research procedures. Universal acceptance and incorporation of multimodal analgesia requires assessing potential effects on study outcome. The focus of this study was to assess effects on embryo survival after multimodal analgesia comprising an opioid and nonsteroidal antiinflammatory drug (NSAID) compared with opioid-only analgesia during embryo transfer procedures in transgenic mouse production. Mice were assigned to receive either carprofen (5 mg/kg) with buprenorphine (0.1 mg/kg; CB) or vehicle with buprenorphine (0.1 mg/kg; VB) in a prospective, double-blinded placebo controlled clinical trial. Data were analyzed in surgical sets of 1 to 3 female mice receiving embryos chimeric for a shared targeted embryonic stem-cell clone and host blastocyst cells. A total of 99 surgical sets were analyzed, comprising 199 Crl:CD1 female mice and their 996 offspring. Neither yield (pups weaned per embryo implanted in the surgical set) nor birth rate (average number of pups weaned per dam in the set) differed significantly between the CB and VB conditions. Multimodal opioid-NSAID analgesia appears to have no significant positive or negative effect on the success of producing novel lines of transgenic mice by blastocyst transfer.

Topics: Analgesia; Animals; Buprenorphine; Carbazoles; Combined Modality Therapy; Double-Blind Method; Embryo Transfer; Female; Injections, Subcutaneous; Mice; Mice, Transgenic; Prospective Studies; Treatment Outcome

Eighty-four female cats undergoing ovariohysterectomy in a blinded, randomised, prospective clinical study were assigned to one of three groups of 28 to receive either 0.01 mg/kg buprenorphine (group B), 4 mg/kg carprofen (group C), or the same doses of both drugs (group BC). A dynamic and interactive visual analogue scale (DIVAS) from 0 to 100 mm, and a simple descriptive scale (SDS) from 0 to 4 were used to evaluate the cats' degree of analgesia and sedation for 24 hours postoperatively. There was no significant difference in the cats' sedation scores by SDS or DIVAS, and no difference in their pain scores by DIVAS. By SDS, the cats in group BC had significantly lower pain scores than the cats in group C (P<0.001) and group B (P<0.05). Nine of the cats in group B, nine in group C and five in group BC required rescue analgesia, and the cats in group C required rescue earlier than those in group B (P<0.05).

Topics: Analgesics, Opioid; Anesthesia, General; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Buprenorphine; Carbazoles; Cats; Drug Therapy, Combination; Female; Hysterectomy; Ovariectomy; Pain Measurement; Pain, Postoperative; Prospective Studies; Time Factors; Treatment Outcome

To compare the analgesic effects of buprenorphine, carprofen, and their combination in dogs undergoing ovariohysterectomy.. Prospective, randomized blinded clinical study.. 60 dogs.. Treatments were buprenorphine 0.02 mg kg(-1), intramuscularly (IM) (group B); carprofen 4 mg kg(-1), subcutaneously (SC) (group C); or a combination of both (group CB). Anesthesia was induced with propofol and maintained with isoflurane. A Dynamic Interactive Visual Analog Scale (DIVAS, 0-100 mm) and the Glasgow Composite Pain Scale (GCMPS, 0-24) were used to evaluate comfort and sedation at baseline, 2, 4, 6, and 24 hours after extubation. Rescue analgesia was provided with buprenorphine (0.02 mg kg(-1)). Wound swelling measurements (WM) and a visual inflammation score (VIS) of the incision were made after surgery and 2, 4, 6, and 24 hours later. p < 0.05 was considered significant.. Group C required more propofol (5.0 +/- 1.4 mg kg(-1)) compared with B (3.3 +/- 1.1 mg kg(-1)) and CB (3.2 +/- 0.7 mg kg(-1)); respectively, p = 0.0002 and 0.0001. Rescue analgesia was required in nine dogs. B had a higher GCMPS and DIVAS III score at 6 hours (2.6 +/- 2.5) and (23 +/- 22.5 mm) compared with C (1.0 +/- 1.3, 6 +/- 7.3 mm) and CB (1.5 +/- 1.4, 8 +/- 10.7 mm); respectively, p = 0.02 and 0.006. Group C had a lower sedation score at 2 hours (43 +/- 23.6 mm) compared with B (68 +/- 32.1 mm) and BC (69 +/- 22.1 mm); respectively, p = 0.03 and 0.004. Group B had a higher WM score at 2 hours (3 +/- 0.8 mm) compared with C (2 +/- 0.6 mm) p = 0.01 and at 6 hours (3 +/- 1 mm) compared with C (2 +/- 0.8 mm) and CB (2 +/- 0.8 mm); respectively, p = 0.01 and 0.008. VIS was not different between groups.. All treatments provided satisfactory analgesia for the first 6 hours and at 24 hours. C and CB pain score and WS were superior to B at 6 hours. No superior analgesic effect was noted when the drugs were combined.

Topics: Analgesics, Opioid; Anesthesia, General; Animals; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Carbazoles; Dogs; Drug Therapy, Combination; Female; Hysterectomy; Injections, Intramuscular; Injections, Subcutaneous; Pain Measurement; Pain, Postoperative; Preanesthetic Medication; Prospective Studies; Treatment Outcome

Four combinations of drugs--ketamine-xylazine, ketamine-xylazine-acepromazine (KXA), ketamine-xylazine-buprenorphine, and ketamine-xylazine-carprofen--were compared for their ability to produce anesthesia in BALB/c mice. Induction time, anesthetic duration, blood pressure, pulse rate, and time to recovery were recorded. The anesthesia induced by each anesthetic combination was assessed by using reflex responses to standardized stimuli. The KXA combination produced stable physiologic parameters and was associated with the longest duration of anesthesia (40 +/- 8 min); immobility was produced in all other groups (38 +/- 5 min), but a surgical plane of anesthesia could not be confirmed. All anesthetic protocols produced significant hypotension. No deaths occurred. We recommend KXA as a safe and reliable anesthetic for mice requiring a surgical plane of anesthesia.

Topics: Acepromazine; Anesthesia; Anesthetics; Animals; Blood Pressure; Buprenorphine; Carbazoles; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Heart Rate; Injections, Intraperitoneal; Ketamine; Laboratory Animal Science; Mice; Mice, Inbred BALB C; Xylazine

A model of nociceptive threshold determination was developed for evaluation of NSAID analgesia in cats. In a crossover study, eight cats received carprofen (4 mg/kg), buprenorphine (0.01 mg/kg) or saline (0.3 ml) subcutaneously before intradermal kaolin injection on the antebrachium to induce mild inflammation. Pressure thresholds were measured at the injected site using blunt-ended pins advanced by manual inflation of a bladder within a bracelet. Bladder pressure was recorded as threshold (PT) at the behavioural end point. Baseline PT were recorded before kaolin injection (time 0). PT was measured at 2-10 h intervals for 52 h. PT below the lower 95% confidence interval (CI) of baseline values indicated hyperalgesia. After saline, hyperalgesia was detected from 2-6 h, 22-26 h, and at 30 and 36 h. After carprofen, PT remained within the 95% CI. After buprenorphine, PT remained within the 95% CI except at 2h. Carprofen and to some extent buprenorphine, prevented inflammatory hyperalgesia.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Carbazoles; Cat Diseases; Cats; Cross-Over Studies; Female; Hyperalgesia; Inflammation; Male; Pain

This study compared the efficacy of buprenorphine, carprofen, and a combination of the 2 analgesics in female baboons. Physiologic and behavioral parameters were assessed at baseline and postoperatively for 6 d by use of continuous noninvasive physiologic monitoring and twice-daily videotaping. Prior to surgery, all animals received a pre-emptive dose of either 0.01 mg/kg buprenorphine intramuscularly, 2.2 mg/kg carprofen intramuscularly, or a combination of 0.01 mg/kg buprenorphine and 2.2 mg/kg carprofen intramuscularly. All animals in the carprofen (n = 4) and buprenorphine+carprofen (n = 4) treatment groups appeared to have sufficient analgesia. Three of 4 animals in the buprenorphine group had adequate analgesia. The fourth animal had an elevated heart rate and spent less time standing during the postoperative period. In this study, the use of carprofen or a combination of carprofen plus buprenorphine provided more reliable postoperative analgesia than buprenorphine alone.

Topics: Analgesics; Animals; Body Weight; Buprenorphine; Carbazoles; Drug Therapy, Combination; Feeding Behavior; Female; Hydrocortisone; Pain Measurement; Pain, Postoperative; Papio anubis

Twenty-eight dogs were randomly allocated into two groups. They were premedicated with either 10 or 20 microg/kg buprenorphine and 0.05 mg/kg acepromazine administered intramuscularly, and then anaesthetised with intravenous thiopentone to effect and maintained with isoflurane in 100 per cent oxygen. The dogs underwent routine castration, and a second dose of 10 microg/kg buprenorphine was administered four hours after the first or 20 microg/kg six hours after the first dose. Levels of pain and sedation were scored on a visual analogue scale and in terms of the dogs' requirement for rescue analgesia, and mechanical nociceptive thresholds were measured at the hock and wound at premedication and one, two, three, four, five, six, seven, 10 and 21 to 22 hours later. Pain scores were low in both groups, with a trend for lower scores in the high dose group; administration of the second dose of buprenorphine further decreased the pain scores. Buprenorphine produced good preoperative sedation and the level of sedation decreased over time after surgery. Administration of the second high dose of buprenorphine did not increase the level of sedation. Both doses of buprenorphine prevented hyperalgesia at the wound and hock postoperatively. Three dogs given the low dose and one dog given the high dose required rescue analgesia with carprofen.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Carbazoles; Conscious Sedation; Dogs; Dose-Response Relationship, Drug; Injections, Intramuscular; Male; Orchiectomy; Pain Measurement; Pain, Postoperative; Postoperative Care; Time Factors; Treatment Outcome

A placebo-controlled, randomized blind study was conducted in cats (n = 60) after fracture repair to compare the analgesic effects as well as the side-effects of carprofen, buprenorphine and levomethadone during a 5-day treatment. Cats with severe shock symptoms or increases in blood urea nitrogen (BUN) and creatinine were excluded from the study. The cats were randomly assigned to four groups (n= 15). In group 1, carprofen was administered upon extubation at an initial dose of 4 mg/kg body weight, followed by one-third of that dose three times daily on days 2 to 5. In group 2, buprenorphine was administered in a single dose of 0.01 mg/kg body weight upon extubation and subsequently every 8 h. Levomethadone (group 3) was applied according to the same scheme at a dosage of 0.3 mg/kg body weight each time. The placebo (group 4) was given at the same time intervals as the opioids. Examinations were carried out prior to anaesthesia, between 30 min and 8 h after extubation, and on the following 4 days, 1 h after administration of the analgesics or the placebo as well as 1 h before the next administration. Pain and sedation evaluation was carried out with a visual analogue system (VAS) and with the aid of a numerical estimation scale (NRS). Pain was also scored by measuring mechanical nociceptive threshold of traumatized tissue. Plasma glucose and cortisol concentration, heart rate, respiration rate, blood pressure and body temperature were measured. Furthermore, a complete blood count and clinical chemistry including BUN, creatinine, alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), arterial blood pressure (AP), total protein and electrolytes of the cats were checked on the day of admission as well as on the last day of this study (day 5). Defaecation and urination as well as wound healing were monitored. On the basis of the mechanical nociceptive threshold of the traumatized tissue, concentrations of plasma glucose and cortisol and pain assessment using NRS and VAS, carprofen was found to have better anti-nociceptive efficacy when compared with the two opioid analgesics, while the analgesic effect of levomethadone was similar to that of buprenorphine. However, the carprofen group also showed comparably high median NRS and VAS pain scores in addition to occasional broad deviations from the group mean on the first post-operative treatment day. Sedative effects were detected for buprenorphine and levomethadone; in addition, symptoms of central exci

Topics: Analgesics; Analgesics, Opioid; Animals; Buprenorphine; Carbazoles; Cats; Fractures, Bone; Methadyl Acetate; Orthopedics; Pain Measurement; Pain, Postoperative; Postoperative Care; Random Allocation; Treatment Outcome

Complete Freund's adjuvant (CFA)-induced arthritis in rats is a common animal model for studying chronic inflammatory pain. However, modelling of the disease is associated with unnecessary pain and impaired animal wellbeing, particularly in the immediate post-induction phase. Few attempts have been made to counteract these adverse effects with analgesics. The present study investigated the effect of buprenorphine on animal welfare, pain-related behaviour and model-specific parameters during the disease progression in a rat model of CFA-induced monoarthritis. The aim was to reduce or eliminate unnecessary pain in this model, in order to improve animal welfare and to avoid suffering, without compromising the quality of the model. Twenty-four male Sprague Dawley rats were injected with 20 μl of CFA into the left tibio-tarsal joint to induce monoarthritis. Rats were treated with either buprenorphine or carprofen for 15 days during the disease development, and were compared to a saline-treated CFA-injected group or a negative control group. Measurements of welfare, pain-related behaviour and clinical model-specific parameters were collected. The study was terminated after 3 weeks, ending with a histopathologic analysis. Regardless of treatment, CFA-injected rats displayed mechanical hyperalgesia and developed severe histopathological changes associated with arthritis. However, no severe effects on general welfare were found at any time. Buprenorphine treatment reduced facial pain expression scores, improved mobility, stance and lameness scores and it did not supress the CFA-induced ankle swelling, contrary to carprofen. Although buprenorphine failed to demonstrate a robust analgesic effect on the mechanical hyperalgesia in this study, it did not interfere with the development of the intended pathology.

Topics: Analgesics, Opioid; Animals; Ankle Joint; Arthritis, Experimental; Behavior, Animal; Body Weight; Buprenorphine; Carbazoles; Corticosterone; Disease Models, Animal; Facial Pain; Freund's Adjuvant; Hyperalgesia; Male; Rats; Rats, Sprague-Dawley

Providing postoperative analgesia to rats by oral administration, compared with injections, reduces stress from frequent handling and is technically easier for investigators. The purpose of this study was to investigate whether bacon-flavored tablets containing gabapentin, carprofen or a combination of both drugs effectively attenuates postoperative mechanical and thermal hypersensitivity in a rat model of incisional pain. Forty-eight Sprague-Dawley rats were randomly assigned to 1 of 5 treatment groups: placebo tablet; a single, subcutaneous injection of buprenorphine sustained release at 1.2 mg/kg; gabapentin 90 mg/tablet; carprofen 5 mg/tablet; gabapentin 90 mg and carprofen 5 mg/tablet (gabapentin/carprofen). Tablets were given to rats on days -3, -2, -1, 0 (surgery), 1, and 2. Rats were anesthetized using isoflurane. A 1 cm skin incision was made aseptically on the plantar surface of the left hindpaw and closed by using suture. Mechanical (von Frey monofilament) and thermal (Hargreaves method) hypersensitivity were tested daily, and analyzed on days -1, 1, 2, and 3. The amount of tablet consumed was recorded daily; postoperatively rats consumed 101 to 133 mg/kg of gabapentin, 5.5 to 5.8 mg/kg of carprofen, and 86-137/1.9-3 mg/kg of gabapentin/carprofen, respectively. Both the gabapentin and carprofen groups displayed attenuated mechanical hypersensitivity on all 3 postsurgical days and decreased thermal hypersensitivity on Day 3. The gabapentin/ carprofen group showed attenuated mechanical hypersensitivity on Day 2 and 3, but no significant reduction of thermal hypersensitivity. These data suggest that both gabapentin and carprofen, given orally by flavored tablet, effectively attenuate postoperative mechanical hypersensitivity for 3 d after surgery in a rat model of incisional pain.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Carbazoles; Drug Therapy, Combination; Flavoring Agents; Gabapentin; Laboratory Animal Science; Male; Pain, Postoperative; Postoperative Period; Rats; Rats, Sprague-Dawley; Surgical Wound; Tablets

The pathways of circulation and clearance of cerebrospinal fluid (CSF) in the spine have yet to be elucidated. We have recently shown with dynamic in vivo imaging that routes of outflow of CSF in mice occur along cranial nerves to extracranial lymphatic vessels. Here, we use near-infrared and magnetic resonance imaging to demonstrate the flow of CSF tracers within the spinal column and reveal the major spinal pathways for outflow to lymphatic vessels in mice. We found that after intraventricular injection, a spread of CSF tracers occurs within both the central canal and the spinal subarachnoid space toward the caudal end of the spine. Outflow of CSF tracers from the spinal subarachnoid space occurred predominantly from intravertebral regions of the sacral spine to lymphatic vessels, leading to sacral and iliac LNs. Clearance of CSF from the spine to lymphatic vessels may have significance for many conditions, including multiple sclerosis and spinal cord injury.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Carbazoles; Cerebrospinal Fluid; Contrast Media; Lumbosacral Region; Lymphatic System; Lymphatic Vessels; Magnetic Resonance Imaging; Mice, Inbred C57BL; Mice, Transgenic; Sacrum; Subarachnoid Space

In animal research, authorities require a classification of anticipated pain levels and a perioperative analgesia protocol prior to approval of the experiments. However, data on this topic is rare and so is the reported use of analgesics. We determined surrogate parameters of pain and general well-being after subarachnoid hemorrhage (SAH), as well as the potential for improvement by different systemic analgesia paradigms. Brain injury was induced by filament perforation to mimic SAH. Sham-operated mice were included as surgical control groups with either neck or no-neck preparation. Mice with controlled cortical impact (CCI) injury were included as a control group with traumatic brain injury (TBI), but without neck preparation. Mice were randomized to buprenorphine, carprofen, meloxicam, or vehicle treatment. 24 h after SAH, CCI or sham surgery, pain and stress levels were assessed with a visual assessment score and the amount of food intake was recorded.. Neck preparation, which is required to expose the surgical field for SAH induction, already increased pain/stress levels and sham surgeries for both CCI and SAH reduced food intake. Pain/stress levels were higher and food intake was lower after SAH compared with CCI. Pain/stress levels after CCI without analgesic treatment were similar to levels after SAH sham surgery. Pain treatment with buprenorphine was effective to reduce pain after SAH, whereas lower pain/stress intensity levels after CCI were not improved.. This study emphasizes the importance of pain and stress assessment after surgeries and the efficacy of buprenorphine to improve pain and comfort levels after experimental SAH.

Topics: Animals; Brain Injuries, Traumatic; Buprenorphine; Carbazoles; Eating; Male; Meloxicam; Mice; Pain Measurement; Stress, Psychological; Subarachnoid Hemorrhage

The principles of Refinement, Replacement and Reduction (3R's) should be taken into account when animals must be used for scientific purpose. Here, a Reduction / Refinement approach was applied to the procedure of spinal cord injury (SCI), an animal model used in rehabilitation medicine research, in order to improve the quality of experiments, avoiding unnecessary suffering. The aims of this investigation were 1- to assess acute surgical pain in mice subjected to SCI, 2- to compare the efficacy of commonly used analgesia (three buprenorphine subcutaneous injection in 48 hours, 0,15 mg/kg each) with a combination of opioid and NSAID (one subcutaneous injection of 5 mg/kg carprofen before surgery followed by three buprenorphine subcutaneous injection in 48 hours, 0,15 mg/kg each) and 3- to test if Infrared Thermography (IRT) could be a potential new Refinement method to easily assess thermoregulation, an important metabolic parameter. Finally, we aimed to achieve these goals without recruiting animals on purpose, but using mice already scheduled for studies on SCI. By using behaviours analysis, we found that, despite being commonly used, buprenorphine does not completely relieve acute surgical pain, whereas the combination of buprenorphine and carprofen significantly decreases pain signs by 80%. IRT technology turned out to be a very useful Refinement tool being a non invasive methods to measure animal temperature, particularly useful when rectal probe cannot be used, as in the case of SCI. We could find that temperatures constantly and significantly increased until 7 days after surgery and then slowly decreased and, finally, we could observe that in the buprenorphine and carprofen treated group, temperatures were statistically lower than in the buprenorphine-alone treated mice. To our knowledge this is the first work providing an analgesic Refinement and a description of thermoregulatory response using the IRT technology, in mice subjected to SCI.

Topics: Analgesics; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Carbazoles; Disease Models, Animal; Infrared Rays; Male; Mice; Mice, Inbred C57BL; Pain Measurement; Pain, Postoperative; Rehabilitation Research; Spinal Cord Injuries; Thermography

The urgent need for more effective analgesic treatment options has prompted a re-evaluation of the behavioral tests used to assess pain in pre-clinical research, with an emphasis on inclusion of more voluntary, un-evoked behavioral assessments of pain. In order to validate voluntary gait analysis and a voluntary mechanical conflict-avoidance assay, we tested mouse models of neuropathy (spared nerve injury) and inflammation (complete Freund's adjuvant) alongside reflexive measures of mechanical and thermal hypersensitivity. To establish whether the observed changes in behavioral responses were pain-related, known analgesics (buprenorphine, gabapentin, carprofen) were also administered. Spared nerve injury persistently altered several gait indices, whereas complete Freund's adjuvant caused only transient changes. Furthermore, known analgesics could not reverse these gait changes, despite demonstrating their previously established efficacy in reflexive measures of mechanical and thermal hypersensitivity. In contrast, the mechanical conflict-avoidance assay demonstrated aversion in mice with neuropathy and inflammation-induced hypersensitivity, which could both be reversed by analgesics. We conclude that voluntary gait changes in rodent neuropathic and inflammatory pain models are not necessarily indicative of pain-related adaptations. On the other hand, mechanical conflict-avoidance represents a valid operant assay for quantifying pain-related behaviors in mice that can be reversed by known analgesics.

Topics: Analgesics; Animals; Buprenorphine; Carbazoles; Disease Models, Animal; Female; Freund's Adjuvant; Gabapentin; Gait; Inflammation; Male; Mice; Mice, Inbred C57BL; Neuralgia; Pain Measurement

To investigate the pharmacokinetics of buprenorphine and its main active metabolite, norbuprenorphine, after administration of an intravenous loading dose followed by constant rate infusion (CRI) in dogs.. Prospective, clinical study.. A total of seven healthy dogs undergoing elective ovariectomy.. Buprenorphine was administered as a loading dose (intravenous bolus of 15 μg kg. Buprenorphine showed a two-compartment kinetic profile. Maximum concentration was 23.92 ± 8.64 ng mL. The results suggest that a buprenorphine CRI can be a useful tool for providing analgesia in postoperative patients, considering its minor side effects and the advantages of a CRI compared to frequent boluses. The negligible contribution of norbuprenorphine to the therapeutic effect was confirmed.

Topics: Analgesia; Analgesics, Opioid; Animals; Buprenorphine; Carbazoles; Dogs; Female; Ovariectomy; Pain Measurement; Postoperative Period; Prospective Studies; Time Factors

Guinea pigs (Cavia porcellus) are a frequently used species in research, often involving potentially painful procedures. Therefore, evidence-based recommendations regarding analgesia are critically needed to optimize their wellbeing. Our laboratory examined the efficacy of carprofen and extended-release (ER) buprenorphine, alone and as a multimodal combination, for relieving postsurgical pain in guinea pigs. Animals were assessed by using evoked (mechanical hypersensitivity), nonevoked (video ethogram, cageside ethogram, time-to-consumption test), and clinical (weight loss) measurements for 96 h during baseline, anesthesia-analgesia, and hysterectomy conditions. In addition, ER buprenorphine was evaluated pharmacologically. Guinea pigs treated with a single analgesic showed increased mechanical sensitivity for at least 96 h and indices of pain according to the video ethogram for as long as 8 h, compared with levels recorded during anesthesia-analgesia. In contrast, animals given both analgesics demonstrated increased mechanical sensitivity and behavioral evidence of pain for only 2 h after surgery compared with anesthesia-analgesia. The cageside ethogram and time-to-consumption tests failed to identify differences between conditions or treatment groups, highlighting the difficulty of identifying pain in guinea pigs without remote observation. Guinea pigs treated with multimodal analgesia or ER buprenorphine lost at least 10% of their baseline weights, whereas weight loss in carprofen animals was significantly lower (3%). Plasma levels for ER buprenorphine exceeded 0.9 ng/mL from 8 to 96 h after injection. Of the 3 analgesia regimens evaluated, multimodal analgesia provided the most effective pain control in guinea pigs. However the weight loss in the ER buprenorphine-treated animals may need to be considered during analgesia selection.

Topics: Acetaminophen; Analgesics, Opioid; Animals; Buprenorphine; Carbazoles; Drug Therapy, Combination; Female; Guinea Pigs; Hysterectomy; Pain Management; Pain Measurement; Pain, Postoperative; Specific Pathogen-Free Organisms

Postoperative analgesia in laboratory rats is complicated by the frequent handling associated with common analgesic dosing requirements. Here, we evaluated sustained-release buprenorphine (Bup-SR), sustained-release meloxicam (Melox-SR), and carprofen gel (CG) as refinements for postoperative analgesia. The aim of this study was to investigate whether postoperative administration of Bup-SR, Melox-SR, or CG effectively controls behavioral mechanical and thermal hypersensitivity in a rat model of incisional pain. Rats were randomly assigned to 1 of 5 treatment groups: saline, 1 mL/kg SC BID; buprenorphine HCl (Bup HCl), 0.05 mg/kg SC BID; Bup-SR, 1.2 mg/kg SC once; Melox-SR, 4 mg/kg SC once; and CG, 2 oz PO daily. Mechanical and thermal hypersensitivity were tested daily from day-1 through 4. Bup HCl and Bup-SR attenuated mechanical and thermal hypersensitivity on days 1 through 4. Melox-SR and CG attenuated mechanical hypersensitivity-but not thermal hypersensitivity-on days 1 through 4. Plasma concentrations, measured by using UPLC with mass spectrometry, were consistent between both buprenorphine formulations. Gross pathologic examination revealed no signs of toxicity in any group. These findings suggest that postoperative administration of Bup HCl and Bup-SR-but not Melox-SR or CG-effectively attenuates mechanical and thermal hypersensitivity in a rat model of incisional pain.

Topics: Analgesics; Animals; Body Weight; Buprenorphine; Carbazoles; Delayed-Action Preparations; Male; Meloxicam; Pain, Postoperative; Random Allocation; Rats; Rats, Sprague-Dawley; Thiazines; Thiazoles

In connection with bilateral maxillary sinus augmentation, the acute effects of the nonsteroidal anti-inflammatory drug carprofen on facial expressions and long-term effects on bone formation were evaluated in 18 male New Zealand White rabbits. A 10×10mm bone window was drilled in the maxilla, the sinus membrane elevated and a titanium mini-implant inserted. One of two test materials was randomly inserted unilaterally and bovine bone chips (control) on the contralateral side in the created space. Rabbits were randomly allocated to receive buprenorphine plus carprofen (n=9) or buprenorphine plus saline (n=9) postoperatively. Buprenorphine was administered subcutaneously every 6h for 3days in a tapered dose (0.05-0.01mg/kg) and carprofen (5mg/kg) or saline administered subcutaneously 1h before, and daily for 4days postoperatively. To assess pain, clinical examination, body weight recording and scoring of facial expressions from photos taken before, and 6-13h after surgery were performed. Twelve weeks after surgery the rabbits were euthanized and sections of maxillary bones and sinuses were analysed with histomorphometry and by qualitative histology. Carprofen had no effect on mean facial expression scores, which increased from 0.0 to 3.6 (carprofen) and 4.3 (saline), of a maximum of 8.0. Neither did carprofen have an effect on bone formation or implant incorporation, whereas the test materials had. In conclusion, treatment with 5mg/kg carprofen once daily for 5days did not reduce facial expression scores after maxillary sinus augmentation in buprenorphine treated rabbits and did not affect long term bone formation.

Topics: Animals; Bone Transplantation; Buprenorphine; Carbazoles; Cattle; Dental Implantation, Endosseous; Dental Implants; Facial Expression; Male; Maxillary Sinus; Osteogenesis; Rabbits

Buprenorphine and carprofen, 2 of the most commonly used analgesics in mice, must be administered every 8 to 12 h to provide sustained analgesia. Sustained-release (SR) formulations of analgesics maintain plasma levels that should be sufficient to provide sustained analgesia yet require less frequent dosing and thus less handling of and stress to the animals. The pharmacokinetics of SR formulations of buprenorphine (Bup-SR), butorphanol (Butp-SR), fentanyl (Fent-SR), carprofen (Carp-SR), and meloxicam (Melox-SR) were evaluated in mice over 72 h and compared with those of traditional, nonSR formulations. Bup-SR provided plasma drug levels greater than the therapeutic level for the first 24 to 48 h after administration, but plasma levels of Bup-HCl fell below the therapeutic level by 4 h. Fent-SR maintained plasma levels greater than reported therapeutic levels for 12 h. Therapeutic levels of the remaining drugs are unknown, but Carp-SR provided plasma drug levels similar to those of Carp for the first 24 h after administration, whereas Melox-SR had greater plasma levels than did Melox for the first 8 h. Butp-SR provided detectable plasma drug levels for the first 24 h, with a dramatic decrease over the first 4 h. These results indicate that Bup-SR provides a stable plasma drug level adequate for analgesia for 24 to 48 h after administration, whereas Carp-SR, Melox-SR, Fent-SR, and Butp-SR would require additional doses to provide analgesic plasma levels beyond 24 h in mice.

Topics: Analgesics; Animals; Buprenorphine; Butorphanol; Carbazoles; Delayed-Action Preparations; Female; Meloxicam; Mice; Pain; Thiazines; Thiazoles

Venous thrombosis (VT) is a significant cause of morbidity and mortality in humans. Surgical animal models are crucial in studies investigating the pathogenesis of this disease and evaluating VT therapies. Because inflammation is critical to both the development and resolution of VT, analgesic medications have the potential to adversely affect multiple parameters of interest in VT research. The objective of this study was to determine how several common analgesics affect key variables in a murine ligation model of deep vein thrombosis. Male C57BL/6 mice were randomly assigned to receive either local (bupivacaine) or systemic parenteral analgesia (buprenorphine, tramadol, or carprofen) or 0.9% NaCl (control). All mice underwent laparotomy and ligation of the inferior vena cava, and treatment was continued until euthanasia at 6 or 48 h after surgery. Analysis of harvested tissues and blood included: hematology, thrombus weight, serum and vein-wall cytokines (IL1β, IL6, IL10, TNFα), soluble P-selectin, and vein-wall leukocyte infiltration. Compared with 0.9% NaCl, all of the analgesics affected multiple parameters important to VT research. Carprofen and tramadol affected the most parameters and should not be used in murine models of VT. Although they affected fewer parameters, a single dose of bupivacaine increased thrombus weight at 6 h, and buprenorphine was associated with reduced vein wall macrophages at 48 h. Although we cannot recommend the use of any of the evaluated analgesic dosages in this mouse model of VT, buprenorphine merits additional investigation to ensure the highest level of laboratory animal care and welfare.

Topics: Analgesics; Anesthetics, Local; Animals; Bupivacaine; Buprenorphine; Carbazoles; Disease Models, Animal; Inflammation; Ligation; Male; Mice; Mice, Inbred C57BL; Random Allocation; Tramadol; Vena Cava, Inferior; Venous Thrombosis

The authors examined the potential of the cyclooxygenase 2 (COX-2) inhibitor carprofen to reproducibly induce anastomotic leakage. In experiment 1, an anastomosis was constructed in both ileum and colon of 20 rats, and they were given carprofen (5 mg/kg subcutaneously every 24 hours) or buprenorphine (0.02 mg/kg subcutaneously every 12 hours). In another 20 rats an anastomosis was constructed in either ileum or colon, and all received carprofen (experiment 2). Animals were sacrificed after 3 days. In experiment 1, the ileal dehiscence rate was 60% in the carprofen group and 0% in the buprenorphine group (P = .0108). Colonic anastomoses in both groups remained patent. In experiment 2, the anastomotic leakage rate was 80% in ileum and 0% in colon. Thus, COX-2 inhibitors can severely interfere with intestinal healing, particularly in the ileum. Perioperative administration of carprofen yields a unique model for anastomotic leakage, which allows translational research on the effectiveness of perisuture line reinforcement.

Topics: Analgesics, Opioid; Anastomotic Leak; Animals; Buprenorphine; Carbazoles; Collagen; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Ileum; Male; Matrix Metalloproteinase 2; Pain; Perioperative Period; Pressure; Rats; Rats, Wistar; Surgical Wound Dehiscence; Weight Loss

Postoperative pain management in animals is complicated greatly by the inability to recognize pain. As a result, the choice of analgesics and their doses has been based on extrapolation from greatly differing pain models or the use of measures with unclear relevance to pain. We recently developed the Mouse Grimace Scale (MGS), a facial-expression-based pain coding system adapted directly from scales used in nonverbal human populations. The MGS has shown to be a reliable, highly accurate measure of spontaneous pain of moderate duration, and therefore is particularly useful in the quantification of postoperative pain. In the present study, we quantified the relative intensity and duration of postoperative pain after a sham ventral ovariectomy (laparotomy) in outbred mice. In addition, we compiled dose-response data for 4 commonly used analgesics: buprenorphine, carprofen, ketoprofen, and acetaminophen. We found that postoperative pain in mice, as defined by facial grimacing, lasts for 36 to 48 h, and appears to show relative exacerbation during the early dark (active) photophase. We find that buprenorphine was highly effective in inhibiting postoperative pain-induced facial grimacing in mice at doses equal to or lower than current recommendations, that carprofen and ketoprofen are effective only at doses markedly higher than those currently recommended, and that acetaminophen was ineffective at any dose used. We suggest the revision of practices for postoperative pain management in mice in light of these findings.

Topics: Acetaminophen; Analgesics; Animals; Animals, Laboratory; Buprenorphine; Carbazoles; Dose-Response Relationship, Drug; Facial Expression; Ketoprofen; Mice; Pain Measurement; Pain, Postoperative; Research Design; Time Factors; Video Recording

The purpose of this study was to determine the level of pain elicited by mammary fat pad removal surgery and the effects of postoperative analgesics on recovery. Female FVB mice were anesthetized, and mammary fat pad removal was performed. After surgery, mice received carprofen, buprenorphine, a combination of carprofen and buprenorphine, or saline treatment. Additional mice received anesthesia but no surgery or treatment. Food and water intake, body weight, wheel running activity, and a visual assessment score were recorded daily for 4 d after surgery and compared with presurgical findings. Corticosterone metabolites in fecal samples were analyzed at 12 and 24 h postsurgically and compared with baseline values. All surgical groups had significantly decreased food intake at 24 h, with a return to baseline by 48 h. The combination treatment resulted in a significantly decreased water intake and body weight at 24 h. All surgical groups had significantly decreased wheel running activity at 24 h only. The visual assessment scores indicated mild pain for all surgical groups, with the buprenorphine treated mice showing the highest pain index scores, as compared with nonsurgical controls. Fecal corticosterone metabolite levels did not differ significantly between any of the groups or across time. The parameters used in this study did not indicate that administration of these analgesic regimens improved recovery as compared with that of saline-treated mice. Care should be taken when using visual assessment scores to evaluate pain in mice, given that analgesics may have side effects that inadvertently elevate the score.

Topics: Adipose Tissue; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Carbazoles; Drug Therapy, Combination; Female; Mammary Glands, Animal; Mice; Mice, Inbred Strains; Pain Measurement; Pain, Postoperative; Random Allocation; Treatment Outcome

To evaluate a prototype pressure stimulus device for use in the cat and to compare with a known thermal threshold device.. Eight healthy adult cats weighing between 3.0 and 4.9 kg.. Pressure stimulation was given via a plastic bracelet taped around the forearm. Three 2.4 mm diameter ball bearings, in a 10-mm triangle, were advanced against the craniolateral surface of the antebrachium by manual inflation of a modified blood pressure bladder. Pressure in the cuff was recorded at the end point (leg shake and head turn). Thermal threshold was also tested. Stimuli were stopped if they reached 55 degrees C or 450 mmHg without response. After four pressure and thermal threshold baselines, each cat received SC buprenorphine 0.01 mg kg(-1), carprofen 4 mg kg(-1) or saline 0.3 mL in a three period cross-over study with a 1-week interval. The investigator was blinded to the treatment. Measurements were made at 0.25. 0.5, 0.75, 1, 2, 3, 4, 6, 8, and 24 hours after injection. Data were analyzed by using ANOVA.. There were no significant changes in thermal or pressure threshold after administration of saline or carprofen, but thermal threshold increased from 60 minutes until 8 hours after administration of buprenorphine (p < 0.05). The maximum increase in threshold from baseline (DeltaT(max)) was 3.5 +/- 3.1 degrees C at 2 hours. Pressure threshold increased 2 hours after administration of buprenorphine (p < 0.05) when the increase in threshold above baseline (DeltaP(max)) was 162 +/- 189 mmHg.. This pressure device resulted in thresholds that were affected by analgesic treatment in a similar manner but to a lesser degree than the thermal method. Pressure stimulation may be a useful additional method for analgesic studies in cats.

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Carbazoles; Cat Diseases; Cats; Cross-Over Studies; Double-Blind Method; Female; Hot Temperature; Injections, Subcutaneous; Male; Pain; Pain Measurement; Pressure; Sodium Chloride

Prevention of unnecessary pain in laboratory animals requires reliable and practically useful tools for assessing pain severity and analgesic efficacy. We have used a behaviour-based pain scoring system to determine the duration of pain resulting from laparotomy, and the duration of analgesia afforded by orally administered (p.o.) buprenorphine and subcutaneously administered (s.c.) carprofen or buprenorphine in rats. One hour before laparotomy Fisher 344 rats received either saline as a control (0.2 ml/100 g s.c.), carprofen (5 mg/kg s.c.) or buprenorphine (0.05 mg/kg s.c. or 0.4 mg/kg p.o.). The rats were housed singly for 10-min periods of behaviour recording, beginning 30 min after completing surgery. Recording was repeated at three time points every 2 h. The behaviour of controls was distinct from that of the analgesic-treated animals throughout recording; however, the major signs of pain (back-arching, staggering and writhing) were prominent during only the first 270 min in the saline group. This was followed by a period of more subtle differences between the saline- and drug-treated groups. It was concluded that the most acutely painful effects of surgery in this model lasted for between 270 and 390 min, and that this was alleviated throughout its duration by subcutaneously administered carprofen or buprenorphine, and also buprenorphine administered orally. The study demonstrates a clinically relevant and practically useful approach to assessing the duration of post-surgical abdominal pain and analgesic effects in rats.

Topics: Abdominal Pain; Administration, Oral; Analgesics, Opioid; Animal Welfare; Animals; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Carbazoles; Drug Therapy, Combination; Injections, Subcutaneous; Laparotomy; Male; Rats; Rats, Inbred F344

Rats subjected to hypophysectomy make up one of the largest groups of experimental animals in Europe, since there is a legal demand for batch testing of industrially produced growth hormones. To describe the clinical performance of rats having undergone hypophysectomy, animals were examined postoperatively by monitoring behaviour, body temperature and food intake. Behavioural changes were observed in rats that had only been anaesthetized, as well as in sham-operated rats, while no behavioural deviations could be shown in hypophysectomized rats. On the first day after surgery all rats had declining body temperature and food intake; and this change was not reversed by treatment with carprofen, buprenorphine or oxytetracycline. The mortality rate in rats treated with buprenorphine was increased, as was the mortality rate in rats hypophysectomized when weighing more than 100 g. As there seemed to be no differences whether methohexital or a combination of fentanyl, fluanison and midazolam was used, the latter anaesthesia is recommended due to its analgesic potential. For post-surgical analgesic treatment, carprofen is recommended rather than buprenorphine. At best, the use of hypophysectomized rats should be replaced in industrial batch testing by an existing in vitro method.

Topics: Analgesics, Opioid; Anesthesia, Intravenous; Anesthetics, Intravenous; Animal Welfare; Animals; Behavior, Animal; Body Temperature; Buprenorphine; Butyrophenones; Carbazoles; Eating; Fentanyl; Hypophysectomy; Male; Methohexital; Midazolam; Oxytetracycline; Postoperative Complications; Rats; Rats, Inbred Strains

Rats underwent a midline laparotomy and received buprenorphine, buprenorphine together with carprofen, flunixin or carprofen alone while a control group received saline. Food and water intakes and body weight were reduced following surgery in the saline control group. The degree of depression of these variables was significantly reduced by the administration of either buprenorphine or carprofen. In all groups of rats locomotor activity was depressed following surgery. Analgesic administration had little influence on these changes in activity, although administration of two doses of buprenorphine (0.05 mg/kg, 9 h interval) reduced the degree of depression in comparison to the saline control group. If the depression in food and water consumption is related to the presence of post-operative pain, then these findings suggest that analgesics should be administered to rats following surgical procedures.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Buprenorphine; Carbazoles; Clonixin; Drinking; Drug Therapy, Combination; Eating; Laparotomy; Male; Motor Activity; Pain, Postoperative; Rats; Rats, Wistar