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Effects of buprenorphine, carprofen and saline on thermal and mechanical nociceptive thresholds in cats
Veterinary Anaesthesia and Analgesia, 2007, 34, 344–350
doi:10.1111/j.1467-2995.2006.00331.x
RESEARCH PAPER
Effects of buprenorphine, carprofen and saline on thermal and mechanical nociceptive thresholds in cats Paulo VM Steagall* DVM, Polly M Taylor MA, VetMB, PhD, Diplomate ECVA, Juliana T Brondani* Luna* DVM, IVAS CVA, MSc, PhD, Diplomate ECVA, Mike J Dixon PhD & Tatiana H Ferreira* DVM
DVM, MSc,
Stelio PL
*Department of Veterinary Surgery and Anaesthesiology, Faculty of Veterinary Medicine and Animal Science, UNESP, Botucatu, Sa˜o Paulo, Brazil Taylor Monroe, Little Downham, Ely, UK
Correspondence: Paulo Vinicius Mortensen Steagall, FMVZ, UNESP 18618-000, Botucatu, SP, Brazil. E-mail: [email protected]
Abstract Objective To evaluate a prototype pressure stimulus device for use in the cat and to compare with a known thermal threshold device. Animals Eight healthy adult cats weighing between 3.0 and 4.9 kg. Methods 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 °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. Results 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 344
administration of buprenorphine (p < 0.05). The maximum increase in threshold from baseline (DTmax) was 3.5 ± 3.1 °C at 2 hours. Pressure threshold increased 2 hours after administration of buprenorphine (p < 0.05) when the increase in threshold above baseline (DPmax) was 162 ± 189 mmHg. Conclusions and clinical relevance 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. Keywords analgesia, buprenorphine and carprofen, cats, pain.
Introduction It is widely accepted that pain relief is an important component of veterinary treatment of animals. Pain causes stress and sympathetic nervous system activity, affects food intake and metabolism, and modifies behavior (Lascelles & Waterman-Pearson 1997). Animals suffering pain may have impaired respiration, immunosuppression, and central nervous system sensitization, leading to chronic pain (Lascelles & Waterman-Pearson 1997; Taylor 2003). The severity and clinical importance of feline pain is probably underestimated. Epidemiological studies show that cats receive fewer analgesics when
Mechanical vs thermal nociceptive stimulation in cats PVM Steagall et al.
compared to dogs (Hansen & Hardie 1993; Dohoo & Dohoo 1996; Watson et al. 1996; Lascelles et al. 1999; Raekallio et al. 2003; Hugonnard et al. 2004; Williams et al. 2005). This is probably because pain in cats is more difficult to recognize, and there is particular concern about both opioid and nonsteroidal anti-inflammatory drug (NSAID) toxicity in this species (Dohoo & Dohoo 1996; Lascelles & Waterman-Pearson 1997). For instance, 24.3% of veterinarians did not use analgesics after orthopedic surgery in cats, in spite of the recognition that such procedures cause moderate to severe pain (Dohoo & Dohoo 1996). In another study, it was reported that around 40% and 60%, respectively, of veterinarians did not use analgesics in cats undergoing ovariohysterectomy or castration (Raekallio et al. 2003). Even when cats received analgesics, the most commonly used were not the most effective (Dohoo & Dohoo 1996). Recently, increased attention has been paid to pain management in cats, and it is now generally regarded as an essential component of clinical veterinary care in this species (Taylor 2003; Taylor & Robertson 2004). Knowledge of analgesic pharmacology in cats is, however, still limited, and any investigations that improve our fundamental understanding in this field will ultimately help to improve clinical feline pain management. A means of assessing pain objectively is required for any investigation into pain and analgesia. Such systems must not injure the animal and must produce repeatable data. A thermal threshold device was developed and validated for cats and has been used in several studies (Dixon et al. 2000, 2002; Robertson et al. 2003a, 2005a,b; Lascelles & Robertson 2004a,b; Wegner et al. 2004). This device is used on unrestrained cats and it also incorporates rapid termination of the stimulus upon detection of a response and a cut-out point to prevent tissue damage when analgesics are used. Data from studies using this device to study opioids indicate a close relation between analgesic effects and clinical efficacy (Dixon et al. 2002; Robertson et al. 2003a, 2005a,b; Lascelles & Robertson 2004a,b). However, it is well recognized that more than one type of stimulus is required to evaluate pain and analgesia comprehensively; clinical pain results from activation of a range of receptors, and different analgesics act via a variety of mechanisms (Dixon et al. 2002). The thermal threshold device has had limited application to study of NSAID analgesia in cats, and a pressure stimulus was considered likely
to have greater potential for these investigations (Taylor et al. 2003). The aim of this study was to validate a prototype mechanical nociceptive threshold testing device developed for use in cats (Dixon et al. 2000, 2007) and to compare it with a thermal threshold device (Dixon et al. 2002). Opioids and NSAIDs are the two most widely accepted analgesic drug types in clinical use; the opioid, buprenorphine, and the NSAID carprofen were selected from these two groups for use in the study. Buprenorphine, a partial mu (MOP) agonist has been previously studied in cats using the thermal device (Robertson et al. 2003a,b, 2005a,b; Murrell et al. 2007). Carprofen is extensively used for perioperative analgesia in cats in the UK. Saline was used as a control. Materials and methods The study was approved by the Ethical Committee for Animal Experimentation, Faculty of Medicine, University of Sa˜o Paulo State (protocol 434). Cats Eight neutered adult domestic cats, two male and six female, were studied. All cats were housed according to the Principles of the University Research Ethical Committee. Before the study began, the cats were wormed, vaccinated against Chlamydia psittaci, panleukopenia, calicivirus and feline rhinotracheitis, and biochemical analyses and a complete blood count were performed. Polymerase chain reaction against feline immunodeficiency virus (FELV) and feline leukemia virus (FIV) were negative for all cats used in the study. Health checks were made at regular intervals between testing sessions. The cats were group housed and fed dry cat food. On study days they were moved to single cage housing and the feed was supplemented with canned food. Water was available ad libitum. During testing, cats were housed individually in a quiet environment in cages 80 cm high, 120 cm wide, and 60 cm long. Cages were equipped with wall mirrors, toys, a bed, and a litter tray. All cats had been well handled and familiarized with the procedure for several weeks prior to the studies. Measurements Thermal and pressure thresholds were measured by applying a mild, transient heat or pressure stimulus
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to elicit pain (Dixon et al. 2000, 2002, 2007). For each test, care was taken to ensure that the cats were awake but not otherwise distracted; they were unrestrained and not sleeping, eating, or playing. Thermal threshold A small probe containing a heater element and a temperature sensor was held against the shaved thorax using an elasticated band and a pressure bladder (Fig. 1) (Dixon et al. 2002). The bladder was inflated manually to 100 mm Hg to ensure consistent contact between probe and skin. During testing the probe was connected to the control unit with a light ribbon cable. When activated, the probe heated at 0.6 °C second)1 with an automatic cut-off at 55 °C if not stopped earlier. At each test, the heater was activated and then switched off as soon as the cat reacted; this was usually a skin flick, a jump forward, a turn to bite the band, or occasionally vocalization. At the point of reaction, the probe temperature was recorded as the thermal threshold. Prior to any drug administration, four measurements were made at 15minute intervals and their mean value taken as the control thermal threshold. Pressure threshold A lightweight plastic bracelet weighing about 5 g was taped around the forearm (Fig. 1) (Dixon et al. 2007). This held three pressure pins, each tipped
with a 2.4-mm diameter ball bearing, in a 10-mm equilateral triangle. The pins were advanced against the craniolateral surface of the antebrachium by manual inflation of a modified 2 cm square blood pressure bladder positioned directly behind the pins (Dixon et al. 2007). The cuff was connected to a three-way stopcock, a 30-mL syringe and a pressure transducer via noncompliant arterial manometer tubing. The transducer was calibrated using a mercury column. The syringe was compressed manually at 1.5 mL second)1 until the cat reacted. Reactions were a leg shake, a head turn, or occasionally vocalization. Cuff pressure was recorded immediately (using the hold facility on a digital voltmeter) and the pressure released. A cut-off pressure to prevent skin damage if the cat did not react was provided automatically when the syringe was fully compressed at a pressure of 650 mmHg. If this point was reached, pressure was released immediately. Prior to any drug treatment, four baseline measurements were made at 15-minute intervals and their mean value taken as the control pressure threshold. Drug treatment After the pre-treatment pressure and thermal threshold readings had been made, each cat received subcutaneous 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 between treatments, sufficient time to ensure there are no residual effects from carprofen (Taylor et al. 1996). Thermal and pressure measurements were made at 15, 30, and 45 minutes, and at 1, 2, 3, 4, 6, 8, and 24 hours after the injection. Thermal testing was followed by pressure testing at each time point. Two or three cats were tested on the same day but they were housed in separate cages. The observer was unaware which treatment had been given. Statistical analysis
Figure 1 Cat number 1 relaxing during testing between applications of the stimuli. The thermal probe is held against the thorax with an elasticated band. The pressure stimulus is produced by inflation of a pressure bladder within the bracelet taped around the cat’s foreleg. The inflated bladder moves three ball bearings mounted on short pins onto the skin. 346
Data within each treatment group were analyzed for changes with time by using one-way repeatedmeasures ANOVA followed by Dunnett’s test. The treatments were compared by using two-way ANOVA and a Bonferroni post-test (Graphpad Prism software, version 4.00; Graphpad Software Inc., San Diego, CA, USA). p < 0.05 was regarded as significant. Further analysis was carried out by comparison of thermal and pressure thresholds after
Ó 2007 The Authors. Journal compilation Ó 2007 Association of Veterinary Anaesthetists, 34, 344–350
Mechanical vs thermal nociceptive stimulation in cats PVM Steagall et al.
buprenorphine and carprofen treatment with a reference range taken from the saline series (Dixon et al. 2002). The reference range was generated by taking the mean of the 10 thresholds for each cat measured during the 24 hours after saline treatment, and using these means to generate 95% confidence intervals (CI) for the group of cats when not given an analgesic. Thresholds from the carprofen- and buprenorphine-treated cats lying outside of the 95% CI were considered to indicate hyper- or hypoalgesia. Results There were no effects of cat or time on the saline group. There were no significant changes in either thermal or pressure threshold after saline or carprofen administration. Thermal threshold increased from 60 minutes until 8 hours after buprenorphine administration (p < 0.05) (Fig. 2). The maximum increase in threshold from baseline (DTmax) was 3.5 ± 3.1 °C at 2 hours. Pressure threshold increased 2 hours after buprenorphine administration (p < 0.05) achieving a maximum increase above baseline (DPmax) of 162 ± 189 mmHg (Fig. 3). Thermal thresholds after buprenorphine administration were significantly higher than after saline or carprofen administration at 2 and 3 hours, respectively. Pressure thresholds after buprenor-
Figure 3 Mean ± SD pressure thresholds after subcutaneous administration of buprenorphine (0.01 mg kg)1), carprofen (4 mg kg)1), or saline (0.3 mL kg)1) at time 0. Horizontal lines represent upper and lower 95% confidence intervals (CI) for saline. The reference range was generated by taking the mean of the 10 thresholds for each cat measured during the 24 hours after saline treatment, and using these means to generate 95% CI.
phine administration were significantly higher than after saline or carprofen administration at 2 hours. Mean thermal thresholds after buprenorphine were above the upper 95% CI (indicating hypoalgesia) from 1–8 hours after treatment. Mean pressure thresholds after buprenorphine were above the upper 95% CI from 2–3 hours and from 6–8 hours after treatment. Mean thermal and pressure thresholds after saline and carprofen administration remained within the 95% CI. Discussion
Figure 2 Mean ± SD thermal thresholds after subcutaneous administration of buprenorphine (0.01 mg kg)1), carprofen (4 mg kg)1), or saline (0.3 mL kg)1) at time 0. Horizontal lines represent upper and lower 95% confidence intervals (CI) for saline. The reference range was generated by taking the mean of the 10 thresholds for each cat measured during the 24 hours after saline treatment, and using these means to generate 95% CI.
Pain is a multifactorial entity, and cannot be studied by a single method. Clinical trials make an important contribution to the study of pain and analgesics in cats, but the data, from visual analog and numerical scales, are subjective, making direct comparisons between treatments difficult (Lascelles et al. 1995; Slingsby & Waterman-Pearson 2000; Dobbins et al. 2002; Al-Gizawiy & Rude´ 2004). Neuroendocrine assays measuring b-endorphin, catecholamines, and cortisol concentrations in plasma have been correlated with pain in cats (Benson et al. 1991; Lin et al. 1993; Cambridge et al. 2000). However, factors other than pain commonly affect these hormones. Changes in environment during hospitalization and physiological changes resulting from anesthesia and surgery may all affect neuroendocrine and adrenocortical
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responses (Lin et al. 1993). Hence, endocrinology alone is inappropriate for pain assessment, although it may contribute to the overall picture. Pharmacokinetic investigation also plays a role in the study of analgesia, and with some drugs, such as fentanyl, plasma concentration correlates well with analgesia (Robertson et al. 2005a). However, with others, such as buprenorphine, there is considerable hysteresis between analgesic effect and plasma concentration, so some measure of pharmacodynamics must also be included (Robertson et al. 2005b). The route of opioid administration may influence the onset, duration, and intensity of drug effect. Recent studies demonstrated that the thermal antinociceptive effects of 0.1 mg kg)1 hydromorphone given intramuscularly and intravenously in cats had a similar onset but a slightly shorter duration of action and less intense effect when given intramuscularly (Lascelles & Robertson 2004a; Wegner et al. 2004). The subcutaneous route is preferred in cats as injection is less painful and stressful, but nausea and vomiting have been reported when morphine and hydromorphone were given by the SC route (Robertson & Taylor 2004). The feline thermal threshold system has been successful in contributing to pain and analgesia research in cats where the onset, magnitude, and the duration of effect of several opioids has been determined (Dixon et al. 2002; Robertson et al. 2003a,b, 2005a,b; Taylor et al. 2003; Lascelles & Robertson 2004a,b; Wegner et al. 2004; Murrell et al. 2007), but additional stimuli are needed for comprehensive coverage which can be related more closely to clinical pain. Nociception is produced by mechanical, thermal, or chemical stimuli, activating dermal receptors and afferent Ad and C fibers in the neural afferent pathways (Muir 2002). Pain perception then occurs in the cerebral cortex, after the motor neuron and brain stem response (Slingsby et al. 2001). Several devices have been developed for measuring mechanical thresholds in cats. Slingsby & Waterman-Pearson (2000) developed a system using a force transducer in cats after ovariohysterectomy. This was compressed against the surgical incision until the cat reacted. A second system was developed where a sensor under an index finger was pressed onto a castration wound to measure the force required to elicit a response (Slingsby et al. 2001). In both cases, postoperative hyperalgesia was under test, and the cats had to be restrained. 348
The thermal device (Dixon et al. 2002) was developed for use in unrestrained cats, and the pressure device (Dixon et al. 2007) was developed with the same aim. Hence the force transducers used by Slingsby & Waterman-Pearson (2000) and Slingsby et al. (2001) were not considered suitable. As with the thermal system, it was developed for cats; and is light, well tolerated and allows reproducible testing without injury, in unrestrained cats in a familiar environment (Dixon et al. 2007). This avoids stress and the need for either chemical or mechanical restraint, which may all modify the nociceptive threshold (Dixon et al. 2002). A safety cut-off to prevent injury is incorporated, and the stimulus is stopped, and the threshold recorded, as soon as a reaction is observed. It was expected that a mechanical stimulus would stimulate different nociceptors than a thermal stimulus. In this model, application of the mechanical device to the craniolateral aspect of the antebrachium may mean that the stimulus could include receptors in the skin as well as muscle and periosteum and it is likely that both Ad and C fibers were activated, whereas the thermal stimulus mainly affects C fibers. These differences in neural responses to the stimuli may account for differences in the response to the drugs administered. This pressure stimulus appeared to fulfill the requirements of a threshold testing device. A previous study indicated that it was well tolerated by cats and that data are repeatable and reproducible as long as testing is not more frequent than 15-minute intervals (Dixon et al. 2007). The present study confirms the original report, that the system was tolerated by the cats, and buprenorphine increased the threshold values consistent with the analgesic effect detected simultaneously with the thermal system. The increase in pressure threshold after buprenorphine administration followed a similar pattern to the thermal thresholds (Robertson et al. 2003a,b, 2005b), increasing above the upper 95% CI at 2 hours, and remaining high until 8 hours. Pressure threshold decreased below the upper CI at 4 hours but increased again later. This effect is difficult to explain, was not reflected in the thermal thresholds, and may be a result of difficulties with a new methodology. In general however, this study suggested that the pressure threshold testing device should make a useful contribution to analgesic research in cats. As indicated in the earlier paper (Dixon et al. 2007), the increase in pressure in the cuff and the force applied to the animal are not linear, and the force
Ó 2007 The Authors. Journal compilation Ó 2007 Association of Veterinary Anaesthetists, 34, 344–350
Mechanical vs thermal nociceptive stimulation in cats PVM Steagall et al.
actually applied to the tissues is unknown. The cutoff pressure of 650 mmHg in the cuff was arbitrary and did not necessarily translate to a point at which tissue damage occurs whereas the thermal cut-off point is set to a value just below that at which tissue injury has been recognized (burns). A review of the results of this study highlights a significant benefit of laboratory studies of pain and analgesia. A number of investigations into the effects of buprenorphine in cats have been undertaken using the same thermal threshold device, allowing some comparison between different treatment methodologies (Taylor et al. 2001; Robertson et al. 2003a,b, 2005b; Murrell et al. 2007). These studies, taken together with the present data, enable consideration of the effect of route of administration of buprenorphine. In spite of achieving similar plasma buprenorphine concentrations, maximum mean thermal threshold was around 54 °C after intravenous administration, 51 °C after mucosal and IM routes (Robertson et al. 2003b, 2005b), around 45 °C after SC administration in the present study and did not increase at all when a buprenorphine patch alone was used (Murrell et al. 2007). These data suggest that the route of administration is important in allowing buprenorphine to reach the effector site; routes leading to slow uptake may not achieve sufficient concentration gradients to drive the drug into the biophase, although they may be sufficient to maintain it there subsequently. In the present study, carprofen did not increase thermal or pressure thresholds. This is consistent with other laboratory studies of NSAID analgesia where it is well recognized that acute analgesiometric methods are inappropriate, as NSAID analgesia depends on the presence of inflammation (Le Bars et al. 2001). The pressure device was originally developed to study analgesia in a small inflamed site, where the thermal system had limited value (Taylor et al. 2003). Its value in this respect has yet to be evaluated fully (Dixon et al. 2007). In conclusion, the prototype pressure device detected mechanical thresholds which were affected by the analgesic treatment, in a manner similar to the thermal method. Pressure stimulation appears to be a useful stimulus for analgesic studies in cats. References Al-Gizawiy MM, Rude´ EP (2004) Comparison of preoperative carprofen and postoperative butorphanol as
postsurgical analgesics in cats undergoing ovariohysterectomy. Vet Anaesth Analg 31, 164–174. Benson GJ, Wheaton LG, Thurmon JC et al. (1991) Postoperative catecholamine response to onychectomy in isoflurane-anesthetized cats. Vet Surg 20, 222–225. Cambridge AJ, Tobias KM, Newberry RC et al. (2000) Subjective and objective measurements of postoperative pain in cats. J Am Vet Med Assoc 217, 685–690. Dixon MJ, Robertson SA, Taylor PM (2000) Development of nociceptive threshold testing devices for evaluation of analgesics in cats. Vet Anaesth Analg 27, 54. Dixon MJ, Robertson SA, Taylor PM (2002) A thermal threshold testing device for evaluation of analgesics in cats. Res Vet Sci 72, 205–210. Dixon MJ, Taylor PM, Steagall PVM et al. (2007) Development of a pressure nociceptive threshold testing device for evaluation of analgesics in cats. Res Vet Sci 82, 85–92. Dobbins S, Brown NO, Shofer FS (2002) Comparison of the effects of buprenorphine, oxymorphone hydrochloride, and ketoprofen for postoperative analgesia after onychectomy or onychectomy and sterilization in cats. J Am Anim Hosp Assoc 38, 507–514. Dohoo SE, Dohoo IR (1996) Postoperative use of analgesics in dogs and cats by Canadian veterinarians. Can Vet J 37, 546–551. Hansen B, Hardie E (1993) Prescription and use of analgesics in dogs and cats in a veterinary teaching hospital: 258 cases (1983–1989). J Am Vet Med Assoc 202, 1485–1494. Hugonnard M, Leblond A, Keroack S et al. (2004) Attitudes and concerns of French veterinarians towards pain and analgesia in dogs and cats. Vet Anaesth Analg 31, 154–163. Lascelles BDX, Robertson SA (2004a) Antinociceptive effects of hydromorphone, butorphanol, or the combination in cats. J Vet Intern Med 18, 190–195. Lascelles BDX, Robertson SA (2004b) Use of thermal threshold response to evaluate the antinociceptive effects of butorphanol in cats. Am J Vet Res 65, 1085– 1089. Lascelles BDX, Waterman-Pearson AE (1997) Analgesia in cats. In Pract 19, 203–213. Lascelles BDX, Cripps P, Mirchandani S et al. (1995) Carprofen as an analgesic for postoperative pain in cats: dose titration and assessment of efficacy in comparison to pethidine hydrochloride. J Small Anim Pract 36, 535–541. Lascelles BDX, Capner CA, Waterman-Pearson AE (1999) Current British veterinary attitudes to perioperative analgesia for cats and small mammals. Vet Rec 145, 601–604. Le Bars D, Gozariu M, Cadden SW et al. (2001) Animal models of nociception. Pharmacol Rev 53, 597–652. Lin HC, Benson GJ, Thurmon JC et al. (1993) Influence of anesthetic regimens on the postoperative catecholamine
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response associated with onychectomy in cats. Am J Vet Res 54, 1721–1724. Muir WW III (2002) Pain and stress. In: Handbook of Veterinary Pain Management. Gaynor JS, Muir WW III (eds). Mosby, St Louis, MO, USA, pp. 46–59. Murrell JC, Robertson SA, Taylor PM et al. (2007) Use of a transdermal matrix patch of buprenorphine in eats: preliminary pharmacokinetic and pharmacodynamic data. Vet Rec 160, 578–583. Raekallio M, Heinonen KM, Kuusaari J et al. (2003) Pain alleviation in animals: attitudes and practices of Finnish veterinarians. Vet J 165, 131–135. Robertson SA, Taylor PM (2004) Pain management in cats – past, present and future. Part 2. Treatment of pain – clinical pharmacology. J Feline Med Surg 6, 321–333. Robertson SA, Taylor PM, Lascelles BDX et al. (2003a) Changes in thermal threshold response in eight cats after administration of buprenorphine, butorphanol and morphine. Vet Rec 153, 462–465. Robertson SA, Taylor PM, Sear JW (2003b) Systemic uptake of buprenorphine by cats after oral mucosal administration. Vet Rec 152, 675–678. Robertson SA, Taylor PM, Sear LW et al. (2005a) Relationship between plasma concentrations and analgesia after intravenous fentanyl and disposition after other routes of administration in cats. J Vet Pharmacol Ther 28, 87–93. Robertson SA, Taylor PM, Sear JW et al. (2005b) PK-PD modeling of buprenorphine in cats: intravenous and oral transmucosal administration. J Vet Pharmacol Ther 28, 453–460. Slingsby LS, Waterman-Pearson AE (2000) Postoperative analgesia in the cat after ovariohysterectomy by use of
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carprofen, ketoprofen, meloxicam or tolfenamic acid. J Small Anim Pract 41, 447–450. Slingsby LS, Jones A, Waterman-Pearson AE (2001) Use of a new finger-mounted device to compare mechanical nociceptive thresholds in cats given pethidine or no medication after castration. Res Vet Sci 70, 243–246. Taylor PM (2003) Pain management in dogs and cats – more causes and locations to contemplate. Vet J 165, 186–187. Taylor PM, Robertson SA (2004) Pain management in cats – past, present and future. Part 1. The cat is unique. J Feline Med Surg 6, 313–320. Taylor PM, Delatour P, Landoni FM et al. (1996) Pharmacodynamics and enantioselective pharmacokinetics of carprofen in the cat. Res Vet Sci 60, 144–151. Taylor PM, Robertson SA, Dixon MJ et al. (2001) Morphine, pethidine and buprenorphine disposition in the cat. J Vet Pharmacol Ther 24, 391–398. Taylor PM, Robertson SA, Dixon MJ (2003) Adaptation of thermal threshold analgesiometry for NSAIDs in cats: effects of ketoprofen. Vet Anaesth Analg 30, 92. Watson ADJ, Nicholson A, Church DB et al. (1996) Use of anti-inflammatory and analgesic drugs in dogs and cats. Aust Vet J 74, 203–210. Wegner K, Robertson SA, Kollias-Baker C et al. (2004) Pharmacokinetic and pharmacodynamic evaluation of intravenous hydromorphone in cats. J Vet Pharmacol Ther 27, 329–336. Williams VM, Lascelles BDX, Robson MC (2005) Current attitudes to, and use of, perioperative analgesia in dogs and cats by veterinarians in New Zealand. NZ Vet J 53, 193–202. Received 15 February 2006; accepted 12 June 2006.
Ó 2007 The Authors. Journal compilation Ó 2007 Association of Veterinary Anaesthetists, 34, 344–350
doi:10.1111/j.1467-2995.2006.00331.x
RESEARCH PAPER
Effects of buprenorphine, carprofen and saline on thermal and mechanical nociceptive thresholds in cats Paulo VM Steagall* DVM, Polly M Taylor MA, VetMB, PhD, Diplomate ECVA, Juliana T Brondani* Luna* DVM, IVAS CVA, MSc, PhD, Diplomate ECVA, Mike J Dixon PhD & Tatiana H Ferreira* DVM
DVM, MSc,
Stelio PL
*Department of Veterinary Surgery and Anaesthesiology, Faculty of Veterinary Medicine and Animal Science, UNESP, Botucatu, Sa˜o Paulo, Brazil Taylor Monroe, Little Downham, Ely, UK
Correspondence: Paulo Vinicius Mortensen Steagall, FMVZ, UNESP 18618-000, Botucatu, SP, Brazil. E-mail: [email protected]
Abstract Objective To evaluate a prototype pressure stimulus device for use in the cat and to compare with a known thermal threshold device. Animals Eight healthy adult cats weighing between 3.0 and 4.9 kg. Methods 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 °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. Results 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 344
administration of buprenorphine (p < 0.05). The maximum increase in threshold from baseline (DTmax) was 3.5 ± 3.1 °C at 2 hours. Pressure threshold increased 2 hours after administration of buprenorphine (p < 0.05) when the increase in threshold above baseline (DPmax) was 162 ± 189 mmHg. Conclusions and clinical relevance 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. Keywords analgesia, buprenorphine and carprofen, cats, pain.
Introduction It is widely accepted that pain relief is an important component of veterinary treatment of animals. Pain causes stress and sympathetic nervous system activity, affects food intake and metabolism, and modifies behavior (Lascelles & Waterman-Pearson 1997). Animals suffering pain may have impaired respiration, immunosuppression, and central nervous system sensitization, leading to chronic pain (Lascelles & Waterman-Pearson 1997; Taylor 2003). The severity and clinical importance of feline pain is probably underestimated. Epidemiological studies show that cats receive fewer analgesics when
Mechanical vs thermal nociceptive stimulation in cats PVM Steagall et al.
compared to dogs (Hansen & Hardie 1993; Dohoo & Dohoo 1996; Watson et al. 1996; Lascelles et al. 1999; Raekallio et al. 2003; Hugonnard et al. 2004; Williams et al. 2005). This is probably because pain in cats is more difficult to recognize, and there is particular concern about both opioid and nonsteroidal anti-inflammatory drug (NSAID) toxicity in this species (Dohoo & Dohoo 1996; Lascelles & Waterman-Pearson 1997). For instance, 24.3% of veterinarians did not use analgesics after orthopedic surgery in cats, in spite of the recognition that such procedures cause moderate to severe pain (Dohoo & Dohoo 1996). In another study, it was reported that around 40% and 60%, respectively, of veterinarians did not use analgesics in cats undergoing ovariohysterectomy or castration (Raekallio et al. 2003). Even when cats received analgesics, the most commonly used were not the most effective (Dohoo & Dohoo 1996). Recently, increased attention has been paid to pain management in cats, and it is now generally regarded as an essential component of clinical veterinary care in this species (Taylor 2003; Taylor & Robertson 2004). Knowledge of analgesic pharmacology in cats is, however, still limited, and any investigations that improve our fundamental understanding in this field will ultimately help to improve clinical feline pain management. A means of assessing pain objectively is required for any investigation into pain and analgesia. Such systems must not injure the animal and must produce repeatable data. A thermal threshold device was developed and validated for cats and has been used in several studies (Dixon et al. 2000, 2002; Robertson et al. 2003a, 2005a,b; Lascelles & Robertson 2004a,b; Wegner et al. 2004). This device is used on unrestrained cats and it also incorporates rapid termination of the stimulus upon detection of a response and a cut-out point to prevent tissue damage when analgesics are used. Data from studies using this device to study opioids indicate a close relation between analgesic effects and clinical efficacy (Dixon et al. 2002; Robertson et al. 2003a, 2005a,b; Lascelles & Robertson 2004a,b). However, it is well recognized that more than one type of stimulus is required to evaluate pain and analgesia comprehensively; clinical pain results from activation of a range of receptors, and different analgesics act via a variety of mechanisms (Dixon et al. 2002). The thermal threshold device has had limited application to study of NSAID analgesia in cats, and a pressure stimulus was considered likely
to have greater potential for these investigations (Taylor et al. 2003). The aim of this study was to validate a prototype mechanical nociceptive threshold testing device developed for use in cats (Dixon et al. 2000, 2007) and to compare it with a thermal threshold device (Dixon et al. 2002). Opioids and NSAIDs are the two most widely accepted analgesic drug types in clinical use; the opioid, buprenorphine, and the NSAID carprofen were selected from these two groups for use in the study. Buprenorphine, a partial mu (MOP) agonist has been previously studied in cats using the thermal device (Robertson et al. 2003a,b, 2005a,b; Murrell et al. 2007). Carprofen is extensively used for perioperative analgesia in cats in the UK. Saline was used as a control. Materials and methods The study was approved by the Ethical Committee for Animal Experimentation, Faculty of Medicine, University of Sa˜o Paulo State (protocol 434). Cats Eight neutered adult domestic cats, two male and six female, were studied. All cats were housed according to the Principles of the University Research Ethical Committee. Before the study began, the cats were wormed, vaccinated against Chlamydia psittaci, panleukopenia, calicivirus and feline rhinotracheitis, and biochemical analyses and a complete blood count were performed. Polymerase chain reaction against feline immunodeficiency virus (FELV) and feline leukemia virus (FIV) were negative for all cats used in the study. Health checks were made at regular intervals between testing sessions. The cats were group housed and fed dry cat food. On study days they were moved to single cage housing and the feed was supplemented with canned food. Water was available ad libitum. During testing, cats were housed individually in a quiet environment in cages 80 cm high, 120 cm wide, and 60 cm long. Cages were equipped with wall mirrors, toys, a bed, and a litter tray. All cats had been well handled and familiarized with the procedure for several weeks prior to the studies. Measurements Thermal and pressure thresholds were measured by applying a mild, transient heat or pressure stimulus
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to elicit pain (Dixon et al. 2000, 2002, 2007). For each test, care was taken to ensure that the cats were awake but not otherwise distracted; they were unrestrained and not sleeping, eating, or playing. Thermal threshold A small probe containing a heater element and a temperature sensor was held against the shaved thorax using an elasticated band and a pressure bladder (Fig. 1) (Dixon et al. 2002). The bladder was inflated manually to 100 mm Hg to ensure consistent contact between probe and skin. During testing the probe was connected to the control unit with a light ribbon cable. When activated, the probe heated at 0.6 °C second)1 with an automatic cut-off at 55 °C if not stopped earlier. At each test, the heater was activated and then switched off as soon as the cat reacted; this was usually a skin flick, a jump forward, a turn to bite the band, or occasionally vocalization. At the point of reaction, the probe temperature was recorded as the thermal threshold. Prior to any drug administration, four measurements were made at 15minute intervals and their mean value taken as the control thermal threshold. Pressure threshold A lightweight plastic bracelet weighing about 5 g was taped around the forearm (Fig. 1) (Dixon et al. 2007). This held three pressure pins, each tipped
with a 2.4-mm diameter ball bearing, in a 10-mm equilateral triangle. The pins were advanced against the craniolateral surface of the antebrachium by manual inflation of a modified 2 cm square blood pressure bladder positioned directly behind the pins (Dixon et al. 2007). The cuff was connected to a three-way stopcock, a 30-mL syringe and a pressure transducer via noncompliant arterial manometer tubing. The transducer was calibrated using a mercury column. The syringe was compressed manually at 1.5 mL second)1 until the cat reacted. Reactions were a leg shake, a head turn, or occasionally vocalization. Cuff pressure was recorded immediately (using the hold facility on a digital voltmeter) and the pressure released. A cut-off pressure to prevent skin damage if the cat did not react was provided automatically when the syringe was fully compressed at a pressure of 650 mmHg. If this point was reached, pressure was released immediately. Prior to any drug treatment, four baseline measurements were made at 15-minute intervals and their mean value taken as the control pressure threshold. Drug treatment After the pre-treatment pressure and thermal threshold readings had been made, each cat received subcutaneous 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 between treatments, sufficient time to ensure there are no residual effects from carprofen (Taylor et al. 1996). Thermal and pressure measurements were made at 15, 30, and 45 minutes, and at 1, 2, 3, 4, 6, 8, and 24 hours after the injection. Thermal testing was followed by pressure testing at each time point. Two or three cats were tested on the same day but they were housed in separate cages. The observer was unaware which treatment had been given. Statistical analysis
Figure 1 Cat number 1 relaxing during testing between applications of the stimuli. The thermal probe is held against the thorax with an elasticated band. The pressure stimulus is produced by inflation of a pressure bladder within the bracelet taped around the cat’s foreleg. The inflated bladder moves three ball bearings mounted on short pins onto the skin. 346
Data within each treatment group were analyzed for changes with time by using one-way repeatedmeasures ANOVA followed by Dunnett’s test. The treatments were compared by using two-way ANOVA and a Bonferroni post-test (Graphpad Prism software, version 4.00; Graphpad Software Inc., San Diego, CA, USA). p < 0.05 was regarded as significant. Further analysis was carried out by comparison of thermal and pressure thresholds after
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buprenorphine and carprofen treatment with a reference range taken from the saline series (Dixon et al. 2002). The reference range was generated by taking the mean of the 10 thresholds for each cat measured during the 24 hours after saline treatment, and using these means to generate 95% confidence intervals (CI) for the group of cats when not given an analgesic. Thresholds from the carprofen- and buprenorphine-treated cats lying outside of the 95% CI were considered to indicate hyper- or hypoalgesia. Results There were no effects of cat or time on the saline group. There were no significant changes in either thermal or pressure threshold after saline or carprofen administration. Thermal threshold increased from 60 minutes until 8 hours after buprenorphine administration (p < 0.05) (Fig. 2). The maximum increase in threshold from baseline (DTmax) was 3.5 ± 3.1 °C at 2 hours. Pressure threshold increased 2 hours after buprenorphine administration (p < 0.05) achieving a maximum increase above baseline (DPmax) of 162 ± 189 mmHg (Fig. 3). Thermal thresholds after buprenorphine administration were significantly higher than after saline or carprofen administration at 2 and 3 hours, respectively. Pressure thresholds after buprenor-
Figure 3 Mean ± SD pressure thresholds after subcutaneous administration of buprenorphine (0.01 mg kg)1), carprofen (4 mg kg)1), or saline (0.3 mL kg)1) at time 0. Horizontal lines represent upper and lower 95% confidence intervals (CI) for saline. The reference range was generated by taking the mean of the 10 thresholds for each cat measured during the 24 hours after saline treatment, and using these means to generate 95% CI.
phine administration were significantly higher than after saline or carprofen administration at 2 hours. Mean thermal thresholds after buprenorphine were above the upper 95% CI (indicating hypoalgesia) from 1–8 hours after treatment. Mean pressure thresholds after buprenorphine were above the upper 95% CI from 2–3 hours and from 6–8 hours after treatment. Mean thermal and pressure thresholds after saline and carprofen administration remained within the 95% CI. Discussion
Figure 2 Mean ± SD thermal thresholds after subcutaneous administration of buprenorphine (0.01 mg kg)1), carprofen (4 mg kg)1), or saline (0.3 mL kg)1) at time 0. Horizontal lines represent upper and lower 95% confidence intervals (CI) for saline. The reference range was generated by taking the mean of the 10 thresholds for each cat measured during the 24 hours after saline treatment, and using these means to generate 95% CI.
Pain is a multifactorial entity, and cannot be studied by a single method. Clinical trials make an important contribution to the study of pain and analgesics in cats, but the data, from visual analog and numerical scales, are subjective, making direct comparisons between treatments difficult (Lascelles et al. 1995; Slingsby & Waterman-Pearson 2000; Dobbins et al. 2002; Al-Gizawiy & Rude´ 2004). Neuroendocrine assays measuring b-endorphin, catecholamines, and cortisol concentrations in plasma have been correlated with pain in cats (Benson et al. 1991; Lin et al. 1993; Cambridge et al. 2000). However, factors other than pain commonly affect these hormones. Changes in environment during hospitalization and physiological changes resulting from anesthesia and surgery may all affect neuroendocrine and adrenocortical
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responses (Lin et al. 1993). Hence, endocrinology alone is inappropriate for pain assessment, although it may contribute to the overall picture. Pharmacokinetic investigation also plays a role in the study of analgesia, and with some drugs, such as fentanyl, plasma concentration correlates well with analgesia (Robertson et al. 2005a). However, with others, such as buprenorphine, there is considerable hysteresis between analgesic effect and plasma concentration, so some measure of pharmacodynamics must also be included (Robertson et al. 2005b). The route of opioid administration may influence the onset, duration, and intensity of drug effect. Recent studies demonstrated that the thermal antinociceptive effects of 0.1 mg kg)1 hydromorphone given intramuscularly and intravenously in cats had a similar onset but a slightly shorter duration of action and less intense effect when given intramuscularly (Lascelles & Robertson 2004a; Wegner et al. 2004). The subcutaneous route is preferred in cats as injection is less painful and stressful, but nausea and vomiting have been reported when morphine and hydromorphone were given by the SC route (Robertson & Taylor 2004). The feline thermal threshold system has been successful in contributing to pain and analgesia research in cats where the onset, magnitude, and the duration of effect of several opioids has been determined (Dixon et al. 2002; Robertson et al. 2003a,b, 2005a,b; Taylor et al. 2003; Lascelles & Robertson 2004a,b; Wegner et al. 2004; Murrell et al. 2007), but additional stimuli are needed for comprehensive coverage which can be related more closely to clinical pain. Nociception is produced by mechanical, thermal, or chemical stimuli, activating dermal receptors and afferent Ad and C fibers in the neural afferent pathways (Muir 2002). Pain perception then occurs in the cerebral cortex, after the motor neuron and brain stem response (Slingsby et al. 2001). Several devices have been developed for measuring mechanical thresholds in cats. Slingsby & Waterman-Pearson (2000) developed a system using a force transducer in cats after ovariohysterectomy. This was compressed against the surgical incision until the cat reacted. A second system was developed where a sensor under an index finger was pressed onto a castration wound to measure the force required to elicit a response (Slingsby et al. 2001). In both cases, postoperative hyperalgesia was under test, and the cats had to be restrained. 348
The thermal device (Dixon et al. 2002) was developed for use in unrestrained cats, and the pressure device (Dixon et al. 2007) was developed with the same aim. Hence the force transducers used by Slingsby & Waterman-Pearson (2000) and Slingsby et al. (2001) were not considered suitable. As with the thermal system, it was developed for cats; and is light, well tolerated and allows reproducible testing without injury, in unrestrained cats in a familiar environment (Dixon et al. 2007). This avoids stress and the need for either chemical or mechanical restraint, which may all modify the nociceptive threshold (Dixon et al. 2002). A safety cut-off to prevent injury is incorporated, and the stimulus is stopped, and the threshold recorded, as soon as a reaction is observed. It was expected that a mechanical stimulus would stimulate different nociceptors than a thermal stimulus. In this model, application of the mechanical device to the craniolateral aspect of the antebrachium may mean that the stimulus could include receptors in the skin as well as muscle and periosteum and it is likely that both Ad and C fibers were activated, whereas the thermal stimulus mainly affects C fibers. These differences in neural responses to the stimuli may account for differences in the response to the drugs administered. This pressure stimulus appeared to fulfill the requirements of a threshold testing device. A previous study indicated that it was well tolerated by cats and that data are repeatable and reproducible as long as testing is not more frequent than 15-minute intervals (Dixon et al. 2007). The present study confirms the original report, that the system was tolerated by the cats, and buprenorphine increased the threshold values consistent with the analgesic effect detected simultaneously with the thermal system. The increase in pressure threshold after buprenorphine administration followed a similar pattern to the thermal thresholds (Robertson et al. 2003a,b, 2005b), increasing above the upper 95% CI at 2 hours, and remaining high until 8 hours. Pressure threshold decreased below the upper CI at 4 hours but increased again later. This effect is difficult to explain, was not reflected in the thermal thresholds, and may be a result of difficulties with a new methodology. In general however, this study suggested that the pressure threshold testing device should make a useful contribution to analgesic research in cats. As indicated in the earlier paper (Dixon et al. 2007), the increase in pressure in the cuff and the force applied to the animal are not linear, and the force
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actually applied to the tissues is unknown. The cutoff pressure of 650 mmHg in the cuff was arbitrary and did not necessarily translate to a point at which tissue damage occurs whereas the thermal cut-off point is set to a value just below that at which tissue injury has been recognized (burns). A review of the results of this study highlights a significant benefit of laboratory studies of pain and analgesia. A number of investigations into the effects of buprenorphine in cats have been undertaken using the same thermal threshold device, allowing some comparison between different treatment methodologies (Taylor et al. 2001; Robertson et al. 2003a,b, 2005b; Murrell et al. 2007). These studies, taken together with the present data, enable consideration of the effect of route of administration of buprenorphine. In spite of achieving similar plasma buprenorphine concentrations, maximum mean thermal threshold was around 54 °C after intravenous administration, 51 °C after mucosal and IM routes (Robertson et al. 2003b, 2005b), around 45 °C after SC administration in the present study and did not increase at all when a buprenorphine patch alone was used (Murrell et al. 2007). These data suggest that the route of administration is important in allowing buprenorphine to reach the effector site; routes leading to slow uptake may not achieve sufficient concentration gradients to drive the drug into the biophase, although they may be sufficient to maintain it there subsequently. In the present study, carprofen did not increase thermal or pressure thresholds. This is consistent with other laboratory studies of NSAID analgesia where it is well recognized that acute analgesiometric methods are inappropriate, as NSAID analgesia depends on the presence of inflammation (Le Bars et al. 2001). The pressure device was originally developed to study analgesia in a small inflamed site, where the thermal system had limited value (Taylor et al. 2003). Its value in this respect has yet to be evaluated fully (Dixon et al. 2007). In conclusion, the prototype pressure device detected mechanical thresholds which were affected by the analgesic treatment, in a manner similar to the thermal method. Pressure stimulation appears to be a useful stimulus for analgesic studies in cats. References Al-Gizawiy MM, Rude´ EP (2004) Comparison of preoperative carprofen and postoperative butorphanol as
postsurgical analgesics in cats undergoing ovariohysterectomy. Vet Anaesth Analg 31, 164–174. Benson GJ, Wheaton LG, Thurmon JC et al. (1991) Postoperative catecholamine response to onychectomy in isoflurane-anesthetized cats. Vet Surg 20, 222–225. Cambridge AJ, Tobias KM, Newberry RC et al. (2000) Subjective and objective measurements of postoperative pain in cats. J Am Vet Med Assoc 217, 685–690. Dixon MJ, Robertson SA, Taylor PM (2000) Development of nociceptive threshold testing devices for evaluation of analgesics in cats. Vet Anaesth Analg 27, 54. Dixon MJ, Robertson SA, Taylor PM (2002) A thermal threshold testing device for evaluation of analgesics in cats. Res Vet Sci 72, 205–210. Dixon MJ, Taylor PM, Steagall PVM et al. (2007) Development of a pressure nociceptive threshold testing device for evaluation of analgesics in cats. Res Vet Sci 82, 85–92. Dobbins S, Brown NO, Shofer FS (2002) Comparison of the effects of buprenorphine, oxymorphone hydrochloride, and ketoprofen for postoperative analgesia after onychectomy or onychectomy and sterilization in cats. J Am Anim Hosp Assoc 38, 507–514. Dohoo SE, Dohoo IR (1996) Postoperative use of analgesics in dogs and cats by Canadian veterinarians. Can Vet J 37, 546–551. Hansen B, Hardie E (1993) Prescription and use of analgesics in dogs and cats in a veterinary teaching hospital: 258 cases (1983–1989). J Am Vet Med Assoc 202, 1485–1494. Hugonnard M, Leblond A, Keroack S et al. (2004) Attitudes and concerns of French veterinarians towards pain and analgesia in dogs and cats. Vet Anaesth Analg 31, 154–163. Lascelles BDX, Robertson SA (2004a) Antinociceptive effects of hydromorphone, butorphanol, or the combination in cats. J Vet Intern Med 18, 190–195. Lascelles BDX, Robertson SA (2004b) Use of thermal threshold response to evaluate the antinociceptive effects of butorphanol in cats. Am J Vet Res 65, 1085– 1089. Lascelles BDX, Waterman-Pearson AE (1997) Analgesia in cats. In Pract 19, 203–213. Lascelles BDX, Cripps P, Mirchandani S et al. (1995) Carprofen as an analgesic for postoperative pain in cats: dose titration and assessment of efficacy in comparison to pethidine hydrochloride. J Small Anim Pract 36, 535–541. Lascelles BDX, Capner CA, Waterman-Pearson AE (1999) Current British veterinary attitudes to perioperative analgesia for cats and small mammals. Vet Rec 145, 601–604. Le Bars D, Gozariu M, Cadden SW et al. (2001) Animal models of nociception. Pharmacol Rev 53, 597–652. Lin HC, Benson GJ, Thurmon JC et al. (1993) Influence of anesthetic regimens on the postoperative catecholamine
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response associated with onychectomy in cats. Am J Vet Res 54, 1721–1724. Muir WW III (2002) Pain and stress. In: Handbook of Veterinary Pain Management. Gaynor JS, Muir WW III (eds). Mosby, St Louis, MO, USA, pp. 46–59. Murrell JC, Robertson SA, Taylor PM et al. (2007) Use of a transdermal matrix patch of buprenorphine in eats: preliminary pharmacokinetic and pharmacodynamic data. Vet Rec 160, 578–583. Raekallio M, Heinonen KM, Kuusaari J et al. (2003) Pain alleviation in animals: attitudes and practices of Finnish veterinarians. Vet J 165, 131–135. Robertson SA, Taylor PM (2004) Pain management in cats – past, present and future. Part 2. Treatment of pain – clinical pharmacology. J Feline Med Surg 6, 321–333. Robertson SA, Taylor PM, Lascelles BDX et al. (2003a) Changes in thermal threshold response in eight cats after administration of buprenorphine, butorphanol and morphine. Vet Rec 153, 462–465. Robertson SA, Taylor PM, Sear JW (2003b) Systemic uptake of buprenorphine by cats after oral mucosal administration. Vet Rec 152, 675–678. Robertson SA, Taylor PM, Sear LW et al. (2005a) Relationship between plasma concentrations and analgesia after intravenous fentanyl and disposition after other routes of administration in cats. J Vet Pharmacol Ther 28, 87–93. Robertson SA, Taylor PM, Sear JW et al. (2005b) PK-PD modeling of buprenorphine in cats: intravenous and oral transmucosal administration. J Vet Pharmacol Ther 28, 453–460. Slingsby LS, Waterman-Pearson AE (2000) Postoperative analgesia in the cat after ovariohysterectomy by use of
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carprofen, ketoprofen, meloxicam or tolfenamic acid. J Small Anim Pract 41, 447–450. Slingsby LS, Jones A, Waterman-Pearson AE (2001) Use of a new finger-mounted device to compare mechanical nociceptive thresholds in cats given pethidine or no medication after castration. Res Vet Sci 70, 243–246. Taylor PM (2003) Pain management in dogs and cats – more causes and locations to contemplate. Vet J 165, 186–187. Taylor PM, Robertson SA (2004) Pain management in cats – past, present and future. Part 1. The cat is unique. J Feline Med Surg 6, 313–320. Taylor PM, Delatour P, Landoni FM et al. (1996) Pharmacodynamics and enantioselective pharmacokinetics of carprofen in the cat. Res Vet Sci 60, 144–151. Taylor PM, Robertson SA, Dixon MJ et al. (2001) Morphine, pethidine and buprenorphine disposition in the cat. J Vet Pharmacol Ther 24, 391–398. Taylor PM, Robertson SA, Dixon MJ (2003) Adaptation of thermal threshold analgesiometry for NSAIDs in cats: effects of ketoprofen. Vet Anaesth Analg 30, 92. Watson ADJ, Nicholson A, Church DB et al. (1996) Use of anti-inflammatory and analgesic drugs in dogs and cats. Aust Vet J 74, 203–210. Wegner K, Robertson SA, Kollias-Baker C et al. (2004) Pharmacokinetic and pharmacodynamic evaluation of intravenous hydromorphone in cats. J Vet Pharmacol Ther 27, 329–336. Williams VM, Lascelles BDX, Robson MC (2005) Current attitudes to, and use of, perioperative analgesia in dogs and cats by veterinarians in New Zealand. NZ Vet J 53, 193–202. Received 15 February 2006; accepted 12 June 2006.
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