Dose-related thermal antinociceptive effects of intravenous hydromorphone in cats

Veterinary Anaesthesia and Analgesia, 2007, 34, 132 138 doi:10.1111/j.1467-2995.2006.00311.x RESEARCH PAPER Dose-related thermal antinociceptive effects of intravenous hydromorphone in cats Kirsten Wegner DVM & Sheilah A Robertson BVMS (Hons), PhD, Diplomate ACVA, Diplomate ECVA Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA Correspondence: Sheilah A Robertson, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, P.O. Box 100136, Gainesville, FL 32610-0136, USA. E-mail: robertsonsmail.vetmed.ufl.edu Abstract Objective To describe the dose-related thermal antinociceptive effects of intravenous (IV) hydromorphone in cats. Study design Randomized, blinded, crossover design. Animals Seven adult cats (3.5 7.4 kg), two spayed females, and five neutered males. Methods Hydromorphone (0.025, 0.05, or 0.1 mg kg )1 ) was administered IV. Skin temperature and thermal threshold were measured before and at selected time points to 720 minutes postadministration. Statistical analysis of mean thermal threshold and skin temperatures over time for each dose and between doses was by way of a split-plot model and post hoc Bonferroni t-tests. p < 0.05 was considered significant. Results A significant difference from baseline for mean thermal threshold was identified for the 0.05 mg kg )1 dose (5 80 minutes, peak thermal threshold 46.9 ± 6.2 C) and 0.1 mg kg )1 dose (5 200 minutes, peak thermal threshold 54.9 ± 0.2 C). The thermal threshold was significantly greater after the 0.1 mg kg )1 dose from 5 to 200 minutes compared to the 0.025 mg kg )1 and 0.5 mg kg )1 doses. The thermal threshold was significantly greater from 35 to 80 minutes for the 0.05 mg kg )1 dose when compared with the 0.025 mg kg )1 dose. Skin temperature was significantly increased from 35 to 140 minutes following the 0.1 mg kg )1 dose. Conclusions A dose-related antinociceptive effect was demonstrated for IV hydromorphone in cats. Clinical relevance Hydromorphone at doses less than 0.1 mg kg )1 has a modest antinociceptive effect and a short duration of action. At a dose of 0.1 mg kg )1 IV, onset of analgesia is rapid with a clinically useful duration of effect, but is associated with a rise in skin temperature. Keywords analgesia, antinociception, cat, hydromorphone, dose, temperature. Introduction Drugs have been underutilized for pain management in cats (Hansen & Hardie 1993; Lascelles et al. 1999). Concern among veterinary practitioners about adverse effects associated with opioids (Dohoo & Dohoo 1996) and non-steroidal anti-inflammatory agents (Runk et al. 1999), combined with the difficulty of recognizing pain in cats (Lascelles & Waterman 1997; Cambridge et al. 2000; Lamont 2002) have made the provision of analgesia in this species a challenge. In addition, analgesic dosing has been largely empirical or extrapolated from other species because of the limited number of feline-specific analgesic studies (Wright 2002). However, in a recent review of the status of feline 132

analgesic studies, Robertson & Taylor (2004) reported that pharmacokinetic (Lee et al. 2000; Taylor et al. 2001; Robertson et al. 2003b), laboratory-based (Briggs et al. 1998; Robertson et al. 2003a) and clinical studies of opioids in cats (Glerum et al. 2001; Dobbins et al. 2002; Gellasch et al. 2002) are providing evidence-based information for use by the practitioner. The development of a feline thermal threshold testing device (Dixon et al. 2002) has allowed direct laboratory comparison of onset, magnitude, and duration of the thermal antinociceptive effect of several opioids in cats, as well as the assessment of behavior and adverse side effects in the unrestrained animal. Opioids studied include the l-receptor agonists morphine (Robertson et al. 2003a), meperidine (Dixon et al. 2002), fentanyl (Robertson et al. 2005b), and hydromorphone (Lascelles & Robertson 2004a; Wegner et al. 2004), the partial l-agonist buprenorphine (Robertson et al. 2005a), and the l-antagonist, j-agonist butorphanol (Lascelles & Robertson 2004a,b). The dose of each opioid assessed by thermal threshold testing in cats has been chosen to reflect common clinical usage (Dixon et al. 2002; Robertson et al. 2003a; Wegner et al. 2004). More importantly, doses of opioids such as buprenorphine, studied in cats using the thermal threshold system, have also been shown to be clinically efficacious (Stanway et al. 2002; Robertson et al. 2005a). The duration of effect of pethidine on thermal antinociception reported by Dixon et al. (2002) correlated closely with that reported in clinical trials (Slingsby & Waterman- Pearson 1998). The dose-dependent undesirable side effects of opioids, including neuroexcitatory behavior and hyperalgesia have been described in several species including the rat, cat, and humans (Yaksh et al. 1986; Milne et al. 1996; Walker & Zacny 1999; Hill & Zacny 2000; Quigley et al. 2003). The glucuronide metabolites of both morphine and hydromorphone have been implicated as a cause of these undesirable side effects in rats and humans (van Crugten et al. 1997; Smith 2000). In cats, hyperthermia was identified as an adverse side effect of high-dose (1 mg kg )1 ) morphine administration (Clark & Cumby 1978), and a recent retrospective study has implicated hydromorphone use in post-anesthetic hyperthermia (Niedfeldt & Robertson 2006). Because clinical use of opioids such as hydromorphone is often a balance between the dose that produces analgesia and the dose that produces unacceptable side effects (Smith 2000), species-specific experimental dose effect studies are essential. Hydromorphone is a pure l-agonist approximately five to seven times more potent than morphine in humans (Dunbar et al. 1996; Quigley & Wiffen 2003). Cost and availability have made this drug a popular choice for perioperative analgesia in small animals in North America (Pettifer & Dyson 2000). The dose effect characteristics of hydromorphone in humans have been described (Coda et al. 1997), but to the knowledge of the authors, no dose effect study of hydromorphone in cats has been reported. The objective of the present study was to investigate the dose-related changes in thermal threshold following intravenous (IV) administration of 0.025, 0.05, and 0.1 mg kg )1 of hydromorphone in cats. Materials and methods Thermal threshold studies All studies were approved by the Institutional Animal Care and Use Committee at the University of Florida. Seven adult cats, two spayed females, and five castrated males were used in the study. Cats were determined to be healthy based on physical examination and results of a complete blood count and serum chemistry analysis. Cats weighed an average of 5.45 kg (range 3.5 7.4 kg). All cats were conditioned to the testing protocol and the interval between studies was at least 1 week. Three doses of IV hydromorphone (Dilaudid Ò, 2 mg ml )1 ; Abbott Laboratories Inc., North Chicago, IL, USA) were selected for study: 0.025, 0.05, and 0.1 mg kg )1. These doses were selected as encompassing currently utilized clinical doses of hydromorphone (Pettifer & Dyson 2000). Order of treatment was randomized, and the tester (KW) was blinded to the treatment. On the day before testing, the cats were anesthetized with isoflurane in oxygen; a 22 SWG cephalic venous catheter was placed, and one side of the craniolateral thorax was shaved. On the day of testing, cats were transported in pairs to the laboratory and housed individually in large cages with a resting perch, litter box, and toys. The feline thermal threshold system described in detail by Dixon et al. (2002) was utilized in this study. Briefly, a small probe containing a heater element and temperature sensor fixed together in thermally conducting epoxy was held against the shaved skin of the lateral thorax of the cat with an elastic band. A pressure bladder overlying the probe ensured Ó 2007 The Authors. Journal compilation Ó 2007 Association of Veterinary Anaesthetists, 2007, 34, 132 138 133

even contact with the skin. Skin temperature was recorded before every test, and then a thermal stimulus was applied via the heater element. When the cat responded by jumping, flinching, or turning toward the probe, the stimulus was terminated, and the threshold temperature recorded. To protect the cats from thermal injury, the stimulus was discontinued at 55 C if no response was observed. Baseline thermal thresholds were established in triplicate for each cat before administration of hydromorphone. An IV injection of one of the three test doses was administered over 15 30 seconds via the cephalic catheter and followed with 0.5 ml of heparinized saline. Doses were drawn up in advance by a person not involved in testing; volumes in the syringe barrel were obscured by tape. Thermal threshold testing began 5 minutes after drug administration, and was repeated every 15 minutes for 3 hours, then every 30 minutes to 7 hours postdosing, and again at 8 and 12 hours after treatment. Skin temperature was recorded before each thermal threshold test. Observations of behavior and side effects, including nausea, vomiting, mydriasis, and changes in activity and awareness were made throughout the entire testing period. Statistical analysis Thermal threshold and skin temperatures were analyzed with the following factors: cat (seven), periods (three), doses (three; 0.025, 0.05, 0.1 mg kg )1 ), and with a repeat factor of time (20:0 720 minutes). Data conformed to and were analyzed using SAS PROC MIXED (SAS Institute Inc., Cary, NC, USA) according to the split-plot model as follows: Y ¼ mean + dose + period + cat + error 1 + time + dose time + error 2, where Y is the thermal threshold or skin temperature. Post hoc tests were by means of a Bonferroni t-test. Significance was set at p < 0.05 such that for m ¼ 3 comparisons with respect to dose, critical p ¼ (0.05/3) ¼ 0.017, and for m ¼ 19 comparisons with respect to baseline, critical p ¼ (0.05/19) ¼ 0.0026. Data are presented as mean ± SD, except where noted. Results Mean pre-treatment baseline thermal threshold was as follows: 0.025 mg kg )1, 40.7 ± 1.2 C; 0.05 mg kg )1, 41.0 ± 3.0 C; and 0.1 mg kg )1, 41.5 ± 0.5 C. There was no significant change in thermal threshold at any time after administration of the 0.025 mg kg )1 dose. For hydromorphone at 0.05 mg kg )1, the mean peak thermal threshold of 46.9 ± 6.2 C occurred 5 minutes after administration, and remained significantly above baseline values for 80 minutes post-dosing. The thermal threshold for the 0.1 mg kg )1 dose was significantly above baseline from 5 to 200 minutes after administration, with the mean peak of 54.9 ± 0.2 C occurring at 20 minutes post-administration (Fig. 1). Significant differences between mean thermal threshold for the 0.1 versus 0.05 and 0.025 mg kg )1 dose at corresponding time points were noted between 5 and 200 minutes. There was also a significant difference between the thermal threshold following the 0.05 and 0.025 mg kg )1 dose between 35 and 80 minutes post-administration (Fig. 1). There was no control group (no hydromorphone) in the current study, but thermal threshold data following saline injection from five of the seven cats collected during a separate study showed a mean thermal threshold of 42.5 ± 1.5 C and demonstrated no significant change from baseline over the 8-hour study period (Robertson & Taylor, unpublished data). The mean baseline thermal threshold for all cats at all hydromorphone doses in this study was 41.1 ± 0.8 C; the 95% confidence interval for the mean untreated (saline) thermal threshold is shown in Fig. 1. Skin temperatures were significantly increased above baseline (36.7 ± 0.9 C) at 35, 50, 110, and 140 minutes after administration of hydromorphone at 0.1 mg kg )1 IV. The peak skin temperature of 37.6 ± 0.9 C occurred at 50 minutes. A significant difference between skin temperature for the 0.025 and 0.05 mg kg )1 doses and the skin temperature for 0.1 mg kg )1 occurred at 35 minutes after drug administration (Fig. 2). One cat developed a skin temperature increase of 2.0 C, and when rectal temperature was measured, a peak of 40.3 C occurred at 380 minutes following the 0.1 mg kg )1 dose. This cat s skin temperature began to increase and the cat began panting 320 minutes post-dosing, but no other behavioral changes were observed. This cat s rectal temperature returned to baseline value within 720 minutes of hydromorphone administration; no other cat developed overt signs of hyperthermia. No adverse excitatory behavioral effects related to drug administration were noted during the study. 134 Ó 2007 The Authors. Journal compilation Ó 2007 Association of Veterinary Anaesthetists, 2007, 34, 132 138

58.0 a, b 0.025 mg kg 0.05 mg kg 0.1 mg kg 53.0 48.0 c c c 43.0 38.0 0 20 50 110 170 230 Time (minutes) 290 350 410 500 Figure 1 Thermal threshold (mean ± SD) following IV hydromorphone at 0.025, 0.05, and 0.1 mg kg )1 in seven cats. Significant changes from baseline: () 0.1 mg kg )1 significant (critical p < 0.0026) with respect to baseline TT, 5 200 minutes; () 0.05 mg kg )1 significant (critical p < 0.0026) with respect to baseline TT, 5 80 minutes. Significant differences between doses: (a) 0.1 mg kg )1 significant (critical p < 0.017) with respect to 0.025 mg kg )1, 5 200 minutes; (b) 0.1 mg kg )1 significant (critical p < 0.017) with respect to 0.05 mg kg )1, 5 200 minutes; (c) 0.05 mg kg )1 significant (critical p < 0.017) with respect to 0.025 mg kg )1, 35 80 minutes; ( ) upper and lower limits of 95% confidence interval for saline treatment. 40.0 0.025 mg kg 39.0 38.0 a b 0.05 mg kg 0.1 mg kg 37.0 36.0 35.0 34.0 0 20 50 110 170 230 T ime (minutes) 290 350 410 500 Figure 2 Changes in skin temperature following administration of hydromorphone at 0.025, 0.05, and 0.1 mg kg )1 IV in seven cats. Data shown as mean ± SD. For the 0.05 mg kg )1 dose, the lower bar seen on the SD represents the upper limit of the SD for all points. The upper bar is the value for the SD for the 0.1 mg kg )1 dose. () 0.1 mg kg )1 dose significant (critical p < 0.0026) with respect to baseline; (a) 0.1 mg kg )1 dose significant (critical p < 0.017) with respect to 0.025 mg kg )1 ; (b) 0.1 mg kg )1 dose significant (critical p < 0.017) with respect to 0.05 mg kg )1. Discussion The results of this study demonstrated clear doserelated differences in thermal threshold over time in cats to which IV hydromorphone was administered. The lowest dose of 0.025 mg kg )1 hydromorphone is below that suggested for small animals (Pettifer & Dyson 2000). However, many clinicians use lower Ó 2007 The Authors. Journal compilation Ó 2007 Association of Veterinary Anaesthetists, 2007, 34, 132 138 135

doses of opioids in cats when compared with other species (Wright 2002). The 0.05 mg kg )1 dose selected for this study was similar to the low-end dose suggested for clinical analgesia (Pettifer & Dyson 2000). A significant elevation in mean thermal threshold was noted between 5 and 80 minutes following administration of 0.05 mg kg )1 hydromorphone in the cats of this study. However, the peak thermal threshold of 46.9 ± 6.2 C for 0.05 mg kg )1 hydromorphone observed at 5 minutes post-dose and the 80-minute duration of action were modest in comparison to the peak thermal threshold and duration observed for the 0.1 mg kg )1 dose of hydromorphone as in previous studies conducted in our laboratory (Wegner et al. 2004). In the previous study, the onset of analgesia following a 0.1 mg kg )1 IV dose of hydromorphone was 15 minutes, with a thermal threshold of 53.7 ± 1.4 C; the peak thermal threshold of 54.5 ± 1.2 C was recorded at 45 minutes postdose. In the current study, the peak thermal threshold of 54.9 ± 0.23 C was recorded at 20 minutes post-dose, although the mean thermal threshold recorded at 5 minutes following administration of 0.1 mg kg )1 hydromorphone was 53.6 ± 3.2 C, suggesting a similar peak thermal threshold onset and temperature in both studies. However, in the previous study, the reported duration of significant effect was 450 minutes following hydromorphone administration when compared with a significant duration of effect of 200 minutes in the present study. Lascelles & Robertson (2004a) described a similar onset of antinociception in cats following a 0.1 mg kg )1 intramuscular dose of hydromorphone, but reported an intermediate duration of effect lasting 345 minutes. The cats studied by Lascelles & Robertson (2004a) and Wegner et al. (2004) were from the same research population, while the cats in the present study were from a different research population. Lascelles & Robertson (2004b) reported marked inter-cat variation in response to butorphanol administration within the former cat population. Significant inter-individual differences in effects following bolus doses of opioids have also been reported in experimental human studies (Chapman et al. 1990; Coda et al. 1997). Pharmacogenetic variations in opioid receptors and in other modulators of opioid effects, many of which have clinical relevance, have been described for humans and experimental animals (Lötsch et al. 2004). While a partial sequence of the feline l-opioid receptor exists (Billet et al. 2001), more extensive characterization of individual genetic variation in this species has yet to be reported. It is likely that cats possess similar pharmacogenetic variation to that of other species, which may explain the inter-individual variation in response to opioids observed in this and other studies. Previous studies in cats using the thermal threshold system have demonstrated that a rise in the mean threshold of 2.5 C above baseline following opioid administration is significant and likely to be associated with clinical analgesia (Dixon et al. 2002; Lascelles & Robertson 2004a). The results of the current study are supportive of this relationship for both the 0.1 and 0.05 mg kg )1 hydromorphone doses. This consistency affirms the sensitivity and repeatability of the thermal threshold testing system despite inter-individual variations in response to the drug assessed. In addition, the magnitude of the increase in thermal threshold has been related to clinical efficacy of opioids in cats (Wegner et al. 2004; Robertson et al. 2005a). Therefore, based on the results of this study, greater clinical analgesic effect may be expected in cats following a 0.1 mg kg )1 dose of hydromorphone than for lower doses. The significant increase in skin temperature following the 0.1 mg kg )1 hydromorphone dose noted in our study is similar to that observed by Wegner et al. (2004). However, the onset, duration, and magnitude of skin temperature elevation in our cats are considerably smaller than those previously reported. For example, a mean peak skin temperature of 37.6 ± 0.9 C (0.9 C above baseline), was noted 80 minutes after hydromorphone administration in this study, while a mean peak skin temperature increase of 1.6 C above baseline was noted at 135 minutes post-dose in the previous study. One cat in the present study displayed panting behavior during a period when skin temperature increased up to 2.0 C above baseline, peaking at 380 minutes after hydromorphone administration. A rectal temperature of 40.3 C was recorded at that time. It is likely that as with antinociception, there is a difference between cats in their hyperthermic response. A recent retrospective evaluation of post-anesthetic hyperthermia in cats (Niedfeldt & Robertson 2005) revealed that perioperative use of hydromorphone in a clinical setting was significantly correlated with the development of post-anesthetic hyperthermia. Of the 125 cats studied, 60% of the 74 cats which received hydromorphone, with or without the non-steroidal anti-inflammatory drug 136 Ó 2007 The Authors. Journal compilation Ó 2007 Association of Veterinary Anaesthetists, 2007, 34, 132 138

ketoprofen, had post-anesthetic rectal temperatures over 40.0 C. Many of these cats received at least 0.1 mg kg )1 hydromorphone by the IV, intramuscular, or subcutaneous route during their perianesthetic management. Two cats with severe post-anesthetic hyperthermia (>41.6 C) were successfully treated with naloxone which rapidly reduced their rectal temperature (Niedfeldt & Robertson 2005). In a prospective clinical study, hydromorphone was associated with post-anesthetic hyperthermia for up to 5 hours in cats (Posner et al. 2005). Thus, the detrimental l-opioid effects of hydromorphone on central thermoregulation in cats may preclude its use despite its potent analgesic properties. In summary, significant differences in thermal threshold with respect to both dose and time were described following IV administration of hydromorphone to cats. There was a clear dose-related difference in the magnitude and duration of antinociceptive effect after administration of IV hydromorphone. Significant increases in skin temperature were noted only following the 0.1 mg kg )1 dose and clinical signs of hyperthermia were noted in one cat. Based on these findings, while the use of hydromorphone doses of less than 0.1 mg kg )1 may reduce the incidence of clinical hyperthermia in cats, the analgesia obtained from lower doses may be only modest and of short duration. The potent analgesia obtained from a 0.1 mg kg )1 dose of hydromorphone in cats provides a clinically useful duration of action, but the undesirable side effect of hyperthermia should be considered when this drug is chosen for pain relief in cats. Acknowledgements This work was supported in part by a grant from the University of Florida College of Veterinary Medicine and by Abbott Laboratories. The authors gratefully acknowledge Dr J. Hauptman, Michigan State University, for statistical analysis and Ms Wendy Davies for technical assistance. References Billet O, Billaud JN, Phillips TR (2001) Partial characterization and tissue distribution of the feline mu opiate receptor. Drug Alcohol Depend 62, 125 129. Briggs SL, Sneed K, Sawyer DC (1998) Antinociceptive effects of oxymorphone butorphanol acepromazine combination in cats. Vet Surg 27, 466 472. 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. Chapman CR, Hill HF, Saeger L et al. (1990) Profiles of opioid analgesia in humans after intravenous bolus administration: alfentanil, fentanyl and morphine compared on experimental pain. Pain 43, 47 55. Clark WG, Cumby HR (1978) Hyperthermic responses to central and peripheral injections of morphine in the cat. Br J Pharmacol 63, 65 71. Coda B, Tanaka A, Jacobson RC et al. (1997) Hydromorphone analgesia after intravenous bolus administration. Pain 71, 41 48. Dixon MJ, Robertson SA, Taylor PM (2002) A thermal threshold testing device for evaluation of analgesics in cats. Res Vet Sci 72, 205 210. 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. Dunbar PJ, Chapman CR, Buckley FP et al. (1996) Clinical analgesic equivalence for morphine and hydromorphone with prolonged PCA. Pain 68, 265 270. Gellasch KL, Kruse-Elliot KT, Osmond CS et al. (2002) Comparison of transdermal administration of fentanyl versus intramuscular administration of butorphanol for analgesia after onychectomy in cats. J Am Vet Med Assoc 220, 1020 1024. Glerum LE, Egger CM, Allen SW et al. (2001) Analgesic effect of the transdermal fentanyl patch during and after feline ovariohysterectomy. Vet Surg 30, 351 358. 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. Hill JL, Zacny JP (2000) Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers. Psychopharmacol 152, 131 139. Lamont LA (2002) Feline perioperative pain management. Vet Clin North Am Small Anim Pract 32, 747 763. Lascelles BDX, Waterman A (1997) Analgesia in cats. In Pract 19, 203 213. Lascelles BDX, Capner CA, Waterman-Pearson A (1999) A survey of current British veterinary attitudes to perioperative analgesia for cats and small mammals. Vet Rec 145, 601 604. 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 Ó 2007 The Authors. Journal compilation Ó 2007 Association of Veterinary Anaesthetists, 2007, 34, 132 138 137

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