Assessment of a carbon dioxide laser for the measurement of thermal nociceptive thresholds following intramuscular administration of analgesic drugs in pain‐free female cats

ObjectiveTo assess the potential of a thermal carbon dioxide (CO₂) laser to explore antinociception in pain-free cats.Study designExperimental, prospective, blinded, randomized study.AnimalsSixty healthy adult female cats with a (mean ± standard deviation) weight of 3.3 ± 0.6 kg.MethodsCats were systematically allocated to one of six treatments: saline 0.2 mL per cat; morphine 0.5 mg kg⁻¹; buprenorphine 20 μg kg⁻¹; medetomidine 2 μg kg⁻¹; tramadol 2 mg kg⁻¹, and ketoprofen 2 mg kg⁻¹. Latency to respond to thermal stimulation was assessed at baseline and at intervals of 15–30, 30–45, 45–60, 60–75, 90–105 and 120–135 minutes. Thermal thresholds were assessed using time to respond behaviourally to stimulation with a 500 mW CO₂ laser. Within-treatment differences in response latency were assessed using Friedman’s test. Differences amongst treatments were assessed using independent Kruskal–Wallis tests. Where significant effects were identified, pairwise comparisons were conducted to elucidate the direction of the effect.ResultsCats treated with morphine (X² = 12.90, df = 6, p = 0.045) and tramadol (X² = 20.28, df = 6, p = 0.002) showed significant increases in latency to respond. However, subsequent pairwise comparisons indicated that differences in latencies at specific time-points were significant (p < 0.05) only for tramadol at 60–75 and 90–105 minutes after administration (21.9 and 43.6 seconds, respectively) in comparison with baseline (11.0 seconds). No significant pairwise comparisons were found within the morphine treatment. Injections of saline, ketoprofen, medetomidine or buprenorphine showed no significant effect on latency to respond.Conclusions and clinical relevanceThe CO₂ laser technique may have utility in the assessment of thermal nociceptive thresholds in pain-free cats after analgesic administration and may provide a simpler alternative to existing systems. Further exploration is required to examine its sensitivity and comparative utility.     

Pharmacokinetic–pharmacodynamic modelling of the antinociceptive effect of a romifidine infusion in standing horses

ObjectiveTo evaluate the effect of a romifidine infusion on antinociception and sedation, and to investigate its relationship with plasma concentration.Study designProspective, experimental, nonrandomized trial.AnimalsA total of 10 healthy adult warmblood horses.MethodsRomifidine (loading dose: 0.08 mg kg^–1, infusion: 0.03 mg kg^–1 hour^–1) was administered intravenously over 120 minutes. Romifidine plasma concentrations were determined by capillary electrophoresis. Sedation quality and nociceptive thresholds were evaluated at regular time points before, during and after romifidine administration. The nociceptive withdrawal reflex was elicited by electrical stimulation at the thoracic limb using a dedicated threshold tracking algorithm and recorded by electromyography at the deltoid muscle. A pharmacokinetic–pharmacodynamic model was established and correlation between romifidine plasma concentration and main output variables tested.ResultsA two compartmental model best described the romifidine pharmacokinetic profile. The nociceptive thresholds increased compared with baseline in all horses from 10 to 146 minutes after romifidine administration (p < 0.001). Peak effect reached 5.7 ± 2.3 times the baseline threshold (mean ± standard deviation). The effect/concentration relationship followed a counter-clockwise hysteresis loop. The mean plasma concentration was weakly correlated to nociceptive thresholds (p < 0.0071, r = 0.392). The sedative effects were significant until 160 minutes but variable, not correlated to plasma concentration (p = 0.067), and weakly correlated to nociceptive thresholds (p < 0.0001, r = 0.33).Conclusions and clinical relevanceRomifidine elicited a marked antinociceptive effect. Romifidine-induced antinociception appeared with a delayed onset and lasted longer than sedation after discontinuing its administration.     

A comparative study of xylazine-induced mechanical hypoalgesia in donkeys and horses

ObjectiveTo compare the effects of xylazine on mechanical nociceptive thresholds in donkeys and horses.Study designRandomized, controlled, crossover, Latin-square, operator-blinded design.AnimalsSix 3.1 ± 0.89 year old standard donkeys weighing 145.0 ± 30.5 kg and six 9.6 ± 4.4 year old Thoroughbred horses weighing 456.0 ± 69.0 kg.MethodsEach animal received one of four doses of xylazine (0.5, 0.7, 0.9, and 1.1 mg kg^?1), or acepromazine (0.05 mg kg^?1) or saline solution (0.9%) intravenously and mechanical nociceptive thresholds were assessed over 90 minutes. The areas under the threshold change versus time curve values for 60 minutes (AUC_0-60) post-drug administration were used to compare the effect of treatment. A 1-week interval was allowed between successive trials on each animal.ResultsAll doses of xylazine, but not acepromazine or saline, increased mechanical thresholds for up to 60 minutes. Xylazine-induced hypoalgesia was dose-dependent and corresponding AUC_0-60 values for each treatment were not significantly different between donkeys and horses (p≥ 0.0697).ConclusionThe hypoalgesic effects of xylazine at four different doses were not different between donkeys and horses.Clinical relevanceXylazine induced a similar degree of mechanical hypoalgesia in donkeys and horses suggesting that similar doses are needed for both species with regard to analgesia.     

Thermal and mechanical nociceptive threshold testing in pregnant sheep

ObjectiveAnalgesic regimes were compared in pregnant ewes after laparotomy by measuring thermal (TT) and mechanical (MT) nociceptive thresholds.Study designProspective randomised experimental study.AnimalsPregnant ewes at 121 days gestation underwent laparotomy as part of another research project.MethodsThermal and mechanical thresholds were measured before, and 2, 6, 24 and 48 hours after surgery. Thermal stimuli were delivered to the lateral aspect of the metatarsus via a skin-mounted probe, and mechanical stimuli to the contralateral site via a pneumatically driven 1.5 mm diameter pin. Each test was performed five times, alternating thermal and mechanical stimuli, with ten minutes between thermal stimuli. At the end of surgery ewes received either: 75 μg hour^?1 transdermal fentanyl patch (medial thigh) (group FP) (n = 8), or 3 μg kg^?1hour^?1 intra-peritoneal medetomidine via an osmotic pump (group IPM) (n = 8) inserted immediately prior to closure. Data were analysed using the Kruskal–Wallis RS Test (p < 0.05). Once a significant effect was identified, pairwise comparisons were performed using paired Wilcoxon RS tests. To compensate for multiple hypotheses testing, p < 0.005 was considered significant.ResultsPrior to surgery mean ± SD TT was 56.1 ± 5.0 °C (FP) and 55.6 ± 5.0 °C (IPM); MT was 5.3 ± 2.6 N (FP) and 8.0 ± 5.0 N (IPM). In FP there was no significant change in either TT or MT over time. In IPM there was no significant change in MT over time but TT increased at two hours to 59.2 ± 3.0 °C (p = 0.003). Skin temperature (ST) ranged from 33.0 to 34.7 °C and did not change over time. There were no significant differences between groups in TT, MT or ST.Conclusions and clinical relevanceAdministration of intra-peritoneal medetomidine (3 μg kg^?1hour^?1) by an osmotic pump increases the thermal nociceptive threshold in the immediate post operative period in pregnant sheep, suggesting that this agent may have a role in providing post-operative analgesia.     

Pharmacokinetic and pharmacodynamic modelling of intravenous,intramuscular and subcutaneous buprenorphine in conscious cats

ObjectiveTo describe simultaneous pharmacokinetics (PK) and thermal antinociception after intravenous (IV), intramuscular (IM) and subcutaneous (SC) buprenorphine in cats.Study designRandomized, prospective, blinded, three period crossover experiment.AnimalsSix healthy adult cats weighing 4.1 ± 0.5 kg.MethodsBuprenorphine (0.02 mg kg^?1) was administered IV, IM or SC. Thermal threshold (TT) testing and blood collection were conducted simultaneously at baseline and at predetermined time points up to 24 hours after administration. Buprenorphine plasma concentrations were determined by liquid chromatography tandem mass spectrometry. TT was analyzed using anova (p < 0.05). A pharmacokinetic-pharmacodynamic (PK-PD) model of the IV data was described using a model combining biophase equilibration and receptor association-dissociation kinetics.ResultsTT increased above baseline from 15 to 480 minutes and at 30 and 60 minutes after IV and IM administration, respectively (p < 0.05). Maximum increase in TT (mean ± SD) was 9.3 ± 4.9 °C at 60 minutes (IV), 4.6 ± 2.8 °C at 45 minutes (IM) and 1.9 ± 1.9 °C at 60 minutes (SC). TT was significantly higher at 15, 60, 120 and 180 minutes, and at 15, 30, 45, 60 and 120 minutes after IV administration compared to IM and SC, respectively. IV and IM buprenorphine concentration-time data decreased curvilinearly. SC PK could not be modeled due to erratic absorption and disposition. IV buprenorphine disposition was similar to published data. The PK-PD model showed an onset delay mainly attributable to slow biophase equilibration (t_1/2k_e0 = 47.4 minutes) and receptor binding (k_on = 0.011 mL ng^?1 minute^?1). Persistence of thermal antinociception was due to slow receptor dissociation (t_1/2k_off = 18.2 minutes).Conclusions and clinical relevanceIV and IM data followed classical disposition and elimination in most cats. Plasma concentrations after IV administration were associated with antinociceptive effect in a PK-PD model including negative hysteresis. At the doses administered, the IV route should be preferred over the IM and SC routes when buprenorphine is administered to cats.     

Effect of low dose rate ketamine infusions on thermal and mechanical thresholds in conscious cats

ObjectiveTo determine the thermal and mechanical antinociceptive effects of two different subanesthetic constant rate infusions of racemic ketamine in cats.Study designProspective, randomized, blinded, experimental study.AnimalsEight healthy adult domestic shorthair cats (two intact females and six neutered males).MethodsThe thorax and the lower thoracic limbs of each cat were shaved for thermal (TT) and mechanical threshold (MT) testing and a cephalic catheter was placed. Three intravenous treatments of equivalent volume were given as loading dose (LD) followed by an infusion for 2 hours: (K5) 0.5 mg kg^?1 ketamine followed by 5 μg kg^?1 minute^?1 ketamine infusion, (K23) 0.5 mg kg^?1 ketamine followed by 23 μg kg^?1 minute^?1 ketamine infusion or (S) 0.9% saline solution. Effects on behavior, sedation scores, MT and TT were obtained prior to drug treatment and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.25, 2.5 2.75, 3 hours then every 0.5 hours for 7 hours and 10, 12, 14 and 26 hours after loading dose administration.ResultsKetamine induced mild sedation for the period of the infusion, no adverse behavioral effects were observed. Thermal threshold was significantly higher than baseline (K5: 44.5 ± 0.7 °C; K23: 44.5 ± 0.5 °C) at 15 minutes in the K5 group (46.8 ± 3.5 °C) and at 45 minutes in the K23 group (47.1 ± 4.1 °C). In the K23 group TT was significantly increased compared to S and K5 at 45 minutes. In K5 at 15 minutes MT (9.6 ± 4.0 N) was different to baseline (6.1 ± 0.8 N) and to the S group (5.9 ± 2.3 N).Conclusion and clinical relevanceLow dose rate ketamine infusions minimally affect thermal and mechanical antinociception in cats. Further studies with different nociceptive testing methods are necessary to assess whether ketamine could be a useful analgesic in cats.     

A comparison of the antinociceptive effects of xylazine, detomidine and romifidine on experimental pain in horses

Objective To study the analgesic potency of the α₂‐agonist romifidine in the horse using both an electrical current and a mechanical pressure model for nociceptive threshold testing. In addition, a comparison was made with doses of detomidine and xylazine that produce equivalent degrees of sedation. Study design Randomized, placebo‐controlled, blinded cross‐over study. Animals Six adult Swiss warmblood horses, one mare and five geldings, weighing from 530 to 650 kg and aged 6–15 years. Methods Nociceptive thresholds were measured using an electrical stimulus applied to the coronary band and using a pneumatically operated pin pressing on the cannon bone. Measurements were made immediately before and every 15 minutes for 2 hours after IV injection of the test substances. Lifting of the foot indicated the test end point. Results The three α₂‐agonists caused a temporary increase in nociceptive thresholds with a maximal effect within 15 minutes and a return to baseline levels within 1 hour. Using electrical current testing nociceptive thresholds were significantly different from placebo (mean ± SD) for detomidine at 15 minutes (from control 5.8 ± 0.9 to 23.3 ± 3.9 mA, p = 0.0066) and 30 minutes (from control 6.6 ± 1.1 to 18.8 ± 3.3 mA, p = 0.0091). The difference was significant for romifidine at 15 minutes only (from control 5.8 ± 0.9 to 18.7 ± 3.8 mA, p = 0.0066). With mechanical pressure testing nociceptive thresholds were significantly different from control for detomidine at 15 minutes (from 3.2 ± 0.2 to 6.2 ± 0.5 N, p = 0.00076) and 30 minutes (from 3.2 ± 0.7 to 5.7 ± 0.8 N, p = 0.0167). The difference was significant for xylazine at 15 minutes (from control 3.2 ± 0.2 to 5.6 ± 0.7 N, p = 0.0079). At 15 minutes the order of magnitude of the measured antinociceptive effect was significantly different between the two pain tests for both romifidine and detomidine, but not for xylazine. For romifidine, the increase of mean thresholds compared to placebo was 4.0 ± 1.3 times placebo levels with the electrical current test compared to 1.3 ± 0.3 times for the mechanical pressure test (p = 0.037). For detomidine, the increase of mean thresholds compared to placebo was 5.4 ± 1.7 times control levels with the electrical current test compared to 2.0 ± 0.2 times for the mechanical pressure test (p = 0.040). This represents a 2.7 (romifidine) and 3.4 times (detomidine) greater increase in thresholds using electrical current testing compared to the use of mechanical pressure testing. Conclusion and clinical relevance This study demonstrates the analgesic potential of α₂‐agonists in the horse for somatic pain and that they can have quantitatively different antinociceptive effects according to the antinociceptive test used.     

Comparison of intraperitoneal ropivacaine and ropivacaine–dexmedetomidine for postoperative analgesia in cats undergoing ovariohysterectomy

ObjectiveTo investigate the intraperitoneal (IP) administration of ropivacaine or ropivacaine–dexmedetomidine for postoperative analgesia in cats undergoing ovariohysterectomy.Study designProspective, randomized, blinded, positively controlled clinical study.AnimalsA total of 45 client-owned cats were enrolled.MethodsThe cats were administered intramuscular (IM) meperidine (6 mg kg⁻¹) and acepromazine (0.05 mg kg⁻¹). Anesthesia was induced with propofol and maintained with isoflurane. Meloxicam (0.2 mg kg⁻¹) was administered subcutaneously in all cats after intubation. After the abdominal incision, the cats were administered one of three treatments (15 cats in each treatment): IP instillation of 0.9% saline solution (group Control), 0.25% ropivacaine (1 mg kg⁻¹, group ROP) or ropivacaine and dexmedetomidine (4 μg kg⁻¹, group ROP–DEX). During anesthesia, heart rate (HR), electrocardiography, noninvasive systolic arterial pressure (SAP) and respiratory variables were monitored. Sedation and pain were assessed preoperatively and at various time points up to 24 hours after extubation using sedation scoring, an interactive visual analog scale, the UNESP-Botucatu multidimensional composite pain scale (MCPS) and mechanical nociceptive thresholds (MNT; von Frey anesthesiometer). Rescue analgesia (morphine, 0.1 mg kg⁻¹) IM was administered if the MCPS ≥6. Data were analyzed using the chi-square test, Tukey test, Kruskal–Wallis test and Friedman test (p < 0.05).ResultsHR was significantly lower in ROP–DEX compared with Control (p = 0.002). The pain scores, MNT, sedation scores and the postoperative rescue analgesia did not differ statistically among groups.Conclusions and clinical relevanceAs part of a multimodal pain therapy, IP ropivacaine–dexmedetomidine was associated with decreased HR intraoperatively; however, SAP remained within normal limits. Using the stated anesthetic protocol, neither IP ropivacaine nor ropivacaine–dexmedetomidine significantly improved analgesia compared with IP saline in cats undergoing ovariohysterectomy.     

Use of nociceptive threshold testing in cats in experimental and clinical settings: a qualitative review

ObjectiveThe objective of this study was to review the scientific articles on the use of nociceptive threshold testing (NTT) in cats and to summarize the clinical and experimental applications in this species.Databases usedPertinent literature was searched with PubMed, Scopus, Web of Science, Universitätsbibliothek Basel (swissbib Basel Bern) and Google Scholar. The search was then refined manually based first on article titles and abstracts, and subsequently on full texts.ConclusionsOf the four classical acute nociceptive models used for NTT, thermal and mechanical are most commonly used in cats. Thermal stimulation is applicable in experimental settings and has been used in pharmacodynamics studies assessing feline antinociception. Although mechanical stimulation is currently less used in cats, in the future it might play a role in the evaluation of clinical feline pain. However, the low response reliability after stimulus repetition within a narrow time interval represents a major limitation for the clinical use of mechanical thresholds in this species. Challenges remain when thermal thresholds are used to investigate analgesics that have the potential to affect skin temperature, such as opioids and α2-adrenergic agonists, and when a model of inflammatory pain is reproduced in experimental cats with the purpose of evaluating non-steroidal anti-inflammatory drugs as analgesics.     

Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses

ObjectiveTo compare the pharmacokinetics and pharmacodynamics of hydromorphone in horses after intravenous (IV) and intramuscular (IM) administration.Study designRandomized, masked, crossover design.AnimalsA total of six adult horses weighing [mean ± standard deviation (SD))] 447 ± 61 kg.MethodsHorses were administered three treatments with a 7 day washout. Treatments were hydromorphone 0.04 mg kg^⁻1 IV with saline administered IM (H-IV), hydromorphone 0.04 mg kg^⁻1 IM with saline IV (H-IM), or saline IV and IM (P). Blood was collected for hydromorphone plasma concentration at multiple time points for 24 hours after treatments. Pharmacodynamic data were collected for 24 hours after treatments. Variables included thermal nociceptive threshold, heart rate (HR), respiratory frequency (f_R), rectal temperature, and fecal weight. Data were analyzed using mixed-effects linear models. A p value of less than 0.05 was considered statistically significant.ResultsThe mean ± SD hydromorphone terminal half-life (t_1/2), clearance and volume of distribution of H-IV were 19 ± 8 minutes, 79 ± 12.9 mL minute^⁻1 kg^⁻1 and 1125 ± 309 mL kg^⁻1. The t_1/2 was 26.7 ± 9.25 minutes for H-IM. Area under the curve was 518 ± 87.5 and 1128 ± 810 minute ng mL^⁻1 for H-IV and H-IM, respectively. The IM bioavailability was 217%. The overall thermal thresholds for both H-IV and H-IM were significantly greater than P (p < 0.0001 for both) and baseline (p = 0.006). There was no difference in thermal threshold between H-IV and H-IM. No difference was found in physical examination variables among groups or in comparison to baseline. Fecal weight was significantly less than P for H-IV and H-IM (p = 0.02).Conclusions and clinical relevanceIM hydromorphone has high bioavailability and provides a similar degree of antinociception to IV administration.IM hydromorphone in horses provides a similar degree and duration of antinociception to IV administration.     

Pharmacokinetic‐pharmacodynamic modelling of intravenous buprenorphine in conscious horses

ObjectiveDescribe the pharmacokinetics of buprenorphine and norbuprenorphine in horses and to relate the plasma buprenorphine concentration to the pharmacodynamic effects.Study designSingle phase non-blinded study.AnimalsSix dedicated research horses, aged 3–10 years and weighing 480–515 kg.MethodsThermal and mechanical nociceptive thresholds, heart and respiratory rates and locomotor activity were measured before and 15, 30, 45 &; 60 minutes and 2, 4, 6, 8, 12 &; 24 hours post-administration of 10 μg kg⁻¹ buprenorphine IV. Intestinal motility was measured 1, 6, 12 &; 24 hours after buprenorphine administration. Venous blood samples were obtained before administration of buprenorphine 10 μg kg⁻¹ IV and 1, 2, 4, 6, 10, 15, 30, 45 &; 60 minutes, and 2, 4, 6, 8, 12 &; 24 hours afterwards. Plasma buprenorphine and norbuprenorphine concentrations were measured using a liquid chromatography-tandem mass spectroscopy (LC-MS/MS) assay with solid-phase extraction. A non-compartmental method was used for analysis of the plasma concentration–time data and plasma buprenorphine concentrations were modelled against two dynamic effects (change in thermal threshold and mechanical threshold) using a simple Emax model.ResultsPlasma buprenorphine concentrations were detectable to 480 minutes in all horses and to 720 minutes in two out of six horses. Norbuprenorphine was not detected. Thermal thresholds increased from 15 minutes post-buprenorphine administration until the 8–12 hour time points. The increase in mechanical threshold ranged from 3.5 to 6.0 Newtons (median: 4.4 N); and was associated with plasma buprenorphine concentrations in the range 0.34–2.45 ng mL⁻¹.Conclusions and clinical relevanceThe suitability of the use of buprenorphine for peri-operative analgesia in the horse is supported by the present study.     

Thermal antinociceptive pharmacodynamics of 0.1 mg kg−1 hydromorphone administered intramuscularly in cats and effect of concurrent butorphanol administration

Hydromorphone (HY) has not been objectively assessed as an analgesic in cats. It has been suggested that butorphanol (B) can have a synergistic action with pure μ‐agonists. The aim of this study was to assess the antinociceptive activity of a single dose of HY, and to examine the effect of concurrent B administration on the thermal threshold (TT). Thermal thresholds were measured following IM administration of HY, B, a combination of B and HY (HY‐B), or saline (S). Six cats (four spayed females, two castrated males, 4.75–6.8 kg) were used. Each cat received HY (0.1 mg kg^?1), B (0.4 mg kg^?1), HY (0.1 mg kg^?1), and B (0.4 mg kg^?1) (HY‐B), or S (0.05 mL kg^?1) in a randomized, blinded, cross‐over study design. Each cat received each treatment, with at least 12 days interval between the treatments. All injections were IM randomized to left or right quadriceps using a 24 SWG needle. Twenty‐four hours prior to each study, the thorax of each of the cats was shaved. On the day of the study, TT was measured using a thorax‐mounted thermal threshold‐testing device specifically developed for cats. Skin temperature was recorded before each test and then the heater was activated. When the cat responded by flinching, turning, or jumping, the stimulus was terminated and the threshold temperature was recorded. Three baseline thresholds were recorded over 1 hour before IM injection of test drug. Thermal threshold cut‐off was 55.5 °C. TT was measured at 5 and 15 minutes, every 15 to 360 minutes, every 30 minutes to 8 hours, every hour to 12 hours, and at 24 hours post‐injection. Threshold data were analyzed using an anova with a repeat factor of time. Behavioral adverse effects (dysphoria) were associated with B administration, but not with HY or HY‐B administration (these produced calm euphoria). The control group was stable over time (p = 0.22) (mean threshold 40.15 °C). Overall, there was no period effect, no significant effect of administering B, but a significant effect (raised TT) of administering HY or HY‐B. If the mean value of one of the experimental groups differed from the control group (40.075 °C) by more than 2.355 °C (>42.425 °C), that mean was significantly different from control at p < 0.05 (Bonferroni's t‐tests). This occurred between 15 and 165 minutes for B, from 15 to 345 minutes for HY, and between 15 and 540 minutes for HY‐B. In this model, HY provided up to 5.75 hours of antinociception at 0.1 mg kg^?1, and concurrent administration of butorphanol (0.4 mg kg^?1) decreased the intensity of antinociception over the first 2 hours, but extended the duration of significant antinociception to about 9 hours.     

Adaptation of thermal threshold analgesiometry for NSAIDs in cats: effects of ketoprofen

Nonsteroidal anti‐inflammatory drugs (NSAIDs) are widely used to provide analgesia in clinical veterinary medicine, but there are few objective data evaluating this effect under controlled conditions in cats. Analgesia is more difficult to detect with acute analgesiometry after NSAIDs than after opioids. This investigation aimed to adapt the feline thermal analgesiometry method previously employed with opioids ( Dixon et al. 2002 ) for use with NSAIDs. Ketoprofen, a COX1 inhibitor licensed for cats was chosen. Six cats (2 neutered, four entire females, weighing 2.2–5.4 kg) were studied in two blinded randomized crossover trials each at least 2 weeks apart. Thermal thresholds (TT) were measured using the thermal threshold‐testing device previously developed for cats. A heater element and temperature sensor in a small probe were held at constant pressure against the cats' shaved thorax with an elasticized band. Skin temperature was recorded before each test, then the heater activated. When the cat responded by flinching, turning or jumping the heater was turned off and the temperature recorded. In the first study TT were measured following subcutaneous (SC) injection of ketoprofen (2 mg kg^?1) or a similar volume of saline. In the second study, prior to TT, and under isoflurane restraint, a mild inflammatory focus was produced at the probe site by five SC injections of 5 mg kaolin in 0.1 mL saline at each corner and in the center of a 1.5‐cm square. Saline or ketoprofen as in the first study were injected at the same time. Three baseline temperatures were recorded before any injections were given. Thermal thresholds were measured at 1 and 2 hours and then two‐hourly for 24 hours. Data were analysed using anova . Baseline skin temperature increased (37.3 ± 0.5–38.1 ± 0.8 °C) 24 hours after saline injection in study 2 (p < 0.05) but did not change after any other treatment. Thermal thresholds decreased (40.0 ± 1.3 to 39.1 ± 0.4 °C) 16 hours after ketoprofen in study 1 (p < 0.05) and increased (41.6 ± 1.5–44.8 ± 6.1 °C) 16–24 hours after ketoprofen in study 2 (p < 0.05), with no significant changes after saline. No obvious increase in sensitivity to thermal stimulation after kaolin injection was detected although obvious inflammation was present for up to 36 hours and the cats responded to digital pressure at the treated site. The method detected some effects of a COX1 selective NSAID and may be suitable for future NSAID studies in cats. However, a pressure stimulus ( Dixon et al. 2000) may prove better than thermal, and it requires investigation.     

Changes in thermal threshold response in eight cats after administration of buprenorphine, butorphanol and morphine

Thermal thresholds were measured in eight cats after the intramuscular administration of morphine (0.2 mg/kg), buprenorphine (0.01 mg/kg) or butorphanol (0.2 mg/kg), doses commonly used in clinical practice; 0.9 per cent saline (0.3 ml) was injected as a control. Groups of six cats were used and each cat participated in at least two treatments, according to a randomised design. The investigator was blinded to the treatments. The thermal thresholds were measured with a testing device developed specifically for cats, and measurements were made before and five, 30, 45 and 60 minutes and two, four, six, 12 and 24 hours after the injections. There was no significant change in thermal threshold after the injection of saline. With butorphanol, the threshold was increased only at five minutes after the injection and was decreased two hours after the injection; with morphine it was increased from between four and six hours after the injection, and with buprenorphine it was increased from between four and 12 hours after the injection.     

Modulation of nociceptive withdrawal reflexes evoked by single and repeated nociceptive stimuli in conscious dogs by low-dose acepromazine

ObjectivesTo investigate the modulation of the nociceptive withdrawal reflex (NWR) and temporal summation (TS) by low‐dose acepromazine (ACP) in conscious dogs. To assess the short‐ and long‐term stability of the reflex thresholds.Study designRandomized, blinded, placebo‐controlled cross‐over experimental study.AnimalsEight adult male Beagles.MethodsThe NWR was elicited using single transcutaneous electrical stimulation of the ulnar nerve. Repeated stimuli (10 pulses, 5 Hz) were applied to evoke TS. The responses of the deltoideus muscle were recorded and quantified by surface electromyography and the behavioural reactions were scored. Each dog received 0.01 mg kg^?1 ACP or an equal volume saline intravenously (IV) at 1 week intervals. Measurements were performed before (baseline) and 20, 60 and 100 minutes after drug administration. Sedation was scored before drug administration and then at 10 minutes intervals. Data were analyzed with Friedman repeated measures analysis of variance on ranks and Wilcoxon signed rank tests.ResultsAcepromazine resulted in a mild tranquilization becoming obvious at 20 minutes and peaking 30 minutes after injection. Single (I_t) and repeated stimuli (TS_t) threshold intensities, NWR and TS characteristics and behavioural responses were not affected by the ACP at any time point. Both I_t and TS_t were stable over time.Conclusions and clinical relevanceIn dogs, 0.01 mg kg^?1 ACP IV had no modulatory action on the NWR evoked by single or repeated stimuli, suggesting no antinociceptive activity on phasic nociceptive stimuli. The evidence of the stability of the NWR thresholds supports the use of the model as an objective tool to investigate nociception in conscious dogs. A low dose of ACP administered as the sole drug, can be used to facilitate the recordings in anxious subjects without altering the validity of this model.     

Antinociceptive and Behavioral Effects of Methadone Alone or in Combination with Detomidine in Conscious Horses

The antinociceptive and behavioral effects of methadone (MET) alone or combined with detomidine (DET) were studied in horses. Intravenous treatments were randomly administered in a two-phase crossover study. In phase 1, six horses were treated with saline (control) or 0.2 or 0.5 mg/kg methadone (MET_0.2; MET_0.5, respectively). In phase 2, six horses were treated with 0.01 mg/kg DET alone or with DET combined with 0.2 mg/kg MET (DET/MET_0.2). Thermal nociceptive threshold (TNT) and electrical nociceptive thresholds (ENT) were recorded by using a heat projection lamp and electrodes placed in the coronary band of the thoracic limbs, respectively. Spontaneous locomotor activity (SLA) was studied by movement sensors in the stall (phase 1). Chin-to-floor distance was assessed in phase 2. In phase 1, the TNT increased significantly for 30 minute after MET_0.5 but not after saline or MET_0.2. Hyperesthesia and ataxia were observed in 2 of 6 and 6 of 6 horses after MET_0.2 and MET_0.5, respectively. SLA increased significantly for 120 minutes after MET in a dose-dependent way, but not after placebo. In phase 2, DET and DET/MET_0.2 significantly increased the TNT and ENT above baseline for 15 and 30 minutes, respectively; thresholds were significantly higher with DET/MET_0.2 than with DET at the same times. Chin-to-floor distance decreased significantly from baseline for 30 minutes, and no excitatory behavior was observed in both treatments. Although the higher dose of MET induced short-acting antinociception, the associated adverse effects may contraindicate its clinical use. The lower dose of MET potentiated DET-induced antinociception without adverse effects, which might be useful under clinical circumstances.     

Determination of acute tolerance and hyperalgesia to remifentanil constant rate infusion in dogs undergoing sevoflurane anaesthesia

ObjectiveTo determine if acute opioid tolerance (AOT) or opioid-induced hyperalgesia (OIH) could develop and limit the remifentanil-induced reduction in the sevoflurane minimum alveolar concentration (MAC). The response to mechanical nociceptive threshold (MNT) was evaluated and related to OIH.Study designA crossover, randomized, experimental animal study.AnimalsA total of nine Beagle dogs.MethodsThe dogs were anaesthetized with sevoflurane in 50% oxygen. Baseline sevoflurane MAC was measured (MACb1). Remifentanil (0.3 μg kg^–1 minute^–1) or 0.9% saline constant rate infusion (CRI) was administered intravenously (IV). Sevoflurane MAC was determined 20 minutes after CRI was initiated (MACpostdrug1), 30 minutes after MACpostdrug1 determination (MACpostdrug2) and after 1 week (MACb2). The MNT was determined at baseline (before anaesthesia), 3 and 7 days after anaesthesia. An increase of MACpostdrug2 ≥0.25% compared to MACpostdrug1 was considered evidence of AOT. A decrease in MNT at 3 and 7 days or an increase in MACb2 or both with respect to MACb1 were considered evidence of OIH.ResultsRemifentanil CRI reduced sevoflurane MACpostdrug1 by 43.7% with respect to MACb1. MACpostdrug2 was no different from MACpostdrug1 with the saline (p = 0.62) or remifentanil (p = 0.78) treatments. No significant differences were observed in the saline (p = 0.99) or remifentanil (p = 0.99) treatments between MACb1 and MACb2, or for MNT values between baseline, 3 and 7 days.Conclusion and clinical relevanceIn dogs, under the study conditions, remifentanil efficacy in reducing sevoflurane MAC did not diminish in the short term, suggesting remifentanil did not induce AOT. Hyperalgesia was not detected 3 or 7 days after the administration of remifentanil. Contrary to data from humans and rodents, development of AOT or OIH in dogs is not supported by the findings of this study.     

Effects of buprenorphine, carprofen and saline on thermal and mechanical nociceptive thresholds in cats

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 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. 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 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. 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.     

Analgesic effect of the mint terpenoid L-carvone in sheep

ObjectiveTo determine whether L-carvone increases the voltage threshold response to a noxious electrical stimulus in sheep.Study designProspective, blinded, randomized, crossover experimental study.AnimalsA group of six healthy adult sheep.MethodsSheep were instrumented with cranial dorsothoracic subcutaneous copper electrodes. A stimulator delivered a 10 ms square-wave stimulus at 50 pps starting at 0.1 V with a 0.2 V second^–1 ramp. The stimulus stopped once two observers who were blinded to treatment noted a behavioral pain response or when a 15 V cut-off was reached. Next, 0.15 mL kg^–1 of either a 50% L-carvone solution or a saline-vehicle control was administered intramuscularly, and electrical threshold responses were measured every 5–15 minutes over a 6 hour period using methods identical to the baseline. One week following the first treatment (L-carvone or control), sheep were studied using identical methods with the second treatment (control or L-carvone). Drug and time effects were evaluated using a two-way repeated measures analysis of variance, and pairwise comparisons were evaluated with Holm-Sidák tests with values of p < 0.05 considered significant.ResultsL-carvone significantly increased voltage threshold responses for most time points up to 75 minutes compared with baseline and with saline control. The last time point with a significantly different response between L-carvone and saline treatments was 5 hours after drug administration. The saline-vehicle control decreased voltage threshold responses at several time points after 3 hours.Conclusions and clinical relevanceIntramuscular L-carvone is analgesic in sheep, although the ethanol-propylene glycol vehicle may cause mild hyperalgesia. This study demonstrates that a food-derived compound can be used to relieve pain in a food-producing animal.