Measuring pain in dogs and cats using structured behavioural observation.

The contemporary approach to pain measurement in people and animals seeks to measure the affective (emotional) component of the pain experience using structured questionnaires with formal scoring methodology. Chronic pain has wide-ranging impacts which affects the quality of life (QOL) of the individual, whether that is a person or an animal. Accordingly instruments to measure chronic pain are designed to measure its impact on QOL and are called health-related quality of life (HRQL) instruments. In veterinary science instruments to measure pain are based on behavioural observation by the veterinary surgeon/nurse in the case of acute pain and by the owner in the case of chronic pain. The development of HRQL instruments is an expanding field in veterinary science, not just for the measurement of pain, but for other chronic diseases, and it has a wide application in pharmaceutical research and clinical practice to improve patient care. This review highlights the challenges involved in creating such measures for dogs and cats, seeking to provide the reader with an understanding of their development process. It then provides an overview of the current status with regard to acute and chronic pain measurement.

Development of a behaviour-based measurement tool with defined intervention level for assessing acute pain in cats.

OBJECTIVES: To develop a composite measure pain scale tool to assess acute pain in cats and derive an intervention score. METHODS: To develop the prototype composite measure pain scale-feline, words describing painful cats were collected, grouped into behavioural categories and ranked. To assess prototype validity two observers independently assigned composite measure pain scale-feline and numerical rating scale scores to 25 hospitalised cats before and after analgesic treatment. Following interim analysis the prototype was revised (revised composite measure pain scale-feline). To determine intervention score, two observers independently assigned revised composite measure pain scale-feline and numerical rating scale scores to 116 cats. A further observer, a veterinarian, stated whether analgesia was necessary. RESULTS: Mean ± sd decrease in revised composite measure pain scale-feline and numerical rating scale scores following analgesia were 2 · 4 ± 2 · 87 and 1 · 9 ± 2 · 34, respectively (95% confidence interval for mean change in revised composite measure pain scale-feline between 1 · 21 and 3 · 6). Changes in revised composite measure pain scale-feline and numerical rating scale were significantly correlated (r = 0 · 8) (P < 0001). Intervention level score of ≥4/16 was derived for revised composite measure pain scale-feline (26 · 7% misclassification) and ≥3/10 for numerical rating scale (14 · 5% misclassification). CLINICAL SIGNIFICANCE: A valid instrument with a recommended analgesic intervention level has been developed to assess acute clinical pain in cats that should be readily applicable in practice.

Evaluation of facial expression in acute pain in cats.

OBJECTIVES: To describe the development of a facial expression tool differentiating pain-free cats from those in acute pain. METHODS: Observers shown facial images from painful and pain-free cats were asked to identify if they were in pain or not. From facial images, anatomical landmarks were identified and distances between these were mapped. Selected distances underwent statistical analysis to identify features discriminating pain-free and painful cats. Additionally, thumbnail photographs were reviewed by two experts to identify discriminating facial features between the groups. RESULTS: Observers (n = 68) had difficulty in identifying pain-free from painful cats, with only 13% of observers being able to discriminate more than 80% of painful cats. Analysis of 78 facial landmarks and 80 distances identified six significant factors differentiating pain-free and painful faces including ear position and areas around the mouth/muzzle. Standardised mouth and ear distances when combined showed excellent discrimination properties, correctly differentiating pain-free and painful cats in 98% of cases. Expert review supported these findings and a cartoon-type picture scale was developed from thumbnail images. CLINICAL SIGNIFICANCE: Initial investigation into facial features of painful and pain-free cats suggests potentially good discrimination properties of facial images. Further testing is required for development of a clinical tool.

LPS alters placental inflammatory and endocrine mediators and inhibits fetal neurite growth in affected offspring during late gestation.

INTRODUCTION: During pregnancy, maternal infection at different stages of gestation increases the risk of developing several psychiatric and neurological disorders later in life for affected offspring. As placental health is intrinsically linked to neurodevelopmental outcome, maternal infection may adversely affect the placenta at or before the gestational stages it affects fetal neurodevelopment. Here we examined this premise. METHODS: Pregnant-Sprague Dawley rats were administered saline or lipopolysaccharide by intraperitoneal injection on embryonic days 12-18. We then examined a number of key placental inflammatory and endocrine mediators, along with fetal, birth and neuronal characteristics at different stages of development. RESULTS: Maternal exposure to lipopolysaccharide at later gestational ages significantly increased pro-inflammatory IL-1ß expression and reduced placental HSD11B2 expression. This was accompanied by a reduction in placental weight and embryo number without an effect on embryo weight or crown-rump length. In utero lipopolysaccharide exposure at later gestational ages also impaired the growth of neurons from affected offspring. DISCUSSION: These data show that maternal infection at later gestational ages modifies placental inflammatory and endocrine mediators that may adversely affect the growth of developing neurons in affected offspring.

Development, validation and reliability of a web-based questionnaire to measure health-related quality of life in dogs.

OBJECTIVES: To describe the development, preliminary validation and reliability testing of a shortened web-based form of GUVQuest, a structured questionnaire to measure health-related quality of life in dogs. METHODS: The original 109 items were reduced using expert judgement and factor analysis. Validity was established by factor analysis and in a subsequent field trial using a "known groups" approach and classical test theory. Test-retest reliability was assessed using intraclass correlation coefficients. RESULTS: The instrument comprises 46 items each of which is rated by dog owners using a 7-point Likert scale. Factor analysis revealed a sensible structure containing four health-related quality of life domains (vitality, pain, distress and anxiety) accounting for 64·1% of the variability in the data. The field test involving 125 dogs demonstrated very good discriminative properties and intraclass correlation coefficient values of greater than 0·6. CLINICAL SIGNIFICANCE: This is the first report of a valid and reliable companion animal health-related quality of life instrument, the contemporary approach to animal welfare measurement, which is presented in a web-based format, with automated production of a health-related quality of life profile. It offers major advantages to dog owners, practitioners and researchers.

Quality of life is reduced in obese dogs but improves after successful weight loss.

Obesity is thought to affect quality of life, but limited objective data exist to support this supposition. The current study aim was to use a questionnaire to determine health-related quality of life (HRQOL) both before and after weight loss, in obese client-owned dogs. Fifty obese dogs were included, and represented a variety of breeds and genders. Prior to weight loss, owners were asked to complete a validated standardised questionnaire to determine HRQOL. Thirty of the dogs successfully completed their weight loss programme and reached target, and owners then completed a follow-up questionnaire. The completed questionnaire responses were transformed to scores corresponding to each of four factors (vitality, emotional disturbance, anxiety and pain), and scored on a scale of 0-6. Changes in the scores were used to explore the sensitivity of the questionnaire, and scores were correlated with responses to direct questions about quality of life and pain, as well as weight loss. Dogs that failed to complete their weight loss programme had lower vitality and higher emotional disturbance scores than those successfully losing weight (P=0.03 for both). In the 30 dogs that completed, weight loss led to an increased vitality score (P<0.001), and decreased scores for both emotional disturbance (P<0.001) and pain (P<0.001). However, there was no change in anxiety (P=0.09). The change in vitality score was positively associated with percentage weight loss (r(P)=0.43, P=0.02) and percentage body fat loss (r(P)=0.39, P=0.03). These results indicate demonstrable improvement in HRQOL for obese dogs that successfully lose weight.

Animal-based measurements of the severity of mastitis in dairy cows.

A range of clinical parameters were studied to assess their usefulness as objective markers of the severity of clinical mastitis in dairy cows. Cows with moderate clinical mastitis had significantly higher rectal temperatures and heart and respiratory rates than cows with mild clinical mastitis or control cows. The difference in temperature between quarters did not vary significantly between the control cows and the cows with mastitis, but there was a larger difference between quarter temperatures in the cows with moderate mastitis than in the cows with mild mastitis or the control cows. The hock-to-hock distance in the control cows was significantly smaller than in the cows with mild to moderate mastitis, but there was no significant difference in the distance either between the cows with mild mastitis and those with moderate mastitis, or between the cows with mastitis in the front quarters and those with mastitis in the hind quarters. The mechanical threshold to pain of the cows with mild and moderate mastitis was significantly lower than that of the control cows.

Pain assessment following experimental maxillofacial surgical procedure in sheep.

The aim of this study was to investigate the severity and duration of postoperative pain and hyperalgesia in sheep undergoing mandibular reconstructive surgery. Stimulus-evoked sensitivity at the surgical site and an area remote from injury, the ipsilateral and contralateral forelimbs, was measured as objective indicators of altered pain processing in adult female sheep (n = 7). Responses were recorded before surgery and one, two, three, seven and 14 days afterwards. Concentrations of the acute-phase protein haptoglobin were measured in serum as a marker of inflammation before and at one and seven days after surgery. A significant decrease in forelimb mechanical withdrawal thresholds (secondary hyperalgesia) and response thresholds to punctate stimulation of the area surrounding the surgical incision (allodynia) was detected one day after surgery and persisted for at least three days, despite intra- and postoperative analgesic treatment. Concentrations of haptoglobin were significantly increased one day post-surgery, indicating the presence of a significant acute inflammatory response, and returned to pre-surgical concentrations by seven days. These data provide a deeper insight into understanding the impact of surgery in experimental animals, and may assist in formulating more effective analgesic and antihyperalgesic treatment regimens postoperatively.

Acute phase proteins in bovine milk in an experimental model of Staphylococcus aureus subclinical mastitis.

The objectives were to establish the origin of 2 acute phase proteins in milk during subclinical bovine mastitis and to characterize the relationship between those proteins in milk and blood. Haptoglobin (Hp) and mammary-associated serum amyloid A (M-SAA3) appear in milk during mastitis, whereas Hp and serum amyloid A increase in serum during mastitis. The concentrations of these proteins were determined in an experimental model using a field strain of Staphylococcus aureus to induce subclinical mastitis in dairy cows. The expression of mRNA coding for these proteins was assessed and the presence of M-SAA3 in mammary tissues was determined using immunocytochemistry. Increases of M-SAA3 and Hp in milk occurred within 12 h of Staphylococcus aureus infusion, with peak concentrations occurring 3 d after infusion of the bacteria. The increase of acute phase proteins in milk (15 h) preceded the increase in serum concentrations of both proteins (24 h). Expression of mRNA for M-SAA3 and Hp increased in both mammary and hepatic tissues 48 h after infusion of the mammary glands. In mammary tissue, the increase of M-SAA3 mRNA was greater than the increase in Hp mRNA expression, whereas in hepatic tissue, the increase in M-SAA3 mRNA was less than that for Hp mRNA. Immunocytochemistry demonstrated that M-SAA3 protein was present within secretory epithelial cells at significantly higher levels in infected mammary glands than in control tissues. These proteins, which have host defense and antibacterial activities, may play a significant role in the early response to invasion of mammary tissues by pathogenic bacteria.

Changes in the Doppler waveform of the ovine femoral artery following infusion of vasoactive agents: a preliminary study.

The aim of this study was to investigate whether femoral artery pulsatility index (PI) can be used as an indicator of vasomotor tone in the digit of an ungulate species by measuring the change in PI induced by infusion of vasoactive agents in halothane-anaesthetised sheep. Intra-arterial infusion of the vasoconstrictor phenylephrine (9 microg min(-1)) tended to increase waveform PI (3.89-6.24, n=4, P=0.100). Infusion of a low dose (3 microg min(-1)) of the vasodilator sodium nitroprusside did not alter femoral artery PI, however infusion of a higher dose (30 microg min(-1)) tended to increase PI (5.39-6.70, n=5, P=0.059). During these studies heart rate, mean ABP and p(a)CO(2) did not change significantly. The tendency for PI to increase in response to vasodilation was unexpected and the mechanism involved is unclear. It appears that femoral artery PI cannot be used to predict vasomotor tone in the digit of the anaesthetised sheep.

Behavioral evidence supporting a differential role for spinal group I and II metabotropic glutamate receptors in inflammatory hyperalgesia in sheep.

A differential role for metabotropic glutamate receptors (mGluRs) in spinal nociception in normal animals has previously been identified. The present study examined the contribution of group I and group II mGluRs to the development and maintenance of inflammatory hyperalgesia produced by unilateral intradermal injection of carrageenan into the lower forelimb in sheep. Carrageenan (7.5 mg in 500 micro l) produced a significant bilateral reduction in forelimb mechanical withdrawal thresholds. Intrathecal administration of saline-vehicle or the group II mGluR antagonist (2S)-alpha-ethylglutamate (EGLU; 570 nmol) had no effect on either the development or maintenance of hyperalgesia. However, intrathecal administration of the group I mGluR antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; 450 nmol) before carrageenan blocked the development of ipsilateral hyperalgesia, and when given 2 h after carrageenan, reversed both ipsilateral and contralateral hyperalgesia. Intrathecal administration of the group II mGluR agonist (2S,1S,2S)-2-(carboxycyclopropyl)glycine (L-CCG-I; 620 nmol) given either before or after carrageenan treatment produced analgesia and anti-hyperalgesia, an effect abolished by co-administration of EGLU (570 nmol). The magnitude of the analgesic response, assessed by the area under the response curve, was significantly greater than that produced by LCCG-I in normal animals. These data demonstrate that the development and maintenance of inflammatory hyperalgesia is dependent on activation of group I mGluRs in spinal cord. In addition, the analgesic and anti-hyperalgesic actions of group II mGluRs suggest that these receptors play a crucial role in modulating acute inflammatory hyperalgesia.

Plasma disposition, faecal excretion and in vitro metabolism of oxibendazole following oral administration in horses.

Oxibendazole (OBZ) was administered to eight horses at an oral dose of 10 mg kg(-1) bodyweight each. Parent OBZ could only be detected in plasma at the 0.5 and 1.0 hours post administration sampling times and the mean maximum plasma concentration was 0.008 microg ml(-1). Parent OBZ was detected in faeces between 12 and 72 hours after administration and the highest dry faecal concentration was detected at 24 hours. An unidentified metabolite was detected in plasma between 0.5 and 72 hours. The unidentified metabolite in the plasma of treated horses corresponded to the second eluted metabolite in the in vitro study. Metabolism of OBZ to its metabolite in vitro was significantly inhibited by co-incubation with the cytochrome P450 inhibitor piperonyl butoxide. These results indicated that first-pass metabolism decreases OBZ bioavailability in horses. The in vitro metabolism of OBZ was significantly inhibited by piperonyl butoxide and this could be utilised to extend the exposure of nematodes to the parent molecule.

Analgesia of newborn lambs before castration and tail docking with rubber rings.

This study assessed the effects of suckled sucrose and parenteral carprofen treatment on behavioural measurements of discomfort and serum haptoglobin concentration in lambs following rubber ring castration and/or tail docking. Twenty-eight male and 20 ewe lambs were allocated to either a male or ewe lamb control group (n=4) or to one of three male and two ewe lamb treatment groups (n=8). Male lambs in one treatment group received carprofen subcutaneously (0.5 mg/kg) 30 minutes before castration and docking. Lambs in all other treatment groups suckled sucrose or colostrum immediately before castration and/or tail docking. Behavioural measurements of discomfort were made following castration or tail docking in treatment groups and also in control animals which were not castrated or tail docked. Blood sampling of animals in treatment groups for analysis of serum haptoglobin, an acute phase protein used as an indicator of an acute inflammatory response, was performed before castration or docking and at 24 and 48 hours after castration or docking. Control lambs were blood sampled at 0, 24 and 48 hours following behavioural assessment Neither suckled sucrose nor carprofen treatment altered discomfort behaviour associated with castration or tail docking. Haptoglobin levels following castration or tail docking remained close to the detection limits of the assay and were similar to those recorded in control animals.

Plasma pharmacokinetics and faecal excretion of ivermectin, doramectin and moxidectin following oral administration in horses.

The present study was carried out to investigate whether the pharmacokinetics of avermectins or a milbemycin could explain their known or predicted efficacy in the horse. The avermectins, ivermectin (IVM) and doramectin (DRM), and the milbemycin, moxidectin (MXD), were each administered orally to horses at 200 microg/kg bwt. Blood and faecal samples were collected at predetermined times over 80 days (197 days for MXD) and 30 days, respectively, and plasma pharmacokinetics and faecal excretion determined. Maximum plasma concentrations (Cmax) (IVM: 21.4 ng/ml; DRM: 21.3 ng/ml; MXD: 30.1 ng/ml) were obtained at (tmax) 7.9 h (IVM), 8 h (DRM) and 7.9 h (MXD). The area under the concentration time curve (AUC) of MXD (92.8 ng x day/ml) was significantly larger than that of IVM (46.1 ng x day/ml) but not of DRM (53.3 ng x day/ml) and mean residence time of MXD (17.5 days) was significantly longer than that of either avermectin, while that of DRM (3 days) was significantly longer than that of IVM (2:3 days). The highest (dry weight) faecal concentrations (IVM: 19.5 microg/g; DRM: 20.5 microg/g; MXD: 16.6 microg/g) were detected at 24 h for all molecules and each compound was detected (> or = 0.05 microg/g) in faeces between 8 h and 8 days following administration. The avermectins and milbemycin with longer residence times may have extended prophylactic activity in horses and may be more effective against emerging and maturing cyathostomes during therapy. This will be dependent upon the relative potency of the drugs and should be confirmed in efficacy studies.

Biphasic modulation of nociceptive processing by the cyclic AMP-protein kinase A signalling pathway in sheep spinal cord.

A role for the cyclic AMP (cAMP)-protein kinase A (PKA) transduction cascade in nociceptive processing has been identified. This study examined the effects of intrathecal treatment with the cAMP analogue 8-Bromo-cAMP and the PKA inhibitor H-89 dihydrochloride on nociceptive thresholds to mechanical stimulation in six adult sheep to define further the role of cAMP in spinal nociception. Treatment with 420 nmol 8-Br-cAMP induced significant hypoalgesia to noxious stimulation, while a 10-fold higher dose (4.2 micromol) induced mechanical hyperalgesia. Both of these behaviours were blocked by H-89 (38-380 nmol). Treatment with high dose H-89 (380 nmol) alone significantly increased nociceptive thresholds. These results demonstrate that activation of the cAMP-PKA signalling pathway modulates acute nociceptive events in spinal cord in a biphasic manner, and suggest that significant tonic activity exists in this pathway.

Evaluation and optimisation of a target-controlled infusion system for administering propofol to dogs as part of a total intravenous anaesthetic technique during dental surgery.

The performance of a modified target-controlled infusion system was investigated in 16 dogs undergoing routine dental work, by comparing the predicted concentrations of propofol in venous blood samples with direct measurements; the optimum targets for the induction and maintenance of anaesthesia were also identified. The performance of a target-controlled infusion system is considered clinically acceptable when the median prediction error, a measure of bias, is not greater than +/-10 to 20 per cent, and the median absolute performance error, a measure of the accuracy, is not greater than 20 to 30 per cent. The results fell within these limits indicating that the system performed adequately. The optimal induction target was 3 microg/ml, and anaesthesia of adequate depth and satisfactory quality was achieved with maintenance targets of between 2.5 and 4.7 microg/ml propofol. The system was easy to use and the quality of anaesthesia was adequate for dental work.