Assessment of Sensory Thresholds in Dogs using Mechanical and Hot Thermal Quantitative Sensory Testing.

Quantitative sensory testing (QST) is used to evaluate the function of the somatosensory system in dogs by assessing the response to applied mechanical and thermal stimuli. QST is used to determine normal dogs' sensory thresholds and evaluate alterations in peripheral and central sensory pathways caused by various disease states, including osteoarthritis, spinal cord injury, and cranial cruciate ligament rupture. Mechanical sensory thresholds are measured by electronic von Frey anesthesiometers and pressure algometers. They are determined as the force at which the dog exhibits a response indicating conscious stimulus perception. Hot thermal sensory thresholds are the latency to respond to a fixed or ramped temperature stimulus applied by a contact thermode. Following a consistent protocol for performing QST and paying attention to details of the testing environment, procedure, and individual study subjects are critical for obtaining accurate QST results for dogs. Protocols for the standardized collection of QST data in dogs have not been described in detail. QST should be performed in a quiet, distraction-free environment that is comfortable for the dog, the QST operator, and the handler. Ensuring that the dog is calm, relaxed, and properly positioned for each measurement helps produce reliable, consistent responses to the stimuli and makes the testing process more manageable. The QST operator and handler should be familiar and comfortable with handling dogs and interpreting dogs' behavioral responses to potentially painful stimuli to determine the endpoint of testing, reduce stress, and maintain safety during the testing process.

Serum artemin is not correlated with sensitivity within dogs with naturally occurring osteoarthritis pain.

Osteoarthritis (OA) pain is associated with peripheral and central sensitization in humans and results in widespread increased sensitivity across the body. Sensitization contributes to the OA-associated pain (OAP) state. We recently identified increased levels of an endogenous neurotrophic factor, artemin (ARTN), in dogs with OAP compared to healthy pain-free controls. Circulating ARTN released from damaged tissues in OA, may play a central role in widespread sensitivity and pain. However, the relationship between ARTN and somatosensory sensitivity remains unknown. The study aimed to assess the relationship between serum ARTN concentrations and measures of sensitivity in dogs with OAP using quantitative sensory testing. We hypothesized that there would be a positive association between circulating ARTN and increased sensitivity to mechanical and thermal stimuli in dogs with OAP. We used linear and logistic regression models to assess the relationship between ARTN, sensitization, and pain within a cohort of 43 dogs with spontaneous OAP. Serum ARTN was not associated with the degree of sensitization within dogs with OAP. Further, across dogs with varying OAP severity, we did not find any association between ARTN, and clinical measures of joint pain and disability. Although a relationship between ARTN and joint pain was not ruled out.

Quantitative sensory testing in dogs with painful disease: A window to pain mechanisms?

Evaluation of the response to externally applied physical stimuli, such as pressure, heat, or cold is termed quantitative sensory testing (QST). QST may be used to identify and quantify alterations (gain or loss) in function of the sensory systems which detect and mediate these phenomena in both man and animals, and potentially discriminate peripheral and central sensitisation. It has been postulated that evaluation of QST parameters may predict response to analgesics, ultimately increasing the individualisation of treatment for pain. However, while there do appear to be correlations between QST measures and responses to analgesics in man, there is currently insufficient evidence to recommend QST to direct clinical treatments. The use of psychophysical testing, such as QST, in non-verbal subjects presents additional challenges, and requires familiarity with species and individual responses. This narrative review describes the investigations into QST in clinical populations of dogs to date, and discusses the potential benefits and limitations of such testing.

Replicate effects and test-retest reliability of quantitative sensory threshold testing in dogs with and without chronic pain.

OBJECTIVE: To evaluate replicate effects and test-retest reliability of mechanical and thermal quantitative sensory testing (QST) in normal dogs and dogs with osteoarthritis (OA)-associated pain. STUDY DESIGN: A prospective clinical study. ANIMALS: A total of 54 client owned dogs (OA, n=31; controls, n=23). METHODS: Mechanical [electronic von Frey (EVF) and blunt pressure] and thermal (hot and cold) sensory thresholds were obtained in dogs with OA-associated pain and control dogs at two visits, 7 days apart, to assess test-retest reliability. Thresholds were measured at the OA-affected joint (hip or stifle), over the tibial muscle and over the midpoint of the metatarsals. Five replicates were obtained for each modality at each site bilaterally. RESULTS: Overall, there was no significant effect of replicates on QST response. EVF thresholds were significantly lower at the second visit in OA dogs at the affected and metatarsal sites (p=0.0017 and p=0.0014, respectively). Similarly for control dogs, EVF thresholds were significantly lower at the second visit at the metatarsal site (p=0.001). Significantly higher hot thermal latencies were seen in OA dogs at the affected and tibial testing sites (p=0.014 and p=0.012, respectively), and in control dogs at the tibial site (p=0.004). CONCLUSIONS: In QST, a replicate does not show a strong effect. However, QST results show variability over time, particularly for EVF and hot thermal stimuli. CLINICAL RELEVANCE: If QST is to be used clinically to evaluate a sensitized state, the variability over time needs to be accounted for in the study design.

Alfaxalone Anaesthesia Facilitates Electrophysiological Recordings of Nociceptive Withdrawal Reflexes in Dogs (Canis familiaris).

Naturally occurring canine osteoarthritis represents a welfare issue for affected dogs (Canis familiaris), but is also considered very similar to human osteoarthritis and has therefore been proposed as a model of disease in humans. Central sensitisation is recognized in human osteoarthritis sufferers but identification in dogs is challenging. Electromyographic measurement of responses to nociceptive stimulation represents a potential means of investigating alterations in central nociceptive processing, and has been evaluated in conscious experimental dogs, but is likely to be aversive. Development of a suitable anaesthetic protocol in experimental dogs, which facilitated electrophysiological nociceptive withdrawal reflex assessment, may increase the acceptability of using the technique in owned dogs with naturally occurring osteoarthritis. Seven purpose bred male hound dogs underwent electromyographic recording sessions in each of three states: acepromazine sedation, alfaxalone sedation, and alfaxalone anaesthesia. Electromyographic responses to escalating mechanical and electrical, and repeated electrical, stimuli were recorded. Subsequently the integral of both early and late rectified responses was calculated. Natural logarithms of the integral values were analysed within and between the three states using multi level modeling. Alfaxalone increased nociceptive thresholds and decreased the magnitude of recorded responses, but characteristics of increasing responses with increasing stimulus magnitude were preserved. Behavioural signs of anxiety were noted in two out of seven dogs during recordings in the acepromazine sedated state. There were few significant differences in response magnitude or nociceptive threshold between the two alfaxalone states. Following acepromazine premedication, induction of anaesthesia with 1-2 mg kg-1 alfaxalone, followed by a continuous rate infusion in the range 0.075-0.1 mg kg-1 min-1 produced suitable conditions to enable assessment of spinal nociceptive processing in dogs, without subjecting them to potentially aversive experiences. This methodology may be appropriate for obtaining electrophysiological nociceptive withdrawal reflex data in client-owned dogs with naturally occurring osteoarthritis.

Comparison of thermal and mechanical quantitative sensory testing in client-owned dogs with chronic naturally occurring pain and normal dogs.

Detecting dogs with central sensitization (CS) secondary to chronic pain is hampered by the current inability to measure this condition. The current study aimed to use quantitative sensory testing (QST) to measure (CS) in normal dogs and dogs with painful degenerative joint disease (DJD). It was hypothesized that QST would differ between these two groups of animals. Mechanical and thermal sensory thresholds obtained in animals with DJD-associated pain on two time points 28 days apart were compared with those of normal dogs. Values of sensory thresholds in DJD dogs obtained 28 days after the first evaluation were significantly lower than the results on the first day of evaluation but no differences were found when these results were compared with those of normal dogs. In conclusion, whether QST is different between dogs with chronic pain and normal dogs needs further investigation using a larger group of animals and age, weight and sex matched groups.

Widespread somatosensory sensitivity in naturally occurring canine model of osteoarthritis.

Osteoarthritis (OA)-associated pain is a leading cause of disability. Central sensitization (CS), as a result of OA, is recognized as an important facet of human patients' chronic pain and has been measured in people using quantitative sensory testing (QST) testing. The spontaneous canine OA model has been suggested as a good translational model, but CS has not been explored in this model. In this study, QST was performed on dogs with and without spontaneous hip or stifle OA to determine whether OA is associated with CS in this model. Mechanical (von Frey and blunt pressure) and thermal (hot and cold) sensory thresholds obtained in dogs with chronic OA-associated pain (n = 31) were compared with those of normal dogs (n = 23). Dogs were phenotyped and joint-pain scored, and testing was performed at the OA-affected joint, cranial tibial muscle, and dorsal metatarsal region. QST summary data were evaluated using mixed-effect models to understand the influence of OA status and covariates, and dogs with OA and control dogs were compared. The presence of OA was strongly associated with hyperalgesia across all QST modalities at the index joint, cranial tibial muscle, and metatarsal site. Mechanical QST scores were significantly moderately negatively correlated with total joint-pain scores. The spontaneous canine OA model is associated with somatosensory sensitivity, likely indicative of CS. These data further validate the canine spontaneous OA model as an appropriate model of the human OA pain condition.

A canine-specific anti-nerve growth factor antibody alleviates pain and improves mobility and function in dogs with degenerative joint disease-associated pain.

BACKGROUND: There is a critical need for proven drugs other than non-steroidal anti-inflammatory drugs for treatment of degenerative joint disease (DJD) pain in dogs. Antibodies against nerve growth factor (NGF) are analgesic in rodent models and in humans with DJD. This pilot study aimed to evaluate the efficacy of a novel caninised anti-NGF antibody (NV-01) for the treatment of DJD pain in dogs. In a randomized, parallel group, stratified, double masked, placebo controlled, proof of principle clinical pilot study design, 26 dogs with DJD received NV-01 (200 mcg/kg IV) or placebo on day 0 (D0). In addition to objective accelerometry measures, owners completed clinical metrology instruments (Client-Specific Outcome Measures [CSOM], Canine Brief Pain Inventory [CBPI] and Liverpool Osteoarthritis in Dogs Index [LOAD]) on D0, D14 and D28. CBPI subscales (pain severity [PS] and pain interference [PI]), CSOM and LOAD scores were evaluated within and between groups for change over time. Recognized success/failure criteria were applied and success compared between groups. RESULTS: CBPI PS and PI scores significantly improved in the NV-01 group (PS: D0-14, P = 0.012 and D0-28, P = 0.019; PI: D0-14, P = 0.012 and D0-28, P = 0.032) but not in the placebo group. CSOM scores showed similar patterns with a significant difference between within-group changes at D14 and D28 (P = 0.038 and P = 0.009, respectively), and significantly more successes at D28 (P = 0.047). LOAD scores significantly improved in the NV-01 group (D0-14, P = 0.004 and D0-28, P = 0.002) but not in the placebo group. There were significant differences between the groups for change in LOAD score at D14 (P = 0.014) and D28 (P = 0.033). No side effects were noted. Activity in the NV-01 group increased over the study period compared to placebo (P = 0.063) and the difference between the groups for change in activity over the time period 9am-5pm (8 hours) was significant (P = 0.006). CONCLUSIONS: These pilot data demonstrate a positive analgesic effect of anti-NGF antibody in dogs suffering from chronic pain. The magnitude of the effect appeared identical to that expected with an NSAID.

Initial evaluation of nighttime restlessness in a naturally occurring canine model of osteoarthritis pain.

Chronic pain due to osteoarthritis (OA) can lead to significant disruption of sleep and increased restlessness. Our objective was to assess whether naturally occurring canine OA is associated with nighttime restlessness and so has potential as a model of OA-associated sleep disturbance. The study was designed as a two-part prospective masked, placebo-controlled study using client-owned dogs (Part A n = 60; Part B n = 19). Inclusion criteria consisted of OA-associated joint pain and mobility impairment. The primary outcome measure for both parts was nighttime accelerometry. In Part B, quality of sleep was assessed using a clinical metrology instrument (Sleep and Night Time Restlessness Evaluation Score, SNoRE). Part A included dogs receiving two weeks of non-steroidal anti-inflammatory drug (NSAID) preceded with two weeks of no treatment. Part B was a crossover study, with NSAID/placebo administered for two weeks followed by a washout period of one week and another two weeks of NSAID/placebo. Repeated measures analysis of variance was used to assess differences between baseline and treatment. There were no significant changes in accelerometry-measured nighttime activity as a result of NSAID administration. SNoRE measures indicated significant improvements in aspects of the quality of nighttime sleep that did not involve obvious movement. These results reflect the few similar studies in human OA patients. Although accelerometry does not appear to be useful, this model has potential to model the human pain-related nighttime sleep disturbance, and other outcome measures should be explored in this model.