Analgesic efficacy of intra‐articular morphine in experimentally induced radiocarpal synovitis in horses

ObjectiveTo compare the analgesic effect of intra-articular (IA) and intravenous (IV) morphine in horses with experimentally induced synovitis.AnimalsEight adult horses.Study designRandomized, observer blinded, double dummy trial with sequential crossover design.MethodsRadiocarpal synovitis was induced by IA injection of lipopolysaccharide on two occasions separated by a 3-week washout period. In one study period horses received treatment IA; morphine IA (0.05 mg kg^?1) plus saline IV and in the other study period they received treatment IV; saline IA plus morphine IV (0.05 mg kg^?1). Lameness and pain were evaluated repeatedly by two observers throughout each of the two 168-hour study periods. Pain was evaluated by use of a visual analogue scale of pain intensity (VAS) and a composite measure pain scale (CMPS). Comparison of treatments was performed by analysis of variance with repeated measurements. Significance level was set to p ≤ 0.05. Inter-observer agreement and agreement between the VAS and CMPS was assessed by use of the Bland–Altman method.ResultsIntra-articular injection of LPS elicited a marked synovitis resulting in lameness and pain. IA morphine resulted in significantly less lameness than IV morphine (p = 0.03). CMPS (p = 0.09) and VAS (p = 0.10) pain scores did not differ significantly between treatments. Inter-observer agreement of the CMPS was classified as good, but only fair for the VAS. Agreement between the two pain scales was considered fair.Conclusions and clinical relevanceAn analgesic effect of IA morphine was demonstrated by significantly reduced lameness scores. The results support the common practice of including IA morphine in a multimodal analgesic protocol after arthroscopic surgery, although further studies in clinical cases are needed. The employed CMPS had good reproducibility, and was easy to use, but may have limited sensitivity at mild intensity pain.     

A pilot study of the effects of acupuncture treatment on objective and subjective gait parameters in horses

Objectives

To investigate whether acupuncture can alter gait in horses as assessed by objective and subjective parameters.

Pharmacokinetics of intra‐articular morphine in horses with lipopolysaccharide‐induced synovitis

ObjectiveTo describe the pharmacokinetics of intra-articularly (IA) administered morphine.Study designExperimental randomized, cross-over study.AnimalsEight adult healthy mixed breed horses aged 6.5 ± 2.3 (mean ± SD) years and weighing 535 ± 86 kg.MethodsUnilateral radiocarpal synovitis was induced by IA injection of 3 μg lipopolysaccharide (LPS) on two occasions (right and left radiocarpal joint, respectively) separated by a 3-week wash-out period. Treatments were administered 4 hours post-LPS-injection: Treatment IA; preservative free morphine IA (0.05 mg kg^?1) plus saline intravenous (IV) and treatment IV; saline IA plus preservative free morphine IV (0.05 mg kg^?1). Concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide (M6G) were determined repeatedly in serum and synovial fluid (SF) by high-performance liquid chromatography mass spectrometry, at 2 and 4 hours and then at 4 hours intervals until 28 hours post-treatment.ResultsInjection of LPS elicited a marked and comparable synovitis in all LPS-injected radiocarpal joints. IA administered morphine was detectable in SF of all eight joints 24 hours post-treatment and in 6/8 joints 28 hours post-treatment. The terminal half-life of morphine in SF was estimated to be 2.6 hours. IA administration of morphine resulted in mean serum concentrations of morphine below 5 ng mL^?1 from 2 to 28 hours after treatment.Conclusions and clinical relevanceIntra-articularly administered morphine remained within the joint for at least 24 hours. At the same time only very low serum concentrations of morphine and M6G were detected. The present results suggest that IA morphine at 0.05 mg kg^?1 may be used for IA analgesia lasting at least 24 hours and give strong support to the theory that previously observed analgesic and anti-inflammatory effects of IA morphine in horses are most likely to be mediated peripherally.     

Influence of an n‐3 long‐chain polyunsaturated fatty acid‐enriched diet on experimentally induced synovitis in horses

Dietary n‐3 long‐chain polyunsaturated fatty acid (LCPUFA) supplementation has previously been shown to modify joint‐related inflammation in several species, although information in the horse is lacking. We investigated whether dietary supplementation with n‐3 LCPUFA would modify experimentally induced synovitis in horses. Twelve, skeletally mature, non‐pregnant mares were randomly assigned to either a control diet (CONT) or an n‐3 long‐chain fatty acid‐enriched treatment diet (N3FA) containing 40 g/day of n‐3 LCPUFA for 91 days. Blood samples taken on days 0, 30, 60 and 90, and synovial fluid collected on days 0 and 90 were processed for lipid composition. On day 91, joint inflammation was stimulated using an intra‐articular (IA) injection of 100 ng of recombinant equine IL‐1beta (reIL‐1β). Synovial fluid samples taken at post‐injection hours (PIH) 0, 4, 8 and 24 were analysed for prostaglandin E₂ (PGE₂), matrix metalloproteinase (MMP) activity and routine cytology. Synovium and articular cartilage samples collected at PIH 8 were analysed for gene expression of MMP 1 and MMP 13, interleukin‐1beta (IL‐1β), cyclooxygenase 2 (COX‐2), tumour necrosis factor‐alpha and the aggrecanases, a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)‐4 and ADAMTS‐5. A 90‐day feeding period of n‐3 LCPUFA increased serum phospholipid and synovial fluid lipid compositions of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) compared to CONT horses. The reIL‐1β injection caused an inflammatory response; however, there was no effect of dietary treatment on synovial fluid PGE2 content and MMP activity. Synovial tissue collected from N3FA horses exhibited lower expression of ADAMTS‐4 compared to CONT horses. Despite the presence of EPA and DHA in the synovial fluid of N3FA horses, dietary n‐3 LCPUFA supplementation did not modify synovial fluid biomarkers compared to CONT horses; however, the lower ADAMTS‐4 mRNA expression in N3FA synovium warrants further investigation of n‐3 LCPUFA as a joint therapy.     

Use of a soluble epoxide hydrolase inhibitor as an adjunctive analgesic in a horse with laminitis

HistoryA 4‐year old, 500 kg Thoroughbred female horse diagnosed with bilateral forelimb laminitis and cellulitis on the left forelimb became severely painful and refractory to non‐steroidal anti‐inflammatory therapy (flunixin meglumine on days 1, 2, 3 and 4; and phenylbutazone on days 5, 6 and 7) alone or in combination with gabapentin (days 6 and 7).Physical examinationPain scores assessed independently by three individuals with a visual analog scale (VAS; 0 = no pain and 10 = worst possible pain) were 8.5 on day 6, and it increased to 9.5 on day 7. Non‐invasive blood pressure monitoring revealed severe hypertension.ManagementAs euthanasia was being considered for humane reasons, a decision was made to add an experimental new drug, trans‐4‐{4‐[3‐(4‐Trifluoromethoxy‐phenyl)‐ureido]‐cyclohexyloxy}‐benzoic acid (t‐TUCB), which is a soluble epoxide hydrolase (sEH) inhibitor, to the treatment protocol. Dose and frequency of administration were selected based on the drug potency against equine sEH to produce plasma concentrations within the range of 30 nmol L^?1 and 2.5 μmol L^?1. Pain scores decreased sharply and remarkably following t‐TUCB administration and blood pressure progressively decreased to physiologic normal values. Plasma concentrations of t‐TUCB, measured daily, were within the expected range, whereas phenylbutazone and gabapentin plasma levels were below the suggested efficacious concentrations.Follow upNo adverse effects were detected on clinical and laboratory examinations during and after t‐TUCB administration. No new episodes of laminitis have been noted up to the time of writing (120 days following treatment).ConclusionsInhibition of sEH with t‐TUCB was associated with a significant improvement in pain scores in one horse with laminitis whose pain was refractory to the standard of care therapy. No adverse effects were noticed. Future studies evaluating the analgesic and protective effects of these compounds in painful inflammatory diseases in animals are warranted.     

The use of force plate measurements to titrate the dosage of a new COX‐2 inhibitor in lame horses

Reasons for performing study: Lameness is a highly prevalent condition in horses and the principal cause of removal from athletic activity. In clinical studies to evaluate nonsteroidal anti‐inflammatory drug therapies, force plates are commonly used to assess improvement of lameness objectively. Hypothesis: To use a force plate to determine the optimal dose of a new COX‐2 inhibitor (firocoxib) that will reduce lameness, when administered orally to horses once daily. Methods: Sixty‐four horses that exhibited chronic lameness presumed due to osteoarthritis, including navicular disease, in at least one of the frontlimbs and at a stable level of severity, were included. Horses were treated per os s.i.d. for 7 days as follows: vehicle control, firocoxib at 0.05, 0.1 or 0.25 mg/kg bwt. Force plate analysis of each horse was done for the selected (most) lame frontlimb at trot. Once between Days ?19 and ?4 (initial examination), and again on Day ?2 or ?1 (baseline), pretreatment force plate assessments were performed, and thereafter horses were assessed on Days 0, 2 and 6, approximately 10 h post treatment each time. Peak vertical force (PVF) and lameness grades at initial examination and at baseline, and their change from baseline in the 4 different treatment groups were analysed statistically at a significance level of P<0.05. Results: The PVF results were found to be superior to vehicle control already at Day 0 for 0.25 mg/kg bwt and at Days 2 and 6 for 0.1 and 0.25 mg/kg bwt (P<0.05). Mean clinical lameness for both concentrations decreased >1 grade at Day 6. Conclusions and clinical relevance: With the dosage of 0.25 mg/kg bwt lameness did not improve more than with 0.1 mg/kg bwt. Thus, 0.1 mg/kg bwt s.i.d. was considered to be the effective dose at reducing chronic lameness in horses presumed due to osteoarthritis, including navicular disease.     

In vitro effects and in vivo efficacy of a novel cyclooxygenase-2 inhibitor in dogs with experimentally induced synovitis

OBJECTIVE: To determine cyclooxygenase-2 (COX-2) selectivity, pharmacokinetic properties, and in vivo efficacy of ML-1,785,713 in dogs. ANIMALS: 21 healthy male and female mixed-breed dogs and 24 healthy male Beagles. PROCEDURE: Selectivity of ML-1,785,713 for inhibiting COX-2 was determined by comparing the potency for inhibiting cyclooxygenase-1 (COX-1) with that of COX-2 in canine blood. Pharmacokinetic properties were determined after i.v. (2 mg/kg) and oral (8 mg/kg) administration in female mixed-breed dogs. In vivo efficacy was evaluated in male mixed-breed dogs with urate crystal-induced synovitis. Prophylactic efficacy was evaluated by administering ML-1,785,713 two hours before induction of synovitis whereas therapeutic efficacy was determined by administering ML-1,785,713 one hour after induction of synovitis. RESULTS: Blood concentrations that resulted in 50% inhibition of COX-1 and COX-2 activity in vitro were 119.1 microM and 0.31 microM, respectively, and selectivity ratio for inhibiting COX-2 relative to COX-1 was 384. ML-1,785,713 had high oral bioavailability (101%), low systemic clearance (77 mL/min/kg), and an elimination half-life of 5.9 hours. ML-1,785,713 was efficacious when administered prophylactically and therapeutically to dogs with urate crystal-induced synovitis. CONCLUSIONS AND CLINICAL RELEVANCE: ML-1,785,713 is a novel, potent COX-2 inhibitor that is the most selective COX-2 inhibitor described for use in dogs to date. ML-1,785,713 has oral bioavailability and low systemic clearance that is comparable to other non-steroidal anti-inflammatory drugs. It is effective after prophylactic and therapeutic administration in attenuating lameness in dogs with urate crystal-induced synovitis. Drugs that specifically inhibit COX-2 and not COX-1 at therapeutic doses may have an improved tolerability profile, compared with nonselective non-steroidal anti-inflammatory drugs.     

Evaluation of the diagnostic accuracy of skeletal scintigraphy in lame and poorly performing sports horses

Skeletal scintigraphy is an established imaging modality, however, its validity as a diagnostic test in lame or poorly performing sports horses has not been determined. The objective of this retrospective cross‐sectional analytical study was to determine the accuracy of skeletal scintigraphy as an indiscriminate screening test in sports horses. All sports horses that underwent scintigraphic examination between March 2008 and December 2014 for which a definitive diagnosis was reached were included. Examinations were evaluated blindly. Characteristics of increased radiopharmaceutical uptake were recorded and subjectively categorized as possibly relevant or non‐relevant. Kappa statistics were used to assess agreement between test results and final diagnosis. There were 1222 positive clinical diagnoses in 480 horses, of which 687 regions (56.4%) had no associated increased radiopharmaceutical uptake and 99 regions (8.1%) had non‐relevant increased radiopharmaceutical uptake. The sensitivity of increased radiopharmaceutical uptake for identification of final diagnosis was low (43.8%) and specificity was high (94.0%). The agreement was fair (κ = 0.36). Relevance categorization improved the test; the sensitivity for final diagnosis was low (35.7%), specificity was high (98.9%), and the agreement was moderate (κ = 0.45). The agreements of increased radiopharmaceutical uptake and relevance categorization with final diagnosis were only substantial for feet (κ = 0.67 and κ = 0.66, respectively) and proximal aspect of the forelimb (elbow, shoulder, and scapula combined) (κ = 0.69 and 0.78, respectively). Scintigraphic examination is unlikely to lead to a full and correct diagnosis of the cause(s) of lameness or poor performance in sports horses when used as an isolated or indiscriminate screening tool.     

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.     

Gait abnormalities and ridden horse behaviour in a convenience sample of the United Kingdom ridden sports horse and leisure horse population

The objectives of this study were to compare horses’ gaits in hand and when ridden; to assess static and dynamic saddle fit for each horse and rider; to apply the Ridden Horse Pain Ethogram (RHpE) and relate the findings to gait abnormalities consistent with musculoskeletal pain, rider position and balance and saddle fit; and to document noseband use and its relationship with mouth opening during ridden exercise. Data were acquired prospectively from a convenience sample of horses believed by their owners to be working comfortably. All assessments were subjective. Gait in hand and when ridden were evaluated independently, by two assessors, and compared using McNemar’s test. Static tack fit and noseband type were recorded. Movement of the saddle during ridden exercise, rider position, balance and size relative to the saddle was documented. RHpE scores were based on assessment of video recordings. Multivariable Poisson regression analysis was used to determine factors which influenced the RHpE scores. Of 148 horses, 28.4% were lame in hand, whereas 62.2% were lame ridden (P<0.001). Sixty per cent of horses showed gait abnormalities in canter. The median RHpE score was 8/24 (interquartile range 5, 9; range 0, 15). There was a positive association between lameness and the RHpE score (P<0.001). Riding School horses had higher RHpE scores compared with General Purpose horses (P = 0.001). Saddles with tight tree points (P = 0.001) and riders seated at the back of the saddle rather than the middle (P = 0.001) were associated with higher RHpE scores. Horses wearing crank cavesson compared with cavesson nosebands had higher RHpE scores (P = 0.006). There was no difference in mouth opening, as defined by the RHpE, in horses with a noseband with the potential to restrict mouth opening, compared with a correctly fitted cavesson noseband, or no noseband. It was concluded that lameness or gait abnormalities in canter may be missed unless horses are assessed ridden.     

Pharmacokinetics,metabolism and excretion of celecoxib,a selective cyclooxygenase‐2 inhibitor,in horses

Celecoxib, a nonsteroidal anti‐inflammatory drug, is frequently used to treat arthritis in humans with minimal gastrointestinal side effect compared to traditional NSAIDs. The primary aim of this study was to determine the pharmacokinetic profile of celecoxib—a selective cyclooxygenase‐2 (COX‐2) inhibitor in horses. Six horses were administered a single oral dose of celecoxib at 2 mg/kg (body weight). After oral dosing, the drug reached a maximum concentration (mean ± SD) in blood of 1,088 ± 324 ng/ml in 4.58 hr. The elimination half‐life was 13.60 ± 3.18 hr, and the area under the curve was 24,142 ± 1,096 ng hr ml^?1. The metabolism of celecoxib in horses was via a single oxidative pathway in which the methyl group of celecoxib is oxidized to a hydroxymethyl metabolite and is further oxidized to form a carboxylic acid metabolite. Celecoxib is eliminated mainly through faeces as unchanged drug and as metabolites in urine. Therefore, instructions for a detection time following therapeutic dosing of celecoxib can be set by the racing practitioner and veterinarians to control illegal use in horse racing based on the results of this study.     

Osseous cyst‐like lesions in the feet of lame horses: Diagnosis by standing low‐field magnetic resonance imaging

Osseous cyst‐like lesions (OCLLs) were diagnosed by standing low‐field magnetic resonance (MR) imaging in 9 mature horses (age range 6–17 years). All horses had been subjected to a routine lameness evaluation (including standard foot radiographs) with no diagnosis being reached prior to MR imaging. The duration of lameness ranged from one month to one year. OCLLs were diagnosed in 12 feet. The site of the lesions included the distal phalanx in 11 feet (subchondral bone in 4, insertion of collateral ligaments of the distal interphalangeal joint in 4, insertion of the distal sesamoidean impar ligament in 3) and the subchondral bone of the distal aspect of the middle phalanx in one foot. OCLLs were characterised by discrete spherical or elliptical areas of high or intermediate signal in all MR sequences. In most cases the lesion was surrounded by a rim of bone with abnormally low signal.     

Pharmacokinetics and effects of cetirizine in horses with insect bite hypersensitivity

Horses with insect bite hypersensitivity (IBH) have difficulty in completely avoiding allergens, so effective treatment options are required. A randomised, placebo controlled and double blinded field study was conducted to determine the pharmacokinetics and efficacy in reducing dermatitis of the antihistamine cetirizine given orally at 0.4 mg/kg twice daily for 3 weeks. The influence of protection blankets and stabling were also investigated.The estimated maximum plasma concentration (C_max) and trough plasma concentration of cetirizine were 135 ng/mL and 18 ng/mL, respectively. There was no difference in dermatitis reduction between the treatment and placebo groups (P = 0.77). The findings indicated that cetirizine was of no apparent benefit in treating IBH at the dose rate tested. The use of blankets and stabling were shown to have favourable influence on the dermatitis (P < 0.05) and may be the preferred options to prevent this condition.     

Clinical features and diagnosis of sacroiliac joint region pain in 296 horses: 2004–2014

There has been no large‐scale study of the clinical signs of sacroiliac (SI) joint region pain and its association with lameness and/or thoracolumbar pain. Horses with a positive response to infiltration of local anaesthetic solution around the SI joint regions (SI block) and/or abnormal radiopharmaceutical uptake (RU) in the region of the SI joints were included. History, clinical signs, diagnostic imaging findings, response to SI block, and concurrent lameness and/or thoracolumbar pain were recorded. Horses (n = 296) were divided into 2 groups: SI joint region pain only (Group 1, n = 43) and SI joint region pain and concurrent source(s) of pain (Group 2, n = 253). Clinical signs in Group 1 included increased tension in the longissimus dorsi muscles (40%), restricted flexibility of the thoracolumbar region (44%), trunk stiffness during exercise (61%) and poor hindlimb impulsion (56%). When ridden 65% had a poor contact with the bit, in 81% canter quality was worse than trot, and 35% bucked or kicked out with a hindlimb during canter. In both Groups 1 and 2 clinical signs were seen in a significantly greater proportion of horses during ridden work than lungeing (P<0.0001). Following SI block, 98% of horses showed dramatic improvement in clinical signs, including greater overall movement through the trunk, increased hindlimb impulsion and better quality canter. Abnormal RU in the SI joint regions was seen in 85/180 (47%) horses. Of horses with a positive response to SI block that underwent scintigraphy, only 43% had abnormal RU. Per rectum ultrasonographic examination of the SI joint region revealed abnormalities in 41/129 (32%) horses. Clinical signs of SI joint region pain are worse when horses are ridden. Sacroiliac joint region diagnostic analgesia is a useful, safe but nonspecific block. Ultrasonography and scintigraphy can provide additional information in some horses, but negative results do not preclude SI joint region pain.     

Cardiac troponin I and the occurrence of cardiac arrhythmias in horses with experimentally induced endotoxaemia

Branding is the traditional and well-established method used to mark horses, but recently microchip transponders for implantation have become available. In this study, behaviour, physiological stress variables and skin temperature in foals were determined in response to hot-iron branding (n=7) and microchip implantation (n=7). Salivary cortisol concentrations increased in response to branding (1.8 ± 0.2 ng/mL) and microchip implantation (1.4 ± 0.1ng/mL), but cortisol release over time did not differ. In response to both manipulations there was a transient increase in heart rate (P<0.001) and heart rate variability (P<0.01). Branding and microchip implantation induced a comparable aversive behaviour (branding, score 3.86 ± 0.85; microchip, score 4.00 ± 0.82). Both techniques thus caused similar physiological and behavioural changes indicative of stress. Acutely, implantation of a microchip was as stressful as branding in foals. Branding caused a necrotising skin burn lasting at least 7 days. Moreover branding, but not microchip implantation (P<0.001), was accompanied by a generalized increase in skin temperature which was comparable to low degree post-burn hypermetabolism in humans.