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.     

Pharmacokinetics and antinociceptive effects of the soluble epoxide hydrolase inhibitor t‐TUCB in horses with experimentally induced radiocarpal synovitis

This study determined the pharmacokinetics, antinociceptive, and anti‐inflammatory effects of the soluble epoxide hydrolase (sEH ) inhibitor t ‐TUCB (trans ‐4‐{4‐[3‐(4‐Trifluoromethoxy‐phenyl)‐ureido]‐cyclohexyloxy}‐benzoic acid) in horses with lipopolysaccharide (LPS )‐induced radiocarpal synovitis. A total of seven adult healthy mares (n  = 4–6/treatment) were administered 3 μg LPS into one radiocarpal joint and t ‐TUCB intravenously (i.v.) at 0 (control), 0.03, 0.1, 0.3, and 1 mg/kg in a blinded, randomized, crossover design with at least 3 weeks washout between. Two investigators independently assigned pain scores (at rest, walk and trot) and lameness scores before and up to 48 hr after t ‐TUCB /LPS . Responses to touching the joint skin to assess tactile allodynia, plasma, and synovial fluid (SF ) t ‐TUCB concentrations were determined before and up to 48 hr after t ‐TUCB /LPS . Blood and SF were collected for clinical laboratory evaluations before and up to 48 hr after t ‐TUCB /LPS . Areas under the curves of pain and lameness scores were calculated and compared between control and treatments. Data were analyzed using repeated measures ANOVA with Dunnett or Bonferroni post‐test. p  < .05 was considered significant. Data are mean ± SEM . Compared to control, pain, lameness, and tactile allodynia were significantly lower with 1 mg/kg t ‐TUCB , but not the other doses. For 0.1, 0.3, and 1 mg/kg t ‐TUCB treatments, plasma terminal half‐lives were 13 ± 3, 13 ± 0.5, and 24 ± 5 hr, and clearances were 68 ± 15, 48 ± 5, and 14 ± 1 ml hr^?1 kg^?1. The 1 mg/kg t ‐TUCB reached the SF at high concentrations. There were no important anti‐inflammatory effects. In conclusion, sEH inhibition with t ‐TUCB may provide analgesia in horses with inflammatory joint pain.     

Intra‐articular opioid analgesia is effective in reducing pain and inflammation in an equine LPS induced synovitis model

Reasons for performing study: Intra‐articular administration of morphine as a local analgesic and anti‐inflammatory drug is widely used in human medicine. In equids, little is known about its clinical analgesic and anti‐inflammatory efficacy. Objectives: To use an inflammatory orthopaedic pain model to investigate the analgesic and anti‐inflammatory effects of intra‐articularly administered morphine as a new treatment modality in horses with acute arthritis. Methods: In a crossover study design, synovitis was induced in the left or right talocrural joint by means of intra‐articular injection of 0.5 ng lipopolyssacharide (LPS). The effect of 120 mg morphine, intra‐articularly administered at 1 h after induction of synovitis, was evaluated using both physiological and behavioural pain variables. Synovial fluid was sampled at 0, 4, 8, 28 and 52 h after induction of synovitis and analysed for total protein concentration, leucocyte count and for prostaglandin E₂, bradykinin and substance P concentrations by ELISA. Ranges of motion of metatarsophalangeal and talocrural joints were measured as kinematic variables with the horses walking and trotting on a treadmill under sound and lame conditions. Clinical lameness scores and several behavioural variables related to the perception of pain were obtained. Results: LPS injection caused marked transient synovitis, resulting in increased concentrations of inflammatory synovial fluid markers, clinical lameness, joint effusion and several behavioural changes, such as increased time spent recumbent, decreased limb loading at rest and decreased time spent eating silage. Intra‐articular morphine resulted in a significant decrease in synovial white blood cell count, prostaglandin E₂ and bradykinin levels and improvement in clinical lameness, kinematic and behavioural parameters, compared to placebo treatment. Conclusions: Intra‐articular morphine offers potent analgesic and anti‐inflammatory effects in horses suffering from acute synovitis. Potential relevance: Local administration of opioids may be useful for horses with acute inflammatory joint pain and offers possibilities for multimodal analgesic therapies without opioid‐related systemic side effects.     

Clearance of corticosteroids following intra‐articular administration of clinical doses to racehorses

Over the last few years there has been a nationwide cooperative effort to establish threshold concentrations and withdrawal time guidelines for corticosteroid use in racehorses. As dosing regimens are specific to individual horses and highly variable, it is not possible to establish regulatory guidelines for every dosing scenario and therefore they are often based on single dose administration studies. The goal of the study described here was to assess the applicability of current regulatory recommendations for intra‐articular corticosteroids based on clinical protocols used by practitioners. A total of 58 Thoroughbred and 82 Quarter Horse racehorses received varying doses of triamcinolone acetonide, methylprednisolone acetate, isoflupredone or betamethasone intra‐articularly in various joints by the treating practitioner. Blood samples were collected at 0, 7, 10, 14, 21, 28 and 35 days post drug administration and serum samples analysed by liquid chromatography mass spectrometry for quantitation of drug concentrations. Serum elimination varied depending upon the dose and the number and specific joints treated. Serum concentrations fell below the ARCI threshold guidance by Day 7 (100 pg/ml) for both triamcinolone acetonide (2–40 mg dose) and isoflupredone acetate (4–30 mg dose) and Day 21 (100 pg/ml) for methylprednisolone acetate (20–600 mg dose). Betamethasone fell below the regulatory threshold (10 pg/ml) by 7 days for all Quarter Horses and for 7/10 Thoroughbreds studied. Drug concentrations were below the regulatory threshold by Day 10 in the remaining 3 horses receiving betamethasone.     

Comparison of cervical epidural morphine with intravenous morphine administration on antinociception in adult horses using thermal threshold testing

ObjectiveTo compare the antinociceptive effects of morphine administered via cervical epidural catheter to intravenously administered morphine using a thermal threshold (TT) testing model in healthy adult horses.Study designProspective, randomized, blinded experimental study.AnimalsA total of six university-owned adult horses.MethodsHorses were instrumented with a cervical (C1–C2) epidural catheter and TT testing device with probes at withers and thoracic limb coronary bands. All horses underwent three TT testing cycles including cervical epidural morphine administration (treatment EpiM; 0.1 mg kg^–1), systemic morphine administration (treatment SystM; 0.1 mg kg^–1) and no morphine administration (treatment Control). Baseline TT was established prior to treatments, and TT was tested at 15, 30, 60, 90, 120, 150, 180, 240, 300, 360, 420, 480, 600 and 720 minutes following treatment. Horses underwent a 5 day washout period between treatments and the order of treatment was randomized. Differences between treatments were analyzed with repeated measures anova.ResultsSystemic and epidural morphine administration resulted in significantly higher TT values compared with baseline and control treatment. The duration of effect was significantly longer in treatment EpiM (10–12 hours) than in treatment SystM (1.5–2.0 hours). Horses in treatment EpiM had significantly higher TT values at time points 180–600 minutes (withers) and 300–600 minutes (coronary band) than horses in treatment SystM.Conclusions and clinical relevanceCervical epidural administration of morphine provided antinociceptive effects as measured by increased TT for 10–12 hours compared with 1.5–2.0 hours for intravenously administered morphine. No complications or adverse effects were noticed following epidural placement of a C1–C2 catheter and administration of morphine. The use of a cervical epidural catheter can be considered for analgesia administration in treatment of thoracic limb and cervical pain in the horse.     

Analgesic and gastrointestinal effects of epidural morphine in horses after laparoscopic cryptorchidectomy under general anesthesia

ObjectiveTo evaluate the hypothesis that epidural morphine (0.1 mg kg^?1) decreases pain in horses after laparoscopic surgery without adversely affecting gastrointestinal (GI) motility.Study designRandomized clinical trial.AnimalsEighteen horses undergoing laparoscopic cryptorchidectomy under general anesthesia.MethodsHorses were randomly assigned to receive either epidural morphine (0.1 mg kg^?1) or no epidural before the start of surgery. Pain behaviors were assessed during the first two post-operative days using a numerical rating scale. Barium-filled spheres were administered through a nasogastric tube before anesthesia. GI motility was assessed by recording manure production, by quantitating the spheres in the manure, and by abdominal auscultation of intestinal sounds. Heart rates and cortisol concentrations were also measured during the post-operative period.ResultsPain scores increased for 12 hours after surgery in the control group and were significantly higher than in the morphine group for the first 6 hours. Pain scores remained unaltered in the morphine group throughout the observation period. Heart rate and plasma cortisol concentrations did not differ between groups or with time. No signs of colic were observed in any horse.Conclusion and clinical relevanceEpidural morphine (0.1 mg kg^?1) did not adversely affect GI motility in horses after laparoscopic surgery under general anesthesia.     

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.     

Severe supracondylar lysis of the third metatarsal bone due to intra‐articular haemorrhage with similarities to human pigmented villonodular synovitis: A differential diagnosis to intra‐articular neoplasia

This report describes a case of severe supracondylar lysis of the third metatarsal bone of a mature Cob gelding. The gelding presented with moderate to severe lameness and soft tissue swelling in the distal metatarsal region. A mass was present plantar to the third metatarsal bone and dorsal to the suspensory ligament branches. The mass was removed surgically, and was found to be a large blood coagulum within an enlargement of the plantar pouch of the metatarsophalangeal joint. The mass was pedunculated and attached to a region of abnormal synovium. This synovium was identified histologically as being an area of villonodular synovitis. The lesion had similarities with human pigmented villonodular synovitis. Removal of the abnormal tissue resulted in resolution of the lameness and of the lysis of the third metatarsal bone. Haemarthrosis should be considered in the list of differential diagnoses for focally mineralised soft tissue masses found within an articulation, and may be associated with pigmented villonodular synovitis.     

Efficacy of orally administered gabapentin in horses with chronic thoracic limb lameness

ObjectiveTo evaluate the analgesic effects of orally administered gabapentin on horses with chronic thoracic limb lameness.Study designRandomized, crossover design.AnimalsA total of 14 adult horses with chronic thoracic limb lameness.MethodsFollowing baseline measurement of lameness, horses were administered each of four treatments orally in grain: treatment G, gabapentin (20 mg kg^–1) twice daily for 13 doses; treatment F, firocoxib (171 mg once, then 57 mg once daily for six doses); treatment GF, gabapentin and firocoxib at previously stated doses and frequencies; or treatment C, grain only as a control. Treatments were administered in a randomized, crossover design, separated by 2 weeks. Subjective lameness score (SLS), inertial sensor vector sum (VS) calculations, peak vertical ground reaction force (PVGRF) measurements and vertical impulse (VI) calculations were determined immediately prior to each initial treatment dose and 2–4 hours after the final treatment dose for each treatment. Mean change in SLS, VS, PVGRF and VI for each treatment were compared among treatments.ResultsThe rank change in SLS of treatment GF was significantly greater than that of treatments C (p = 0.01) and G (p = 0.01) but not of treatment F (p = 0.08). No differences in VS (p = 0.4), PVGRF (p = 0.4) or VI (p = 0.1) were observed among treatments.Conclusions and clinical relevanceGabapentin, as administered here, did not improve subjective or objective measures of lameness in horses with chronic thoracic limb musculoskeletal pain. Although subjective evaluation identified an improvement in lameness with treatment GF, it was not different from that observed with treatment F. Higher oral dosing and longer treatment regimens of gabapentin may be indicated for the treatment of chronic musculoskeletal pain in horses.     

Intra‐abdominal hypertension in horses

Intra‐abdominal hypertension (IAH) may lead to a multiple organ dysfunction syndrome associated with significant dysfunction of the cardiovascular, respiratory, renal, gastrointestinal and central nervous systems of human patients. A recent prospective multicentre epidemiological investigation in man concluded that IAH was associated with an increased risk of mortality in critically ill patients. In this review, we present current information pertaining to the potential clinical importance of IAH in the context of equine clinical practice. In conclusion, consideration of intra‐abdominal pressure should be a part of the clinical assessment of patient well‐being in critically ill equine patients.     

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.

Risk of intra‐articular injection with longitudinal ultrasound‐guided injection of collateral ligaments of the equine distal interphalangeal joint

Desmopathy of the collateral ligaments of the distal interphalangeal joint is a common cause of equine foot lameness and carries a poor prognosis with conservative management. Intralesional injections may improve healing, although accuracy of radiographically guided injections is significantly less than when guided by MRI, which requires special needles. Longitudinal ultrasound‐guided injection of the distal collateral ligament has not been evaluated objectively. In this prospective, anatomic study, seven equine cadaver limbs (14 collateral ligaments) were injected with methylene blue dye and radiographic contrast medium using ultrasound to guide the needle longitudinally into the collateral ligaments until contacting bone. The insertion site of the needle proximal to the coronary band was measured on the limb and the needles left in place for radiography and CT to evaluate the needle angulation, location of the contrast medium, and whether the contrast entered the distal interphalangeal joint. The limbs were frozen and sectioned with a band saw to identify the location of the dye. Fifty percentage of injections were in or around the collateral ligaments. However, the percentage of “successful” injections, defined as in the collateral ligament but not in the joint, was only 36%. All legs had dye and contrast in the joint after both ligaments had been injected. There were no significant differences between the needle angle and entry site for “successful” and “unsuccessful” injections. Findings from this study indicates that the success rate is low for injecting the distal portions of the distal interphalangeal joint collateral ligaments using ultrasound guidance alone.     

Comparison of direct and indirect methods of intra‐abdominal pressure measurement in normal horses

Objectives – To develop a direct method for measuring intra‐abdominal pressures in the standing horse, identify a reference interval for direct intra‐abdominal pressures, compare these pressures to indirect intra‐abdominal pressures measured from the bladder, and determine the optimal bladder infusion volume for indirect pressure measurement. Design – Prospective, experimental study. Setting – A university‐based equine research facility. Animals – Ten healthy adult horses, 5 males and 5 females. Interventions – Direct intra‐abdominal pressures were measured through an intraperitoneal cannula and zeroed at the height midway between the height of the tuber ishii and point of the shoulder. Indirect measurements of intra‐abdominal pressure were performed by measuring intravesicular pressures through a transurethral catheter zeroed at the tuber ishii. Measurements and Main Results – Direct pressure measurements obtained in the standing horse were subatmospheric (mean, ?1.80 cm H₂O; SD, 1.61 cm H₂O; 95% CI, ?2.80 to ?0.80) and were shown to decrease as the horse's weight increased (Pearson's r=?0.67, P=0.04), with no effect of head position (P=0.15). Mean baseline indirect pressure measurements (mean, ?8.63 cm H₂O; SD, 4.37 cm H₂O; 95% CI, ?13.05 to ?4.21) were significantly different from the pressures measured directly from the abdomen (P<0.001). Indirect pressure measurements were noted to increase with increasing volumes infused into the bladder, and were statistically different at a volume of 100 mL (P=0.004). There was low to moderate correlation between direct and indirect pressure measurements of intra‐abdominal pressure over a range of fluid volumes infused into the bladder (Pearson's correlation range ?0.38 to 0.58). Conclusion – Pressures measured directly in the standing horse were subatmospheric, and increased as the horse's weight increased. Indirect pressures measured were altered by increasing volumes infused in the bladder. There was no significant correlation between the 2 methods of intra‐abdominal pressure measurement.     

Endocrine evaluation after an intra‐articular therapeutic dosage of dexamethasone in horses

This study investigated whether a single intra‐articular administration (IA) of dexamethasone (DEX) in horses at therapeutic dosage could exert a systemic effect by influencing the hypothalamic‐pituitary‐adrenal axis activity as a consequence of (limited) absorption and systemic distribution. The results indicated that DEX was detectable in urine collected 12–48 h after IA administration and that injection was accompanied by a reduced urine excretion of cortisol, 6β‐hydroxycortisol (6βOHF) and two other metabolites of cortisol lasting up to 48 h post‐DEX administration. The systemic effects in horses treated with DEX by IA route are similar to those that typically occur with short‐term treatment including the reduction in urinary cortisol concentration.