Intra-articular opioid analgesia is effective in reducing pain and inflammation in an equine LPS induced synovitis model J. P. A. M. VAN LOON*, J. C. DE GRAUW, M. VAN DIERENDONCK † , J. J. L’AMI, W. BACK and P. R. VAN WEEREN Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University; and † Equus Research, Stroe, The Netherlands. Keywords: horse; analgesia; morphine; intra-articular; inflammatory; behaviour Summary 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. Introduction In the last decade, an increase in interest in local analgesic procedures in equine veterinary medicine has evolved (Robinson and Natalini 2002; Muir 2005). Although the clinical use of intra- articularly (IA) administered local anaesthetic solutions and steroidal anti-inflammatory drugs is widespread in horses (Schumacher et al. 2003; Kristiansen and Kold 2007), the IA administration of opioids has not received much attention in the equine species. There is abundant scientific and clinical evidence for the analgesic and anti-inflammatory properties of IA administered opioids in man, both in acute and chronic joint pain (Likar et al. 1997; Gupta et al. 2001; Kalso et al. 2002). In dogs, IA morphine has been described to produce effective analgesia following arthrotomy (Day et al. 1995; Sammarco et al. 1996). In horses, however, literature on IA use of morphine is very limited. Sheehy et al. (2001) showed synovial membranes of horses to contain mu-opioid receptors and Raekallio et al. (1996) described disposition and local effects of IA morphine in normal ponies. In a recent study, Santos et al. (2009) investigated the effects of IA ropivacaine and morphine on lipopolysaccharide (LPS)-induced synovitis in horses by means of subjective pain scales only. To completely understand the mechanism of action of new treatments for joint disorders, not only functional effects (quality of locomotion) but also physiological effects at tissue level and effects on pain perception should be evaluated comprehensively and quantitatively. Several studies have evaluated orthopaedic pain in horses (Price et al. 2003; Bussieres et al. 2008) and various approaches to the assessment of pain have been used, but composite evaluation of pain related parameters, including both behavioural and physiological elements, has produced the most accurate and reliable results so far (Raekallio et al. 1997). Because orthopaedic pain resulting from synovitis is mostly accompanied by a certain level of lameness in horses (Caron 2003), lameness evaluation needs to be incorporated when assessing acute orthopaedic pain in horses. Objective lameness evaluation can be performed by means of kinetic and kinematic gait analysis (Khumsap et al. 2003; Ishihara et al. 2009). At the physiological level, inflammatory synovial fluid markers, such as substance P, prostaglandin E2 (PGE2) and bradykinin, have been related to inflammatory pain in horses, dogs and man (Suzuki et al. 2003; Trumble et al. 2004; de Grauw et al. 2006). Further evaluation of *Corresponding author. Email: j.p.a.m.vanloon@uu.nl [Paper received for publication 16.07.09; Accepted: 15.09.09] © 2010 EVJ Ltd 412 EQUINE VETERINARY JOURNAL Equine vet. J. (2010) 42 (5) 412-419 doi: 10.1111/j.2042-3306.2010.00077.x