Intra-articular morphine in horses: clinical properties in lipopolysaccharide-induced synovitis

TY - BOOK

T1 - Intra-articular morphine in horses

T2 - clinical properties in lipopolysaccharide-induced synovitis

AU - Lindegaard, Casper

PY - 2009

Y1 - 2009

N2 - Regardless of species, optimal pain management of animals subjected to various painful procedures is of outmost importance for several reasons, including animal welfare considerations, improved convalescence and improved final outcome. One way of improving pain management in horses is through the principles embodied in "multimodal analgesia". This concept is based on combining various analgesic drugs acting at different levels in the nociceptive pathway, thereby achieving additive and in some situations even synergistic effects of the administered drugs. Consequently, the dose of each drug can be reduced, eventually leading to reduced occurrence of side-effects. Intra-articular (IA) morphine has been shown to provide potent analgesia lasting up to 24 hours after arthroscopic surgery in humans. Furthermore, IA morphine has been shown to possess significant anti-inflammatory properties in humans and laboratory animals. Recent discovery of opioid receptors in the synovial membrane of horses has made it reasonable to expect IA morphine to be analgesic in horses too. Treatment with IA morphine after arthroscopic surgery, or for other painful joint diseases, might therefore be an important contribution to a multimodal analgesia protocol. Despite that no research has investigated this issue in horses so far, IA injection of morphine after arthroscopic surgery has become common practice in several veterinary university teaching hospitals in Europe and USA. The aims of this thesis were to investigate the analgesic and anti-inflammatory effects, including pharmacokinetics, of IA morphine under inflammatory joint conditions in horses.To pursue potential answers for these issues, the effects of IA morphine were studied in an experiment including 8 horses. The study was carried out as a randomized, observer blinded, double dummy trial with sequential cross-over design. Each horse received two treatments; Treatment "IA morphine" consisting of morphine 0.05 mg/kg IA + saline intra-venous (IV) and treatment "IV morphine" consisting of morphine 0.05 mg/kg IV + saline IA. The two treatments were given in randomized order separated by a three week washout period. Before each treatment, radiocarpal synovitis was induced by IA injection of lipopolysaccharide (LPS). For each of the two 168-hours study periods, local and systemic measures of pain and inflammation as well as blood and synovial fluid (SF) samples for pharmacological analysis were obtained repeatedly. Pain was evaluated by degree of lameness as well as using a visual analogue scale of pain intensity (VAS) and a composite measure pain scale (CMPS), developed for this purpose. Intra-articular injection of LPS elicited a marked synovitis resulting in lameness and pain. Intra-articularly administered morphine showed a significant analgesic effect as measured by reduced lameness scores, less administered rescue analgesia and lower pain scores. A significant anti-inflammatory effect was demonstrated by reduced joint swelling, reduced SF serum amyloid A (SAA) and protein contents as well as reduced serum SAA. The anti-inflammatory effect was more pronounced late in the course of the inflammatory reaction. Analysis of concentrations of morphine and the two major metabolites, morphine-3- and morphine-6-glucuronide (M3G and M6G, respectively) in blood and SF after IA treatment showed that morphine could be detected in the SF 24 hours after administration in all horses, whereas serum concentrations of morphine and the analgesically active metabolite M6G, remained below clinically relevant concentrations from 2 hours after administration. Furthermore, it appeared that morphine pharmacokinetics in horses were similar to those reported in man. The developed CMPS showed good inter-observer agreement and it is suggested that this pain-scale can be employed for evaluation of orthopaedic pain in equine patients.A good analgesic and anti-inflammatory effect of IA morphine compared to the same dose administered IV, was demonstrated. In combination with the results of the pharmacologic analysis, this is highly suggestive of a peripherally mediated effect of IA morphine.

AB - Regardless of species, optimal pain management of animals subjected to various painful procedures is of outmost importance for several reasons, including animal welfare considerations, improved convalescence and improved final outcome. One way of improving pain management in horses is through the principles embodied in "multimodal analgesia". This concept is based on combining various analgesic drugs acting at different levels in the nociceptive pathway, thereby achieving additive and in some situations even synergistic effects of the administered drugs. Consequently, the dose of each drug can be reduced, eventually leading to reduced occurrence of side-effects. Intra-articular (IA) morphine has been shown to provide potent analgesia lasting up to 24 hours after arthroscopic surgery in humans. Furthermore, IA morphine has been shown to possess significant anti-inflammatory properties in humans and laboratory animals. Recent discovery of opioid receptors in the synovial membrane of horses has made it reasonable to expect IA morphine to be analgesic in horses too. Treatment with IA morphine after arthroscopic surgery, or for other painful joint diseases, might therefore be an important contribution to a multimodal analgesia protocol. Despite that no research has investigated this issue in horses so far, IA injection of morphine after arthroscopic surgery has become common practice in several veterinary university teaching hospitals in Europe and USA. The aims of this thesis were to investigate the analgesic and anti-inflammatory effects, including pharmacokinetics, of IA morphine under inflammatory joint conditions in horses.To pursue potential answers for these issues, the effects of IA morphine were studied in an experiment including 8 horses. The study was carried out as a randomized, observer blinded, double dummy trial with sequential cross-over design. Each horse received two treatments; Treatment "IA morphine" consisting of morphine 0.05 mg/kg IA + saline intra-venous (IV) and treatment "IV morphine" consisting of morphine 0.05 mg/kg IV + saline IA. The two treatments were given in randomized order separated by a three week washout period. Before each treatment, radiocarpal synovitis was induced by IA injection of lipopolysaccharide (LPS). For each of the two 168-hours study periods, local and systemic measures of pain and inflammation as well as blood and synovial fluid (SF) samples for pharmacological analysis were obtained repeatedly. Pain was evaluated by degree of lameness as well as using a visual analogue scale of pain intensity (VAS) and a composite measure pain scale (CMPS), developed for this purpose. Intra-articular injection of LPS elicited a marked synovitis resulting in lameness and pain. Intra-articularly administered morphine showed a significant analgesic effect as measured by reduced lameness scores, less administered rescue analgesia and lower pain scores. A significant anti-inflammatory effect was demonstrated by reduced joint swelling, reduced SF serum amyloid A (SAA) and protein contents as well as reduced serum SAA. The anti-inflammatory effect was more pronounced late in the course of the inflammatory reaction. Analysis of concentrations of morphine and the two major metabolites, morphine-3- and morphine-6-glucuronide (M3G and M6G, respectively) in blood and SF after IA treatment showed that morphine could be detected in the SF 24 hours after administration in all horses, whereas serum concentrations of morphine and the analgesically active metabolite M6G, remained below clinically relevant concentrations from 2 hours after administration. Furthermore, it appeared that morphine pharmacokinetics in horses were similar to those reported in man. The developed CMPS showed good inter-observer agreement and it is suggested that this pain-scale can be employed for evaluation of orthopaedic pain in equine patients.A good analgesic and anti-inflammatory effect of IA morphine compared to the same dose administered IV, was demonstrated. In combination with the results of the pharmacologic analysis, this is highly suggestive of a peripherally mediated effect of IA morphine.

M3 - Ph.D. thesis

SN - 078-87-7611-303-2

BT - Intra-articular morphine in horses

PB - Department of Large Animal Sciences, University of Copenhagen

ER -