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

Casper Lindegaard

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

Abstract

Optimal smertebehandling af dyr der udsættes for forskellige smertefulde procedurer er yderst vigtigt pga. dyrevelfærdsmæssige årsager såvel som mulighed for forbedret rekonvalescens og forbedret endeligt resultat. Forbedret smertebehandling hos heste kan blandt andet opnås gennem "balanceret smertebehandling". Dette koncept er baseret på at anvende en kombination af flere forskellige smertestillende stoffer som hver især virker på forskellige niveauer af smertesignalets vej til hjernen. Denne kombination af forskellige typer analgetika giver en additiv, og i nogle tilfælde også synergistisk effekt. Dette medfører at dosen af hvert enkelt analgetikum kan reduceres, hvilket fører til at mængden af bivirkninger reduceres.

Intraartikulært (IA) administreret morfin har vist sig at virke smertestillende i op til 24 timer efter artroskopisk kirurgi hos mennesker. Derudover er det vist at IA morfin også besidder betydelige antiinflammatoriske egenskaber i mennesker og forsøgsdyr. Intraartikulært administreret morfin anvendes derfor som en del af en balanceret smertebehandlingsprotokol efter artroskopisk kirurgi, eller ved andre smertefulde ledlidelser hos mennesker.

For nylig har opdagelsen af opioid receptorer i ledkapslen hos heste ført til en forventning om lignende egenskaber af IA morfin hos heste. På trods af at der indtil videre ikke er udført nogen forskning på området, er intraartikulær injektion af morfin blevet fast procedure efter artroskopisk kirurgi på adskillige veterinær-universiteter i Europa og USA.

Formålet med denne afhandling var at undersøge den smertestillende og antiinflammatoriske effekt, samt farmakokinetikken af IA morfin hos heste med ledinflammation. For at undersøge dette blev der udført et forsøg med lipopolysaccharid-induceret synovitis hos 8 heste. Studiet blev udført som et randomiseret, blændet, double dummy forsøg med sekventielt cross-over design. Alle heste modtog 2 behandlinger: "IA morfin" som bestod af morfin 0,05 mg/kg IA + fysiologisk saltvand IV og "IV morfin" som bestod af morfin 0,05 mg/kg IV + fysiologisk saltvand IA. De to behandlinger blev givet i tilfældig rækkefølge med en 3 ugers restitutions periode ind imellem. Før administration af forsøgsbehandlingerne blev der ved IA injektion af lipopolysaccharid (LPS), induceret synovitis i et radiocarpalled. I hver af de to 7-dages forsøgsperioder blev forskellige lokale og systemiske inflammations- og smerteparametre målt. Derudover blev der fortaget farmakologiske undersøgelser på blod og ledvæske. Smerte blev vurderet vha. halthed samt smerte vurderet på subjektiv smerteskala (Visuel analog skala, VAS) og en adfærdsbaseret smerteskala (Composite Measure Pain Scale, CMPS).

Hos alle heste inducerede de intraartikulære LPS injektioner led-inflammation (synovitis) og deraf følgende smerte og halthed.

Morfin injiceret IA havde en signifikant smertestillende effekt, målt ved signifikant reduceret halthed, lavere forbrug af rescue analgesi samt lavere smertescorer. Den anvendte CMPS smerteskala viste god overensstemmelse mellem observatørerne og det forslås at den kan anvendes til vurdering af ortopædisk smerte hos heste.

Derudover sås en signifikant antiinflammatorisk effekt, som kom til udtryk ved reduceret ledhævelse, reduceret indhold af SAA og protein i ledvæsken samt reduceret SAA i blodet. Den antiinflammatoriske effekt syntes mest udtalt sent i den inflammatoriske proces.

Ved analyser for morfin og de to metabolitter morfin-3- og morfin-6-glucuronid (hhv. M3G og M6G) fandtes morfin i ledvæsken fra alle 8 heste 24 timer efter den intraartikulære injektion. Samtidig var serum koncentrationerne af morfin og den aktive metabolit M6G under klinisk relevante niveauer fra 2 timer efter behandlingen og frem. Derudover blev det vist at farmakokinetikken af IA morfin hos heste er sammenlignelig med det som er observeret hos mennesker.

Da behandling med morfin IA resulterede i mindre smerte og inflammation end behandling med samme dosis morfin givet systemisk indikerer dette, sammen med resultaterne af de farmakologiske undersøgelser, at effekten af IA morfin er medieret perifert.

Originalsprog	Engelsk

Forlag	Department of Large Animal Sciences, University of Copenhagen
Antal sider	140
ISBN (Trykt)	078-87-7611-303-2
Status	Udgivet - 2009

Citationsformater

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title = "Intra-articular morphine in horses: clinical properties in lipopolysaccharide-induced synovitis",

abstract = "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.",

author = "Casper Lindegaard",

year = "2009",

language = "English",

isbn = "078-87-7611-303-2",

publisher = "Department of Large Animal Sciences, University of Copenhagen",

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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 -

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

Abstract

Fingeraftryk

Citationsformater