Vet Times The website for the veterinary profession https://www.vettimes.co.uk Pharmacokinetics of meloxicam in rabbit, bird and reptile species Author : Elisabetta Mancinelli Categories : Exotics, Vets Date : April 25, 2016 WSAVA has developed global guidelines on the recognition, assessment and management of pain in companion animals (www.wsava.org). Image: Fotolia/NiDerLander. Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage (IASP, 2015). It is generally accepted any procedure or disease likely to cause pain in human beings, should be expected to cause pain in an animal (Kohn et al, 2007; Lichtenberger and Ko, 2007). Pain can delay healing, lower immune responses and increase morbidity and mortality (Barter, 2011). Appropriate analgesia is, therefore, expected to allow a more rapid return to a normal behaviour in mammals (Hardie et al, 1997). An optimal pain management plan involves the use of multiple drugs, acting at different levels of the pain pathway (multimodal analgesia), so smaller doses of each drug can be used, thereby enhancing pain relief and reducing the likelihood of side effects (Lichtenberger and Ko, 2007; Fisher, 2010). The aim is to improve patient comfort, but also to prevent undesirable effects, such as activation of 1 / 7
the sympathetic nervous system, complement cascade, cytokine systems, and arachidonic acid cascade (Barter, 2011), which may result in a variety of pathological outcomes, including tachycardia, hypertension, reduced renal perfusion, hyperglycaemia, altered cardiac output, increase myocardial oxygen demand, altered physiological and endocrinological function, immune system suppression, and pathological lesions. Any attempt, therefore, must be made to reduce pain and stress, including provision of adequate pain relief at appropriate times (pre-emptive analgesia may help reduce pain and postoperative stress; Page et al, 1998). Selection of the appropriate analgesic protocol should include knowledge of pain physiology and the pharmacokinetic properties of that specific drug in a particular species (Kohn et al, 2007; Lichtenberger and Ko, 2007). Therefore, difficulties arise when pharmacokinetic studies for the use of different pain killers in selected species are not known and dosages and/or protocols are extrapolated from one species to another without much consideration for speciesspecific anatomic, physiological and behavioural differences. The major classes of analgesic drugs used for management of acute and chronic pain in exotic animal practice include opioids, NSAIDs and local anaesthetics. Among these, NSAIDs are probably the most commonly prescribed veterinary analgesics. NSAIDs act both centrally and peripherally to block nociception and decrease inflammation, thereby limiting the information directed to the CNS. They exert their therapeutic effect by inhibition of cyclooxygenase (COX) enzymes, which block the conversion of arachidonic acid to pro-inflammatory prostaglandin mediators (Hawkins, 2006). They are generally used to prevent and alleviate acute postoperative and traumatic pain. The main concerns are related to the inhibition of prostaglandins synthesis, which may lead to side effects, such as impaired renal function, gastrointestinal erosions and bleeding disorders (Lichtenberger and Lennox, 2009). The main advantages of using these drugs are their prolonged duration of action and the fact they are not controlled drugs (Lichtenberger and Ko, 2007). Meloxicam has certainly become one of the most commonly used NSAIDs in companion exotic animal medicine. Because of its greater COX-2 selective activity, it may be associated with decreased side effects (for example, inhibition of platelet function, gastrointestinal ulceration and renal function impairment; Jones and Budsberg, 2000). This article aims to review the latest data on meloxicam in selected exotic species. Rabbits Many authors recommend the use of meloxicam in stable normovolaemic animals post-surgery, when they start eating and in the presence of normal renal values, in view of possible intraoperative risks of bleeding and hypotension (Lichtenberger and Ko, 2007). Several studies have been performed to evaluate efficacy, analgesic effects, safety and side effects of meloxicam administered to rabbits at different dosages and via various routes (Turner et al, 2006a and 2006b; 2 / 7
Karachalios et al, 2007; Leach et al, 2009; Carpenter et al, 2009; Cooper et al, 2009; Fredholm et al, 2013; Goldschlager et al, 2013; Eshar and Weese, 2014; Delk et al, 2014; Mehraj Khan and Rampal, 2014). Rabbits seem to be able to metabolise meloxicam faster than dogs, humans and rats. The drug appears to be clinically safe in rabbits when used at appropriate dosages, but dosages as high as 1mg/kg may be necessary to achieve a clinically effective concentration in this species. Significant alteration of the hard faecal microbiota did not appear to be a considerable adverse effect in rabbits treated for 21 days with oral meloxicam at a dose of 1mg/kg (Eshar and Weese, 2014). In one study, 1mg/kg followed by 0.5mg/kg was not sufficient to completely control pain after ovariohysterectomy (Leach et al, 2009). Therefore, multimodal analgesia should be considered for the relief of pain associated with this surgery. Avian The pharmacokinetic properties of meloxicam have been evaluated in several avian species, including chickens, ostriches, ducks, turkeys, pigeons (Baert and De Backer, 2003), vultures (Naidoo et al, 2008), ring-necked parakeets (Wilson et al, 2004), Hispaniolan Amazon parrots (Amazona ventralis; Molter et al, 2013), African grey parrots (Psittacus erithacus erithacus; Montesinos et al, 2011), red-tailed hawks (Buteo jamaicensis), and great-horned owls (Bubo virginianus; Lacasse et al, 2013). Cole et al (2009) concluded meloxicam at a dosage of 1mg/kg IM every 12 hours significantly improved weight bearing in Hispaniolan Amazon parrots with experimentally induced arthritis, but a dosage of 0.5mg/kg every 12 hours did not. Other authors focused their research on the adverse effects meloxicam may have on the renal, gastrointestinal, or haemostatic systems in certain avian species (Pereira and Werther, 2007; Montesinos et al, 2009; Desmarchelier et al, 2012; Dijkstra et al, 2015). These studies suggest, despite the fact meloxicam is generally considered a drug with a large therapeutic range and relative safety, compared with other NSAIDs, species-specific dosage, efficacy and potential adverse effects need to be taken into consideration. The simple extrapolation of a dose from one species to another should be done with extreme caution. Therefore, if meloxicam administered at a dose of 1.6mg/kg PO every 12 hours for 15 days has been found to be therapeutic on the basis of pharmacodynamic and pharmacokinetic data available in healthy Hispaniolan Amazon parrots, without resulting in clinical evident adverse effects, the same may not be true for other avian species or unhealthy individuals. Therefore, assessment of specific organ function may be required in some cases to ascertain suitability of meloxicam use for individual patients. Reptiles 3 / 7
NSAIDs are also used widely in reptile clinical practice for their analgesic and anti-inflammatory properties; however, only a few pharmacokinetic studies have been published concerning reptile species. Further studies would, therefore, be necessary to evaluate a degree of efficacy and side effects that may vary with the type of NSAIDs selected and the species they are administered. One study evaluated the analgesic efficacy of meloxicam in ball pythons administered at a dose of 0.3mg/kg IM before surgical placement of an arterial catheter showing no physiologic changes (for example, heart rate, blood pressure, plasma epinephrine, and cortisol) indicative of analgesia (Olesen et al, 2008). Another study determined plasma concentrations of meloxicam administered at 0.2mg/kg PO as a single dose to green iguanas were at levels considered analgesic in mammals, and these levels were measurable up to 24 hours after administration, suggesting some effect in this species (Divers et al, 2010). A dose of 0.4mg/kg IM increased the tolerance to an electric stimulus applied to bearded dragons (Greenacre et al, 2008). Pharmacokinetics have also been evaluated in red ear sliders (Trachemys scripta elegans; Rojo-Solis et al, 2009) and yellow-bellied slider turtles (Trachemys scripta scripta; Di Salvo et al, 2015). In this last study, mean blood concentration of meloxicam was above that considered to be effective to induce an anti-inflammatory effect in the horse only when the drug was administered intracoelomically (IC) and IM, but not PO. The data potentially suggests IC and IM administrations as suitable routes for treatment in the turtle. Conversely, the very low plasma concentrations obtained after PO administration could render this route of administration not applicable for turtle treatments. However, the effective therapeutic concentration of meloxicam in turtles is still not known, and further studies are needed to suggest an appropriate dose and administration interval. Clauss et al (2007) and Lai et al (2015) investigated the pharmacokinetics of meloxicam after one dose by IV administration and after parenteral (IV, IM) administration, respectively, to loggerhead sea turtles (Caretta caretta). The latter study found it unlikely meloxicam at 0.1mg/kg is an appropriate choice, particularly in longterm pain management protocols in this species. Unfortunately, the lack of efficacy studies and the few pharmacokinetic investigations published so far with respect to NSAID administration in reptile species, appropriate dosages and frequency of administration can only be extrapolated. However, clinicians aware of the deleterious side effects documented in other species, such as avian and mammalian species (for example, renal impairment, gastrointestinal ulceration/inflammation, haematologic abnormalities), should use these drugs with extreme caution in reptiles too. Due to the complex topic please refer to the literature provided for more in depth 4 / 7
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