The use of analgesia in exotic pet medicine remains in its infancy, due to minimal pharmacokinetic studies and a lack of understanding in identifying signs of pain. The majority of analgesia administered to exotic pets in the UK is done so through off-licence use of medications through the prescribing cascade. Veterinary surgeons must provide analgesia to any species showing signs of pain but many may be unsure of the options available to them.
Many of our small mammals are prey species and therefore mask signs of pain in order to avoid predation. Recent research has developed a number of “grimace scales” for rabbits (Keating et al., 2012), mice (Langford et al., 2010) and rats (Sotocinal et al., 2011) in order to identify signs of pain. Whilst these are currently unavailable for other species, signs of pain are presumed to be similar, generally including hunched posture, abdominal pressing, vocalisation and reluctance to move (Allweiler, 2016) and defensive or guarding behaviours (Figure 1). Some patients are reluctant to show these behaviours when observed, with guinea pigs more demonstrative of pain when observed remotely rather than directly (Ellen et al., 2016).
Meloxicam and carprofen seem to be the most studied of all NSAIDs (Flecknell, 2018); however, vast differences in dose rates do occur. Higher dose rates of meloxicam have been reported as beneficial in mice (Wright-Williams et al., 2007) compared to rats (Ogino et al., 1997). Meloxicam is widely used in practice, as injectable and oral forms are easily sourced and titrated based on species, and currently meloxicam for cats is licensed for use in guinea pigs in the UK. It is important to consider the gastrointestinal comparative anatomy between different small mammal species, as hindgut fermenters such as rabbits and guinea pigs vastly differ in drug absorption compared with omnivorous rodents or carnivorous mustelids. Dosing of NSAIDs should always be based on the most up-to-date scientific data for the species in question.
Buprenorphine is the most commonly used opioid analgesic in rodents (Stokes et al., 2009). It is a partial mu agonist and is widely thought of as sufficient for normal levels of post-operative pain (Flecknell, 2018). Pure mu agonists such as morphine and methadone can be considered in situations where increased intra- and post-operative pain is expected; however, their duration of action is shorter than that of buprenorphine (Gades et al., 2000). Some concern has surrounded the use of opioids and their tendency to cause ileus in hindgut fermenters, but in clinical practice this is rare (Flecknell, 2018) and it is more likely that the lack of provision of adequate analgesia is responsible for any post-operative ileus observed.
Tramadol is a weak opioid with good oral bioavailability (Flecknell, 2018). Pharmacokinetics of tramadol have been studied in rabbits (Souza et al., 2008), rats (Taylor et al., 2016) and mice (Wolfe et al., 2015) with varying levels of efficacy and so more proven analgesics should be considered prior to, or in combination with, tramadol.
Local anaesthetics are an excellent component of multimodal analgesia, especially when used for peri- and post-operative pain. They are often overlooked due to the relatively small doses required; however, dose rates and toxic doses are similar to those of our other companion species (Flecknell, 2018). Volumes can be diluted with water for injection and administered either by infiltration, splash blocks, topical cream formulations, nerve blocks or epidural injections.
Pain in birds can be difficult to identify, but as knowledge of bird behaviour increases, so does our understanding of their response to pain. Both reductions and severe increases in preening behaviours to the point of feather destructive behaviours (Figure 2) can be indications of pain (Hawking and Paul-Murphy, 2011), as can isolation from a flock, lethargy, hyporexia and aggression (Lierz and Korbel, 2012).
A study of intramuscular and oral administration of meloxicam following orthopaedic procedures in pigeons showed doses of 0.5mg/kg provided ineffective analgesia, but doses of 2mg/kg resulted in greater degrees of weightbearing on the affected limb (Desmarchelier et al., 2012). Evidence of pain following experimentally induced arthritis in Hispaniolan parrots was greatly reduced by administration of intramuscular meloxicam at 1mg/kg, compared to doses of 0.5mg/kg and below (Cole et al., 2009). Both these studies indicate that avian patients require far higher doses of meloxicam compared to their mammalian counterparts.
Opioids are useful for moderate to severe pain in birds. There are considerable species differences in distribution of opioid receptors, and due to an early study in pigeons showing 76 percent of receptors in the forebrain were kappa receptors (Reiner et al., 1989), it was assumed that butorphanol was the opioid of choice for avian patients. Recently, studies in American kestrels have shown an increased thermal withdrawal threshold (TWT) after administration of intramuscular buprenorphine (Ceulemans et al., 2014; Guzman et al., 2018), indicating its efficacy in falcons. However, a similar study failed to show any change in TWT after intramuscular administration of buprenorphine in cockatiels (Guzman et al., 2018). A study comparing intramuscular buprenorphine and butorphanol in African grey parrots showed that buprenorphine had no significant effect on withdrawal from a noxious stimulus, but butorphanol did increase TWT. This indicates buprenorphine is not useful for psittacine species, whereas butorphanol remains an appropriate analgesic. Similar studies evaluating the efficacy of intramuscular hydromorphone in orange-winged Amazon parrots (Guzman et al., 2017) and cockatiels (Houck et al., 2018) showed an increased TWT in orange-winged Amazons, however no change in TWT in cockatiels.
Local anaesthetics in birds appear to require much higher dose rates (Hocking et al., 1997). Given the lack of research and the concern for toxicities, they are seldom used (Lierz and Korbel, 2012).
There is a misconception that reptiles do not feel as much pain as their mammalian and avian counterparts, as their signs of pain are far more subtle. Debate centres around whether reptiles feel pain or merely react to noxious stimuli (Perry and Nevarez, 2018); however, we should assume an animal can feel pain until proven otherwise and treat as such. Pain assessment should be carried out at a distance if possible, as green iguanas have been shown to reveal a greater response to painful stimuli when the observer is not visible (Fleming and Robertson, 2012). Signs of pain should be considered similar to those of mammalian patients, such as hunched posture, guarding of the affected area, excessive scratching, foot or tail flicking, exaggerated flight response or poor appetite (Mosley, 2011), as well as specific behaviours such as withdrawing into their shell in chelonians (Figure 3).
The body temperature of a reptile plays an important role in drug absorption, as does anatomic variations between species (Mosley, 2011). Reptiles should always be at their preferred optimum temperature zone when drugs are administered to ensure maximal absorption. It is recommended that drug administration into the caudal body of reptiles is avoided, as concerns have been raised due to renal first-pass effects and potential nephrotoxicity. Whilst this is not consistent between species (Holz et al., 1997), it is best to avoid administration of potentially nephrotoxic drugs, such as NSAIDs, into the tail and hindlimbs of reptiles.
Pharmacokinetic data for NSAIDs in reptiles is poor and their efficacy has not been proven despite multiple studies (Perry and Nevarez, 2018). Non-selective COX inhibitors have been advocated as a study of eastern box turtles demonstrated COX-1 and COX-2 proteins are expressed within the turtle tissues (Royal et al., 2012).
Butorphanol has been shown to have little or no effect in red-eared sliders (Sladky et al., 2007), bearded dragons and corn snakes (Sladky et al., 2008), but these same studies demonstrated antinociceptive effects of morphine in red-eared sliders and bearded dragons. Buprenorphine has been shown to not be efficacious in green iguanas (Greenacre et al., 2006) and red-eared sliders (Mans et al., 2012). However, the study by Mans et al. showed that hydromorphone was efficacious, indicating that pure mu receptor agonists should be used for analgesia in reptiles.
Tramadol has been shown to increase TWT when administered orally and subcutaneously in red-eared sliders (Baker et al., 2011) and intramuscularly in yellow-bellied sliders (Giorgi et al., 2015), indicating it is useful for analgesia and likely a good choice for outpatient analgesia for long-term patients such as those suffering thermal burns.
Use of local anaesthesia is in its early stages in reptile medicine but is being used in clinical practice with success. Intrathecal lignocaine, bupivacaine and morphine have been shown to successfully block motor function of the cloacal sphincter and hindlimbs as well as provide analgesia to the hindlimbs for up to 48 hours (Mans et al., 2011). Toxicity can be avoided by following the known toxic doses of local anaesthetics in mammals (Mosley, 2011).