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Analgesia in Small Exotic Mammals: A Review
IN SMALL ANIMAL MEDICINE AND SURGERY
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Analgesia in Small Exotic Mammals: A Review SAMANTHA SWISHER, DVM ANGELA LENNOX, DVM, DABVP-AVIAN, EXOTIC COMPANION MAMMALS; ECZM-SMALL MAMMAL AVIAN & EXOTIC ANIMAL CLINIC OF INDIANAPOLIS 9330 WALDEMAR RD, INDIANAPOLIS, IN 46268 The benefits of analgesia in veterinary patients are well understood and described. Provision of effective analgesia improves recovery times from surgical procedures, reduces the risk of pain-induced anorexia and digestive tract stasis, and is essential for patient welfare and owner satisfaction. In the past, many clinicians avoided the use of analgesic drugs in exotic animals due to concerns about patient safety, many of which proved unfounded or have been resolved with the advent of safer drug protocols. However, recent research has underlined the importance of developing species-specific, evidence-based analgesic protocols, as the pharmacokinetics and pharmacodynamics of many common drugs vary substantially among species. ASSESSING PAIN IN SMALL MAMMALS There have been tremendous advances in the assessment of pain in companion animals in recent years. However, identifying pain in exotics species presents some unique challenges: 1. Most exotic small mammals are prey species and have not been domesticated for as long as dogs and cats, so they have a tendency to mask signs of pain when an observer is present. This has been repeatedly documented in the laboratory animal literature. Signs of pain are much more apparent when animals are monitored by video camera or telemetry than when an experimenter is in the room.
2. There is significant variability in the behavioral repertoire of different species of exotic companion mammals. Identifying changes in behavior suggestive of pain requires that the observer first have a good understanding of normal behavior and that algorithms for pain scoring need to be species-specific.
“Analgesic protocols should be based on species-specific pharmacokinetic and pharmacodynamic studies whenever possible.” There are some general strategies that apply across many species for identifying pain. Painful animals tend to be less active and display a decrease in normal activities, such as eating, grooming, and nesting behaviors. If the animal is litter-box-trained, they may be too painful to move to the box and may urinate where they are sitting. Many species will adopt a hunched posture or display tooth grinding. Painful animals tend to be less interactive with their environment, and their eyes may have a glazed appearance. Behavior changes are most likely to be apparent in animals that are in a familiar, secure environment and are not aware that they are being observed. Some of these changes can also be associated with sedation from analgesic therapy, and this distinction can sometimes be difficult to make. Physiologic parameters, such as elevated heart rate and respiratory rate, may be helpful, but these can also be affected by stress.
OPIOIDS Opioids are an essential component of anesthesia and post-operative analgesia for small mammals, especially those that are not good candidates for non-steroidal anti-inflammatory drugs (NSAID) administration. Historically, some clinicians have hesitated to use opioids in small herbivores due to concerns about their effects on gastrointestinal (GI) motility. However, recent studies indicate that the effects of opioids (especially partial mu agonists like buprenorphine) are minimal.1 Given the known detrimental effects of pain on GI motility, the benefits of appropriate opioid administration likely outweigh the risks. Pharmacokinetic data is not available for most opioids in most species. Pharmacokinetic and pharmacodynamic studies of buprenorphine in rodents (rats,2,3 mice,4 guinea pigs5) suggest that these species may require much higher doses/kg bodyweight than dogs and cats
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in order to achieve plasma concentrations associated with analgesia in humans. A recent study demonstrated that fentanyl administered as a continuous rate infusion could reduce minimum alveolar concentration (MAC) by up to 63% without adverse effects, though dosage recommendations were not provided.6 While the use of hydromorphone and oxymorphone has become increasingly common in exotic mammal practice, there are no pharmacokinetic or pharmacodynamics studies available for either of these drugs in exotic mammals. In the authors’ experience, these drugs are well-tolerated at doses similar to or slightly higher than the doses recommended for dogs and cats. In dogs and cats, the kappa-agonist butorphanol is known to provide weaker analgesia than mu agonists. This is assumed to be true for small mammals as well, but it has not been investigated. NSAIDS A variety of NSAIDs have been investigated for use in small mammals, including carprofen, ketoprofen, meloxicam, and tepoxalin. However, the most commonly used NSAID in clinical exotics practice is meloxicam. Recent pharmacokinetic and pharmacodynamics studies have indicated that small mammals may require much higher doses of meloxicam/kg of bodyweight than their canine and feline counterparts. Pharmacokinetic studies in rabbits indicate that a dose of 1 mg/kg is required to achieve plasma levels of meloxicam that provide analgesia in
other species.7 Pharmacodynamic studies in rats support doses of 1 to 2 mg/kg.2 Unfortunately, information about the safety of such high doses of meloxicam is limited to a handful of short-term studies conducted primarily on young, healthy animals. LOCAL ANESTHESIA As in other species, local anesthesia can be a valuable addition to analgesic protocols for small mammal surgeries. Several recent papers have described the use of femoral and sciatic nerve blocks for hind limb surgeries in rabbits8 and guinea pigs.9 Additionally, the use of lidocaine as a continuous rate infusion for MAC reduction was described in rabbits.10 OTHER DRUGS Most studies of the use of tramadol for analgesia in small mammals have been disappointing. Even at a relatively high dose (11 mg/kg), one study failed to find adequate plasma concentrations of tramadol or o-desmethyltramadol in rabbits.11 A companion study investigating the pharmacodynamics of tramadol (4.4 mg/kg, IV) in rabbits failed to find a clinically significant effect on MAC.12 Another study comparing buprenorphine and tramadol in rats found tramadol to be inadequate to control incisional pain.3 The authors have used gabapentin in small mammals without adverse effects, but pharmacokinetic and pharmacodynamic data are lacking for exotic species.
CONCLUSIONS 1. Analgesics are recommended for small exotic mammals in the same situations for which they are indicated in dogs and cats. 2. While dosages for many drugs are often extrapolated from other species, analgesic protocols should be based on species-specific pharmacokinetic and pharmacodynamic studies whenever possible, as dramatic species variation in drug metabolism may exist. REFERENCES 1. Deflers H, Bolen G, Gandar F, et al. Influence of buprenorphine on the European rabbit (Oryctolagus cuniculus) gastrointestinal motility. Presented at the First International Conference on Avian, Reptile, and Exotic Medicine, Wiesbaden, Germany, April 23, 2013. 2. Bourque SL, Adams MA, Nakatsu K, et al. Comparison of buprenorphine and meloxicam for post-surgical analgesia in rats: effects on body weight, locomotor activity. J Am Assoc Lab Anim Sci 2010;49:617-622. 3. McKeon GP, Pacharinsak C, Long CT, et al. Analgesic effects of tramadol, tramadolgabapentin, and buprenorphine in an incisional block model of pain in rats (Rattus norvegicus). J Am Assoc Lab Anim Sci 2011;50:192-197. 4. Healy JR, Tonkins JL, Kamarec SR, et al. Evaluation of an improved sustainedrelease buprenorphine formulation for use in mice. Am J Vet Res 2013;75:619-625. 5. Sadar MJ, Knych H, Drazenovich T, et al. Pharmacokinetics of buprenorphine in the guinea pig (Cavia porcellus): intravenous and oral transmucosal administration. Proceedings of the Association of
A D V A N C E S
Exotic Mammal Veterinarians Conference, Orlando, FL, October 19-24, 2014. 6. Barter LS, Hawkins MG, Pypendop BH. Effects of fentanyl on isoflurane minimum alveolar concentration in New Zealand White rabbits (Oryctolagus cuniculus). Am J Vet Res 2015;76:111-115. 7. Fredholm DV, Carpenter JW, KuKanich B, et al. Pharmacokinetics of meloxicam in rabbits after oral administration of single and multiple doses. Am J Vet Res 2013;74:636-641. 8. d’Ovidio D, Rota S, Noviello E, et al. Nerve stimulator-guided sciatic-femoral block in pet rabbits (Oryctolagus cuniculus) undergoing hind limb surgery: a case series. J Exotic Pet Med 2014;23:91-95. 9. Aguiar J, Mogridge G, Hall J. Femoral fracture repair and sciatic and femoral nerve blocks in a guinea pig. J Small Anim Pract 2014;55:635-639. 10. Schnellbacher RW, Carpenter JW, Mason DE, et al. Effects of lidocaine administration via continuous rate infusion on the minimum alveolar concentration of isoflurane in New Zealand White rabbits (Oryctolagus cuniculus). Am J Vet Res 2013;74:13771384. 11. Souza MJ, Greenacre CB, Cox SK. Pharmacokinetics of orally administered tramadol in domestic rabbits. Am J Vet Res 2008;69:979-982. 12. Egger CM, Souza MJ, Greenacre CB, et al. Effect of intravenous administration of tramadol hydrochloride on the minimum alveolar concentration of isoflurane in rabbits. Am J Vet Res 2009;945-949.
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777!$6!.#%3).3-!,,!.)-!,#/-
6/,5-% )335% s ./6%-"%2
Analgesia in Small Exotic Mammals: A Review SAMANTHA SWISHER, DVM ANGELA LENNOX, DVM, DABVP-AVIAN, EXOTIC COMPANION MAMMALS; ECZM-SMALL MAMMAL AVIAN & EXOTIC ANIMAL CLINIC OF INDIANAPOLIS 9330 WALDEMAR RD, INDIANAPOLIS, IN 46268 The benefits of analgesia in veterinary patients are well understood and described. Provision of effective analgesia improves recovery times from surgical procedures, reduces the risk of pain-induced anorexia and digestive tract stasis, and is essential for patient welfare and owner satisfaction. In the past, many clinicians avoided the use of analgesic drugs in exotic animals due to concerns about patient safety, many of which proved unfounded or have been resolved with the advent of safer drug protocols. However, recent research has underlined the importance of developing species-specific, evidence-based analgesic protocols, as the pharmacokinetics and pharmacodynamics of many common drugs vary substantially among species. ASSESSING PAIN IN SMALL MAMMALS There have been tremendous advances in the assessment of pain in companion animals in recent years. However, identifying pain in exotics species presents some unique challenges: 1. Most exotic small mammals are prey species and have not been domesticated for as long as dogs and cats, so they have a tendency to mask signs of pain when an observer is present. This has been repeatedly documented in the laboratory animal literature. Signs of pain are much more apparent when animals are monitored by video camera or telemetry than when an experimenter is in the room.
2. There is significant variability in the behavioral repertoire of different species of exotic companion mammals. Identifying changes in behavior suggestive of pain requires that the observer first have a good understanding of normal behavior and that algorithms for pain scoring need to be species-specific.
“Analgesic protocols should be based on species-specific pharmacokinetic and pharmacodynamic studies whenever possible.” There are some general strategies that apply across many species for identifying pain. Painful animals tend to be less active and display a decrease in normal activities, such as eating, grooming, and nesting behaviors. If the animal is litter-box-trained, they may be too painful to move to the box and may urinate where they are sitting. Many species will adopt a hunched posture or display tooth grinding. Painful animals tend to be less interactive with their environment, and their eyes may have a glazed appearance. Behavior changes are most likely to be apparent in animals that are in a familiar, secure environment and are not aware that they are being observed. Some of these changes can also be associated with sedation from analgesic therapy, and this distinction can sometimes be difficult to make. Physiologic parameters, such as elevated heart rate and respiratory rate, may be helpful, but these can also be affected by stress.
OPIOIDS Opioids are an essential component of anesthesia and post-operative analgesia for small mammals, especially those that are not good candidates for non-steroidal anti-inflammatory drugs (NSAID) administration. Historically, some clinicians have hesitated to use opioids in small herbivores due to concerns about their effects on gastrointestinal (GI) motility. However, recent studies indicate that the effects of opioids (especially partial mu agonists like buprenorphine) are minimal.1 Given the known detrimental effects of pain on GI motility, the benefits of appropriate opioid administration likely outweigh the risks. Pharmacokinetic data is not available for most opioids in most species. Pharmacokinetic and pharmacodynamic studies of buprenorphine in rodents (rats,2,3 mice,4 guinea pigs5) suggest that these species may require much higher doses/kg bodyweight than dogs and cats
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A D V A N C E S
in order to achieve plasma concentrations associated with analgesia in humans. A recent study demonstrated that fentanyl administered as a continuous rate infusion could reduce minimum alveolar concentration (MAC) by up to 63% without adverse effects, though dosage recommendations were not provided.6 While the use of hydromorphone and oxymorphone has become increasingly common in exotic mammal practice, there are no pharmacokinetic or pharmacodynamics studies available for either of these drugs in exotic mammals. In the authors’ experience, these drugs are well-tolerated at doses similar to or slightly higher than the doses recommended for dogs and cats. In dogs and cats, the kappa-agonist butorphanol is known to provide weaker analgesia than mu agonists. This is assumed to be true for small mammals as well, but it has not been investigated. NSAIDS A variety of NSAIDs have been investigated for use in small mammals, including carprofen, ketoprofen, meloxicam, and tepoxalin. However, the most commonly used NSAID in clinical exotics practice is meloxicam. Recent pharmacokinetic and pharmacodynamics studies have indicated that small mammals may require much higher doses of meloxicam/kg of bodyweight than their canine and feline counterparts. Pharmacokinetic studies in rabbits indicate that a dose of 1 mg/kg is required to achieve plasma levels of meloxicam that provide analgesia in
other species.7 Pharmacodynamic studies in rats support doses of 1 to 2 mg/kg.2 Unfortunately, information about the safety of such high doses of meloxicam is limited to a handful of short-term studies conducted primarily on young, healthy animals. LOCAL ANESTHESIA As in other species, local anesthesia can be a valuable addition to analgesic protocols for small mammal surgeries. Several recent papers have described the use of femoral and sciatic nerve blocks for hind limb surgeries in rabbits8 and guinea pigs.9 Additionally, the use of lidocaine as a continuous rate infusion for MAC reduction was described in rabbits.10 OTHER DRUGS Most studies of the use of tramadol for analgesia in small mammals have been disappointing. Even at a relatively high dose (11 mg/kg), one study failed to find adequate plasma concentrations of tramadol or o-desmethyltramadol in rabbits.11 A companion study investigating the pharmacodynamics of tramadol (4.4 mg/kg, IV) in rabbits failed to find a clinically significant effect on MAC.12 Another study comparing buprenorphine and tramadol in rats found tramadol to be inadequate to control incisional pain.3 The authors have used gabapentin in small mammals without adverse effects, but pharmacokinetic and pharmacodynamic data are lacking for exotic species.
CONCLUSIONS 1. Analgesics are recommended for small exotic mammals in the same situations for which they are indicated in dogs and cats. 2. While dosages for many drugs are often extrapolated from other species, analgesic protocols should be based on species-specific pharmacokinetic and pharmacodynamic studies whenever possible, as dramatic species variation in drug metabolism may exist. REFERENCES 1. Deflers H, Bolen G, Gandar F, et al. Influence of buprenorphine on the European rabbit (Oryctolagus cuniculus) gastrointestinal motility. Presented at the First International Conference on Avian, Reptile, and Exotic Medicine, Wiesbaden, Germany, April 23, 2013. 2. Bourque SL, Adams MA, Nakatsu K, et al. Comparison of buprenorphine and meloxicam for post-surgical analgesia in rats: effects on body weight, locomotor activity. J Am Assoc Lab Anim Sci 2010;49:617-622. 3. McKeon GP, Pacharinsak C, Long CT, et al. Analgesic effects of tramadol, tramadolgabapentin, and buprenorphine in an incisional block model of pain in rats (Rattus norvegicus). J Am Assoc Lab Anim Sci 2011;50:192-197. 4. Healy JR, Tonkins JL, Kamarec SR, et al. Evaluation of an improved sustainedrelease buprenorphine formulation for use in mice. Am J Vet Res 2013;75:619-625. 5. Sadar MJ, Knych H, Drazenovich T, et al. Pharmacokinetics of buprenorphine in the guinea pig (Cavia porcellus): intravenous and oral transmucosal administration. Proceedings of the Association of
A D V A N C E S
Exotic Mammal Veterinarians Conference, Orlando, FL, October 19-24, 2014. 6. Barter LS, Hawkins MG, Pypendop BH. Effects of fentanyl on isoflurane minimum alveolar concentration in New Zealand White rabbits (Oryctolagus cuniculus). Am J Vet Res 2015;76:111-115. 7. Fredholm DV, Carpenter JW, KuKanich B, et al. Pharmacokinetics of meloxicam in rabbits after oral administration of single and multiple doses. Am J Vet Res 2013;74:636-641. 8. d’Ovidio D, Rota S, Noviello E, et al. Nerve stimulator-guided sciatic-femoral block in pet rabbits (Oryctolagus cuniculus) undergoing hind limb surgery: a case series. J Exotic Pet Med 2014;23:91-95. 9. Aguiar J, Mogridge G, Hall J. Femoral fracture repair and sciatic and femoral nerve blocks in a guinea pig. J Small Anim Pract 2014;55:635-639. 10. Schnellbacher RW, Carpenter JW, Mason DE, et al. Effects of lidocaine administration via continuous rate infusion on the minimum alveolar concentration of isoflurane in New Zealand White rabbits (Oryctolagus cuniculus). Am J Vet Res 2013;74:13771384. 11. Souza MJ, Greenacre CB, Cox SK. Pharmacokinetics of orally administered tramadol in domestic rabbits. Am J Vet Res 2008;69:979-982. 12. Egger CM, Souza MJ, Greenacre CB, et al. Effect of intravenous administration of tramadol hydrochloride on the minimum alveolar concentration of isoflurane in rabbits. Am J Vet Res 2009;945-949.
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