Pain is considered to have two components: physical discomfort caused by injury or disease and emotional suffering. Are animals capable of feeling emotional pain? This has been difficult to prove scientifically as only humans and nonhuman primates have a neocortex, the so-called “thinking” area of the brain.Most studies of pain in animals examine their responses to nociceptive stimuli, but does that also indicate an emotional component? For this reason, some scientists and veterinarians prefer to use the terms nociception and anti-nociception in reference to pain in animals, other than nonhuman primates.
Determining if a drug provides analgesia
Pharmacokinetic (PK) studies can be performed, which indicate the changes in a drug’s plasma concentration over time in a particular species. These types of studies can also examine the effect of different routes of administration on plasma concentrations.
Pharmacodynamic studies measure the effect produced by the drug using various methods, including surgical pain models, thermal pain models, weight-bearing studies, and MAC (minimum anesthetic concentration, minimum alveolar concentration) reduction studies. Analgesic efficacy of NSAIDs is difficult to determine as these drugs are highly protein-bound, tend to accumulate in areas of inflammation, and may have a longer duration of analgesic effect than predicted from plasma levels alone. Finally, there is significant species variability (even within different avian orders), and it may not be wise to extrapolate doses from other species.
Veterinarians should exercise caution with extrapolation of these published studies to their clinical patients, as these studies are often performed on young, healthy animals, and the drugs evaluated may have different effects on painful and/or ill animals.
Rabbit analgesia
How can you tell if a rabbit is painful?
As rabbits are prey animals, they hide signs of pain and discomfort more than a predator species, such as a domestic dog. The initial evaluation of pain should be made before any physical contact or restraint of the patient, and ideally, when the patient cannot see the observer. In addition, a rabbit’s behavior will also be altered by the sight and smell of predators. All these items are almost impossible to limit/control in the veterinary practice environment; however, a clinician should be aware of these factors and attempt to limit them as much as possible.
Body position and posture should be evaluated—painful rabbits may have a contracted abdomen and/or a hunched posture (Figure 1). Tooth grinding is an inconsistent sign of pain in rabbits in the author’s experience.
More objective evaluations of pain in rabbits have been developed recently, including several published pain scales.1 The rabbit grimace scale is one of the most used.2 This scale evaluates five facial action units: orbital tightening, check flattening, nostril shape, whisker shape and position, and ear shape and position.
A numerical value can be assigned to a patient based on a published scale and monitored over time both pre-and post-analgesia administration.
Opioids
As with other mammals, the use of opioids, such as hydromorphone, are indicated in rabbits for painful procedures and conditions, such as laparotomies. There are limited studies evaluating clinically appropriate pharmacokinetics and analgesic properties of hydromorphone in rabbits. The recommended dose is 0.1-0.4 mg/kg every four to six hours, and this can be administered by IV, SC, and IM.3
Buprenorphine is the most used opioid in rabbits, and the recommended dosage range is wide (0.03-0.1 mg/kg every four to six, IV, SC, or IM).3 Interestingly, the bioavailability of subcutaneous buprenorphine is approximately 50 percent compared with the intramuscular route, indicating this may be a more appropriate route of administration in this species.4
In addition, the duration of action of buprenorphine (0.05 mg/kg SC) was found to be shorter than expected, with plasma concentrations remaining above those considered analgesic in other species for only four hours.
Oral transmucosal buprenorphine has also been evaluated in rabbits at a dosage of 0.15 mg/kg every eight hours—unfortunately, this route required a large volume (and thus large expense) and achieved lower plasma concentrations compared with parenteral routes.3 Therefore, oral transmucosal route for buprenorphine is not recommended in this species.
Sustained-release analgesics are becoming more popular in veterinary medicine as they significantly reduce frequency of analgesic administration. In the case of long-acting opioids, an effective sustained-release formulation also could shorten post-operative hospitalization times.
A study evaluated the safety and clinical effectiveness of a compounded sustained-release formulation of buprenorphine (1 mg/mL) for post-operative analgesia in New Zealand white rabbits.5 The rabbits received either regular buprenorphine (0.02 mg/kg SC every 12 hours for three days) or a single dose of SR buprenorphine (0.12 mg/kg SC). They found it to be equally effective as regular buprenorphine, and no adverse effects were noted. It is important to note the dose of regular buprenorphine was likely not adequate as several rabbits exhibited signs of severe pain just before the next dose was due.
NSAIDs
Meloxicam is the most commonly used analgesic for rabbits in the author’s practice, and there have been several PK and safety studies evaluating its use in this species.
Initial PK studies found a single (1 mg/kg PO) and multiple doses (1 mg/kg PO every 24 hours for five days) achieved adequate plasma concentrations in rabbits that provided analgesia in other species—no significant bloodwork changes were noted in any animal in that study.6
A subsequent study also found similar plasma concentrations when meloxicam was administered at 1 mg/kg PO every 24 hours for 29 days—no bloodwork or necropsy changes were noted at the end of that study in any animal.⁷
Continuous rate infusions (CRIs)
Inhalant anesthetics are commonly used in rabbits due to ease of administration (mask/chamber induction), and rapid recovery. However, rabbits are profoundly sensitive to the negative cardiovascular effects of inhalant anesthetics, and they experience more severe hypotension than other mammals. Therefore, the addition of pre-medications or continuous rate infusions are often utilized to reduce the total amount of inhalant anesthetics administered to the rabbit patient.
A study examining the effects of a lidocaine CRI on the minimum alveolar concentration (MAC) of isoflurane in rabbits found lidocaine, both at 50 μg/kg/min and 100 μg/kg/min reduced MAC by 11 and 22 percent, respectively.⁸
A lidocaine CRI (100 μg/kg/min) has also been compared to buprenorphine (0.06 mg/kg SC every eight hours) for post-ovariohysterectomy analgesia in rabbits.⁹ In that study, a lidocaine CRI provided a superior outcome in respect to fecal output, appetite, and lower cortisone and glucose levels.
Lidocaine CRIs are now commonly used for not only post-operative analgesia in rabbits, but also for treatment of other painful conditions, such as rabbit gastrointestinal syndrome (RGIS) also known as gastrointestinal stasis.
Gabapentin
Gabapentin is an effective analgesic in other species, specifically for neuropathic and chronic pain. A dosage of gabapentin at 25 mg/kg SC did reach plasma concentrations that provide analgesia in humans.10
The PK of a single oral dose of gabapentin have recently been evaluated—those authors found 25 mg/kg and 50 mg/kg doses reached similar plasma concentrations and no adverse effects were noted.11 Those same authors evaluated the use of gabapentin at 25 mg/kg PO as an anxietolytic in rabbits.12 The results suggested that gabapentin did decrease reactivity without significant effect on physiologic parameters such as heart rate, respiratory rate, and rectal temperature.
Effects on GI motility
Many clinicians are concerned about administration of opioids causing ileus in hind-gut fermenting mammals, such as rabbits, especially those patients already diagnosed with RGIS (ileus).
Experimentally, both mu and kappa agonists can inhibit motility in the isolated rabbit intestine (in vitro). High doses of mu opioids in vitro and in vivo have led to ileus in rabbits. However, these doses are typically experimental and much higher than doses used for clinical analgesia.
There is conflicting published evidence of whether or not buprenorphine causes ileus in rabbits—one study showed the drug increased pyloric and duodenal contractions13 while others have shown it decreases fecal output compared with control rabbits.14,15 While it is true all opioids have the potential to cause ileus in rabbits and other species, acute and chronic pain can have significant negative impacts on gastrointestinal motility.
Rodent analgesia
How can you tell if a rodent is painful?
Clinical signs of pain in rodents are similar to rabbits and include a hunched posture, lack of or increased grooming, and decreased activity levels. There are also several studies showing the presence of an observer may alter the behavior of rodents, and thus compound the ability to accurately take behavioral assessments of these prey species.
Grimace scales in the rat and mouse have also been developed mainly for laboratory rodents, but can be easily transcribed to the pet rodent.16,17 A behavioral ethogram for assessing post-operative pain has also been validated in guinea pigs.18
Buprenorphine
A recent study evaluated the safety and efficacy of high-concentration buprenorphine (1.8 mg/mL) in rats at doses of 0.075, 0.15, or 0.3 mg/kg SC in a randomized, crossover study.19 Self-injurious behaviors (self-biting, cage biting) were observed for up to eight hours after injection for all treatments, despite provision of thermal antinociception. Pica and some self-injurious behaviors have since been reported for all formulations of buprenorphine, especially in rats.20
Many clinicians have utilized transmucosal (buccal, OTM) administration of buprenorphine in rabbits and rodents. A study examining the pharmacokinetics of buprenorphine at 0.2 mg/kg IV and transmucosally in guinea pigs found a single OTM dose of 0.2 mg/kg buprenorphine results in plasma buprenorphine concentrations above those known to be analgesic in rats for approximately four hours.21 IV administration at the same dose in guinea pigs lasted for approximately seven hours. The large volume, frequent administration, and expense make this route of administration less than ideal in this species.
The analgesic efficacy and safety of buprenorphine in chinchillas has also been examined.22 No analgesic efficacy (as measured by limb withdrawal latencies following a thermal noxious stimulus) was achieved at 0.05 or 0.1 mg/kg SC. 0.2mg/kg SC buprenorphine did provide thermal antinociception, but only for less than six hours. Inconsistent effects on fecal output and food intake were noted, but no sedative effects were reported in chinchillas in contrast with guinea pigs.
Sustained-release buprenorphine has been evaluated in several rodent species. Significant analgesia for 48 hours was noted in mice administered a SR buprenorphine at 1.5 mg/kg SQ, and no adverse effects were noted.23 Three doses of sustained-release buprenorphine (0.15, 0.3, and 0.6 mg/kg SC) have been evaluated in guinea pigs.24 Therapeutic levels at 72 hours were only found in guinea pigs administered with the highest dose and males treated with the 0.3 mg/kg dose. A dose-dependent reduction of fecal output was also noted amongst all treatment groups.
Meloxicam
The pharmacokinetics of a single dose of meloxicam (1.5 mg/kg PO and IV) were recently evaluated in guinea pigs, and based on that study, this dose would likely need to be administered more frequently than once every 24 hours.25 However, multiple dose and safety studies have still not been performed in this species to date. No evidence-based information has been published to date on this dosage and efficacy of this drug in chinchillas.
Conclusion
Clinical analgesia in rabbits and rodents are in an area of ongoing research. Therefore, veterinarians treating these species should remain up to date on the literature to ensure the doses of analgesics utilized in these species remains safe and effective.
The recent development of grimace scales for rabbits, rats, and mice provides veterinary teams with a quick and objective measure to monitor for pain and response to analgesics in these species.
Olivia A. Petritz, DVM, DACZM, graduated from Purdue University, and then completed several internships and a residency in the field of zoo and exotic animal medicine. Dr. Petritz became a diplomate in the American College of Zoological Medicine in 2013 and specializes in zoological companion animals (exotic pets). Petritz started an exotics service at a specialty hospital in Los Angeles following her residency and is currently an associate professor of avian and exotic animal medicine at North Carolina State University.
References
- Miller, Amy L., and Matthew C. Leach. “Pain recognition in rabbits.” Veterinary Clinics: Exotic Animal Practice 26.1 (2023): 187-199.
- Keating, Stephanie CJ, et al. “Evaluation of EMLA cream for preventing pain during tattooing of rabbits: changes in physiological, behavioural and facial expression responses.” PloS one 7.9 (2012): e44437.
- Ozawa, Sarah, Alessia Cenani, and David Sanchez-Migallon Guzman Lv. “Treatment of pain in rabbits.” Veterinary Clinics: Exotic Animal Practice 26.1 (2023): 201-227.
- Askar, Raad, et al. “Bioavailability of subcutaneous and intramuscular administrated buprenorphine in New Zealand White rabbits.” BMC veterinary research 16 (2020): 1-10.
- DiVincenti, Louis, Luiz AD Meirelles, and Robin A. Westcott. “Safety and clinical effectiveness of a compounded sustained-release formulation of buprenorphine for postoperative analgesia in New Zealand white rabbits.” Journal of the American Veterinary Medical Association 248.7 (2016): 795-801.
- Fredholm, Daniel V., et al. “Pharmacokinetics of meloxicam in rabbits after oral administration of single and multiple doses.” American journal of veterinary research 74.4 (2013): 636-641.
- Delk, Katie W., et al. “Pharmacokinetics of meloxicam administered orally to rabbits (Oryctolagus cuniculus) for 29 days.” American journal of veterinary research 75.2 (2014): 195-199.
- Schnellbacher, Rodney W., et al. “Effects of lidocaine administration via continuous rate infusion on the minimum alveolar concentration of isoflurane in New Zealand White rabbits (Oryctolagus cuniculus).” American journal of veterinary research 74.11 (2013): 1377-1384.
- Schnellbacher, Rodney W., et al. “Effects of intravenous administration of lidocaine and buprenorphine on gastrointestinal tract motility and signs of pain in New Zealand White rabbits after ovariohysterectomy.” American journal of veterinary research 78.12 (2017): 1359-1371.10. Kozer, Eran, et al. “The effect of amitriptyline, gabapentin, and carbamazepine on morphine-induced hypercarbia in rabbits.” Anesthesia & Analgesia 107.4 (2008): 1216-1222.
- Burton, Mollie, et al. “Pharmacokinetics of gabapentin after single, oral administration in domestic rabbits (Oryctolagus cuniculus).” Journal of Exotic Pet Medicine 45 (2023): 1-5.
- Conway, Rachel E., et al. “Behavioral and physiologic effects of a single dose of oral gabapentin in rabbits (Oryctolagus cuniculus).” Topics in Companion Animal Medicine 53 (2023): 100779.
- Deflers, Hélène, et al. “Influence of a single dose of buprenorphine on rabbit (Oryctolagus cuniculus) gastrointestinal motility.” Veterinary anaesthesia and analgesia 45.4 (2018): 510-519.
- Martin-Flores, Manuel, et al. “Effects of buprenorphine, methylnaltrexone, and their combination on gastrointestinal transit in healthy New Zealand white rabbits.” Journal of the American Association for Laboratory Animal Science 56.2 (2017): 155-159.
- Feldman, Erica R., et al. “Effects of cisapride, buprenorphine, and their combination on gastrointestinal transit in New Zealand white rabbits.” Journal of the American Association for Laboratory Animal Science 60.2 (2021): 221-228.
- Oliver, Vanessa, et al. “Psychometric assessment of the Rat Grimace Scale and development of an analgesic intervention score.” PLoS One 9.5 (2014): e97882.
- Oliver, Vanessa L., and Daniel SJ Pang. “Pain Recognition in Rodents.” Veterinary Clinics: Exotic Animal Practice 26.1 (2023): 121-149.
- Ellen, Yvette, Paul Flecknell, and Matt Leach. “Evaluation of using behavioural changes to assess post-operative pain in the guinea pig (Cavia porcellus).” PloS one 11.9 (2016): e0161941.
- Allen, Molly, Nicole Nietlisbach, and Rebecca A. Johnson. “Evaluation of self-injurious behavior, food intake, fecal output, and thermal withdrawal latencies after injection of a high-concentration buprenorphine formulation in rats (Rattus norvegicus).” American journal of veterinary research 79.2 (2018): 154-162.
- Oates, Rhonda, and Danielle K. Tarbert. “Treatment of Pain in Rats, Mice, and Prairie Dogs.” Veterinary Clinics: Exotic Animal Practice 26.1 (2023): 151-174.
- Sadar, Miranda J., et al. “Pharmacokinetics of buprenorphine after intravenous and oral transmucosal administration in guinea pigs (Cavia porcellus).” American journal of veterinary research 79.3 (2018): 260-266.
- Fox, Lana, and Christoph Mans. “Analgesic efficacy and safety of buprenorphine in chinchillas (Chinchilla lanigera).” Journal of the American Association for Laboratory Animal Science 57.3 (2018): 286-290.
- Kendall, Lon V., et al. “Efficacy of sustained-release buprenorphine in an experimental laparotomy model in female mice.” Journal of the American Association for Laboratory Animal Science 55.1 (2016): 66-73.
- Zanetti, Andrea S., et al. “Pharmacokinetics and Adverse Effects of 3 Sustained-release Buprenorphine Dosages in Healthy Guinea Pigs (Cavia porcellus).” Journal of the American Association for Laboratory Animal Science 56.6 (2017): 768-778.
- Moeremans, Ilse, et al. “Pharmacokinetics and absolute oral bioavailability of meloxicam in guinea pigs (Cavia porcellus).” Veterinary anaesthesia and analgesia 46.4 (2019): 548-555.