- As prey species, rabbits and rodents are good at hiding signs of pain. Assessment of pain often relies upon subtle behavioral changes or pain may be inferred by the absence of normal behaviors. Predator species, like the ferret, are more likely to show overt signs of pain.
- Adequate analgesia is required in the treatment of many small mammal diseases. Non-steroidal anti-inflammatory drugs, like the selective COX-2 inhibitor meloxicam, are very commonly used in exotic companion mammals. Opioids are also useful in many painful conditions.
- Chemical restraint is commonly used for diagnostic and therapeutic procedures in small mammals. Sedation is a valuable option in patients for which general anesthesia presents moderate to significant risk, in particular the geriatric, ill, or critical patient. Midazolam is often used and this sedative can be paired with opioids, such as butorphanol and buprenorphine.
Exotic companion mammals, like ferrets, rabbits and guinea pigs, are popular pets (Fig 1) (AVMA 2012). Veterinarians face unique challenges when providing analgesia and sedation in these species due to small patient size and behavioral differences. Fortunately, there is a growing body of information available as clinicians share their experiences and the number of pharmacologic studies increases.
This article is based upon a PowerPoint shared by Thomas Donnelly, BVSc, DACLAM, DABVP (Exotic Companion Mammal), DECZM (Small Mammal)
Stress response to pain
The stress response to severe pain incites a host of profound physiologic changes (Table 1). It is imperative that pain be recognized and managed as soon as possible to prevent or halt the onset of adverse effects (Fig 2). For instance, rabbits suffering anorexia for more than 1 to 2 days can rapidly develop potentially fatal gastrointestinal stasis. Pain can also contribute to immunosuppression, and the risk of infection must be considered with conditions like subclinical respiratory disease.
|Table 1. Physiologic response to pain (Wenger 2012)|
Prey species hide signs of pain
Normal behavior can be displayed in prey species, like rabbits and rodents, as an instinctive response to avoid predation. In fact, prey animals often hide signs of pain and illness until disease is quite advanced (Fig 3).
Pain in prey species
The key to effective assessment of pain is knowledge of species-specific, and optimally, animal-specific changes in appearance and behavior. Veterinarians must often rely upon subtle changes. Pain in a rabbit or rodent is often inferred from the absence of normal behaviors, such as alertness, mobility, grooming, good appetite, and general condition. There are also clinical signs specific to abdominal or gastrointestinal pain and respiratory compromise (Fig 4) (Table 2). These parameters are particularly helpful when assessing chronic pain, however signs of pain tend to be most obvious when the animal is unaware that it is being observed. Many clinical signs of discomfort can also be caused by conditions other than pain.
|Table 2. Potential signs of pain in rabbits and rodents (Bays 2013, Hedley 2013, Keating 2012, Wenger 2012, Committee on Recognition and Alleviation of Pain in Laboratory Animals 2009)
|Inappetence||Animals in pain markedly reduce their intake of food and water, or frequently stop eating all together, resulting in rapid weight loss
Fecal pellets reduced or absent in number, smaller size
Porphyrin tears in rodents
Eyes partially closed or squinting, dull, and/or unfocused
Bulging eyes in guinea pigs
Strained facial expression, including orbital tightening, and changes in ear and whisker position, in rodents
Visit the NC3RS website for information on the rabbit grimace scale*
|Altered behavior||Aggressiveness when normally docile
Decreased social activity, isolation
Lethargy, decreased interest in surroundings, hiding
Teeth grinding or bruxism can be a sign of abdominal pain
Licking, chewing, scratching, rubbing, or plucking hairs at affected site that can progress to self mutilation
Overgrooming, lack of grooming
Polyphagia of bedding material
Animals may vocalize when approached or handled or when a specific body area is touched or palpated
Animals may also exhibit restlessness (e.g., lying down and getting up, shifting weight, circling, or pacing) or disturbed sleeping patterns
|Guarding||The animal alters its posture to avoid moving or causing contact with or handling of that region
Lethargy, reluctance to move or immobility, slow postural adjustments
Hunched or tucked posture
Tensing or stinting on palpation
Pressing abdomen into floor
Lameness, stiff movements
|Altered posture or gait||Head extended and elevated
Ataxia or lameness
Stretching with back arched
|Respiratory||Increased frequency and depth of respirations
Rapid, shallow breathing
|Metabolic||Polyuria/polydipsia, particularly with dental disease or gastrointestinal pain|
|*Although the grimace scale has been validated (Hampshire and Robertson 2015), it is difficult to use on a daily basis in the clinical patient (Tom Donnelly, written communication, Sep 2017)|
Pain in predator species
Predator species like the ferret are more likely to show overt signs of pain, as observed in cats and dogs. Ferrets with abdominal pain or weakness will display a reluctance to curl up at rest (Fig 5). Abdominal pain in the ferret can also be associated with loud teeth grinding or bruxism.
Analgesia is defined as “the relief of pain or noxious stimulation without loss of consciousness” (West et al 2007). Analgesia should be used for any potentially painful procedure or disease condition, even if no obvious signs of pain are observed (Fig 6). Multimodal analgesia, using combinations such as opioids with non-steroidal anti-inflammatory drugs, targets pain both centrally and peripherally. Ideally, analgesics should be administered pre-emptively for maximal effect at preventing pain.
Depending on the underlying problem, there are also non-pharmacological ways to reduce pain and distress, including soft food (for dental disease), bandaging, and other types of nursing care. For the house rabbit or guinea pig, having a bonded companion in the same cage can also reduce stress tremendously.
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used analgesics in exotic companion mammals. The COX-2 inhibitor, meloxicam (Metacam®, Boehringer Ingelheim) is particularly popular. Meloxicam (1 mg/kg q24h) can be administered by subcutaneous or intramuscular injection (Delk 2014, Fredholm 2013). Alternatively, the honey-flavored oral formulation is available for outpatient care and is palatable to most small exotic mammals.
As in other species, avoid NSAIDs with renal and hepatic impairment, bleeding disorders, enteritis, gastritis, hypotension, or hypovolemia. The risks of gastrointestinal ulceration should also be considered, particularly in the hypovolemic patient or with long-term use.
Lower NSAID doses in ferrets (as in cats) and DO NOT use NSAIDs in ferrets when gastrointestinal ulceration is suspected (e.g. vomiting, diarrhea, and/or melena is observed).
Buprenorphine (Buprenex®, Reckitt & Colman) is a slow-onset, long-acting, partial mu agonist indicated for the treatment of mild to moderate pain. Buprenorphine has both sedative and analgesic properties. Buprenorphine (0.01-0.05 mg/kg SC, IM, IV/IO q6-12h) is the most commonly used opioid in many exotic companion mammals (Hedley 2013, Hawkins and Pascoe 2012). The recommended dose range is slightly higher in rats and mice (0.05-0.1 mg/kg q6-12h) (Hawkins and Pascoe 2012).
Potential adverse effects can include drowsiness, nausea, anorexia, and respiratory depression. Although decreased respiratory rate and associated mild hypoxemia is well tolerated in healthy animals, exercise caution when administering buprenorphine to small mammals predisposed to respiratory depression, such as rabbits suspected of pasteurellosis or rats thought to suffer from mycoplasmosis. Additionally, buprenorphine can exhibit a plateau or “ceiling effect” in which administration of additional drug produces either detrimental effects, no additional analgesia, or prolonged analgesia (Hawkins and Pascoe 2012).
Opioids can reduce gastrointestinal (GI) motility in small herbivores, but this does not appear to be clinically relevant. Pain is an important cause of GI stasis and the beneficial effects of buprenorphine are believed to outweigh the potential negative effects.
Buprenorphine can be antagonized with naloxone (0.01-0.04 mg/kg IV q 2-3 minutes to effect) (Kukanich and Papich 2009).
Butorphanol (Torbugesic®, Fort Dodge) is an agonist-antagonist opioid. Butorphanol (0.1-0.5 mg/kg SC, IM, IV/IO; 0.1-0.2 mg/kg/h constant rate infusion or CRI) produces greater sedation than buprenorphine but less analgesia. Frequent drug administration is required ranging from every 2-4 hours (Flecknell 2006).
Morphine sulfate (1-2 mg/kg SC, IM, IV/IO) is a potent mu opioid agonist with an intermediate duration of 2-4 hours (Bays 2013, Hedley 2013). Consider morphine for particularly painful procedures. Potential side effects include nausea and respiratory depression.
Fentanyl citrate (2-7 µg/kg/h IV/IO CRI) (Abbott Laboratories) has potent analgesic properties with a length of action of approximately 20 minutes. Side effects of this full mu opioid receptor agonist can include respiratory depression and sedation. Buprenorphine or butorphanol can be used to reverse these signs (Thomas and Lerche 2017).
Due to their small size, most exotic mammals are not well suited for use of fentanyl transdermal patches, however rabbits tolerate this treatment modality well (Wenger 2012, Foley and Henderson 2001).
Hydromorphone (Dilaudid-HP®, Purdue Pharma) (Table 3) and oxymorphone hydrochloride (0.05-0.2 mg/kg IM, SC q6-8h, ferret, rabbit) (Teva) are potent mu opioid receptor agonists effective for moderate to severe pain (Allweiller 2016, Flecknell 2001). Potential adverse effects can include respiratory depression, sedation, nausea, and gastrointestinal ileus (Plumb 2011).
|Table 3. Recommended hydromorphone doses in select exotic companion mammals (Allweiler 2016, Kukanich and Papich 2009, Lichtenberger 2008)|
|Rabbit||0.05-0.2 mg/kg||SC, IM, IV/IO||q6-8h|
|Rabbit, guinea pig, hamster, rat, mouse||0.3-0.7 mg/kg||SC, IM||q4h|
|CRI: Constant rate infusion|
Local anesthetics are increasingly used in practice for incisional line blocks, ring blocks, local infiltration, or splash-blocks during surgical closure. Regional blocks can also be used for procedures such as dental extractions or epidurals. Topical anesthetic gels and creams, such as EMLA® cream (Astrazeneca), as well as sprays and topical refrigerants can also be used to facilitate clinical procedures, such as phlebotomy and catheterization. It is advantageous to clip the hair before applying topical creams or gels. When using lidocaine to aid in phlebotomy or catheterization, Lennox (2009) has recommended the following approach: Apply lidocaine gel over the site; wait 5 minutes and then roll the skin laterally away from the target vessel and inject lidocaine. Roll the skin back in place, and wait 10 minutes for the drug to take full effect.
Topical or local anesthetic drug dosages must be carefully calculated in exotic companion mammals. Take care not to exceed the toxic threshold because of small patient size. To provide a more convenient volume for administration, drugs can be diluted with saline.
Lidocaine (2-4 mg/kg) is a short-acting agent with a rapid onset. Its effect usually lasts only 30–60 minutes (Allweiler 2016). The use of lidocaine CRI as part of multimodal analgesia has been described for rabbit gastrointestinal surgery, similar to its use in equine abdominal surgeries. Lidocaine (2 mg/kg IV) is administered after anesthetic induction, followed within 5 minutes by a CRI at 50 µg/kg/min (Thomas Donnelly, written communication, 2015).
Bupivicaine (1-2 mg/kg) (Marcaine®, AstraZeneca) is a local agent with a slower onset (Allweiler 2016). Duration usually lasts between 180–480 minutes, possibly up to 6-8 hours. Bupivicaine has a relatively low therapeutic index and should be used with caution ((Hedley 2013, Lennox 2013, Plumb 2011).
Epidural analgesia is an alternative method for delivering analgesia to the caudal half of the body. Epidurals can be used for abdominal or perineal surgery as well as orthopedic procedures involving the pelvic limb or spine. Some opioids can also travel cranially to provide supplemental analgesia for chest and thoracic limb procedures. Morphine is commonly used in epidural analgesia because it is highly potent and relatively long lasting. Other agents used include buprenorphine, oxymorphone, and hydromorphone, as well as local anesthetics like bupivacaine.
Visit Epidural Anesthesia in Small Mammals for illustrative video and text.
Historically, general anesthesia has been used in exotic companion mammals for non-invasive procedures like sample collection and radiography. Unfortunately, general anesthesia incurs risk, even under the best circumstances (Table 4). Isoflurane and sevoflurane are naturally hypotensive, and adverse effects are dose dependent. When these inhalant agents are used alone, higher doses are needed, which in turn further increases risk. Although these principles apply to all species, the risk associated with general anesthesia is higher in exotic companion mammals due to a host of reasons, ranging from the stress of induction in prey species to the more pronounced physiologic effects of anesthesia with small patient size (Wenger 2013, Brodbelt 2006). Anesthetic risk is of course higher in ill or debilitated exotic companion mammals.
|Table 4. Overall risk of anesthetic-related death (Brodbelt 2006)|
Other small mammals 1.7%
Guinea pigs 3.8%
Sedation is a state characterized by central depression accompanied by drowsiness during which the patient is generally unaware of its surroundings but responsive to noxious manipulation (ACVA 2009, Thurmon and Short 2007).
Sedation is a valuable option in those patients for which anesthesia presents moderate to significant risk, in particular the geriatric, ill, or critical patient.
Sedation alone is often adequate for minor procedures such as diagnostic sample collection, placement of an intravenous catheter, and imaging (Lennox 2009). Sedation can also be useful for general reduction of anxiety and stress. For instance, patients in respiratory distress benefit can benefit from low-dose sedation to reduce the anxiety associated with their clinical condition (Lichtenberger and Lennox 2012). Another situation where sedation becomes important is for patients that cannot be completely examined while awake, such as the hedgehog.
Commonly used sedatives include midazolam and opioids, such as butorphanol and buprenorphine.
A popular sedative combination in small mammals is midazolam (0.1-0.25 mg/kg SC, IM) with butorphanol (0.1-0.3 mg/kg SC, IM).
Extremely anxious or fractious patients may require higher dosages. When some patient movement is disadvantageous, as with diagnostic imaging, the midazolam-butorphanol combination can benefit from the addition of low-dose ketamine and proper manual restraint.
Painful procedures, such as intraosseous (IO) catheter placement, often require the addition of local anesthetics or general anesthesia. Local anesthesia can be administered in the form of injectable lidocaine or topical anesthetic products applied 10 minutes prior to catheterization. With IO catheter placement, lidocaine can be infused into the skin and subcutaneous tissue, down to the level of the periosteum.
Midazolam hydrochloride (1-2 mg/kg) (Hospira, Inc.) is a benzodiazepine tranquilizer with sedative and anxiolytic properties. Midazolam is usually administered intramuscularly (IM). In some cases where IM is challenging the subcutaneous route is used, although the onset of action will be delayed. Midazolam shows a wide margin of safety in many species. The effect of midazolam on blood pressure and other parameters like respiration is dose dependent, but relatively mild, especially when administered IM as opposed to IV. The clinical effect of midazolam can range from a slight decrease in activity to lateral recumbency, and will vary with the species involved. For instance, ferrets tend to display a much more pronounced effect with midazolam than the subtle effect observed in rats and mice at the same dose (Lennox 2013).
The opioid agents butorphanol and buprenorphine are analgesic, but they also provide mild sedation in most small mammals (Fig 7). Opioids work synergistically when combined with midazolam, allowing a reduction in the amount of both drugs used. The use of opioids is contraindicated with respiratory disease.
Ketamine has a unique mechanism of action that involves blockade of N-methyl-D-aspartic acid receptors in the central nervous system, as well as blockade of peripheral sodium channels and mu opioid receptors (Petrenko et al 2003). Low-dose ketamine (Table 5) (Ketaset®, Fort Dodge) can be an effective addition to an opioid-midazolam combination for increasing the level of sedation in patients with trauma and/or hemodynamic instability (Grimm et al 2011). Ketamine also offers good superficial analgesic properties at low doses (Grimm et al 2011). Low-dose ketamine, also known as “sub-anesthetic” or “sub-dissociative” dose ketamine, refers to doses less than 1 mg/kg IV. Low-dose ketamine produces analgesia with no dissociative effects, which makes it ideal as a continuous rate infusion (Allweiler 2016, Gao et al 2016). Ketamine CRI has been used as a part of multimodal analgesia in rabbit surgeries to reduce post-operative pain. As part of a multimodal analgesia regimen, ketamine also reduces the dose of opioid required for pain relief.
|Table 5. Suggested ketamine doses for rabbits (Hedley 2013)|
|Loading dose||0.25-0.50 mg/kg IV bolus|
|CRI during general anesthesia||0.30-0.60 mg/kg/h IV
5-10 µg/kg/min IV
|CRI in the conscious patient||0.12-0.30 mg/kg/h IV
2-5 µg/kg/min IV
|CRI: constant rate infusion|
Alfaxalone (Alfaxan®, Jurox), is a neuroactive steroid derivative of pregnanedione (a metabolite of progesterone) that is rapidly metabolized and non-cumulative, with less cardiovascular effects than propofol. This disassociative anesthetic agent has no analgesic effects. A dosage of 4-6 mg/kg IM induced loss of the righting reflex in healthy rabbits (Huynh et al 2015).
The basic goals of monitoring are to ensure adequate patient oxygenation and maintain hemodynamic stability. Routine monitoring of the heavily sedated small mammal should include intermittent palpation of pulse rate, rhythm and quality; observation of mucous membrane color and capillary refill time, observation of respiratory rate and pattern, auscultation, as well as assessment of oxygen saturation using pulse oximetry (Fig 8) (Lennox 2013, ACVA 2009). Monitor blood pressure when possible, particularly with IV drug administration. Supplemental oxygen, an endotracheal tube, and materials for catheter placement should also be readily available. If the patient is sedated to the point where protective airway reflexes are lost, it should be monitored as if under general anesthesia (Lennox 2013, ACVA 2009).
Recommend dosage regimens
|Table 6. Recommended analgesia and sedation regimens (Allweiler 2016, Huynh et al 2015, Delk 2014, Fredholm 2013, Hedley 2013, Hawkins and Pascoe, 2012, Kukanich and Papich 2009)|
|Buprenorphine||0.01-0.03||SC, IM, IV/IO||q6-10h||Ferret|
|0.01-0.05||SC, IM, IV/IO||q6-10h||Rabbit|
|0.01-0.05||q6-12h||Chinchilla, gerbil, hamster|
|Butorphanol||0.1-0.5||SC, IM, IV/IO||q2-4h||Ferret|
|0.2-2.0||Chinchilla, gerbil, hamster|
|1.0-2.0||q4h||Guinea pig, mouse, rat|
|Fentanyl||0.02-0.03 mg/kg/h||CRI||Ferret, intraoperative|
|0.001-0.004 mg/kg/h||CRI||Ferret, postoperative|
|0.002-0.007 mg/kg/h||IV/IO||CRI||2.0-7.0 µg/kg/h|
|Hydromorphone||0.05-0.1||SC, IM, IV/IO||Ferret, rabbit|
|0.3-0.7||SC, IM||q4h||Rabbit, guinea pig, hamster, rat, mouse|
|0.30-0.60 mg/kg/h||IV/IO||CRI||Rabbit under general anesthesia|
|0.12-0.30 mg/kg/h||IV/IO||CRI||Conscious rabbit patient|
|Meloxicam||1.0||PO, SC, IM||q24h|
|Morphine||1.0-2.0 mg/kg||SC, IM, IV/IO||q2-4h|
|Naloxone||0.01-0.04||IV||q2-3 min to effect|
|Oxymorphone||0.05-0.2||SC, IM||q6-8h||Ferret, rabbit|
|Tramadol||5.0||Rabbit, rodents (Frequency on q12-24 recommended in rabbits by Allweiler 2016)|
|PO: per os SC: subcutaneous IM: intramuscular IV: intravenous IO: intraosseous h: hour min: minutes|
The approach to analgesia and sedation in exotic companion mammals faces special challenges, including small patient size and unique features of the prey species mentality.
For instance, recognition of pain is more difficult in rabbits and rodents because many small mammals excel at hiding the signs of pain commonly observed in predator species. Instead pain in a rabbit or rodent is often inferred from the patient’s clinical condition as well as the absence of normal behaviors. Adequate analgesia is required in the treatment of many small mammal diseases. As in all species, multimodal analgesia or combining NSAIDs with an opioid drug, should be considered when significant pain is involved.
The diagnostic and therapeutic plan frequently requires some form of chemical restraint in exotic mammal medicine. Historically, general anesthesia using sevoflurane or isoflurane has been used. Although this modality still has its place, a safer option for the debilitated or critically ill small mammal is sedation. Commonly used sedatives include midazolam paired with opioids, such as butorphanol and buprenorphine.
References and further reading
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American College of Veterinary Anesthetists. ACVA Monitoring Guidelines Update, 2009. Available at www.acvaa.org/docs/Small_Animal_Monitoring_2009.doc. Accessed April 22, 2017.
American Veterinary Medical Association. U.S. pet ownership statistics. Source: 2012 U.S. Pet Ownership & Demographics Sourcebook. AVMA website. Available at https://www.avma.org/KB/Resources/Statistics/Pages/Market-research-statistics-US-pet-ownership.aspx. Accessed April 25, 2017.
Bays TB. Recognizing Signs of Pain and Pain Management in Exotics. 65th Convention of the Canadian Veterinary Medical Association, 2013.
Bednarski RM. Anesthesia management of dogs and cats. In: Grimm KA, Tranquilli WJ, Lamont LA (eds). Essentials of Small Animal Anesthesia and Analgesia: 292.
Biernert A, Płotek W, Wiczling P, et al. The influence of the time of day on midazolam pharmacokinetics and pharmacodynamics in rabbits. Pharmacol Rep 66(1):143-152, 2014.
Brodbelt DC. The Confidential Enquiry into Perioperative Small Animal Fatalities. PhD thesis. Royal Veterinary College, University of London & The Animal Health Trust. 2006
Cannon CZ, Kissling GE, Goulding DR, et al. Analgesic effects of tramadol, carprofen or multimodal analgesia in rats undergoing ventral laparotomy. Lab Anim (NY). March 2011;40(3):85-93.
Committee on Recognition and Alleviation of Pain in Laboratory Animals, National Research Council. Recognition and alleviation of pain in laboratory animals. National Research Council. Washington, DC: National Academies Press; 2009.
Delk KW, Carpenter JW, KuKanich B, et al. Pharmacokinetics of meloxicam administered orally to rabbits (Oryctolagus cuniculus) for 29 days. Am J Vet Res 75(2):195-199, 2014.
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Flecknell PA. Anaesthesia and perioperative care. In: Meredith A & Flecknell PA (eds). BSAVA Manual of Rabbit Medicine and Surgery, 2nd ed. British Small Animal Veterinary Association UK; 2006:154-156.
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Foley PL, Henderson AL, Bisonette EA, et al. Evaluation of fentanyl transdermal patches in rabbits: blood concentrations and physiologic response. Comp Med 51:239-244, 2001
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