Analgesia in Small Mammals

Key Points

  • The goal of analgesia is to minimize pain and distress.
  • Carefully consider the choice of analgesic drug and timing of administration.
  • Prevent “pain windup” by administering opioid analgesia before injury.
  • Combinations of analgesics from different classes are more likely to be effective than a single agent used alone.
  • Ranges of different analgesics are available, including non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and local anesthetics.
  • Gentle handling of tissues can reduce the degree of postoperative pain.
  • Pain assessment is more challenging in small mammals. Signs of pain may include immobility, reduced grooming, hunched posture, abdominal press, aggression, and reduced appetite.

Introduction

As in other species, to manage pain successfully, one must know when pain might occur. Several common medical disorders can result in acute pain such as otitis, conjunctivitis, and acute gastrointestinal disease. Chronic pain can arise from conditions such as arthritis, which commonly develops in older rodents, particularly rats (Rattus norvegicus), dental disease and neoplasia. Management of traumatic and postsurgical pain also requires analgesia. In rabbits and rodents, unrelieved postsurgical pain can be a major factor in the anorexia that is often seen during the postoperative period. Reducing or preventing inappetance is important in small mammals because their energy reserves are significantly lower than in larger species such as dogs and cats. Anorexia can also promote potentially fatal gastrointestinal stasis.

rat closeup Rebecca Lai

Is your patient in pain? Will the clinical procedure or technique planned cause pain?

Pain management is challenging in small mammals. There are practical difficulties associated with recognizing pain and monitoring the efficacy of pain relief therapy. Nevertheless virtually every available analgesic drug has undergone extensive testing in small mammals. Safe dosages are available for a range of drugs in several common laboratory species (Table 1). The main problem is extrapolating available doses from one species to another and translating doses that are effective in anti-nociceptive tests into those that are appropriate for clinical use. Important concepts in pain prevention include multimodal analgesia and pre-emptive analgesia.

 

Preemptive analgesia

The goal of preemptive analgesia is to prevent the noxious stimuli that occur in response to peripheral injury from reaching the central nervous system (CNS). In addition to preventing this “windup” of pain perception, preemptive analgesia also aims to reduce or eliminate peripheral inflammation, which increases input into the CNS thereby aggravating central hypersensitivity. Changes in the central processing of noxious stimuli can be suppressed to a greater extent by administration of opioid analgesic before, rather than after injury.

Administration of an opioid as a preanesthetic medication potentiates the effects of the anesthetic agents administered. Volatile anesthetics, such as isoflurane or sevoflurane, are generally preferable because they are simple, relatively safe to administer to most small mammals, and it is easy to adjust the maintenance concentration. If buprenorphine (Buprenex®, Reckitt & Colman) is administered 30 to 60 minutes before anesthetic induction, the time taken to reach a surgical plane of anesthesia is shorter and recovery is smoother because the animal does not experience postsurgical pain.

 

Multi-modal analgesia

Multimodal analgesia is based on the premise that because there are numerous pain pathways involving a variety of different neurotransmitters, it is unlikely that a single class of analgesic will be completely effective in controlling pain. Analgesic combinations also allow agents to be used at lower doses, thereby reducing the risk of undesirable side effects.

Multimodal analgesia also has practical advantages. Pre-emptive analgesia is not always appropriate in small, stressed patients and analgesics must sometimes be administered post-induction or postoperatively. Many opioids act rapidly within 10 to 15 minutes of subcutaneous injection, whereas it can be an hour before significant analgesic effects are noted after NSAID administration. Therefore administer a relatively short-acting opioid such as butorphanol (Torbugesic®, Fort Dodge) or pethidine/meperidine (Demerol®, Sanofi-Aventis) during recovery to provide immediate pain relief, and concurrently administer an NSAID to provide more prolonged analgesia.

Opioids

Opioids are often required for control of major trauma or postsurgical pain. Butorphanol and buprenorphine are widely popular agonist/antagonists that have been used to provide analgesia in a variety of species. Buprenorphine has the advantage of having a prolonged duration of action of 6-12 hours in many species including rabbits and rodents. The opioid agonist, pethidine (meperidine) has been used widely in the United Kingdom but has a relatively short duration of action in many species (<2 hours). The analgesic effects of butorphanol typically last 3-4 hours.

All opioids can produce some degree of respiratory depression, but when administered at clinically effective doses this is rarely a serious problem in small mammals. Opioids may also cause sedation or excitement, but these effects varying considerably with the species. Finally, opioids may cause vomiting, delayed gastric emptying, and increased intestinal peristalsis. These effects may preclude their use in certain experiments but generally these effects are of minimal clinical significance.

Tramadol

Tramadol (Ultram®, Ortho-McNeil-Janssen) is an opioid agonist that also has analgesic action mediated by inhibition of serotonin and noradrenaline reuptake in the spinal cord. Tramadol has been advocated as an alternative to more potent opioids because of its second mode of action, however it is metabolized relatively rapidly in several species.

Non-steroidal anti-inflammatory drugs

When pain is considered to be mild to moderate, non-steroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen (Ketofen®, Fort Dodge), carprofen (Rimadyl®, Pfizer), and meloxicam (Metacam®, Boehringer Ingelheim) are often sufficient. The palatable oral preparation of meloxicam makes it particularly useful when additional drug doses are required.

The most significant problems associated with NSAID administration are gastrointestinal disturbances, notably ulceration and hemorrhage, nephrotoxicity, and interference with platelet function. Other problems such as blood dyscrasias and liver toxicity can also occur. Adverse effects are rarely significant when these drugs are used to control postsurgical pain in otherwise healthy, young adult animals. Exercise caution when using NSAIDs in animals that may have preexisting organ damage. Chronic renal disease is very common in hamsters (Mesocricetus auratus), rats, and guinea pigs (Cavia porcellus).

Local anesthetics

Local anesthetics can be used to provide post-operative pain relief and as adjuncts to general anesthesia. A longer lasting local agent such as bupivicaine (Marcaine®, AstraZeneca) may be infiltrated into the wound margins or used to provide a local or regional nerve block. Epidural or spinal administration of drugs has been described in ferrets (Mustela putorious furo), rabbits (Oryctolagus cuniculus), guinea pigs, and small rodents.

 

Practical recommendations for pain prevention

Surgical pain management

Gentle handling of tissues can reduce the degree of postoperative pain. Stretching and pulling on sensitive structures triggers nociceptive nerve endings. Even though the pet is anesthetized, these nerve impulses trigger changes in the central nervous system (CNS) that result in increased pain during the postoperative period. Rough handling and crushing of tissues also releases substances that intensify the inflammatory response thereby increasing the degree of postsurgical pain.

In my research facility, if the procedure is relatively minor, then only a single dose of analgesic is administered. In some circumstances, a potent NSAID such as meloxicam may be used. For any surgical procedure, an opioid such as buprenorphine is administered either pre-operatively or immediately after anesthetic induction if an inhalant anesthetic is used. Buprenorphine is routinely given in combination with an NSAID for 8-24 hours. This is followed by an NSAID alone for 24-36 hours. Following more invasive procedures, such as laparotomy or orthopedic surgery, opioid administration is continued for up to 48 hours depending upon the species and the expertise of the surgeon. Continue analgesic administration for 72 hours after major surgery.

Management of arthritic pain

Take special care if analgesics are administered long term to manage painful conditions such as arthritis. Fortunately in my experience, oral administration of low doses NSAIDs for relatively long periods can have very positive effects on the quality of life for arthritic rodents. A regimen cycle of 2-3 weeks of treatment, followed by 7-day breaks seems to reduce the risk of undesirable side effects.

Also look for other means of reducing arthritic pain such as providing additional soft bedding. Feed a soft diet rather than a hard pellet to improve food intake, especially if mandibular joint arthritis is present. Also consider the water bottles and change their design or location if they require the animal to adopt a posture that could exacerbate joint pain.

 

Recovery and monitoring

Pain assessment in small mammals is more difficult than in dogs and cats for a variety of reasons. Changes in behavior provide the most useful indicators of pain; yet veterinarians are often less familiar with the normal behavior of small mammals. Aside from a lack of familiarity with these species, assessment is also difficult because the changes associated with pain are often quite subtle. Additionally many small mammals are prey species, and even caregivers can be viewed as potential predators. In the presence of predators, the response of prey species can be to freeze and remain immobile thereby making an assessment of normal behavior virtually impossible. Even when the animal has been well socialized to human contact, unfamiliar surroundings can be extremely stressful again resulting in a masking of pain-related behavior.

Patients must be provided with a postoperative recovery area appropriate to their particular needs. Allowing a small mammal to recover in the same room as predator species such as cats can be stressful and can also change their behavior patterns, masking signs of pain. Lighting should be subdued but adequate to allow easy observation. Higher intensity lighting must be readily available to allow more detailed examination. The recovery area should be warm and quiet. Provide an ambient temperature should be 27-30ºC (80-86ºF) for adult animals and 35-37ºC (95-98.6ºF) for neonates. Maintain a general room temperature at 21-25ºC (70-77ºF) and provide supplemental heating using warming lamps or heating pads. Although an incubator is ideal, use caution in patients less than 2 kg since many commercially available incubators do not maintain stable temperatures and these patients can suffer from transient hypothermia or hyperthermia. If available, incubators designed for use in human neonates provide excellent conditions for small rodents.

In an effort to assess the patient, carefully observe the animal while undisturbed. Fear and pain can appear similarly. As with other species, many of the changes described here are associated not merely with the presence of pain, but they must be interpreted with the clinical history of the animal.

Both rabbits and small rodents can become completely immobile when experiencing moderate to severe postoperative pain. They will usually position themselves in the farthest corner of their enclosure or try to hide under bedding. When housed in small groups, rodents and rabbits may separate themselves from their cage mates. The animal will usually remain immobile even when approached but will attempt to escape when handled. While moving, the gait may be altered. To complicate matters, nocturnal species such as the rat, hamster, and gerbil are normally relatively inactive during the day. Painful rabbits and rodents may also show a hunched posture.

The painful animal may also groom less frequently. Patients may exhibit piloerection and soiling of the coat. In rats this can lead to build up of reddish-brown secretions or porphyrin tears around the eyes and nose.

Ferrets and rabbits with abdominal pain may loudly grind their teeth, and rats exhibit a characteristic stretching and back-arching behavior following abdominal surgery. Other signs of abdominal pain in rabbits and rodents may include frequent twitching and pressing the ventral abdomen onto the ground.

The painful animal may become unusually aggressive, especially if it is unable to escape from restraint or examination. The animal may also vocalize, sometimes at an abnormal pitch. Remember some of these species are capable of vocalizing at frequencies outside the range of human hearing.

Finally, small mammals often demonstrate reduced appetite if pain is not alleviated effectively. Reductions in food intake are particularly important in rabbits, guinea pigs, and chinchillas because they can trigger gastrointestinal disturbances that can potentially prove fatal. Always weigh animals prior to surgery, so that weight reduction can be detected.

 

Conclusion

Provided that a few simple principles are observed, providing analgesia in small mammals presents few practical difficulties. The greater challenge is determining the adequacy of the analgesia provided. It is also crucial to keep abreast of changes in analgesia therapy. There are relatively few studies on the efficacy of analgesics in clinically relevant situations. Most information has therefore been obtained from clinical experience. For instance dose rates of analgesics may be extrapolated from other species. Continued review of analgesic use is therefore important because recommendations will change more frequently than they will in companion animal species.

 

Table 1. Analgesics for use in small laboratory animals

ANALGESIC Ferret Guinea Pig Hamster and Gerbil Mouse Rabbit Rat
Buprenorphine 0.01-0.03 mg/kg IM, SC, IV q6-12h 0.05 mg/kg SC q6-12h 0.1 mg/kg SC q6-8h 0.1 mg/kg SC q6-12h 0.01-0.05 SC 6-12h 0.05 SC
Butorphanol 0.4 IM 4h 2 SC 4h 1-2 SC 4h 0.1-0.5 SC 2 SC
Carprofen 4 SC  24h 5 SC 12h 4 SC 24h1.5 PO 12h 5 SC, PO 24h
Ketoprofen 3 IM 24h 5 IM, PO 24h
Meloxicam 0.3-0.6 SC, PO 24h 1-2 SC, PO
Morphine 0.5 IM, SC 4-6h 2-5 SC, IM 4h 2-5 SC, IM 4h 2-5 SC, IM 4h 2-5 SC, IM 4h
Meperidine 5-10 IM 2-4h 10-20 SC, IM 2-3h 10-20 SC, IM 2-3h 10 SC, IM 2-3h 10 SC, IM 2-3h
All doses listed are in mg/kg. IM: intramuscular, SC: subcutaneous, IV: intravenous, PO: per os. h: hours

References