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Recognition and Alleviation of Pain in Laboratory Animals (2009)

Chapter: 3 Recognition and Assessment of Pain

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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Suggested Citation:"3 Recognition and Assessment of Pain." National Research Council. 2009. Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: The National Academies Press. doi: 10.17226/12526.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

3 Recognition and Assessment of Pain T his chapter begins with a presentation of the clinical signs and behav- iors that veterinarians use to recognize animals in pain. It then pro- vides a review of methods for pain assessment, with a focus on techniques for specific laboratory animal species. It concludes with species- specific clinical signs and behavioral responses to pain. INTRODUCTION Recognizing pain and assessing its intensity are both essential for its effective management. If pain is not recognized, then it is unlikely to be treated; failure to appreciate the intensity of pain will hamper the selection of an appropriately potent analgesic, raise doubts about the effectiveness of the administered dose, and result in less than optimal treatment. In humans, self-report of pain is the “gold standard” by which other assessment tech- niques may be judged, although there are limitations and biases even when using this approach (see Chapter 1). For animals, as for humans who can- not self-report (e.g., the very young and those with cognitive impairment; Ranger et al. 2007; Zwakhalen et al. 2006), other assessment tools are necessary. Since the publication of the first edition of this report (NRC 1992), there have been considerable advances in scientists’ understanding of animal pain and numerous attempts to develop methods of assessing pain. Yet few validated assessment techniques are available. In most circumstances pain is assessed based on an animal’s clinical appearance and overall behavior. Although this approach can be unreliable, it is usually effective in detect- 4

48 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS ing severe pain in many species. It is also effective when pain is localized to one limb (causing lameness) or to a specific body area (resulting in a marked behavioral response if that area is palpated). The ability to assess pain in laboratory animals will improve with the development of validated, objective schemes for particular species and types of procedures. Some schemes of this type are in development, while others (e.g., assessment of postsurgical pain in dogs [Morton et al. 2005] or of pain after abdominal surgery in rats [Roughan and Flecknell 2001, 2003]) have reached the point that they can be used to assess pain in the particular species in a variety of situations. It is also possible that some of the behaviors noted may occur in other species: contraction of the abdomi- nal muscles following abdominal surgery is observed in rats and has also been reported in mice (Wright-Williams et al. 2007) and rabbits (Leach et al. 2009). Regardless of the assessment technique, however, it is important that it be done by a team that includes researchers, veterinarians, and animal care staff. PAIN RECOGNITION: CLINICAL SIGNS AND BEHAVIOR There are no generally accepted objective criteria for assessing the degree of pain that an animal is experiencing. Species vary widely in their response to pain, and often animals of the same species show different responses to different types of pain. Box 3-1 presents a basic algorithm for pain assessment that may serve until the development of species-specific pain assessment methods. A team approach and cooperative spirit among all interested parties—researchers, veterinarians, and animal care staff—will benefit the welfare of the animal in pain. It is important that clinical evaluations and assessment protocols be carried out by individuals with a detailed knowledge of the normal and abnormal behavior and appearance of the species concerned. Further, the effects of the observer on the behavior of the animal should be considered; for example, some species, such as rabbits and guinea pigs, may remain immobile, especially if the observer is an unfamiliar person. In these cases, it may be necessary to observe the animal via a camera or viewing panel. When assessing behavioral changes, it is often helpful to have a checklist that may incorporate a grading scheme (see the scoring system developed by Morton and Griffiths in 1985). However, because different individuals often fail to agree on the score that should be assigned (Beynen et al. 1987) it may be simpler to note the presence or absence of a specific clinical sign. Changes in successive observations could indicate an improvement or deterioration in the animal’s condition. Although many observations will not be specific indicators of pain, a structured examination is always help- ful in monitoring an animal’s progress during a study. Table 3-1 presents a number of behavioral signs usually associated with pain.

4 RECOGNITION AND ASSESSMENT OF PAIN BOX 3-1 Pain Assessment Protocol The following approach can be helpful for assessing pain in particular animal models: • Prepare a checklist of the examinations to be undertaken, allow space for a general comment, and perhaps include an overall assessment tool (e.g., a visual analogue scale (VAS) score sheet). Familiarize all staff who will be involved in the assessment with this checklist and any other assessment tools that will be used. Whenever possible, the same staff member should conduct each assessment of the same animal. Specific training must be provided for new or inexperienced staff. • Begin by observing the animal without disturbing it. If the animal’s behavior changes markedly in the presence of an observer (e.g., as is the case with nonhuman primates, rabbits, and guinea pigs) it may be more practical to as- sess postoperative or postprocedural behavior by setting up a video camera or viewing panel. • Assess the animal's response to the observer (the technician who routinely cares for the animal may be best able to assess this). • Examine the animal and assess its response to gentle palpation or handling of any presumed painful areas (e.g., the site of surgery, the site of a lesion) when practicable. • Weigh the animal, record its food and water consumption if possible, and exam- ine the cage or pen for signs of normal or abnormal urination or defecation. • Administer analgesic treatment if necessary, and repeat the assessment out- lined above 30-60 minutes after treatment to determine whether the drug and the dose administered have been effective. In the absence of certainty about the presence of pain, assessing the response to an analgesic can be helpful. • Review these protocols regularly. • Remember that: ° the signs described here can be caused by conditions other than pain, ° the signs may vary between animals of the same species, even after the same procedure, and ° the signs will vary between different strains and breeds. Animals in pain reduce their overall level of activity, as observed, for example, in mice following surgery (Clark et al. 2004; Karas 2002; Wright- Williams et al. 2007). It has been suggested that changes in heart rate, respiratory rate, and blood pressure can be used to assess pain, but these clinical parameters are often unreliable or nonspecific (e.g., similar changes may be observed in stressed or distressed animals; NRC 2008). Consistent changes in these parameters in animals expected to be in pain have not been demonstrated (Cambridge et al. 2000; Holton et al. 1998; Price et al. 2003). Given the range of factors (e.g., fear, excitement) that can alter heart and respiratory rate, this is not surprising, as even handling can cause major

0 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS TABLE 3-1 Behavioral Signs of Persistent Pain Sign Explanation Guarding The animal alters its posture to avoid moving or causing contact to a body part, or to avoid the handling of that body area. Abnormal Different species show different changes in their external appearance, but appearance obvious lack of grooming, changed posture, and a changed profile of the body are all observable signs. In species capable of some degree of facial expression, the normal expression may be altered. Altered Behavior may be depressed; animals may remain immobile, or be reluctant behavior to stand or move even when disturbed. They may also exhibit restlessness (e.g., lying down and getting up, shifting weight, circling, or pacing) or disturbed sleeping patterns. Large animal species may grunt, grind their teeth, flag their tail, stomp, or curl their lips (especially sheep and goats). Primates in pain often roll their eyes. Animals in pain may also show altered social interactions with others in their group. Vocalization An animal may vocalize when approached or handled or when a specific body area is touched or palpated. It may also vocalize when moving to avoid being handled. Mutilation Animals may lick, bite, scratch, shake, or rub a painful area. Sweating In species that sweat (horses), excessive sweating is often associated with some types of pain (e.g., colic). Inappetence Animals in pain frequently stop eating and drinking, or markedly reduce their intake, resulting in rapid weight loss. changes in heart rate, respiratory rate, and blood pressure. Recently, how- ever, more sophisticated analysis of heart rate variability has been of value as an adjunct to pain assessment (Arras et al. 2007; Rietmann et al. 2004). PAIN ASSESSMENT METHODS As discussed above, methods for assessing pain in laboratory animals remain highly subjective and are based largely on preconceived ideas about the appearance and behavior of animals in response to pain. Attempts to apply the Morton and Griffiths (1985) scoring scheme were largely unsuc- cessful (Beynen et al. 1987), primarily because the variables selected for inclusion were not fully identified and the ratings (0-3) not sufficiently well characterized (this scheme has proven much more successful in the devel- opment of humane endpoints for studies that may cause distress rather than pain; NRC 2008). In addition to the lack of known effective pain assessment methods, it is not uncommon for a study to include the administration of an analgesic

1 RECOGNITION AND ASSESSMENT OF PAIN without any attempt to evaluate its effectiveness. For example, a recent survey of pain control in laboratory animals in the United Kingdom found that, although all the institutions in the survey used analgesics, almost none used methods of pain assessment to confirm that the treatment was effective (Hawkins 2002). Behavioral Changes Objective measures likely to indicate pain include changes in general locomotor activity (e.g., guarding a specific area or avoiding weight-bearing on an injured limb; Duncan et al. 1991; Flecknell and Liles 1991; Mala- vasi et al. 2006) and in food and water intake and body weight (Liles and Flecknell 1992, 1993a,b). These measures are also useful to assess analgesic drug efficacy, although because they are retrospective they cannot be used to modify analgesic therapy for a particular animal. They are, however, effective as a simple measure of postoperative recovery and as a means of adjusting future analgesic regimens for similar animals undergoing similar surgical procedures. Influences of Analgesics on Behaior The use of analgesics warrants certain cautions. Some analgesics, nota- bly opioids, cause marked behavioral changes in healthy, pain-free animals, which can confound attempts to assess pain (Roughan and Flecknell 2000). Buprenorphine stimulates activity in normal mice (Cowan et al. 1977; Hayes et al. 2000), so behavioral changes after the use of this drug during surgery could be due to the provision of effective pain relief or a nonspecific drug effect. In contrast, NSAIDs have only very minor effects on behavior in healthy, pain-free animals, so this problem is not significant with the use of these analgesics (Roughan and Flecknell 2001; Wright-Williams et al. 2007). Further, significant behavioral signs of postsurgical pain in rodents may persist only 6 to 8 hours after some procedures (Roughan and Flecknell 2004), so these results may be due to administration of analgesics to ani- mals that were not experiencing pain. In these circumstances side effects such as sedation or nausea may be of much greater significance. For more information on other behavioral measures readers are referred to Chapter 1, especially Box 1-4. Moreover, the influence of analgesics on body weight following surgery is not always easy to interpret. In some studies, after an initial presumed beneficial effect, animals that had undergone surgery and not received postoperative analgesics gained more weight over a 2- to 3-day period than their counterparts under an analgesic regime (Sharp et al. 2003).

2 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS Behaioral Assessment Studies in Rats, Mice, and Rabbits Investigators have described specific behavioral changes following abdominal surgery and ureteral calculosis in rats (Giamberardino et al. 1995; Gonzalez et al. 2000; Roughan and Flecknell 2000) and these behav- iors have been incorporated in a practicable pain assessment tool for use in laboratory rats after abdominal surgery (Roughan and Flecknell 2002). During the initial development of the scheme, rat behavior was evaluated both before and after a midline laparotomy with appropriate untreated and anesthetic and analgesic controls. An initial study using buprenorphine as the analgesic was inconclusive because of the marked effects of this opioid on normal behavior (Roughan and Flecknell 2001). A subsequent study using carprofen and ketoprofen successfully identified behaviors that differentiated rats that had (1) under- gone surgery from those that had simply been anesthetized and (2) received analgesics after surgery from those that had not. These studies required detailed analysis of considerable periods of videotaped behavior including filming at night under red light. The utility of these behaviors was further demonstrated in rats undergoing surgery as part of an unrelated research project that entailed placing the animals in an observation cage for a 15- minute period and assessing the frequency of the pain-related behaviors. Again, it was possible to differentiate animals receiving analgesics from untreated controls, and to demonstrate a dose-related effect of the NSAID meloxicam (Roughan and Flecknell 2003). When experienced staff (animal technicians, research workers, and veterinarians) first viewed selected video recordings from these animals, they were unable to correctly identify the treatment groups. However, after watching a short recording illustrating the key behaviors, their ability to identify animals that had or had not received analgesics greatly improved (Roughan and Flecknell 2006). These studies suggest that key behaviors can be identified and used to score pain following one type of surgical procedure in rats. In addition, the studies underscore the importance of proper training of even experienced personnel with the introducton of new techniques. It is not yet clear whether behavioral changes in rats after vari- ous surgical procedures will differ greatly in type or will be drawn from a common group of abnormal, pain-related behaviors. Recent studies in mice have indicated that they experience similar pain-related changes in behavior after abdominal surgery (Wright-Williams et al. 2007) and that these behaviors might form the basis of a murine pain scoring scheme. However, the rapid movement of mice makes observations less reliable. In addition, the effects of the analgesics used in these studies were less predictable than in rats as were the effects of opioids, which, as mentioned above, affect behavior in normal animals. These studies also

3 RECOGNITION AND ASSESSMENT OF PAIN found a major difference in the frequency of pain-related behaviors in the two different strains of mice used (C3He and C57Bl6). Other studies (e.g., Karas 2002) have shown changes in the frequency of normal activity in mice after surgery, and it may be possible to develop a scoring system based on a combination of changes in abnormal and normal activity. In some instances, changes in a specific locomotor pattern, or gait, can be assessed objectively using a variety of techniques (Gabriel et al. 2007). Force plates and other means of assessing limb use and gait have been used to evaluate the severity of arthritis in laboratory and companion animals as well as the efficacy of analgesic therapy (Gabriel et al. 2007; Hazewinkel et al. 2008). The linking of clinical signs to behavioral alterations after administration of an analgesic facilitates pain assessment. A small number of studies have attempted to assess postsurgical pain in rabbits. Initial attempts to develop a behavior-based scheme failed because of the animals’ reaction to the presence of an observer (Roughan and Fleck- nell 2004), and a similar study produced inconclusive results (Parga 2002). More recently, a detailed assessment of behavior before and after surgery, using remotely operated cameras, revealed clearly identifiable abnormal behaviors as well as changes in the frequency of normal behaviors. The effects of analgesics were limited. Further work is required before clear recommendations can be made about the usefulness of these behaviors (Leach et al. 2009). A problem with all of these behavior-based schemes is that in many instances the animals studied were anesthetized with regimens (e.g., isoflu- rane or sevoflurane) that resulted in rapid recovery of consciousness. When recovery is delayed, or is associated with prolonged sedation, animals may fail to express pain behavior and scoring may therefore not be reliable. The scoring system may also be influenced by other factors, such as the animals’ fear and apprehension, or unexpected variations in behavior between differ- ent strains (Wright-Williams et al. 2007). Nevertheless, detailed behavioral observations are a step forward in developing a practical and useful pain scoring system for use after surgery in laboratory animals. What is not yet known is whether similar systems can be used to develop a means of iden- tifying and quantifying other types of pain in animals, including chronic pain. Deeloping Objectie Pain Assessment Tools: Companion Animals Initial methods for scoring pain in companion animals were largely subjective and seriously flawed. Some studies, however, demonstrated that behavioral assessments could be used to evaluate the effects of surgery and analgesia (e.g., the use of visual analogue scores to assess pain following ovariohysterectomy in dogs [Lascelles et al. 1997] and cats [Slingsby and

4 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS Waterman-Pearson 1998]). Additional scoring schemes for use in dogs have since been developed (Firth and Haldane 1999; Holton et al. 2001), and numerous studies use VAS, numerical rating systems, simple descriptive scores, or a mix of the three approaches (Brodbelt et al. 1997; Mathews et al. 2001). These different approaches highlight the problems involved in developing pain assessment schemes (Holton et al. 1998); for example, • the assessment criteria are frequently highly subjective, • the study designs do not include untreated (surgery and no analge- sia) controls, • the study designs do not include anesthesia and analgesia (and no surgery) control groups, and/or • only a single dosage is assessed rather than a range of doses. Firth and Haldane (1999) videotaped dogs before and after surgery and, after making detailed observations, identified behaviors that were probable indicators of pain. In common with other behavior-based scoring schemes, they hypothesized that behaviors that appeared only after surgery, or that increased or decreased greatly after surgery, could be pain-related. If admin- istration of an analgesic normalized these behavioral changes, this provided additional evidence that the changes were due to pain. The scheme set out by Firth and Haldane has been developed further and recommended as a tool suitable for clinical use (Gaynor and Muir 2002). Holton and colleagues (2001) adopted a different approach. This group sought to identify descriptors of pain by consulting with experienced small animal clinicians, and then used sophisticated analytical techniques to reduce these descriptors to a set of words or phrases that could be devel- oped into a multidimensional pain scale. Unfortunately, validation in a placebo-controlled, blinded study has yet to be completed. It is important to note that the development of a pain score essentially based on the opinion of clinician experts is almost certain to result in a self-fulfilling scheme that will detect pain and predict which animals will receive additional analgesics, since it will be used by clinicians whose opinion shaped its development. Because this is a common problem in pain scoring of both animals and humans, these schemes should be devel- oped further and validated through randomized, blind, placebo-controlled trials. Placebo-controlled studies in animals, however, pose significant ethical and practical difficulties. Because most schemes include some behavioral assessments, and because anesthetics and analgesics, notably opioids, can markedly change behavior in normal, pain-free animals, lack of appropriate controls (i.e., postprocedural animals that receive no anesthetic or analge- sic) can make the results highly questionable. The inclusion, however, of

 RECOGNITION AND ASSESSMENT OF PAIN such control groups may cause significant ethical dilemmas to researchers that undertake pain assessment studies, most of which are carried out in veterinary schools. Deliberately withholding analgesics in circumstances believed likely to result in pain may be considered unacceptable by students who learn that animals experience pain and should receive analgesics. Stud- ies of pain with human participants require an intervention analgesia pro- tocol so that subjects assessed as experiencing pain above a predetermined level are removed from the study and given an analgesic. This approach has been used in a number of veterinary clinical studies (Grisneaux et al. 1999; Lascelles et al. 1995). Measurement of Nociceptive Responses A wide variety of methods for measuring nociceptive response apply to either momentary or more longer-lasting noxious stimuli for research purposes (Hogan 2002; Le Bars et al. 2001).1 Although these have limited application for assessing pain in other situations (e.g., after surgery), they do provide insight into potential pain-related behaviors and can help predict effective analgesic drug dose rates. Techniques that measure momentary nociceptive responses involve the application of a brief noxious stimulus followed by quantification of the animal’s response. Administration of anal- gesics usually modifies this response, for example by prolonging the latency of withdrawal of a limb or tail from the noxious stimulus. In addition to the use of such techniques in small laboratory animals, they have been applied to studies in larger species to assess analgesic efficacy and detect the occur- rence of hyperalgesia after injury (Dixon et al. 2002; KuKanich et al. 2005; Ley and Waterman 1996; Pypendop et al. 2006; Slingsby et al. 2001; Veis- sier et al. 2000; Welsh and Nolan 1995). Although primarily used as a means of screening for potential analge- sics in drug discovery programs, the results of nociception measurement have been used to estimate dose rates of analgesics for clinical use in both large and small animals. Such extrapolations, however, must be made with caution. In one study, estimates of appropriate doses of buprenorphine based on tail flick tests resulted in a recommended dose of 0.5 mg/kg in rats (Flecknell 1984), 10 times higher than that proven to be effective in postoperative pain scoring systems (Roughan and Flecknell 2004). Since high doses of this agent can have undesirable side effects, it is important to approach these extrapolations very carefully. Although the results of these tests may not predict clinical efficacy, they 1 The committee acknowledges the publication of pertinent work on both small laboratory rodents and larger animal species. Readers who wish to delve into this topic are urged to begin with the cited references and expand their reading through them.

6 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS do illustrate the very wide variation in response among different strains of rodents (Mogil et al. 1999; Morgan et al. 1999) and thus reinforce the importance of developing pain scoring schemes. If appropriate schemes cannot be used, then dose rates are probably best estimated based on the results of inflammatory pain models such as the late-phase formalin test (Roughan and Flecknell 2002; Appendix A provides details). Biological Markers of Nociceptor Activation Although biomarkers of nociceptor activation can be used only as research tools, they can indicate whether a particular procedure could cause pain. For example, the early gene product c-fos (Coggeshall 2005) has been used as a marker of nociceptor activity in a number of species (Lykkegaard et al. 2005; Svendsen et al. 2007). Such assessments are pos- sible only within a short time after the animal is euthanized and so are not suitable for routine clinical use. As discussed in Chapter 2, nociceptor activation and some of the other peripheral and central changes associated with pain and tissue dam- age result in alterations of sensory thresholds, notably hyperalgesia and allodynia (the perception of previously nonnoxious stimuli as noxious). These changes have been used as indicators of both nociceptor activity and the efficacy of analgesic therapy in both laboratory and clinical stud- ies (Lascelles et al. 1997; Whiteside et al. 2004). Although these methods essentially measure peripheral changes, it is reasonable to assume that in conscious animals such changes indicate that pain has been experienced and may still be present. Brain Activity Imaging Recent imaging studies have demonstrated that exposure to noxious stimuli activates a range of cortical and subcortical areas—both primary somatosensory cortex and areas associated with the affective component of pain in humans (Hess et al. 2007). Although such activation does not demonstrate awareness of pain in animals, it clearly indicates activation of the cortical areas considered necessary for the affective component of pain (see also Box 1-3). The use of imaging offers a novel approach for detecting central processing of nociceptive information in animals and may enable a more objective assessment of the potential for particular procedures or conditions to cause pain. PAIN ASSESSMENT: SPECIES-SPECIFIC CLINICAL SIGNS There is a remarkable lack of validated behavioral signs of pain in many species (Viñuela-Fernández et al. 2007). The following sections pres-

 RECOGNITION AND ASSESSMENT OF PAIN ent a number of species-specific clinical manifestations based on expert clinical opinion and best practices. Although the signs described typically accompany or indicate pain, many are not specific to pain and may occur as general signs of ill health or as responses to stress or distress (readers are encouraged to consult the ethograms and tables with species-specific clini- cal signs indicating pain, distress, or discomfort in the appendix of the 2008 NRC report Recognition and Alleiation of Distress in Laboratory Animals). Nonhuman Primates Nonhuman primates show remarkably little reaction to surgical proce- dures or to injury, especially in the presence of humans, and might look well until they are gravely ill or in severe pain. Viewing an animal from a distance or by video can aid in detecting subtle clinical changes. A nonhu- man primate that appears sick is likely to be critically ill and might require rapid attention. A nonhuman primate in pain has a general appearance of misery and dejection. It might huddle in a crouched posture with its arms across its chest and its head forward with a “sad” facial expression or a grimace and glassy eyes. It might moan or scream,2 avoid its companions, and stop grooming. A monkey in pain can also attract altered attention from its cagemates, varying from a lack of social grooming to attack. The animal may show acute abdominal pain through facial contortions, clenching of teeth, restlessness, and shaking accompanied by grunts and moans. Head pain may be manifest by head pressing against the enclosure surface. Self- directed injurious behavior may be a sign of more intense pain. Primates in pain usually refuse food and water. If an animal is well socialized or trained to perform tasks as part of a research protocol, changes in response to famil- iar personnel or in willingness to cooperate may indicate pain. Dogs Dogs in pain generally appear less alert and quieter than normal although small breeds are generally more reactive to environmental changes than large dogs. Dogs in pain may move stiffly or be unwilling to move, and if in severe pain may lie still or adopt an abnormal posture to minimize discomfort. In less severe pain, dogs can appear restless and more alert. Other apparent potential changes include inappetence, shivering, and increased respiration with panting. Dogs in pain may bite, scratch, or guard painful regions and if handled may be unusually appre- hensive or aggressive. Their response to a familiar handler may be differ- 2Loud and persistent vocalization is an occasional but unreliable expression of pain as it is more likely to signify alarm or anger.

8 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS ent; for example, a dog in pain may fail to wag its tail or may shrink away. Incessant licking is sometimes associated with localized pain. Pain in one limb usually results in limping or holding up of the affected limb with no attempt to use it. Spontaneous barking is unlikely; dogs are more likely to whimper or howl, especially if unattended, and may growl without appar- ent provocation. However, lack of vocalization or excessive vocalization is not a reliable indicator of pain. Cats With cats, which are less noticeably reactive to environmental changes than dogs, a general lack of well-being is an important indication of pain. A cat in pain is generally quiet and has an apprehensive facial expression (e.g., its forehead may appear creased). The animal may cry, yowl, growl, or hiss if approached or made to move. It tends to hide or to separate itself from other cats. Its posture becomes stiff and abnormal, varying with the site of pain. If the pain is in the head or ears, the animal might tilt its head toward the affected side. A cat with generalized pain in both the thorax and abdomen may crouch or hunch. If the pain is only thoracic, the head, neck, and body might be extended. A cat with abdominal or back pain might stand or lie on its side with its back arched or walk with a stilted gait. Incessant licking is sometimes associated with localized pain. Pain in one limb usually results in limping or holding up of the affected limb with no attempt to use it. Cats in severe or chronic pain look ungroomed and behave markedly differently from normal. Touching or palpation of a painful area might produce an immediate violent reaction and an attempt to escape. A reduction in food and water intake may be an indicator of pain. Laboratory Rodents Rats and mice are the two rodent species most widely used in research generally and in pain-related studies specifically, so it is important that researchers and institutional animal care and use committees recognize when these animals are in pain (for additional information see Chapter 1: Boxes 1-3 and 1-4, Chapter 4, and Appendix A). Rats and mice in acute pain may vocalize and become unusually aggressive when handled. Because rodents also vocalize at ultrasonic frequencies inaudible to humans, the absence of audible vocalization does not necessarily signify the absence of acute pain. Inappetence or a change in feeding activity may become evi- dent; for example, the animals may eat bedding or their offspring. If they are housed with others, the normal group behavior or grooming might change. Rodents in pain may separate from their cagemates and attempt to hide, or they may no longer exhibit nest-building behavior. In rats, porphyrin secre-

 RECOGNITION AND ASSESSMENT OF PAIN tion (“red tears”) may appear around the eyes and nose, although this is a general response to stress of any kind. Normal guinea pigs stampede and squeal when startled, when attempts are made to handle them, or when strangers are in the room, but sick guinea pigs and those in pain usually remain quiet. However, because a normal guinea pig’s initial response to the presence of an observer is also to remain immobile, assessing signs of pain can be extremely difficult. Guinea pigs in pain reduce their food and water consumption and may become anorexic. As with rabbits, this behavior can exacerbate the ileus (i.e., gut stasis) that may occur following surgery and can result in a fatal enterotoxemia. There is virtually no information about signs of pain in hamsters and gerbils, although it is assumed that when in pain they, like rats and mice, will show decreased activity, piloerection, and an ungroomed appearance. As with other species they may adopt an abnormal posture, which may be particularly obvious when moving. Respiration may change. Rabbits Rabbits in pain may appear apprehensive, anxious, dull, or inactive, assume a hunched appearance, attempt to hide, and squeal or cry. But sometimes they show aggressive behavior with increased activity and exces- sive scratching and licking. Reactions to handling are exaggerated, and acute pain might result in vocalization. With abdominal pain, they may show back arching when moving, contraction of the abdominal muscles, and pressing of the abdomen to the ground. Although teeth-grinding has been identified as an indicator of pain, it is not a reliable behavioral sign and studies to support its usefulness as a pain indicator have not yet been done. The respiratory rate of the animals may increase and they may eat and drink less. As with rodents, surgery in rabbits can result in ileus and this, coupled with pain-associated inappetence, can lead to the development of a fatal enterotoxemia. As with other species, a general lack of grooming may be associated with pain. Ungulates The greatest progress in developing objective behavior-based methods of assessing the response to pain and injury has been in farm animals. Behavioral and endocrine indicators of pain in lambs, cattle, and pigs have been established by a number of research groups (Hay et al. 2003; Lester et al. 1996; Mellor and Stafford 2000; Molony et al. 2002; Noonan et al. 1994) and vocalization patterns in piglets have been analyzed as potential indicators of pain (Puppe et al. 2005; Weary et al. 1998). These measures have been developed largely to aid in the evaluation of the welfare benefits

60 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS of modifying standard agricultural practices such as tail docking, castration, and dehorning. It has been repeatedly demonstrated that use of local anes- thetics, either alone or in conjunction with modifications to the techniques commonly used, can reduce pain-related behaviors in lambs and cattle (Mellor and Stafford 2000). These studies not only allowed ranking of the degree of pain caused by different procedures but also highlighted some of the problems associated with the use of behavioral signs as indicators of pain. For example, lambs castrated using a rubber ring to constrict the neck of the scrotum show a series of very easily identified abnormal behaviors associated with pain. Lambs castrated surgically without anesthesia remain largely immobile for prolonged periods but the endocrine stress response produced by this method is even greater than that produced by rubber ring occlusion (Lester et al. 1991). Because the types of behaviors observed in lambs undergoing these different procedures varied, it was not possible to use behavior alone to rank the degree of pain. However, the behavioral responses could be used to compare methods of reducing the pain associ- ated with each procedure (Molony et al. 2002). Horses Horses in acute pain show reluctance to be handled and other varied responses (Ashley et al. 2005; Driessen and Zarucco 2007): periods of rest- lessness, interrupted feeding with food held in the mouth uneaten, anxious appearance with dilated pupils and glassy eyes, increased respiration and pulse rate with flared nostrils, profuse sweating, and a rigid stance. Horses in pain also grind their teeth, switch their tails, or play with their water bucket. For animals in prolonged pain, behavior may change from restless- ness to depression with head lowered. In pain associated with skeletal dam- age, there is reluctance to move; the animal may hold its limbs in unusual positions (e.g., it may stand “parked” with the weight on the hind feet and one front foot “pointed” ahead of the other), and the head and neck in a fixed position. Horses with abdominal or thoracic pain may look at, bite, or kick their abdomen; get up and lie down frequently; walk in circles; stand “parked” with elbows adducted; and sweat, roll, and injure themselves as a result of these activities, with bruising especially around the eyes. Cattle Cattle in pain often appear dull and depressed, hold their heads low, and show little interest in their surroundings. Their overall activity may be reduced (Hudson et al. 2008). Other observable changes include inap- petence, weight loss, grunting, grinding of teeth, and, in milking cows, decreased milk yield (Hernandez et al. 2002, 2005). Severe pain often

61 RECOGNITION AND ASSESSMENT OF PAIN results in rapid, shallow respiration. On handling, the animals may react violently or adopt a rigid posture to immobilize the painful region. Localized pain may be associated with persistent licking or kicking at the offending area and, when the pain is severe, bellowing. Generally, signs of abdominal pain are similar to those in horses, but less marked. Rigid posture can lead to a lack of grooming because of an unwillingness to turn the neck. With acute abdominal conditions, such as intestinal strangulation, cattle adopt a characteristic stance with one hind foot placed directly in front of the other. The behavior of calves after dehorning and castration without anesthe- sia has been described in detail (Molony et al. 1995; Stafford and Mellor 2005) and includes decreased rumination and feeding and an increased incidence of ear flicking, tail flicking, and head shaking. After castra- tion using a rubber ring, calves showed restlessness, foot stamping/kick- ing, stretching, and adjustments of posture (“easing quarter”); in contrast, after crushing (Burdizzo) or surgical castration the most marked behavioral change was “statue” standing (Molony et al. 1995). Sheep and Goats Signs of pain in sheep and goats are generally similar to those in cattle, but sheep, in particular, tolerate severe injury without overt signs of pain or distress. There is a general reluctance to move, coupled with changes in posture, movement, and facial expression. Pain can also cause cessation of rumination, eating, and drinking, and increased curling of the lips; but, as in other species, these are not reliable indicators of pain. Goats are more likely than cattle to vocalize in response to pain. They may also grind their teeth, have rapid and shallow breathing, change posture frequently, and appear agitated (stamping their feet). Dairy goats quickly decrease produc- tion and lose body weight and general body condition. After castration or tail docking, lambs show very characteristic signs of pain by standing and lying repeatedly, wagging their tails, occasionally bleating, and displaying neck extension, dorsal lip curling, kicking, rolling, and hyperventilation (Molony et al. 2002). Pigs Pigs in pain might show changes in their overall demeanor, social behavior, gait, and posture as well as an absence of bed making. They may become apathetic and unwilling to move and may hide in bedding if possible. Pigs normally squeal and attempt to escape when handled, and pain can accentuate these reactions or cause adults to become aggressive. Squealing is also characteristic when painful areas are palpated. More

62 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS moderate pain may simply reduce activity levels and make the animal less responsive to familiar handlers and reluctant to feed or drink (Harvey-Clark et al. 2000; Malavasi et al. 2006). Birds and Poultry Birds in pain show escape reactions, vocalization, and excessive move- ment. Small species struggle less and emit fewer distress calls than large spe- cies. Head movements increase in extent and frequency. There may also be an increase in heart and respiratory rates. Birds in chronic pain may exhibit a passive immobility characterized by a crouched posture with closed or partially closed eyes and head drawn toward the body. They may also become inappetent and inactive with a drooping, miserable appearance, holding their wings flat against the body and their neck retracted. There may be reduced perching or birds may remain at the bottom of the cage. When a bird is handled, its escape reaction may be replaced by immobility. Birds with limb pain avoid use of the affected limb and refrain from extension. Reptiles Acute pain in reptiles is characterized by flinching and muscle contrac- tions. There might be aversive movements away from the unpleasant stimu- lus and attempts to bite. Chronic and persistent pain may be associated with inappetence, lethargy, and weight loss, although it is difficult to associate any of these signs of lack of well-being specifically with pain. Fish It is difficult to determine the nature of the response to pain in fish or whether their experience is similar to that observed in mammals (ILAR 2009; Rose 2002; Sneddon 2006; see Chapter 1). Although there have been few species-specific studies, there is evidence that fish exhibit a pronounced initial response to injuries or to contact with nociceptive stimuli or chemical algesics (Sneddon 2003; Sneddon et al. 2003a,b; Reilly et al. 2008; Ashley et al. 2009) but their response to chronic stimuli has not been characterized. Generally, fish react to noxious stimuli (such as puncture with a hypodermic needle) with strong muscular movements, and when exposed to a noxious environment (such as an acidic solution) show abnormal swimming behav- ior, attempts to jump from the water, and more rapid opercular movements. Such effects indicate some, perhaps considerable, distress, but it is not pos- sible to state unequivocally that it is pain-induced distress. Recent research has identified nociceptors in fish (Ashley et al. 2006, 2007; Sneddon 2002; Sneddon et al. 2003a) that are physiologically similar

63 RECOGNITION AND ASSESSMENT OF PAIN to mammalian nociceptors. In vivo administration of a noxious stimulus resulted in aberrant behaviors (rocking on the substrate and rubbing of the affected area) and adverse changes in physiology in rainbow trout over a period of 3 to 6 hours (Sneddon et al. 2003a,b); morphine reduced the incidence of these behaviors (Sneddon 2003; Sneddon et al. 2003b). Recent research has also shown that, after a one-time subcutaneous injection of 1% acetic acid to the lower and upper frontal lip, trout do not show appropriate neophobic or antipredator behaviors when compared to behavioral impair- ments associated with pain (Ashley et al. 2009; Sneddon et al. 2003b). Goldfish given electric shock display agitated swimming behavior but the threshold for this response increases if morphine is injected, while naloxone blocks the morphine effect (Jansen and Greene 1970). Work by Ehrensing and colleagues (1982) showed that the endogenous opioid antagonist MIF-1 downregulates sensitivity to opioids in goldfish, which then do not show an escape response to electric shock. Studies have shown that goldfish are able to learn to avoid noxious, potentially painful stimuli such as electric shock (Portavella et al. 2002, 2004). Learned avoidance of a stimulus associated with a noxious experi- ence has also been observed in other fish species including common carp and pike (Esox lucius), which avoided hooks in angling trials (Beukema 1970a,b; Overmier and Hollis 1983, 1990). Amphibians Amphibian species such as anurans (frogs and toads) and urodeles (salamanders) are commonly used in laboratory animal research settings (Schaeffer 1997), but there is no objective means to assess the presence and severity of pain in amphibians, especially since they do not exhibit any facial expression (Hadfield and Whitaker 2005). Some exotic animal clinicians use nonspecific clinical signs such as decrease in avoidance movement (e.g., when approached by a handler) or decrease in appetite as indicators of pain in these animals. Research has shown that amphibians are able and motivated to learn to avoid noxious stimuli (Strickler-Shaw and Taylor 1991). CONCLUSIONS AND RECOMMENDATIONS Further studies to develop robust, reliable, broadly applicable pain assessment tools are required. The general assumption is that the magnitude of the clinical signs and behavioral changes observed correlates closely with the intensity of pain. The extent to which these behavior-based assess- ments reflect the affective component of pain is uncertain and requires an improved understanding of the nature of pain, consciousness, and affective

64 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS state in animals (see Box 1-2 in Chapter 1). Further, the lack of overlap between the assessment techniques used by veterinarians, pain researchers (Appendix A), and psychologists (Box 1-4) is an impediment to progress toward a broadly shared understanding. The committee offers the following conclusions and recommen- dations: 1. Pain in animals is difficult to assess and greatly depends on the com- bination of a structured clinical examination and good knowledge of the normal appearance and behavior of the animals involved. 2. Observing animals’ response to analgesic treatment can help refine clinical assessment schemes. 3. As more objective pain assessment schemes are developed, they should be adopted. The paucity of information for species other than farm animals, rats, and mice is detrimental to the animals’ wel- fare and well-being as well as the quality of scientific research. 4. Responses of animals in analgesic drug tests and in models of pain can be used in efforts to identify (1) specific behaviors for use in assessment schemes and (2) sources of variation and factors that may influence pain intensity and analgesic efficacy. REFERENCES Arras M, Rettich A, Cinelli P, Kasermann HP, Burki K. 2007. Assessment of post-laparotomy pain in laboratory mice by telemetric recording of heart rate and heart rate variability. BMC Vet Res Aug 2:3-16. Ashley FH, Waterman-Pearson AE, Whay HR. 2005. Behavioural assessment of pain in horses and donkeys: Application to clinical practice and future studies. Equine Vet J 37(6): 565-575. Ashley PJ, Sneddon LU, McCrohan CR. 2006. Properties of corneal receptors in a teleost fish. Neurosci Lett 410(3):165-168. Ashley PJ, Sneddon LU, McCrohan CR. 2007. Nociception in fish: Stimulus-response properties of receptors on the head of trout Oncorhynchus mykiss. Brain Res 1166:47-54. Ashley PJ, Ringrose S, Edwards KL, Wallington E, McCrohan CR, Sneddon LU. 2009. Effect of noxious stimulation upon anti-predator responses and dominance status in rainbow trout. Anim Behav 77(2):403-410. Beukema JJ. 1970a. Acquired hook-avoidance in the pike Esox lucius L. fished with artificial and natural baits. J Fish Biol 2:155-160. Beukema JJ. 1970b. Angling experiments with carp: Decreased catchability through one trial learning. Neth J Zool 20:81-92. Beynen AC, Baumans V, Bertens AP, Havenaar R, Hesp AP, Van Zutphen LF. 1987. Assessment of discomfort in gallstone-bearing mice: A practical example of the problems encountered in an attempt to recognize discomfort in laboratory animals. Lab Anim 21(1):35-42. Brodbelt DC, Taylor PM, Stanway GW. 1997. A comparison of preoperative morphine and buprenorphine for postoperative analgesia for arthrotomy in dogs. J Vet Pharmacol Ther 20(4):284-289.

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68 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS Rietmann TR, Stauffacher M, Bernasconi P, Auer JA, Weishaupt MA. 2004. The association between heart rate, heart rate variability, endocrine and behavioural pain measures in horses suffering from laminitis. J Vet Med A Physiol Pathol Clin Med 51(5):218-225. Rose JD. 2002. The neurobehavioral nature of fishes and the question of awareness and pain. Rev Fish Sci 10:1-38. Roughan JV, Flecknell PA. 2000. Effects of surgery and analgesic administration on spontaneous behaviour in singly housed rats. Res Vet Sci 69(3):283-288. Roughan JV, Flecknell PA. 2001. Behavioural effects of laparotomy and analgesic effects of ketoprofen and carprofen in rats. Pain 90(1-2):65-74. Roughan JV, Flecknell PA. 2002. Buprenorphine: A reappraisal of its antinociceptive effects and therapeutic use in alleviating post-operative pain in animals. Lab Anim 36(3):322-343. Roughan JV, Flecknell PA. 2003. Evaluation of a short duration behaviour-based post-operative pain scoring system in rats. Eur J Pain 7(5):397-406. Roughan JV, Flecknell PA. 2004. Behaviour-based assessment of the duration of laparotomy- induced abdominal pain and the analgesic effects of carprofen and buprenorphine in rats. Behav Pharmacol 15(7):461-472. Roughan JV, Flecknell PA. 2006. Training in behaviour-based post-operative pain scoring in rats—An evaluation based on improved recognition of analgesic requirements. Appl Anim Behav Sci 96(3-4):327-342. Schaeffer D. 1997. Anesthesia and analgesia. In: Kohn DF, ed. Nontraditional Laboratory Ani- mal Species in Anesthesia and Analgesia in Laboratory Animals. San Diego: Academic Press. Sharp J, Zammit T, Azar T, Lawson D. 2003. Recovery of male rats from major abdominal sur- gery after treatment with various analgesics. Contemp Top Lab Anim Sci. 42(6):22-27. Slingsby LS, Waterman-Pearson AE. 1998. Comparison of pethidine, buprenorphine and ketoprofen for postoperative analgesia after ovariohysterectomy in the cat. Vet Rec 143(7):185-189. Slingsby LS, Jones A, Waterman-Pearson AE. 2001. Use of a fingermounted device to compare mechanical nociceptive thresholds in cats given pethidine or no medication after castra- tion. Res Vet Sci 70:243-246. Sneddon LU. 2002. Anatomical and electrophysiological analysis of the trigeminal nerve in a teleost fish, Oncorhynchus mykiss. Neurosci Lett 319(3):167-171. Sneddon LU. 2003. The evidence for pain perception in fish: The use of morphine as an an- algesic. Appl Anim Behav Sci 83:153-162. Sneddon LU. 2006. Ethics and welfare: Pain perception in fish. B Eur Assoc Fish Pat 26(1): 6-10. Sneddon LU, Braithwaite VA, Gentle MJ. 2003a. Do fishes have nociceptors? Evidence for the evolution of a vertebrate sensory system. Proc R Soc Lond B Biol Sci 270(1520): 1115-1121. Sneddon LU, Braithwaite VA, Gentle MJ. 2003b. Novel object test: Examining nociception and fear in the rainbow trout. J Pain 4(8):431-440. Stafford KJ, Mellor DJ. 2005. Dehorning and disbudding distress and its alleviation in calves. Vet J 169(3):337-349. Strickler-Shaw S, Taylor DH. 1991. Lead inhibits acquisition and retention learning in bullfrog tadpoles. Neurotoxicol Teratol 13:167-173. Svendsen O, Kok L, Lauritzan B. 2007. Nociception after intraperitoneal injection of a socium pentobarbitone formulation with and without lidocain in rats quantified by expression of neuronal c-fos in the spinal cord: A preliminary study. Lab Anim 41(2):197-203. Veissier II, Rushen J, Colwell D, de Passillé AM. 2000. A laser-based method for measuring thermal nociception of cattle. Appl Anim Behav Sci 66(4):289-304.

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The use of animals in research adheres to scientific and ethical principles that promote humane care and practice. Scientific advances in our understanding of animal physiology and behavior often require theories to be revised and standards of practice to be updated to improve laboratory animal welfare.

Recognition and Alleviation of Pain in Laboratory Animals, the second of two reports revising the 1992 publication Recognition and Alleviation of Pain and Distress in Laboratory Animals from the Institute for Laboratory Animal Research (ILAR), focuses on pain experienced by animals used in research. This book aims to educate laboratory animal veterinarians; students, researchers and investigators; Institutional Animal Care and Use Committee members; and animal care staff and animal welfare officers on the current scientific and ethical issues associated with pain in laboratory animals. It evaluates pertinent scientific literature to generate practical and pragmatic guidelines for recognizing and alleviating pain in laboratory animals, focusing specifically on the following areas: physiology of pain in commonly used laboratory species; pharmacologic and non-pharmacologic principles to control pain; identification of humane endpoints; and principles for minimizing pain associated with experimental procedures. Finally, the report identifies areas in which further scientific investigation is needed to improve laboratory animal welfare.

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