Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 47
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
OCR for page 48
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.
OCR for page 49
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
OCR for page 50
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
OCR for page 51
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).
OCR for page 52
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
OCR for page 53
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
OCR for page 54
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
OCR for page 55
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.
OCR for page 56
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-
OCR for page 57
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.
OCR for page 60
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
OCR for page 61
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
OCR for page 62
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
OCR for page 63
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
OCR for page 64
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.
OCR for page 65
6
RECOGNITION AND ASSESSMENT OF PAIN
Cambridge AJ, Tobias KM, Newberry RC, Sarkar DK. 2000. Subjective and objective measure-
ments of postoperative pain in cats. JAVMA 217(5):685-690.
Clark MD, Krugner-Higby L, Smith LJ, Heath TD, Clark KL, Olson D. 2004. Evaluation of
liposome-encapsulated oxymorphone hydrochloride in mice after splenectomy. Comp
Med 54(5):558-563.
Coggeshall RE. 2005. Fos, nociception and the dorsal horn. Prog Neurobiol 77(5):299-352.
Cowan A, Doxey JC, Harry EJ. 1977. The animal pharmacology of buprenorphine, an oripavine
analgesic agent. Br J Pharmacol 60(4):547-554.
Dixon MJ, Robertson SA, Taylor PM. 2002. A thermal threshold testing device for evaluation
of analgesics in cats. Res Vet Sci 72:205-210.
Driessen B, Zarucco L. 2007. Pain: From diagnosis to effective treatment. Clin Tech Equine P
6(2):126-134.
Duncan IJ, Beatty ER, Hocking PM, Duff SR. 1991. Assessment of pain associated with degen-
erative hip disorders in adult male turkeys. Res Vet Sci 50(2):200-203.
Ehrensing RH, Michell GF, Kastin AJ. 1982. Similar antagonism of morphine analgesia by MIF-1
and naloxone in Carassius auratus. Pharmacol Biochem Behav 17(4):757-761.
Firth AM, Haldane SL. 1999. Development of a scale to evaluate postoperative pain in dogs.
JAVMA 214(5):651-659.
Flecknell PA. 1984. Relief of pain in laboratory animals. Lab Anim 18:147-160.
Flecknell PA, Liles JH. 1991. The effects of surgical procedures, halothane anaesthesia and
nalbuphine on locomotor activity and food and water consumption in rats. Lab Anim
25(1):50-60.
Gabriel AF, Marcus MA, Honig WM, Walenkamp GH, Joosten EA. 2007. The CatWalk method:
A detailed analysis of behavioral changes after acute inflammatory pain in the rat. J Neu-
rosci Methods 163(1):9-16.
Gaynor JS, Muir W. 2002. Handbook of Veterinary Pain Management. St. Louis, MO: Mosby.
Giamberardino MA, Valente R, de Bigontina P, Vecchiet L. 1995. Artificial ureteral calculosis
in rats: Behavioural characterization of visceral pain episodes and their relationship with
referred lumbar muscle hyperalgesia. Pain 61(3):459-469.
Gonzalez MI, Field MJ, Bramwell S, McCleary S, Singh L. 2000. Ovariohysterectomy in the rat:
A model of surgical pain for evaluation of pre-emptive analgesia? Pain 88(1):79-88.
Grisneaux E, Pibarot P, Dupuis J, Blais D. 1999. Comparison of ketoprofen and carprofen ad-
ministered prior to orthopedic surgery for control of postoperative pain in dogs. JAVMA
215(8):1105-1110.
Hadfield CA, Whitaker BR. 2005. Amphibian emergency medicine and care. Semin Avian Exot
Pet 14(2 Spec Iss):79-89.
Harvey-Clark CJ, Gilespie K, Riggs KW. 2000. Transdermal fentanyl compared with parenteral
buprenorphine in post-surgical pain in swine: A case study. Lab Anim 34(4):386-398.
Hawkins P. 2002. Recognizing and assessing pain, suffering and distress in laboratory animals: A
survey of current practice in the UK with recommendations. Lab Anim 36(4):378-395.
Hay M, Vulin A, Génin S, Sales P, Prunier A. 2003. Assessment of pain induced by castration
in piglets: Behavioral and physiological responses over the subsequent 5 days. Appl Anim
Behav Sci 82(3):201-218.
Hayes KE, Raucci JA Jr, Gades NM, Toth LA. 2000. An evaluation of analgesic regimens for
abdominal surgery in mice. Contemp Top Lab Anim 39(6):18-23.
Hazewinkel HAW, van den Brom WE, Theyse LFH, Pollmeier M, Hanson PD. 2008. Compari-
son of the effects of firocoxib, carprofen and vedaprofen in a sodium urate crystal induced
synovitis model of arthritis in dogs. Res Vet Sci 84(1):74-79.
Hernandez J, Shearer JK, Webb DW. 2002. Effect of lameness on milk yield in dairy cows.
JAVMA 220(5):640-644.
OCR for page 66
66 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS
Hernandez JA, Garbarino EJ, Shearer JK, Risco CA, Thatcher WW. 2005. Comparison of milk
yield in dairy cows with different degrees of lameness. JAVMA 227(8):1292-1296.
Hess A, Sergejeva M, Budinsky L, Zeilhofer HU, Brune K. 2007. Imaging of hyperalgesia in
rats by functional MRI. Eur J Pain 11(1):109-119.
Hogan Q. 2002. Animal pain models. Reg Anesth Pain Med 27(4):385-401.
Holton L, Reid J, Scott EM, Pawson P, Nolan A. 2001. Development of a behaviour-based scale
to measure acute pain in dogs. Vet Rec 148(17):525-531.
Holton LL, Scott EM, Nolan AM, Reid J, Welsh E. 1998. Relationship between physiological
factors and clinical pain in dogs scored using a numerical rating scale. J Small Anim
Pract 39(10):469-474.
Hudson C, Whay H, Hixley J. 2008. Recognition and management of pain in cattle. In Practice
30:126-134.
ILAR. 2009. Pain and Distress in Fish. ILAR J 50:327-418.
Jansen GA, Greene NM. 1970. Morphine metabolism and morphine tolerance in goldfish.
Anesthesiology 32(3):231-235.
Karas AZ. 2002. Postoperative analgesia in the laboratory mouse, Mus musculus. Lab Anim
(NY) 31(7):49-52.
KuKanich B, Lascelles BD, Papich MG. 2005. Assessment of a von Frey device for evalua-
tion of the antinociceptive effects of morphine and its application in pharmacodynamic
modeling of morphine in dogs. Am J Vet Res 66:1616-1622.
Lascelles BD, Capner C, Waterman AF. 1995. Survey of perioperative analgesic use in small
animals. Vet Rec 137(26):676.
Lascelles BD, Cripps PJ, Jones A, Waterman AE. 1997. Post-operative central hypersensitivity and
pain: The pre-emptive value of pethidine for ovariohysterectomy. Pain 73(3):461-471.
Le Bars D, Gozariu M, Cadden SW. 2001. Animal models of nociception. Pharmacol Rev
53(4):597-652.
Leach MC, Allweiler S, Richardson C, Roughan JV, Flecknell PA. 2009. Behavioural effects of
ovarohysterectomy and oral administration of meloxicam in laboratory housed rabbits.
Res Vet Sci 87(2):336-347.
Lester SJ, Mellor DJ, Ward RN, Holmes RJ. 1991. Cortisol responses of young lambs to castra-
tion and tailing using different methods. New Zeal Vet J 39(4):134-138.
Lester SJ, Mellor DJ, Holmes RJ, Ward RN, Stafford KJ. 1996. Behavioural and cortisol responses
of lambs to castration and tailing using different methods. New Zeal Vet J 44:45-54.
Ley SJ, Waterman AE, Livingston A. 1996. Measurement of mechanical thresholds, plasma
cortisol and catecholamines in control and lame cattle: A preliminary study. Res Vet Sci
61:172-173.
Liles JH, Flecknell PA. 1992. The effects of buprenorphine, nalbuphine and butorphanol alone
or following halothane anaesthesia on food and water consumption and locomotor move-
ment in rats. Lab Anim 26(3):180-189.
Liles JH, Flecknell PA. 1993a. The effects of surgical stimulus on the rat and the influence of
analgesic treatment. Br Vet J 149(6):515-525.
Liles JH, Flecknell PA. 1993b. The influence of buprenorphine or bupivacaine on the post-
operative effects of laparotomy and bile-duct ligation in rats. Lab Anim 27(4):374-380.
Lykkegaard K, Lauritzen B, Tessem L, Weikop P, Svendsen O. 2005. Local anaesthetics attenu-
ates spinal nociception and HPA-axis activation during experimental laparotomy in pigs.
Res Vet Sci 79(3):245-251.
Malavasi LM, Nyman G, Augustsson H, Jacobson M, Jensen-Waern M. 2006. Effects of epi-
dural morphine and transdermal fentanyl analgesia on physiology and behaviour after
abdominal surgery in pigs. Lab Anim 40(1):16-27.
Mathews KA, Pettifer G, Foster R, McDonell W. 2001. Safety and efficacy of preoperative
administration of meloxicam, compared with that of ketoprofen and butorphanol in dogs
undergoing abdominal surgery. Am J Vet Res 62(6):882-888.
OCR for page 67
6
RECOGNITION AND ASSESSMENT OF PAIN
Mellor DJ, Stafford KJ. 2000. Acute castration and/or tailing distress and its alleviation in lambs.
New Zeal Vet J 48(2):33-43.
Mogil JS, Wilson SG, Bon K, Lee SE, Chung K, Raber P, Pieper JO, Hain HS, Belknap JK, Hubert
L, Elmer GI, Chung JM, Devor M. 1999. Heritability of nociception I: Responses of 11
inbred mouse strains on 12 measures of nociception. Pain 80(1-2):67-82.
Molony V, Kent JE, McKendrick IJ. 2002. Validation of a method for assessment of an acute
pain in lambs. Appl Anim Behav Sci 76(3):215-238.
Molony V, Kent JE, Robertson IS. 1995. Assessment of acute and chronic pain after different
methods of castration of calves. Appl Anim Behav Sci 46:33-48.
Morgan D, Cook CD, Picker MJ. 1999. Sensitivity to the discriminative stimulus and antinoci-
ceptive effects of mu opioids: Role of strain of rat, stimulus intensity, and intrinsic efficacy
at the mu opioid receptor. J Pharmacol Exp Ther 289(2):965-975.
Morton DB, Griffiths PH. 1985. Guidelines on the recognition of pain, distress and discomfort
in experimental animals and an hypothesis for assessment. Vet Rec 116(16):431-436.
Morton CM, Reid J, Scott EM, Holton LL, Nolan AM. 2005. Application of a scaling model to
establish and validate an interval level pain scale for assessment of acute pain in dogs.
Am J Vet Res 66(12):2154-2166.
Noonan GJ, Rand JS, Priest J, Ainscow J, Blackshaw JK. 1994. Behavioral observation of
piglets undergoing tail docking, teeth clipping and ear notching. Appl Anim Behav Sci
39:203-213.
NRC (National Research Council). 1992. Recognition and Alleviation of Pain and Distress in
Laboratory Animals. Washington: National Academy Press.
NRC. 2008. Recognition and Alleviation of Distress in Laboratory Animals. Washington: Na-
tional Academies Press.
Overmier JB, Hollis KL. 1983. Teleostean telencephalon in learning. In: David RE, Northcutt G,
eds. Fish Neurobiology Vol II: Higher Brain Areas and Functions. Ann Arbor: University
of Michigan. pp. 265-284.
Overmier JB, Hollis KL. 1990. Fish in the think tank: Learning, memory and integrated behav-
ior. In: Olton D, Kesner R, eds. The Neurobiology of Comparative Cognition. Hillsdale,
NJ: Erlbaum. pp. 205-236.
Parga, ML. 2002. Assessment of the efficacy of meloxicam and development of a pain-scoring
system based on behaviour in rabbits undergoing elective surgery. In: Proceedings of the
45th Annual BSAVA Congress Congress, 4th-7th April 2002, Birmingham, UK.
Portavella M, Vargas JP, Torres B, Salas C. 2002. The effects of telencephalic pallial lesions on
spatial, temporal, and emotional learning in goldfish. Brain Res Bull 57(3-4):397-399.
Portavella M, Torres B, Salas C. 2004. Avoidance response in goldfish: Emotional and temporal
involvement of medical and lateral telencephalic pallium. J Neurosci 24(9):2335-2342.
Price J, Catriona S, Welsh EM, Waran NK. 2003. Preliminary evaluation of a behaviour-based
system for assessment of post-operative pain in horses following arthroscopic surgery. Vet
Anaesth Analg 30(3):124-137.
Puppe B, Schön PC, Tuchscherer A, Manteuffel G. 2005. Castration-induced vocalisation in
domestic piglets, Sus scrofa: Complex and specific alterations of the vocal quality. Appl
Anim Behav Sci 95(1-2):67-78.
Pypendop BH, Ilkiew JE, Robertson SA. 2006. Effect of intravenous administration of lidocaine
on the thermal threshold in cats. Am J Vet Res 67:16-20.
Ranger M, Johnston CC, Anand KJS. 2007. Current controversies regarding pain assessment in
neonates. Sem Perinatol 31(5):283-288.
Reilly SC, Quinn JP, Cossins AR, Sneddon LU. 2008. Behavioural analysis of a nociceptive
event in fish: Comparisons between three species demonstrate specific responses. Appl
Anim Behav Sci 114:248-249.
OCR for page 68
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.
OCR for page 69
6
RECOGNITION AND ASSESSMENT OF PAIN
Viñuela-Fernández I, Jones E, Welsh EM, Fleetwood-Walker SM. 2007. Pain mechanisms
and their implication for the management of pain in farm and companion animals. Vet
J 174(2):227-239.
Weary DM, Braithwaite LA, Fraser D. 1998. Vocal response to pain in piglets. Appl Anim
Behav Sci 56(2-4):161-172.
Welsh EM, Nolan AM. 1995. Effect of flumixin meglumine on the threshold to mechanical
stimulation in healthy and lame sheep. Res Vet Sci 58:61-66.
Whiteside GT, Harrison J, Boulet J, Mark L, Pearson M, Gottshall S, Walker K. 2004. Pharmaco-
logical characterisation of a rat model of incisional pain. Br J Pharmacol 141(1):85-91.
Wright-Williams SL, Courade JP, Richardson CA, Roughan JV, Flecknell PA. 2007. Effects of
vasectomy surgery and meloxicam treatment on faecal corticosterone levels and behav-
iour in two strains of laboratory mouse. Pain 130(1-2):108-118.
Zwakhalen SMG, Hamers JPH, Berger MPF. 2006. The psychometric quality and clinical use-
fulness of three pain assessment tools for elderly people with dementia. Pain 126(1-3):
210-220.
OCR for page 70
