Pain 73 (1997) 461–471

Post-operative central hypersensitivity and pain: the pre-emptive

value of pethidine for ovariohysterectomy

B.D.X. Lascelles a,b,*, P.J. Cripps a, A. Jones a, A.E. Waterman a

a
Department of Clinical Veterinary Science, Division of Companion Animal Studies, Langford House, Langford, Bristol, BS18 7DU, UK
b
Department of Clinical Veterinary Science, University of Cambridge, Queen’s Veterinary School Hospital, Madingley Road, Cambridge, CB3 OES, UK

Received 23 April 1997; revised version received 5 August 1997; accepted 27 August 1997

Abstract

The effect of timing of analgesic drug administration on the severity of post-operative pain was investigated in dogs undergoing
ovariohysterectomy using both subjective visual assessment scoring systems (VAS) and objective mechanical nociceptive threshold
measurements using a novel handheld anti-nociceptiometric device. Forty dogs undergoing routine elective ovariohysterectomy were
included in a randomised and double-blind study and assigned to one of three groups: (i) pre-operative analgesics; (ii) post-operative
analgesics; (iii) no analgesics (saline injections). The analgesic used was pethidine (a short acting predominantly m-opioid agonist), at a
dose of 5.0 mg/kg (intramuscular). The post-operative administration of pethidine resulted in significantly higher sedation scores and
significantly lower pain scores in the early post-operative period, but the dogs given pethidine pre-operatively had significantly lower pain
scores than both the other groups at 8, 12 and 20 h post-extubation (P , 0.01, ANOVA). Mechanical thresholds measured at the distal tibia
demonstrated the development of allodynia at 12 and 20 h post-extubation, and this was significantly prevented by the pre- (P , 0.01 at 12
h, P , 0.05 at 20 h, Kruskal-Wallis and post hoc Dunn’s), but not by the post-operative administration of pethidine. Mechanical
nociceptive thresholds measured at the ventral midline (site of surgery) demonstrated post-operative hyperalgesia in all groups; this
hyperalgesia was least in the pre-operative pethidine group. In summary, this study clearly shows pethidine to be an effective analgesic
in dogs, albeit of short duration of action, when administered post-operatively, and, importantly, that it has a positive benefit in terms of
post-operative outcome measures, when administered pre-operatively, possibly as a result of blocking or preventing the development of
central sensitisation following surgical stimulation.  1997 International Association for the Study of Pain. Published by Elsevier Science
B.V.

Keywords: Pre-emptive; Analgesia; Dog; Opioid; Ovariohysterectomy; Central hypersensitivity

1. Introduction clinical setting has produced equivocal results as regards

Laboratory studies investigating the pre-emptive effect of
opioids have shown that pre-injury treatment with opioids
(Woolf and Wall, 1986b; Dickenson and Sullivan, 1987)
prevents or markedly decreases the development of central
hypersensitivity, but that these treatments are far less effec-
tive if administered after the injury is initiated (Woolf and
Wall, 1986a; Dickenson and Sullivan, 1987; Chapman and
Dickenson, 1993). Transposition of this argument to the
* Corresponding author.
whether or not the use of analgesics in a pre-emptive man-
ner produces any clinical benefit in terms of post-operative
pain. However, poor experimental design and confounding
variables have confused the issue (Katz, 1995). In order to
bridge the gap between basic scientific studies and the clin-
ical situation, Lascelles et al. (1995a) investigated a clinical
surgical procedure in a randomised double-blind placebo-
controlled study in rats. They found a clear marked reduc-
tion in post-operative hyperalgesia produced as a result of
surgery, when pethidine was administered pre-operatively
as opposed to post-operatively. The study reported here was
designed to take these investigations to the next logical
level, that is, to investigate the value of pre-emptive opioid

0304-3959/97/$17.00  1997 International Association for the Study of Pain. Published by Elsevier Science B.V.
PII S0304-3959 (97 )0 0141-3
462 B.D.X. Lascelles et al. / Pain 73 (1997) 461–471
analgesia on the development of post-operative pain and
hyperalgesia in the wholly clinical setting.
Simple visual appraisal is still the mainstay of the assess-
ment of clinical pain in animals. The visual analogue scale
system (VAS) has been widely used in the clinical setting to
assess post-operative pain in dogs (Mbugua et al., 1989;
Mburu, 1991; Reid and Nolan, 1991; Dodman et al.,
1992; Nolan and Reid, 1993; Lascelles et al., 1994a) and
recently in cats (Lascelles et al., 1995b).
Since the work of Goldscheider (1984) and Von Frey
(1897) who studied pain evoked in man by the use of pres-
sure stimuli, mechanical stimuli have been used in man and
animals to produce quantifiable nociceptive stimuli in order
to quantify changes in response to drug therapy and to assess
hyperalgesic states. In trying to design a mechanical device
for use in dogs, attempts have been made to quantify the
forces applied to the toes of dogs using a pair of Doyen
intestinal forceps (Martin et al., 1963); later a pneumatic
device was used (Martin et al., 1974, 1976). Hamlin et al.
(1988) used aluminium pliers with concave working ends to
enable a measured force to be applied to a varying number
of toes that were 5–15 mm in diameter. The major disad-
vantage of these techniques was that they could only be
applied to the toes, and, there was no way to control the
rate of application of the stimulus. These, and the other
systems described for producing a quantifiable noxious
mechanical stimulus in animals, have been used solely in
experimental animals, except for the studies of Ley and
colleagues (Ley et al., 1989, 1990, 1994, 1995) where a
mechanical stimulus was applied to sheep suffering from
the clinical condition, footrot. However, recently, in an
attempt to quantify pain associated with clinical conditions,
researchers have turned their attention to developing
devices which can be used at the site of pain. In man, Schiff-
man et al. (1988) described a pressure algometer for the
assessment of tenderness of muscle in the myofascial pain
syndrome in clinical patients. Atkins et al. (1992) and Bend-
tsen et al. (1994) described an electronic method for mea-
suring joint tenderness in rheumatoid arthritis and tender
myofascial tissues respectively, and recently Richmond et
al. (1993) used von Frey hairs to compare pre- and post-
operative intravenous morphine treatments in women
undergoing ovariohysterectomy. Based on the work of
Nolan et al. (1987) later modified by Livingston et al.
(1992), a novel handheld anti-nociceptiometric device (Las-
celles et al., 1994b) was developed, designed to be used at
various parts of the body. In this study, it was used to assess
Table 1
Mean body weight, and duration of anaesthesia and surgery for the three treatment groups
Drug protocol Weight, kg (±SEM)
Pre-operative pethidine (n = 10) 20.50 (2.22)
Post-operative pethidine (n = 10) 16.84 (1.62)
No analgesics (saline injections) (n = 20) 18.44 (1.67)
mechanical thresholds pre- and post-operatively, in order to
investigate the development of hyperalgesia as a result of
surgery.
The aim of this study was to investigate, using both sub-
jective visual assessment scoring systems and objective
mechanical nociceptive threshold measurements, whether
the timing of analgesic drug administration influenced the
quality of post-operative pain relief. The analgesic studied
was the opioid pethidine. Pethidine has been widely and
effectively used in man as an analgesic (Stambaugh et al.,
1976) and has also been shown to be an effective analgesic
in the clinical setting in dogs (Waterman and Kalthum,
1989), albeit with a short duration of action. It was decided
to study pethidine in these experiments because of its effi-
cacy as an analgesic and its short duration of action,
enabling it to be given to cover the surgical period, and
yet not lasting too long into the post-operative period.
Thus, the difference in outcome between just covering the
surgical period and just covering the immediate post-opera-
tive period could be examined.
2. Materials and methods
2.1. Animals
Forty dogs admitted to the surgical unit of the Division’s
Small Animal Hospital for elective ovariohysterectomy
were used in this study. They were of mixed breeds and
of between 10 and 25 kg in weight. Informed owner consent
for the use of the dogs was obtained, and the testing proce-
dure was carried out under a Home Office licence. None of
the dogs had any concurrent disease or were on any analge-
sic or anti-inflammatory medication. The dogs were
admitted at 08.30 h and remained in the clinic for 24 h,
after which time they returned to their owners. Patient
details are recorded in Table 1.
2.2. Anaesthesia and surgical procedure
Each dog was given a full physical examination on
admission and again after pre-medication. Pre-medication
consisted of acepromazine maleate (ACP, C-Vet), 0.05 mg/
kg sub-cutaneously, given about 1 h prior to the induction of
anaesthesia. Anaesthesia was induced with thiopentone
sodium (Intraval sodium, 2.5% solution, Rhone Merieux)
at 10 mg/kg i.v., using the cephalic vein in the forelimb
Duration of anaesthesia, Duration of surgery,
min (±SEM) min (±SEM)
45 (4) 32 (2)
48 (4) 33 (3)
49 (4) 35 (2)
 B.D.X. Lascelles et al. / Pain 73 (1997) 461–471
opposite to the side chosen for threshold testing in any par-
ticular dog. Following endotracheal intubation, anaesthesia
was maintained using halothane (Fluothane, RMB) deliv-
ered in an oxygen and nitrous oxide mixture, ratio 1:2,
delivered by a non-rebreathing non-coaxial Lack circuit.
The duration of anaesthesia was kept to between 40 and
60 min and recorded. Ovariohysterectomy was performed
via a ventral midline approach after appropriate clipping
and surgical preparation of the area. The incision was
from the umbilicus to a point half way to the level of the
pubic brim. Both ovarian pedicles were ligated using 0 poly-
glactin 910 (Vicryl, Ethicon), as was the cervical stump. The
muscle layers were apposed with simple interrupted 2/0
polyglactin 910 (Vicryl, Ethicon) sutures; a simple contin-
uous suture (polyglactin 910, 2/0) was placed in the fascial
layer and simple interrupted 3/0 polydioxanone (PDS, Ethi-
con) skin sutures were placed. The length of surgery was
kept to between 20 and 40 min in total, and the actual time
taken recorded. The duration of anaesthesia and surgery for
the groups are recorded in Table 1.
2.3. Analgesic regimen
The forty bitches were divided into three groups; one
group received pethidine (Pethidine, 50 mg/ml solution,
Arnolds Veterinary Products) prior to surgery, one group
received pethidine after surgery, and one group was given
saline, as summarised in Table 2. The dose of pethidine used
was 5.0 mg/kg, given as an intra-muscular (i.m.) injection
into the quadriceps on the opposite side to that on which
testing was carried out. The volume of saline used was 0.1
ml/kg, equal to the volume of pethidine used. All dogs
received two injections.
2.4. Assessment of outcome measures
Assessments (both visual and mechanical) were carried
out pre- and post-operatively at the following times: prior to
sedation, after sedation (just prior to induction), 20 min after
extubation, 1, 2, 4, 8, 12 and 20 h after extubation. At each
assessment time point, the dogs were muzzled, then
assessed using the VAS system as outlined below, and
also nociceptive threshold measurements were taken in the
manner described below. The dogs were muzzled to prevent
any accidental biting. At each assessment, the VAS assess-
ments were performed first and then the threshold measure-
ments were taken. The side of the dog to be tested (i.e., right
or left ear, forelimb and hindlimb) was determined prior to
Table 2
Three treatment groups into which 40 dogs were randomly allocated for analgesic administration
Drug protocol
Pre-operative pethidine (n = 10)
Post-operative pethidine (n = 10)
Saline (no analgesics) (n = 20
463
initiating the study by random allocation using shuffled
cards. No provision was made for supplementary analgesia
at any time. However, the dogs were constantly monitored,
and if a dog was found to be in extreme discomfort, it was
excluded from the study.
2.5. Subjective scoring system
The subjective, visual assessments made were dynamic
and interactive assessments, that is, the animals were
assessed initially whilst undisturbed. They were then
approached, talked to and the cage door was opened, all
the time noting how they reacted and behaved. They were
then gently handled, encouraged to walk and move around,
and finally the incision and surrounding area of the abdomen
and flank was palpated. By doing this, it was hoped to get a
complete picture of how sedated they were and how much
pain each animal was in.
Sedation was assessed by observation of the dog’s pos-
ture, its degree of mental alertness and its ability to stand
and walk. The degree of pain/discomfort present was
assessed by observation of the patient for signs of crying,
whimpering, restlessness, discomfort and by its response to
firm pressure applied to the region of surgery.
In this system, at each assessment, a mark was made on a
100-mm visual analogue scale (VAS), on which 0 (extreme
left) corresponded to either ‘no sedation’ or ‘no pain’ and
100 (extreme right) corresponded to either ‘fast asleep’ or
‘worst pain possible’ a dog could be in. This point (100 mm)
was ‘the worst possible’ pain a dog that had just undergone
ovariohysterectomy could be in. For each time point a mark
was made at the appropriate place on the 100-mm scale.
Conversion of the VAS to numerical form was made by
measuring the length of the line from 0 to the mark in
millimetres.
2.6. Nociceptive thresholds testing
A clinical mechanical algometer was used to obtain
threshold values (Lascelles et al., 1994b). It consisted of a
handheld pen-like device (probe) which incorporated a load
cell. The force applied to the end of the probe was trans-
mitted to the load cell, and a voltage output was produced.
This voltage output was taken to a transducer and amplifier,
and once the system was calibrated, a reading could be
obtained in Newtons. Linked to the system was a rate mea-
suring device (continual rate of application of force (CRAF)
meter) to enable the probe to be applied at a constant rate.
20–30 min prior to surgery On extubation
5.0 mg/kg pethidine i.m. 0.1 ml/kg saline i.m.
0.1 ml/kg saline i.m. 5.0 mg/kg pethidine i.m.
0.1 ml/kg saline i.m. 0.1 ml/kg saline i.m.
464 B.D.X. Lascelles et al. / Pain 73 (1997) 461–471
The whole system was portable, and was incorporated into a
single unit. The probe was robust enough to withstand con-
stant use and abuse (such as being bitten by the dog). The
calibration of the system was carried out using an accurate
load beam over a range of 15 N. The device had previously
been validated in human volunteers, and preliminary inves-
tigations had been carried out to verify the use of the alg-
ometer as an ‘antinociceptiometric’ device in dogs receiv-
ing narcotic analgesics (Lascelles et al., 1994a).
When in use, the probe was applied at right angles to the
skin at each point, and applied at a constant rate of applica-
tion as determined by the CRAF meter. The rate chosen for
application of the probe was 16 N over 10 s (1.6 N/s). Prior
to use each day, the CRAF meter was tested by doing a
series of 10 readings over 30 min, pressing onto a work
surface to ensure the correct rate of application.
The points chosen on the dog for testing were the pinna,
the distal radius, the distal tibia and the wound. These points
were chosen after preliminary testing of various parts of the
body in a series of dogs (Lascelles et al., 1994a). Testing
was carried out with the dog in lateral recumbency for the
pinna, distal radius and distal tibia, and in lateral recum-
bency or standing for the wound.
The pinna was tested in the midline about one-third of the
way from the tip to the base. The radius was tested over a
bony prominence at the distal end on the dorsal aspect, with
the leg held in a position of approximately 75% extended.
The tibia was tested at a place on the distal latero-dorsal
surface where bone could be palpated through the skin,
again with the leg held in approximately 75% extension.
The abdomen was tested at a point one-quarter of the way
to the pubic brim (mid point of surgical wound just to one
side of the midline). The pinna was tested first, then the
radius, the tibia and lastly the abdomen. A response to the
application of the probe, and, thus, the end point of a read-
ing, was taken to be either a shake of the head or vocalisa-
tion in the case of the pinna; a withdrawal of the limb or
vocalisation in the case of limb testing; and guarding the
abdomen, vocalisation or aggression in the case of abdom-
inal testing. No attempt was made to distinguish between a
spinal reflex response or a response resulting from integra-
tion of the signals at higher centres.
2.7. Statistical analysis
All data were examined for normality, using a correlation
test for normality as performed using Minitab (Minitab
release 8 extended version, Microsoft Corporation). If this
examination indicated that the data were normally distrib-
uted, parametric statistics were performed. Where balanced
two-way ANOVA tests were run; a further test of whether or
not parametric statistics were appropriate was carried out by
running a correlation test for normality on the residual
values, which were expected to be normally distributed,
calculated by the ANOVA programme (Minitab). Non-
parametric tests were used when preliminary examination
of the data indicated that the conditions required to perform
analysis of variance and other parametric tests were not
fulfilled (see above). The tests used (Kruskal–Wallis,
Mann–Whitney and Dunn’s) were performed using the soft-
ware package Instat.
The details of the dogs (weight, duration of anaesthesia,
and duration of surgery) were examined using a one-way
analysis of variance (ANOVA) on each variable.
The VAS data were examined using a two-way analysis
of variance test (ANOVA). Results were considered at two
levels of significance, P , 0.05 and P , 0.01.
The values for the threshold data were calculated as a
percentage change from pre-sedation values and the results
examined using a Kruskal–Wallis non-parametric test to
look for significant differences between groups at a given
time point. If differences were indicated, where these lay
was investigated using a post-hoc Dunn’s test, which
adjusted the levels of significance for the fact that multiple
comparisons were being carried out. Results were consid-
ered at two levels of significance, P , 0.05 and P , 0.01.
3. Results
There were no differences between the three groups with
respect to body weight, duration of anaesthesia or duration
of surgery. None of the dogs was found to be in extreme
discomfort, and so none was excluded from the study. Due
to the inherent difficulties of using clinical cases for
research in a clinical setting, it was not possible to achieve
a tighter spread than 20–30 min prior to the start of surgery
for the pre-operative injection.
3.1. VAS sedation scores
Overall, all the dogs showed signs of being sedated at the
post-sedation time point, and showed a greater level of
sedation immediately post-operatively, with the level of
sedation gradually declining to zero at 20 h post-extubation.
At the post sedation assessment time point, the dogs that had
recently received pethidine (the pre-operative pethidine
group) were significantly more sedated than the other two
groups. At 20 min post-extubation, the group that received
pethidine on extubation (post-operative pethidine group)
were significantly more sedated than the other two groups,
but the dogs that received pethidine prior to surgery were
still significantly more sedated than those that had not
received any analgesics. Again, at 1 h post-extubation, the
dogs that had received pethidine post-operatively were still
significantly more sedated than the other dogs. By 2 h post-
extubation, the dogs in the post-operative pethidine group
were more sedated than the pre-operative pethidine dogs.
There were no other significant differences between the
groups at any other time points; however, the dogs that
had pethidine pre-operatively had the lowest sedation scores
at 4, 8 and 12 h post-extubation (see Fig. 1).
 B.D.X. Lascelles et al. / Pain 73 (1997) 461–471
Fig. 1. VAS sedation scores in dogs both pre- and post-ovariohysterectomy
receiving pethidine either pre- or post-operatively or saline. Histograms
represent the mean ± SEM values. *P , 0.05, **P , 0.01, using an
ANOVA parametric test.
3.2. VAS pain scores
Overall, the dogs that received pethidine were assessed to
be in less pain than the dogs that had received only saline
injections, with the dogs that had received pethidine post-
operatively showing the lowest scores in the early post-
operative period, while the dogs that received the pethidine
pre-operatively showed the lowest scores in the later post-
operative period.
At the first two post-operative assessment time points, the
dogs that had been given pethidine post-operatively had the
lowest VAS pain scores, which were significantly lower
than both the other two groups, which were not dissimilar
from each other. By 2 and 4 h post-extubation, there were no
significant differences between the groups; however, the
dogs that received pethidine pre-operatively had the lowest
mean scores. This trend was continued and accentuated at 8,
12 and 20 h post-extubation, when the dogs that received
pethidine pre-operatively were assessed to be in signifi-
cantly less pain than those that received the pethidine
post-operatively at 8 h post-extubation, and significantly
less than both other groups at 12 and 20 h post-extubation.
The control dogs were assessed to be in the most pain at 2 h
post-extubation, and those that received pethidine post-
operatively reached similar maximum levels of pain, but
not until 8 h post-extubation (see Fig. 2).
3.3. Mechanical thresholds measured at the pinna
Results were obtained in only nine out of the 10 dogs in
the groups receiving carprofen pre- or post-operatively, due
to one dog’s disposition in each group. This dog was unpre-
dictably aggressive when testing was attempted.
Post-sedation, the thresholds in the pre-operative pethi-
dine group, which had just received the pethidine, were
higher than in the other two groups, significantly higher
compared to the control dogs. At 20 min post-extubation,
although the thresholds measured in the dogs that received
pethidine post-operatively were higher than in the other two
465
groups, large variation meant that the differences were not
significant. The thresholds in the post-operative pethidine
group were still raised at 1 h post-extubation, significantly
so with respect to both the other two groups. There were no
other differences between the groups at any other assess-
ment time points. Table 3 shows the median, maximum and
minimum values for the percentage change from baseline
values for mechanical thresholds measured at the pinna, and
an indication of where the significant differences lay.
3.4. Mechanical thresholds measured at the distal radius
Results were obtained in only nine out of the 10 dogs in
the pre-operative carprofen group due to the disposition of
the one dog.
At the post-sedation assessment time point, the thresholds
in the dogs that had just received pethidine were raised
compared to the other two groups, but the variation in the
results was too great for the differences to be significant. At
20 min post-extubation, the thresholds in all three groups
were raised to similar levels (about 40% increase on base-
line pre-sedation values); the measured thresholds in all
three groups then declined to baseline levels by 8 h post-
extubation. There were no significant differences between
the groups at any time point. Table 4 shows the median,
maximum and minimum values for the percentage change
from baseline values for mechanical thresholds measured at
the distal radius, and an indication of where the significant
differences lay.
3.5. Mechanical thresholds measured at the distal tibia
The tendency was for the dogs that had recently received
pethidine to show raised thresholds compared to the other
two groups. Overall, however, there was a lot of variation in
the readings obtained within a group, hence the large stan-
dard errors. At the post-sedation assessment time point, the
thresholds in the dogs that had just received pethidine were
Fig. 2. VAS pain scores in dogs both pre- and post-ovariohysterectomy
receiving pethidine either pre- or post-operatively or saline. Histograms
represent the mean ± SEM values. *P , 0.05, **P , 0.01, using an
ANOVA parametric test.
466 B.D.X. Lascelles et al. / Pain 73 (1997) 461–471

Table 3
Median values (with maxima and minima) for percentage change from baseline (pre-sedation) values for threshold measurements at the pinna

Post Extubation + Extubation + Extubation + Extubation + Extubation + Extubation + Extubation +

sedation 20 min 1h 2h 4h 8h 12 h 20 h

Pre-operative pethidine
Median 35.6 64.6 40.9 49.7 20.6 −2.3 15.1 −4.9
Maximum 98.2 254.0 66.7 98.0 66.8 66.7 254.0 64.6
Minimum −5.3 1.0 −26.3 −27.5 −24.5 −18.8 −26.3 −27.7
Post-operative pethidine
Median −2.1 113.1 82.2 21.1 24.1 30.0 10.7 3.2
Maximum 139.5 400.0 202.5 152.2 169.4 124.7 81.3 60.3
Minimum −28.1 −26.9 11.0 −11.3 2.7 0.9 −12.9 −23.6
No analgesics
Median −0.6 47.8 34.8 17.2 6.5 0.0 −1.6 −12.7
Maximum 73.5 127.0 93.9 93.9 122.8 113.3 113.3 65.3
Minimum −35.3 −34.9 −13.3 −59.2 −56.0 −53.7 −32.6 −72.4
Significant differences
Pre vs. post P , 0.05*
Pre vs. none P , 0.05*
Post vs. none P , 0.05*

*Kruskal–Wallis non-parametric test, and post-hoc Dunn’s test.

raised compared to the other two groups, but the variation in
the results was too great for the differences to be significant.
Post-operatively, thresholds in all three groups were raised
at 20 min post-extubation, with thresholds in the dogs that
did not receive any analgesics returning to baseline levels
by 1 h post-extubation, and thresholds in the dogs receiving
pethidine returning to baseline levels by 8 h post-extubation.
The dogs that received pethidine post-operatively had sig-
nificantly higher thresholds than the dogs that had not
received any analgesics at 2 h post-extubation. By 8 h
post-extubation there were no significant differences bet-
ween the groups; however, the dogs that had not received
any analgesics started to show hyperalgesia (lowered
thresholds with respect to baseline pre-sedation values).
This hyperalgesia was more pronounced at 12 and 20 h
post-extubation, when these dogs had significantly lower
thresholds than the dogs that received pethidine pre-
operatively. Table 5 shows the median, maximum and mini-
mum values for the percentage change from baseline values
for mechanical thresholds measured at the distal tibia, and
an indication of where the significant differences lay.
3.6. Mechanical thresholds measured at the abdomen or
wound
At the post-sedation time point, the thresholds measured
in the dogs that had just received pethidine were signifi-
cantly raised compared to the dogs in the other two groups.
Immediately post-operatively, thresholds in the pre-opera-
tive pethidine dogs and the control group were decreased,
and the thresholds in the post-operative pethidine dogs
increased, significantly so with respect to the dogs that
had not received any analgesics. At all the later post-opera-
tive assessment time points, the thresholds in all three

Table 4
Median values (with maxima and minima) for percentage change from baseline (pre-sedation) values for threshold measurements at the distal radius

Post Extubation + Extubation + Extubation + Extubation + Extubation + Extubation + Extubation +

sedation 20 min 1h 2h 4h 8h 12 h 20 h

Pre-operative pethidine
Median 1.6 28.3 17.1 8.4 4.2 −2.3 −5.9 −19.7
Maximum 160.2 160.2 38.7 102.3 54.6 10.8 7.0 5.4
Minimum −20.2 −0.2 −28.9 −32.2 −54.0 −45.3 −29.8 −40.1
Post-operative pethidine
Median −1.6 36.0 28.8 27.6 21.4 3.3 −3.3 0.2
Maximum 18.5 84.8 84.8 84.8 42.4 62.0 46.7 41.6
Minimum −9.8 7.0 7.0 8.8 −19.4 −43.4 −23.3 −23.4
No analgesics
Median −2.1 23.5 20.3 17.8 2.6 6.1 −1.4 −4.3
Maximum 20.4 174.3 48.3 74.8 79.2 34.1 17.8 23.5
Minimum −21.2 −26.0 −28.4 −31.1 −43.2 −27.6 −42.3 −45.4

No significant differences.
 B.D.X. Lascelles et al. / Pain 73 (1997) 461–471 467

Table 5
Median values (with maxima and minima) for percentage change from baseline (pre-sedation) values for threshold measurements at the distal tibia

Post Extubation + Extubation + Extubation + Extubation + Extubation + Extubation + Extubation +

sedation 20 min 1h 2h 4h 8h 12 h 20 h

Pre-operative pethidine
Median 16.3 61.0 22.1 26.3 19.5 −5.3 2.4 −2.7
Maximum 137.7 192.5 97.0 79.8 62.5 59.1 14.2 29.6
Minimum −55.1 −12.2 −13.9 −42.8 −50.4 −43.9 −27.8 −29.7
Post-operative pethidine
Median 4.3 65.1 44.4 34.8 10.5 −5.4 −15.5 −21.3
Maximum 24.0 163.2 116.0 136.7 90.1 43.1 26.5 74.2
Minimum −32.1 19.1 −11.4 −25.8 −31.0 −31.7 −33.9 −26.7
No analgesics
Median −0.8 31.5 −6.1 2.5 −1.2 −12.7 −29.0 −26.6
Maximum 31.8 159.1 78.2 106.0 90.1 19.4 17.7 16.7
Minimum −39.0 −38.6 −50.1 −36.0 −53.4 −56.0 −62.2 −64.8
Significant differences
Pre vs. post
Pre vs. none P , 0.01* P , 0.05*
Post vs. none P , 0.01*

*Kruskal–Wallis non-parametric test, and post-hoc Dunn’s test.

groups were decreased. From 2 h post-extubation onwards,
the decrease was least in the dogs that had received pethi-
dine pre-operatively, and greatest in the dogs that had not
received any analgesics. At 20 h post-extubation, this dif-
ference between the pre-operative pethidine group and the
no analgesics group was statistically significant. Table 6
shows the median, maximum and minimum values for the
percentage change from baseline values for mechanical
thresholds measured at the ventral abdomen or wound,
and an indication of where the significant differences lay.
4. Discussion
Until recently, the only form of assessment of pain and
sedation in animals has been that of categorisation (discon-
tinuous scales) (Taylor and Houlton, 1984, 1986; Waterman
and Kalthum, 1989; Thompson and Johnson, 1991), or mul-
tifactorial pain scales (Popilskis et al., 1991), both forms of
discontinuous scoring systems. The VAS system has since
been used to assess the analgesic effect of acetaminophen,
indomethacin, phenylbutazone, carprofen, papaveretum and
flunixin in dogs (Mbugua et al., 1989; Mburu, 1991; Reid
and Nolan, 1991; Nolan and Reid, 1993). The simple
descriptive VAS is now well established for the assessment
of pain in animals and continues to be used for assessment
of post-operative pain in humans when investigating the
pre-emptive value of analgesic strategies (Katz et al.,
1992; Richmond et al., 1993). It remains important, how-
ever, to not only observe the undisturbed animal, but to
interact with, move around and palpate the affected area
of the animal concerned in order to obtain as complete a
picture as possible of how much pain that animal is in (Las-
celles et al., 1995b).
In order to quantify post-operative allodynia and hyper-
algesia, mechanical thresholds were investigated in the dogs
in this study to parallel previous work in rats (Lascelles et
al., 1995a). The nociceptiometric device designed and built
as part of these studies fulfils the criteria laid down by
Beecher (1957) for an ideal method of producing painful
stimuli. Work in horses (Chambers, 1992) and man (Grind-
ley, 1936) has demonstrated that the sensory threshold to
pressure varies with the rate of application. Thus, a system
for controlling the rate of application was also incorporated
and used in this study. Testing of the apparatus on each
testing day ensured the CRAF meter functioned correctly,
allowing the probe to be applied at a constant rate.
Confining testing to four body parts prevented the dogs
becoming upset by the testing procedure but still permitted
allodynia resulting from central hypersensitivity to be
assessed at various parts of the central nervous system.
The pinna seemed to produce consistent results in prelimin-
ary testing, but inconsistent and variable results in subse-
quent experiments. This may have been related to the
influence of tissue temperature on subsequent thresholds.
The ears of the dogs became markedly cooler post-opera-
tively due to peripheral vasoconstriction. Chambers et al.
(1994) measured mechanical nociceptive thresholds in
sheep at various ambient air temperatures, and found thresh-
olds were raised at an ambient air temperature below about
8°C. Whay and Waterman (unpublished observations) have
found similar changes in calves where raised thresholds
were associated with a drop in ambient air and skin tem-
perature. The mean threshold values in this study differed
depending on the part of the body examined: 7.62 N (±0.25)
at the ventral midline, 11.47 N (±0.26) at the distal radius
and 9.94 N (±0.3) at the distal tibia. This was probably due
to the varying constitution of the tissues at the different
testing points. These values are also much higher than the
values reported at the antebrachium of other species (Nolan
468 B.D.X. Lascelles et al. / Pain 73 (1997) 461–471

Table 6
Median values (with maxima and minima) for percentage change from baseline (pre-sedation) values for threshold measurements at the wound

Post Extubation + Extubation + Extubation + Extubation + Extubation + Extubation + Extubation +

sedation 20 min 1h 2h 4h 8h 12 h 20 h

Pre-operative pethidine
Median 26.4 −31.3 −52.9 −42.7 −54.9 −62.8 −55.9 −43.8
Maximum 137.7 39.4 −11.4 −24.1 2.7 −13.2 −21.8 −21.8
Minimum −30.5 −79.9 −89.7 −75.9 −93.1 −81.4 −82.8 −79.5
Post-operative pethidine
Median −4.9 14.9 −50.1 −59.1 −58.1 −67.7 −62.7 −58.9
Maximum 28.9 182.2 −18.9 −20.8 −40.7 −53.1 −55.2 −39.2
Minimum −36.0 −43.0 −65.8 −73.7 −78.8 −75.5 −80.2 −74.4
No analgesics
Median −3.0 −56.0 −46.6 −60.7 −65.2 −73.6 −74.2 −67.3
Maximum 15.1 −23.7 −20.1 −19.2 −40.8 −37.9 −40.4 −45.2
Minimum −26.3 −82.7 −87.6 −89.9 −93.0 −84.4 −88.4 −90.5
Significant differences
Pre vs. post P , 0.05*
Pre vs. none P , 0.05* P , 0.05*
Post vs. none P , 0.01*

*Kruskal–Wallis non-parametric test, and post-hoc Dunn’s test.

et al., 1987; Ley et al., 1989, 1995; Chambers et al., 1990,
1994), The differences between the values of this study and
of other studies probably relates to the fact that the dogs
were not trained in the use of the equipment at all, and to the
fact that differing testing equipment was used, and it is
likely that different values would be obtained with any
modification of the apparatus, especially modification of
the probe tip.
Studies in monkeys (Miron et al., 1989) and cows (Whay
et al., 1996) have shown that diversions of attention alter the
perceived level of a noxious stimulus, and so testing was
always carried out with the minimal number of people pre-
sent, when the dogs were not visibly excited or frightened,
but appeared calm. The dogs were always muzzled to ensure
operator safety as it was found that the response to pressure
on a painful wound was often a biting. This may well have
caused stress to the dogs, but muzzling each dog, which
acted as its own control, at each testing time point, should
have minimised any inconsistencies that may have resulted
from muzzling.
Randomly assigning the testing carried out in a particular
dog to one side or the other and injecting the drugs in the
quadriceps of the other leg was carried out to remove the
possible confounding influence of pain from the site of
injection affecting withdrawal responses. For a similar rea-
son, administration of the induction agents was carried out
via the limb opposite to the side chosen for threshold testing.
The control dogs exhibited significantly decreased
thresholds at the tibia at the later post-operative time points,
similar to the mechanical hyperalgesia which develops in
rats following laparotomy (Lascelles et al., 1995a). Either
the dogs had learned to avoid the stimulus, or central sensi-
tisation had become established as a result of the surgery or
peripheral sensitisation had become established as a result
of the testing procedure, and so the speed of the reflex arc
was changed. The involvement of surgery as a causative
factor in the establishment of this hyperalgesia could have
been investigated by the inclusion of a control group that
only underwent a general anaesthetic, as in the rat study
(Lascelles et al., 1995a). However, this was not possible
in this study as the animals were all clinical cases. There
was no evidence of peripheral tissue damage in any of the
dogs at any of the sites of testing, and as the degree of
hyperalgesia was greater at the distal tibia than the distal
radius or pinna, it seems reasonable to postulate that central
changes in the spinal cord as a result of surgery, were
involved in the development of this mechanical hyperalge-
sia. Anatomical considerations would appear to support this.
The afferent input from a caudal midline abdominal incision
and the female reproductive tract is diffuse and probably
involves the illiohypogastric, illioinguinal, pudendal and
pelvic nerves, entering the spinal cord through dorsal root
ganglia T12–S1. The sciatic nerve serves the area of
mechanical testing on the hindlimb and shares spinal cord
segments served by the afferent input resulting from sur-
gery.
These central changes were significantly attenuated by
the pre-operative administration of pethidine, but not by
the post-operative administration of pethidine. It is thought
that opioids, acting both pre- and post-synaptically in the
dorsal horn, block the passage of nociceptive information
and thus prevent or markedly decrease the release of exci-
tatory amino acids (glutamate) and neuropeptides (sub-
stance P and neurokinin A) that are thought to be the
initial factors in the development of plastic changes in the
central nervous system (Urban and Randic, 1984; Thomp-
son et al., 1990; for review see Coderre et al., 1993). The
interpretation of reflex responses can be problematic as pain
sensation cannot be inferred from reflex responses alone,
and indeed McGrath et al. (1981) showed that reflex activity
 B.D.X. Lascelles et al. / Pain 73 (1997) 461–471
produced by noxious stimulation in humans can be disso-
ciated from pain sensation produced by the same stimulus.
Also, spinal reflexes do not involve critical higher centre
nervous system functions involved in the experience of
pain. They do, however, give an indication of spinal cord
activity. Other potential problems seen with all mechanical
testing systems are that the test itself can produce tissue
damage that may well then alter the response to subsequent
tests due to peripheral hyperalgesia. In addition, the test
stimulus itself may well lead to the onset of stress induced
analgesia. Padawer and Levine (1982) showed that pain pre-
testing, regardless of subsequent manipulations or lack
thereof, resulted in significantly lower post-test pain ratings,
i.e., analgesia, than when pre-testing was not carried out.
However, the testing regimen was the same in all three
treatment groups, and thus the influence of timing of analge-
sic administration can be assessed.
In the immediate/early post-operative period administra-
tion of pethidine to the dogs undergoing ovariohysterect-
omy resulted in significantly lower pain scores using the
VAS system compared to the other treatments, and was
associated with significantly raised mechanical thresholds
compared to the other groups at the pinna and wound, and
raised thresholds at the distal radius and distal tibia. How-
ever, the sedation scores in this group were significantly
greater than the other groups, and this raises the question
of whether the analgesia seen (inferred from low pain scores
and raised thresholds) was real, or just as a result of the dogs
being more asleep and unable to respond. Similar results
were obtained in cats undergoing ovariohysterectomy and
receiving pethidine post-operatively (Lascelles et al.,
1995b). The study in dogs was carried out in a double-
blind manner but retrospective examination of contempora-
neous notes, revealed that the dogs receiving pethidine post-
operatively, although sedated, were not fast asleep, and did
respond to the observer and were aware of their surround-
ings, but very comfortable. However, the period of analge-
sia produced by the post-operative injection was only about
2 h. Waterman and Kalthum (1989) used a dose of 3.5 mg/
kg i.m. given post-operatively, and found plasma levels of
pethidine that equated with reasonable analgesia (deter-
mined by manual palpation and scoring of the pain present)
for up to 2 h after administration. The results of the current
study suggest that a higher dose of pethidine (5.0 mg/kg)
given post-operatively does not provide effective analgesia
for any longer. However, strikingly, and importantly, the
dogs that received pethidine pre-operatively were assessed
to be in significantly less pain at the later post-operative
assessments. From the work of Waterman and Kalthum
(1989) and the results of post-operative administration of
pethidine in this study, it seems unlikely that this could be
due to circulating plasma levels of pethidine from the pre-
operative administration being higher. Rather, the differ-
ence was more likely to be due to the timing of the admin-
istration. It appears that the use of pethidine pre-operatively
to cover the period of surgery has resulted in significantly
469
less pain in the later post-operative period, probably due to a
blocking of the entry of noxious information into the spinal
cord and, thus, prevents cellular wind-up and the onset of
central hypersensitivity (Woolf and Chong, 1993).
Thus, these studies in dogs have demonstrated that central
sensitisation occurs in response to a surgical stimulus in the
clinical situation, and that the pre-operative administration
of pethidine can significantly prevent this, but that the post-
operative administration does not. These studies have also
demonstrated that the amelioration of this central hypersen-
sitivity results in a clear improvement in post-operative out-
come in terms of post-operative pain. However, although
the measured levels of peripheral allodynia (tibia) and
wound hyperalgesia were greater for the post-operative
pethidine group, there were no statistically significant dif-
ferences between the pre- and post-groups despite the sig-
nificant difference in the VAS scores at 12 and 20 h post-
operatively. This may have been because the level of pre-
emptive effect was enough to significantly alter the level of
rostally transmitted nociceptive information, but not to sig-
nificantly alter local spinal cord hypersensitivity.
There are only two other similar reports of the pre-emp-
tive effect of opioids in man. Katz et al. (1992) examined the
pre- versus post-operative administration of an opioid (fen-
tanyl) and found that a single epidural dose of fentanyl
given prior to surgery was more effective in reducing pain
and analgesic requirement after thoracotomy than when the
same drug was administered post surgery. In women under-
going ovariohysterectomy, Richmond et al. (1993) found
that pain thresholds on the abdomen, 10 cm above the
wound, were dramatically reduced, and that this reduction
was significantly prevented by the pre-emptive administra-
tion of either intravenous or intramuscular morphine, but
not by post-operative intravenous morphine, despite signif-
icantly greater morphine use from the PCA pump by the
post-operative intravenous morphine group. At the 20 h
post-extubation time point, significant hyperalgesia was
detected at the wound, which was significantly attenuated
by the pre-operative administration of morphine. Richmond
et al. (1993) made their mechanical threshold measurements
at 24 and 48 h post-operatively, and one is tempted to spec-
ulate what the results would have been had testing been
carried out at later time points in the dog.
It is interesting to speculate whether a greater degree of
post-operative analgesia would be achieved by a larger pre-
operative dose of pethidine. Collis et al. (1995) compared a
20-mg intravenous bolus of morphine administered pre-
operatively with a regimen of 10 mg pre- and 10 mg post-
operatively. Secondary hyperalgesia was prevented in both
groups, and neither regimen appeared to offer any obvious
clinical advantage compared with a lower dose (10 mg)
given pre-operatively. It appears that the matching of noci-
ception and analgesic medication, crucial to exploiting any
clinical benefit of pre-emptive analgesia, was achieved in
the study of Collis et al. (1995). The authors of this study
would not recommend larger doses of pethidine pre-opera-
470 B.D.X. Lascelles et al. / Pain 73 (1997) 461–471
tively as the dose tried here (5.0 mg/kg) (i) produced a
positive pre-emptive effect, and (ii) did seem to be asso-
ciated with laboured breathing in some cases, possibly due
to histamine release, although no evidence of this was seen
from intra-operative blood pressure measurements.
The findings of this study confirm the experimental stu-
dies in the rat (Lascelles et al., 1995a) and are a reassuring
demonstration of the fact that the hypersensitivity which
does develop in clinical situations can be ameliorated. How-
ever, although pre-operative administration of pethidine
resulted in significantly lower VAS pain scores (and at
times when there were no differences between the groups
with respect to sedation), it only resulted in significantly less
central hyperalgesia compared to the control group. The
dogs receiving pethidine post-operatively exhibited a level
of hyperalgesia at the distal tibia midway between the pre-
operative administration group and the control group. How-
ever, it may well be that if testing had carried on for longer,
a greater degree of separation between the groups would
have been seen with respect to central hyperalgesia. These
results also suggest that before the onset of measurable
hyperalgesia, the pain that a dog given pethidine post-opera-
tively perceived was greater than that perceived by the dogs
given pethidine pre-operatively. The trend shown by the
thresholds measured at the wound followed the same pattern
as the VAS results, and again, it might have been that if the
dogs had been followed beyond 20 h post-operatively, the
pre-operative pethidine group may have shown significantly
reduced hyperalgesia not only with respect to the control
group, but also with respect to the post-operative pethidine
group. Following the dogs for longer would also have
allowed comparison of the total amount of pain (AUCs
calculated from the VAS data) suffered by the dogs in the
treatment groups to be compared, and would have estab-
lished whether differing the timing of the analgesic admin-
istration alters the total amount of pain suffered, as
suggested by these data, or merely shifts the pain curve to
the left or right.
When the threshold results at the wound were plotted
against the VAS scores for pain in the dogs receiving pethi-
dine pre- or post-operatively, or no analgesics, there was a
significant negative correlation between the two measures
(P , 0.0001), but the strength of the correlation was not
strong (r = −0.348). However, it does show that there was a
relationship between a qualitative measure of pain (the VAS
system) and a quantitative measure of wound sensitivity
(mechanical thresholds).
5. Clinical significance
These studies have shown that pethidine is an effective
analgesic, albeit of short duration, when administered post-
operatively, and importantly that it has a positive benefit in
terms of post-operative outcome, when administered pre-
operatively, probably as a result of blocking or preventing
the development of central sensitisation as a result of surgi-
cal stimulation. However, this is not to say that a single dose
of an analgesic administered prior to surgery is all the
analgesic medication that is required. These results simply
demonstrate that for a given dose of analgesic by a given
route, administration prior to surgery is more effective than
administration after surgery. Analgesic medication will still
be required in the post-operative period, and this pain may
be more easy to control than if no pre-emptive analgesic
medication had been given. This is the approach advocated
by Woolf and Chong (1993), where they suggest that the
optimal form of pain prevention must be ‘one that is applied
both pre, intra and post-operatively to pre-empt the estab-
lishment of pain hypersensitivity during and after surgery’.
Acknowledgements
This work was funded by the Wellcome Trust. We would
also like to thank the late Professor Pearson for his help with
this work, and also Carole Davis.
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