doi:10.1111/j.1467-2995.2008.00424.x
RESEARCH PAPER
DVM,
*Faculty of Veterinary Medicine, Centro Universitario de Maringa (CESUMAR), Maringa, Parana, Brazil
!Department of Veterinary Surgery and Anesthesiology, Faculdade de Medicina Veterinaria e Zootecnia, Universidade
Estadual Paulista (UNESP), Botucatu, Sao Paulo, Brazil
Correspondence: Eduardo Raposo Monteiro, Cesumar-Hospital Veterinario, Av. Guedner 1610 - Zona 8 -87050-900, Maringa, PR, Brazil.
E-mail: btraposo@hotmail.com
Abstract
Objective To compare the effects of morphine
(MOR), methadone (MET), butorphanol (BUT) and
tramadol (TRA), in combination with acepromazine, on sedation, cardiorespiratory variables, body
temperature and incidence of emesis in dogs.
Study design Prospective randomized, blinded,
experimental trial.
Animals Six adult mixed-breed male dogs weighing
12.0 4.3 kg.
Methods Dogs received intravenous administration
(IV) of acepromazine (0.05 mg kg)1) and 15 minutes later, one of four opioids was randomly
administered IV in a cross-over design, with at least
1-week intervals. Dogs then received MOR 0.5 mg
kg)1; MET 0.5 mg kg)1; BUT 0.15 mg kg)1; or TRA
2.0 mg kg)1. Indirect systolic arterial pressure
(SAP), heart rate (HR), respiratory rate (fR), rectal temperature, pedal withdrawal reflex and sedation were evaluated at regular intervals for
90 minutes.
Results Acepromazine administration decreased
SAP, HR and temperature and produced mild
sedation. All opioids further decreased temperature
Introduction
Neuroleptanalgesic combinations are commonly
used in veterinary medicine to facilitate handling of
small animals, as premedication and to provide
analgesia for minor surgical procedures. Phenothiazine agents, a2-adrenoceptor agonists and opioid
analgesics are the most commonly used drugs to
produce neuroleptanalgesia. When these drugs are
25
! 2009 The Authors. Journal compilation ! 2009 Association of Veterinary Anaesthetists, 36, 2533
! 2009 The Authors. Journal compilation ! 2009 Association of Veterinary Anaesthetists, 36, 2533
27
in dogs receiving MOR. One dog in MOR was assigned an NDS score of 3. In the remaining five
dogs, NDS was either 1 (2/6 dogs) or 2 (3/6 dogs).
In dogs which received BUT, sedation was mild to
moderate; NDS = 1, in three dogs and = 2, in the
remaining three animals. In five of six dogs given
TRA, sedation was not increased after opioid
administration and NDS was 1. Only one of six dogs
in TRA had moderate sedation (NDS = 2) at T15.
From 15 to 60 minutes after treatment administration, NDS was higher in MET than in TRA. There
were no other significant differences between treatments in NDS. Compared with NDS at Time ACP, NDS
was increased in MET from T15 to T60 (Table 3).
As in NDS, the VAS sedation scores were greater
in MET (Table 3). MET had greater VAS scores than
TRA at T60 and T75. There was an increase in VAS
scores in all treatments compared with values at
Time ACP. The differences were significant from
T30 to T75 in MOR, from T30 to T60 in MET and
BUT and at T30 and T45 in TRA (Table 3).
Pulse rate was higher in MET than in MOR from
T30 to T90 and higher in MET than in BUT and
TRA at T30, T60 and T75. A decrease in PR,
compared with values at Time ACP, was observed
from T15 to T90 in MOR and BUT and at T30, T45
and T75 in TRA (Table 1). Bradycardia (PR <
Results
Effects of acepromazine administration (Time ACP)
Mean values of SAP, PR, fR and rectal temperature did
not differ at baseline or at Time ACP among
treatments (Tables 1 and 2). Following acepromazine administration, PR decreased in MOR, BUT and
TRA. Although PR also decreased in MET, the
difference was not statistically significant. Systolic
arterial pressure decreased significantly in MOR, MET
and BUT treatments after acepromazine administration. The change in fR was not significant with
acepromazine administration (Table 1). A decrease
in rectal temperature was observed in all treatments
after acepromazine. The mean reduction for all
treatments was 0.4 "C (Table 2). Acepromazine
resulted in mild sedation in most dogs. The median
NDS was 1.0 in all treatments whereas the median
VAS for each treatment were 3.4, 3.0, 3.5 and 3.1 in
MOR, MET, BUT and TRA respectively (Table 3).
Effects of opioid administration (Times 1590)
The six dogs which received MET had intense
sedation (NDS = 3) at least at one time point.
Sedation ranged from mild to intense (NDS = 13)
Table 1 Mean SD pulse rate (PR), systolic arterial pressure (SAP) and respiratory rate (fR) in six dogs at baseline (BL), at
15 minutes after intravenous (IV) administration of 0.05 mg kg)1 of acepromazine (ACP) and at 15, 30, 45, 60, 75 and
90 minutes after IV administration of 0.5 mg kg)1 of morphine (MOR), 0.5 mg kg)1 of methadone (MET), 0.15 mg kg)1 of
butorphanol (BUT) or 2.0 mg kg)1 of tramadol (TRA)
Time after opioid (treatment) administration (minutes)
BL
PR (beats minute)1)
MOR
99 19*
MET
94 17
BUT
100 23*
TRA
97 14*
SAP (mmHg)
MOR
130 13*
MET
131 16*
BUT
123 9*
TRA
126 10
fR (breaths minute)1)
MOR
38 17
MET
39 27
BUT
45 23
TRA
44 35
ACP
15
30
76
83
84
79
3
10
24
9
60
73
64
68
3*
29
12*
15
59
91
63
62
5*!
37
14*!
10*!
101
113
107
113
5
11
6
6
101
108
101
102
9
8
10
7*
94
106
101
98
27
27
25
26
20
12
10
15
47
40
17
23
52
41
6*"
17
40
36
17
17
45
60
58
85
64
63
9*!
28
18*
11*
58
91
63
65
6*!
31
14*!
19!
7
10
8
8*
95
107
102
98
7
8
8
7*
95
104
103
100
44
37
4*
4
27
34
16
20
16
33
5*
10
24
30
16
17
75
90
58
92
64
62
11*!
30
17*!
18*!
58
89
68
67
10*!
26
16*
22
6
11
9
8*
96
105
106
100
8
11
13
11*
98
107
108
99
8
12
12
13*
8
23
4*
6
23
28
17
17
7
22
4*
6
23
26
18
20
6
13
4*
7
*Significantly different from ACP; !significantly different from MET; "significantly different from MOR (p < 0.05).
28
! 2009 The Authors. Journal compilation ! 2009 Association of Veterinary Anaesthetists, 36, 2533
BL
MOR
MET
BUT
TRA
38.9
38.9
38.9
38.9
ACP
0.3*
0.3*
0.4*
0.1*
38.4
38.5
38.4
38.6
0.3
0.4
0.3
0.4
60
37.1
36.8
37.6
37.9
90
0.2*
0.4*
0.4*!
0.4*!"
36.8
36.4
37.6
37.8
0.2*
0.6*
0.5*!"
0.4*!"
Table 3 Median (25th to 75th percentile range) numeric descriptive scale (NDS) and visual analog scale (VAS) sedation
scores in six dogs at 15 minutes after IV administration of 0.05 mg kg)1 of acepromazine (ACP) and at 15, 30, 45, 60, 75
and 90 minutes after intravenous (IV) administration of 0.5 mg kg)1 of morphine (MOR), 0.5 mg kg)1 of methadone (MET), 0.15 mg kg)1 of butorphanol (BUT) or 2.0 mg kg)1 of tramadol (TRA)
Time after opioid (treatment) administration (minutes)
ACP
NDS
MOR
MET
BUT
TRA
VAS
MOR
MET
BUT
TRA
15
30
45
60
75
90
1.0
1.0
1.0
1.0
(1.01.5)
(1.01.0)
(1.01.5)
(1.01.5)
1.5
3.0
1.5
1.0
(1.02.5)
(2.53.0)*
(1.02.0)
(1.01.5)!
2.0
3.0
1.5
1.0
(1.02.5)
(3.03.0)*
(1.02.0)
(1.01.0)!
2.0
3.0
1.0
1.0
(1.02.5)
(2.53.0)*
(1.02.0)
(1.01.0)!
1.5
3.0
1.0
1.0
(1.02.0)
(2.03.0)*
(1.02.0)
(0.51.0)!
1.5
2.0
1.0
1.0
(1.02.0)
(1.52.0)
(1.02.0)
(0.51.0)
1.0
2.0
1.0
0.5
(1.01.5)
(1.02.0)
(0.52.0)
(0.01.0)
3.4
3.0
3.5
3.1
(2.23.7)
(2.53.8)
(2.44.4)
(2.14.1)
4.9
5.9
6.0
5.1
(4.56.7)
(4.67.0)
(4.56.2)
(3.86.2)
6.0
7.4
6.7
5.3
(5.37.6)*
(6.28.6)*
(6.07.1)*
(4.67.0)*
6.2
7.6
6.8
5.7
(5.67.9)*
(6.68.6)*
(6.27.3)*
(4.27.1)*
6.0
7.7
6.3
5.1
(5.47.6)*
(6.38.2)*
(6.17.0)*
(4.16.3)!
5.8
6.9
5.4
4.1
(5.07.0)*
(5.67.5)
(4.86.4)
(3.45.4)!
4.9
6.1
4.1
3.0
(4.55.6)
(4.16.7)
(3.05.4)
(2.74.2)
*Significantly different from ACP; !significantly different from MET (p < 0.05).
! 2009 The Authors. Journal compilation ! 2009 Association of Veterinary Anaesthetists, 36, 2533
29
Discussion
A limitation of the present study was that not all the
opioids used were employed in equipotent doses for
analgesia. Morphine is the prototype opioid to
which all others are compared with a relative
potency of 1. Methadone was reported to have 1 to
1.5 the potency of MOR whereas BUT is 35 times
more potent than MOR (Wagner 2002). Tramadol
is said to have 1/10 the potency of MOR (Duthie
1998). Thus, the doses of MOR, MET and BUT
employed in the present study (0.5, 0.5 and
0.15 mg kg)1 respectively) may be considered to be
equipotent whereas the dose of TRA (2.0 mg kg)1)
may not. The equipotent dose of TRA to 0.5 mg
kg)1 of MOR would be 5 mg kg)1. However, this
dose is higher than the dose commonly used in
clinical practice (Gaynor 2002; Mastrocinque &
Fantoni 2003). All the doses employed in the present study are within reported clinical ranges for
dogs (Hall et al. 2001b; Gaynor 2002; Wagner
2002; Mastrocinque & Fantoni 2003).
Phenothiazine agents produce mild to moderate
sedation. Peak sedation occurs within 20 minutes
following IV administration of acepromazine.
Although other drugs, such as alpha2-adrenoceptor
agonists, produce dose related sedation, increasing
the dose of a phenothiazine does not result in
enhancement of the degree of sedation and it may
actually intensify the adverse effects (Hall et al.
2001a). When moderate to intense sedation is
desired, phenothiazine derivatives should be administered in combination with other drugs with sedative properties such as opioid analgesics. The degree
of sedation is greater with the combination than
with either agent alone (Smith et al. 2001). In the
present study, acepromazine alone produced mild
sedation. However, when an opioid was administered 15 minutes after the phenothiazine, sedation
was greater than that achieved with acepromazine
alone as judged by our visual analog scale.
The sedative effect of opioids results from their
interaction with l and j receptors (Muir 2002).
However, other factors may influence sedation
produced by opioid administration. In addition to
the type of receptor activated, the dose, differences
in pharmacokinetics, the number of observers
assessing sedation and individual variation may
affect the sedation score. In the present study, we
aimed to minimize the influence of all these factors
in the assessment of sedation by using equipotent
doses, by administering the drugs intravenously, to
30
! 2009 The Authors. Journal compilation ! 2009 Association of Veterinary Anaesthetists, 36, 2533
acepromazine alone. Thus, the combination acepromazine/TRA is not recommended when moderate to
intense sedation is required. Peak sedative effect
appears to occur within 3045 minutes after
administration of all combinations.
Pedal withdrawal reflex was used in the present
study to assess acute somatic pain subjectively.
However, the results of the present study should be
interpreted carefully because drugs that influence
vigilance, motor responses and autonomic reflexes,
such as neuroleptanalgesic combinations, are
thought to affect the subjective experience of pain
making it difficult to differentiate sedative and
analgesic effects of drugs (Ansah et al. 1998). Thus,
one could not ascertain, based on the results of our
study, that better analgesia was provided by the
combination acepromazine/MET.
The effects of acepromazine on HR and arterial
blood pressure of dogs have been previously
reported. Acepromazine causes a decrease in arterial
pressure (Popovic et al. 1972; Turner et al. 1974;
Stepien et al. 1995), which is mediated through
peripheral alpha-1 adrenoceptor block and depression of the vasomotor centre within the hypothalamus, resulting in vasodilation (Thurmon et al.
1996). However, hypotension (SAP < 90 or
MAP < 70 mmHg) was not reported following
acepromazine administration in healthy animals.
The effects of acepromazine on PR in dogs are
variable. Tachycardia in response to a decrease in
arterial blood pressure (Turner et al. 1974), a slight
decrease (Popovic et al. 1972) or no change (Stepien et al. 1995) have been reported. In the study
reported here, a 15% decrease in SAP and a 17%
decrease in PR were observed after acepromazine
administration. Hypotension was not observed in
any of the dogs treated with acepromazine and only
one dog developed bradycardia (PR = 56 beats
minute)1).
The cardiovascular effects of opioids are quite
variable and may be influenced by the drug, its dose
and species involved (Hall et al. 2001a). This class
of drugs seems to affect myocardial contractility
minimally or not at all. However, increased vagal
tone may result in bradycardia (Hall et al. 2001a;
Wagner 2002). A decrease in HR was reported in
dogs treated with MET, oxymorphone and hydromorphone alone (Smith et al. 2001; Monteiro et al.
2008) and following administration of MET, buprenorphine, oxymorphone, hydromorphone or BUT
in combination with acepromazine (Cornick &
Hartsfield 1992; Stepien et al. 1995; Smith et al.
! 2009 The Authors. Journal compilation ! 2009 Association of Veterinary Anaesthetists, 36, 2533
31
! 2009 The Authors. Journal compilation ! 2009 Association of Veterinary Anaesthetists, 36, 2533
! 2009 The Authors. Journal compilation ! 2009 Association of Veterinary Anaesthetists, 36, 2533
33