Veterinary Anaesthesia and Analgesia, 2009, 36, 25–33
RESEARCH PAPER
Comparative study on the sedative effects of morphine,
methadone, butorphanol or tramadol, in combination with
acepromazine, in dogs
Eduardo Raposo Monteiro* DVM, PhD, Adolfo Rodrigues Junior* DVM, Hemir Martins Quirilos Assis*
Daniela Campagnol  DVM, MSc & Juliany Gomes Quitzan* DVM, MSc
*Faculty of Veterinary Medicine, Centro Universitário de Maringá (CESUMAR), Maringá, Paraná, Brazil
 Department of Veterinary Surgery and Anesthesiology, Faculdade de Medicina Veterinária e Zootecnia, Universidade
Estadual Paulista (UNESP), Botucatu, São Paulo, Brazil
Correspondence: Eduardo Raposo Monteiro, Cesumar-Hospital Veterinário, Av. Guedner 1610 - Zona 8 -87050-900, Maringá, 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 aceproma-
zine, 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 min-
utes 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), rec-
tal temperature, pedal withdrawal reflex and seda-
tion 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
doi:10.1111/j.1467-2995.2008.00424.
DVM,
and MOR, BUT and TRA were associated with
further decreases in HR. Tramadol decreased SAP
whereas BUT decreased fR compared with values
before opioid administration. Retching was observed
in five of six dogs and vomiting occurred in one dog
in MOR, but not in any dog in the remaining
treatments. Sedation scores were greater in MET
followed by MOR and BUT. Tramadol was associ-
ated with minor changes in sedation produced by
acepromazine alone.
Conclusions and clinical relevance When used with
acepromazine, MET appears to provide better seda-
tion than MOR, BUT and TRA. If vomiting is to be
avoided, MET, BUT and TRA may be better options
than MOR.
Keywords acepromazine, butorphanol, dog, metha-
done, morphine, tramadol.
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. Phenothi-
azine agents, a2-adrenoceptor agonists and opioid
analgesics are the most commonly used drugs to
produce neuroleptanalgesia. When these drugs are
25
Acepromazine-opioid combinations in dogs ER Monteiro et al.
administered together, synergism seems to occur;
sedation and analgesia being greater than that
achieved with either drug given alone (Hall et al.
2001a).
Phenothiazine derivatives, such as acepromazine,
are often used to produce mild to moderate tran-
quilization/sedation in dogs. This class of drugs, also
named as neuroleptics, interferes with dopamine
transmission within the central nervous system
(Baldessarini & Tarazi 2001). Other advantages
related to the use of acepromazine in dogs include
the reduced requirement of both injectable (Thur-
mon et al. 1996) and inhaled anaesthetics (Heard
et al. 1986; Webb & O’Brien 1988), antiemetic
(Valverde et al. 2004) and anti-arrhythmogenic
effects (Dyson & Pettifer 1997). However, pheno-
thiazine agents do not produce analgesia in dogs
(Hall et al. 2001a).
Opioid analgesics are used primarily to produce
analgesia without resulting in loss of consciousness.
The analgesia produced by this class of drugs is
mediated by stimulation of opioid receptors (l, j
and d) located mainly in the brain and in the dorsal
horn of the spinal cord (Wagner 2002).
Morphine is the prototype opioid to which all
others are compared. Morphine is assigned an
analgesic potency of 1 and although other opioids
are known to have greater analgesic potency, none
has been shown to be more effective in relieving
pain (Wagner 2002). Morphine possesses high
affinity for l receptors where it acts as an agonist,
resulting in analgesia (Hall et al. 2001a). Adverse
effects following MOR administration in dogs
include vomiting (Blancquaert et al. 1986; Valverde
et al. 2004) and release of histamine when admi-
nistered intravenously (Robinson et al. 1988; Gue-
des et al. 2006).
Methadone is a synthetic opioid with high affinity
for l receptors and similar analgesic potency to
MOR (Hall et al. 2001a). It was also reported that
MET might act as an antagonist on N-methyl-
D-aspartate (NMDA) receptors and this property
might contribute to its analgesic effect as well as
prevent development of tolerance (Wagner 2002).
Methadone does not induce emesis (Blancquaert
et al. 1986) and, in humans, it has a low potential
for the release of histamine (Bowdle et al. 2004). In
dogs, methadone alone induced mild sedation
wheras the combination of methadone and acepro-
mazine produced mild to intense sedation with
minimal cardiorespiratory effects (Monteiro et al.
2008).
26 Ó 2009 The Authors. Journal compilation Ó 2009 Association of Veterinary Anaesthetists, 36, 25–33
Tramadol is a synthetic opioid with low affinity
for l receptors and an analgesic potency of one-
tenth of that of MOR (Duthie 1998). However, it
has been reported in the literature that the
analgesic properties of TRA result from both opioid
and nonopioid mechanisms (Miranda & Pinardi
1998). This opioid was shown to inhibit the
reuptake of norepinephrine and serotonin, achiev-
ing spinal modulation of pain and preventing
impulses reaching the brain (Duthie 1998). In
dogs, TRA produced similar analgesia to MOR in
the early postoperative period following ovariohys-
terectomy (Mastrocinque & Fantoni 2003). The
incidence of nausea and vomiting was lower than
with other opioids in humans (Duthie 1998) and it
does not release histamine (Barth et al. 1987). To
the author’s knowledge, there are no data avail-
able about the use of TRA alone or in combination
with tranquilizing/sedative drugs for premedication
in dogs.
Butorphanol is a synthetic opioid with agonist–
antagonist properties. Its analgesic effect results
from activation of j receptors. Conversely, BUT was
also shown to have affinity for l receptors where it
acts as an antagonist. The analgesic potency of BUT
is 3–5 times that of MOR. However, a ceiling effect
was reported with no further increase in analgesia
after 0.8–1.0 mg kg)1 (Wagner 2002). In dogs,
BUT alone or in combination with acepromazine
was associated with minimal cardiopulmonary
depression (Trim 1983; Cornick & Hartsfield
1992) and it was also shown to have an antiemetic
effect (Moore et al. 1994).
The purpose of the present study was to compare
the sedative effects of MOR, MET, BUT and TRA, in
combination with acepromazine, in dogs. It was also
aimed to evaluate the cardiorespiratory effects and
adverse effects of each of the combinations.
We hypothesized that the degree of sedation
provided by administration of acepromazine/opiod
combinations to dogs would vary depending on the
opioid chosen.
Materials and methods
Dogs
Six adult mixed-breed male dogs were used in the
study. Mean ± SD weight of the dogs was
12.0 ± 4.3 kg. Health status was assessed by
means of physical examination, a complete blood
count and serum biochemical analyses; all findings
 Acepromazine-opioid combinations in dogs ER Monteiro et al.
were within reference ranges. The study was
approved by the Animal Care and Use Committee of
the University of Londrina (protocol 43/06).
Study design and experimental protocol
Food but not water was withheld for 12 hours
prior to the experiment. Each dog was allowed to
acclimate to a small quiet room with temperature
at 25 °C for at least 30 minutes before each
experiment was started. Subsequently, the dogs
were instrumented with a Doppler (Doppler model
841-A; Parks Medical Electronics, Aloha, OR, USA)
ultrasonic flow probe placed on the palmar digital
artery with a sphygmomanometer and cuff (cuff
width was 40–50% of limb circumference) placed
above the carpus, to allow determination of indi-
rect systolic arterial pressure (SAP). The accuracy
of the sphygmomanometer was checked prior to
the beginning of the study by means of a mercury
manometer. Pulse rate (PR) was counted from the
amplified doppler flow probe, respiratory rate (fR)
was measured by observing thoracic excursions
and rectal temperature was determined by means
of a digital thermometer. Pedal withdrawal reflex
was evaluated by a toe pinch in the thoracic limb
with a 20-cm haemostat with protective rubber
tubing on each jaw that was clamped to the third
ratchet for 15 seconds, or until a positive response
was observed (crying, withdrawal of the limb or
looking at the stimulated limb). The degree of
sedation was assessed using a numeric descriptive
scale (NDS) and a visual analogue scale (VAS). The
NDS (Valverde et al. 2004) consisted of a scale
ranging from 0 to 3, with 0: no sedation; 1: mild
sedation (less alert but still active); 2: moderate
sedation (drowsy, recumbent but can walk); and 3:
intense sedation (very drowsy, unable to walk).
The VAS consisted of a 10-cm line representing no
sedation at the left end and the most sedation
possible at the right end. An observer was
responsible for placing a mark on the line that
corresponded to the degree of sedation for the
animal. The distance between the left end of the
scale and the mark was considered the VAS score.
To evaluate the degree of sedation, the dog was
observed initially undisturbed and unrestrained on
a stainless steel table with a rubber mat. Subse-
quently, with the dog in lateral recumbency, the
remaining variables were measured. Finally, the
assessor observed if the dog was able to walk when
placed on the floor. A single blinded assessor, who
Ó 2009 The Authors. Journal compilation Ó 2009 Association of Veterinary Anaesthetists, 36, 25–33
was familiar with the dog’s normal behaviour, was
responsible for assessing objective and subjective
data throughout the study. Following determina-
tion of baseline data, each animal had a 20-SWG
cephalic catheter placed for drug administration.
Subsequently, the dogs received IV acepromazine
at 0.05 mg kg)1 (Acepran 0.2%; Univet, São
Paulo, SP, Brazil). The final volume of aceproma-
zine was corrected to a standardized volume of
1 mL with physiologic saline (NaCl 0.9%) and
administered over 1 minute. Fifteen minutes after
acepromazine administration (Time ACP), SAP,
PR, fR, temperature, NDS, VAS and pedal with-
drawal reflex were recorded. Thereafter, dogs were
assigned to receive IV administration of each of
four treatments randomly in a cross-over design as
follows: MOR 0.5 mg kg)1 (Dimorf; Cristália, Ita-
pira, SP, Brazil); MET 0.5 mg kg)1 (Metadon;
Cristália, Itapira, SP, Brazil); BUT 0.15 mg kg)1
(Torbugesic; Fort Dodge, IA, USA); or TRA 2.0 mg
kg)1 (Tramadon; Cristália, Itapira, SP, Brazil). The
final volume of each opioid was corrected to a
standardized volume of 5 mL with physiologic
saline and administered over 5 minutes. A mini-
mum washout period of 7 days was allowed be-
tween treatments. Cardiorespiratory variables,
NDS, VAS and pedal withdrawal reflex were eval-
uated again at 15-minute intervals for 90 minutes
(Times 15, 30, 45, 60, 75 and 90). Temperature
was measured at Times 60 and 90.
Statistical analysis
Differences among treatments in SAP, PR, fR and
temperature were analyzed by a 2-way repeated
measures ANOVA with time and treatment as main
factors. When an overall treatment effect was
detected, the Bonferroni correction for multiple
pairwise comparisons was performed to determine
what treatments differed. The same approach was
used to compare the effect of acepromazine (Time
ACP) on parametric data (SAP, PR, fR and temper-
ature) with mean values at baseline. A one-way
repeated measures ANOVA followed by a Dunnet’s
test was used to detect differences within each
treatment between Time ACP and T15–T90. Vari-
ables not normally distributed (NDS and VAS) were
analyzed by a Friedman test followed by a Dunn’s
multiple comparison test to assess differences
among treatments at all time points and differences
over time. For all analyses, values of p < 0.05 were
considered significant.
27
Acepromazine-opioid combinations in dogs ER Monteiro et al.

in dogs receiving MOR. One dog in MOR was as-

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 aceproma-
zine 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 administra-
tion. 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 15–90)
The six dogs which received MET had intense
sedation (NDS = 3) at least at one time point.
Sedation ranged from mild to intense (NDS = 1–3)
signed 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 adminis-
tration, NDS was higher in MET than in TRA. There
were no other significant differences between treat-
ments 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 <

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 ACP 15 30 45 60 75 90

PR (beats minute)1)
MOR 99 ± 19* 76 ± 3 60 ± 3* 59 ± 5*  58 ± 9*  58 ± 6*  58 ± 11*  58 ± 10* 
MET 94 ± 17 83 ± 10 73 ± 29 91 ± 37 85 ± 28 91 ± 31 92 ± 30 89 ± 26
BUT 100 ± 23* 84 ± 24 64 ± 12* 63 ± 14*  64 ± 18* 63 ± 14*  64 ± 17*  68 ± 16*
TRA 97 ± 14* 79 ± 9 68 ± 15 62 ± 10*  63 ± 11* 65 ± 19  62 ± 18*  67 ± 22
SAP (mmHg)
MOR 130 ± 13* 101 ± 5 101 ± 9 94 ± 7 95 ± 7 95 ± 6 96 ± 8 98 ± 8
MET 131 ± 16* 113 ± 11 108 ± 8 106 ± 10 107 ± 8 104 ± 11 105 ± 11 107 ± 12
BUT 123 ± 9* 107 ± 6 101 ± 10 101 ± 8 102 ± 8 103 ± 9 106 ± 13 108 ± 12
TRA 126 ± 10 113 ± 6 102 ± 7* 98 ± 8* 98 ± 7* 100 ± 8* 100 ± 11* 99 ± 13*
fR (breaths minute)1)
MOR 38 ± 17 27 ± 20 47 ± 52 40 ± 44 27 ± 16 24 ± 8 23 ± 7 23 ± 6
MET 39 ± 27 27 ± 12 40 ± 41 36 ± 37 34 ± 33 30 ± 23 28 ± 22 26 ± 13
BUT 45 ± 23 25 ± 10 17 ± 6*à 17 ± 4* 16 ± 5* 16 ± 4* 17 ± 4* 18 ± 4*
TRA 44 ± 35 26 ± 15 23 ± 17 17 ± 4 20 ± 10 17 ± 6 17 ± 6 20 ± 7

*Significantly different from ACP;  significantly different from MET; àsignificantly different from MOR (p < 0.05).

28 Ó 2009 The Authors. Journal compilation Ó 2009 Association of Veterinary Anaesthetists, 36, 25–33
 Acepromazine-opioid combinations in dogs ER Monteiro et al.

Table 2 Mean ± SD rectal temperature in six dogs at icantly after opioid administration (Table 1).
baseline (BL), at 15 minutes after IV administration of Hypotension (SAP < 90 mmHg) was observed at
0.05 mg kg)1 of acepromazine (ACP) and at 60 and least at one time point in 2/6, 1/6 and 2/6 dogs
90 minutes after intravenous (IV) administration of given MOR, BUT and TRA respectively.
0.5 mg kg)1 of morphine (MOR), 0.5 mg kg)1 of metha-
Respiratory rate was higher in MOR than in BUT
done (MET), 0.15 mg kg)1 of butorphanol (BUT) or
at T15. Other differences in fR among treatments
2.0 mg kg)1 of tramadol (TRA)
were not observed. Respiratory rate decreased in
BUT from T15 to T90 compared with values at Time
Time after opioid
ACP (Table 1). Panting was observed in one of six
(treatment) administration
(minutes)
dogs in MOR and MET.
Rectal temperature decreased after administra-
tion of all treatments at T60 and T90 compared
BL ACP 60 90
with values at Time ACP. At T60, temperature was
lower in MET than in BUT and TRA and lower in
MOR 38.9 ± 0.3* 38.4 ± 0.3 37.1 ± 0.2* 36.8 ± 0.2*
MET 38.9 ± 0.3* 38.5 ± 0.4 36.8 ± 0.4* 36.4 ± 0.6*
MOR than in TRA. At T90, temperature was lower
BUT 38.9 ± 0.4* 38.4 ± 0.3 37.6 ± 0.4*  37.6 ± 0.5* à in MOR and MET than in BUT and TRA. Compared
TRA 38.9 ± 0.1* 38.6 ± 0.4 37.9 ± 0.4* à 37.8 ± 0.4* à with values at Time ACP, rectal temperature at T90
decreased by 2.1, 1.6, 0.8 and 0.8 °C in MET, MOR,
*Significantly different from ACP;  significantly different from BUT and TRA respectively (Table 2).
MET; àsignificantly different from MOR (p < 0.05). Pedal withdrawal reflex was absent in one dog in
MET within 15 minutes after treatment adminis-
60 beats minute)1) was observed at least at one tration and in another dog in the same treatment
time point in 3/6 dogs in MOR, MET and BUT and in from T15 to T60. In the remaining treatments,
4/6 dogs in TRA. pedal withdrawal reflex was present in all dogs
Dogs which received MOR had the lowest values throughout the study.
of SAP. However, significant differences in SAP were Retching was observed in five of six dogs and
not detected among treatments throughout the vomiting was observed in one dog in MOR. Retching
study. Systolic arterial pressure decreased signifi- and vomiting were not observed in any dog in MET,
cantly in dogs receiving TRA from T15 to T90 BUT and TRA. One of six dogs in MOR and two of
compared with Time ACP. In the remaining treat- six dogs in MET defecated during or immediately
ments, SAP values after ACP did not differ signif- after opioid administration.

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 metha-
done (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 15 30 45 60 75 90

NDS
MOR 1.0 (1.0–1.5) 1.5 (1.0–2.5) 2.0 (1.0–2.5) 2.0 (1.0–2.5) 1.5 (1.0–2.0) 1.5 (1.0–2.0) 1.0 (1.0–1.5)
MET 1.0 (1.0–1.0) 3.0 (2.5–3.0)* 3.0 (3.0–3.0)* 3.0 (2.5–3.0)* 3.0 (2.0–3.0)* 2.0 (1.5–2.0) 2.0 (1.0–2.0)
BUT 1.0 (1.0–1.5) 1.5 (1.0–2.0) 1.5 (1.0–2.0) 1.0 (1.0–2.0) 1.0 (1.0–2.0) 1.0 (1.0–2.0) 1.0 (0.5–2.0)
TRA 1.0 (1.0–1.5) 1.0 (1.0–1.5)  1.0 (1.0–1.0)  1.0 (1.0–1.0)  1.0 (0.5–1.0)  1.0 (0.5–1.0) 0.5 (0.0–1.0)
VAS
MOR 3.4 (2.2–3.7) 4.9 (4.5–6.7) 6.0 (5.3–7.6)* 6.2 (5.6–7.9)* 6.0 (5.4–7.6)* 5.8 (5.0–7.0)* 4.9 (4.5–5.6)
MET 3.0 (2.5–3.8) 5.9 (4.6–7.0) 7.4 (6.2–8.6)* 7.6 (6.6–8.6)* 7.7 (6.3–8.2)* 6.9 (5.6–7.5) 6.1 (4.1–6.7)
BUT 3.5 (2.4–4.4) 6.0 (4.5–6.2) 6.7 (6.0–7.1)* 6.8 (6.2–7.3)* 6.3 (6.1–7.0)* 5.4 (4.8–6.4) 4.1 (3.0–5.4)
TRA 3.1 (2.1–4.1) 5.1 (3.8–6.2) 5.3 (4.6–7.0)* 5.7 (4.2–7.1)* 5.1 (4.1–6.3)  4.1 (3.4–5.4)  3.0 (2.7–4.2)

*Significantly different from ACP;  significantly different from MET (p < 0.05).

Ó 2009 The Authors. Journal compilation Ó 2009 Association of Veterinary Anaesthetists, 36, 25–33 29
Acepromazine-opioid combinations in dogs ER Monteiro et al.
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 3–5 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 pres-
ent 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 admin-
istered in combination with other drugs with seda-
tive 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 adminis-
tered 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 Ó 2009 The Authors. Journal compilation Ó 2009 Association of Veterinary Anaesthetists, 36, 25–33
minimize differences in the absorption times and
bioavailability, by using a single blinded observer
and by using a randomized cross-over design to
minimize individual variation.
It has been reported in the literature that admin-
istration of l-opioids alone results in mild to
moderate sedation whereas j-agonists produce mild
sedation (Muir 2002). In a previous study, greater
sedation was achieved when the l-opioid oxymor-
phone was administered in combination with ace-
promazine than the combination of the j-agonist
BUT with acepromazine (Cornick & Hartsfield
1992). In the present study, a trend for better
sedation was also observed when acepromazine was
administered in combination with the l opioids
agonists (MOR and MET). The degree of sedation
produced by the combination acepromazine/BUT
varied with the scoring system used. Greater seda-
tion was recorded with the VAS than with NDS.
This finding is not unexpected as sedation is a
subjective variable.
Tramadol is an opioid with low affinity for l
receptors, which also acts by inhibiting the reuptake
of norepinephrine and serotonin (Gaynor 2002).
This mixed mechanism of action might explain the
analgesic effect produced by TRA administration in
spite of its low affinity for opioid receptors. In
addition to its ability to block these reuptake
mechanisms, TRA is metabolized in the liver to
O-desmethyltramadol (M1), which is a pharmaco-
logically active metabolite. M1 was reported to have
greater affinity for l receptors than TRA itself
(Poulsen et al. 1996) and it is thought that this
metabolite contributes to the analgesic effect of TRA
(Poulsen et al. 1996; Shipton 2000). M1 also
appears to play a role in sedation produced by
TRA as its IV administration resulted in sedation in
dogs whereas IV (4 mg kg)1) or oral (11 mg kg)1)
administration of the parent drug TRA did not
(Kukanich & Papich 2004). In the present study,
the degree of sedation produced by acepromazine/
TRA was lower than that achieved with the other
combinations. It might be hypothesized that the low
affinity of TRA for l receptors or the production of
insufficiently high concentrations of M1 during the
course of observation, or both, may be responsible
for these results.
Results of the present investigation indicate that
acepromazine in combination with MET, MOR or
BUT results in good sedation; this effect being
apparently greater with acepromazine/MET. Tram-
adol has little influence on sedation achieved with
 Acepromazine-opioid combinations in dogs ER Monteiro et al.
acepromazine alone. Thus, the combination acepro-
mazine/TRA is not recommended when moderate to
intense sedation is required. Peak sedative effect
appears to occur within 30–45 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 depres-
sion of the vasomotor centre within the hypothal-
amus, 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 (Step-
ien 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 hydro-
morphone alone (Smith et al. 2001; Monteiro et al.
2008) and following administration of MET, bupre-
norphine, oxymorphone, hydromorphone or BUT
in combination with acepromazine (Cornick &
Hartsfield 1992; Stepien et al. 1995; Smith et al.
Ó 2009 The Authors. Journal compilation Ó 2009 Association of Veterinary Anaesthetists, 36, 25–33
2001; Monteiro et al. 2008). The present study was
in agreement with previous reports. A decrease in
PR was observed after administration of aceproma-
zine with MOR, BUT or TRA. However, PR did not
change significantly after the combination acepro-
mazine/MET and this finding is in contrast with
previous studies. In a previous study performed in
our laboratory, PR decreased after intramuscular
administration of 0.5 mg kg)1 of MET alone or in
combination with acepromazine (0.05 mg kg)1, IM)
(Monteiro et al. 2008). The differences between the
two studies may be due to the routes of adminis-
tration employed (IV versus IM). In another study in
conscious dogs, IV MET (1 mg kg)1) also decreased
HR (Hellebrekers et al. 1989). In the latter study,
the authors suggested that bradycardia was medi-
ated, at least partially, through vasopressin release
after MET administration in doses of 1 mg kg)1 or
higher. Vasoconstriction and increased systemic
vascular resistance occurs as a result of vasopressin
release and induces a compensatory decrease in HR
and cardiac output. These findings suggest that
another mechanism might be involved in the
decrease in PR after MET administration, in addition
to the centrally mediated increase in vagal tone
reported before. It is possible that, at the dose used
in the present study (0.5 mg kg)1, IV), MET did not
induce significantly high concentrations of vaso-
pressin release and consequently, systemic vascular
resistance did not increase. Therefore, a compensa-
tory bradycardia was not observed. Another
hypothesis is that the alpha-adrenergic blocking
properties of acepromazine overwhelmed the vaso-
constriction induced by vasopressin.
Intravenous administration of MOR and meper-
idine results in histamine release; which causes
vasodilation and decreases arterial blood pressure,
this effect being prevented when the drugs are
administered intramuscularly (IM) (Hall et al.
2001a). In addition to the route, the rate of
administration also influences the release of hista-
mine and this effect appears to be attenuated by
slow IV administration (Moss & Rosow 1983). In
the present study, we minimized the release of
histamine by administering the opioids slowly over
5 minutes. Hence, it is not likely that arterial blood
pressure was influenced by histamine release after
administration of MOR or any other treatments.
A decrease in arterial blood pressure has been
reported after administration of acepromazine in
combination with buprenorphine, hydromorphone,
oxymorphone or BUT in dogs, although severe
31
Acepromazine-opioid combinations in dogs ER Monteiro et al.
hypotension was not reported following any of the
combinations (Cornick & Hartsfield 1992; Stepien
et al. 1995; Smith et al. 2001). The reduction in
blood pressure seems to be more pronounced when
higher doses of the phenothiazine (0.22 mg kg)1,
IV) were used (Cornick & Hartsfield 1992) and less
likely to be influenced by increasing doses of opioids
(Stepien et al. 1995). These findings are supported
by a previous study which reported that the alpha-
adrenergic block induced by acepromazine is dose
related (Ludders et al. 1983). In the present study, a
further decrease in SAP compared with mean values
at time ACP was observed only after TRA admin-
istration, but TRA has not yet been reported to
reduce cardiac output or to decrease systemic
vascular resistance in dogs. Additionally, histamine
release, which could result in decreased systemic
vascular resistance, was not observed following
TRA administration in people (Barth et al. 1987).
Further research is required to evaluate the hae-
modynamic effects of TRA in dogs.
Acepromazine has little effect on respiratory
function. Although fR may decrease, blood-gases
are not significantly changed (Popovic et al. 1972;
Turner et al. 1974). Conversely, opioid administra-
tion may result in respiratory depression by decreas-
ing ventilatory response to hypercapnia (Wagner
2002); this effect being more pronounced with the l
agonists than with the j agonists (Hall et al. 2001a).
When opioids are used alone and within clinical dose
ranges in dogs, respiratory depression is unlikely to
occur. This effect becomes more important when
opioids are administered in combination with other
respiratory depressant drugs such as injectable or
inhaled general anaesthetics (Wagner 2002). How-
ever, when opioids were used in conjunction with
acepromazine in healthy dogs, respiratory depres-
sion did not occur. Minimal changes were observed
in pH, bicarbonate concentration, PaCO2 and PaO2
in dogs treated with acepromazine and buprenor-
phine, oxymorphone or BUT (Cornick & Hartsfield
1992; Stepien et al. 1995). In the present study, no
dog had apnoea or obvious cyanosis. However, as
blood-gases were not measured, it cannot be ascer-
tained that respiratory depression did not occur.
The decrease in temperature after administration
of all treatments in the present study was due to the
effects of acepromazine and opioids on thermoregu-
latory mechanisms (Thurmon et al. 1996; Hall et al.
2001a; Wagner 2002). Rectal temperature
decreased more in MOR and MET than in other
treatments. It has been reported that opioids that
32 Ó 2009 The Authors. Journal compilation Ó 2009 Association of Veterinary Anaesthetists, 36, 25–33
cause panting may increase heat loss through
airways (Wagner 2002). However, in the present
study, only one of six dogs in MOR and MET were
panting during the study and panting in these dogs
was not related to the lowest temperatures observed.
Vomition is an adverse effect that may occur after
administration of low lipid soluble opioids such as
MOR, hydromorphone and oxymorphone (Valverde
et al. 2004). This effect is thought to result from
stimulation of d receptors in the chemoreceptor
trigger zone (CTZ) (Blancquaert et al. 1986). The
incidence of vomition after IM administration of
MOR (0.5 mg kg)1) was 75% (Valverde et al.
2004). In the present study, premedication with
acepromazine masked the true emetic effect of the
opioids employed. One of six dogs (17%) vomited
after MOR administration whereas none of the dogs
vomited after MET, BUT and TRA, demonstrating a
higher potential for MOR to induce vomiting in
nonpainful, healthy dogs than for the other opioids
tested, probably because of its lower lipid solubility.
A previous study, using the same doses as the
present one, reported a similar incidence of vomiting
(25%) after acepromazine followed by MOR (Valv-
erde et al. 2004).
Results of the present study suggest that, in the
doses used, all combinations used are well-tolerated
by healthy dogs. The major side effect observed
was bradycardia. Good sedation was achieved with
acepromazine in combination with MET, MOR or
BUT, but not TRA. If vomiting is to be avoided,
MET, BUT and TRA may be better options.
Acknowledgement
Partial funding for this research was provided by
PROBIC-CESUMAR (Programa de Bolsas de Ini-
ciação Cientı́fica – Centro Universitário de Maringá).
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Received 25 July 2007; accepted 4 October 2007.
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