Effects of metoclopramide on emesis in cats sedated

Journal of Feline Medicine and Surgery (2010) 12, 899e903
doi:10.1016/j.jfms.2010.06.008
Effects of metoclopramide on emesis in cats sedated
with xylazine hydrochloride
Saeed Kolahian DVM, PhD 1 *, Seyedhosein Jarolmasjed DVM, DVSc 2
1 Department of Basic Sciences,
Faculty of Veterinary Medicine,
University of Tabriz, Iran
2 Department of Clinical Sciences,
Faculty of Veterinary Medicine,
University of Tabriz, Iran
Date accepted: 22 June 2010
The prophylactic anti-emetic effect of five dosages of metoclopramide (0.2, 0.4,
0.6, 0.8 and 1 mg/kg, IM) was evaluated against saline solution, both injected 1 h
before administration of xylazine in cats. Saline was administered to cats (day 0)
followed by sequentially increasing dosages of metoclopramide at 1-week
intervals. After xylazine injection, all cats were carefully observed to record the
frequency of emesis and the time until onset of the first emetic episode. The
onset of sedation in these cats was also studied. Prior treatment with each
dosage of metoclopramide significantly reduced the frequency of emetic
episodes (P < 0.05). Metoclopramide administration prior to xylazine injection
did not alter the time until onset of the first emetic episode at any of mentioned
dosages, but significantly reduced the time until onset of sedation only at
the dose of 1 mg/kg. Metoclopramide may be used as a prophylactic anti-emetic
in cats sedated with xylazine hydrochloride.
Ó 2010 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.
Xylazine hydrochloride, an a 2 adrenoceptor agonist,
possessing analgesic, sedative, and
muscle relaxant properties, has been widely
used in veterinary practice following its introduction
in 1962. 1 Xylazine-induced emesis occurs frequently
in cats hence increases the risk of aspiration pneumonia.
2 This effect is mediated by a 2 adrenoceptor placed
in chemoreceptor trigger zone (CTZ) of the area postrema
in cats. 3,4 Using an a 2 adrenoceptor antagonist
such as yohimbine, tolazoline, and phentolamine inhibits
xylazine-induced emesis in cats but also prevents
its sedative effects in these animals. 5e7 On the
other hand, it has been shown that dopamine stimulates
the medullary CTZ, producing nausea and vomiting.
Metoclopramide appears to have an anti-emetic
effect due to its antagonism of central and peripheral
dopamine receptors. At higher doses, it acts as a serotonin
(5-HT 3 ) receptor antagonist as well. Metoclopramide
is widely used as an anti-emetic in patients with
chemotherapy-induced nausea and vomiting. 8e13 As
a 2 adrenoceptor, dopamine and 5-HT 3 receptors exist
in CTZ of the area postrema in cats, this study is conducted
to investigate the efficacy of prophylactic administration
of five different dosages of
metoclopramide in preventing vomiting and its effect
*Corresponding author: Tel: þ98 411 3392374; Fax: þ98 411
3357834. E-mail: skolahian@tabrizu.ac.ir
on the time until onset of sedation in cats treated with
xylazine hydrochloride.
Materials and methods
Animals
Eight healthy adult cats (four of each gender) weighing
between 1.7 and 3.3 kg (median, 2.55 kg) were
used in the study. They were vaccinated with Feline
Rhinotracheitis-Calici-Panleukopenia Vaccine (Fort
Dodge Animal Health, IA, USA) and Rabisin (Rabisin-R;
Merial, France), prior to the study. Cats were
housed separately in single cages placed in an air-ventilated
room with temperature controlled at 22 2 C.
They were fed a commercially available food, and water
was available ad libitum. The protocol for the
study was approved by the institutional animal care
and use committee.
Protocol
The prophylactic anti-emetic effect of five dosages of
metoclopramide hydrochloride (0.2, 0.4, 0.6, 0.8 and
1 mg/kg of body weight, intramuscular (IM)) (Pladic;
Caspian) was evaluated against saline (0.9% NaCl) solution
(0.078 ml/kg, IM) as control treatment. Both
treatments were injected 1 h before administration of
xylazine (0.66 mg/kg, IM) (Xylazine, 2%; Alfasan,
1098-612X/10/120899+05 $36.00/0
Ó 2010 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.

900 S Kolahian and S Jarolmasjed
the Netherlands). Saline was administered to cats (day
0) followed by sequentially increasing dosages of metoclopramide
at 1-week intervals (day 7, 14, 21, 28 and
35). All cats were subjected to the same procedures,
and food was withheld on the night preceding each
treatment. Metoclopramide was diluted in saline solution
to achieve an injection volume of 0.2 ml and was
administered as mentioned before. Immediately after
each dosage of metoclopramide injection, cats were
fed 150 g of commercially available food. One hour
later, each cat was administered xylazine (0.66 mg/
kg, IM). A 2% solution of xylazine was diluted with
saline solution to achieve the final injection volume
of 0.2 ml. After xylazine injection, all cats were carefully
observed for 30 min, to record the frequency of
emesis and the time until onset of the first emetic episode.
The effect of metoclopramide on the time until
onset of sedation induced with xylazine was also
studied.
Emetic response
Emesis was scored as an all-or-none response, and
separate episodes of emesis were considered when
the interval between bouts of vomiting exceeded 5 s.
During a 30-min observation period after xylazine injection,
the number of episodes of emesis was
counted. Time until onset of the first emetic episode
was also recorded.
Sedative response
Sedative response was recorded when a cat assumed
sternal or lateral recumbency and was unable
to stand. Time until onset of sedation after administration
of xylazine was recorded.
4.00 0.58, 4.60 0.60, 4.20 0.66 and 5.00
0.63 min, respectively.
The number of episodes of emesis was 6 0.78 for
the saline treatment and 2.88 0.72, 2.75 0.59,
2.00 0.49, 1.14 0.40 and 1.00 0.31 for metoclopramide
at dosages of 0.2, 0.4, 0.6, 0.8, and 1 mg/kg, respectively.
Prior treatment with metoclopramide at
each dosage (0.2, 0.4, 0.6, 0.8, and 1 mg/kg) significantly
reduced the number of episodes of emesis induced
by xylazine (Fig 1).
Time until onset of sedation was 12.50 1.34 min for
the saline treatment and 13.88 1.48, 13.29 2.68,
12.33 3.03, 11.57 1.53 and 10.29 1.51 min for metoclopramide,
using dosages of 0.2, 0.4, 0.6, 0.8, and
1 mg/kg, respectively. Prior treatment with metoclopramide
significantly reduced time until onset of sedation
after administration of xylazine only at 1 mg/kg
dosage (Fig 2).
Discussion
In this study, prior IM treatment with each dosage of
metoclopramide (0.2, 0.4, 0.6, 0.8, and 1 mg/kg) significantly
reduced the frequency of emesis with no significant
effect on the time until onset of the first
emetic episode (latency time of emesis) after xylazine
injection. We showed a significant reductive effect of
metoclopramide on the number of episodes of emesis
at a dose of 0.2 mg/kg. Higher dosages (0.4, 0.6, 0.8
and 1 mg/kg) of metoclopramide did not significantly
affect the latency time of emesis, considering that the
reductive effect on the number of episodes of emesis
was still significant.
Statistical analysis
All data were reported as mean SEM. Data for the
time until onset of sedation, latency of emesis and
frequency of emesis after treatment with metoclopramide
were analysed, using the Wilcoxon
signed-rank test. A value of P < 0.05 was considered
significant.
Results
Prior treatment with meoclopramide at any of these
dosages (0.2, 0.4, 0.6, 0.8, and 1 mg/kg) did not significantly
alter the latency time of emesis (time until
onset of the first emetic episode) in cats
sedated with xylazine hydrochloride. Time until onset
of the first emetic episode (mean SEM) was
3.50 0.50 min when cats were administered saline
solution (control treatment) prior to administration
of xylazine. When cats were administered doses calculated
at 0.2, 0.4, 0.6, 0.8, and 1 mg of metoclopramide/kg
prior to administration of xylazine, time
until first emetic episode was 4.00 0.32,
Fig 1. The effect of five different dosages of metoclopramide
(Meto-0.2, 0.2 mg/kg; Meto-0.4, 0.4 mg/kg; Meto-0.6,
0.6 mg/kg; Meto-0.8, 0.8 mg/kg; and Meto-1, 1 mg/kg)
compared to normal saline (NS) on the number of episodes
of emesis in cats sedated with xylazine hydrochloride
(0.66 mg/kg IM). Results are presented as means SEM.
*P < 0.05, **P ¼ 0.008, ***P < 0.001, compared to control
treatment (NS).

Metoclopramide, emesis and xylazine
901
Fig 2. The effect of five different dosages of metoclopramide
(Meto-0.2, 0.2 mg/kg; Meto-0.4, 0.4 mg/kg; Meto-0.6,
0.6 mg/kg; Meto-0.8, 0.8 mg/kg; and Meto-1, 1 mg/kg)
compared to NS on the time until onset of sedation in cats
sedated with xylazine hydrochloride (0.66 mg/kg IM).
Results are presented as means SEM. *P < 0.05, compared
to control treatment (NS).
Anti-dopaminergic agents like metoclopramide
have been widely used (and still are) as anti-emetics
for the prevention of nausea and vomiting during radiotherapy,
14 cancer chemotherapy, 15e19 pregnancy, 20
following surgery (postoperative nausea and vomiting)
21 and during a migraine attack. 22 The prominent
mechanism of action is the blockade of dopamine D 2
receptors in the area postrema and vomiting centre. 23
The effect of metoclopramide on xylazine-induced
emesis in cats has been studied previously by Topal
et al at a dose of 0.4 mg/kg. 24 Topal’s study showed
metoclopramide does not have any effect on the frequency
of emetic episodes induced by xylazine
(2 mg/kg) in cats. 24 Our findings contradicted Topal’s,
showing that five different dosages of metoclopramide
(0.2, 0.4, 0.6, 0.8 and 1 mg/kg) are effective on
the number of episodes of emesis induced by xylazine
(0.66 mg/kg). The inefficiency of metoclopramide reported
in Topal’s study could be due to the higher
dosage of xylazine used in their study. This dosage
of xylazine was three times higher than the effective
dose to induce emesis in 95% of cats injected with
xylazine hydrochloride. 25,26
Previously it was shown that prior treatment with
dexamethasone (4, 8 mg/kg) effectively prevents xylazine-induced
emesis in cats. It was hypothesised
that the potential anti-emetic mechanism of dexamethasone
may involve the emetic pathway of a 2
adrenoceptors. 27 Glucocorticoid receptors and a 2
adrenoceptors are abundant and coexist in the area
postrema and nucleus of the solitary tract in the
medulla oblongata. 28,29 The medulla oblongata has
substantial neuronal activity in regulation of the
emetic reflex. 30 It has been shown in decerebrated
cats sedated with xylazine that dexamethasone exerts
its central anti-emetic action through an activation of
the glucocorticoid receptors in the bilateral nucleus
tractus solitarii (NTS) in the medulla and prevents xylazine-induced
emesis through an activation of the a 2
adrenoceptors in these cats. 31 Maropitant, a potent
neurokinin-1 receptor antagonist, administered at
adosageof1mg/kgviathesubcutaneous,intravenous
or per oral route 2 h before xylazine challenge,
reduced the mean number of emetic events by 76,
100 and 90%, respectively, compared to untreated
cats. Maropitant has been shown to have a low affinity
at adrenergic receptors including the a 2 adrenergic
receptor. 32 Maropitant is highly selective for the
neurokinin-1 receptor and did not prevent xylazineinduced
emesis by antagonising the a 2 adrenoceptors.
32 In line with these findings we showed prior
treatment with metoclopramide is effective in prevention
of xylazine-induced emesis in cats, but the mechanism(s)
involved in this effect is not completely clear.
It is well known that NTS is richly supplied with
many kinds of vomiting-related neurotransmitters
and neuromodulators, such as opioid, gamma-aminobutyric
acid, adrenaline, noradrenaline, dopamine,
serotonin, histamine and substance P. 33 Also, some
authors have hypothesised that the bilateral NTS
may be the common final pathway that leads to the
vomiting centre. 34 It is assumed that metoclopramide,
a dopamine and serotonin receptor antagonist, like
other previously mentioned drugs (Dexamethasone,
Maropitant) does not inhibit a 2 adrenoceptor for its
anti-emetic action and completes its anti-emetic action
on xylazine-induced emesis via inhibiting dopamine
and serotonin (5-HT 3 ) receptors in the bilateral
NTS in this nervous pathway. Clarification of the
mechanism of this effect remains to be studied in
detail.
Our results showed that metoclopramide in any of
mentioned dosages did not compromise the time until
onset of sedation of cats injected with xylazine hydrochloride.
Furthermore, metoclopramide at a dose of
1 mg/kg significantly reduced the time until onset of
sedation after administration of xylazine.
In this study, increasing dosages of metoclopramide
at 1-week intervals were administered to the cats. It is
also possible to perform a randomised cross-over
treatment design for this kind of study. Applying
cross-over study design would have allowed the consideration
of period effect (diminished emetic effect
with each week), which was not possible in this study.
Comparing results gained by the two mentioned
study designs may clarify the efficacy of metoclopramide
in preventing xylazine-induced emesis in cats
more accurately.
In conclusion, the results of the present study indicate
that metoclopramide (0.2, 0.4, 0.6, 0.8 and 1 mg/
kg, IM) significantly reduces the frequency of emetic

902 S Kolahian and S Jarolmasjed
episodes induced by xylazine with no effect on the
time until onset of the first emetic episode. Metoclopramide
may be used as a prophylactic anti-emetic
in cats treated with xylazine hydrochloride.
Acknowledgement
This study was financially supported by Research
Council of University of Tabriz (project number 27/
3634).
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