Basrah Journal of Veterinary Research,Vol.19, No.3, 2020. Proceeding of the 17th International
Conference. College of Veterinary Medicine. University of Basrah. Iraq
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EVALUATION THE SEDATIVE AND ANALGESICEFFECTFOR
MIXTURE OF TRAMADOL AND METOCLOPRAMIDE IN
SHEEP
Manahel Allawi Al-jborI
Department of Physiology, Biochemistry and Pharmacology ,Collage Of Veterinary
Medicine, University of Mosul, Mosul
Keyword: Tramadol, Metoclopramide, Analgesia.
Corresponding Author: manahela310@gmail.com
ABSTRACT
The aim of study was to explore the analgesic and sedative effects of tramadol
and metoclopramide co-adminstration in sheep. Injection of tramadol intramuscular at
5mg/kg body weight in sheep produced deep sedation, recompense and analgesia in
comparison with dose of 2.5mg/kg body weight which produced only mild sedation
and failed as analgesic dose. Intramuscular injection of metoclopramide at 20mg/kg
body weight in sheep produced deep sedation, recompense and analgesia in
comparisons with dose of 10 mg/kg which produced only sedation and failed as
analgesic dose. Intramuscular injection of metoclopramide at dose20mg/kg or
tramadol at 5mg/kg body weight in sheep each alone were produced deep sedation,
recumbence and analgesia while metoclopramide at 10mg/kg body weight or tramadol
a(t2.5mg/kg b. W) produced only mild sedation and each dose felid to produced
analgesia in sheep. Concomitant administration of tramadol at dose2.5mg/kg body
weight to sheep and metoclopramide at dose 10mg/kg body weight intramuscular as
sedatives not analgesia dose produced a significant increase in sedation score and
produced deep sedation with recompense as well as good analgesia in comparison
with control group and group of tramadol or metoclopramide alone.
INTRODUCTION
Tramadol is an opioid analgesic drug that are giving for patient suffering from
moderate, sever or chronic pain (1). This drug has been used a pre-anesthetic
(2).tramadol is a drug that combined with Mu-receptor in the central nervous system
Basrah Journal of Veterinary Research,Vol.19, No.3, 2020. Proceeding of the 17th International
Conference. College of Veterinary Medicine. University of Basrah. Iraq
107
and inhibition nor epinephrine and serotonin reuptake (3, 4, 5). tramadol use to relief
pain sings anxiety, depression(6) and after anesthesia in cow ,dog and mice (7,
8).Metoclopramide is agastroprokinetic agent and antiemetic in animals(9)(10) and
human (11). This drug act antagonize of dopamine and inhibition of serotonin
receptors5-HT3 (12) and Cholinergic activity(13) metoclopramide has analgesic
effect in mice (14) and human (15) . Many researchers were used metoclopramide and
fixed the analgesic effect to this drug when used alone or combination with other
drug. Metoclopramide was used with ketamine in mice(16).another study used it alone
or as a combination with Diphenhydramine in mice and introduced analgesia(17)but
not found studies use metoclopramide with tramadol in sheep .Therefore, suggest
performing of this study to evaluate the analgesic effect of tramadol alone or as a
combination with metoclopramide in a sedative dose in sheep and to study the effect
of this mixture as for analgesia.
MATERIAL AND METHOD
Twenty ewe from local market weighing about (35-40)kg with aged about(1-1.5)years
were selected for this study. The animals fed with standard diet and water with kept
standard animal housing condition.
First Experiment: Detection the Sedative and analgesic dose of tramadol which
injected intramuscular in sheep.In this experiment the animals were divided randomly
into three groups each every group consist of five animal, in the first group (control
group)was injected with normal saline solution while the animals in the second and
third groups were injected with tramadol hydrochloride(Tramadol HCL
ampul50mg/ml G.L. pharm Gmbh,8502a lannach Austria),the constriction of this
drug100mg/2ml at(2.5,5)mg/kg body weight intramuscular in sheep respectivly.The
dose of tramadol was obtained from previous study(18). Detection of sedative scores
pre and after 15,30,45,60 minute from tramadol injection according to (19)as fallows;
0: normal animal (no sedation)
1: dropping of head with normal walking
2: ataxia
3: lying but able to rise
Basrah Journal of Veterinary Research,Vol.19, No.3, 2020. Proceeding of the 17th International
Conference. College of Veterinary Medicine. University of Basrah. Iraq
108
4: recumbence and Loss of righting reflex.
Detection of analgesia by using of electrical stimulates to measuring of pain
threshold after stimulating the nasal mucous membrane for ewe(noxious stimulation) .
The nociception threshold was detected after attachment the electrical polar of
electrical stimulation to the nasal mucous membrane and record the volt that which
the sheep moved the head for the source of stimulation then detection the pain
threshold befor the base line and after injection of the drug within 30 minutes.
Second Experiment: Detection of Sedative and analgesic dose by metoclopramide
which injected intramuscular in sheep.In this method the animals also divided into
three group of animals each group consist of five animals. First group represented as
control group which injected with normal saline solutions while second and third
groups injected with metoclopramide at dose(10,20 mg/kg )/ intra muscular in sheep
respectively. Detection of sedative score after injection of animal by same method in
the first experiment. Using of electrical stimulator by same method in first experiment
to measuring the pain threshold
Third Experiment: In this experiment the animals divided into four groups. each
group consist of5animals.first group of animal (control group) injected with normal
saline at(1ml/kg intramuscular) while second group injected with tramadol at dose 2.5
mg/kg and third group injected with metoclopramide at dose 10mg/kg while the
animals in the fourth group injected with tramadol at2.5mg/kg and metoclopramide
10mg/kg intramuscular separately. Detection of sedative score and analgesic effect
of each other group by same method in the first experiment.
Statically Analysis: The parametric Data which include more than 2 factors statically
analyze by tow Way analysis of variance (20). The non-parametric data analyze by
using Mann-Whitney test (21) the data inform scores and the Significant difference
plane least from0.05.
RESULTS
Injection of sheep with tramadol at 2.5mg/kg body weight intra muscular
Produced mild sedation and calm of the animal was significant increase in sedation
scores at minute (15,30,45,60) after injection in comparison with zero time of the
Basrah Journal of Veterinary Research,Vol.19, No.3, 2020. Proceeding of the 17th International
Conference. College of Veterinary Medicine. University of Basrah. Iraq
109
same dose as well as significant increased at the time minute (45,60) in comparison
with the time( 15) of the same dose. When injection of sheep with tramadol at the
5mg/kg body weight intra muscularly in sheep there was a significant increase in the
sedative scores in the animals treated with tramadol at minute(15,30,45,60)in
comparison with zero time of the same dose and significant increase at minute
(45,60)in comparison with time minute (15) at the same dose .This dose was the good
analgesic dose in comparison with dose at 2.5 mg/kg of tramadol which failed to
produce analgesia in the treated animals.
Injection of metoclopramide at dose(10mg/kg) intramuscular body weight
produced mild sedation and increased in The onset time of sedation, there was
significant increase in sedation scores at minute (15,30,45,60) in comparison with
zero time of the same dose, as well as a significant increase in sedation scores at
minute(30,45,60) in comparison with minute (15) of the same dose .injection of
metoclopramide at dose 20mg/kg b.w. i.m. in sheep produced deep sedation (head
down, ataxia ,recompense and significant increase in sedation scores at minute
(30,45,60) in comparison with minute(15)of the same dose. this dose was produced a
good analgesia in the animals in comparison with dose (10 mg/kg b.w. of
metoclopramide. There was a significant increase in pain thresholds at the minute(30)
after injection in comparison with zero time of the same dose as well as increased in
pain threshold in comparison with the control group and group treated with
metoclopramide at10mg/kg b.w.
Basrah Journal of Veterinary Research,Vol.19, No.3, 2020. Proceeding of the 17th International
Conference. College of Veterinary Medicine. University of Basrah. Iraq
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Table(1)Sedation scores which result from Tramadol and metoclopramide injection
each alone or as a combination in muscle in sheep.
*The Value significant different at minute 15 at plan least from 0.05 at the same dose.
a: Value significant different at minute30 at plan least from 0.05 at the same dose .
b:The Value significantly differ from control group at plan least from 0.05 at the same time.
c:The Value significantly differ from tramadol group at 2.5mg/kg plan least from 0.05 at the same
time.
d:The Value significantly differ from tramadol group at 5mg/kg plan least from 0.05 at the same time
e:The Value significantly differ from metoclopramide group at 10mg/kg plan least from 0.05 at the
same time
f:.The Value significantly differ from metoclopramide group at 20mg/kg plan least from 0.05 at the
same time.
Basrah Journal of Veterinary Research,Vol.19, No.3, 2020. Proceeding of the 17th International
Conference. College of Veterinary Medicine. University of Basrah. Iraq
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(Figure 1) Sedation scores which result from Tramadol and metoclopramide injection
each alone or as a combination in muscle in sheep.
In this experiment the animals which injected with tramadol at(2.5)mg/kg i.m.
or metoclopramide at(10mg/kg b.w.) each alones sedatives not analgesic dose this
doses produced mild sedation and not produce analgesia while concomitants injection
at the same dose of tramadol and metoclopramide produced deep sedation and
decrease in the onset of sedation .
There was significant increase in the sedative scores at minute (45,60) in
comparison with minute (15) of the same dose and significant increase in pain
threshold compare with animal treated with tramadol or metoclopramides each alone.
The combination of tramadol and metoclopramide at(sedative dose not
analgesic)induced good analgesia in comparison with control group and group treated
with tramadol or metoclopramide each alone.
0 1 2 3 4 5
Basrah Journal of Veterinary Research,Vol.19, No.3, 2020. Proceeding of the 17th International
Conference. College of Veterinary Medicine. University of Basrah. Iraq
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(Table2):Change in voltage caused to pain as a result from tramadol or
metoclopramide injection in muscle in sheep .
*:The Value significantly differ from control groupat plan least from 0.05 at the same time.
a: The Value significantly differ from tramadol group at 2.5mg/kg plan least from 0.05 at the same
time.
b:The Value significantly from ramadol group at 5mg/kg plan least from 0.05 at the same time.
c: The Value significantly differ from metoclopramide group at 10mg/kg plan least from 0.05 at the
same time.
d: The Value significanlyt differ from metoclopramide group at 10mg/kg plan least from 0.05 at the
same time.
Basrah Journal of Veterinary Research,Vol.19, No.3, 2020. Proceeding of the 17th International
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(Figure 2) Change in voltage caused to pain as a result from tramadol or
metoclopramide injection in muscle in sheep.
DISCUSSION
Tramadol is centrally acting agent activity at M-opioid adrenergic and and 5-
hydroxytryptamine (5-HT) receptors the mechanism of action as are-uptake inhibitor
of nor epinephrine and serotonin and agonist of the M-opioid receptor(4).Tramadol
used to relief mild to moderate pain in human and veterinary medicine(22) also used
preoperatively in veterinary anesthesia to reduces the dose of volatile anesthetics and
opioids agent (23).
Metoclopramide is anti-emetic drug recently many studies refers to the analgesic
effect of metoclopramide alone ( 15) or as combination with other analgesic effect of
ketamine(16) or with tramadol(24). Intramuscular injection of tramadol at(2.5mg/kg
b.w) produced mild sedation without recompense and analgesia while at(5mg/kgb.w)
produced deep sedation and sings of sedation was appear(drooping of head with
normal walking, ataxia, lying and recompense)as well as produced good analgesia
this agreement with previous studies(19) the analgesic effect result from mechanism
that is are-uptake inhibitor of nor epinephrine and serotonin and agonist of M-opioid
receptor(4).intramuscular injection of metoclopramide in sheep produced sedative
effect in form dependant dose this result agreement with(14) which refer
metoclopramide produced sedation on the central nervous system in chick also
0
*
*a
*b
*ac
*abcd
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Basrah Journal of Veterinary Research,Vol.19, No.3, 2020. Proceeding of the 17th International
Conference. College of Veterinary Medicine. University of Basrah. Iraq
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injection of metoclopramide produced analgesic effect in form dependant dose this
result agreement with perilously study(17)(16) which refer to the analgesic effect of
metoclopramide in mice this analgesic action due to antagonism action to D receptors
which related with opioid system (25) this drug has been increased prolactin(26) as
well as agonist of serotonin 5HT(27) and alter ca across through cell membrane(28).
Combination of metoclopramide and tramadol in sedatives not analgesic dose which
produced deep sedation and analgesia this interaction was a synergism interaction
because each drug act on different receptor (pharmacodynamics) and produced their
analgesic effect. This combination succeeds to produce analgesia and reduced the side
effect for this drug.
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