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1735-2657/08/72-157-160
IRANIAN JOURNAL OF PHARMACOLOGY & THERAPEUTICS
Copyright © 2006 by Razi Institute for Drug Research (RIDR)
IJPT | July 2008 | vol. 7 | no. 2 | 157-160
IJPT 7:157-160, 2008
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Effects of Tramadol on Electrocardiogram, Mean
Electrical Axis and Respiration in Kagani Goats
(Capra hircus)
R. RAINA, P. K. VERMA, N. K. PANKAJ, S. PRAWEZ and A. K. SRIVASTAVA
For author affiliations, see end of text.
Received January 18, 2008; Revised August 10, 2008; Accepted August 25, 2008
This paper is available online at http://ijpt.iums.ac.ir
ABSTRACT
The effects of tramadol on electrocardiogram (ECG), mean electrical axis and respiratory rates were stud-
ied in adult kagani goats after intramuscular administration of tramadol at 1 mg/kg b.wt as a prelude to its
clinical use as an analgesic in veterinary practice. The ECG was monitored by standard bipolar leads and
discernible electrocardiographic features were observed in lead II. The normal electrocardiographic pa-
rameters in healthy goats were; P-wave (0.04 ± 0.005 mV, 48 ± 4.29 ms), QRS complex (0.38 ± 0.037
mV, 84 ± 2.86 ms), T-wave (0.11 ± 0.005 mV, 76 ± 1.28 ms), PR, ST, QT intervals were 152 ± 5.72, 280
± 7.29, 368 ± 18.60 ms, respectively. These parameters were not significantly different in goats up to 3h
post treatment. Except significant reduction in T-wave amplitude (p<0.05) at 0.5h, no other significant
change was observed. Reduction in T-wave indicates early re-polarization phenomenon and is indicative
of some transient cardio-acceleratory effect of the drug. The mean electrical axis (56.740 ± 0.60) before
treatment didn’t show significant differences up to 3h of post-treatment. The rate of respiration prior to
treatment was observed 19.6 ± 2.57min-1 and administration of tramadol didn’t produce any significant
change on respiration up to 3h post treatment.
Keywords: Tramadol, Electrocardiogram, Mean electrical axis, Respiration, Kagani goats
Tramadol, a codeine analog, is a centrally acting
synthetic analgesic and the drug owes its analgesic
action to its weak opioid (µ) receptor agonist activity
and inhibition of uptake of nor-epinephrine and
serotonin. Tramadol is as effective as meperidine in the
amelioration of labor pain and cause less respiratory
depression in humans. The drug is also being considered
to be a better alternative in comparison to other opioid
analgesics in humans because of high analgesic potency
and minimal respiratory depression at analgesic doses
[1]. The analgesic activity of tramadol is due to both
parent as well as its O-demethylated metabolite and this
metabolite is 4-6 times more potent than the parent [ 2 ].
Tramadol is supplied as a racemic mixture, which is
more effective than either of the enantiomer alone. The
(+) enantiomer binds to the μ receptor and inhibit
serotonin uptake whereas (-) enantiomer inhibit nor-
epinephrine uptake and blocks α2 receptors [ 3 ]. In vitro
and in vivo studies also suggested that only (+)ve
enantiomer of tramadol-induce vasodilatation at high
doses indicating that tramadol can be used safely at
therapeutic dose [ 4 ]. The vasodilation induced by
tramadol is due to both nitric oxide production from
endothelium and a direct effect on smooth muscle
mediated via interaction with the μ receptors [ 4 , 5 ].
Electrocardiographic studies are infrequently
reported in animals [ 6 , 7 ]. The electrocardiographic
parameters have greatest value in recognizing and
diagnosing arrhythmias in animals [ 8 ]. Variability in
normal duration and amplitude of different
electrocardiographic parameters are useful in evaluating
the side effects of commonly used therapeutic drugs [ 9 ].
Mean electrical axis values (MEA) determine the site,
size and direction of the conduction system of the heart,
which is individual or a breed characteristic [ 10].
Studies on effects of tramadol on electrocardiographic
parameters, mean electrical axis and respiration in goats
are scarce. The study was pursued with the objective to
determine different electrocardiographic parameters in
normal goats and the effect of tramadol on these
parameters at analgesic dose.
158 | IJPT | July 2008 | vol. 7 | no. 2 Raina et al.
Fig 1 a. Electrocardiograms of Lead II of goat before (A) and after 0.5h (B) tramadol treatment, using physiograph Medicaid,
Chandigah, India. Sensitivity 500µv and chart speed, 2.5 cm per second.
0
0.05
0.1
0.15
0.2
0 30 60 90 120 150 180
Tim e afte r tr e atm en t (m in)
Am plitude (m V)
0
10
20
30
40
50
60
70
80
Duration (ms)
Voltage (mV)
D u ration (m s )
Fig 1 b. Graphical representation amplitude (mV) and duration (ms) of T-wave before and after administration of
tramadol
MATERIALS AND METHODS
Healthy kagani goats (Capra hircus) of either sex
aged 2-3 years were selected for the study. The animals
were housed in the animal shed of Faculty of Veterinary
Sciences, at R.S. Pura, Jammu (INDIA). All animals
were maintained under standard condition of feeding
and management. The animals were fed green fodder
and concentrates at standard rates and free access to
water. The studies were conducted in the month April-
June when ambient temperature varied in between 35 -
400C. During recording of electrocardiogram (ECG)
goats were made to stand on wooden plane. Needle
electrodes were inserted subcutaneously proximal to the
olecranon on the caudal aspect of the right and left fore-
legs for the right and left arm wires, respectively and in
the external aspect of the stifle joint of the right and left
leg wires, respectively [ 11]. The three standard bipolar
limb leads (I, II, and III) and augmented unipolar limb
leads (aVR, aVL and aVF) were recorded on paper us-
ing a three channel physiograph (Medicaid, Chandigah,
India). A commercial human pharmaceutical prepara-
tion of Tramadol (Cadilla Health Care, Ahmadabad,
India) was administered intramuscularly at the dose rate
of 1mg kg-1body wt. Recording of ECG parameters
were done before and after the administration of drug.
Most of the opioids like pentazocine provide effective
analgesia for (1-6 h) when they are used in a dose range
of 0.4-2mg kg-1 intramuscularly [ 12]. Therefore, a dose
of 1mg kg-1 body wt. was selected. The reported half
life of drug in dogs is 0.80±0.12h [ 2 ]. Therefore the
recording of ECG parameters and respiration were done
at different pre-determined time intervals up to 3h of
post administration. The mean electrical axis was calcu-
lated by the method of described by Dragutin and co-
workers in 1999 [ 13]. The results obtained were ana-
lyzed statistically using paired t-test between mean ob-
tained before and after treatment [ 14].
RESULTS AND DISCUSSION
Present investigation employed human technique of
Einthoven’s triangle in ventral plane quite successfully
in goats in standing position [ 15]. It was observed that
various components were quite discernible in unipolar
and bi-polar limb leads. Therefore, comparisons were
based on lead II electrocardiogram. Table 1 depicts the
recorded values during the experiments on goats on du-
ration and amplitude of P wave, duration of the QRS
complex, mean electrical axis, duration of PR and QT
intervals, S-T segment and respiration before and at
different predetermined time intervals post administra-
tion of tramadol.
Effects of Tramadol on Electrocardiogram ijpt.iums.ac.ir | 159
Table 1. Comparative electrocardiographic parameter and respiration in Kagani goat and effect of Tramadol hydrochloride @ 1mg.kg-1 intramuscu-
lar administration
After Treatment (min.)
Parameter Control 30 60 90 120 150 180
Voltage
(mV) 0.04±0.005 0.06±0.007 0.045±0.003 0.045±0.007 0.04±0.005 0.04±0.005 0.04±0.005
P - wave Duration
(ms) 48±4.29 40±1.78 44±6.44 40±3.57 40±1.78 44±2.86 40±3.57
Voltage
(mV) 0.38±0.037 0.40±0.047 0.39±0.029 0.37±0.031 0.375±0.049 0.37±0.0375 0.37±0.044
QRS complex Duration
(ms) 84±2.86 80±1.78 76±2.86 88±5.72 82±3.22 82±3.22 82±3.22
Voltage
(mV) 0.11±0.005 0.06±0.012* 0.09±0.019 0.08±0.008 0.07±0.007 0.06±0.009 0.07±0.004
T - wave Duration
(ms) 76±7.85 64±1.76 68±10.0 72±7.87 60±7.15 60±715 64±8.58
PR interval (ms) 152±5.72 176±8.58 160±7.15 176±8.58 168±5.72 168±11.4 192±5.72
ST interval (ms) 280±7.29 292±11.4 280±7.15 284±4.65 264±8.58 284±2.86 272±5.72
QT interval (ms) 368±18.60 360±7.15 360±7.15 364±4.65 344±8.58 352±5.72 344±8.58
Mean Electrical Axis 56.74±3.6 55.52±2.64 57.1±4.6 56.9±2.46 57.3±4.4 56.36±3.02 56.52±4.78
Respiration (min-1) 19.6±2.57 18.6±3.57 17±1.71 19.8±2.28 20.2±3.50 20±3.35 20±4.17
Values are expressed as mean ± S.E. of recording six adult animals
Mean treatment values are different from the mean control values at 5% (p<0.05)
In present study prior to treatment the amplitude and
duration of P-wave signifying atrial depolarization were
0.04±0.005 mV and 48±4.29 ms, respectively which is
comparable with kids and lambs [ 5 ] but lesser than
0.229±0.06 mV reported for dogs [ 16]. The administra-
tion of tramadol didn’t produce significant changes in
the amplitude and duration of P-wave up to 3 h post
administration.
Control values of ventricular depolarization repre-
sented by amplitude of QRS complex is 0.38±0.037 mV
which is higher than the reported values of
(0.17±0.086mV) in kids but is comparable to cats
(0.427±0.25mV) [ 5 , 17]. The higher QRS amplitude in
goats in the present study indicates higher systolic pres-
sure [ 17]. In the present study duration of QRS complex
was 84±2.86ms is lower than in kids (93±7ms) but
higher than reported values in dogs (54±0.01ms), cats
(32±0.007ms) and llamas (50.0±8.00ms) [ 16, 17, 18].
Administration of tramadol didn’t effect duration and
amplitude of QRS complex. Tilley, 1985 has suggested
that longer QRS complex duration to be a resultant of a
heart block or enlargement of either of ventricle or both
ventricles.
Significant reduction in T-wave amplitude
(0.06±0.009mV) at 0.5h post administration was ob-
served as compared to control (0.11±0.005mV) and
representative recording is shown in fig.1a and b. How-
ever, no such significant reduction in duration of T-
wave was observed. The decrease prominence T-wave
indicate re-polarization phenomenon of the ventricles
particularly basal part is rather rapid and the next car-
diac cycle begins quickly thereby indicative of cardio
accelerator effect of tramadol. The control duration of
ST and QT intervals are higher than the reported values
of kids 220±12ms, 313±13ms, but comparable with
llamas 230±46, 360±60ms respectively [ 7 , 18]. How-
ever no significant change was observed in these inter-
vals up to 3h of post treatment compared to pretreat-
ment values. Determination of electrical axis of heart is
an important aid for understanding deviation of impulse
conduction in the heart and can help in diagnosis of
pathological conditions of heart. In the present study
tramadol didn’t significantly affect the mean electrical
axis values (56.740 ± 0.60) in goats. The respiration rates
reported for goats are in the range of 12-25 min-1 [ 19]
and tramadol didn’t affect significantly respiration rates
(19.6±2.57 min-1). Conversely opiate substitutes like,
pentazocine causes significant reduction in respiration
in kids [ 7 ]. Finding also suggested that tramadol also
provides a cardio-protective effect against myocardial
ischemia-reperfusion in isolated rat heart [ 20].
From the results it can be concluded that at the dose
rate 1mg kg-1 in goats, tramadol is a safe analgesic due
to its mild and transient effect on ECG events without
effecting respiration.
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CURRENT AUTHOR ADDRESSES
R. Raina, Division of Pharmacology & Toxicology, Faculty of Veteri-
nary Sciences & Animal Husbandry, SKUAST-J, R.S. Pura
181102, Jammu (J & K), INDIA. E-mial:
drpawankv@yahoo.co.in (Corresponding author)
P. K. Verma, Junior Scientist, Division of Pharmacology and Toxicol-
ogy, Faculty of Veterinary Sciences and Animal Husbandry, R.S.
Pura, Jammu (J&K), INDIA.
N. K. Pankaj, Junior Scientist, Division of Pharmacology and Toxi-
cology, Faculty of Veterinary Sciences and Animal Husbandry,
R.S. Pura, Jammu (J&K), INDIA.
S. Prawez, Junior Scientist, Division of Pharmacology and Toxicol-
ogy, Faculty of Veterinary Sciences and Animal Husbandry, R.S.
Pura, Jammu (J&K), INDIA.
A. K. Srivastava, Director, National Dairy Research Institute, Karnal
Haryana, INDIA.