الفهرس 
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Abstract
Chronic pain is one of the most common problems in medicine. Despite the recent introduction of new pain-killers, opioid analgesic drugs are still considered the most effective therapies for the treatment of moderate to severe pain. Tramadol, synthetic codeine analog, is a weak μ- receptor agonist and centrally acting analgesic. It has received widespread acceptance in human medicine since it was first introduced in 1977 in Germany. The mechanism of tramadol analgesic action is complex and may be due to opioid and non-opioid mechanisms.
Tramadol was approved for marketing as a safe analgesic in 1995. It was recommended for the management of acute and chronic pain of moderate to severe intensity associated with a variety of diseases or problems, including osteoarthritis, diabetic neuropathy, and neuropathic pain. The manufacturer initially claimed that it produced only very weak narcotic effects. The inadequate product labeling and lack of an established abuse potential have led to the safety feeling of many physicians to prescribe it to recovering narcotic addicts. As a consequence, numerous reports of abuse and dependence have been received. Epidemiological reports have showed that tramadol abuse has recently increased in the US, China, Iran and Egypt.
The widespread use of tramadol as a substance of abuse and its use as an off-label treatment for premature ejaculation have urged the need for studying its effects on the male reproductive system.
This study was conducted on 30 fertile male Wister Albino rats weighing 150-200 gms each. Animals were divided into two main groups: group I (Control group): included 5 rats. Each animal received 1ml/day (0.9%) normal saline by oral tube (a process called gavage). group II (Tramadol treated groups): included 25 rats. They were given tramadol in variable
doses which were equivalent to different human adult doses according to
Paget and Branes, (1964) conversion tables orally once daily for 18 weeks
(equivalent to 4.5 years in an adult human male). Tramadol treated group were
divided into five equal groups: group II a: received tramadol in a dose of
(0.9) mg daily which equals 50mg in an adult 70 kg human male, group II b:
received tramadol in a dose of (1.8) mg daily which equals 100 mg in an adult
70 kg human male, group II c: received tramadol in a dose of (9) mg daily
which equals 500 mg in an adult 70 kg human male, group II d: received
tramadol in a dose of (18) mg daily which equals 1000 mg in an adult 70 kg
human male, group II e: received tramadol in a dose of (27) mg daily which
equals 1500 mg in an adult 70 kg human male.
At the end of experiment (After 18 weeks): The rats were dissected under
ether anesthesia and complete aseptic measures. The testes and epididymis
were removed and processed for light and electron microscopic examination.
Morphological changes were assessed in testis and epididymis using light
(hematoxylin, eosin & masson trichrome stains were used) and electron
microscopy. Morphometric analysis of different parameters of testis and
epididymis was done. Sperm morphology assessment was done by counting
abnormal sperms (either head or tail) in 1000 sperm in each rat. The assessed
parameters were analyzed statistically using SPSS method.
Statistical analysis of the presenting data revealed the following:
Progressive decrease in the mean value of seminiferous tubule
diameters with progressive increase in tramadol dose in
tramadol treated groups in relation to control group where this
decrease was significant in group II c and highly significant in
groups II d & II e.
Highly significant decrease in mean values of germinal
epithelial height in all tramadol treated groups in relation to
control groups.
Highly significant progressive increase in the mean values of
seminiferous tubule basement membrane thickness at
progressive increments in tramadol doses in all tramadol
treated rat groups.
Significant progressive decrease in the mean values of
Johnson spermatogenic score at progressive increments of
tramadol doses in tramadol treated rat groups.
Highly significant increase in the number of rats with
decreased seminiferous tubule count/ cut section (with
different degrees) in tramadol treated rat groups in comparison
with control group.
Highly significant increase in the number of rats with distorted
seminiferous tubule morphology in tramadol treated rat groups
in comparison with control group.
Highly significant increase in the number of rats with
spermatogenic cell affection (whether cellular dissociation
from each other or cytoplasmic vaculation) in tramadol treated
rat groups in comparison with control group.
Non-significant increase in the number of rats with decreased
or absent spermatids in groups II c, II d, II e (at tramadol dose
45mg/kg).
Significant increase in the number of rats with decreased
Sertoli cell number or abnormal Sertoli cell vacuolation in
tramadol treated rat groups in comparison with control group.
Significant increase in the number of rats with decreased or
distorted Leydig cell number in tramadol treated rat groups in
comparison with control group.
Highly significant increase in the number of rats with
interstitial blood vessel congestion and interstitial edema in
tramadol treated rat groups in comparison with control group.
Significant increase in mean numbers of abnormal sperms in
tramadol treated rat groups (II b, II c, II d & II e) in
comparison with control group (p value 0.05), while there
was no such significant increase in group II a (at tramadol dose
4.5mg/kg).
Non-significant increase in mean numbers of sperms with head
abnormalities in all tramadol treated rat groups (except group
II b where the increase was significant (p value < 0.05)) in
comparison with control group.
Significant increases in the mean numbers of sperms with
abnormal tails in groups II c, II d & II e when compared with
control group.
Significant decrease in the mean values of epididymal duct
diameters at progressive increments of tramadol dose in all
studied rat groups where these decrements were significant in
groups II a, II b, II c & II d in comparison with control group
and highly significant in group II e in comparison with control
group.
Highly significant decrease in mean values of epididymal
epithelial height in groups II a, II c & II d in comparison with
control group while there was a significant decrease in mean
value of epididymal epithelial height in group II e in
comparison with control group.
The mean value of epididymal epithelial height in group II b
was lower than that of control group (though non-significant).
Significant increase in the number of rats with decreased
average epididymal duct count/ cut section in tramadol treated
rat groups in comparison with control group.
Highly significant increase in the number of rats with distorted
epididymal duct morphology in tramadol treated rat groups in
comparison with control group.
Significant increase in the number of rats with distorted
epididymal epithelium in tramadol treated rat groups in
comparison with control group.
Highly significant increase in the number of rats with abnormal
epididymal duct epithelial thickness (whether increased or
decreased) in tramadol treated rat groups in comparison with
control group.
Non-significant increase in the number of rats with epididymal
intercellular vaculation in tramadol treated rat groups in
comparison with control group.
Highly significant increase in the number of rats with
epididymal intracellular vaculation (whether focal or diffuse)
in tramadol treated rat groups in comparison with control
group.
Significant increase in the number of rats with epididymal
epithelial exfoliation in duct lumens in tramadol treated rat
groups in comparison with control group.
Non-significant increase in the number of rats with epididymal
epithelial necrosis in tramadol treated rat groups in comparison
with control group.
Significant increase in the number of rats with affected
principal, basal & clear cells in tramadol treated rat groups in
comparison with control group.
Highly significant increase in the number of rats with
decreased or absent epididymal stereocilia in tramadol treated
rat groups in comparison with control group.
Highly significant increase in the number of rats with distorted
epididymal stereocilia in tramadol treated rat groups in
comparison with control group.
Significant increase in the number of rats with separated
epididymal basement membrane in tramadol treated rat groups
in comparison with control group.
Highly significant increase in the number of rats with increased
epididymal basement membrane thickness in tramadol treated
rat groups in comparison with control group.
Highly significant increase in the number of rats with increased
epididymal interstitial tissue density (whether mild, moderate
or marked increase) in tramadol treated rat groups in
comparison with control group.
Highly significant increase in the number of rats with
epididymal interstitial edema/ fibrosis/ congested blood vessels
in tramadol treated rat groups in comparison with control
group.
Highly significant increase in the number of rats with
epididymal interstitial fibrosis (with different severities of
fibrosis) in tramadol treated rat groups in comparison with
control rat group.
Significant increase in the number of rats with epididymal
interstitial inflammation (with different severities) in tramadol
treated rat groups in comparison with control rat group.
Electron microscopic examination of testicular sections revealed
abnormal ultrastructure of testis of tramadol treated rats in comparison
with the control. There were irregularities and thickening of the basement
membranes of seminiferous tubules with abnormalities of the myoid
cells. Structural abnormalities of Sertoli cells with disruption of the blood
testis barrier, abnormal morphology of spermatogonia, primary
spermatocytes and spermatid with marked vacuolations, decrease of
mitochondrial denisty with abnormal morphology and obvious wide
spacing between the spermatogenic cells. The interstitial cell of Leydig
showed abnormal morphology with ill-defined organelles and fading
nuclei especially with high tramadol doses.
Light microscopic examination of sperm smears stained with eosin,
from the tramadol treated groups, revealed increased percentage of
sperms with abnormal morphology in a dose dependent manner. The
head abnormalities included detached head, absent hook, pin shaped or
globular head, while tail abnormalities included short, angulated, curved
or coiled tail. Other abnormalities detected were fused or amalgamated
spermatozoa.
Electron microscopic examination of epididymis revealed abnormal
ultrastructure of epididymis of tramadol treated rats in comparison with
the control. There were marked intercellular and intracellular
vacuolations disrupting the blood-epididymal barrier, lysosome
accumulation, reduction of stereocillia. Abnormalities of all cells of the
epididymis were noticed. There were irregularities of the basement
membrane with thickening of the muscle layer of the epididymis.