Chronic Tramadol Administration Research Articles

High-Intensity Interval Training Ameliorates Tramadol-Induced Nephrotoxicity and Oxidative Stress in Experimental Rats.

Tramadol (TRA) is an opioid analgesic widely prescribed for moderate-to-severe pain; however, its abuse and chronic use have been associated with kidney damage. Considering the protective role of exercise training in reducing organ damage, this study aimed to assess the influence of high-intensity interval training (HIIT) on a male rat's kidney following chronic TRA administration. In this experimental study, 30 male Wistar rats were assigned to the following groups: control (CON; animals received normal saline five days a week in the first month and three days a week in the second month), exercise (EXE; animals conducted HIIT training according to exercise protocol five days a week for two months), TRA (animals received TRA 50 mg/kg (i.p.) as described for the CON group), EXE-TRA (animals received TRA and conducted exercise protocol), and EXE-SL (animals received normal saline and conducted exercise protocol). Then, serum IL-6 and IL-10 levels, tissue malondialdehyde (MDA), total antioxidant capacity (TAC), glutathione peroxidase (GPx), superoxide dismutase (SOD), and levels of albumin, urea, and creatinine (CR), along with pathological changes in the kidney, were measured. A p-value of <0.05 was considered significant using GraphPad Prism v.9 (GraphPad Software, La Jolla, California, USA). The inflammatory cytokines IL-6 and IL-10 were significantly increased in the EXE and EXE-TRA groups compared to the TRA group. Chronic administration of TRA in the TRA group decreased antioxidant indicators TAC, GPx, and SOD in kidney tissue while increasing oxidative stress MDA compared to the CON group (p<0.05). In contrast, the EXE-TRA group showed higher levels of TAC, GPx, and SOD, while MDA decreased compared to the TRA group. Additionally, serum levels of urea and CR were increased in the TRA group compared to the CON group, whereas these levels were decreased in the EXE-TRA group compared to the TRA group. The inflammatory effect of HIIT training, due to severe hyperemia and mild inflammatory cell infiltration, was seen in all EXE groups. Pathological findings confirmed TRA-induced kidney damage through moderate hyaline cast presence and severe apoptosis in the TRA group. Other findings were in line with the above results. These findings confirm the nephrotoxicity of chronic use of TRA through biochemical and oxidative markers and pathological outcomes. In addition, the result suggests that HIIT has the potential to mitigate the detrimental effects of TRA through reversing biochemical and oxidative markers, including TRA-induced apoptosis. Consequently, considering its restorative properties, HIIT could be explored as a prospective nephroprotective approach for long-term TRA treatment.

Effect of tramadol on apoptosis and synaptogenesis in hippocampal neurons: The possible role of µ-opioid receptor.

Tramadol is a synthetic opioid with centrally acting analgesic activity that alleviates moderate to severe pain and treats withdrawal symptoms of the other opioids. Like other opioid drugs, tramadol abuse has adverse effects on central nervous system components. Chronic administration of tramadol induces maladaptive plasticity in brain structures responsible for cognitive function, such as the hippocampus. However, the mechanisms by which tramadol induces these alternations are not entirely understood. Here, we examine the effect of tramadol on apoptosis and synaptogenesis of hippocampal neuronal in vitro. First, the primary culture of hippocampal neurons from neonatal rats was established, and the purity of the neuronal cells was verified by immunofluorescent staining. To evaluate the effect of tramadol on neuronal cell viability MTT assay was carried out. The western blot analysis technique was performed for the assessment of apoptosis and synaptogenesis markers. Results show that chronic exposure to tramadol reduces cell viability of neuronal cells and naloxone reverses this effect. Also, the level of caspase-3 significantly increased in tramadol-exposed hippocampal neurons. Moreover, tramadol downregulates protein levels of synaptophysin and stathmin as synaptogenesis markers. Interestingly, the effects of tramadol were abrogated by naloxone treatment. These findings suggest that tramadol can induce neurotoxicity in hippocampal neuronal cells, and this effect was partly mediated through opioid receptors.

The effects of quercetin on seizure, inflammation parameters and oxidative stress in acute on chronic tramadol intoxication

BackgroundTramadol is a widely used synthetic opioid for moderate to severe pain. Some studies have shown that tramadol can increase oxidative stress in different tissues of the body. Quercetin is also a substance with various biological effects, including antioxidant, anti-inflammatory, hepatoprotective, nephroprotective, and cardioprotective activities. The current investigation aimed at determining the effects of quercetin, with or without naloxone, on tramadol intoxication.MethodsThis study was performed on 30 male Wistar rats divided into five groups: Group I) control group: intraperitoneal injections of normal saline 0.9% for 14 days; Group II) tramadol: 25 mg/kg for 14 days, and then a 50 mg/kg acute dose injection on the last day; Group III) acute quercetin (single dose): tramadol injection as with the second group plus 100 mg/kg of quercetin on the last day; Group IV) chronic quercetin: tramadol injection similar to the second group plus quercetin 100 mg/kg for 14 days; Group V) quercetin plus naloxone: tramadol injection similar to the second group plus injection of quercetin 100 mg/kg + intravenous naloxone 2 mg/kg on the last day, followed by a 4 mg/kg/h injection of naloxone for six hours. The rats were monitored for six hours on the last day, relating to the number and severity of seizures. Finally, the samples were prepared for biochemical investigation of the serum level of oxidative stress markers (MDA, SOD, NOx), inflammatory factors (IL-6, TNF-α), biochemical parameters (ALT, AST, creatinine, glucose) and hematological assay. The liver, heart, kidney, cortex, cerebellum, and adrenal tissues were collected to investigate the redox state.ResultsNone of the treatments had positive effects on the number and severity of seizures. Chronic administration of quercetin led to alteration of some blood parameters, including reduced hemoglobin level and elevated platelet counts. Acute on chronic tramadol administration resulted in a significant rise in AST, where different treatments failed to reduce their levels down to the control group.Conclusionchronic administration of quercetin showed decreased oxidative/nitrosative stress in the liver, kidney, adrenal, and heart tissues. Quercetin plus naloxone decreased oxidative stress in the heart and adrenal tissues, but adverse effects on the brain cortex and hepatic function. Single-dose quercetin reduced cardiac oxidative stress.

Effects of chronic tramadol administration on cognitive flexibility in mice.

Tramadol is widely used for pain relief especially in seniors. However, long-term use of tramadol has serious adverse effects, including cognitive impairment. Besides its memory effects, already demonstrated in animals, a recent clinical report suggests that tramadol could also affect executive function in seniors. Several studies have hypothesized that the anti-muscarinic properties of tramadol could be responsible for the deleterious effects of tramadol on cognition. We aimed at investigating the effects of chronic administration of tramadol on cognitive flexibility in adult male mice, as assessed by a visual discrimination reversal task using a touchscreen device. The effects of tramadol were further compared to those of scopolamine, a reference muscarinic antagonist. We found that, during the early phase of the reversal task, when cognitive flexibility is most in demand, both tramadol-treated mice (20mg/kg, s.c., twice a day) and scopolamine-treated mice (0.5mg/kg, s.c., twice a day) needed more correction trials and showed a higher perseveration index than saline-treated mice. Therefore, tramadol affects cognitive flexibility, and its anticholinergic properties could be at least partly involved in these deficits. In view of these deleterious cognitive effects of tramadol, physicians should be cautious when prescribing this analgesic, especially in seniors who are more vulnerable to adverse drug events and in which alternative prescription should be preferred whenever possible.

The effects of naloxone, diazepam, and quercetin on seizure and sedation in acute on chronic tramadol administration: an experimental study

BackgroundTramadol is a widely used synthetic opioid. Substantial research has previously focused on the neurological effects of this drug, while the efficacy of various treatments to reduce the associated side effects has not been well studied. This study aimed to evaluate the protective effects of naloxone, diazepam, and quercetin on tramadol overdose-induced seizure and sedation level in male rats.MethodsThe project was performed with 72 male Wistar rats with an average weight of 200–250 g. The rats were randomly assigned to eight groups. Tramadol was administered intraperitoneally at an initial dose of 25 mg/kg/day. On the 14th day, tramadol was injected at 75 mg/kg, either alone or together with naloxone, diazepam, and quercetin (acute and chronic) individually or in combination. The rats were monitored for 6 h on the last day, and the number, the duration, and the severity of seizures (using the criteria of Racine) were measured over a 6-h observation period. The sedation level was also assessed based on a 4-point criterion, ranging from 0 to 3. Data were analyzed in SPSS software using Kruskal–Wallis, Chi-square, regression analysis, and generalized estimating equation (GEE) tests. The significance level was set at P < 0.05.ResultsThe naloxone-diazepam combination reduced the number, severity, and cumulative duration of seizures compared to tramadol use alone and reduced the number of higher-intensity seizures (level 3, 4) to a greater extent than other treatments. Naloxone alone reduced the number and duration of seizures but increased the number of mild seizures (level 2). Diazepam decreased the severity and duration of seizures. However, it increased the number of mild seizures (level 2). In comparison with the tramadol alone group, the acute quercetin group exhibited higher numbers of mild (level 2) and moderate (level 3) seizures. Chronic quercetin administration significantly increased the number of mild seizures. In the GEE model, all groups had higher sedation levels than the saline only group (P < 0.001). None of the protocols had a significant effect on sedation levels compared to the tramadol group.ConclusionThe combined administration of naloxone and diazepam in acute-on-chronic tramadol poisoning can effectively reduce most seizure variables compared to tramadol use alone. However, none of the treatments improved sedation levels.

Mitochondrial dysfunction and oxidative stress are involved in the mechanism of tramadol-induced renal injury

Tramadol (TMDL) is an opioid analgesic widely administered for the management of moderate to severe pain. On the other hand, TMDL is commonly abused in many countries because of its availability and cheap cost. Renal injury is related to high dose or chronic administration of TMDL. No precise mechanism for TMDL-induced renal damage has been identified so far. The current study aimed to evaluate the potential role of oxidative stress and mitochondrial impairment in the pathogenesis of TMDL-induced renal injury. For this purpose, rats were treated with TMDL (40 and 80 ​mg/kg, i.p, 28 consecutive days). A significant increase in serum Cr and BUN was detected in TMDL groups. On the other hand, TMDL (80 ​mg/kg) caused a substantial increase in urine glucose, ALP, protein, and γ-GT levels. Moreover, urine Cr was significantly decreased in TMDL-treated rats (40 and 80 ​mg/kg). Renal histopathological alterations included inflammation, necrosis, and tubular degeneration in the kidney of TMDL-treated animals. Reactive oxygen species (ROS) formation, increased oxidized glutathione (GSSG), lipid peroxidation, and protein carbonylation was increased, whereas total antioxidant capacity and reduced glutathione levels were considerably decreased in TMDL groups. Significant mitochondrial impairment was also detected in the form of mitochondrial depolarization, adenosine-tri-phosphate (ATP) depletion, mitochondrial permeabilization, lipid peroxidation, and decreased mitochondrial dehydrogenase activity in the kidney of TMDL (80 ​mg/kg)-treated animals. These data suggest mitochondrial impairment and oxidative stress as mechanisms involved in the pathogenesis of TMDL-induced renal injury.

Effect of tramadol on the male reproductive system and sexual health

ObjectivesThe aim of this study was to review the literature as regards the potential effects of chronic tramadol administration on the male reproductive system and sexual health in humans and experimental animals in vivo and in vitro in published studies.Materials and methodsWe searched electronic databases from 2006 to 2016, including PubMed MEDLINE, Medscape, EMBASE, EBCSO Academic Search Complete, Cochrane Systematic Reviews Database, and Google-Scholar.Study selectionThe articles that studied the effect of chronic tramadol administration on the male reproductive system and sexual health in both humans and laboratory animals were selected. The initial search selected articles that met the inclusion criteria. If the studies did not fulfill the inclusion criteria, they were excluded.Data extractionStudy quality assessment included the following: whether ethical approval was gained, eligibility criteria specified, appropriate controls, adequate information, and defined assessment measures.Data synthesisComparisons were made using a structured review with the results tabulated.ConclusionThis review demonstrates a significant damage to testicular tissue with chronic tramadol administration. Tramadol was demonstrated to affect male reproductive hormones by decreasing serum testosterone and gonadotrophins and increasing estradiol and prolactin. As regards its effect on sexual function, it was demonstrated that it is neither more effective nor safer compared with other drugs used in the treatment of premature ejaculation. Moreover, it may be associated with erectile dysfunction.

Toxicology of tramadol following chronic exposure based on metabolomics of the cerebrum in mice

Tramadol is an opioid used as an analgesic for treating moderate or severe pain. The long-term use of tramadol can induce several adverse effects. The toxicological mechanism of tramadol abuse is unclear. Metabolomics is a very useful method for investigating the toxicology of drug abuse. We investigated the impact of chronic tramadol administration on the cerebrum of mice, focusing on the metabolites after tramadol administration. The mice received 20 or 50 mg/kg body weight tramadol dissolved in physiological saline daily for 5 weeks via oral gavage. Compared with the control group, the low dose tramadol group showed seven potential biomarkers, including gamma-hydroxybutyric acid, succinate semialdehyde, and methylmalonic acid, which were either up- or down-regulated. Compared with the control group, the high dose tramadol group showed ten potential biomarkers, including gamma-hydroxybutyric acid, glutamine, and O-phosphorylethanolamine, which were either up- or down-regulated. The up-regulated gamma-hydroxybutyric acid and the down-regulated succinate semialdehyde revealed that the neurotransmitter system was disrupted after tramadol abuse. Compared with the low dose tramadol group, there were twenty-nine potential biomarkers in the high dose tramadol group, mainly related to the pentose phosphate pathway and glycerophospholipid metabolism. In conclusion, metabolomics in the tramadol abuse group demonstrated that long-term tramadol abuse can result in oxidative damage, inflammation, and disruption of the GABA neurotransmitter system, which will help to elucidate the toxicology of tramadol abuse.

Chemotherapeutic Potential of Epimedium brevicornum Extract: The cGMP-Specific PDE5 Inhibitor as Anti-Infertility Agent Following Long-Term Administration of Tramadol in Male Rats.

Epimedium brevicornum Maxim (EbM) is a well-known Chinese herb that has been widely used for the treatment of several diseases. The main purpose of this study is to examine the role of Epimedium brevicornum extract in certain andrological parameters in rats as a natural modulator for adverse viewpoints associated with chronic administration of tramadol (TAM). Fifty rats were categorized into five groups. Untreated rats were known as Group I, whereas rats in Groups II and III were administered 2.43 g/kg/day of E. brevicornum extract and 50 mg/kg/day of TAM for 130 consecutive days, respectively. Both of Groups IV and V were administered TAM for 65 successive days, followed by concomitant use of both drugs for another 65 days, with the E. brevicornum extract at doses of 0.81 and 2.43 g/kg/day, respectively. TAM showed an injurious effect on sperm attributes, serum hormones, tissue malondialdehyde, superoxide dismutase, and nitric oxide. Elevation of the apoptotic marker Bax and a reduction of Bcl2 were recorded. Histopathological abnormalities have been reported in rat testicles. Rats treated with E. brevicornum extract with TAM showed an improvement in all the parameters tested. It could be presumed that E. brevicornum extract plus TAM exhibits a promising effect on the enhancement of male anti-infertility effects.

Tramadol administration induced hippocampal cells apoptosis, astrogliosis, and microgliosis in juvenile and adult male mice, histological and immunohistochemical study

ABSTRACT Tramadol is a common analgesic, frequently used for relieving moderate or severe pain and widely used to delay ejaculation. However, repeated large doses have several adverse effects, especially on the brain tissue. So, this study was designed to assess the potentially deleterious effects of chronic administration of tramadol on principal fields of the hippocampus in adult and juvenile male albino mice. Thirty swiss male albino mice were divided equally into three groups: Group Ia (control adult) 3 months old, Group Ib (control juvenile) 3-week postnatal mice, Group II (tramadol treated adult mice) and Group III (tramadol treated juvenile mice). Both treated groups received tramadol tablets dissolved in water in a dose of 40mg/kg for 1 month by gastric tube. Tramadol treated groups showed degenerative changes in dentate gyrus (DG) granule cells, pyramidal neurons of CA1and CA3 fields in the form of electron-dense or rarified cytoplasm, dilated rER and mitochondrial changes. Additionally, immunohistochemical results revealed significantly increased in caspase 3 positive cells in different hippocampal principal fields. Astrogliosis and microgliosis were proved by the increased immunoreactivity of astrocytes to glial fibrillary acidic protein (GFAP) and microglia to CD68. Morphometric findings showed a significant reduction of both surface area of granule and pyramidal cells, and in thickness of DG, CA1, CA3 layers. Moreover, most of these morphological changes were aggravated in the juvenile-treated group. So, it can be concluded that tramadol abuse can induce an altered morphological change on the principal fields of the hippocampus in adult and juvenile mice.

Effect of tramadol dependence on male sexual dysfunction.

Tramadol dependence became an increasing and alarming problem in the Egyptian community. Wide availability of tramadol as a pain killer and its role in the treatment of premature ejaculation may be the most apparent causes of increased magnitude of the problem among youth who believe that tramadol has a positive impact on their sexual functions. This study aimed to explore the real impact of chronic tramadol administration on sexual functions in males dependent on tramadol. The study was carried on 80 subjects (50 subjects were tramadol dependent group and 30 subjects represented the control group). Personal, family and past histories were obtained from all the participants in addition to the toxicological history from tramadol dependent group. Urine screening for tramadol was done for all cases of history of tramadol dependence then confirmation by HPLC technique to measure tramadol blood level was done. Both groups were investigated for serum testosterone and prolactin level. Curiosity (22%) and treatment of premature ejaculation (20%) were the main motives for dependence. Erectile dysfunction and decreased libido occurred in 44% and 48% of tramadol dependent group respectively. Significant increase in erectile dysfunction and decreased libido was noted as the duration of dependence increased. Additionally, significant decrease in serum testosterone level and increase in serum prolactin level as tramadol daily dose and duration increased was found. In conclusion, men who take tramadol for premature ejaculation or any other purpose must know that they are very susceptible to many sexual dysfunctions.

Tramadol induces changes in Δ-FosB, µ-opioid receptor, and p-CREB level in the nucleus accumbens and prefrontal cortex of male Wistar rat

ABSTRACTBackground: Besides the analgesic effect of tramadol, prolonged exposure to tramadol can induce adaptive changes thereby leading to dependence and tolerance. Tramadol induces its effect via µ-opioid receptor (MOR). However, tramadol has other targets such as serotonin and epinephrine transporters.Objective: CREB and ΔFosB are transcriptional factors, which are involved in the behavioral abnormalities underlying drug abuse. In this study, the effects of acute and chronic tramadol treatments on MOR, ΔFosB, and CREB levels were studied.Methods: For this purpose, 36 male Wistar rats were used. The animals were divided into two main groups. A total of 18 animals received tramadol (0, 5, and 10 mg/kg) acutely and 18 animals received the same doses for the following 14 days. One hour after the last injection, the NAC and PFC were dissected and kept at −80°C in liquid nitrogen. Using western blotting technique, the levels of MOR, ΔFosB, and p-CREB were evaluated.Results: In the NAC, acute tramadol exposure increases the levels of MOR and p-CREB. Moreover, chronic tramadol administration in this region results in elevated levels of MOR, ΔFosB and p-CREB compared with saline-treated rats. The levels of MOR and p-CREB in the PFC increased in both acute and chronic tramadol exposure. Also, ΔFosB levels increased only following chronic tramadol administration. The results revealed that adaptive changes occurred during drug exposure.Conclusion: We concluded that both CREB and ΔFosB played a role in tramadol dependence. Additionally, increased MOR levels during tramadol treatments might be due to receptor desensitization.

Chronic exposure to the opioid tramadol induces oxidative damage, inflammation and apoptosis, and alters cerebral monoamine neurotransmitters in rats

Tramadol is an opioid used as analgesic for treating moderate or sever pain. The long-term use of tramadol can induce several deleterious effects. We investigated the impact of chronic tramadol administration on the cerebrum of rats, focusing on oxidative damage, inflammation, apoptosis and changes in monoamine neurotransmitters. Rats received 30 or 60 mg/kg body weight tramadol dissolved in physiological saline daily for 8 weeks via oral gavage. Tramadol-induced rats showed significantly increased cerebral lipid peroxidation and nitric oxide, and deceased GSH content and activity and expression of the antioxidant enzymes. Tramadol administration for 8 weeks resulted in increased serum pro-inflammatory cytokines (TNF-α and IL-6) and expression of NF-κB, iNOS, TNF-α and IL-6 in the cerebrum of rats. Monoamine neurotransmitters, 8-oxo-7,8-dihydro-2′-deoxyguanosine, and gene and protein expression levels of p53 and Bax were significantly increased in the cerebrum of tramadol-induced rats. In contrast, chronic tramadol administration down-regulated Bcl-2 both gene and protein expression in the cerebrum of rats. In conclusion, our results indicate that the neurotoxic effect of chronic tramadol consumption is mediated via oxidative stress, inflammation and apoptosis. Tramadol provoked lipid peroxidation, up-regulated inflammation and apoptosis markers and altered neurotransmission in the cerebrum of rats.

CORRELATION BETWEEN CHRONIC TRAMADOL ADMINISTRATION AND DISTURBANCES ACTIVITY OVARIAN FOLLICLES AND ENDOMETRIUM IN FEMALE RATS

إن دراسة الباحثين للتأثير السمي لعقار الترامادول على الجهاز التناسلي للإناث لازال محدودا ويحتاج لمزيد من الجهد لمعرفته وتأكيده, لذا كان الهدف من هذا البحث هو دراسة العلاقة بين التعرض المزمن لعقار الترامادول و إمكانية حدوث اعتلال في نشاط المبيض والرحم لإناث الفئران, اشتملت الدراسة على عدد خمسة وعشرون من إناث الفئران البالغين قسموا إلى أربع مجموعات للدراسة (ِA,B,C,D) تم إعطاؤهم جرعات مختلفة من عقار الترامادول وبطرق مختلفة والمجموعة الضابطة (CON) تم إعطاؤها محلول ملح للمقارنة, تم تشريح الفئران و استئصال المبيض والرحم وذلك لعمل التحليل النسيجي لهن. وأسفرت نتائج الدراسة عموما عن وجود نقص بسيط ومتوسط في عدد بويضات المبيض مع وجود حويصلات بالرحم نتيجة التعرض المزمن لعقار الترامادول, وأن هذا الضرر يزداد ليصبح شديداً بزيادة جرعات الترامادول, كما أسفرت الدراسة- أيضاً- عن حدوث اعتلال في أنسجة المبيض ونقص في عدد الجريبات المتزايدة في المبيض و تم استبدالها بجريبات تالفة و تكيسات كما وجد خلل و ضمور في غدد و بطانة الرحم, وأن هذه الآثار السلبية تتزايد بزيادة جرعات الترامادول, كما حدث تعافي لهذه التغيرات الخلوية (المبيض والرحم) سواء كان جزئيا أو كليا وذلك عند وقف إعطاء عقار الترامادول للفئران. لذا بناءً على ما سبق نوصى بمزيد من الدراسة لتوضيح هذه النتائج وتطبيقها على الإنسان ودراستها إكلينيكيا لمعرفة تأثير هذا العقار على الجهاز التناسلي للذكور(الخصية) والإناث (الرحم والمبيض) وخصوصا في الحالات التي لا يوجد لديها سبب واضح للعقم أو لتأخر الإنجاب.

العلاقة بين إمكانية التعرض المزمن لعقار الترامادول وحدوث اعتلال في النشاط التناسلي والإنجابي لدى الذكور

هدف هذا البحث إلى دراسة العلاقة بين إمكانية التعرض المزمن لعقار الترامادول وحدوث اعتلال في النشاط التناسلي والإنجابي لدى الذكور, وقد شملت هذه الدراسة مائه حالة من وحده السموم بمستشفى الأزهر بدمياط الجديدة, كما تم اختيار عشرون حالة كمجموعة ضابطة, تم أخذ موافقتهم على إجراء البحث, وتم الكشف عن نواتج عقار الترامادول, مستخدمين في ذلك "جهاز الفصل الكروماتوجرافى السائلي عالي الجودة" وتم عمل بعض التحاليل الروتينية في الدم, كما تم فحص السائل المنوي ميكروسكوبيا لكل الحالات, كما تم الفحص الإكلينيكي لهم, مع الأخذ في الاعتبار اعتلال الجهاز (العصبي, الهضمي, رسم القلب وأشعة تليفزيونية (دوبلر) لاستبعاد وجود دوالي بالخصية. وأسفرت نتائج الدراسة عموما عن وجود علاقة قوية ذات دلالة إحصائية بين التعرض المزمن لعقار الترامادول وحدوث اعتلال في نتائج ومكونات السائل المنوي لدى الذكور البالغين, حيث زادت نسبة اللزوجة بنسبة (70%) والنقص في (كمية, وعدد, وحركة والتقدم للسائل المنوي) حيث كانت (49%)(88%)(77%) و(77%) على التوالي وذلك بالمقارنة بالمجموعة الضابطة. لذا بناءً على ما سبق نوصى بأنه: يجب على الأزواج المتعاطين لعقار الترامادول لفترات طويلة مثلاً لتأخير سرعة القذف أن يدركوا تأثيره السيئ والسلبي على الصحة الإنجابية وأن ما يحدث عكس ما يعتقدون وذلك على المدى الطويل.

Mitochondrial impairments contribute to spatial learning and memory dysfunction induced by chronic tramadol administration in rat: Protective effect of physical exercise

Despite the worldwide use of tramadol, few studies have been conducted about its effects on memory and mitochondrial function, and controversial results have been reported. Recently, there has been an increasing interest in physical exercise as a protective approach to neuronal and cognitive impairments. Therefore, the aim of this study was to investigate the effects of physical exercise on spatial learning and memory and brain mitochondrial function in tramadol-treated rats. After completion of 2-week (short-term) and 4-week (long-term) treadmill exercise regimens, male Wistar rats received tramadol (20, 40, 80mg/kg/day) intraperitoneally for 30days. Then spatial learning and memory was assessed by Morris water maze test (MWM). Moreover, brain mitochondrial function was evaluated by determination of mitochondrial reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), mitochondrial swelling and cytochrome c release from mitochondria. Chronic administration of tramadol impaired spatial learning and memory as well as brain mitochondrial function as indicated by increased ROS level, MMP collapse, increased mitochondrial swelling and cytochrome c release from mitochondria. Conversely, treadmill exercise significantly attenuated the impairments of spatial learning and memory and brain mitochondrial dysfunction induced by tramadol. The results revealed that chronic tramadol treatment caused memory impairments through induction of brain mitochondrial dysfunction. Furthermore, pre-exposure to physical exercise markedly mitigated these impairments through its positive effects on brain mitochondrial function.

Coadministration of tramadol with aripiprazole and venlafaxine--The effect on spatial memory functions in male rats.

The impairment of memory functions is very common in patients with chronic pain, particularly in patients with existing cognitive disorders. Results of some studies confirmed that tramadol (TRM), a frequently prescribed analgesic drug, improves memory functions in humans. However, there are no studies on the effect of co-administration of TRM with antidepressants or antipsychotics on memory; therefore, the aim of this study was to evaluate the effect of concomitant use of TRM with a second generation antipsychotic-aripiprazole (ARI) and an antidepressant-venlafaxine (VEN) on memory using an animal model. The effect of TRM (5mg/kg)+ARI (1.5mg/kg) and TRM (5mg/kg)+VEN (20mg/kg) on memory in Wistar rats was examined using the Morris water maze test after single and chronic administration (7 and 14 days). It was observed that a single and chronic administration of TRM, VEN or ARI alone, but not a combination of TRM+VEN or TRM+ARI (except for 14 days of treatment) can improve memory in rats compared to the control group. After 14 days of administration, both combinations achieved improvement similar to each drug individually and improved spatial memory in rats compared to the control animals. It can be assumed that chronic treatment with combinations of TRM+VEN or TRM+ARI is unlikely to cause memory impairment and interfere with either any antidepressant effect of VEN or any antipsychotic effect of ARI in patients suffering from chronic pain using TRM.

Effects of chronic tramadol administration on testicular tissue in rats: an experimental study.

In a prospective experimental study, the effects of chronic tramadol administration on gonadotrophic and sex hormones, histopathological and morphometrical alterations in rat testicular tissue were investigated in a laboratory setting. Tramadol was given alone to adult male albino rats. Gonadotrophic and serum sex hormone levels were measured and testicular pathological and morphometric changes were observed in treated vs. After 30 days of treatment, tramadol induced a decrease in LH, FSH and testosterone serum levels. Histologically, degenerative changes in the seminiferous tubules were observed. They showed shrinkage, separation of tubular basement membrane, disorganisation and vacuolisation of spermatogenic layers. Morphometric analysis revealed significant decrease in the mean values of the tubular diameter and epithelial height. Ultrastructural abnormalities were detected in all cells of spermatogenic lineage in addition to the appearance of apoptotic cells. Sertoli cell vacuolation, huge lipid droplets and disrupted Sertoli cell junctions were observed. Leydig cells showed euchromatic nuclei and dilated smooth endoplasmic reticulum. In view of these findings, it is concluded that tramadol induces alterations in sex hormonal levels in conjunction with disruption of the normal histological structure of rat testis. This might lead to the risk of male infertility. Therefore, tramadol should be used with caution with appropriate dose monitoring.

Physical dependence potential of daily tramadol dosing in humans.

Tramadol is an atypical, mixed-mechanism analgesic involving both opioid and catecholamine processes that appears to have low abuse potential and may be useful as a treatment for opioid dependence. The current study assessed the level of physical dependence and opioid blockade efficacy produced by daily maintenance on oral tramadol. Nine residential opioid-dependent adults were maintained on two doses of daily oral tramadol (200 and 800 mg) for approximately 4-week intervals in a randomized, double-blind, crossover design. The acute effects of intramuscular placebo, naloxone (0.25, 0.5, and 1.0 mg), and hydromorphone (1.5, 3.0, and 6.0 mg) were tested under double-blind, randomized conditions. Outcomes included observer- and subject-rated measures and physiologic indices. Challenge doses of naloxone resulted in significantly higher mean peak withdrawal scores compared to placebo. Withdrawal intensity from naloxone was generally greater during 800 versus 200 mg/day tramadol maintenance. Mean peak ratings of agonist effects were elevated at higher hydromorphone challenge doses, but did not differ significantly between tramadol doses. Physiologic measures were generally affected by challenge conditions in a dose-dependent manner, with few differences between tramadol maintenance dose conditions. Chronic tramadol administration produces dose-related opioid physical dependence, without producing dose-related attenuation of agonist challenge effects. Tramadol may be a useful treatment for patients with low levels of opioid dependence or as a treatment for withdrawal during opioid detoxification, but does not appear to be effective as a maintenance medication due to a lack of opioid cross-tolerance.

Antidepressant-like effect of tramadol in the unpredictable chronic mild stress procedure: possible involvement of the noradrenergic system

Tramadol, which inhibits the reuptake of noradrenaline and serotonin, is effective in animal models of depression. Its antidepressant-like effects may be mediated mainly by the noradrenergic system. This study investigated the role of the noradrenergic system in the antidepressant-like effects of tramadol and desipramine in the unpredictable chronic mild stress model. We assessed the involvement of beta-adrenoreceptors, particularly beta2-receptors in the activity of these drugs. In addition, we measured the level of noradrenaline and its metabolite 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the locus coeruleus, hypothalamus, hippocampus and cerebellum in stressed mice. Unpredictable chronic mild stress induced a degradation of coat state and decreased grooming behaviour in the splash test, which was reversed by the chronic administration of tramadol (20 mg/kg) and desipramine (10 mg/kg). The nonselective beta-adrenoreceptor antagonist propranolol (5 mg/kg, intraperitoneally) and the selective beta2-receptor antagonist ICI 118,551 (2 mg/kg, intraperitoneally) reversed the antidepressant-like effects of tramadol and desipramine. Moreover, chronic tramadol and desipramine treatment increased the level of noradrenaline (NA) and MHPG in the locus coeruleus but not in the cerebellum, whereas only MHPG level was increased in the hypothalamus. Tramadol, however, increased the levels of MHPG and NA in the hippocampus, whereas desipramine only increased NA level. These data support the view that the noradrenergic system plays an important role in the antidepressant-like action of tramadol.