Catechin hydrate alleviates tramadol-induced ovarian and uterine injury through regulation of oxidative and ER stress, apoptosis, steroidogenesis, and hormonal imbalance.

This study reports the first bioanalytical method for simultaneous estimation of Tramadol HCl and dexketoprofen trometamol in rat plasma using Tapentadol as an internal standard. A validated LC-MS/MS method was developed following USFDA guidelines. Analytes were extracted from plasma by protein precipitation technique using acetonitrile. Chromatographic separation was achieved on a Waters Symmetry Shield RP-18 column (250 × 4.6 mm, 5 μm) with an isocratic mobile phase of acetonitrile and 0.1% formic acid in HPLC grade water (30:70 v/v) at a flow rate of 1.0 mL/min, yielding a 7-min runtime. Detection was performed using electrospray ionization with ion transitions of m/z 222.3398 → 70.0307 for Tapentadol, m/z 264.4351 → 96.4527 for Tramadol HCl, and m/z 376.4239 → 100.4520 for dexketoprofen trometamol. The method showed good accuracy, with mean recoveries of 92.79%-98.15% for Tramadol HCl and 91.78%-98.37% for dexketoprofen trometamol. Excellent linearity was obtained, with r2 values of 0.99983 (22.5-900 ng/mL) and 0.99963 (7.5-300 ng/mL), respectively. All validation parameters met acceptable criteria. The method is suitable for evaluating pharmacokinetic parameters that indicate drug efficacy and safety.

Chronic tramadol (TRA) exposure has been reported to induce inflammatory responses in testicular tissue, whereas exercise training exerts immunomodulatory effects within the testes. Accordingly, this study investigated whether exercise training protocols (ETPs) during the post-withdrawal period modulate testicular inflammation via the TLR4/NF-κB-mediated inflammatory signaling pathway. In this experimental study, adult Wistar rats (n=36; sex: male; age: 8 weeks; body weight: 180-220 g) were randomly assigned to a control group and tramadol-treated groups. The control group received normal saline. TRA was administered at a dose of 40 mg/kg, via intraperitoneal route, for 60 days. TRA withdrawal was induced by stopping TRA administration after 60 days and maintained for an additional 60 days. Following withdrawal, tramadol-exposed rats were allocated to a withdrawal-only group or to low-, moderate-, or high-intensity continuous exercise training groups. At the end of the experimental period, testicular tissue samples were collected. The expression or levels of IL-6, IL-10, COX-II, TLR4, NF-κB, TNF-α, and iNOS parameters were evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, immunofluorescence staining, and Western blotting methods. The TRA administration increased the expression of TLR4, NF-κB, IL-6, and TNF-α. These elevations were reduced after withdrawal and were more markedly attenuated in exercise-trained groups. IL-10 levels were decreased in the tramadol-only group but were restored during withdrawal with exercise training. TRA exposure was associated with increased numbers of iNOS+ and COX-II+ somatic and germ cells; these alterations were reversed after withdrawal, particularly in exercised animals. Despite TRA cessation, residual immune dysregulation persisted, characterized by elevated TLR4, NF-κB, IL-6, and TNF-α expression. Exercise training following TRA withdrawal could restore inflammatory balance by suppressing TLR4 and NF-ΚB signaling, normalizing pro- and anti-inflammatory cytokine profiles, and possibly attenuating the iNOS/NO/COXII pathway in Wistar rats.

Scorpion powders have been used in traditional Chinese medicine for centuries to treat inflammation, pain, and cancer. Buthus martensii Karsch is the most frequently investigated scorpion species, whereas the Libyan species of B. occitanus remains pharmacologically unexplored. To study the potential analgesic effect of a Buthus occitanus ethanolic tail extract (BOETE) collected from Tarhona, Libya, in albino mice. Adult male and female albino mice (weighing 19–30 g, n = 7 per group) received intraperitoneal injections of either vehicle (0.9 % saline), BOETE (300 or 1000 mg/kg), or tramadol HCl (20 mg/kg). Thirty minutes post-injection, thermal nociception was quantified with the hot-plate (55 ± 1 °C) and tail-immersion (50 ± 1°C) tests; cut-off latencies were set at 30 s, respectively, to prevent tissue damage. Both doses of BOETE significantly increased reaction times compared to vehicle in the hot-plate assay (p < 0.05). In contrast, the extract at either dose did not prolong latency in the tail-immersion test compared to the saline group, and tramadol hydrochloride produced the largest analgesic effect during tail immersion. A promising analgesic effect was obtained by BOETE against thermal stimulation in mice, supporting its traditional use as an analgesic. These findings warrant further studies to isolate the bioactive components and elucidate the underlying mechanisms of action.

Modulation of tramadol-induced hyperthermia by risperidone and ambient temperature in rats.

To describe the pharmacokinetic parameters of tramadol and its main metabolites, O-desmethyltramadol (M1) and N-desmethyltramadol, and clinically detectable adverse effects after a single orally administered high dose of tramadol in rabbits (Oryctolagus cuniculus). 6 experimental and 1 control healthy intact male rabbits of commercial origin were included in February 2025. Following administration of a 30-mg/kg oral dose of tramadol, plasma concentrations of tramadol, M1, and N-desmethyltramadol were determined by UHPLC-MS at 12 predetermined time points. Pharmacokinetic parameters were calculated using commercial software. Fecal production and sedation were evaluated before and after the experiment. The mean tramadol maximum plasmatic concentration was 91 ± 38 ng/mL, the average time to reach maximum plasmatic concentration was 40 minutes, the terminal half-life was 4.0 ± 2.4 hours, and the mean area under the curve from the first dose to infinity was 192 ± 45 ng/hmL. The M1 metabolite reached concentrations compatible with previously described analgesic effects in rabbits after 10 minutes and for up to 3 hours after administration in some individuals, whereas tramadol did not reach analgesic concentrations. Mild sedation was detected in 4 rabbits at the 20 minute- to 6-hour time points, and fecal production increased from 24 to 48 hours after tramadol administration. No clinically relevant adverse effects were noted. Administration of 30 mg/kg tramadol, PO, in rabbits results in plasma concentrations of M1 compatible with analgesia. The short duration of action warrants further studies with long-acting formulations of tramadol.

Tramadol (TM) abuse negatively affects the central nervous system, especially brain regions like the hippocampus involved in cognition. Recent studies have demonstrated neuroprotective effects of Vitamin C (Vit C) in various neurological diseases. No study has yet examined the effects of Vit C on tramadol-induced synaptic plasticity impairment. Therefore, we aimed to investigate the neuroprotective effects of Vit C on cognitive performance and synaptic plasticity in tramadol-exposed rats. Fifty-two juvenile male rats (30 days old) were divided into four groups: TM (30mg/kg/day, intraperitoneally in the first week, 40mg/kg/day in the second week and 50mg/kg/day in third and fourth weeks), Vit.C (200mg/kg/day, orally for 4 weeks), TM + Vit.C (as in the TM and Vit C groups, Vit C administered half an hour prior to TM), and Ctrl (0.25 mL saline/day for 4 weeks). Behavioral tests (open field, Morris water maze, novel object recognition) assessed locomotor activity and memory. In vivo recordings evaluated synaptic plasticity, and hippocampal oxidative stress markers [malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC)] were measured according to the manufacturers' protocols with ELISA. TM caused learning and memory deficits, reduced long-term potentiation (LTP) induction, and disrupted the oxidative stress balance in the hippocampus. In contrast, Vit C inhibited these changes. These findings suggest that Vit C can attenuate cognitive impairments associated with chronic TM consumption, likely through modulation of hippocampal oxidative stress and enhancement of LTP induction. Therefore, Vit C could be a promising candidate for further investigation as a potential therapeutic agent to mitigate cognitive dysfunction associated with TM use.

Beyond opioid and SNRI-like actions: Proteomic insights into the effects of tramadol and O-desmethyltramadol in zebrafish larvae.

Present study has compared local anaesthetic efficacy of two agents, 5% tramadol with adrenaline 1:80,000 and 2% lignocaine with adrenaline 1:80,000 for bilateral maxillary premolar extraction under supra-periosteal injection. This prospective, split-mouth, double-blinded, randomised, clinical study was conducted on 69 patients requiring extraction of maxillary premolars bilaterally for orthodontic reasons. The study group received 5% tramadol hydrochloride, and the control group received 2% lignocaine hydrochloride. Parameters evaluated were pain on injection, onset and duration of anaesthesia, and post-extraction analgesia. Current study observed longer duration of anaesthesia for lignocaine than that of tramadol, p < 0.001. Lesser perception of post-extraction pain and longer duration of analgesia was observed on tramadol side compared to lignocaine, p = 0.001. Consumption of analgesic tablets was more in lignocaine group, p = 0.022. Tramadol can be safely employed as an alternative to conventional local anaesthetic agents through supra-periosteal injection due to its dual local anaesthetic and analgesic action.

ABSTRACT Tramadol (TRM) is a centrally acting analgesic drug used for management of moderate to severe pain. Granulocyte colony-stimulating factor (G-CSF) is a cytokine that has the ability to mobilize stem cells from the bone marrow to the peripheral circulation. This study was performed to evaluate the histological and biochemical alterations in the adrenal cortex after intake of tramadol and the possible protective role of G-CSF on it. Fifty adult male albino rats were divided into three groups: Group I as a control group, group II (TRM treated group) received a daily dose of 80 mg/kg body weight orally via gastric tube for 12 weeks and group III (TRM+G-CSF-treated group) received subcutaneous injections of 100 μg/kg body weight of G-CSF for seven consecutive days, then TRM from the 8th day to the end of the experiment in the same dose as group II. At the end of the experiment, blood samples were taken for hormonal essay and tissue samples were processed. Light and electron microscopic studies were done. Morphometric and statistical studies were carried out. The study revealed that TRM induced histological and ultrastructural degenerative changes, decreased serum levels of aldosterone, cortisol, and dehydroepiandrosterone, as well as a strong positive Bax immune reaction. However, G-CSF reversed these alterations and showed a strong positive CD34 immune reaction. In conclusion: G-CSF improved histological, biochemical and immunohistochemical metrics in the rat adrenal cortex after tramadol-induced injury.

Design of a MoS2@Au SERS substrate with synergistic electromagnetic and chemical enhancement for ultra-sensitive detection of tramadol hydrochloride

Tramadol, a widely used opioid analgesic, has been linked to neuropsychiatric side effects, including anxiety, when used chronically. These effects are believed to arise from disruptions in multiple neurotransmitter systems, including GABA, glutamate, dopamine, and serotonin. Valproic Acid (VAL), known for its mood-stabilizing and neuroprotective properties, may have the potential to counteract these effects. This study aimed to investigate the behavioral and neurochemical changes induced by chronic tramadol administration in rats and to evaluate the therapeutic potential of VAL in reversing these effects. Twenty-four male Sprague Dawley rats were divided into four groups: Control, Tramadol (TRA), Valproic Acid (VAL), and Tramadol + Valproic Acid (TRA + VAL). Behavioral assessments were conducted using the Open Field Test (OFT) and Light/Dark Box (LDT). After testing, levels of GABA, glutamate, dopamine, serotonin, acetylcholine, and norepinephrine were measured in the hypothalamus and cerebral cortex using LC-MS/MS. Chronic tramadol treatment led to anxiety-like behaviors, as seen in reduced center time in the OFT and shorter latency to enter dark areas in the LDT. These behavioral disruptions were accompanied by decreased levels of GABA in the hypothalamus and cerebral cortex. Co-treatment with VAL restored GABA levels and normalized behavior. The levels of most other neurotransmitters were also affected by tramadol, but not normalized by valproate. VAL mitigates tramadol-induced neurobehavioral disturbances by restoring key neurotransmitter imbalances in GABA. These findings support the therapeutic potential of VAL in managing opioid-induced mood and behavioral disruptions in opioid use disorder.

The work is planned to design orally disintegrating tablets (ODT) also known as Mouth dissolving tablets (MDT) of tramadol hydrochloride for rapid dissolving in mouth within 60 seconds, by using a method called as Direct compression method, Since oral route is considered as one of the most convenient method of administration, it is being selected where, all 15 formulations have undergone numerous evaluation parameters by using various excipients. Among which F15 have confirmed rapid dissolving nature in mouth.

BackgroundNon-medical use of tramadol has emerged as a significant public health concern in Ghana, particularly among young commercial drivers. Despite its growing prevalence, there is a lack of mixed-methods research exploring both the quantitative patterns and underlying motivations for the inappropriate use of tramadol. This study adopts a concurrent triangulation mixed-methods design to investigate the key factors driving tramadol use among young commercial drivers in the Tamale Metropolis.MethodsA total of 434 participants were recruited through convenience sampling for the quantitative component, while 50 individuals who use tramadol participated in seven focus group discussions using snowball sampling. The study examined patterns of tramadol use, reasons for consumption, modes of intake, and sources of supply among young commercial drivers.ResultsThe findings indicate that 60.1% of participants used tramadol for non-medical purposes, with 41.5% consuming it daily. The primary motivation for use was to enhance physical performance (39.2%), followed by pain relief (19.4%). Regarding the mode of consumption, 43.5% mixed tramadol powder with energy drinks, while 31.6% swallowed the tablets with water. On average, participants consumed 155 mg of tramadol daily, often in unauthorized high-dose formulations. Alarmingly, 72.8% of users sourced tramadol from the black market.ConclusionThe study highlights the widespread misuse of high-dose, non-prescribed tramadol among commercial drivers in the Tamale Metropolis. The illicit supply chain and unregulated distribution exacerbate the crisis. Addressing this issue requires stringent regulation of drug importation and distribution, alongside targeted awareness campaigns to educate young drivers about the risks associated with the inappropriate use of tramadol.Clinical trial numberNot applicable

Abstract Background and Aims The management of medications in hemodialysis (HD) patients with cancer requires meticulous evaluation of the metabolic pathways. Consequently, in practice of palliative care for advanced cancer, HD patients may have difficulty in controlling renal metabolic drugs, leading to suboptimal pain control. Nonetheless, the specific status of palliative care for advanced cancer in HD patients have been documented only through limited case reports and remain insufficiently elucidated. The aim of this study is to elucidate real-world palliative care strategies for advanced cancer in HD patients by comparing with those implemented in non-HD patients. Method In our study, patients diagnosed with stage III or IV cancer were identified from the cancer registry data collected from 69 hospitals in Osaka Prefecture, Japan, between January 2019 and December 2021. To obtain more detailed information on treatment and pharmaceutical intervention, we integrated these data with Japan's Diagnosis Procedure Combination (DPC) data, resulting in the creation of a consolidated dataset. From this dataset, information on maintenance HD, the practice of palliative care, and the use of opioid analgesics—such as morphine sulfate, morphine hydrochloride, hydromorphone, oxycodone, fentanyl, and tramadol hydrochloride—was extracted. The patient characteristics, cancer types, the practice of palliative care, and the use of opioid analgesics were analyzed and compared between patients on maintenance HD and the non-HD. Results Among 57,917 patients diagnosed with stage Ⅲ or Ⅳ cancer, 377 patients (0.7%) were identified as receiving maintenance HD. The median age was 73 years (interquartile range: 68–79) for HD patients and 73 years (66–80) for non-HD patients, with no significant difference (P = 0.411). A higher proportion of HD patients were male compared to non-HD patients (78.8% vs. 61.2%, P &amp;lt; 0.001). There was no significant difference of cancer type between the two groups. HD patients had a higher prevalence of the practice of palliative care compared to non-HD patients (14,3% vs 10.4, P = 0.020). There was no significant difference in use of opioid analgesics (76.1% vs 72.7%, P = 0.462). However, regarding the opioid types, HD patients had a higher prevalence of fentanyl (65.3% vs 59.1%, P = 0.024) and tramadol hydrochloride (23.6% vs 14.2%, P &amp;lt; 0.001) use, and a lower prevalence of morphine hydrochloride (4.2% vs 8.2%, P = 0.004) and hydromorphone (1.9% vs 3.9%, P = 0.043) use compared to non-HD patients. There was no significant difference in use of morphine sulfate (0% vs 0.9%, P = 0.054) and oxycodone (13.3% vs 14.0%, P = 0.766). Conclusion In cancer patients with stage Ⅲ or Ⅳ, HD patients received a greater implementation of palliative care practices compared to non-HD patients. Although the use of opioid was comparable, the selection of drug types differed. Our findings indicate that HD patients received comprehensive palliative care through the use of pharmacological drugs targeting non-renal metabolic pathways.

A specific, linear, precise, accurate, robust and rugged reverse phase high performance liquid chromatography method is developed and validated for the estimation of Tramadol Hydrochloride in its capsule dosage form. The chromatographic separation is achieved on a Thermo, Hypersil BDS C8 column (250mm X 4.6mm, 5µm) with UV detection at 270nm. The optimized mobile phase consisted of acetonitrile and 0.2% v/v trifluoro acetic acid buffer (29.5:70.5% V/V) pumped at a flow rate of 1mL/min. Tramadol Hydrochloride is eluted at 6.36min (retention time). Based on the obtained validation results, the method is found to be specific, linear, precise, accurate, robust and rugged for Tramadol hydrochloride and it’s Impurity-A. The limit of detection and quantitation of Tramadol Hydrochloride are found to be 0.80µg/mL and 2.42µg/mL respectively. The limit of detection and quantitation of Impurity-A are found to be 0.51µg/mL and 1.54µg/mL respectively. The stability and filter integrity tests were performed and are found to be passed for Tramadol hydrochloride standard and sample solution. The proposed method can be successfully applied for the estimation of Tramadol Hydrochloride and its related compounds in its capsule dosage form.

pH-sensitive hydrogel from Colocasia esculenta mucilage for controlled tramadol release.

Background: Drug combinations with complementary mechanisms of action are able to achieve effective analgesia at lower doses, thereby reducing the risk of adverse effects (AEs). This study evaluated the analgesic efficacy and tolerability of two fixed-dose combinations (FDCs) of ibuprofen/tramadol (IBU/TRA) compared with tramadol and a placebo. Methods: This multicenter, randomized, double-blind, dose-finding, pilot clinical trial compared IBU/TRA (400/37.5 mg and 400/75 mg) with 100 mg of tramadol and a placebo in patients with moderate-to-severe pain following dental surgery. The primary endpoints were pain intensity at 6 h (PI6h) and the pain intensity difference from baseline to 6 h (PID6h). PID7h, the sum of pain intensity differences from baseline to 7 h (SPID0–7h), pain relief (PAR7h), total pain relief (TOTPAR7h), the use of rescue medication and AEs were also assessed. Results: Seventy-two patients were randomized and evaluated. Both FDCs showed superiority over the placebo for PI6h and PID6h (p < 0.05) but were not significantly different from 100 mg of tramadol. The statistical superiority of FDCs over the placebo was observed for PID7h, SPID0–7h, PAR7h and TOTPAR7h. The percentage of patients receiving rescue medication was higher in the placebo (94.1%) and tramadol (52.6%) groups than the FDC groups (35.3% and 36.8% for 400/37.5 mg and 400/75 mg, respectively). A post hoc analysis showed that the FDCs had a superior analgesic efficacy to 100 mg of tramadol in the SPID0–4h (p < 0.005). The incidence of AEs was comparable between treatment groups. Conclusions: Both FDCs of IBU/TRA provided superior analgesic efficacy compared to the placebo. We propose using SPID0–4h as the preferred variable for evaluating the efficacy of this type of drug combination.

Celecoxib (CLB) and tramadol (TRD) are frequently co-administered in clinical practice due to their complementary mechanisms in managing acute and chronic pain. Their combination has recently been formulated into a fixed-dose oral medication, representing the first FDA-approved multimodal analgesic targeting COX-2 and central opioid receptors simultaneously. However, the strong spectral overlap between CLB and TRD complicates their simultaneous determination using traditional spectrophotometric methods. In this study, a chemometric-assisted spectrophotometric method was developed for the simultaneous quantification of CLB and TRD without prior separation. The classical least squares (CLS) were ultimately selected due to its suitability when pure spectra are available, its robustness with small calibration sets, and its greater interpretability for routine quality control. A five-level, two-factor experimental design produced 25 binary mixtures, split into 13 calibration and 12 validation samples. After spectral preprocessing and removal of non-informative regions, the CLS model was applied to 81 variables across the 210–290 nm range. The model achieved mean recovery values of 99.85% for CLB and 99.99% for TRD in the calibration set, and 101.29% for CLB and 99.52% for TRD in the validation set, demonstrating excellent accuracy and consistency across both datasets. Linearity was established in the range of 6–14 µg/mL for both drugs, with detection limits of 0.55 µg/mL (CLB) and 0.67 µg/mL (TRD). The method showed excellent selectivity in the presence of common co-formulated drugs and was successfully applied to determine both analytes in commercial Seglentis® tablets. This developed method provides a rapid, accurate, and cost-effective solution for routine quality control of complex pharmaceutical formulations.

This research describes a new method for estimating tramadol hydrochloride in pharmaceutical formulations using Molecularly Imprinted Solid-Phase Extraction (MISPE) as a sample extraction technique. Acrylamide was used as the functional monomer, trimethylolpropane Trimethacrylate as the cross-linker, and tramadol hydrochloride as the template molecule to make Molecularly Imprinted Polymer (MIP). The new molecularly imprinted polymer was characterized using UV-Vis spectroscopy, Fourier transform infrared spectroscopy, and a scanning electron microscope. The adsorption isotherm of the prepared polymer was determined under the optimum conditions using spectrophotometry at a wavelength of 272 nm. The method's linear dynamic range was found to be 5–140 µg/mL, and the limits of detection (LOD) and quantification (LOQ) were 0.62 and 1.87 µg/mL, respectively. Relative Standard Deviation (RSD%) was less than 2% five times in intra-day and inter-day. This method was successfully utilized to determine tramadol hydrochloride in pharmaceutical formulations with recoveries in the 93.04–104.3% range.