Tramadol Influences Cellular Metabolism and Autophagy in Germ and Sertoli Cells; Exercise Training as A Potential Ameliorative Strategy.

OBJECTIVE: Dysregulation of lipid and carbohydrate/fatty acid (FA) balance in Sertoli and germ cells alters the NADP+/ NADPH ratio, resulting in metabolic autophagy in testicles. Tramadol (TRA) adversely affects spermatogenesis development, and it is not reversed within short periods of time after withdrawal. Therefore, the present study aimed to examine the boosting effect of different exercise training protocols (ETPs) on TRA-induced detrimental effects after withdrawal. MATERIALS AND METHODS: In this experimental study, 36 mature Wistar rats were separated into control and TRAsole (administered 40 mg/kg of TRA and euthanized 60 days after TRA administration), Con-TRA (stopped TRA administration after 60 days, and continued for additional 60 days after withdrawal), TRA+low-intensity (TRA+LICT), TRA+ moderate-intensity (TRA+MICT), and TRA+high-intensity continuous (TRA+HICT) ETPs-induced groups (n=6/ group, ETPs were initiated for 60 days after stopping TRA administration). Next, the intracytoplasmic carbohydrate and lipids/FAs content, testicular lactate and lactate dehydrogenase (LDH) levels, relative ratios of NADP+/NADPH, serum testosterone levels, and the Leydig cells steroidogenic activity, the mRNA levels of Beclin-1, p62, LC3-I, and Atg7 as well as the LC3-I/II+ germ and somatic cells mean distributions were analyzed. RESULTS: The LICT and MICT could ameliorate the TRA-induced carbohydrates/lipids, FAs imbalance, increase lactate, LDH and testosterone levels, re-balance the NADP+/NADPH ratio, and reregulate the autophagy and steroidogenic activities in the Leydig and Sertoli cells. CONCLUSION: Collectively, LICT and MICT can ameliorate the TRA-induced metabolic-oxidative autophagy by rebalancing energy survey in testicles and down-regulating autophagy reactions in Sertoli cells and rebalancing it in the Leydig cells.

Assessment of metabolic interaction between curcumin and tramadol using the isolated perfused rat liver.

Introduction: The presence of phytochemicals in herbal medicines can lead to herb-drug interactions, altering the levels of these compounds and conventional drugs in the bloodstream by influencing CYP450 activity. Considering curcumin's effect on the CYP enzymes responsible for tramadol metabolism, it is essential to assess the potential interaction between curcumin and tramadol when administered together. Materials and methods: The pharmacokinetics of tramadol were examined in rats receiving either single or multiple doses of curcumin (80 mg/kg) compared to rats without curcumin treatment. Tramadol liver perfusion was conducted on all rat groups and perfusate samples were collected at specified intervals. Tramadol and its main metabolite were detected using an HPLC system coupled with a fluorescence detector. Results: Tramadol concentrations were notably higher in the co-administered group compared to both the control and treatment groups. Conversely, lower concentrations of M1 were observed in the co-administered and treatment groups compared to the control group. The AUC0-60 parameters for tramadol were as follows: 32944.8 ± 1355.5, 22925.7 ± 1650.1, and 36548.0 ± 2808.4 ng⋅min/ml for the control, treatment, and co-administered groups, respectively. Both the co-administered and treatment groups exhibited a lower AUC0-60 of M1 compared to the control group. The lack of significant difference in Cmax and AUC0-60 of M1 between the treatment and co-administered groups suggests that single and multiple doses of curcumin have comparable effects on CYP2D6. Conclusions: These results indicate a potential for drug interactions when curcumin and tramadol are taken together. Furthermore, the influence of curcumin on tramadol metabolism varied between single and multiple oral administrations of curcumin. Hence, it is vital to highlight this interaction in clinical settings and conduct additional research to fully understand the clinical implications of combining curcumin and tramadol.

Safety and Efficacy of Combined Injection of Pure-µ-Opioid Agonist with Tramadol as an Opioid Induction Agent for Opioid-Naïve Cancer Patients.

Background: Tramadol is known to provide synergistic analgesia when used in combination with morphine. Objectives: The aims of this study were: (1) to introduce an opioid combination therapy using pure-µ-opioid receptor agonist (OPI) + tramadol injections (OPI + tramadol) and (2) to elucidate safety and efficacy of this combination therapy for opioid-naïve cancer pain patients. Methods: Opioid-naïve patients referred to our palliative care team (in Japan) who were unable to take oral medications and received OPI + tramadol as opioid induction agents were retrospectively investigated on the electric medical chart. OPI + tramadol dosage was adjusted to achieve the patient's pain as Numerical Rating Scale ≤4/10 or Support Team Assessment Schedule-Japanese ≤1. Patients' demography, doses of OPI and tramadol administered, and adverse events were analyzed. Results: A total of 44 patients were included. The primary organs of malignancy were pancreas (11), stomach (5), lung (4), breast (4), liver (4), and others (13). OPI injections administered were hydromorphone (39), morphine (6), oxycodone (1), and fentanyl (1). The starting doses of OPI (morphine equivalent) and tramadol were 6.05 ± 1.63 and 67.8 ± 13.6 mg/day, respectively, and the final doses of OPI (morphine equivalent) and tramadol were 8.14 ± 3.85 and 80.0 ± 28.5 mg/day, respectively. Treatment goals were achieved in all patients. There were three patients in whom OPI was switched owing to inadequate analgesia and no new side effects other than those known to occur when OPI or tramadol is administered appeared. Conclusion: The results suggest that this innovative and unique opioid therapy can be safely and effectively introduced to opioid-naïve cancer patients who are relatively close to the end of life.

The influence of tramadol on bowel function: A randomised, placebo-controlled trial.

Tramadol is a weak opioid used to treat moderate pain. Stronger opioids inhibit gastrointestinal function, but little is known about the gastrointestinal effects of tramadol. Our aim was to investigate if tramadol causes opioid-induced bowel dysfunction (OIBD). Twenty healthy male participants (mean age 24 [range 20-31] years) were included. Tramadol (extended-release formulation, 200 mg/day) or placebo was administered for 10 days in two study periods separated by 3 weeks. Gastrointestinal transit times and segmental volume, motility and water content were investigated with the 3D-transit system and magnetic resonance imaging. Bowel movements and gastrointestinal symptoms were recorded daily. Tramadol prolonged colonic transit time (34 h vs. 25 h, p < 0.001) and increased small bowel motility (p < 0.01) and water content (p = 0.002) compared to placebo. Across all days of treatment, tramadol reduced the number of mean daily bowel movements (p = 0.001) and increased mean stool consistency (p = 0.006). Gastrointestinal symptom scores increased with tramadol (indigestion: +358%, p = 0.01; constipation: +475%, p = 0.01). Additionally, more participants fulfilled the diagnostic criteria for constipation after tramadol treatment compared to placebo (40% vs. 0%, p < 0.001). This study showed that tramadol treatment is associated with OIBD, and management of constipation and other bowel symptoms should, therefore, be prioritised when treating pain patients with tramadol.

Bioenergetics disruption, oxidative stress, and inflammation as underlying mechanisms of tramadol-induced nephrotoxicity.

Tramadol (TR), a commonly prescribed pain reliever for moderate to severe pain, has been associated with kidney damage. This study investigates TR-induced nephrotoxicity mechanisms, focusing on its effects on renal proximal tubular cells (PTCs). The study findings demonstrate that TR disrupts PTC bioenergetic processes, leading to oxidative stress and inflammation. Significant toxicity to PTCs was observed with estimated effective concentration 50 values of 9.8 and 11.5 µM based on 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays, respectively. TR also interferes with the function of PTC transporters, including organic cation uptake transporter 1, organic cation transporter 2, P-glycoprotein, and multidrug resistance protein 2. Furthermore, bioenergetics assays showed that TR reduced the activities of mitochondrial complexes I and III, adenosine triphosphate production, mitochondrial membrane potential, and oxygen consumption rate while increasing lactate release. TR also increased the production of reactive oxygen species, lipid peroxidation thiobarbituric acid reactive substances end products, and the expression of the NRf2 gene while decreasing reduced glutathione (GSH-R) stores and catalase and superoxide dismutase antioxidant activities. Additionally, TR increased the production of inflammatory cytokines (TNF-α and IL-6) and their coding genes expression. Interestingly, the study found that antioxidants like GSH-R, inhibitors of IL-6 and TNF-α, and mitochondrial activating Co-Q10 could protect cells against TR-induced cytotoxicity. The study suggests that TR causes nephrotoxicity by disrupting bioenergetic processes, causing oxidative stress and inflammation, but antioxidants and agents targeting mitochondria may have protective and curative potential.

Comparative Experimental Study of using Tramadol & Nefopam in Pain Management.

BACKGROUND: Pain is a disturbing sensory and emotive sentiment triggered mainly by tissue-damaging stimuli. This study aimed to evaluate the potential effect of tramadol and nefopam on acute pain. METHODS: Thirty Sprague-Dawley rats (each 200-250 g) were randomly allocated into three sets (n=10). The nefopam group was treated with nefopam (3.5 mg/kg) by intraperitoneal (IP) injection; the tramadol group was given tramadol (50mg/kg) by IP injection, and the control group was treated with normal saline. Two main methods were proposed for assessing and monitoring rat pain: hot plate and tail-flick techniques using tail immersion. RESULTS: It was revealed a significant change (p<0.0001) in the outcome in the animal groups that received nefopam (3.5mg/kg/IP) and tramadol (50mg/kg/IP) in the prospect of hot plate test (hand paw lick parameter) and tail flick test. Regarding the hot plate test (jumping parameter), there was no significant change (p>0.05) in animals treated with tramadol and nefopam compared to the control group. Moreover, a considerable difference between the hot plate test (hand paw lick parameter) and the tail-flick test was detected between tramadol and nefopam-treated groups. However, no significant variance (P=0.101) was detected between the two groups in the hot plate test (jumping parameter). CONCLUSION: Tramadol showed better analgesic activity over nefopam in suppressing pain stimuli in acute settings with modest to severe pain, making tramadol a favourable choice for short-term management of postoperative pain.

Tramadol-Induced Fatal Angioedema: A Rare Case.

Angioedema is a non-pitting edema that involves the subcutaneous and submucosal layers of the face, lips, neck, oral cavity, larynx, and gut. It may become life-threatening when it involves tissues of the larynx. Angioedema can be triggered by exposure to drugs such as angiotensin-converting enzyme inhibitors (ACE inhibitors), opioid drugs, and nonsteroidal anti-inflammatory drugs (NSAIDs). Tramadol is an opioid analgesic medication that may also induce angioedema, but the incidence of tramadol-induced angioedema is very rare in literature to date. It has been postulated that tramadol may cause fatal angioedema in the presence of underlying diseases such as systemic lupus erythematosus (SLE) or concomitant drugs such as NSAIDs. We describe the case of a patient with SLE who experienced fatal angioedema following tramadol intake.

Effects of pregabalin combined with tramadol/paracetamol on acute pain in patients with CT-guided puncture localization of pulmonary nodules.

OBJECTIVE: To investigate the effects of pregabalin combined with tramadol/paracetamol on acute pain in patients with CT-guided puncture localization of pulmonary nodules. MATERIALS AND METHODS: In this randomized, placebo-controlled and single-center study, 120 patients were allocated randomly to four groups: the control group (Group P), the pregabalin-placebo group (Group BP), the tramadol/paracetamol-placebo group (Group AP), and the pregabalin-tramadol/paracetamol group (Group AB). The primary outcome was the NRS (Numerical Rating Scale) score. Other outcomes included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), pulse oxygen saturation (SpO2), the incidence of moderate to severe pain, the analgesia recovery ratio, the incidence of adverse drug reactions and patients' satisfaction. RESULTS: No significant interaction was detected between the interventions (P = 0.752). The NRS score of the Taking pregabalin group and the Taking tramadol/paracetamol group were significantly lower than those of the Not-taking pregabalin group and the Not-taking tramadol/paracetamol group respectively (P < 0.05). There was significant difference in the NRS scores among the four groups (P < 0.001). The NRS score of Group AB was significantly lower than that of Group P (P < 0.001), Group BP (P < 0.001) and Group AP (P = 0.001). At the same time, the NRS scores of Group BP (P < 0.001) and Group AP (P < 0.001) were significantly lower than those of Group P, but there was no significant difference between Group BP and Group AP (P = 1.000). The SBP, DBP, HR, the incidence of moderate to severe pain and the analgesia recovery ratio of Group AB were significantly lower than those of Group P (P < 0.05), while the SpO2 and the number of people who were very satisfied were significantly higher than those of Group P (P < 0.05). There was no significant difference in the incidence of adverse drug reactions among the four groups (P = 0.272). CONCLUSIONS: The combination or single use of pregabalin and tramadol/paracetamol can effectively relieve the acute pain after localization. Pregabalin combined with tramadol/paracetamol has the best analgesic effect and significantly reduces the hemodynamic fluctuations, with high safety and low incidence of adverse drug reactions, which has a certain clinical popularization and application value.

Increasing age and lethal opiate use.

Opioid abuse is a leading cause of drug-related morbidity and mortality worldwide. It has been suggested that the age of opiate users in Australia is rising. To evaluate this further in a local population, toxicology and pathology case files from Forensic Science SA, Adelaide, South Australia, were examined for all cases with lethal opioid levels from 2000 to 2019 (n = 499; M:F 2.3:1; age range 18-91 years, median age 42 years). The median age of opiate deaths increased significantly by approximately 16 years (p = 0.007, R2 = 0.34) with a significant increase in total deaths in the 45-54 years and 55-64 years age groups (p = 0.009, R2 = 0.32) (p = < 0.001, R2 = 0.54). Deaths due to heroin overdose showed the lowest median age (39 years, n = 184), with deaths from tramadol toxicity having the highest (50.5 years, n = 32). Recent changes in the demographic profile of opioid users in cases of lethal overdose involve an aging population. Forensic and clinical practitioners should be aware of significant opioid abuse in certain individuals at older ages as this raises the possibility that this may exacerbate the effects of age-related chronic diseases in this group and/or contribute to fatalities.

Comparative Bioavailability of a Novel Fixed-dose Combination Etoricoxib and Tramadol.

Multimodal analgesia is defined as using several drugs or techniques simultaneously to target different pain pathways or receptors to avoid pain propagation. This study evaluated the pharmacokinetic profile and comparative bioavailability of etoricoxib 90 mg and tramadol 50 mg dosing alone (reference drugs) or in a novel fixed-dose combination (test drug) under fasting conditions in Mexican healthy volunteers. This was a randomized, open-label, 3-way, crossover, single-dose, prospective, and longitudinal study with a 14-day washout period. Eligible subjects were healthy Mexican adult volunteers. The drugs were dosing orally, according to the randomization sequence, after 10 hours of fasting and 4 hours before breakfast with 250 mL of water at room temperature. Serial blood samples were collected before and after dosing, both drugs were quantified using high-performance liquid chromatography coupled with tandem mass spectrometry. Forty-two subjects were enrolled and 38 completed the study (28 men and 14 women, mean age 25.2 years, mean weight 66.6 kg). Test products were considered to have comparative bioavailability if confidence intervals of natural log-transformed for (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration-time curve form 0 up to last sampling time (AUC0-t), and (area under the plasma drug concentration-time curve from 0 up to infinity (AUC0-∞) data were within the range of 80%-125%. Non-serious adverse events were observed. The results demonstrate that the pharmacokinetic profile and bioavailability of the etoricoxib/tramadol fixed-dose combination are comparable to those of the reference products.

Combined antiallodynic effects of Neurotropin®-tramadol and Neurotropin®-mirogabalin in rats with L5-spinal nerve ligation.

We aimed to examine the efficacy of combination therapies of Neurotropin® with tramadol and Neurotropin with mirogabalin for neuropathic pain management. A neuropathic pain model (L5 spinal nerve ligation model: L5-SNL) using male Wistar rats was generated through tight ligation of the left fifth lumbar nerve using silk sutures. Mechanical allodynia was assessed using the 50% paw withdrawal threshold. The combined antiallodynic effects were evaluated using isobolographic analyses. Small intestinal transit was evaluated using the charcoal meal test, and motor coordination using the rota-rod test. Neurotropin (50-200 NU/kg, p.o.), tramadol (7.5-60 mg/kg, p.o.), and mirogabalin (3-30 mg/kg, p.o.) showed a dose-dependent antiallodynic effect in L5-SNL rats. The combined antiallodynic effects of Neurotropin and tramadol were additive or synergistic, whereas those of Neurotropin and mirogabalin were additive. Neurotropin (100-400 NU/kg, p.o.) did not affect the small intestinal transit, whereas tramadol (30-100 mg/kg, p.o.) significantly inhibited it. Neurotropin (100-400 NU/kg, p.o.) did not affect the walking time, whereas mirogabalin (10-100 mg/kg, p.o.) significantly decreased it. Neurotropin dose-dependently ameliorated mechanical allodynia in rats, and combination therapy with Neurotropin-tramadol or Neurotropin-mirogabalin may alleviate neuropathic pain without aggravating the adverse effects of tramadol and mirogabalin.

Celecoxib-tramadol co-crystal in patients with moderate-to-severe pain following bunionectomy with osteotomy: Secondary analyses by baseline pain intensity and use of rescue medication of a phase 3, randomized, double-blind, factorial, active- and placebo-controlled trial.

BACKGROUND: In the randomized, phase 3, SUSA-301 trial, celecoxib-tramadol co-crystal (CTC) provided significantly greater analgesia compared with celecoxib, tramadol, or placebo in adults with acute, moderate-to-severe, postoperative pain. This post hoc, secondary analysis further evaluated the use of rescue medication and the incidence of treatment-emergent adverse events (TEAEs). METHODS: Patients (N = 637) were randomized 2:2:2:1 to receive oral CTC 200 mg twice daily (BID; n = 184), tramadol 50 mg four times daily (QID; n = 183), celecoxib 100 mg BID (n = 181), or placebo QID (n = 89). Post hoc analyses were conducted on the use of rescue medications up to 4 and 48 h post-study drug dose, stratified by baseline pain intensity (moderate/severe), and on the incidence of TEAEs, stratified by rescue medication use. RESULTS: A significantly lower proportion of patients received any rescue medication within 4 h post-study dose with CTC (49.5%) versus tramadol (61.7%, p = 0.0178), celecoxib (65.2%, p = 0.0024), and placebo (75.3%, p = 0.0001); this was also seen for oxycodone use. Fewer patients in the CTC group received ≥3 doses of rescue medication compared with the other groups, irrespective of baseline pain intensity. In patients who did not receive opioid rescue medication, CTC was associated with a lower incidence of nausea and vomiting TEAEs versus tramadol alone. In patients who received rescue oxycodone, the incidence of nausea was similar in the CTC and tramadol groups, and higher versus celecoxib and placebo. CONCLUSION: Celecoxib-tramadol co-crystal was associated with reduced rescue medication use and an acceptable tolerability profile compared with tramadol or celecoxib alone in adults with acute, moderate-to-severe, postoperative pain.

Analyzing water hyacinth plants from two South African rivers for the detection of seven pharmaceuticals and their metabolites.

Water hyacinth plants (Eichhornia crassipes Mart.) collected from two South African rivers were analyzed in order to investigate their suitability for judging the presence of pharmaceuticals in the water. Thereby, a number of drugs, including amitriptyline, atenolol, citalopram, orphenadrine, lidocaine, telmisartan, and tramadol, could be detected. Particularly for the latter substance, relatively high concentrations (more than 5000 ng g-1 dry plant material) were detected in the water plants. Subsequently, the plant extracts were also screened for drug-derived transformation products, whereby a series of phase-one metabolites could be tentatively identified.

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

INTRODUCTION: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Association of the OPRM1 variant rs1799971 (A118G) and clinical manifestations in tramadol poisoned patients: a cross-sectional study.

INTRODUCTION: The opioid receptor mu1 is a protein coding gene that can have different codes for a protein and may have variations (polymorphisms) affecting how opioids work. The aim of this study was to investigate the prevalence of the most common opioid receptor mu1 polymorphism (A118G) and any relationship between this polymorphism and features following tramadol overdose. MATERIALS AND METHODS: This was a cross-sectional study of patients admitted with tramadol poisoning to an Iranian hospital. These patients were not taking any other drugs or medications and had no history of seizures. RESULTS: The results showed that among the 83 patients included in the study, 57 (69 per cent) had the AA genotype, 25 (30 per cent) had the AG genotype, and one (1 per cent) had the GG genotype for the opioid receptor mu1 A118G polymorphism. Nausea and/or vomiting occurred in nine (11 per cent) patients and dizziness in 38 (46 per cent) patients. Serious adverse events included seizures in 51 (60 per cent) patients and respiratory failure requiring mechanical ventilation in 21 (25 per cent) patients. However, there was no significant association between the opioid receptor mu1 A118G polymorphism and these adverse events. DISCUSSION: In our study, the frequency of the A allele was greater than the G allele, and the AA genotype was more prevalent than AG. The GG genotype was the least common among the polymorphisms of opioid receptor mu1 rs1799971. There was no significant association between the opioid receptor mu1 A118G polymorphism and symptoms in tramadol-poisoned patients. Although these allele proportions are similar to the results reported in other Caucasian populations, they are dissimilar to the findings in Chinese and Singaporean populations. In these Asian studies, the predominant allele was the G allele. It has been suggested that a mutated G allele will decrease the production of opioid receptor mu1-related messenger ribonucleic acid and related proteins, leading to fewer mu-opioid receptors in the brain. CONCLUSIONS: This study found no significant association between the opioid receptor mu1 A118G polymorphism and adverse outcomes in tramadol-poisoned patients. However, more research is needed to draw more definitive conclusions due to the limited evidence and variability of opioid receptor mu1 polymorphisms in different populations.

Crizotinib inhibits the metabolism of tramadol by non-competitive suppressing the activities of CYP2D1 and CYP3A2.

Objectives: To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction. Methods: Liver microsomal catalyzing assay was developed. Sprague-Dawley rats were administrated tramadol with or without selected tyrosine kinase inhibitors. Samples were prepared and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for analysis. Besides, liver, kidney, and small intestine were collected and morphology was examined by hematoxyline-eosin (H&E) staining. Meanwhile, liver microsomes were prepared and carbon monoxide differential ultraviolet radiation (UV) spectrophotometric quantification was performed. Results: Among the screened inhibitors, crizotinib takes the highest potency in suppressing the metabolism of tramadol in rat/human liver microsome, following non-competitive inhibitory mechanism. In vivo, when crizotinib was co-administered, the AUC value of tramadol increased compared with the control group. Besides, no obvious pathological changes were observed, including cell morphology, size, arrangement, nuclear morphology with the levels of alanine transaminase (ALT) and aspartate transaminase (AST) increased after multiple administration of crizotinib. Meanwhile, the activities of CYP2D1 and CYP3A2 as well as the total cytochrome P450 abundance were found to be decreased in rat liver of combinational group. Conclusions: Crizotinib can inhibit the metabolism of tramadol. Therefore, this recipe should be vigilant to prevent adverse reactions.

Unraveling the Hippocampal Molecular and Cellular Alterations behind Tramadol and Tapentadol Neurobehavioral Toxicity.

Tramadol and tapentadol are chemically related opioids prescribed for the analgesia of moderate to severe pain. Although safer than classical opioids, they are associated with neurotoxicity and behavioral dysfunction, which arise as a concern, considering their central action and growing misuse and abuse. The hippocampal formation is known to participate in memory and learning processes and has been documented to contribute to opioid dependence. Accordingly, the present study assessed molecular and cellular alterations in the hippocampal formation of Wistar rats intraperitoneally administered with 50 mg/kg tramadol or tapentadol for eight alternate days. Alterations were found in serum hydrogen peroxide, cysteine, homocysteine, and dopamine concentrations upon exposure to one or both opioids, as well as in hippocampal 8-hydroxydeoxyguanosine and gene expression levels of a panel of neurotoxicity, neuroinflammation, and neuromodulation biomarkers, assessed through quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of hippocampal formation sections showed increased glial fibrillary acidic protein (GFAP) and decreased cluster of differentiation 11b (CD11b) protein expression, suggesting opioid-induced astrogliosis and microgliosis. Collectively, the results emphasize the hippocampal neuromodulator effects of tramadol and tapentadol, with potential behavioral implications, underlining the need to prescribe and use both opioids cautiously.

Neuroprotective potential of solanesol against tramadol induced zebrafish model of Parkinson's disease: insights from neurobehavioral, molecular, and neurochemical evidence.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and subsequent depletion of dopamine in the striatum. Solanesol, an alcohol that acts as a precursor to coenzyme Q10, possesses potential applications in managing neurological disorders with antioxidant, anti-inflammatory, and neuromodulatory potential. In this study, a zebrafish model was employed to investigate the effects of solanesol in tramadol induced PD like symptoms. Zebrafish were administered tramadol injections (50 mg/kg) over a 20-day period. Solanesol was administered at doses of 25, 50, and 100 mg/kg, three hours prior to tramadol administration from day 11 to day 20. Behavioral tests assessing motor coordination were conducted on a weekly basis using open field and novel diving tank apparatus. On day 21, the zebrafish were euthanized, and brain tissues were examined for markers of oxidative stress, inflammation, and neurotransmitters level. Chronic tramadol treatment resulted in motor impairment, reduced antioxidant enzyme levels, enhanced release of proinflammatory cytokines in the striatum, and disrupted neurotransmitter balance. However, solanesol administration mitigated these effects and exhibited a neuroprotective effect against neurodegenerative alterations in the zebrafish model of PD. This was evident through improvements in behavior, modulation of biochemical markers, attenuation of neuroinflammation, restoration of neurotransmitters level, and enhancement of mitochondrial activity. The histopathological study also confirmed that solanesol dose dependently restored neuronal cell density which confirmed its neuroprotective potential. Further investigations are required to elucidate the underlying mechanisms of solanesol neuroprotective effects and evaluate its efficacy in human patients.

Neuroprotective effects: Solanesol has shown significant neuroprotective effects in a zebrafish model of Parkinson's disease induced by chronic tramadol usage.Improved behavioral performance: Administration of solanesol resulted in improved motor coordination in the open field test (OFT) and novel diving apparatus in the tramadol-induced zebrafish model of PD.Decreased inflammation: Solanesol treatment significantly reduced pro-inflammatory cytokine levels in the tramadol-induced zebrafish model of PD, indicating its anti-inflammatory properties.Restored oxidative parameters: Solanesol administration restored oxidative stress parameters, as well as catecholamine and neurotransmitter levels in the tramadol-induced zebrafish model of PD.Histopathological improvement: Solanesol administration prevented histopathological alterations induced by tramadol, indicating its ability to protect against neuronal damage in the zebrafish model of PD.

Dexketoprofen Trometamol and Tramadol Hydrochloride Fixed-Dose Combination in Moderate to Severe Acute Low Back Pain: A Phase IV, Randomized, Parallel Group, Placebo, Active-Controlled Study (DANTE).

INTRODUCTION: Dexketoprofen/tramadol 25/75 mg (DKP/TRAM) is a fixed-dose combination of a cyclooxygenase inhibitor and opioid receptor agonist. To better understand the efficacy and safety of DKP/TRAM in the treatment of moderate to severe acute lower back pain (LBP) with or without radiculopathy, we carried out a large explorative phase IV international, multicenter, prospective, randomized, double-blind, parallel group, placebo-controlled study (DANTE). METHODS: A total of 538 patients with or without a history of LBP and experiencing acute LPB of moderate to severe intensity [Numerical Rating Scale-Pain Intensity (NRS-PI) score > 5] were randomized 4:4:1:1 to DKP/TRAM 25/75 mg every 8 h (n = 211), tramadol (TRAM) 100 mg (n = 207), placebo-matched DKP/TRAM (n = 59), or placebo-matched TRAM (n = 61). RESULTS: The proportion of patients achieving the primary endpoint, defined as the time to first achieve NRS-PI score < 4 or pain intensity reduction ≥ 30% from drug intake up to 8 h after the first dose, was higher in the DKP/TRAM arm than in the placebo group, but the difference was not statistically significant (46.1% vs. 42.6%, respectively; hazard ratio 1.11; 95% confidence interval 0.775, 1.595; p = 0.566). DKP/TRAM achieved superiority over TRAM in total pain relief at 4, 6, and 8 h (p < 0.05). Conversely, in relation to the secondary endpoints, a significantly greater reduction in NRS-PI score was seen with DKP/TRAM versus placebo starting from 1 h, and this reduction remained numerically lower throughout 8 h. Summed pain intensity difference values were also significantly lower at 4, 6, and 8 h with DKP/TRAM compared to TRAM (p < 0.05). Overall, DKP/TRAM was well tolerated. CONCLUSION: Although the primary endpoint was not met, secondary efficacy analyses suggest the superiority of DKP/TRAM over placebo and TRAM alone in terms of total pain relief. DKP/TRAM can be considered to be an effective and safe option for the treatment of moderate to severe acute LBP. DANTE STUDY REGISTRATION: EudraCT number: 2019-003656-37; ClinicalTrials.gov Identifier: NCT05170841.

Tramadol intoxication in children: An emerging issue.

BACKGROUND: Prescribing tramadol in children raises safety concerns. In Europe, tramadol is still approved and licensed for use in children over 1-3 years of age, depending on the country. In this context, the authors report a case of a tramadol overdose in a 5-year-old-child with a medical history of homozygous sickle cell disease. METHODS: Tramadol and M1 were quantified using liquid chromatography with a diode array detection method. CYP2D6 genotype was determined using a next generation sequencing platform (MISeq, Illumina). RESULTS: Tramadol and M1 were quantified in blood respectively at 5.48 and 1.32µg/mL at admission, at 0.77 and 0.35µg/mL 12hours later, and at 0.32 and 0.18µg/mL 20hours later. The patient was predicted as a CYP2D6 normal metabolizer (*35/*29). CONCLUSION: One of the most important difficulties with the use of tramadol in children relates to its pharmacokinetic (PK) properties. Indeed, tramadol's PK is characterized by a great variability related to: (i) anatomical/physiological factors that impact the volume of distribution (Vd); (ii) CYP2D6 genetic polymorphisms. Considering such an issue is particularly relevant to prevent poisoning. In the reported case, the plasma elimination half-life was estimated at 6.3h, significantly more than those reported in 2-8 year-old children (about 3h). This discrepancy does not seem related to genetic polymorphisms but rather to the Vd. Indeed, the patient was predicted to be a CYP2D6 normal metabolizer (*35/*29). The case presented here highlights the risk associated with the tramadol use in children and emphasizes the importance of considering PK variability among this population. Such variability necessitates greater caution in prescribing tramadol in children and highlights the importance of therapeutic education for families of children treated with this painkiller.