Tramadol Research Articles

N-Palmitoylethanolamide enhances antinociceptive effect of tramadol in neuropathic rats.

The efficacy of opioids in the treatment of chronic pain is limited; however, the adverse effects they produce are considerable. N-palmitoylethanolamide (PEA), a bioactive lipid mediator with structural similarities to endocannabinoids, has exhibited notable anti-inflammatory and analgesic effects in preclinical models. The objective of this study was to investigate the antinociceptive properties, motor coordination (MC), and constipation effects of tramadol and PEA in combination within a neuropathic pain model. The antinociceptive effects of tramadol (TRA) and PEA in various combination ratios were assessed using a CCI model of neuropathic pain in 126 male Wistar rats, divided into 21 groups: vehicles, GBP (1.0-177.78 mg/kg), TRA (1.0-31.62 mg/kg), PEA (0.0316-10 mg/kg), or TRA (1.0-10 mg/kg) with PEA (0.0316-1.0 mg/kg), all compounds were administered orally. The results of the dose-response analyses indicated that PEA was approximately five and eightfold more potent than tramadol in producing anti-hyperalgesic and anti-allodynic effects, respectively. The results of the surface of synergistic interaction (SSI) analysis indicated that the combination of TRA 10 mg/kg + PEA 0.0316 mg/kg exhibited the most pronounced anti-hyperalgesic effects and the most favorable anti-allodynic outcomes among the various combinations. No significant differences in MC or constipation were observed between the vehicle and optimal combination group. The results of this study demonstrate that sub-antinociceptive doses of tramadol, when combined with PEA, significantly enhance the antinociceptive efficacy of tramadol without the induction of typical opioid-associated side effects. These findings propose a novel approach to the treatment of pain.

Evaluation of three different drugs administered through intraligamentary route for reduction of intraoperative pain of symptomatic irreversible pulpitis in mandibular molars – A randomized triple-blind single-center clinical study

Abstract Introduction: Managing intraoperative pain while initiating root canal treatment necessitates the use of supplementary injection techniques. Aim: The study sought to assess and compare the anesthetic efficacy of 0.5% bupivacaine and 50 mg/ml tramadol hydrochloride versus 2% lignocaine administered as supplemental intraligamentary injection as an adjuvant to an inferior alveolar nerve block (IANB) for mandibular molars with symptomatic irreversible pulpitis (SIP) and normal apical tissues during access cavity preparation. Materials and Methods: Two hundred and two individuals with mandibular molars diagnosed with SIP with normal apical tissues and exhibiting moderate-to-intense pain were given 2 ml of IANB containing 2% lignocaine and 1:80,000 epinephrine. The Visual Analog Scale (VAS) was used to record intraoperative discomfort. Individuals who scored more than 5 on the VAS were deemed to need further anesthesia. The intraligamentary medication was given to 99 of these patients after they were randomly assigned to 3 groups (2% lignocaine, 0.5% bupivacaine, and 50 mg/ml tramadol). VAS score was again recorded. If the patient reported no pain during the opening of the access, it was deemed a success. The post hoc Tukey’s test, paired t-test, and one-way analysis of variance were the statistical methods used to examine the data. Results: Maximum reduction in pain was in bupivacaine followed by lignocaine and tramadol (P < 0.05). Subgroup analysis using post hoc Tukey’s honestly significant difference test showed a maximum difference between bupivacaine and tramadol (1.273, P > 0.05) (95% confidence interval [CI]), followed by lignocaine and bupivacaine (−1.182, P < 0.05) (95% CI) and lignocaine and tramadol (0.091, P > 0.05) (95% CI). Conclusion: Bupivacaine was most effective in reduction of intraoperative pain when used as an intraligamentary drug during access cavity preparation followed by lignocaine. Tramadol was the least successful drug for achieving effective pulpal anesthesia.

Green and High Throughput HPTLC Method for Simultaneous Estimation of Celecoxib and Tramadol Hydrochloride in their Newly Approved Analgesic Combination and Spiked Plasma with Dichromic Green and Blue Assessments.

The FDA "Food and Drug Administration" recently approved a novel co-crystal formulation of Celecoxib (CEX) and Tramadol (TRM) for the treatment of adults suffering from moderate to severe pain in several conditions. This novel combination has advantages over co-administration of the two drugs individually as better patient compliance, synergism and lower therapeutic cost. This work presents the first "High performance Thin Layer Chromatographic" (HPTLC) quantitative analytical technique for CEX and TRM simultaneous assay in bulk, their new dosage form and plasma.The proposed HPTLC assay is based on separation of CEX and TRM on silica gel 60 F254 sheets followed by densitometric scanning at 270nm. The plates' development was carried out using a mobile phase of ethyl acetate-methanol-ammonia (5:5:0.05, v/v). The two drugs showed linearity of 0.025-1μg.band-1& for plasma analysis linearity range was 0.2-10μg.mL-1plasma. The proposed chromatographic technique was validated and showed satisfying validation characteristics of linearity, selectivity, precision and accuracy. In addition, the assay was evaluated by AGREE, AGREEprep, ComplexMoGAPI and BAGI for greenness and blueness to ensure the method's environmental sustainability and its safety for routine quality control assay of this novel combination.

Distribution of CYP2D6 multiplication, CYP2D6*5, and clinical implications in postoperative patients receiving tramadol analgesia in the Minangkabau ethnic group, Indonesia

Background Cytochrome P450 2D6 (CYP2D6) is an important enzyme that metabolizes commonly used drugs, such as tramadol hydrochloride (a widely used opioid analgesic). Genetic polymorphisms of CYP2D6 have been shown to influence the pharmacodynamic properties of administered drugs. This study aimed to screen 63 postoperative patients (wild-type, CYP2D6*5, and CYP2D6 multiplication) of Minangkabau ethnicity in West Sumatera, Indonesia, who received tramadol using a modified long PCR method, and to investigate the clinical impact of tramadol on these patients. This study had a retrospective clinical trial registry number NCT06642480. Methods The Reported Long PCR was modified using different DNA polymerases, optimizing annealing, and the number of step PCR to detect wild-type, CYP2D6*5, and multiplication CYP2D6. To ensure accurate PCR, the size of the PCR product was monitored: wild-type (5kb), CYP2D6*5 (6kb), and CYP2D6 multiplication genotype (10 kb). The wild-type PCR product was used as the internal control. The method was applied to screen 63 postoperative patients of Minangkabau ethnicity who received tramadol. The clinical impact was investigated and analyzed using analysis of variance (ANOVA) followed by a chi-square test. Result The Long PCR was successfully modified with a two-step PCR at 68°C °C as the annealing and extension temperatures. The screened genotype patients were dominated by the wild-type, followed by CYP2D6*5, and multiplication CYP2D6 with percentages of 89%, 6,3%, and 4,7% respectively. A total of 6.3% of CYP2D6*5 cases were classified as heterozygous and predicted as intermediate metabolizers. In addition, sex and age did not affect postoperative tramadol analgesia treatment, whereas weight had a significant impact (p=0.008). Conclusion The percentages of CYP2D6*5 and CYP2D6 multiplication genotypes were similar to those observed in another Asian population. Based on statistical analysis, tramadol was effective as an analgesic treatment for postoperative Minangkabau ethnicity patients with wild-type, CYP2D6*5, and multiple CYP2D6 genotypes. Further studies with larger sample sizes and longer follow-up periods are required to confirm these findings.

Analgesic effect of lateral femoral cutaneous nerve block to the pericapsular nerve group (PENG) block in primary total hip arthroplasty: a randomized clinical trial.

Adequate hip joint and surgical incision analgesia represent a challenge in the postoperative period of primary total hip arthroplasty (THA). This study aimed to evaluate whether the combination of the lateral femoral cutaneous nerve block (LFCN block) and the pericapsular nerve group block (PENG block) influences postoperative analgesia and rescue opioids, in primary THA surgeries. A trial was proposed with 74 patients for THA surgeries under spinal anesthesia, where 37 received PENG block (GPENG) and the other 37, PENG block and LFCN block (GPENG+LFC). The primary outcome was the presence and intensity of pain at rest and on movement, using the Numeric Rating Scale. The secondary main outcome was the total consumption of opioids. The follow-up was 48 h. Significantly fewer patients reported pain in the GPENG+LFC compared to GPENG: at rest, in 4 h (17 [45.95%] vs. 28 [75.68%] respectively, P=0.088), 12 h (4 [10.81%] vs. 17 [45.95%] respectively, P=0.016), and 24 h (4 [10.81%] vs. 13 [35.14%] respectively, P=0.0252); on movement, in 4 h (17 [45.95%] vs. 30 [81.08%] respectively, P=0.0002), 12 h (4 [10.81%] vs. 19 [51.35%] respectively, P=0.0003), and 24 h (5 [13.51%] vs. 14 [37.84%] respectively, P=0.0166). Total opioid consumption was significantly lower in GPENG+LFC compared to GPENG up to 48 hours postoperatively (1200 mg of tramadol and 6 mg of nalbuphine vs. 2400 mg and 21 mg respectively, P=0.0188). The combination of the LFCN block and the PENG block, compared to the sole PENG block, results in better analgesia at rest and on movement up to 24 h and a reduction in the total consumption of opioids up to 48 h after THA.

Outside-in hair contamination by blood containing opiates and opioids

Hair analysis for drugs has become extensively used for forensic investigation in recent years. To best interpret hair drug content in post-mortem conditions, the extent of external contamination by biological fluids, such as blood, must be taken into account to avoid false positive results. The present study evaluated opiates and opioids incorporation into hair from blood containing different concentrations of morphine (MOR), 6-mono-acetyl morphine (6-AM), codeine (COD), dihydrocodeine (DHC), tramadol (TRA), oxycodone (OXY), methadone (MET), 2-ethylidene-1,5-dimethyl-3,3- diphenyl pyrrolidine (EDDP), buprenorphine (BUP) and norbuprenorphine (NBUP). The hair strands contaminated by brief soaking into blood were stored at room temperature (RT) or at 4°C during 6 hours, 1, 3, 7 or 14 days. After decontamination by extensive washing, we show that all opiates and opioids were incorporated into hair within a few hours at RT and 4°C, without significant changes over time. The concentrations of opiates and opioids in hair reached the cut-off levels established by the Society of Hair Testing (SoHT) for therapeutic (MET, COD), or toxic or lethal (all other molecules) blood concentrations. The metabolite to parent drug concentration ratios were determined for NBUP/BUP, MOR/6-AM and EDDP/MET and could be helpful as indicators of blood external contamination.

Is the Use of a Buprenorphine Transdermal Patch More Effective Than Oral Medications for Postoperative Analgesia After Arthroscopic Rotator Cuff Repair? A Randomized Clinical Trial.

Appropriate analgesic protocols for patients following arthroscopic rotator cuff repair remain controversial. Although transdermal buprenorphine patches might potentially provide better pain control and fewer side effects, it is worth noting that there is limited evidence for this given a lack of direct comparisons with oral pain regimens. Among patients undergoing arthroscopic rotator cuff repair, and compared with an analgesic approach using oral tramadol plus celecoxib: (1) Does perioperative use of buprenorphine patches provide better pain relief by a clinically important margin? (2) Does perioperative use of buprenorphine patches improve shoulder joint function recovery? (3) Does perioperative use of buprenorphine patches have a lower frequency of adverse reactions? This was a prospective, single-center, randomized controlled trial. We included patients who underwent arthroscopic rotator cuff repair for partial- or full-thickness rotator cuff tears < 3 cm in size in the anterior to posterior direction as estimated by preoperative MRI and excluded those who had obesity, were pregnant, had opioid dependence, had history of cardiac bypass surgery or ipsilateral rotator cuff repair, had allergies to trial medications, were taking anticoagulants or antidepressants, were being treated with other postsurgical pain management methods, or had severe liver or kidney dysfunction. Based on these criteria, 64% (72 of 112) of patients were eligible. The patients were randomly assigned into either the control group (oral tramadol and celecoxib) or the experimental group (buprenorphine patches). The control group received 100 mg of tramadol and 200 mg of celecoxib every 12 hours for 2 weeks after surgery. The experimental group received buprenorphine patches about 48 hours before surgery without any oral medication. A medication journal was given to the patients to self-report their compliance in taking the drugs. The dosage regimen adhered strictly to protocol. After enrollment, 11% (4 of 36) of patients in the control group and 17% (6 of 36) of patients in the experimental group could not be fully analyzed because of loss to follow-up or missing data. The surveillance period was 3 months, and there was no crossover between groups. The groups did not differ at baseline in terms of demographic parameters and relevant clinical characteristics, including age, gender, BMI, American Society of Anesthesiologists classification, tear size, concomitant procedures, and number of anchors. The outcomes were (1) numeric rating scale (NRS) for pain score at rest or with movement, which ranges from 0 to 10, where 0 indicates no pain, and 10 indicates the worst pain; (2) the American Shoulder and Elbow Surgeons (ASES) score for joint function, which ranges from 0 to 100, with higher scores indicating better shoulder joint function; and (3) the incidence of postoperative adverse reactions. We defined the minimum clinically important difference on the NRS as 2 of 10 points and on the ASES score as 15 of 100 points, based on anchor-based approaches reported in other studies. We found no clinically important between-group differences in NRS pain scores at any time point, either at rest or with movement. Likewise, we found no clinically important between-group differences in ASES scores at any time point. Postoperative dizziness or drowsiness (20% [6 of 30 patients] versus 44% [14 of 32 patients]; p = 0.04) and nausea (10% [3 of 30 patients] versus 34% [11 of 32 patients]; p = 0.02) during the hospital stay were slightly lower in the experimental group compared with the control group. In this randomized trial, we found no clinically important advantages in pain or function to the use of buprenorphine patches after arthroscopic rotator cuff repair, and insufficient evidence exists to confirm whether the minor differences in transient side effects could justify the use of a new and largely untested analgesic approach in this context. That being so, we recommend against the routine use of buprenorphine patches for this indication. In general, we found that pain levels were low after the procedure in both groups. Future studies, therefore, should focus on the efficacy of buprenorphine patches for more invasive or more painful procedures. Level I, therapeutic study.

Assessing Tramadol Hydrochloride as an Alternative to Lignocaine Hydrochloride in Dental Implant Procedures: A Randomized Trial.

To evaluate tramadol hydrochloride, an atypical opioid with potential analgesic properties, as a viable alternative to lignocaine hydrochloride in supraperiosteal anesthesia for dental implants. A split-mouth, double-blind, randomized controlled trial was conducted in patients requiring maxillary dental implants. Patients meeting inclusion criteria received either 5% tramadol hydrochloride with adrenaline or 2% lignocaine hydrochloride with adrenaline via supraperiosteal infiltration. Onset, duration of anesthesia, visual analog scale (VAS) pain scores, and adverse effects were recorded. Forty patients were included, with a mean age of 39.35 years, 62.5% male. No significant differences were observed in VAS pain scores between tramadol (2.08 ± 1.328) and lignocaine (2.05 ± 1.260) groups (p = 0.931). Onset of anesthesia showed no significant difference between the tramadol (128.00 ± 18.207 seconds) and lignocaine (128.30 ± 18.287 seconds) groups (p = 0.736). The duration of anesthesia was comparable between tramadol (59 ± 12.092 minutes) and lignocaine (59.90 ± 11.705 minutes) groups (p = 0.0736). Adverse effects included nausea in two tramadol and one lignocaine patient. Tramadol hydrochloride demonstrated comparable local anesthetic efficacy to lignocaine hydrochloride in dental implant surgery Clinical significance: Both drugs provided effective pain control with similar onset and duration of anesthesia. Tramadol may offer an alternative for patients with lignocaine contraindications, although further studies are warranted to validate its safety and efficacy in dental procedures. How to cite this article: Parlawar AN, Mundada BP. Assessing Tramadol Hydrochloride as an Alternative to Lignocaine Hydrochloride in Dental Implant Procedures: A Randomized Trial. J Contemp Dent Pract 2024;25(7):639-644.

The Analgesic and Side Effects of Tramadol Hydrochloride Immediate-Release and Extended-Release Tablets in Patients With Chronic Low Back Pain.

There are no established treatments for low back pain. Conventional treatments includephysiotherapyand pharmacological treatments, such as non-steroidal anti-inflammatory drugs (NSAIDs). Recently, analgesics with mechanisms of action different from those of NSAIDs have emerged. Tramadol formulations have especially attracted attention for being effective among patients in whom NSAIDs are not entirely effective. However, they are associated with side effects that can disrupt treatment. Tramadol hydrochloride immediate-release and extended-release tablets havebeen recently launched. Herein, we report our experience with these formulations in chronic low back pain patients. To investigate the incidence of side effects and the analgesic effect of tramadol hydrochloride immediate-release and extended-release tablets in patients with chronic low back pain. This was a multicenter retrospective observational study. The study included patients prescribed tramadol hydrochloride immediate-release and extended-release tablets for chronic low back pain at 13 facilities in Japan between January 2021 and December 2023. The primary outcome was the incidence of side effects observed during the study period. The secondary outcomes were changes in the visual analog scale (VAS) score. The incidence of side effects was 37.7% (40/106 cases), which included constipation, nausea, drowsiness, and dizziness in 23 (21.7%), 13 (12.3%), 4 (3.8%), and 2 (1.9%) cases, respectively. The rate of treatment discontinuation owing to side effects was relatively low (16/106 cases, 15.1%). Furthermore, after four weeks of treatment, we found a significant reduction in the VAS scores for low back pain from baseline. This study shows the incidence of side effects following the administration of tramadol hydrochloride immediate-release and extended-release tablets. Regarding the breakdown of side effects, constipation, nausea, drowsiness, and dizzinesswere noted. Regarding pain evaluation, we found a significant reduction in the VAS scores for low back pain from baseline after four weeks of treatment, suggesting that tramadol hydrochloride immediate-release and extended-release tablets may provide excellent analgesic effects owing to their pharmacokinetic properties that ensure stable tramadol concentrations in the bloodstream.

Elevated temperature increases the susceptibility of D. magna to environmental mixtures of carbamazepine, tramadol and citalopram

The joint risks assessment of thermal stress and rising loads of pharmaceuticals (PhACs) in surface waters is a relevant topic in aquatic ecotoxicology. This study investigated the relevance of increased water temperature to alter the acute toxicity of environmentally relevant carbamazepine (CBZ), citalopram (CIT) and tramadol (TRA) concentrations as mixtures (ECs) and delayed outcomes in Daphnia magna. Responses of detoxification and antioxidant pathways in premature daphnids post an acute 24 h (pulsed) exposure to the PhACs mixtures and delayed responses as the reproductive output over 14 days recovery were investigated under 21- and 26 °C incubation. Biphasic modulation in glutathione S-transferase (GST) activity and significant inhibition of superoxide dismutase (SOD) activity were observed in both thermal regimes with significant shift in effective thresholds from 10-fold ECs at 21 °C to ECs at 26 °C incubation. Significant induction in catalase (CAT) activity and oxidative stress development were recorded at elevated temperatures from the 10-fold ECs dose onward. Pulsed exposures at 26 °C also led to significant decrease in the reproduction of daphnids above the 10-fold ECs of PhACs. The Integrated Biomarker Response scoring (IBRv2) approach outlined a 1.8-fold increase in alterations of daphnids exposed to 100-fold ECs of PhACs at 26 °C.

Exploring the potential of beta-cyclodextrin-based MIL-101(Cr) for pharmaceutical removal from wastewater: A combined density functional theory and molecular simulations study

Pharmaceutical contaminants pose significant risks to ecosystems and human health, necessitating effective removal strategies. This research focuses on developing advanced adsorbents for removing pharmaceutical pollutants from the environment. Metal-organic frameworks (MOFs), specifically MIL-101(Cr) functionalized with biodegradable beta-cyclodextrin (β-CDex), were investigated as potential nanocomposite adsorbents for the removal of ketorolac (KTRK), naproxen (NPXN), and tramadol (TRML). The study employed molecular simulations and density functional theory (DFT) calculations to explore the interactions between the pollutants and adsorbents. Analyses of DFT results, including electrostatic potential, ionization energy, density of states, and molecular orbital analysis, provided insights into the reactivity of pollutants and adsorbents. Additionally, the structural properties of the adsorbents, such as fractional free volume, radius of gyration, and system energies, were thoroughly examined. Molecular dynamics (MD) and Monte Carlo (MC) simulations were used to evaluate the adsorption capacities of MIL-101(Cr) for the target pharmaceutical pollutants. The results demonstrated the superior adsorption performance of the nanocomposite adsorbent, particularly for KTRK, with an adsorption energy of −1934 kcal/mol, compared to the pristine MIL-101(Cr), which had an adsorption energy of −1916 kcal/mol. This enhanced adsorption is attributed to the optimal molecular fit, guest-host solid interactions, and the selective encapsulation capabilities of β-CDex. This research highlights the potential of MOF-based nanocomposites as effective and sustainable solutions for pharmaceutical pollution. By advancing the understanding of molecular interactions through simulations, this study contributes to developing innovative adsorbents for wastewater treatment and the protection of water resources.

Anesthetic protocol for exploratory laparotomy in giant anteater (myrmecophaga tridactyla): case report

The movement of the giant anteater (Myrmecophaga tridactyla) in search of water and food causes a large number of accidents. The objective of this study is to describe the anesthetic protocol used in an exploratory laparotomy to control internal bleeding in a giant anteater. The animal was treated at the “Luiz Quintiliano de Oliveira” Veterinary Hospital of the Araçatuba School of Veterinary Medicine (UNESP) with a history of being run over. Midazolam was administered to restrain and position the animal during the physical and ultrasound examination, tramadol hydrochloride as premedication, and ketamine and midazolam for induction. Finally, anesthesia was maintained under inhalation anesthesia with isoflurane. Bradycardia during the transoperative period was corrected with a bolus of hypertonic solution (7.5% NaCl) and hydroxyethyl starch (Voluven®). The animal showed a satisfactory anesthetic recovery. Therefore, it is concluded that the anesthetic protocol is declared adequate for this procedure in giant anteaters.

Effectiveness of Lignocaine Tramadol Hydrochloride Combination in Bier’s Block on Post-Operative Analgesia

Background: Bier’s block has been most commonly used for hand and wrist surgery. Though it reduces the potential complication of general anaesthesia, significant post-operative pain is very common just after tourniquet release. Many adjuvants have been used so far with local anaesthetic to produce a dense block and to provide adequate post–operative analgesia. Of them, Tramadol Hydrochloride was used very successfully as it has got less potential side effects. This study was done to see the effect of Tramadol Hydrochloride in Bier’s block for post-operative analgesia after tourniquet release. Methods: This study was carried out in the Department of Anaesthesiology, Bangladesh Medical College Hospital, Dhaka, during the period of July ’2011 to march ’2012. A total sixty patients aged 20-60 years of ASA-1 and ASA-2 undergoing hand and wrist surgery of less than 40-minute duration were enrolled for the study. The effectiveness of combination of Lignocaine and Tramadol Hydrochloride as an anaesthetic solution in Bier’s block was assessed in terms of reduction of tourniquet pain, quality of anaesthesia, the time of first analgesic demand, and the amount of total analgesic needed in post-operative 24-hours period. Patients in control group (Gr-L) received 40 ml of 0.5% Lignocaine and patients in trial group (Gr-LT) received 38 ml of Lignocaine with 2ml (100mg) of Tramadol Hydrochloride as an anaesthetic solution. Patients were observed post-operatively for 24 hours. Pain was assessed in terms of VAS. Results: Tourniquet pain was significantly less in Gr-LT (p&lt;0.000). Post-operative analgesia was also significantly prolonged in Gr-LT (109.61±12.32 min) than in Gr-L (75.8±9.30 min). The number of total analgesic demand in post-operative 24 hours period was also significantly reduced in Gr-LT (P&lt;0.000).Conclusion: The Lignocaine and Tramadol Hydrochloride mixture in Bier’s block provides adequate post-operative analgesia and causes less analgesic demand in post-operative period.

Minocycline Acts as a Neuroprotective Agent Against Tramadol-Induced Neurodegeneration: Behavioral and Molecular Evidence.

Previous evidence indicates that tramadol (TRA) can lead to neurodegenerative events and minocycline (MIN) has neuroprotective properties. The current research evaluated the neuroprotective effects of MIN for TRA-promoted neurodegeneration. Sixty adult male rats were placed into the following groups: 1 (received 0.7 ml/rat of normal saline, IP), 2 (received 50 mg/kg of TRA, i.p.), 3, 4, 5 (administered TRA as 50 mg/kg simultaneously with MIN at 20, 40, and 60 mg/kg, IP, respectively), and 6 (received MIN alone as 60 mg/kg, IP). The treatment procedure was 21 days. An open field test (OFT) was used to measure motor activity and anxiety-related behavior. Furthermore, oxidative stress; hippocampal inflammation; apoptotic parameters as well as activity of mitochondrial complexes I, II, III, and IV; ATP levels; and mitochondrial membrane potential (MMP) were evaluated. In addition, histomorphological alteration was assessed in two regions of the hippocampus: Cornu Ammonis (CA1) and dentate gyrus (DG). MIN treatment could inhibit TRA-induced anxiety and motor activity disturbances (P < 0.05). In addition, MIN could attenuate reactive oxygen species (ROS), H2O2, oxidized glutathione (GSSG), and malondialdehyde (MDA) level (P < 0.05), while there was increased reduced glutathione (GSH), total antioxidant capacity (TAC), ATP, MMP, and BCL2 levels (P < 0.05) and also elevation of SOD, GPX, GSR (P < 0.05), and mitochondrial complexes I, II, III, and IV activity (P < 0.05) in TRA-treated rats. In consistence with these findings, MIN could reduce TNF/TNF-α, IL1B/IL1-β, BAX, and CASP3 levels (P < 0.05) in TRA-treated rats. MIN also restored the quantitative (P < 0.05) and qualitative histomorphological sequels of TRA in both CA1 and DG areas of the hippocampus. MIN probably has repositioning capability for inhibition of TRA-induced neurodegeneration via modulation of inflammation, oxidative stress, apoptosis, and mitochondrial disorders.

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.

Facile Synthesis of Reduced Graphene Oxide/Mn3O4 Nanocomposite as a Platform for the Voltammetric Determination of Tramadol

AbstractWe describe a simple hydrothermal method for preparing a nanocomposite of reduced graphene oxide/Mn3O4 (rGO/Mn3O4), and its use in electrochemically detecting tramadol (TRA). The sensor was constructed by using a glassy carbon electrode modified with a rGO/Mn3O4 nanocomposite (rGO/Mn3O4/GCE) as an electro‐catalyst. The electrochemical properties of TRA at rGO/Mn3O4/GCE were studied using cyclic voltammetry (CV), chronoamperometry, and differential pulse voltammetry (DPV) in a phosphate buffer solution (PBS) with a pH of 8.0. The oxidation peak currents of TRA on rGO/Mn3O4/GCE increased compared to the bare GCE. This enhancement was attributed to the high surface area and excellent electron transfer performance of the rGO/Mn3O4 nanocomposite on the surface of the electrode. Under optimal conditions, the oxidation peak currents exhibited a linear increase with the concentration of TRA within the range of 0.5 to 700.0 μM, and a detection limit (LOD) of 0.16 μM was achieved. This study has shown that the rGO/Mn3O4/GCE can effectively be used to analyze TRA in real specimens.

Chiral Switches of Tramadol Hydrochloride, a Potential Psychedelic Drug-Past and Future.

The chiral opioid analgesic tramadol was patented (1962) as a cis- and trans-racemates mixture. A first chiral switch led to the (±)-cis-(1RS,2RS) racemate, patented and approved as Tramal (1980), preferred over the (+)-cis-(1R,2R)-enantiomer. Consecutive chiral switches of (±)-cis-tramadol to (+)-cis-(1R,2R)-tramadol/salts were patented. This Viewpoint calls for developing (+)-cis-(1R,2R)-tramadol medicines and recognizing tramadol medicines as potential psychedelics to overcome the spreading tramadol crisis.

BIOEQUIVALENCE STUDY BETWEEN TWO FORMULATIONS OF TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN COATED TABLETS IN HEALTHY MALE AND FEMALE SUBJECTS UNDER FASTING CONDITIONS

Objective:To evaluate bioequivalence between a new formulation of Tramadol Hydrochloride/Acetaminophen and Ultracet® coated tablets in healthy subjects under fasting conditions. Methods:The present study was conducted as an open-label, monocentric, randomized, 2 x 2 crossover study on 40 healthy subjects in a state of fasting. The objective of the study was to compare the pharmacokinetic profiles of two formulations of tramadol hydrochloride and acetaminophen-coated tablets. The concentrations of the analytes in human plasma were measured using a validated UPLC-MS/MS method. Results:The geometric mean of the test/reference ratio, confidence intervals, and power of the test for the pharmacokinetic parametersCmax and AUC0-t, were determined by statistical analysis, in accordance with the Anvisas guidelines. The geometric mean ratio (90% CI) of the test drug/reference drug for acetaminophen was found to be 82.69% to 100.00% for Cmax and 95.36% to 100.34% for AUC0-t. The results for tramadol hydrochloride were 89.01% to 99.25% for Cmax and 94.86% to 100.71% for AUC0-t. The power of the test was greater than 98%. Conclusion:Both formulations demonstrated bioequivalent profiles, indicating that they are interchangeable in accordance with the Brazilian criteria. This is evidenced by the fact that the confidence intervals for Cmax and AUC0-t ratios were within 80% and 125%, respectively, as stipulated in Anvisa resolution RE nº 1170/2006.

Does Tramadol Exposure Have Unfavorable Effects on Hippocampus? A Review Study.

Tramadol, one of the most common opioid pain relievers, acts upon the µ-receptor in the central nervous system (CNS) to alleviate pain associated with various situations like postoperative pain, arthritis, and muscular pain. Additionally, it has been utilized to address depression and anxiety disorders. Extensive research has shown that tramadol can potentially inflict irreversible harm on different regions of the CNS, including the cerebrum, cerebellum, amygdala, and, notably, the hippocampal formation. However, the precise mechanism behind these effects remains unclear. Within this study, we conducted a comprehensive examination of the impacts of tramadol on the CNS, specifically focusing on hippocampal formation. In this study, we collected relevant articles published between 2000 and 2022 by conducting searches using specific keywords, including tramadol, tramadol hydrochloride, central nervous system, hippocampus, and hippocampal formation, in various databases. The results of this study proposed several processes by which tramadol may impact the CNS, including the induction of apoptosis, autophagy, excessive production of free radicals, and dysfunction of cellular organelles. These processes ultimately lead to disturbances in neural cell function, particularly within the hippocampus. Furthermore, it is revealed that tramadol administration led to a significant decrease in the neural cell count and the volume of various regions within the brain and spinal cord. Consequently, neuropsychological impairments, such as memory formation, attention deficits, and cognitive impairment, may happen. This finding highlights the potential impacts of tramadol on neural structures and warrants further investigation.

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).

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). 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). 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. 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. EudraCT number: 2019-003656-37; ClinicalTrials.gov Identifier: NCT05170841.