Cucurbita Pepo L. Seed Oil Modulates Dyslipidemia and Neuronal Dysfunction in Tramadol-Induced Toxicity in Wistar Albino Rats.

Objective: The modulating effects of Cucurbita pepo seed oil (CPSO) on dyslipidemia and neuronal dysfunction in tramadol toxicity were studied. Methods: Fifty-six albino rats were divided into seven groups of eight rats each after a 2-week acclimatization period. All animals had unrestricted access to water and feed, and treatments were administered orally once daily for 42 days. Glutamate dehydrogenase and glutaminase activities were assessed using brain homogenate, while lipid profiles were analyzed in serum samples. Results: Tramadol toxicity was evidenced by significant (P < 0.05) increases in brain glutamate dehydrogenase along with significant (P < 0.05) decreases in the activities of glutaminase in the group administered only tramadol. Also, serum levels of total cholesterol, LDL-C and triglycerides also increased significantly (P < 0.05) following administration of tramadol with decreased level of HDL-C (P < 0.05). However, treatment with CPSO significantly restored the activities and levels of the altered biochemical parameters in a dose-dependent manner. The results of the biochemical investigation using the lipid profile and the enzymes of glutamate metabolism were corroborated by the results obtained from the histopathological examination of the brain. Conclusion: The results of this study therefore suggest that tramadol-induced dyslipidemia and neuronal dysfunction be managed and prevented by the administration of Cucurbita pepo seed oil.

Role of Pregabalin in Pre-Operative and Post-Operative Pain Management of Lower Limb Orthopedic Surgeries.

Introduction: Post-operative pain after orthopedic surgery has remained a challenging problem, which prolongs hospital stay and early rehabilitation. Pregabalin comes under the class of gabapentinoids that have been used in postoperative pain in arthroplasty and spine surgeries but studies regarding its role as pre-emptive analgesia in orthopedic limb surgeries are very few. Aims: To compare the efficacy of pre-operative pregabalin with a placebo drug in early post-operative pain management for lower limb orthopedics surgeries. Materials and Methods: A randomized double blinded prospective study was undertaken. Sixty patients were enrolled with age between 18 and 70 years and were divided into 2 groups. Group A - received 150 mg of oral pregabalin capsule, and Group B - received matched color empty capsules. Standard spinal anesthesia was given. Breakthrough analgesia was given with an injection of tramadol 50 mg intravenous. Assessment of pain was done with a Visual Analog Scale (VAS) at 6, 12, 24, and 48 h. Results: In comparison to Group B, Group A had a significantly lower postoperative VAS score and required much less breakthrough analgesia within the 1st 24 h after surgery. Conclusion: In orthopedic lower limb fracture surgeries, pre-emptive pregabalin of 150 mg provides adequate postoperative analgesia with relatively few unfavorable side effects.

Evaluation of the effect of CYP2D6 and OCT1 polymorphisms on the pharmacokinetics of tramadol: Implications for clinical safety and dose rationale in paediatric chronic pain.

AIMS: Our investigation aimed to assess the dose rationale of tramadol in paediatric patients considering the effect of CYP2D6/OCT1 polymorphisms on systemic exposure. Recommendations were made for the oral dose of tramadol to be used in a prospective study in children (3 months to < 18 years old) with chronic pain. METHODS: Intravenous pharmacokinetic and genotype data from neonatal patients (n = 46) were available for this analysis. The time course of tramadol and O-desmethyltramadol (M1) concentrations was characterized using a nonlinear mixed effects approach in conjunction with extrapolation principles. Clinical trial simulations were then implemented to explore the effects of polymorphism, maturation and developmental growth on the disposition of tramadol and M1. Reported efficacious exposure range in adult subjects were used as reference. RESULTS: The pharmacokinetics of tramadol and M1 was characterized by a two-compartment model. The total clearance of tramadol (CLPP) comprised CYP2D6-mediated metabolism (CLPM) and other pathways (CLPO). Age-related changes in CLPM, CLPO and M1 clearance (CLMO) were described by a sigmoid function, with CYP2D6 as a covariate on CLPP and CLPM,  and OCT1 on CLMO. Simulation scenarios including different CYP2D6/OCT1 combinations revealed that steady-state concentrations are above the putative ranges for analgesia in >15% and >70% of subjects after doses of 3 and 8 mg/kg, respectively. CONCLUSIONS: In the absence of genotyping, reference exposure ranges can be used to define the dose rationale for tramadol in paediatric chronic pain. However, a starting dose of 0.5 mg/kg/day should be considered, followed by stepwise titration to the desired analgesic response.

Tramadol use and incident dementia in older adults with musculoskeletal pain: a population-based retrospective cohort study.

We aimed to assess the association of tramadol use with the risk of dementia. This population-based retrospective cohort study using the Korean National Health Insurance Service database included a total of 1,865,827 older adult patients aged 60 years or older with common musculoskeletal pain between January 1, 2003, and December 31, 2007. Individuals who were newly dispensed tramadol (N = 41,963) were identified and propensity score-matched with those who were not (N = 41,963). Over a maximum of 14-year follow-up, the incidence rates (events per 1000 person-years) of all-cause dementia were 6.1 for nonusers, 6.2 for those with cumulative tramadol use of 1-14 days, 7.7 for those with 15-90 days of use, and 8.0 for those with > 90 days of use. Longer cumulative duration of tramadol use was associated with an increased risk of all-cause dementia compared with nonuse (1 to 14 days: aHR 1.06, 95% CI 0.96-1.17; 15 to 90 days: aHR 1.14, 95% CI 1.10-1.35; and more than 90 days: aHR 1.18, 95% CI 1.00-1.39; test for trend: P < 0.001). The results showed a similar pattern for Alzheimer's disease and were robust across subgroup and sensitivity analyses, but not for vascular dementia. This study found that exposure to tramadol was associated with an increased risk of dementia. Taking this potential risk into consideration, clinicians should carefully weigh potential benefits and risks when prescribing tramadol to older adults with musculoskeletal pain.

Pain Management in Animals with Oncological Disease: Opioids as Influencers of Immune and Tumor Cellular Balance.

Advancements in understanding pain physiopathology have historically challenged animals' absence of pain senses. Studies have demonstrated that animals have comparable neural pain pathways, suggesting that cats and dogs likely experience pain similarly to humans. Understanding brain circuits for effective pain control has been crucial to adjusting pain management to the patient's individual responses and current condition. The refinement of analgesic strategies is necessary to better cater to the patient's demands. Cancer pain management searches to ascertain analgesic protocols that enhance patient well-being by minimizing or abolishing pain and reducing its impact on the immune system and cancer cells. Due to their ability to reduce nerve sensitivity, opioids are the mainstay for managing moderate and severe acute pain; however, despite their association with tumor progression, specific opioid agents have immune-protective properties and are considered safe alternatives to analgesia for cancer patients.

Multimodal Analgesia Approach in Acute Low Back Pain Management: A Phase III Study of a Novel Analgesic Combination of Etoricoxib/Tramadol.

INTRODUCTION: Pain and disability management are crucial for a speedy recovery. Combining analgesics with different mechanisms of action provides greater pain relief with lower doses, promoting efficient multimodal analgesia. This study evaluated the efficacy and safety between two fixed-dose combinations (FDC): etoricoxib/tramadol compared to paracetamol/tramadol for the management of acute low back pain (LBP) in a 7-day treatment. METHODS: We conducted a phase IIIb, prospective, randomized, and multicenter study in patients with acute LBP treated with etoricoxib 90 mg/tramadol 50 mg (one packet of granules diluted in 100 ml of water, once a day [QD], for 7 days) or paracetamol 975 mg/tramadol 112.5 mg (one tablet of 325 mg/37.5 mg, three times a day [TID], for 7 days) to assess the efficacy (in terms of pain and disability improvement) and safety. RESULTS: One hundred and twenty-four patients were randomized to receive either etoricoxib/tramadol QD (n = 61) or paracetamol/tramadol TID (n = 63). From the magnitude of change in pain evaluations, differences were observed between the treatment groups at 3 [p = 0.054, CI 95% - 0.648 (- 0.010 to 1.306)] and 5 days (p = 0.041). The proportion of patients with a 30% reduction in Visual Analogue Scale (VAS) score was statistically significant when comparing the treatment groups on the third day of follow-up [p = 0.008, CI 95% 0.241 (0.061-0.421)]. An improvement in LBP's disability to perform activities of daily routine (Oswestry and Roland-Morris questionnaires) was observed in both treatment groups. A total of 79 adverse events (AEs) (38 [48.1%] with etoricoxib/tramadol and 41 [51.9%] with paracetamol/tramadol) were reported. The most frequent AEs were nausea (17.7%) and dizziness (16.4%). CONCLUSIONS: The results show the clinical benefits of etoricoxib/tramadol FDC, such as the sparing effect of tramadol dose per day, early therapeutic response rate compared with paracetamol/tramadol; which translates into faster pain relief, better adherence, less tramadol drug dependency, and a reduction of related AEs incidence. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04968158.

Biochemical and Pharmacological Assessments of Tramadol Abuse on Human Male Fertility: Relation to Seminal Plasma 8-Hydroxyguanosine and Zinc.

Tramadol is a pain killing drug highly used worldwide. There is a knowledge gap for fertility consequences of analgesic addiction in men. In this observational study, we investigated the hazards of tramadol abuse on human male reproductive function. A total of 30 tramadol addicts and 30 healthy controls have participated in the study. History and clinical examination of the included subjects were performed. Biochemical and molecular assays were measured in all participants include serum reproductive hormones (calculated free testosterone, FSH, LH, prolactin and estradiol) using ELISA techniques, semen analysis, seminal plasma zinc and selenium assays using colorimetric kits, seminal plasma tramadol concentrations using Gas Chromatography-Mass Spectrometry (GC-MS), and seminal plasma 8-hydroxyguanosine (8-OHG) using high performance liquid chromatography were measured. Tramadol abuse significantly decreased semen parameters quality. Additionally, tramadol abuse significantly decreased testosterone (P = 0.001) and increased prolactin serum levels (P = 0.000). Tramadol abusers showed significantly higher levels of 8-OHG (P < 0.0001) with significantly lower levels of zinc and selenium in their seminal plasma compared with the controls (P < 0.0001, and 0.0002 respectively). Also, tramadol addicts displayed positive correlations between seminal plasma levels of 8-OHG (r = 0.905, P = 0.00) and sperm abnormal forms (r = 0.610, P = 0.000) with seminal plasma tramadol levels. Seminal plasma levels of zinc (r = - 0.815, P = 0.00), sperm motility (r = - 0.484, P = 0.007), and vitality (r = - 0.430, P = 0.018) were negatively correlated with seminal plasma levels of tramadol. Our data suggest that tramadol abuse may impair male fertility by increasing oxidative damage of sperms and reducing testosterone and the antioxidants trace elements in testicular tissues. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-023-01141-4.

Tramadol Effects on Brain Activity During Cognitive and Emotional Empathy for Pain: A Randomized Controlled Study.

Pain is perceived not only by personal experience but also vicariously. Pain empathy is the ability to share and understand other's intentions and emotions in their painful conditions, which can be divided into cognitive and emotional empathy. It remains unclear how centrally acting analgesics would modulate brain activity related to pain empathy and which component of pain empathy would be altered by analgesics. In this study, we examined the effects of the analgesic tramadol on the brain activity for pain empathy in healthy adults. We used 2 tasks to assess brain activity for pain empathy. In experiment 1, we used a well-established picture-based pain empathy task involving passive observation of other's pain. In experiment 2, we developed a novel pain empathy task to assess brain activity during cognitive and emotional empathy for pain separately in a single task. We conducted a double-blind, placebo-controlled within-subject crossover study with functional magnetic resonance imaging for 33 participants in experiment 1 and 31 participants in experiment 2, respectively. In experiment 1, we found that tramadol decreased activation in the supramarginal gyrus during observation of other's pain compared with placebo. Supramarginal gyrus activation correlated negatively with the thermal pain threshold. In experiment 2, we found that tramadol decreased activation in angular gyrus in cognitive empathy for pain compared with placebo but did not change brain activity in emotional empathy for pain. PERSPECTIVE: Centrally acting analgesics such as tramadol may have not only analgesic effects on self-experienced pain but also on the complex neural processing of pain empathy.

Effect of secondary and tertiary wastewater treatment methods on opioids and the subsequent environmental impact of effluent and biosolids.

Opioids are widely distributed, potent prescription analgesics that are known to be diverted for illicit use. Their prevalence of use is reflected by high concentrations of parent compounds and/or metabolites found in samples collected from wastewater treatment plants. Given that treatment byproducts enter the environment through several routes, the consequences of insufficient removal by treatment methods include unwanted environmental exposure and potential to disrupt ecosystems. Activated sludge treatment has been widely investigated for a large suite of prescription opioids but the same cannot be said for UV and chlorination. Additionally, the biosolid cycle of opioids has been overlooked previously. This study aimed to determine the extent to which secondary and tertiary wastewater treatment methods remove opioids from influent, and the associated environmental exposure for those persistent, as well as the fate of opioids in biosolids. Membrane bioreactor treatment proved effective for natural and semi-synthetic opioids while the effect of UV treatment was negligible. Chlorination was the most effective treatment method resulting in effluent with concentrations below theoretical predicted no-effect concentration. Biosolids are not subjected to any additional biological or chemical treatment after membrane bioreactor treatment and the levels detected in biosolid used as fertiliser had several opioids at potentially hazardous concentrations, indicated by a QSAR theoretical model. This data indicates a potential issue regarding the treatment process of biosolids and reliance on chlorination for effluent treatment that should be investigated in other treatment plants.

Safety of Co-Crystal of Tramadol-Celecoxib (CTC) in Patients with Acute Moderate-to-Severe Pain: Pooled Analysis of Three Phase 3 Randomized Trials.

INTRODUCTION: Multi-modal analgesia is desirable for the management of acute pain since it can provide effective pain relief at lower doses, thereby aiding tolerability. Co-crystal of tramadol-celecoxib (CTC) provides effective analgesia in models of acute pain. Co-crystallization can alter the pharmacokinetics of individual components, potentially improving tolerability. We sought to better understand the safety and tolerability of CTC in patients with acute postoperative pain. METHODS: We conducted a pooled analysis of safety data from three phase 3 randomized controlled trials in adults with acute moderate-to-severe pain following oral surgery, bunionectomy, and elective abdominal hysterectomy. We present data for CTC 200 mg twice daily (BID) and its comparators: tramadol 50 mg four times daily (QID) (one trial), tramadol 100 mg QID (two trials), celecoxib 100 mg BID (two trials), and placebo (three trials). RESULTS: In total, n = 551 patients received CTC 200 mg BID, n = 183 received tramadol 50 mg QID, n = 368 received tramadol 100 mg QID, n = 388 received celecoxib 100 mg BID, and n = 274 received placebo. The prevalence of adverse events (AEs) related to study drug up to 48 h was numerically lower with CTC 200 mg BID (35.9%) than with tramadol 50 mg QID (47.5%) and 100 mg QID (44.8%) but greater than with celecoxib 100 mg BID (12.4%) and placebo (20.4%). The most frequent AEs related to study drug up to 48 h were somnolence, nausea, dizziness, and vomiting, which occurred more frequently in patients receiving tramadol 100 mg QID than in those receiving CTC 200 mg BID. CONCLUSION: CTC 200 mg BID appears to be better tolerated than tramadol 100 mg QID, possibly because of reduced total exposure to tramadol. This may contribute to a more favorable benefit-risk profile for CTC versus individual components, making it a promising treatment for acute pain. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT03108482, NCT02982161 (EudraCT: 2016-000592-24), NCT03062644 (EudraCT: 2016-000593-38).

Effectiveness of tramadol-including multimodal analgesia in spinal surgery: a single-center, retrospective cohort study.

BACKGROUND: Multimodal analgesia (MMA) is recommended for postoperative pain management; however, studies evaluating the effect of tramadol-including MMA on numerical rating scale (NRS)-based postoperative pain levels and the length of stay (LOS) in the hospital are limited. Therefore, this study aimed to compare the before and after effects of tramadol-including MMA application, and assess its effect on postoperative NRS scores and LOS. METHODS: Patients who underwent spinal surgery under general anesthesia at the Rakuwakai Marutamachi Hospital in fiscal years 2020 and 2022 were included in this study. The outcomes between the pre- and post-intervention groups were compared through propensity score matching. RESULTS: Following propensity score matching, 249 patients were included in each group. MMA application significantly decreased the median LOS from 10 to 9 days (p < 0.001). Additionally, the median NRS scores exhibited a significant decrease from 4 to 3 on postoperative day (POD) 3 (p = 0.0109) and from 3 to 2 on POD 5 (p = 0.0087). Following MMA application, the number of patients receiving additional analgesics decreased significantly, from 38 to 6 (p < 0.001). CONCLUSIONS: The introduction of tramadol-including MMA can effectively reduce postoperative pain and decrease the LOS for patients undergoing spinal surgery.

Pharmacogenetic Approach to Tramadol Use in the Arab Population.

Tramdol is one of most popular opioids used for postoperative analgesia worldwide. Among Arabic countries, there are reports that its dosage is not appropriate due to cultural background. To provide theoretical background of the proper usage of tramadol, this study analyzed the association between several genetic polymorphisms (CYP2D6/OPRM1) and the effect of tramadol. A total of 39 patients who took tramadol for postoperative analgesia were recruited, samples were obtained, and their DNA was extracted for polymerase chain reaction products analysis followed by allelic variations of CYP2D6 and OPRM A118G determination. Numerical pain scales were measured before and 1 h after taking tramadol. The effect of tramadol was defined by the difference between these scales. We concluded that CYP2D6 and OPRM1 A118G single nucleotide polymorphisms may serve as crucial determinants in predicting tramadol efficacy and susceptibility to post-surgical pain. Further validation of personalized prescription practices based on these genetic polymorphisms could provide valuable insights for the development of clinical guidelines tailored to post-surgical tramadol use in the Arabic population.

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.

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.

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.

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.

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.

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.