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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., (© 2024 Esteve Pharmaceuticals S.A and The Author(s). Pain Practice published by Wiley Periodicals LLC on behalf of World Institute of Pain.)

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 (C max ), (area under the plasma drug concentration-time curve form 0 up to last sampling time (AUC 0-t ), and (area under the plasma drug concentration-time curve from 0 up to infinity (AUC 0-∞ ) 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., (© 2024 Laboratorios Silanes. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Objectives: This study aims to determine the usage pattern, effectiveness and safety of oral tramadol 75 mg and dexketoprofen trometamol 25 mg fixed-dose combination (TRAM/DKP FDC) in the short-term treatment of moderate-to-severe acute pain in real-world clinical practice in Asia., Design: Real-world, prospective, multicentre, observational, phase IV study., Setting: 13 tertiary-care hospital sites across the Philippines, Thailand, Malaysia and Singapore., Participants: Adult patients aged 18-80 years prescribed TRAM/DKP FDC for the short-term (up to 5 days) treatment of moderate-to-severe acute pain., Main Outcome Measures: Primary endpoints were the proportion of patients prescribed TRAM/DKP FDC with different types of postsurgical and non-surgical treatments, and the average dosing frequency and duration of TRAM/DKP FDC treatment. Secondary endpoints were the proportion of patients achieving ≥30% pain reduction at 8 hours post the first dose (pain severity was assessed using the 11-point Numeric Pain Rating Scale); patient satisfaction at the end of treatment (based on a 5-point Patient Global Evaluation Scale (PGE)) and safety including the incidence of adverse drug reactions (ADRs)., Results: Among 599 patients (median age 44 years, 61.3% female) enrolled in this study, 68.61% (n=411) were postsurgical and 31.39% (n=188) were non-surgical patients. TRAM/DKP FDC was prescribed in a diverse group of postsurgical patients (eg, orthopaedic, general and cancer surgery) as well as in non-surgical conditions (eg, lower back pain and musculoskeletal pain). In the majority of patients, TRAM/DKP FDC was prescribed every 8 hours (65.94%) and for 5 days (78.80%). There was a significant reduction in pain intensity throughout the study and 65% of patients achieved ≥30% pain reduction from baseline at 8 hours post the first dose of TRAM/DKP FDC on day 1. 95.69% of patients were satisfied with the treatment (rated good, very good and excellent on the PGE scale). Overall, 13.9% of patients reported ADRs; most were mild to moderate in severity. The most common ADRs were nausea, vomiting and dizziness., Conclusion: This study showed that TRAM/DKP FDC was used in diverse types of postsurgical and non-surgical patients in the real-world setting in Asia. It effectively reduced pain and was well tolerated with a high level of patient satisfaction., Competing Interests: Competing interests: BG, AG and DN are employees of A. Menarini Asia-Pacific Holdings Pte. Ltd., Singapore. All other authors report receiving investigator fees for this study from the sponsor., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Tramadol has been associated with chronic opioid use and emergency room (ER) visits. However, little is known about trends in prescription tramadol use in the U.S., Methods: Optum's de-identified Clinformatics® Data Mart Database was used to assess trends in monthly incident and prevalent tramadol use from 2005 to 2021, stratified by sex and age (18-64 vs. ≥65 years). State-specific trends following scheduling of tramadol as Class IV controlled substance in August 2014 were analyzed with random effects regression models. Demographics, comorbidities, initiation setting, dose, and co-dispensing with other opioids and central nervous system (CNS) agents were assessed in people initiating tramadol, stratified by age and initiation year (2005-2010, 2011-2015, 2016-2021). Analyses were performed in 2023 and 2024., Results: During 2005-2021, the mean percentage using tramadol in a given month was 0.88% of younger females, 0.55% of younger males, 1.97% of older females, and 1.14% of older males; 5,729,652 initiations were identified. Since 2014, estimated relative yearly decrease was 4% (95% CI 3%; 5%) in use and 5% (95% CI 4%; 5%) in initiation, with variation across states. Primary care percentage of tramadol initiations declined from 49.2% in 2005-2010 to 37.2% in 2016-2021. During 2016-2021, co-dispensing with other CNS agents occurred in 37.8% of younger and 32.1% of older adults initiating tramadol., Conclusions: Tramadol use was higher in females and older adults, exhibited heterogeneous trends across states, and shifted from primary care to ER and specialist settings over time. Co-dispensing with other CNS agents was common and warrants further monitoring., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Adductor canal block and periarticular infiltration analgesia (PIA) have been shown to relieve pain in total knee arthroplasty (TKA) effectively. However, their analgesic effectiveness has some limitations. Thus, we considered a novel blocking site that could achieve analgesia without affecting the muscle strength of the lower limbs., Methods: Seventy-two patients undergoing primary unilateral total knee arthroplasty were randomized into two groups. One group was treated with adductor canal and popliteal plexus (APB) combined with interspace between the popliteal artery and posterior capsule of the knee (iPACK) and local infiltration anesthesia (LIA) and the other was treated with PIA. The primary outcomes included postoperative pain, as assessed by the visual analog scale (VAS), and the consumption of oral tramadol. Secondary outcomes included functional recovery and daily ambulation distance. Tertiary outcomes included postoperative adverse effects., Results: The APB group had lower VAS scores after surgery at rest and during motion. Compared with the PIA group, the walking distance of the APB group on the second day was greater. The muscle strength of the APB group was lower than that of the PIA group at the early stage. Patients in the APB group also consumed less tramadol than those in the PIA group. There was no difference in the incidence of adverse events between the two groups., Conclusions: APB combined with iPACK and LIA is a novel block for TKA, and it can reduce postoperative pain sooner after TKA without affecting postoperative functional recovery or increasing complications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Post-operative pain control improves patient's satisfaction and affects the period of admission. Local wound infiltration following hernia surgery using xylocaine or bupivacaine has been a common practice. The use of tramadol for such infiltration is relatively new and has not been studied in our environment. This study compared the efficacy of post-operative pain control between Bupivacaine and Tramadol wound infiltration in children who underwent herniotomy and orchidopexy., Materials and Methods: This was a prospective randomised study involving 104 patients. A simple random method was used to allocate the study group into two equal groups (A, n = 52 and B, n = 52) using sealed envelopes with contents labelled A or B. Pre- and post-operative respiratory rate, heart rate, and C-reactive protein (CRP) were all recorded. Time to first and subsequent analgesia was determined using face, legs, activity, cry, consolability (FLACC) pain score., Results: Fifteen patients in Group A and 18 patients in Group B received each two doses of supplemental analgesia within the first 24 h, ( P = 0.527). Time to first analgesia was significantly different between the two groups, (6.93 ± 0.80 h and 6.11 ± 1.08 h, P = 0.020). The mean FLACC pain score at the time of first analgesia in hours was 4.93 ± 0.59 and 4.72 ± 0.67 for Group A and B, respectively, P = 0.350. The changes in CRP were not different in the two groups, ( P = 0.665). Four patients in Group A, but none in Group B had an episode each of post-operative vomiting., Conclusion: Tramadol showed comparable efficacy with bupivacaine in post-operative pain control by wound infiltration in children who had unilateral herniotomy or orchidopexy. Tramadol, however, achieves a longer duration of action before rescue analgesic is required. Caution is necessary to avoid post-operative vomiting., (Copyright © 2024 Copyright: © 2024 African Journal of Paediatric Surgery.)

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., (© 2024 The Author(s). Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Purpose: The objective of this study was to examine the hypothesis that the opioid consumption of patients who receive a rhomboid intercostal block (RIB) or a pectoral nerve (PECS) block after unilateral modified radical mastectomy (MRM) surgery is less than that of patients who receive local anesthetic infiltration., Methods: Eighty-one female patients aged 18-70 years who underwent unilateral MRM surgery with general anesthesia were randomly allocated to three groups. The first group received an RIB with 30 ml of 0.25% bupivacaine on completion of the surgery, and the second received a PECS block with the same volume and concentration of local anesthetic. In the third (control) group, local infiltration was applied to the wound site with 30 ml of 0.25% bupivacaine at the end of the surgery. The patients' total tramadol consumption, quality of recovery (QoR), postoperative pain scores, and sleep quality were evaluated in the first 24 h postoperatively., Results: Both the RIB (58.3 ± 22.8 mg) and PECS (68.3 ± 21.2 mg) groups had significantly lower tramadol consumption compared to the control group (92.5 ± 25.6 mg) (p < 0.001 and p = 0.002, respectively). Higher QoR scores were observed in the RIB and PECS groups than the control group at 6 h post-surgery. The lowest pain values were observed in the RIB group. The sleep quality of the patients in the RIB and PECS groups was better than that of the control group (p < 0.001)., Conclusion: Compared to local anesthetic infiltration, the RIB and PECS blocks applied as part of multimodal analgesia in MRM surgery reduced opioid consumption in the first 24 h and improved the quality of recovery in the early period., (© 2024. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

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., Competing Interests: Declaration of competing interest All authors are employees of Nippon Zoki Pharmaceutical Co., Ltd. The authors indicated no potential conflicts of interest., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

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., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

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 (SpO 2 ), 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 SpO 2 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The multimodal analgesia strategy for acute pain involves using 2 or more analgesic medications with distinct mechanisms of action. This study assessed the bioavailability and tolerability of 2 tramadol hydrochloride (50 mg)/diclofenac sodium (50 mg) fixed-dose combination formulations under fed conditions to attend the Brazilian regulatory requirements for generic product registration. An open-label, randomized, single-dose, 2-period, 2-way crossover trial was conducted, including healthy subjects of both sexes. Subjects received a single dose of either the test or reference formulation of tramadol/diclofenac fixed-dose combination tablets with a 7-day washout period. Blood samples were collected up to 36 hours after dosing for tramadol and 12 hours for diclofenac and quantified using a validated liquid chromatography-tandem mass spectrometry method. Of 56 subjects enrolled, 53 completed the study. The 90% confidence intervals for maximum plasma concentration and area under the concentration-time curve from time 0 to the last quantifiable concentration were within acceptable bioequivalence limits of 80%-125%. Considering the results presented in this study, the test formulation is bioequivalent to the reference formulation and could be interchangeable in medical practice., (© 2024 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Aim: To evaluate tramadol hydrochloride, an atypical opioid with potential analgesic properties, as a viable alternative to lignocaine hydrochloride in supraperiosteal anesthesia for dental implants., Materials and Methods: 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., Results: 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., Conclusion: 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.

Introduction: surgical pain is managed with multi-modal anesthesia in total knee arthroplasty (TKA). It is dubious whether including local infiltrative anaesthesia (LIA) before wound closure provides adequate pain control and decreases morbidity., Material and Methods: this was a retrospective conducted to assess postoperative pain control, morbidity index, and opioid consumption in 116 patients who underwent TKA and were divided into two groups based on LIA (Modified Ranawat Regimen) or normal saline infiltration in the wound., Results: the mean NRS score was significantly lower in LIA group (3.2) as compared to the control group (3.9) in the first 24 hours. Functional milestones were relatively achieved earlier in LIA group but the values were not significant. Tramadol consumption was remarkably higher in the control group as compared to LIA group on day 1 and 2. As per the morbidity index the mean score on day one was 16.18 and 23.40 which decreased to 6.37 and 9.21 by day three in LIA and control group respectively indicating morbidity has decreased but more so in LIA group., Conclusion: our study concludes that use of modified cocktail regimen in the knee effectively decreased morbidity with excellent to good results, declining NRS score, minimal rescue analgesia requirement, early ambulation with better safety.

Objective: To explore preemptive analgesic effect of preoperative intramural tramadol injection in percutaneous kyphoplasty (PKP) of vertebrae following local anesthesia., Methods: From August 2019 to June 2021, 118 patients with thoraco lumbar osteoporotic fractures were treated and divided into observation group and control group, with 59 patients in each gruop. In observation group, there were 26 males and 33 females, aged from 57 to 80 years old with an average of (67.69±4.75)years old;14 patients on T 11 , 12 patients on T 12 , 18 patients on L 1 , 15 patients on L 2 ;tramadol with 100 mg was injected intramuscularly half an hour before surgery in observation group. In control group, there were 24 males and 35 females, aged from 55 to 77 years old with an average of (68.00±4.43) years old;19 patients on T 11 , 11 patients on T 12 , 17patients on L 1 , 12 patients on L 2 ;the same amount of normal saline was injected intramuscularly in control group. Observation indicators included operation time, intraoperative bleeding, visual analogue scale (VAS) evaluation and recording of preoperative (T0), intraoperative puncture(T1), and working cannula placement (T2) between two groups of patients, at the time of balloon dilation (T3), when the bone cement was injected into the vertebral body (T4), 2 hours after the operation (T5), and the pain degree at the time of discharge(T6);adverse reactions such as dizziness, nausea and vomiting were observed and recorded;the record the patient's acceptance of repeat PKP surgery., Results: All patients were successfully completed PKP via bilateral pedicle approach, and no intravenous sedative and analgesic drugs were used during the operation. There was no significant difference in preoperative general data and VAS(T0) between two groups ( P >0.05). There was no significant difference in operation time and intraoperative blood loss between the two groups ( P >0.05). VAS of T1, T2, T3, T4 and T5 in observation group were all lower than those in control group( P <0.05), and there was no significant difference in T6 VAS ( P >0.05). T6 VAS between two groups were significantly lower than those of T0, and the difference was statistically significant ( P <0.05). There was no significant difference in incidence of total adverse reactions between two groups ( P >0.05). There was a statistically significant difference in the acceptance of repeat PKP surgery ( P <0.05)., Conclusion: Half an hour before operation, intramuscular injection of tramadol has a clear preemptive analgesic effect for PKP of single-segment thoracolumbar osteoporotic fracture vertebral body under local anesthesia, which could increase the comfort of patients during operation and 2 hours after operation, and improve patients satisfaction with surgery.

Background: With the rising toll of the opioid crisis, oculoplastic surgeons have been looking at methods to decrease opioid prescription., Objectives: The aim of this study was to identify factors that correlate with opioid usage after oculoplastic surgery., Methods: This was a prospective study conducted at University of Texas Southwestern. All patients who underwent an oculoplastic procedure were eligible for inclusion. Patients enrolled were provided 20 tablets of tramadol 50 mg, to take 1 tablet every 6 hours as needed for pain. At their postoperative week 1 appointment, participants had the remaining number of unused opioid tablets counted. The number of tablets taken were calculated by subtracting the remaining number of tablets from the original prescribed amount., Results: A total of 310 patients were enrolled in our study. Of these, 129 patients met the inclusion criteria. There was a statistically significant difference in the number of tramadol tablets taken between procedures for upper eyelids, lower eyelids, and both eyelids (P < .01). There were no statistically significant differences in tramadol usage when comparing procedures on eyelids with orbit procedures(P = .30), cosmetic with noncosmetic procedures (P = .52), males with females (P = .87), or patients naive to oculoplastic procedures with those undergoing reoperation (P = .58). Longer procedures were correlated with greater tramadol usage (R = 0.28, P < .01)., Conclusions: This is the first study in the literature that has objectively quantified opioid usage after oculoplastic surgery in a prospective manner. Procedures that involve both upper and lower eyelids simultaneously and longer procedures resulted in higher opioid use. Orbital procedures, cosmetic procedures, sex, and procedural naivety were not found to be associated with higher opioid usage., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Proximal femur fractures are common among older individuals and pose challenges in achieving effective post-operative analgesia. Age-related co-morbidities limit the selection of analgesics in this population. This study aimed to compare the safety and effectiveness of transdermal buprenorphine (TDB) patch with traditional analgesics after fixation of an extracapsular fracture of the proximal femur., Methodology: A prospective randomized controlled study was conducted over a 2-year period, involving 60 patients who underwent surgery for extra capsular intertrochanteric fracture fixation. The patients were randomly assigned to two groups by random envelope method. Group A received an intravenous formulation of paracetamol and tramadol for the initial 48 h, followed by an oral formulation. Group B received a transdermal buprenorphine (TDB) patch delivering 5 mcg/hour immediately after surgery, which continued for 2 weeks postoperatively. During the 14-day monitoring period, patients' pain scores were assessed using the Visual Analog Scale (VAS) at rest and during movement. The primary objective was to maintain a VAS score of 4 or lower. Rescue analgesics were administered if the VAS score reached 6. The secondary objectives included evaluating the quantity of rescue analgesics required and monitoring for any adverse effects or complications., Results: Pain scores at rest and during movement were significantly lower in Group B at all-time points (p-value 0.0006 - ≤ 0.0001), and the requirement for rescue analgesia was also significantly lower in this group. The administration of the TDB patch did not result in any significant adverse effects., Conclusion: TDB patch is secure and offers better compliance and analgesia than other analgesics in the postoperative period whilst treating proximal femur extra capsular fracture., Competing Interests: Declaration of competing interest The authors declare there are no financial conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Objectives: New acute pain medications are needed that provide effective analgesia while minimizing side effects and opioid exposure. Clinical trials of co-crystal of tramadol-celecoxib (CTC) have demonstrated an improved benefit/risk profile versus tramadol or celecoxib alone. We pooled data from two phase 3 clinical trials to evaluate the efficacy of CTC 200 mg twice daily (BID) in acute moderate-to-severe pain., Methods: Efficacy data were pooled from STARDOM1 [acute pain following oral surgery (NCT02982161)] and ESTEVE-SUSA-301 [acute pain following bunionectomy (NCT03108482)]. The primary efficacy outcome was sum of pain intensity difference from 0 to 48 h (SPID 0-48 )., Results: A total of 344 patients received CTC 200 mg BID, 342 received tramadol 50 or 100 mg four times a day, 181 received celecoxib 100 mg BID, and 172 received placebo. The least-squares mean difference in SPID 0-48 was -21.8 (p = 0.002) for CTC versus tramadol and -72.8 (p < 0.001) for CTC versus placebo. A similar pattern of SPID 0-48 was observed with CTC versus comparator whether patients had moderate or severe pain at baseline. Reduction in pain intensity was faster and reached mild intensity earlier with CTC versus comparators. Patients were significantly (p ≤ 0.005) less likely to receive rescue medication within 4 or 48 h with CTC compared with tramadol or placebo., Conclusions: This pooled analysis reinforces the efficacy profile of CTC versus tramadol and, given that CTC permits lower daily tramadol dosing and thereby reduces unnecessary opioid use, this highlights its improved benefit/risk profile and its potential for the management of moderate-to-severe pain., (© 2024. The Author(s).)

Background: This non-randomized study aimed to compare the efficacy of two pharmacological treatments, "around-the-clock" analgesic treatment (ACAT) and "on-demand" analgesic treatment (ODAT), for managing postoperative pain following hemorrhoidectomy. Material and Methods: The study, conducted from July 2016 to December 2020, included 5335 hemorrhoidectomy patients. Participants were divided into ACAT (3767) and ODAT (1568) groups. The study was registered at clinicaltrials.gov (NCT04953182). Results: Patients had a mean age of 47.47 years, with 59.98% males. Postoperatively, 14.13% reported severe pain, 36.49% moderate, 34.28% mild, and 15.09% no pain. ACAT group's maximum pain was 3.04 (VAS), ODAT 4.95 (p; average pain was 0.79 (ACAT) and 1.45 (ODAT). Discharge pain was 0.42 (ACAT) and 0.63 (ODAT) VAS. The ACAT group consistently reported lower levels of pain across all measured instances. Higher BMI and younger age were pain risk factors (p=.049, p .001 respectively). ACAT administration resulted in reduced opioid usage, with meperidine showing a 68.38% decrease, morphine 43.57% less, tramadol 46.82% less, oxycodone reduced by 38.74%, and codeine by 53.40%. Additionally, the use of non-opioid analgesics was notably lower in the ACAT group, ranging from 16% to 59% less compared to the ODAT group. Conclusion: Hemorrhoidectomy induces moderate postoperative pain, with only 14% experiencing severe pain. A fixed schedule multimodal pain regimen, regardless of procedure and anesthesia type, reduces pain from moderate to mild post-hemorrhoidectomy. This approach also decreases opioid and non-opioid analgesic requirements. Higher BMI and younger age are identified as risk factors for elevated postoperative pain., (Celsius.)

Purpose: To assess the efficacy and safety of perioperative parenteral administration or submucosal infiltration of tramadol for perioperative pain control on the basis of pain intensity or analgesics consumption and perioperative outcomes in mandibular third molar surgery., Material-Methods: An electronic database search was conducted up to 10 November 2022 to retrieve all randomized controlled trials (RCTs), assessing the analgesic efficacy of parenteral use of tramadol implemented as an adjunct to local anesthesia or intraoperative sedation/general anesthesia, in surgical extraction of mandibular third molars. Modified Jadad scale and Cochrane bias tool were used for the qualitative appraisal., Results: Nineteen RCTs were selected for qualitative analysis. Nine studies involved intravenous, and 5 intramuscular administration of tramadol, while 5 evaluated submucosal infiltration with tramadol. Intravenous or intramuscular tramadol provided a weaker analgesic effect compared with non-steroidal anti-inflammatory drugs (NSAIDs), while intravenous tramadol induced an enhanced analgesic effect than oral tramadol. Parenteral administration of tramadol improved the quality of postoperative analgesia versus placebo. No notable adverse effects were recorded., Conclusions: Parenteral or submucosal infiltration of tramadol constitutes an effective and safe alternative analgesic approach in surgical extraction of mandibular third molars, yet the nociceptive effect of this analgesic modality could not supersede that of NSAIDs., Trial Registration: PROSPERO No CRD42021227574., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: This study investigated the outcomes up to 12 weeks after serial lidocaine infusion for early-onset peripheral neuropathic pain., Methods: This pilot double-blind, randomized, 2-arm placebo-controlled trial recruited 50 participants with onset of peripheral neuropathic pain within the past 6 months and randomized them to either receive lidocaine (3 mg/kg) in normal saline (50 mL) intravenous infusion over 1 hour (lidocaine group) once a week for 4 weeks or 50 mL of normal saline infusion (placebo group) once a week for 4 weeks. Twenty-nine participants completed the protocol; 15 participants were assigned to the lidocaine group and 14 to the placebo group. The outcomes were pain intensity assessed using a numerical rating scale (NRS), quality of life assessed using EuroQol-Five Dimensions-Five Levels questionnaire (EQ-5D-5L), psychological function using the Thai version of the 21-item Depression Anxiety Stress Scales (DASS-21), pain medication use, and adverse effects, all assessed at baseline (BL) and again at 4, 8, and 12 weeks following randomization., Results: The reported tramadol use at 8 and 12 weeks following the first infusion was significantly lower in the lidocaine group (P = .023). No other significant between-group differences were observed at any time point or for any other outcome, and no serious adverse events were observed., Conclusion: Multiple lidocaine infusions of 3 mg/kg once a week for 4 weeks in participants with recent onset of peripheral neuropathic pain demonstrated no significant benefits in pain intensity, quality of life, or psychological outcomes. At most, this treatment may result in less tramadol use., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Multimodal pain management is one component in enhanced recovery after surgery protocol. Here we evaluate the efficacy of tramadol-paracetamol in acute postoperative pain and pain outcome at 12 months after spine surgery in randomized, double-blind, placebo-controlled trial., Methods: We randomized 120 patients undergoing spine surgery to receive, for add-on pain management, two tramadol-paracetamol 37.5 mg/325 mg ( n = 61) or placebo tablets ( n = 59) twice a day for 5 postoperative days. In the hospital, multimodal pain management consisted of dexketoprofen and oxycodone. After discharge, patients were prescribed ibuprofen 200 mg, maximum 1,200 mg/day. Pain, analgesic use, and satisfaction with pain medication were followed up with the Brief Pain Inventory questionnaire before surgery and at 1 and 52 weeks after surgery. The primary outcome was patients' satisfaction with pain medication 1 week after surgery., Results: At 1 week after surgery, patients' satisfaction with pain medication was similarly high in the two groups, 75% [interquartile range, 30%] in the placebo group and 70% [40%] in the tramadol-paracetamol group ( p = 0.949) on a scale: 0% =  not satisfied, 100% = totally satisfied. At 1 week, ibuprofen dose was lower in the placebo group 200 mg [1,000] compared to the tramadol-paracetamol group, 800 mg [1,600] ( p = 0.016). There was no difference in the need for rescue oxycodone. Patients in the tramadol-paracetamol group had more adverse events associated with analgesics during the first postoperative week (relative risk = 1.8, 95% confidence interval, 1.2-2.6)., Conclusion: Add-on pain treatment with tramadol-paracetamol did not enhance patients' satisfaction with early pain management after back surgery., (© 2024 the author(s), published by De Gruyter.)

Background: Multimodal analgesia for total hip arthroplasty (THA) is increasingly employed to reduce early postoperative pain and promote fast patient discharge. The aim of this study was to compare the efficacy and tolerability of tramadol/dexketoprofen (TRAM/DKP, Group A) versus paracetamol + tramadol (PARA+TRAM, Group B) in patients undergoing THA using minimally invasive direct anterior approach (DAA)., Methods: A single-centre, randomised, single-blind, parallel, interventional study conducted in 323 patients undergoing primary THA with DAA was performed. Group A consisted of 188 patients and Group B of 135. The primary endpoints were the change from baseline (measured 2 hours postoperatively) in pain intensity (PI) during the treatment period (48 hours), assessed by visual analogue scale (VAS) at pre-specified postoperative time-points (2, 8, 24, 48 hours) and the total rescue medication (RM) use during the first 24 hours postoperatively., Results: As early as 2 hours after baseline, Group A showed a greater PI reduction from baseline compared to Group B (-26.24% vs. -6.87%; p   <  0.001). A lower mean PI (VAS) score was consistently found over the entire observation period following treatment with TRAM/DKP than with PARA+TRAM as well as more than 2-fold higher proportion of responders at the end of treatment period. More patients in Group B required RM in comparison to those in Group A (15.6% vs. 3.7%, p   <  0.001). Both treatments were well tolerated., Conclusions: After THA, oral TRAM/DKP provides faster and greater pain relief when compared to intravenous PARA+TRAM with limited consumption of RM and favourable tolerability profile. Our study expands the use of TRAM/DKP in the setting of major orthopaedic surgeries., Clinical Trial Registration: clinicaltrials.gov (NCT04178109)., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Pain management is essential after discectomy, the surgical treatment for lumbar disc herniation. This study evaluated the effect of sacral erector spinae plane block (SESPB) versus standard analgesic methods on postoperative analgesia and opioid consumption in lumbar discectomy operations., Methods: Over 18 years of age, ASA 1-3 group, 54 patients undergoing elective lumbar discectomy were included in the prospective, randomized, controlled, double-blind, study. They were randomly divided into groups, SESPB and non-block (control). Both groups completed surgery under general anesthesia. At the end of the surgery, group SESPB received a bilateral 20 cc block with 0.25% bupivacaine at the level of the second sacral vertebra. Both groups received tramadol via a patient-controlled analgesia (PCA) device. The primary outcome was total opioid consumption in the first 24 hours after surgery. Pain assessment by Visual Analog Scale (VAS), rescue analgesic requirements, time to first rescue analgesic requirement and adverse effects were recorded 24 hours postoperatively., Results: Total tramadol consumption was 168.8±143 mg (P<0.04) higher in the control group. The first six-hour VAS scores and the number of rescue analgesic users were lower in the SESPB group (P<0.01). The first rescue analgesic use time was 440±140.3 minutes in SESPB group and 47.5±116.1 minutes in control group (P<0.01). Nausea-vomiting was more frequent in the control group (P<0.01) and patient satisfaction was higher in the SESPB group (P<0.01)., Conclusions: In lumbar discectomy surgery, ultrasound-guided SESPB provided adequate analgesia by reducing opioid consumption and pain scores without complications.

Objective: Erector spinae plane block is an updated method than paravertebral block, possessing a lower risk of complications. This study aimed to compare erector spinae plane and paravertebral blocks to safely reach the most efficacious analgesia procedure in laparoscopic cholecystectomy cases., Methods: The study included 90 cases, aged 18-70 years, classified as American Society of Anesthesiologists I-II, who underwent an laparoscopic cholecystectomy procedure. They were randomly separated into three groups, namely, Control, erector spinae plane, and paravertebral block. No block procedure was applied to Control, and a patient-controlled analgesia device was prepared containing tramadol at a 10 mg bolus dose and a 10-min locked period. The pain scores were recorded with a visual analog scale for 24 h postoperatively., Results: The visual analog scale values at 1, 5, 10, 20, and 60 min at rest and 60 min coughing were found to be significantly higher in Control than in paravertebral block. A significant difference was revealed between Control vs. paravertebral block and paravertebral block vs. erector spinae plane in terms of total tramadol consumption (p=0.006). Total tramadol consumption in the first postoperative 24 h was significantly reduced in the paravertebral block compared with the Control and erector spinae plane groups., Conclusion: Sonography-guided-paravertebral block provides sufficient postoperative analgesia in laparoscopic cholecystectomy surgery. Erector spinae plane seems to attenuate total tramadol consumption.

Objective: A new block, namely, modified thoracoabdominal nerves block through perichondrial approach, is administered below the costal cartilage. We sought to compare the analgesic efficacy of the modified thoracoabdominal nerves block through perichondrial approach block with local anesthetic infiltration at the port sites in an adult population who underwent laparoscopic cholecystectomy., Methods: Patients who will undergo laparoscopic cholecystectomy were randomized to receive bilateral ultrasound-guided modified thoracoabdominal nerves block through perichondrial approach blocks or local anesthetic infiltration at the port insertion sites. The primary outcome was the total amount of tramadol used in the first 12 h postoperatively. The secondary outcomes were total IV tramadol consumption for the first postoperative 24 h and visual analog scale scores., Results: The modified thoracoabdominal nerves block through perichondrial approach group had significantly less tramadol use in the first 12 h postoperatively (p<0.001). The modified thoracoabdominal nerves block through perichondrial approach group's visual analog scale scores at rest (static) and with movement (dynamic) were significantly lower compared with the port infiltration group (p<0.05)., Conclusion: Patients who received modified thoracoabdominal nerves block through perichondrial approach block had significantly less analgesic consumption and better pain scores than those who received port-site injections after laparoscopic cholecystectomy.

Objective: Evaluation of the analgesic, opioid-sparing, anti-inflammatory and adverse effects of the diclofenac and orphenadrine (Neodolpasse) fixed combination for analgesia in the postoperative period of surgical cancer patients., Material and Methods: A randomized, single-center, prospective, comparative study evaluated two analgesic regimens in 40 cancer patients undergoing various open cavity surgeries, including extensive combined interventions associated with the resection of 3 or more organs. The study was conducted following the transfer from the ICU to the surgical department during the early activation period, within the first two postoperative days. In the first group N ( n =20), "Neodolpasse" (a fixed combination of 75 mg Diclofenac and 30 mg Orphenadrine) was administered as an infusion, twice daily. In the second group K ( n =20) analgesia was performed with ketoprofen as an intravenous infusion at a daily dose of 200 mg. Patients in both groups received scheduled prolonged epidural analgesia with 0.2% ropivacaine, and when the severity of pain in a visual analogue scale (VAS) increased to more than 40 mm, so an additional dose of 100 mg tramadol was administered intramuscularly. Daily measurments of blood creatinine level and C-reactive protein were taken, postoperative blood loss was accounted for, as well as postoperative complications according to the Clavien-Dindo classification., Results: The comparative analysis of the indicators of pain syndrome severity showed that the patients in group N exhibited a more pronounced analgesic effect, so on the second postoperative day 30% of patients reported moderate pain (from 50 to 60 mm on the pain scale), on the third day - 15%, and by the fourth day - all 100% of patients experienced pain of low intensity. The additional analgesia with tramadol in group N was required twice less than in the comparison group, and such adverse effects as nausea, drowsiness, and weakness were significantly more common in the ketoprofen group. In both groups, the average blood creatinine level did not exceed permissible values, and the C-reactive protein was elevated at all stages of the study but tended to decrease by the fourth day. The analysis of postoperative complications according to the Clavien-Dindo scale at the time of discharge did not reveal a direct correlation between the occurred complications and the use of NSAIDs. Adverse effects such as anastomotic failure, gastrointestinal complications, or other hemorrhagic manifestations were not recorded., Conclusion: The inclusion of Neodolpasse into multimodal analgesic regimens resulted in the most pronounced analgesic and opioid-sparing effects in surgical cancer patients using laparotomy access. Additionally, the application of short courses of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with a favorable safety profile.

Calvarial craniotomy in animal models involves pain and distress. Moderate to severe pain in laboratory animals requires adequate pain management strategies. According to previous studies, the options available for suitable analgesia for rat calvarial craniotomy are very few. For most analgesic treatments, injectable routes of administration are predominantly used. However, these routes require restraining the animals, which may cause unnecessary pain, distress and suffering. As a well-fare measure, we focused on pain management by oral administration of analgesia. In this particular study, which is a sub-study of a major experiment on bone regeneration with different polymeric scaffold materials, we have compared the analgesic efficacy of intraperitoneal (I/P) and oral administration of tramadol (10 mg/kg) over a period of 96 h post-surgery in rat craniotomy models. The focus of our study is to evaluate the potential pain reduction efficacy of orally administered Tramadol without any restraining involved. We have used various non-invasive methods to assess the pain-alleviating efficacy of tramadol administered through different methods. We found that the efficacy of oral administration of tramadol is comparable to I/P administration in alleviating pain. Additionally, oral administration through drinking water has the benefit of not putting the animal under unwanted restraining stress., (© 2023. Springer Nature Limited.)

Background: Hemorrhoidectomy is a common surgical procedure associated with significant postoperative pain. The conventional analgesic methods used for hemorrhoidectomy often have adverse effects and may not provide adequate pain relief. The sacral erector spinae plane block (ESPB) is a newly introduced technique that has shown promise in various surgical procedures. This prospective, randomized, controlled trial aimed to evaluate the analgesic effects of sacral ESPB following hemorrhoidectomy., Methods: Seventy patients undergoing hemorrhoidectomy were divided into 2 groups: the control group and the sacral ESPB group. Bilateral sacral ESPB was performed in the sacral ESPB group, whereas no intervention was performed in the control group. The numeric rating scale at rest and during the active period (mobilizing) was used as the primary outcome measure. Secondary outcome measures were the cumulative doses of tramadol, the number of patients who required rescue analgesia postoperatively, and quality of recovery-15 Turkish version patient recovery quality., Results: The sacral ESPB group had significantly low numeric rating scale scores at various time points (P < .05). More patients in the control group needed rescue analgesia during the postoperative period (P < .001). The dosages of tramadol consumption after the first 24 hours postoperatively were significantly lower in the sacral ESPB group compared with the control group (P < .001). Furthermore, quality of recovery-15 Turkish version scores were high in the sacral ESPB group (P < .001)., Conclusion: The results suggest that sacral ESPB is an effective method for post-hemorrhoidectomy pain management, reducing the need for additional analgesics and improving patient recovery., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Opinion Statement: Pharmacogenomics is increasingly important to guide objective, safe, and effective individualised prescribing. Personalised prescribing has revolutionised treatments in the past decade, allowing clinicians to maximise drug efficacy and minimise adverse effects based on a person's genetic profile. Opioids, the gold standard for cancer pain relief, are among the commonest medications prescribed in palliative care practice. This narrative review examines the literature surrounding opioid pharmacogenomics and its applicability to the palliative care cancer population. There is currently limited intersection between the fields of palliative care and pharmacogenomics, but growing evidence presents a need to build linkages between the two disciplines. Pharmacogenomic evidence guiding opioid prescribing is currently available for codeine and tramadol, which relates to CYP2D6 gene variants. However, these medications are prescribed less commonly for pain in palliative care. Research is accelerating with other opioids, where oxycodone (CYP2D6) and methadone (CYP2B6, ABCB1) already have moderate evidence of an association in terms of drug metabolism and downstream analgesic response and side effects. OPRM1 and COMT are receiving increasing attention and have implications for all opioids, with changes in opioid dosage requirements observed but they have not yet been studied widely enough to be considered clinically actionable. Current evidence indicates that incorporation of pharmacogenomic testing into opioid prescribing practice should focus on the CYP2D6 gene and its actionable variants. Although opioid pharmacogenomic tests are not widely used in clinical practice, the progressively reducing costs and rapid turnover means greater accessibility and affordability to patients, and thus, clinicians will be increasingly asked to provide guidance in this area. The upsurge in pharmacogenomic research will likely discover more actionable gene variants to expand international guidelines to impact opioid prescribing. This rapidly expanding area requires consideration and monitoring by clinicians in order for key findings with clinical implications to be accessible, meaningfully interpretable and communicated., (© 2022. Crown.)

Introduction: The present study was attempted to evaluate the effect of perianal infiltration of tramadol on postoperative pain in patients undergoing hemorrhoidectomy., Method: This double-blind clinical trial study was carried out on 90 patients with grade 3 and 4 hemorrhoids undergoing hemorrhoidectomy. Patients were randomly assigned into 3 groups of control or bupivacaine or tramadol. Before the surgery, perianal infiltration of .25% bupivacaine or tramadol or normal saline was prescribed to each group, respectively. Data on pain severity (based on the visual analog scale (VAS), the duration of surgery, sedation score, pain at the first defecation, first request time for additional analgesia, nausea and vomiting, and analgesic intakes) were evaluated and analyzed., Results: Duration of surgery was almost similar in all 3 groups ( P = .974). The results showed a significant difference in pain score between 3 groups ( P ≤.05) at all times after the surgery. In addition, the means of sedation scores ( P = .03), pain score at the first defecation ( P = .001), the time to first analgesic request ( P = .001), and ketorolac administration times ( P = .01) were significantly different between 3 groups. Finally, no complication was reported regarding postoperative nausea and vomiting., Conclusion: Given the notable efficacy of tramadol in reducing pain after hemorrhoidectomy and its minor side effects, this medication is suggested as an effective topical anesthetic to decrease pain after hemorrhoidectomy.

Importance: Historically, opioid pain medications have been overprescribed following thyroid and parathyroid surgery. Many narcotic prescriptions are incompletely consumed, creating waste and opportunities for abuse., Objective: To determine whether limiting opioid prescriptions after outpatient thyroid and parathyroid surgery to patients who opt in to narcotic treatment reduces opioid consumption without increasing postoperative pain compared with usual care (routine narcotic prescriptions)., Design, Setting, and Participants: A randomized clinical trial of Postoperative Opt-In Narcotic Treatment (POINT) or routine narcotic prescription (control) was conducted at a single tertiary referral center from June 1 to December 30, 2020. A total of 180 adults undergoing ambulatory cervical endocrine surgery, excluding patients currently receiving opioids, were assessed for eligibility. POINT patients received perioperative pain management counseling and were prescribed opioids only on patient request. Patients reported pain scores (0-10) and medication use through 7 daily postoperative surveys. Logistic regression was used to determine factors associated with opioid consumption., Interventions: Patients in the POINT group were able to opt in or out of receiving prescriptions for opioid pain medication on discharge. Control patients received routine opioid prescriptions on discharge., Main Outcomes and Measures: Daily peak pain score through postoperative day 7 was the primary outcome. Noninferiority was defined as a difference less than 2 on an 11-point numeric rating scale from 0 to 10. Analysis was conducted on the evaluable population., Results: Of the 180 patients assessed for eligibility, the final study cohort comprised 102 patients: 48 randomized to POINT and 54 to control. Of these, 79 patients (77.5%) were women and median age was 52 (interquartile range, 43-62) years. A total of 550 opioid tablets were prescribed to the control group, and 230 tablets were prescribed to the POINT group, in which 23 patients (47.9%) opted in for an opioid prescription. None who opted out subsequently required rescue opioids. In the first postoperative week, 17 POINT patients (35.4% of survey responders in the POINT group) reported consuming opioids compared with 27 (50.0%) control patients (P = .16). Median peak outpatient pain scores were 6 (interquartile range, 4-8) in the control group vs 6 (interquartile range, 5-7) in the POINT group (P = .71). In multivariate analysis, patients with a history of narcotic use were 7.5 times more likely to opt in (95% CI, 1.61-50.11; P = .02) and 4.8 times more likely to consume opioids (95% CI, 1.04-1.52; P = .01). Higher body mass index (odds ratio, 1.11; 95% CI, 1.01-1.23; P = .03) and highest inpatient postoperative pain score (odds ratio, 1.24; 95% CI, 1.04-1.52; P = .02) were also associated with opioid consumption., Conclusions and Relevance: In this trial, an opt-in strategy for postoperative narcotics reduced opioid prescription without increasing pain after cervical endocrine surgery., Trial Registration: ClinicalTrials.gov Identifier: NCT04710069.

Introduction: Video-assisted thoracoscopic lobectomy is the prior recommended treatment for non-small cell lung cancer (NSCLC), with the advantages of small trauma, less postoperative pain, and quick recovery. However, a large number of patients may suffer chronic postsurgical pain (CPSP), which makes the patients unwilling to practice pulmonary exercises, and it would directly affect patient's cough, sputum expectoration, and mobility. Opioids could greatly improve the quality of postoperative analgesia and the quality of life after surgery, but it is accompanied with obvious side effects. A number of clinical studies have proved that acupuncture could improve postoperative pain and reduce opioid use. In this study, we try to conduct a randomized controlled study to evaluate the efficacy and safety of plum-blossom needle acupuncture combined with Tramadol in improving CPSP after lobectomy in NSCLC patients., Methods: Patients will be randomly divided into treatment group (acupuncture plus Tramadol) and control group (sham acupuncture plus Tramadol) with a random number table in 1:1 ratio. The patients, outcome assessor, and statistician will be blinded. The outcomes are changes of numerical rating scale, Karnofsky performance score, brief pain inventory, blood routine, liver and kidney function. The data will be analyzed by SPSS 22.0., Conclusions: The results will help to evaluate the efficacy and safety of plum-blossom needle acupuncture in improving CPSP after lobectomy in NSCLC patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Tramadol is among the most famous analgesic drugs used for the management, treatment and relief of moderate to severe pain conditions. The present study investigated the effects of tramadol on the behavior, mortality, morphometric, hematology and oxidative stress parameters of C. gariepinus juveniles. The 96 h LC 50 value of tramadol determined by probit analysis was 88.76 mg/L. Based on this value, fish were exposed to sublethal concentrations of 4.44, 8.88, 17.75 mg/L tramadol and 0.0 mg/L (control) for the period of 15 days and allowed to recover for 5 days. Fish exposed to tramadol showed some abnormal behavioral responses and mortality increased with increase in the exposure duration and concentrations except for the control. There were variations in hepatosomatic index (HSI) and condition factor (CF) in fish exposed to tramadol. Exposure of C. gariepinus to tramadol elicited reduction in the values of white blood cell (WBC), red blood cell (RBC), hemoglobin (Hb), packed cell volume (PCV) and mean corpuscular volume (MCV) while the values of mean corpuscular hemoglobin (MCH) and the mean corpuscular hemoglobin concentration (MCHC) increased. The values of catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), reduced glutathione (GSH) and lipid peroxidation (LPO) increased significantly in the exposed fish compared with the control. The values of glutathione peroxidase (GPx) however decreased. The results of the present study demonstrate that tramadol is toxic to fish and its use should be monitored in the aquatic environment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Laparoscopic cholecystectomy is a common surgical procedure that frequently results in substantial postoperative pain. Erector spinae plane block (ESPB) has been shown to have beneficial postoperative analgesic effects when used as a part of multimodal analgesia. The aim of this study was to determine whether ESPB improves postoperative recovery quality in patients undergoing laparoscopic cholecystectomy. Evaluation of the effects of ESPB on postoperative pain, opioid consumption, and nausea and vomiting was the secondary objective., Methods: In this prospective double-blind study, 82 patients undergoing laparoscopic cholecystectomy were randomised into one of two groups: a standard multimodal analgesic regimen in Group N (control) or an ESPB was performed in Group E. Preoperative and postoperative recovery quality was measured using the 40-item quality of recovery (QoR-40) questionnaire; postoperative pain was evaluated using the numerical rating scale scores., Results: Postoperative mean (standard deviation) QoR-40 scores were higher in Group E (181 [7.3]) than in Group N (167 [11.4]); P<0.01. With repeated measures, a significant effect of group and time was demonstrated for the global QoR-40 score, P<0.01, indicating better quality of recovery in Group E. Pain scores were significantly lower in Group E than in Group N, both during resting and motion at T1-T8 times (P<0.01 at each time). The total amount of tramadol consumed in the first 24 h was lower in Group E [median 0 mg, inter-quartile range (IQR) (0-140)], than in Group N [median 180 mg, IQR (150-240); P<0.01]., Conclusions: ESPB improved postoperative quality of recovery in patients undergoing laparoscopic cholecystectomy. Moreover, ESPB reduced pain scores and cumulative opioid consumption., Clinical Trial Registration: NCT04112394., Competing Interests: Declarations of interest The authors declare that they have no conflicts of interest., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Tramadol is an opioid extensively used to treat moderate to severe pain; however, prolonged therapy is associated with several tissues damage. Chronic use of tramadol was linked to increased hospitalizations due to cardiovascular complications. Limited literature has described the effects of tramadol on the cardiovascular system, so we sought to investigate these actions and elucidate the underlying mechanisms. Mice received tramadol hydrochloride (40 mg/kg body weight) orally for 4 successive weeks. Oxidative stress, inflammation, and cardiac toxicity were assessed. In addition, eNOS expression was evaluated. Our results demonstrated marked histopathological alteration in heart and aortic tissues after exposure to tramadol. Tramadol upregulated the expression of oxidative stress and inflammatory markers in mice heart and aorta, whereas downregulated eNOS expression. Tramadol caused cardiac damage shown by the increase in LDH, Troponin I, and CK-MB activities in serum samples. Overall, these results highlight the risks of tramadol on the cardiovascular system., (© 2021. The Author(s).)

Background: Tramadol is a synthetic opioid and poisoning is increasing around the world day by day. Various treatments are applied for tramadol poisoning. Due to the unknown effects of tramadol poisoning and some of its treatments on blood glucose levels, this study was conducted to investigate the overdose of tramadol and its common treatments (naloxone, diazepam), and their combination on blood glucose levels in male rats., Methods: This study was conducted in 45 male Wistar rats. The animals were randomly divided into five groups of 9. They received a 75 mg/kg dose of tramadol alone with naloxone, diazepam, and a combination of both of these two drugs. On the last day, animals' tail vein blood glucose levels (BGL) were measured using a glucometer at different times, including before the tramadol injection (baseline) and 1 hour, 3 hours, and 6 hours after wards. The rats were anesthetized and sacrificed 24 h after the last injection. Blood samples were then taken, and the serum obtained was used to verify the fasting glucose concentration. Data were analyzed using SPSS software at a significance level of 0.05 using a one-way analysis of variance (ANOVA) and a generalized estimating equation (GEE)., Results: According to the GEE model results, the diazepam-tramadol and naloxone-diazepam-tramadol groups showed blood glucose levels five units higher than the tramadol group (p < 0.05). The diazepam-tramadol group had significantly higher blood glucose levels than the naloxone-tramadol group (p < 0.05). The mean blood glucose levels before the intervention, 3 hours and 6 hours after the injection of tramadol did not differ between the groups, but the blood glucose levels 1 hour after the injection of tramadol in the group of naloxone-tramadol were significantly lower than in the control group (p < 0.05). Blood glucose levels did not differ between the groups 24 h after injection of tramadol., Conclusion: The results of the present study showed tramadol overdose does not affect blood glucose levels. The diazepam-tramadol combination and the diazepam-naloxone-tramadol combination caused an increase in blood glucose levels., (© 2021. The Author(s).)

Objectives: To characterize the cardiopulmonary and anesthetic effects of alfaxalone at three dose rates in comparison with a ketamine-dexmedetomidine-midazolam-tramadol combination (KDMT) for immobilization of golden-headed lion tamarins (GHLTs) (Leontopithecus chrysomelas) undergoing vasectomy., Study Design: Prospective clinical trial., Animals: A total of 19 healthy, male, wild-caught GHLTs., Methods: Tamarins were administered alfaxalone intramuscularly (IM) at 6, 12 or 15 mg kg -1 , or KDMT, ketamine (15 mg kg -1 ), dexmedetomidine (0.015 mg kg -1 ), midazolam (0.5 mg kg -1 ) and tramadol (4 mg kg -1 ) IM. Immediately after immobilization, lidocaine (8 mg kg -1 ) was infiltrated subcutaneously (SC) at the incision site in all animals. Physiologic variables, anesthetic depth and quality of immobilization were assessed. At the end of the procedure, atipamezole (0.15 mg kg -1 ) was administered IM to group KDMT and tramadol (4 mg kg -1 ) SC to the other groups; all animals were injected with ketoprofen (2 mg kg -1 ) SC., Results: A dose-dependent increase in sedation, muscle relaxation and immobilization time was noted in the alfaxalone groups. Despite the administration of atipamezole, the recovery time was longer for KDMT than all other groups. Muscle tremors were noted in some animals during induction and recovery with alfaxalone. No significant differences were observed for cardiovascular variables among the alfaxalone groups, whereas an initial decrease in heart rate and systolic arterial blood pressure was recorded in KDMT, which increased after atipamezole administration., Conclusions and Clinical Relevance: Alfaxalone dose rates of 12 or 15 mg kg -1 IM with local anesthesia provided good sedation and subjectively adequate pain control for vasectomies in GHLTs. KDMT induced a deeper plane of anesthesia and should be considered for more invasive or painful procedures. All study groups experienced mild to moderate hypothermia and hypoxemia; therefore, the use of more efficient heating devices and oxygen supplementation is strongly recommended when using these protocols., (Copyright © 2021 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Background and Objective: Bioequivalence tests are fundamental step in assessing the equivalence in bioavailability between a test and reference product. In practice, two separate linear mixed models (LMMs) with random subject effects, which have an area under the concentration-time curve (AUC) and the peak concentration (C max ) as the responses, have become the gold standard for evaluating bioequivalence. Recently, Lee et al developed a multivariate hierarchical generalized linear model (HGLM) for several responses that modeled correlations among multivariate responses via correlated random effects. The objective of this study was to apply this multivariate analysis to the bioequivalence test in practice and to compare the performance of multivariate HGLM and separate LMMs., Methods: Three pharmacokinetic datasets, fixed-dose combination (naproxen and esomeprazole), tramadol and fimasartan data were analyzed. We compared the 90% confidence interval (CI) for the geometric mean ratio (GMR) of a test product to a reference product using the multivariate HGLM and two conventional separate LMMs., Results: We found that the 90% CIs for the GMRs of both AUC and C max from the multivariate HGLM were narrower than those from the separate LMMs: (0.843, 1.152) vs (0.825, 1.177) for C max of esomeprazole in fixed-dose combination data; (0.805, 0.931) vs (0.797, 0.941) for C max in tramadol data; (0.801, 1.501) vs (0.762, 1.578) for C max and (1.163, 1.332) vs (1.009, 1.341) for AUC in fimasartan data, consistent with the random subject effects from two separate LMMs being highly correlated in the three datasets (correlation coefficient r = 0.883; r = 0.966; r = 0.832)., Conclusion: This multivariate HGLM had good performance in the bioequivalence test with multiple endpoints. This method would provide a more reasonable option to reduce the 90% CI by adding correlation parameters and thus an advantage especially in evaluating the bioequivalence of highly variable drugs with broad 90% CIs., Competing Interests: The authors have no conflicts of interest to disclose., (© 2021 An and Shin.)

Peripheral tramadol's delivery in the temporomandibular joint (TMJ) leads to significant analgesic outcomes and inflammatory process's resolvent actions. Mechanistically, these properties are apart from the opioid system. Nevertheless, the molecular mechanisms behind these effects are still unclear. Therefore, the present study investigated the hypothesis that adenosine A 1 receptors are involved in the tramadol-induced analgesic and anti-inflammatory effects in the TMJ. Animals were pretreated with an intra-TMJ injection of DPCPX (antagonist of A 1 receptor) or tramadol and subsequent nociceptive challenge with an intra-TMJ injection of 1.5% formalin. For over 45 min, the nociceptive behavior was quantitated, and by the end of this assessment, the animals were euthanized, and the periarticular tissue was collected. Lastly, an in vitro assay of BMDM (Bone Marrow-Derived Macrophages) was performed to investigate tramadol activity in macrophages. The intra-TMJ injection of tramadol ameliorates formalin-induced hypernociception along with inhibiting leukocyte migration. The tramadol's peripheral anti-inflammatory effect was mediated by the adenosine A 1 receptor and was associated with increased protein expression of α2a-adrenoceptor in the periarticular tissues (p < 0.05: ANOVA, Tukey's test). Also, tramadol inhibits formalin-induced leukocyte migration and protein expression of P2X7 receptors in the periarticular tissue (p < 0.05); however, DPCPX did not alter this effect (p > 0.05). Moreover, DPCPX significantly reduced the protein expression of the M2 macrophage marker, MRC1. In BMDM, tramadol significantly reduces inflammatory cytokines release, and DPCPX abrogated this effect (p < 0.05). We identify tramadol's peripheral effect is mediated by adenosine A 1 receptor, possibly expressed in macrophages in the TMJ tissue. We also determined an important discovery related to the activation of A 1 R/α2 a receptors in the tramadol action., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Tramadol is a centrally acting synthetic opioid analgesic and SNRI (serotonin/norepinephrine reuptake-inhibitor) that structurally resembles codeine and morphine. Given the tramadol neurotoxic effect and the body of studies on the effect of tramadol on the cerebellum, this study aims to provide deeper insights into molecular and histological alterations in the cerebellar cortex related to tramadol administration. In this study, twenty-four adult male albino rats were randomly and equally divided into two groups: control and tramadol groups. The tramadol group received 50 mg/kg of tramadol daily for 3 weeks via oral gavage. The functional and structural change of the cerebellum under chronic exposure of tramadol were measured. Our data revealed that treating rats with tramadol not only lead to cerebellum atrophy but also resulted in the actuation of microgliosis, neuroinflammatoin, and apoptotic biomarkers. Our results illustrated a significant drop in VEGF (vascular endothelial growth factor) level in the tramadol group. Additionally, tramadol impaired motor coordination and neuromuscular activity. We also identified several signaling cascades chiefly related to neurodegenerative disease and energy metabolism that considerably deregulated in the cerebellum of tramadol-treated rats. Overall, the outcomes of this study suggest that tramadol administration has a neurodegeneration effect on the cerebellar cortex via several pathways consisting of microgliosis, apoptosis, necroptosis, and neuroinflammatoin., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The use of tramadol is a controversial topic in cycling. In order to provide novel evidence on this issue, we tested 29 participants in a pre-loaded cycling time trial (TT; a 20-min TT preceded by 40-min of constant work-rate at 60% of the VO 2max ) after ingesting 100 mg of tramadol (vs placebo and paracetamol (1.5 g)). Participants performed the Psychomotor Vigilance Task (PVT) at rest and a Sustained Attention to Response Task (SART) during the 60 min of exercise. Oscillatory electroencephalography (EEG) activity was measured throughout the exercise. The results showed higher mean power output during the 20-min TT in the tramadol vs. paracetamol condition, but no reliable difference was reported between tramadol and placebo (nor paracetamol vs. placebo). Tramadol resulted in faster responses in the PVT and higher heart rate during exercise. The main effect of substance was reliable in the SART during the 40-min constant workload (no during the 20-min TT), with slower reaction time, but better accuracy for tramadol and paracetamol than for placebo. This study supports the increased behavioural and neural efficiency at rest for tramadol but not the proposed ergogenic or cognitive (harmful) effect of tramadol (vs. placebo) during self-paced high-intensity cycling.

The objective of this study was to develop a novel acetaminophen and tramadol hydrochloride-loaded soft capsule (ATSC) with enhanced bioavailability of tramadol. The ATSC was manufactured in a pilot-scale batch size with the capsule contents composed of tramadol, acetaminophen, PEG 400 and Capmul MCM at a weight ratio of 37.5:325:177.5:30. Moreover, its dissolution, stability and pharmacokinetics in beagle dogs were carried out compared to commercial tablet. The dissolved amounts of acetaminophen from the ATSC and commercial tablet were not significantly different. However, compared to the latter, the former had significantly higher dissolution rate of tramadol at the initial times. In beagle dogs, the ATSC provided no significant difference in plasma concentrations and AUC of acetaminophen than did the commercial tablet; however, it significantly improved those of tramadol compared to the other, indicating the enhanced oral bioavailability of tramadol. Compared to the commercial tablet, the ATSC had a larger AUC value for tramadol (55.27 ± 11.06 vs. 92.62 ± 21.52 h·ng/ml). In the accelerated long-term stability, the ATSC offered higher than 96% drug content of acetaminophen and tramadol, suggesting that it was stable for at least six months. Therefore, this ATSC would be a recommendable candidate with enhanced oral bioavailability and excellent stability.

The local administration of analgesic combinations by means of degradable polymeric drug delivery systems is an alternative for the management of postoperative pain. We formulated a Tramadol-Dexketoprofen combination (TDC) loaded in poly(vinyl alcohol) (PVA) film. Films were prepared by the solvent casting method using three different molecular weights of PVA and crosslinking those films with citric acid, with the objective of controlling the drug release rate, which was evaluated by UV-vis spectrometry. Non-crosslinked PVA films were also evaluated in the experiments. Differential scanning calorimetry (DSC) analysis of samples corroborated the crosslinking of PVA by the citric acid. Blank and loaded PVA films were tested in vitro for its impact on blood coagulation prothrombin time (PT) and partial thromboplastin time (PTT). The swelling capacity was also evaluated. Crosslinked PVA films of higher-molecular weight showed a prolonged release rate compared with that of the lower-molecular-weight films tested. Non-crosslinked PVA films released 11-14% of TDC. Crosslinked PVA films released 80% of the TDC loaded (p < 0.05). This suggests that crosslinking films can modify the drug release rate. The blank and loaded PVA films induced PT and PTT in the normal range. The results showed that the polymeric films evaluated here have the appropriate properties to allow films to be placed directly on surgical wounds and have the capacity for controlled drug release to promote local analgesia for the control of postoperative pain.