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

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

Tramadol/Diclofenac Fixed-Dose Combination for Acute Pain Management: Bioavailability Assessment of a Generic Product.

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.

Comparison of analgesic efficacy of tramadol, morphine and methadone in cats undergoing ovariohysterectomy.

OBJECTIVES: The aim of this study was to compare the analgesic efficacy and the effect on physiological variables and behavior of the use of tramadol, methadone and morphine as preoperative analgesia in healthy cats undergoing elective ovariohysterectomy. METHODS: Cats undergoing ovariohysterectomy were randomly assigned to receive one of the following premedication treatments intramuscularly: methadone (0.2 mg/kg; n = 10); morphine (0.2 mg/kg; n = 10); or tramadol (3 mg/kg; n = 10). Induction of anesthesia was done with propofol, and maintenance of anesthesia was done with isoflurane. Intraoperative heart rate, arterial blood pressure, respiratory rate, end-tidal isoflurane concentration and frequency of rescue analgesia (fentanyl 2.5 µg/kg) were compared between groups. Postoperative analgesia was assessed using the UNESP-Botucatu Multidimensional Composite Pain Scale, and perioperative serum glucose, cortisol concentrations and postoperative rescue analgesia were evaluated. RESULTS: Intraoperative rescue analgesia was required in 76.5% of cats at some time during surgery, and 27% of cats required postoperative rescue analgesia up to 6 h after extubation. There were no significant differences between groups with respect to intraoperative and postoperative rescue analgesia, pain scale scores and end-tidal isoflurane concentrations. In the immediate postoperative period, after extubation, most of the patients presented with hypothermia; however, 1-6 h postoperatively, hyperthermia was observed in most of the patients, and was most common in the tramadol group. CONCLUSIONS AND CLINICAL RELEVANCE: Under the conditions of this study, methadone, morphine and tramadol produced satisfactory postoperative analgesia in most of the cats undergoing ovariohysterectomy, and the effects lasted up to 6 h postoperatively. Intraoperative analgesia was not sufficient in most cases. Significant cardiovascular or respiratory effects contraindicating the use of these drugs were not found. Postanesthetic hyperthermia occurred with all opioids studied and was more frequent in the tramadol group.

Consideraciones para el uso de tramadol en dolor crónico no oncológico en atención primaria de salud (APS)

Introducción: tramadol es un analgésico opioide usado frecuentemente para el manejo del dolor crónico no oncológico (DCNO). En Chile, es parte del arsenal farmacológico de los centros de atención primaria para el tratamiento de patologías como artrosis de cadera y rodilla. Es considerado seguro y efectivo, sin embargo, existen reportes de efectos adversos serios por polimorfismos hepáticos, interacciones farmacológicas, intoxicaciones, adicción y muerte. La dosis óptima de tramadol es paciente dependiente. Por esto, es necesario contar con orientaciones específicas para prescribir tramadol de manera segura y eficaz según las características de cada paciente. Materiales y métodos: se revisaron guías actualizadas, revisiones sistemáticas y guías de sociedades internacionales sobre el uso de opioides en DCNO y el uso de tramadol en patologías de DCNO como artrosis, lumbago crónico, dolor neuropático y fibromialgia. Resultados: tramadol no está indicado en el tratamiento de cuadros de dolor primario como fibromialgia y en DCNO secundario es un fármaco de segunda línea o no está recomendado. En dolor crónico neuropático (DCN) es segunda línea de tratamiento. En osteoartritis de cadera, rodilla y mano, se reporta efecto analgésico modesto. Sopesar riesgos versus beneficios en estos pacientes. En artritis reumatoide y lumbago crónico se desaconseja su uso. Conclusiones: tramadol es un medicamento seguro y efectivo si se indica, administra, supervisa y descontinúa adecuadamente. Sin embargo, puede asociarse a interacciones farmacológicas, efectos secundarios serios, conductas de abuso y usos ilícitos, por lo que es necesario conocer y manejar adecuadamente su farmacología e indicaciones.

Introduction: Tramadol is an opioid pain medicine commonly used for chronic non-cancer pain (CNCP) management. In Chile, it is part of the pharmacological arsenal available in primary care centers for treating specific CNCP pathologies, such as hip and knee arthrosis. Tramadol is considered a safe and effective drug. Nevertheless, there are reports of serious adverse effects of tramadol, such as poisoning, addiction, and death, probably caused by liver polymorphisms and drug interaction. The optimal dose of tramadol is patient-specific. Specific knowledge is needed to prescribe tramadol in a safe and effective way according to the patient's medical backward. Methods: We review updated guidelines, systematic reviews, and guidelines from international societies about the use of opioids and tramadol in CNCP pathologies such as osteoarthritis, chronic low back pain, neuropathic pain, and fibromyalgia. Results: Tramadol has no role in primary pain treatment, such as fibromyalgia, but is a second-line drug for chronic neuropathic pain (CNP) and some secondary pain syndromes. Tramadol has a modest analgesic effect in osteoarthritis patients. Clinicians should always weigh the risks and benefits before prescribing tramadol. Tramadol use is discouraged in rheumatoid arthritis and chronic lumbago. Conclusions: Tramadol is a safe and effective drug if correctly indicated, administered, supervised, and discontinued. However, it may be associated with pharmacological interactions, serious side effects, abuse behaviors, and illicit uses, and it is necessary that clinicians know and manage its pharmacology and indications appropriately.

Nitric oxide and potassium channels but not opioid and cannabinoid receptors mediate tramadol-induced peripheral antinociception in rat model of paw pressure withdrawal.

Tramadol, an analgesic classified as an "atypical opioid", exhibits both opioid and non-opioid mechanisms of action. This study aimed to explore these mechanisms, specifically the opioid-, cannabinoid-, nitric oxide-, and potassium channel-based mechanisms, which contribute to the peripheral antinociception effect of tramadol, in an experimental rat model. The nociceptive threshold was determined using paw pressure withdrawal. To examine the mechanisms of action, several substances were administered intraplantarly: naloxone, a non-selective opioid antagonist (50 µg/paw); AM251 (80 µg/paw) and AM630 (100 µg/paw) as the selective antagonists for types 1 and 2 cannabinoid receptors, respectively; nitric oxide synthase inhibitors L-NOArg, L-NIO, L-NPA, and L-NIL (24 µg/paw); and the enzyme inhibitors of guanylatocyclase and phosphodiesterase of cGMP, ODQ, and zaprinast. Additionally, potassium channel blockers glibenclamide, tetraethylammonium, dequalinium, and paxillin were used. The results showed that opioid and cannabinoid receptor antagonists did not reverse tramadol's effects. L-NOarg, L-NIO, and L-NPA partially reversed antinociception, while ODQ completely reversed, and zaprinast enhanced tramadol's antinociception effect. Notably, glibenclamide blocked tramadol's antinociception in a dose-dependent manner. These findings suggest that tramadol's peripheral antinociception effect is likely mediated by the nitrergic pathway and sensitive ATP potassium channels, rather than the opioid and cannabinoid pathways.

Use of tramadol as analgesic alternative in Harris hawk (Parabuteo unicinctus).

BACKGROUND: The Harris hawk is a bird of prey susceptible to traumatic injuries because it is useful for several purposes such as conservancy, biological control and falconry. Once received in rehabilitation centres or specialized clinics, it is necessary to provide proper analgesia. OBJECTIVES: The aim of this study is to demonstrate the analgesic efficacy of tramadol in Harris hawks (PISADOL 50 PiSA Agropecuaria, S.A. de C.V. Calle 1 Norte, Manzana 2-25 Parque Industrial Tula Atitalaquia, Hgo, México), by the assessment of nociceptive threshold. METHODS: A total of 24 adult Harris hawks were selected from a rehabilitation centre. The birds were randomly divided into four groups: control (saline solution), 5.0, 15.0 and 30.0 mg/kg of intramuscular tramadol. Nociception was produced with electrical stimuli of 9 V, applied in propatagial skin at 1, 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min, assessing the nociceptive threshold and sedative effects produced by each treatment. RESULTS: No difference was observed between control and tramadol group 5 mg/kg. At 15 mg/kg, the pain threshold increased from 20 to 240 min, with minimal sedative effects. At 30 mg/kg, there was a marked increase in pain threshold from 10 to 300 min, and sedative effects like wing and head drooping for a period of 90 min. CONCLUSIONS: Tramadol can be an analgesic alternative for Harris's hawks, as it decreases the response to painful stimuli in this species when administered by intramuscular route.

Local Tramadol Improves the Anesthetic Success in Patients with Symptomatic Irreversible Pulpitis: A Meta-Analysis.

Symptomatic irreversible pulpitis is a painful clinical condition with a broad inflammatory component. Dental anesthesia in these patients is affected by the inflammatory process, reporting a high incidence of anesthesia failure. The aim of this systematic review and meta-analytical evaluation was to determine the effect of pre-treatment with tramadol in patients with symptomatic irreversible pulpitis, as well as for pain control and adverse effects. This study was registered in PROSPERO (ID: CRD42021279262). PubMed was consulted to identify clinical investigations comparing tramadol and placebo/local anesthetics in patients with symptomatic irreversible pulpitis. Data about the anesthesia, pain control, and adverse effects were extracted. Both the anesthetic success index and the adverse effects of local tramadol and placebo were compared with the Mantel−Haenszel test and odds ratio. Data analysis showed that the local administration of tramadol increased the anesthetic success rate when compared to placebo in patients with symptomatic irreversible pulpitis (n = 228; I2 = 0; OR = 2.2; 95% CIs: 1.30 to 3.79; p < 0.004). However, local administration of tramadol increased the risk of adverse effects when compared to placebo/local anesthetics (n = 288; I2 = 0; OR = 7.72; 95% CIs: 1.37 to 43.46; p < 0.02). In conclusion, this study shows that the local administration of tramadol increases the anesthetic success index when compared to placebo in patients with symptomatic irreversible pulpitis.

Establishing an anesthetic protocol for refinement of intracerebral inoculation procedure

Mouse inoculation test (MIT) is a technique widely used for rabies diagnosis and must be liable to refinement due to animal welfare. The present study aims to compare five different anesthetic associations to stablish a protocol to improve the MIT procedure suitable for animal welfare and safe for a routine of viral isolation in newly weaned mice (3 weeks of age). 80 Swiss-Webster mice (Mus musculus) - 40 females and 40 males, 3-week-old, weight ranging from 11 to 14 grams ­ were used to conduct all procedures. Five anesthetic associations were tested: KX (Ketamine 100 mg/kg and Xylazine 10 mg/kg), KXA (Ketamine 80 mg/kg, Xylazine 5 mg/kg, and Acepromazine 1 mg/kg), KXT (Ketamine 80 mg/kg, Xylazine 5 mg/kg, and Tramadol 5 mg/kg), KXAT (Ketamine 100 mg/kg, Xylazine 10 mg/kg, Acepromazine 2 mg/kg and Tramadol 5 mg/kg) and ATI (Acepromazine 1 mg/kg + Tramadol 5 mg/kg + Isoflurane 5% - 0.5 L/min for induction and 2.5% - 0.5L/min for maintenance). Injectable anesthesia was administered intraperitoneally. We monitored the respiratory rate and body temperature. Response to anesthesia was evaluated according to the induction, surgical anesthesia, and recovery periods. The KXAT and ATI protocols induced surgical anesthesia, with the ATI protocol being the most appropriate and safe to perform the MIT procedure with 100% efficiency, absence of mortality, and rapid recovery of respiratory rate and temperature in the period after the procedure.

Clinical pharmacology of tramadol and tapentadol, and their therapeutic efficacy in different models of acute and chronic pain in dogs and cats.

Opioids are considered the gold standard to manage acute or chronic or mild to severe pain. Tramadol is a widely prescribed analgesic drug for dogs and cats; it has a synthetic partial agonism on µ-opioid receptors and inhibits the reuptake of norepinephrine and serotonin. However, the biotransformation and resultant metabolites differ between species and depend on cytochrome P450 interactions. Dogs mainly produce the inactive N-desmethyl tramadol metabolite, whereas cats exhibit an improved antinociceptive effect owing to rapid active O-desmethyltramadol metabolite production and a longer elimination half-life. Tapentadol, a novel opioid with dual action on µ-receptors and noradrenaline reuptake inhibitory activity, is a promising option in dogs, as it is less reliant on metabolic activation and is unaffected by cytochrome polymorphisms. Although scientific evidence on the analgesic activity of tapentadol in both species remains limited, experimental studies indicate potential benefits in animals. This review summarizes and compares the pharmacology, pharmacokinetics, and therapeutic efficacy of tramadol and tapentadol in dogs and cats with different pain conditions. According to the available data, tramadol seems a more suitable therapeutic option for cats and should preferably be used as a component of multimodal analgesia in both species, particularly dogs. Tapentadol might possess a superior analgesic profile in small animals, but additional studies are required to comprehensively evaluate the activity of this opioid to manage pain in dogs and cats.

Kounis Syndrome: Case Report in Goiânia/BR

Abstract 22-year-old male patient with no heart disease, who was given an ambulatory medication with analgesics due to an acute renal crisis. After the drug administration, the patient presented dyspnea, cyanosis, and hemoptysis. There was suspicion of anaphylactic shock, which was treated, but there was no improvement in the clinical condition. The patient was referred to the Intensive Care Unit, where tests were performed showing elevated cardiac enzymes and Immunoglobulin E and Computed Tomography of Thoracic revealed alveolar hemorrhage. He developed clinical worsening and died after sepsis. The final diagnosis was of kounis syndrome due to the hypersensitivity reaction to the analgesics introduced in the patient, generating an acute coronary syndrome (ACS). The purpose of this case report was to highlight a syndrome that is little reported because it is not part of the differential diagnosis routines of ACS, but it generates important complications.

Safety and efficacy of "on-demand" tramadol in patients with premature ejaculation: an updated meta-analysis

ABSTRACT Introduction: Tramadol has been used for the treatment of premature ejaculation, however, the studies published for the same are not well designed. The primary objective of this study was to explore the literature pertaining to the use of tramadol in patients with PE to determine its safety and efficacy in this population. Materials ande methods: Systematic literature search of various electronic databases was conducted to include all the randomized studies and quasi-randomized studies. Standard PRISMA (Preferred reporting Items for Systematic reviews and Meta-analysis) guidelines were pursued for this review and study protocol was registered with PROSPERO (CRD42019123381). Results: Out of 9 studies included in this review, 5 were randomized controlled trials, and rests of the 4 studies were quasi-randomized studies. Tramadol resulted in significantly higher improvement of IELT with the mean difference (MD) of 139.6 seconds and confidence interval (CI) 106.5-172.6 seconds with a p-value of p <0.00001. All dosages except 25mg fared well as compared to placebo. Tramadol fared better than placebo at 1 month, 2 months, and 3 months after initiation of therapy as compared to the placebo. Tramadol group had reported a significantly higher number of adverse events with treatment as compared to placebo but none of them were serious. Conclusion: Tramadol appears to be an effective drug for the management of PE with a low propensity for serious adverse events. However, evidence obtained from this study is of low to moderate quality. Furthermore, effective dose and duration of therapy remain elusive.

Valoración del riego de adicción a tramadol en pacientes con dolor crónico no oncológico / Risk of addiction in patients with tramadol for chronic no cáncer pain

RESUMEN Objetivo El manejo del dolor crónico no oncológico con analgésicos opioides ha sido de importancia para el control de los síntomas y el restablecimiento de la actividad. Sin embargo, el riesgo de adicción asociado a estos medicamentos es ampliamente conocido y evaluado. Este estudio evalúa el riesgo de adicción que presentaban los pacientes con manejo de tramadol describiendo los factores más frecuentes en la muestra estudiada frente a lo reportado en la literatura. Métodos Una muestra de 76 pacientes de una clínica de dolor que están en manejo con tramadol se les administra un cuestionario con características demográficas y con la escala Opioid Risk Tool para el riesgo de adicción. Resultados El 57,89% de los sujetos fueron mujeres; el 55,20% se encontraba entre los 29 y 59 años. El riesgo de adicción moderado se encontró en el 9,09% de las mujeres y en el 37,05% de los hombres. La inclusión de otras enfermedades como ansiedad y trastorno de estrés postraumático aumenta el riesgo de adicción a severo en 6,06% de los hombres. Conclusiones La valoración del riesgo de adicción a opioides debe tener en cuenta los factores encontrados en la población colombiana.

ABSTRACT Objective The management of chronic non-cancer pain with opioid analgesics has been important for the control of symptoms and the restoration of activity, however, the risk of addiction associated with these drugs is widely known. This study evaluates the risk of addiction presented by patients with tramadol treatment, describing the most frequent factors in the sample studied compared to what was reported in the literature. Methods A sample of 76 patients from a pain clinic who are being managed with tramadol are administered a questionnaire with demographic characteristics and with the Opioid Risk Tool scale for the risk of addiction. Results 57.89% of the subjects were women, 55.20% were affected between 29 and 59 years. A moderate risk of addiction was found in 9.09% of women and 37.05% of men. The inclusion of other diseases such as anxiety and post-traumatic stress disorder increases the risk of addiction to severe in 6.06% of men. Conclusions The assessment of the risk of addiction to opioids must consider the factors found in the Colombian population.

The role of adenosine A1 receptor in the peripheral tramadol's effect in the temporomandibular joint of rats.

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 A1 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 A1 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 A1 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 A1 receptor, possibly expressed in macrophages in the TMJ tissue. We also determined an important discovery related to the activation of A1R/α2a receptors in the tramadol action.

Evaluación del efecto analgésico transoperatorio del tramadol comparado con la lidocaína en caninos oncológico / Assessment of the adverse effect of tramadol compared to lidocaine in the oncologic intraoperative in canines

Introducción: El estudio y tratamiento del dolor ha sido una de las preocupaciones más importantes en los últimos 30 años en el ámbito médico mundial. Desde hace varias décadas a nivel internacional se realizan estudios sobre el efecto del tramadol y la lidocaína como analgésicos intraoperatorio, con el fin de obtener una adecuada analgesia durante el procedimiento quirúrgico y el periodo posoperatorio inmediato. Objetivo: Comparar el efecto analgésico del tramadol y la lidocaína durante el período transoperatorio en caninos programados para intervención quirúrgica. Método: Se realizó un estudio prospectivo, comparativo, con animales programados para tratamiento quirúrgico por presentar tumores periféricos. Se incluyeron 10 animales divididos en 2 grupos. El grupo control (G-C) que recibió lidocaína sin preservo (lidocaína SP) en infusión continua durante el procedimiento quirúrgico y el grupo 1 (G-1) que se le administró tramadol endovenoso previo al acto quirúrgico. Se evaluaron variables hemodinámicas y de oxigenación como indicadores indirectos de dolor transoperatorio. Resultados: La muestra fue homogénea para la edad y el sexo. El comportamiento de las variables hemodinámicas resultó más estable durante la infusión de lidocaína. La saturación periférica de oxígeno fue similar con ambos medicamentos, así como la temperatura. Conclusiones: La infusión intravenosa de lidocaína SP durante el periodo transoperatorio en caninos oncológico demostró una mejor efectividad analgésica en comparación con el tramadol aplicado preoperatoriamente, según los parámetros evaluados(AU)

Introduction: Study and treatment of pain has been one of the most important concerns in the last thirty years in the worldwide medical field. For several decades, international studies have been carried out on the effect of tramadol and lidocaine as intraoperative analgesics, in order to achieve adequate analgesia during surgical procedures and the immediate postoperative period. Objective: To compare the analgesic effect of tramadol and lidocaine during the intraoperative period in canines scheduled for surgical intervention. Method: A prospective, comparative study was carried out with animals scheduled for surgical treatment due to peripheral tumors. Ten animals were included, divided into two groups: the control group, which received lidocaine without preservation in continuous infusion during the surgical procedure, and group 1, which was administered intravenous tramadol prior to the surgical act. Hemodynamic and oxygenation variables were assessed as indirect indicators of intraoperative pain. Results: The sample was homogeneous for age and sex. The behavior of the hemodynamic variables was more stable during the lidocaine infusion. Peripheral oxygen saturation was similar in both drugs, as well as temperature. Conclusions: Intravenous infusion of lidocaine without preservation during the intraoperative period in oncological canines showed better analgesic effectiveness compared to tramadol applied preoperatively, according to the parameters assessed(AU)

Intravenous magnesium sulfate for postoperative analgesia after abdominal hysterectomy under spinal anesthesia: a randomized, double-blind trial.

BACKGROUND AND OBJECTIVES: Abdominal Hysterectomy (AH) is associated with significant inflammatory response and can result in moderate to severe postoperative pain. This study aimed to evaluate the efficacy of magnesium infusion in reducing postoperative pain and analgesic consumption after AH under spinal anesthesia with Intrathecal Morphine (ITM). METHOD: Eighty-six patients were included in this clinical, controlled, randomized, double-blind study. Patients received in Group Mg, MgSO4 50mgkg-1 for 15 minutes followed by 15 mgkg-1h-1 until the end of the surgery; and in Group C, (control) the same volume of isotonic saline. Both groups received 100µg of ITM. All patients received dipyrone+ketoprofen intraoperatively and postoperatively, and dexamethasone intraoperatively only. We evaluated the intensity of pain, tramadol consumption, and adverse events 24hours postoperatively. RESULTS: Serum magnesium concentrations were higher in Group Mg at the end, and one hour after the operation (p=0.000). Postoperative pain scores were reduced in Group Mg at 6 hours at rest and on movement (p<0.05). Tramadol consumption did not show a statistically significant difference between Group Mg and Group C (15.5±36.6mg and 29.2±67.8mg respectively, p=0.53). Hemodynamic variables, the incidence of pruritus, nausea, and vomiting were similar in the two groups. CONCLUSION: Infusion of MgSO4 during AH undergoing spinal anesthesia with ITM reduced at 6 hours at rest and on movement. More studies should be performed to evaluate the potential antinociceptive effect of MgSO4 in scenarios where a multimodal analgesia approach was employed.

Safety and efficacy of "on-demand" tramadol in patients with premature ejaculation: an updated meta-analysis.

INTRODUCTION: Tramadol has been used for the treatment of premature ejaculation, however, the studies published for the same are not well designed. The primary objective of this study was to explore the literature pertaining to the use of tramadol in patients with PE to determine its safety and efficacy in this population. Materials ande methods: Systematic literature search of various electronic databases was conducted to include all the randomized studies and quasi-randomized studies. Standard PRISMA (Preferred reporting Items for Systematic reviews and Meta-analysis) guidelines were pursued for this review and study protocol was registered with PROSPERO (CRD42019123381). RESULTS: Out of 9 studies included in this review, 5 were randomized controlled trials, and rests of the 4 studies were quasi-randomized studies. Tramadol resulted in significantly higher improvement of IELT with the mean difference (MD) of 139.6 seconds and confidence interval (CI) 106.5-172.6 seconds with a p-value of p < 0.00001. All dosages except 25mg fared well as compared to placebo. Tramadol fared better than placebo at 1 month, 2 months, and 3 months after initiation of therapy as compared to the placebo. Tramadol group had reported a significantly higher number of adverse events with treatment as compared to placebo but none of them were serious. CONCLUSION: Tramadol appears to be an effective drug for the management of PE with a low propensity for serious adverse events. However, evidence obtained from this study is of low to moderate quality. Furthermore, effective dose and duration of therapy remain elusive.

Poisoning in domestic cats in Brazil: toxicants, clinical signs, and therapeutic approaches / [Intoxicação em gatos domésticos no Brasil: toxicantes, sinais clínicos e abordagens terapêuticas]

This study evaluated the most common toxic agents affecting domestic cats, the clinical signs of toxicity, and the therapeutic approaches for recovery. A survey on poisoning in cats was conducted among small animal veterinary practitioners from 2017 to 2018. Of the 748 completed questionnaires, 543 (72.6%) were evaluated. Pesticides and household cleaning supplies were the most common causes of poisoning in cats. The toxicant groups included pesticides and household cleaning supplies (organophosphates), human drugs (acetaminophen), plants/plant derivatives (lily), and veterinary drugs (tramadol). The major clinical signs for these four groups of toxicants were (1) acetaminophen poisoning, which caused oxidative erythrocyte damage; (2) muscarinic and nicotinic cholinergic syndrome, which resulted from organophosphate poisoning; (3) acute kidney injury, which resulted from intoxication of lily; and (4) serotonin syndrome, which resulted from tramadol toxicosis. Interventions for treating poisoning in cats were based on the clinical presentation of animals. In the present study, the significant toxins identified to be dangerous for cats were characterized using the obtained data in Brazil as well as the main associated clinical signs and therapy recommended by veterinarians.(AU)

Objetiva-se com este trabalho caracterizar os principais toxicantes para gatos domésticos, bem como os prevalentes sinais clínicos e a terapêutica associada. Uma pesquisa sobre envenenamento em gatos foi realizada entre médicos veterinários no período de 2017 a 2018. Dos 748 questionários preenchidos, 543 (72,6%) foram avaliados. Pesticidas e domissanitários foram os principais causadores de intoxicação em gatos. Entre os grupos tóxicos, destacaram-se, na categoria pesticidas e domissanitários (organofosforados), medicamentos humanos (acetaminofeno), plantas e derivados de planta (lírio) e medicamentos veterinários (tramadol). Os principais sinais clínicos para os quatro grupos de substâncias tóxicas foram: (1) intoxicação por acetaminofeno, que causou dano eritrocitário oxidativo; (2) síndrome colinérgica muscarínica e nicotínica, resultante do envenenamento por organofosforado; (3) lesão renal aguda, causada pela intoxicação por lírio; e (4) síndrome serotoninérgica, resultante da exposição ao tramadol. As intervenções realizadas para o tratamento dos envenenamentos foram justificáveis mediante a apresentação clínica dos animais. Por meio dos dados obtidos, puderam-se caracterizar os principais tóxicos para gatos no Brasil, bem como os principais sinais clínicos associados e a terapêutica preconizada pelos médicos veterinários.(AU)

Pharmacokinetic properties of tramadol and M1 metabolite in Northeast Brazilian donkeys (Equus asinus).

There is currently little information available on the pharmacokinetics and pharmacodynamics of the analgesic opioid tramadol when used in the veterinary medicine of domestic species. In this study, we aimed to determine the pharmacokinetics of tramadol and its active metabolite M1 following intravenous administration of 2 (T2) and 4 (T4) mg/kg to Northeast Brazilian donkeys. Tramadol and M1 plasma levels were quantified using a validated liquid chromatography-tandem mass spectrometry method. We found that plasma levels of tramadol and M1 were higher than those reported as clinically meaningful in humans for at least 3 hr. However, the pharmacokinetic parameter calculation corrected by dose analysis identified no proportional increase with dose for the AUC of tramadol (T2: 2,663 ± 1,827 vs. T4: 2,964 ± 1,038 ng*h/ml) and M1 (T2: 378 ± 237 vs. T4: 345 ± 142 ng*h/ml). This finding appears to be attributable to a significant increase in clearance and a reduction in the terminal half-life of tramadol. The frequency of adverse effects observed at the higher dose indicates that 2 mg/kg administered intravenously would be suitable for donkeys. Clinical studies are required to determine the implications of these observations regarding the pharmacodynamic response to tramadol in Northeast Brazilian donkeys.

Skills and practices of pharmacy staff for dispensing of drugs with fiscalized substances in drugstores and pharmacies

ABSTRACT OBJETIVE To evaluate the skills and practices of pharmacy staff during the dispensing of tramadol (drug with fiscalized substance) in drugstores and pharmacies in Medellin, Colombia. METHODS A cross-sectional study was performed. The simulated patient technique was used. The main outcomes included the information provided on the dispensed drug (tramadol), the use of tools to provide information, and the information provided on drug precautions and use recommendations. RESULTS We visited 305 drugstores and pharmacies. The average dispensing time was 2.3 min (SD 1.1 min). In nine drugstores and pharmacies (3.0%), tramadol was not dispensed because it was not in stock. In 17 drugstores and pharmacies (5.7%), the simulated patients were actively informed by the dispensing pharmacy staff; of these, 16 provided oral information and one provided oral and written information. Eight patients (2.7%) received information regarding tramadol use. However, 99% of patients were not informed about tramadol side effects such as dependence, sedation, or hypnosis, and none of the simulated female patients were informed on the precautions related to tramadol use during pregnancy or lactation. CONCLUSIONS Communication skills and appropriate practices of pharmacy staff are critical to patient self-care. However, this study shows their difficulty in counseling about precautions and use recommendations of drugs with fiscalized substances. These outcomes could inform future studies focusing on the rational use of these drugs in drugstores and pharmacies. It is necessary to improve the pharmacy staff competencies through continuing education programs, to facilitate access to information and training.

Efficacy and Safety of Two Fixed-Dose Combinations of Tramadol Hydrochloride and Diclofenac Sodium in Postoperative Dental Pain.

OBJECTIVE: To evaluate the analgesic efficacy and safety of tramadol hydrochloride/diclofenac sodium fixed-dose combination 25 mg/25 mg (FDC 25/25) and 50 mg/50 mg (FDC 50/50) vs tramadol 50 mg (T50) and diclofenac 50 mg (D50) monotherapies in acute postoperative dental pain. SETTING: Eight sites across Mexico. SUBJECTS: Adults (N = 829) with moderate to severe pain after third molar extraction. DESIGN: Prospective, randomized, double-blind, diclofenac- and tramadol-controlled, parallel-group, noninferiority, phase 3 trial. METHODS: Subjects were randomized to receive three doses (one every eight hours) of oral FDC 25/25, FDC 50/50, T50, or D50 over a 24-hour period. Pain intensity and pain relief were evaluated frequently over the 24 hours postdose. Secondary measures included peak pain relief, onset, and duration of effect. The primary objective was to compare the analgesic efficacy and safety of FDC 50/50 or analgesic noninferiority of FDC 25/25 vs D50 or T50. The primary efficacy end point was total pain relief over four hours after dose 1 (TOTPAR4). RESULTS: TOTPAR4 scores showed that FDC 25/25 was noninferior (P < 0.0001, delta = 1.5) and FDC 50/50 was superior (P < 0.0001) to the individual components. All secondary efficacy measures supported these results. The safety profile of FDC 25/25 and FDC 50/50 was consistent with the known safety profile of D50 and T50 monotherapies, with no unexpected safety findings observed. CONCLUSIONS: Tramadol/diclofenac FDC 25/25 and FDC 50/50 provide superior analgesia for acute pain after third molar extraction than either of the individual components. Minor adverse effects appeared to be related to the higher doses of tramadol.