Opioids in the immune system: from experimental studies to clinical practice

SUMMARY INTRODUCTION: Opioids interact with both innate and adaptive immune systems and have direct effects on opioid receptors located on immune cells. Research on this topic has provided evidence of the opioid influence on the immune response associated with surgical stress. The immunological effects of opioids are currently being investigated, particularly whether they influence the outcome of surgery or the underlying disease regarding important aspects like infection or cancer progression. This review addresses background research related to the influence of the opioid receptor on the immune system, the immunosuppressive effect associated with major opioids during the perioperative period, and their clinical relevance. The objective of the study was to review the effects of opioids on the immune system. Methods: A search strategy was conducted in PubMed, Embase, and the Cochrane databases using the terms "immunosuppression," "immune system," "surgical procedures," "analgesics," "opioids" and "perioperative care." Results: The immunosuppressive effect of opioids was identified over 30 years ago. They include signaling and acting directly through immune cells, including B and T lymphocytes, NK cells, monocytes, and macrophages, as well as activating the downstream pathways of the hypothalamic-pituitary-adrenal (HPA) axis leading to the production of immunosuppressive glucocorticoids in the peripheral and sympathetic nervous system.

RESUMO INTRODUÇÃO: Os opioides interagem com ambos os sistemas imunes, inato e adaptativo, através de efeitos diretos sobre os receptores dos opioides localizados nas células imunes. As pesquisas neste assunto têm fornecido evidência da influência dos opioides sobre a resposta imune associada ao estresse cirúrgico. Os efeitos imunológicos dos opioides estão sendo pesquisados na atualidade, principalmente se eles determinam o resultado da cirurgia ou doença consequente devido a fatos importantes como infecção ou progressão do câncer. Essa revisão tem como alvo ver antecedentes em pesquisa relativa à influência dos receptores dos opioides no sistema imunológico, o efeito imunossupressor associado com opioides maiores durante o período peri-operatório e sua importância clínica. O objectivo da pesquisa foi revisar os efeitos dos opioides no sistema imunológico. MÉTODOS: Uma estrategia de procura foi dirigida na mídia PubMed, e no cadastro de Embase e The Cochrane, usando os termos "imunosuppressão", "sistema imunológico", "procedimentos cirúrgicos", "analgésicos", "opioides" e "cuidado peri-operatório". RESULTADOS: O efeito imunosuppressor dos opioides foi identificado há mais de 30 anos. Os efeitos imunosupressores incluem sinalização e ação diretamente através das células imunes, mesmo com os linfócitos B e T, células NK, monócitos e macrófagos, também como ativando as vias de corrente do eixo hipotálamo- hipófise- adrenal (HPA) levando à produção de glucocorticoides imunossupresores no sistema nervoso periférico e simpático.

Influence of tramadol on functional recovery of acute spinal cord injury in rats

Abstract Purpose: To evaluate the influence tramadol on functional recovery of acute spinal cord injury in rats. Methods: Ten rats were divided into two groups (n = 5). All animals were submitted by a laminectomy and spinal cord injury at eighth thoracic vertebra. In control group, the rats didn't receive any analgesic. In tramadol group, the rats received tramadol 4mg/Kg at 12/12h until 5 days by subcutaneous. Animals were following by fourteen days. Was evaluated the Basso, Beattie, Bresnahan scale (locomotor evaluation) and Rat Grimace Scale (pain evaluation) at four periods. Results: There no difference between the groups in locomotor evaluation in all periods evaluated (p>0.05) and in both groups there was a partial recover of function. The tramadol group show a lower pain levels at the first, third and seventh postoperatively days when comparing to the control group. Conclusion: The tramadol as an analgesic agent don't influence on functional recovery of acute spinal cord injury in rats

Analgesic effects of Marasmius androsaceus mycelia ethanol extract and possible mechanisms in mice

Marasmius androsaceus is a medicinal fungus mainly used to treat various forms of pain in China. This study investigated the analgesic effects of an ethanol extract of M. androsaceus (MAE) and its potential molecular mechanisms. Oral administration of MAE (50, 200, and 1000 mg/kg) had significant analgesic effects in an acid-induced writhing test, a formalin test, and a hot-plate test, with effectiveness similar to tramadol (the positive control drug). The autonomic activity test showed that MAE had no harmful effects on the central nervous system in mice. MAE resulted in significantly enhanced levels of noradrenalin and 5-hydroxytryptamine in serum but suppressed both of these neurotransmitters in the hypothalamus after 30 s of hot-plate stimulation. Co-administration with nimodipine (10 mg/kg; a Ca2+ channel blocker) strongly enhanced the analgesic effect in the hot-plate test compared to MAE alone. Moreover, MAE down-regulated the expression of calmodulin-dependent protein kinase II (CaMKII) in the hypothalamus after a 30-s thermal stimulus. These results suggested that the analgesic ability of MAE is related to the regulation of metabolism by monoamine neurotransmitters and Ca2+/CaMKII-mediated signaling, which can potentially aid the development of peripheral neuropathic pain treatments obtained from M. androsaceus.

Influence of remote ischemic conditioning and tramadol hydrochloride on oxidative stress in kidney ischemia/reperfusion injury in rats

Abstract Purpose: To evaluate the effects of tramadol hydrochloride associated to remote ischemic perconditioning on oxidative stress. Methods: Twenty five male rats (Wistar) underwent right nephrectomy and were distributed into five groups: Sham group (S); Ischemia/Reperfusion group (I/R) with 30 minutes of renal ischemia; Remote ischemic perconditioning group (Per) with three cycles of 10 minutes of I/R performed during kidney ischemia; Tramadol group (T) treated with tramadol hydrochloride (40mg/kg); remote ischemic perconditioning + Tramadol group (Per+T) with both treatments. Oxidative stress was assessed after 24 hours of reperfusion. Results: Statistical differences were observed in MDA levels between I/R group with all groups (p<0.01), in addition there was difference between Tramadol with Sham, Per and Per+T groups (p<0.05), both in plasma and renal tissue. Conclusion: Remote ischemic perconditioning was more effective reducing renal ischemia-reperfusion injury than administration of tramadol or association of both treatments.

Analgesia en primigesta en trabajo de parto con Clorhidrato de Tramadol IM, desde 1 de septiembre de 2013 a 28 de febrero de 2014. Hospital Boliviano Holandés (H.M.B.H.) / Analgesia in primigravida in labor with tramadol hydrochloride IM, from September 1, 2013 to February 28, 2014. Hospital Bolivian Dutch (H.M.B.H.)

Introducción: el trabajo de parto es generalmente un acontecimiento doloroso, 75% de las primigestas en trabajo de parto pueden llegar a presentar dolor intenso asociado con aumento de la presión arterial, el consumo de oxígeno y producen la liberación de catecolaminas que pueden afectar el flujo sanguíneo uterino y comprometer al feto...

Introduction: the labor is usually a painful event; 75% of first time pregnant women in labor could contain intense pain associated with increased blood pressure, oxygen consumption and produce catecholamine release that may affect the flow Uterine blood and engage the fetus...

Tramadol Alleviates Myocardial Injury Induced by Acute Hindlimb Ischemia Reperfusion in Rats / Tramadol Atenua Lesões Miocárdicas Induzidas pela Reperfusão Pós- Isquêmica Aguda de Membros Posteriores em Ratos

AbstractBackground:Organ injury occurs not only during periods of ischemia but also during reperfusion. It is known that ischemia reperfusion (IR) causes both remote organ and local injuries.Objective:This study evaluated the effects of tramadol on the heart as a remote organ after acute hindlimb IR.Methods:Thirty healthy mature male Wistar rats were allocated randomly into three groups: Group I (sham), Group II (IR), and Group III (IR + tramadol). Ischemia was induced in anesthetized rats by left femoral artery clamping for 3 h, followed by 3 h of reperfusion. Tramadol (20 mg/kg, intravenous) was administered immediately prior to reperfusion. At the end of the reperfusion, animals were euthanized, and hearts were harvested for histological and biochemical examination.Results:The levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were higher in Groups I and III than those in Group II (p < 0.05). In comparison with other groups, tissue malondialdehyde (MDA) levels in Group II were significantly increased (p < 0.05), and this increase was prevented by tramadol. Histopathological changes, including microscopic bleeding, edema, neutrophil infiltration, and necrosis, were scored. The total injuryscore in Group III was significantly decreased (p < 0.05) compared with Group II.Conclusion:From the histological and biochemical perspectives, treatment with tramadol alleviated the myocardial injuries induced by skeletal muscle IR in this experimental model.

ResumoFundamento:Lesões a órgãos ocorrem não apenas durante períodos de isquemia, mas paradoxalmente, também durante a reperfusão. Sabe-se que a reperfusão pós-isquêmica (RPI) causa lesões tanto remotas quanto locais no órgão afetado.Objetivo:Este estudo avaliou os efeitos do tramadol no coração como órgão remoto, após RPI aguda dos membros posteriores.Métodos:Trinta ratos Wistar, machos, adultos e saudáveis, foram distribuídos aleatoriamente em três grupos: Grupo I (controle), Grupo II (RPI) e Grupo III (RPI + tramadol). Isquemia foi induzida em ratos anestesiados através do pinçamento da artéria femoral esquerda por 3 horas, seguidas de 3 horas de reperfusão. Tramadol foi administrado (20 mg/kg, IV) imediatamente antes da reperfusão. Ao final da reperfusão, os animais foram sacrificados e seus corações coletados para exames histológicos e bioquímicos.Resultados:Os níveis de superóxido-dismutase (SOD), catalase (CAT) e glutationa-peroxidase (GPx) foram maiores nos grupos I e III que no grupo II (p < 0.05). Em comparação aos outros grupos, os níveis tissulares de malondialdeído (MDA) estavam significativamente mais elevados no grupo II (p < 0.05), o que foi evitado pelo uso de tramadol. Foram pontuadas as alterações histopatológicas, incluindo micro-hemorragia, edema, infiltração por neutrófilos e necrose. A pontuação total das lesões do grupo III foi significativamente menor (p < 0.05) em comparação ao grupo II.Conclusão:Do ponto de vista histológico e bioquímico, o tratamento com tramadol diminuiu as lesões miocárdicas induzidas pela RPI da musculatura esquelética neste modelo experimental.

Local analgesic effect of tramadol is not mediated by opioid receptors in early postoperative pain in rats / O efeito analgésico de tramadol não é mediado por receptores opioides na dor de ratos no pós-operatório imediato / El efecto analgésico del tramadol no está mediado por receptores opiáceos en el dolor en ratones en el postoperatorio inmediato

BACKGROUND AND OBJECTIVES: Tramadol is known as a central acting analgesic drug, used for the treatment of moderate to severe pain. Local analgesic effect has been demonstrated, in part due to local anesthetic-like effect, but other mechanisms remain unclear. The role of peripheral opioid receptors in the local analgesic effect is not known. In this study, we examined role of peripheral opioid receptors in the local analgesic effect of tramadol in the plantar incision model. METHODS: Young male Wistar rats were divided into seven groups: control, intraplantar tramadol, intravenous tramadol, intravenous naloxone-intraplantar tramadol, intraplantar naloxone-intraplantar tramadol, intravenous naloxone-intravenous tramadol, and intravenous naloxone. After receiving the assigned drugs (tramadol 5 mg, naloxone 200 µg or 0.9% NaCl), rats were submitted to plantar incision, and withdrawal thresholds after mechanical stimuli with von Frey filaments were assessed at baseline, 10, 15, 30, 45 and 60 min after incision. RESULTS: Plantar incision led to marked mechanical hyperalgesia during the whole period of observation in the control group, no mechanical hyperalgesia were observed in intraplantar tramadol group, intraplantar naloxone-intraplantar tramadol group and intravenous naloxone-intraplantar tramadol. In the intravenous tramadol group a late increase in withdrawal thresholds (after 45 min) was observed, the intravenous naloxone-intravenous tramadol group and intravenous naloxone remained hyperalgesic during the whole period. CONCLUSIONS: Tramadol presented an early local analgesic effect decreasing mechanical hyperalgesia induced by plantar incision. This analgesic effect was not mediated by peripheral opioid receptors. .

JUSTIFICATIVA E OBJETIVOS: Tramadol é conhecido como um fármaco analgésico de ação central, usado para o tratamento de dor moderada a grave. O efeito analgésico local foi demonstrado, em parte devido ao efeito semelhante ao anestésico local, mas outros mecanismos permanecem obscuros. O papel dos receptores opioides periféricos no efeito analgésico local não é conhecido. Neste estudo, examinamos o papel dos receptores opioides periféricos no efeito analgésico local de tramadol em modelo de incisão plantar. MÉTODOS: Ratos Wistar, jovens e machos, foram divididos em sete grupos: controle, tramadol intraplantar, tramadol intravenoso, tramadol intraplantar-naloxona intravenosa, tramadol intraplantar-naloxona intraplantar, tramadol intravenoso-naloxona intravenosa e naloxona intravenosa. Após receber os medicamentos designados (5 mg de tramadol, 200 mg de naloxona ou NaCl a 0,9%, os ratos foram submetidos à incisão plantar e os limiares de retirada após estímulos mecânicos com filamentos de von Frey foram avaliados no início do estudo e nos minutos 10, 15, 30, 45 e 60 após a incisão. RESULTADOS: A incisão plantar levou à hiperalgesia mecânica acentuada durante todo o período de observação no grupo controle; hiperalgesia mecânica não foi observada nos grupos tramadol intraplantar, tramadol intraplantar-naloxona intraplantar e tramadol intraplantar-naloxona intravenosa. No grupo tramadol intravenoso, um aumento tardio do limiar de retirada (após 45 minutos) foi observado. Os grupos tramadol intravenoso-naloxona intravenosa e naloxona intravenosa permaneceram hiperalgésicos durante todo o período. CONCLUSÕES: Tramadol apresentou efeito analgésico local inicial e diminuiu a hiperalgesia mecânica induzida pela incisão plantar. Esse efeito analgésico não foi mediado por receptores opioides periféricos. .

JUSTIFICACIÓN Y OBJETIVOS: Al tramadol se le conoce como un medicamento analgésico de acción central usado para el tratamiento del dolor moderado a intenso. El efecto analgésico local quedó demostrado, en parte, a causa del efecto similar al del anestésico local, pero otros mecanismos permanecen sin clarificar. El rol de los receptores opiáceos periféricos en el efecto analgésico local no se conoce. En este estudio, examinamos el papel de los receptores opiáceos periféricos en el efecto analgésico local del tramadol en un modelo de incisión plantar. MÉTODOS: Ratones Wistar, jóvenes y machos, fueron divididos en 7 grupos: control, tramadol intraplantar, tramadol intravenoso, tramadol intraplantar-naloxona intravenosa, tramadol intraplantar-naloxona intraplantar, tramadol intravenoso-naloxona intravenosa, y naloxona intravenosa. Después de recibir los medicamentos designados (5 mg de tramadol, 200 µg de naloxona o NaCl al 0,9%), los ratones fueron sometidos a la incisión plantar, y los umbrales de retirada de la pata posteriores a los estímulos mecánicos con filamentos de von Frey fueron evaluados al inicio del estudio y en los minutos 10, 15, 30, 45 y 60 después de la incisión. RESULTADOS: La incisión plantar conllevó hiperalgesia mecánica acentuada durante todo el período de observación en el grupo control; la hiperalgesia mecánica no fue observada en los grupos tramadol intraplantar, tramadol intraplantar-naloxona intraplantar, y tramadol intraplantar-naloxona intravenosa. En el grupo tramadol intravenoso, fue observado un aumento tardío del umbral de retirada (después de 45 min); los grupos tramadol intravenoso-naloxona intravenosa y naloxona intravenosa permanecieron hiperalgésicos durante todo el período. CONCLUSIONES: El tramadol presentó un efecto analgésico local inicial, disminuyendo la hiperalgesia mecánica inducida por la incisión plantar. Ese efecto analgésico no fue mediado por receptores opiáceos periféricos. .

Effects of opioids on local anesthesia in the rat: a codeine and tramadol study

Opioids are central analgesics that act on the CNS (central nervous system) and PNS (peripheral nervous system). We investigated the effects of codeine (COD) and tramadol (TRAM) on local anesthesia of the sciatic nerve. Eighty Wistar male rats received the following SC injections in the popliteal fossa: local anesthetic with epinephrine (LA); local anesthetic without vasoconstrictor (LA WV); COD; TRAM; LA + COD; LA + TRAM; COD 20 minutes prior to LA (COD 20' + LA) or TRAM 20 minutes prior to LA (TRAM 20' + LA). As a nociceptive function, the blockade was considered the absence of a paw withdraw reflex. As a motor function, it was the absence of claudication. As a proprioceptive function, it was the absence of hopping and tactile responses. All data were compared using repeated-measures analysis of variance (ANOVA). Opioids showed a significant increase in the level of anesthesia, and the blockade duration of LA + COD was greater than that of the remaining groups (p < 0.05). The associated use of opioids improved anesthesia efficacy. This could lead to a new perspective in controlling dental pain.

Can you stop this shivering, doctor?

Postoperative shivering and feeling of cold associated with it is rated as worse than pain by some patients. It has been a problem not only after general anesthesia, but also during and after spinal anesthesia. This editorial compliments an original article in this issue of 'Anesthesia, Pain and Intensive Care' on comparison of three different drugs for the treatment of postoperative shivering, and draws attention towards pathogenesis of shivering and its control. Shivering is not a point in time event and its cessation with pharmacological intervention does not guarantee against its recurrence

Effect of addition of tramadol to one MAC sevoflurane on the haemodynamic response to laryngoscopy and tracheal intubation

To evaluate the effect of tramadol 2 mg/kg on haemodynamic response to tracheal intubation where the end tidal concentration of sevoflurane was kept constant at 1 MAC [2%]. study Design: Double blind randomized controlled trial. The Aga Khan University Hospital, Karachi, from January 2009 to April 2009. Thirty-four patients scheduled for surgery under general anaesthesia were randomly allocated to two groups, sevoflurane alone [2%] or sevoflurane [2%] and tramadol [2 mg/kg] combination. Anaesthesia was induced with thiopentone and atracurium and with either tramadol or placebo according to group allocation. Sevoflurane was administrated along with N2O and oxygen through the face mask till end tidal minimum alveolar concentration [MAC] of one [2%] was achieved. Haemodynamic changes were noted at 1, 2 and 3 minutes post induction and every minute upto 7 minutes post-intubation and compared with baseline values. A significant difference in heart rate was seen at 2 and 3 minutes post-induction and 1, 2 and 3 minutes postintubation between two groups with values higher in sevoflurane alone group. No significant difference was seen in systolic, diastolic, and mean blood pressure compared to baseline between the two groups. HR and SBP values following laryngoscopy and tracheal intubation in both groups were less than 20% of baseline. Addition of tramadol 2 mg/kg to 1 MAC sevoflurane displayed further depression of chronotropic response to laryngoscopy and intubation as compared to sevoflurane alone following thiopentone and atracurium induction

Effects of tramadol versus indomethacin on gastric mucosa in rat model of nociception: a structural, immunohistochemical and hormonal study

Background: Tramadol is centrally acting analgesic that is frequently used clinically but its mechanism of action is still unclear

Aim of work: To evaluate tramadol analgesic activity, and its effect on gastric mucosa and hormones

Material and Methods: Thirty two adult male albino rats were used. Rats were divided into three groups: group [I] was injected with 3 doses of physiological saline [2ml kg[-1] every 12 h, i.p.], served as control; group [II] was injected with 3 doses of indomethacin [10 mg kg[-1] every 12 h, i.p.]; and group [III] was injected with 3 doses of tramadol [10 m kg[-1] every 12 h, i.p.]. 30 min after the first dose of injections, all groups were given 10 ml k[-1] of 1% acetic acid-saline i.p. to induce writhing. After 10 min following acetic acid injection, writhes numbers were counted over 20 min. Gastric mucosa was examined macroscopically and microscopically. Gastrin expression was detected by immunohistochemistry. Serum prostaglandin [PG], E2, ghrelin, and histamine concentrations were measured using ELISA kits

Results: Tramadol has lower analgesic effect compared to indomethacin. The gastric ulcer index was significantly lower in tramadol- versus indomethacin-treated group [P <0.0001]. Immunohistochemistry demonstrated higher gastrin immunoreactivity in indomethacin- and tramadol-treated groups versus control. Ghrelin serum levels were significantly suppressed by tramadol and indomethacin versus control that were coincident with gastric mucosal lesions. No significant changes in serum levels of PGE2 and histamine were obtained

Conclusion: Our results suggested that tramadol-induced gastric lesions are probably mediated by reduction of ghrelin and increase in gastrin expression. The antinociceptive and gastric effects of tramadol suggest that tramadol is relatively safe clinically in pain therapy

[Comparison of the effects of chronic administration of morphine and tramadol in infancy on acute pentylenetetrazol-induced seizure in prepubertal rats]

It is demonstrated that morphine and tramadol affects seizure but the mode of action of these drugs on seizure has not been compared yet with increasing of age. The aim of this study was to compare the impact of exposure to these drugs on Pentylenetetrazol-induced seizure in immature rat. Male neonate rats were randomly chosen and divided into three groups namely Saline [n=21], Morphine [n=12] and Tramadol [n=13]. On postnatal days 8-14, Saline group received normal saline and two other groups received morphine and tramadol with additive doses, respectively. On postnatal days 22-28, the saline treated rats divided into three subgroups and received saline [n=8], morphine [n=8] or tramadol [n=5]. Morphine treated rats received saline or morphine [each n=6], and tramadol treated rats received saline [n=7] or tramadol [n=6]. At postnatal day 29, they were evaluated for PTZ-induced seizure. Number of tonic-clonic seizure was increased in all groups compared with control and tramadol+saline groups [P<0.05]. Duration of tonic-clonic seizure was decreased in tramadol+saline group compared with other tramadol groups [P<0.05]. Latency of tonic-clonic seizurewas decreased in tramadol+saline group compared with control rats [P<0.05], But it was increased in saline+tramadol group compared with other groups except to saline group [P<0.05]. Latency of myoclonic contractions in saline+morphine and saline+tramadol groups was lower than in control rats [P<0.05]. Similar age-related changes may occur inchronic exposure to morphine and tramadol in the neonatal period which leads to an increase in severity of seizures in rats on postnatal days 22-28. The effect of morphine and tramadol does not show any significant difference

Evaluation of antinociceptive effect of pregabalin in mice and its combination with tramadol using tail flick test

The development of combination therapy is a coherent approach in severe pain treatment. The present study investigated the antinociceptive effect of pregabalin alone and in combination with tramadol in acute pain modeling. Therefore, three groups of male mice received either pregabalin [1 to 400 mg/Kg], tramadol [10 to 80 mg/Kg] or their combination intraperitoneally. Then latency time, maximum possible effect [%MPE] and area under curve [AUC] were calculated in tail flick test. The antinociceptive indexes were significantly increased in10, 100 and 200 mg/kg of pregabalin while tramadol showed dose-dependent antinociception [effective dose 50% was 54 to 79 mg/Kg]. The antinociceptive effect of 100 mg/Kg of pregabalin [%MPE = 35 +/- 4%] was similar to that of 50 mg/Kg of tramadol. The combination of non-analgesic doses [10 mg/Kg] of tramadol and pregabalin did not increase%MPE and AUC, but the co-administration of 30 mg/Kg of tramadol with pregabalin [10 mg/Kg] increased all antinociceptive indexes significantly compared to the controls and with each drug alone. In conclusion, pregabalin showed a comparable antinociceptive effect to tramadol. The increase in analgesic effect was observed after the combination of low analgesic doses of tramadol with pregabalin, while the combination of non-analgesic doses of each drug reversed the interaction to antagonism. Therefore to increase the analgesic effect in pain management, more attention should be paid to respecting right proportion of drug combination. Further studies that specify the mechanism[s] and statement of interaction are needed to expand these findings to clinical applications

Comparação dos efeitos da infiltração com bupivacaína, lidocaína e tramadol na cicatrização de feridas em ratos / Comparison of the effects of bupivacaine, lidocaine, and tramadol infiltration on wound healing in rats / Comparación de los efectos de la infiltración con bupivacaína, lidocaína y tramadol en la cicatrización de heridas en ratones

JUSTIFICATIVA E OBJETIVOS: O objetivo deste estudo foi o de investigar os efeitos da solução salina, da bupivacaína, lidocaína e da infiltração de tramadol na cicatrização de feridas em ratos. MÉTODOS: Trinta e dois ratos Wistar machos albinos foram alocados aleatoriamente em quatro grupos, que receberam 3 mL de solução salina no grupo controle (Grupo C, n = 8); 3 mL de lidocaína a 2% (Grupo L, n = 8); 3 mL de bupivacaína a 0,5% (Grupo B, n = 8) e 3 mL de tramadol a 5% (Grupo T, n = 8). As medidas de tensão de ruptura, contagem de fibras de colágeno e avaliação histopatológica foram avaliadas nas amostras de tecido retiradas dos ratos. RESULTADOS: A comparação do grupo controle com os grupos onde bupivacaína e lidocaína foram usadas para infiltração da ferida mostrou que nestes últimos a produção de colágeno foi menor e a resistência na tensão de ruptura, enquanto se observou edema mais intenso, vascularização e escores de inflamação significantes (p < 0,0125). Entre o grupo controle e o grupo tramadol não houve diferenças significativas na produção de colágeno, tensão de ruptura e edema, vascularização, e escores de inflamação (p > 0,0125). CONCLUSÃO: Neste estudo, verificou-se que tanto bupivacaína como lidocaína reduziram a produção de colágeno, resistência à ruptura da cicatriz e causaram edema, vascularização e inflamação significantes quando comparadas com o grupo controle. Não houve diferença significativa entre os grupos controle e tramadol para estas variáveis. Os resultados deste estudo experimental preliminar em ratos indicam que o tramadol pode ser utilizado para a anestesia por infiltração em incisões sem efeitos adversos sobre o processo de cicatrização cirúrgica. Estes resultados precisam ser verificados em seres humanos.

BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the effects of saline solution, bupivacaine, lidocaine and tramadol infiltration on wound healing in rats. METHOD: Thirty-two male Wistar Albino rats were randomly separated into four groups, receiving 3 mL saline solution in control group (Group C, n = 8), 3 mL of 2% lidocaine in lidocaine group (Group L, n = 8), 3 mL of 0.5% bupivacaine in bupivacaine group (Group B, n = 8), and 3 mL of 5% tramadol in tramadol group (Group T, n = 8). Breaking-strength measurements, collagen bundle counting, and histopathologic evaluation were evaluated in the tissue samples taken from the rats. RESULTS: Comparing the control group with the groups where bupivacaine and lidocaine were used for wound infiltration, collagen production was lower, breaking-strength measurements showed reduced resistance while significantly high edema, vascularity, inflammation scores were found (p < 0.0125). Between the control and the tramadol group there were no significant differences in collagen production, breaking-strength measurements, and edema, vascularity, inflammation scores (p > 0.0125). CONCLUSION: In our study, we found bupivacaine and lidocaine reduced the collagen production, wound breaking strength, and caused significantly high scores for edema, vascularity, and inflammation when compared to the control group. There was no significant difference between the control and the tramadol group. Results of this experimental preliminary study on rats support the idea that tramadol can be used for wound infiltration anesthesia without adverse effect on the surgical healing process. These results need to be verified in humans.

JUSTIFICATIVA Y OBJETIVOS: El objetivo de este estudio fue investigar los efectos de la solución salina, de la bupivacaína, lidocaína y de la infiltración de tramadol en la cicatrización de heridas en ratones. MÉTODOS: Treinta y dos ratones Wistar machos albinos fueron ubicados aleatoriamente en cuatro grupos que recibieron 3 mL de solución salina en el grupo control (grupo C, n = 8); 3 mL de lidocaína al 2% (grupo L, n = 8); 3 mL de bupivacaína al 0,5% (grupo B, n = 8) y 3 mL de tramadol al 5% (grupo T, n = 8). Las medidas de tensión de ruptura, conteo de fibras de colágeno y evaluación histopatológica se evaluaron en las muestras de tejido retiradas de los ratones. RESULTADOS: La comparación del grupo control con los grupos donde la bupivacaína y la lidocaína fueron usadas para la infiltración de la herida mostró que en esos últimos, la producción de colágeno fue menor, junto con la resistencia en la tensión de ruptura, mientras se observó un edema más intenso, vascularización y puntajes de inflamación significativos (p < 0,0125). Entre el grupo control y el grupo tramadol no hubo diferencias significativas en la producción de colágeno, tensión de ruptura y edema, vascularización y puntaje de inflamación (p > 0,0125). CONCLUSIÓN: En este estudio, verificamos que tanto la bupivacaína como la lidocaína redujeron la producción de colágeno, la resistencia a la ruptura de la cicatriz y causaron edema, vascularización e inflamación significativas cuando se les comparó con el grupo control. No hubo diferencia significativa entre los grupos control y tramadol para estas variables. Los resultados de este estudio experimental preliminar en ratones indican que el tramadol puede ser utilizado para la anestesia por infiltración en incisiones, sin efectos adversos sobre el proceso de cicatrización quirúrgica. Esos resultados necesitan ser verificados en los seres humanos.

Inibição da corrente de cálcio tipo l por tramadol e enantiômeros em miócitos cardíacos de ratos / Inhibition of L-type calcium current by tramadol and enantiomers in cardiac myocytes from rats

FUNDAMENTO: O tramadol é um analgésico de ação central cujo mecanismo de ação envolve a ativação de um receptor opioide. Anteriormente, mostramos que o tramadol e seus enantiômeros apresentavam um efeito inotrópico negativo sobre o músculo papilar no qual o (+)-enantiômero era mais potente que (-)- e (±)-tramadol. OBJETIVO: No presente trabalho, investigamos os efeitos do tramadol e seus enantiômeros na corrente de cálcio tipo L (I Ca-L). MÉTODOS: Os experimentos foram realizados em miócitos ventriculares isolados de ratos Wistar utilizando a técnica de patch-clamp com configuração de célula inteira. RESULTADOS: O tramadol (200 µM) reduziu a amplitude de pico do I Ca-L em potenciais de 0 a +50 mV. Em 0 mV, a I Ca-L foi reduzida em 33,7 ± 7,2 por cento. (+)- e (-)-tramadol (200 µM) produziram uma inibição semelhante da I Ca-L, na qual a amplitude do pico foi reduzida em 64,4 ± 2,8 por cento e 68,9 ± 5,8 por cento, respectivamente a 0 mV (P > 0,05). O tramadol, (+)- e (-)-tramadol mudaram a inativação de estado estacionário de I Ca-L para potenciais de membrana mais negativos. Além disso, tramadol e (+)-tramadol alteraram significativamente a curva de recuperação dependente de tempo da I Ca-L para a direita e reduziram a recuperação de I Ca-L da inativação. A constante de tempo foi aumentada de 175,6 ± 18,6 a 305,0 ± 32,9 ms (P < 0,01) para o tramadol e de 248,1 ± 28,1 ms para 359,0 ± 23,8 ms (P < 0,05) para o (+)-tramadol. O agonista do receptor µ-opioide (DAMGO) não tem nenhum efeito na I Ca-L. CONCLUSÃO: A inibição da I Ca-L induzida por tramadol e seus enantiômeros não teve relação com a ativação de receptores opioides e poderia explicar, pelo menos em parte, seu efeito inotrópico negativo cardíaco.

BACKGROUND: Tramadol is a centrally acting analgesic, whose mechanism of action involves opioid-receptor activation. Previously, we have shown that tramadol and its enantiomers had a negative inotropic effect on the papillary muscle in which the (+)-enantiomer is more potent than (-)- and (±)-tramadol. OBJECTIVE: In this study, we investigated the effects of tramadol and its enantiomers on L-type calcium current (I Ca-L). RESULTS: Tramadol (200 µM) reduced the peak amplitude of I Ca-L at potentials from 0 to +50 mV. At 0 mV, I Ca-L was reduced by 33.7 ± 7.2 percent. (+)- and (-)-tramadol (200 µM) produced a similar inhibition of I Ca-L, in which the peak amplitude was reduced by 64.4 ± 2.8 percent and 68.9 ± 5.8 percent, respectively at 0 mV (p > 0.05). Tramadol, (+)- and (-)-tramadol shifted the steady-state inactivation of I Ca-L to more negative membrane potentials. Also, tramadol and (+)-tramadol markedly shifted the time-dependent recovery curve of I Ca-L to the right and slowed down the recovery of I Ca-L from inactivation. The time constant was increased from 175.6 ± 18.6 to 305.0 ± 32.9 ms (p < 0.01) for tramadol and from 248.1 ± 28.1 ms to 359.0 ± 23.8 ms (p < 0.05) for (+)-tramadol. The agonist of µ-opioid receptor DAMGO had no effect on the I Ca-L. CONCLUSION: The inhibition of I Ca-L induced by tramadol and its enantiomers was unrelated to the activation of opioid receptors and could explain, at least in part, their negative cardiac inotropic effect.

Detection of some pain managing drugs in bone, bone marrow and hair [human and experimental study]

Detection of morphine, fentanyl, and tramadol in human hair and in hair, bone and bone marrow of rats was done using high pressure liquid chromatography [HPKC]. Forty participants were divided into 4 groups control, morphine, tramadol, and fentanyl group. Hair samples were taken after 7 days of exposure to the tested drugs. The animal pat of the experiment consisted of 80 rats. The first 40 rats were divided into 4 subgroups [10 rats each]. The first subgroup was injected with saline IP as a control group, the second subgroup was injected with morphine 20mg/kg SC. The 3[rd] subgroup was injected with fentanyl 60micro g/kg IP and the 4[th] one was injected with tramadol 20mg/kg IP. Hair specimens were collected ten days after injection. The other forty rats were divided into 4 subgroups treated with the same drug doses of the first 40 rats, but morphine and tramadol groups were scarificed after 1 hour and fentanyl group was scarificed after 20 minutes. Femora diaphysis and bone marrow were collected from each sacrificed rat and frozen. After extraction; HPLC was used to evaluate if these drugs could be detected in these tissues after exposure to single therapeutic doses or not. Results showed that all control groups gave negative results. Morphine, fentanyl and tramadol were detected in human hair at levels 20-123pg/mg, 0.6-1.3 and 1.23-4.23 ng/mg respectively. In rats; morphine was detected at level 0.03-0.53, 4.39-12.31 and 9.31-31.20 ng/mg in hair, bone and bone marrow of rats respectively. Fentanyl was detected at level 1.9-6.20, 5.35-22.36 and 18.22-53.49 ng/mg while tramadol was detected at level 1.27-3.92, 9.6-21.6, and 22.62 to 51.31 ng/mg in hair, bone and bone marrow respectively. This study confirmed that morphine, fentanyl and tramadol are detectable even after single use in hair, bone and bone marrow

Ropivacaína isolada e associada ao fentanil ou ao tramadol administrados pela via peridural em cães / Ropivacaine individually and in combination with fentanyl or tramadol, administered by peridural via in dogs

A anestesia peridural é amplamente difundida no meio veterinário, utilizando-se o anestésico local isolado ou associado aos opióides, capazes de promover aumento do efeito analgésico. O objetivo deste estudo foi avaliar a função cardiorrespiratória e analgésica da ropivacaína isolada ou associada ao fentanil ou tramadol. Para tanto, oito cães foram tranqüilizados com acepromazina, submetidos à anestesia peridural com um dos seguintes protocolos: GR (ropivacaína), GRF (ropivacaína + fentanil), GRT (ropivacaína + tramadol), em volume total de 0,25ml kg-1, e foram avaliados os parâmetros: freqüência cardíaca e respiratória, temperatura retal, pressão arterial sistólica, e gasometria do sangue arterial, os bloqueios sensitivo e motor, o grau de sedação e a ocorrência de possíveis efeitos indesejáveis. A diminuição da freqüência cardíaca nos grupos GRF e GRT foi mais intensa e ocorreu hipotermia significativa no GRF. Foi evidenciada sedação severa em GRF e GRT. O período de recuperação foi mais curto nos animais de GRT. O GRT foi o grupo que apresentou bloqueio mais cranial. Foram observadas bradicardia, hipotermia e síndrome de Shiff-Sherrington no período trans-anestésico em animais de todos os grupos. Nas 24 horas de período pós-anestésico, não foram evidenciados efeitos indesejáveis nos grupos. O GRF apresentou maior duração de anestesia e analgesia, enquanto que o GRT apresentou a menor duração de anestesia com analgesia intermediária e o GR apresentou duração intermediária, com menor analgesia. Não foram encontradas alterações respiratórias e hemogasométricas, porém, bradicardia, hipotermia e síndrome de Schiff-Sherrington, alterações trans-anestésicas comuns na anestesia peridural foram encontradas.

Peridural anesthesia is broadly applied in the Veterinary field, using the isolated local anesthetic or in combination with opiates capable to increase the analgesic effect. This research compared analgesia and cardiorespiratory effects of epidural anaesthesia produced by ropivacaine alone or combined with fentanyl or tramadol in eight mixed breed adult dogs after sedation with acepromazina. Drugs were administered on the following protocols: GR (ropivacaine), GRF (ropivacaine + fentanyl), GRT (ropivacaine + tramadol), in 0.25ml kg-1 of total volume. Heart and respiratory rate, rectal temperature, blood pressure and, gasometry of atrial blood were mensured, as well the sensory and motor blockade (latency and period of action), degree of sedation and side effects. The most important decrease of the heart rate occurred in GRF and GRT. Also significant hypothermia in GRF. Intense degree of sedation was observed in GRF and GRT. The period of recovery was shorter in GRT. The most cranial region of blockade occurred in GRT. Bradicardia, hypothermia and Shiff-Sherrington syndrom were observed in the transanesthetic period in animal from all of the groups. During 24 hours after the anaesthesia no side effects were observed. The GRF had the longer period of anesthesia and analgesia, GRT presented the shorter period of anesthesia with intermediate analgesia and, GR presented intermediate period of anesthesia with lower degree of analgesia. Respiratory and hemogasometrics change were not found, but hipotermy, bradicardy and Schiff-Sherrington syndrome, side effects usually seen in peridural anesthesia, were observed in this study.

Efeito analgésico local do tramadol em modelo de dor provocada por formalina em ratos / Local effect of tramadol on formalin evoked flinching behavior in rats / Efecto analgésico local del tramadol en modelo de dolor provocado por formalina en ratones

JUSTIFICATIVA E OBJETIVOS: O cloridrato de tramadol é um fármaco analgésico de ação central, utilizado no tratamento de dores moderadas e intensas. Foi demonstrado efeito analgésico local do tramadol, mas seu mecanismo de ação não foi estabelecido. MÉTODO: Estudou-se o efeito da administração local, sistêmica e por bloqueio de nervo periférico do tramadol sobre o comportamento de elevação da pata gerado pela injeção de 50 µL de formalina a 1 por cento na região dorsal da pata de ratos. O número de elevações da pata foi observado pelo período de 60 minutos. RESULTADOS: A administração local de tramadol em concentrações maiores (2,5 e 5 mg) levou ao bloqueio praticamente completo do comportamento de elevação da pata durante todo o teste. A administração sistêmica e por bloqueio de nervo periférico não afetou o comportamento de elevação da pata na fase I e diminuiu parcialmente na fase II. CONCLUSÕES: O tramadol apresentou efeito analgésico local no modelo de comportamento de elevações da pata com formalina, que é diferente de sua ação central. Esse efeito, nesse modelo, não parece ser ligado a efeito anestésico local.

BACKGROUND AND OBJECTIVES: Tramadol hydrochloride is known as a centrally acting analgesic drug, used for the treatment of moderate to severe pain. A local analgesic effect has been demonstrated, but its mechanism of action remains unclear. METHODS: In this study, we examined the effect of local, systemic and nerve block tramadol on the nociceptive flinching behavior elicited by injection of 50 µL of 1 percent formalin into the dorsal region of hind paw of rats. Nociceptive flinching behavior was observed for 60 minutes. RESULTS: Local tramadol in higher concentrations (2.5 and 5mg) almost eliminated flinching behavior during the entire test. Systemic and neural block tramadol did not affect flinching behavior in phase I and partially decreased it in phase II. CONCLUSIONS: Tramadol presented a local analgesic effect in formalin nociceptive flinching behavior that is different from its central analgesic effect. This analgesic effect, in this model, seems not to be linked to a local anesthetic like effect.

JUSTIFICATIVA Y OBJETIVOS: El clorhidrato de tramadol es un fármaco analgésico de acción central, utilizado en el tratamiento de dolores moderados e intensos. Quedó demostrado un efecto analgésico local del tramadol, pero su mecanismo de acción no fue establecido. MÉTODO: Se estudió el efecto de la administración local, sistémica y por bloqueo de nervio periférico del tramadol sobre el comportamiento de elevación de la pata generado por la inyección de 50 µL de formalina a 1 por ciento en la región dorsal de la pata de los ratones. El número de elevaciones de la pata fue observado durante 60 minutos. RESULTADOS: La administración local de tramadol en concentraciones mayores (2,5 y 5 mg) conllevó al bloqueo prácticamente completo del comportamiento de elevación de la pata durante todo el test. La administración sistémica y por bloqueo de nervio periférico, no afectó el comportamiento de elevación de la pata en la fase I y se redujo parcialmente en la fase II. CONCLUSIONES: El tramadol presentó un efecto analgésico local en el modelo de comportamiento de elevaciones de la pata con formalina, que es diferente de su acción central. Ese efecto, en ese modelo, no parece estar vinculado al efecto anestésico local.

Analgesia postoperatoria con tramdadol vs morfina vía epidural en cirugías electivas de gineco-obstetricia en el Hospital Alemán Nicaragüense, julio 2006 a octubre 2007 / Postoperative analgesia with tramadadol vs morphine via epidural in elective surgeries of gineco-obstetrics in the Nicaraguan German Hospital, July 2006 to October 2007

El presente estudio es un ensayo clínico a simple ciego para el paciente, controlado, cuyo objetivo principal fue valorar la efectividad analgésica que brinda el Tramadol en comparación con la Morfina, aplicados por vía epidural en combinación con anestésicos locales (en este caso, lidocaína con epinefrina 1:200,000). Este ensayo clínico se realizó en el Hospital Alemán Nicaragüense durante el periodo de Julio 2006 a Octubre 2007, en el que se evaluaron a 120 pacientes sometidas a cirugías electivas de ginecoobstetricia, asignadas al azar (Método de la lotería ) en tres grupos: El Grupo I – Recibió 100mg de Tramadol en combinación con lidocaína 2 porciento con epinefrina 1:200,000, a razón de 2ml por cada metámera a bloquear. El Grupo II – Recibió Morfina 2mg más lidocaína con epinefrina 1:200,000. El Grupo III – Recibió únicamente lidocaína 2 porciento con epinefrina 1:200,000 a iguales dosis que los otros grupos. Todo esto con el propósito de poder demostrar que el Tramadol puede ser una excelente alternativa analgésica por vía epidural, al brindar una duración de analgesia postoperatoria aceptable con una mejor estabilidad hemodinámica y menos reacciones adversas. En cuanto a la duración de la analgesia, se encontró que fue mayor en el grupo III (Morfina ) con una duración promedio de 810.65 minutos, seguido por el grupo I ( Tramadol ) con una duración promedio de 323 minutos, y por último el grupo control ( lidocaína con epinefrina sola ) durando la analgesia postoperatoria únicamente 11.85 minutos en promedio. Sin embargo el grupo I (Tramadol ) mostró una notable menor incidencia de reacciones adversas en comparación con el grupo II ( Morfina ). El comportamiento hemodinámico fue similar en los tres grupos, no se presentó hipotensión marcada en ninguna paciente, no fue necesario utilizar vasopresores en ningún caso. Debido a un factor muy importante como es el adecuado relleno vascular previo al bloqueo epidural...

Comparison of caudal bupivacaine and bupivacaine-tramadol for postoperative analgesia in children with hypospadias repair

To compare the effects after caudal bupivacaine alone and bupivacaine-tramadol in young children with hypospadias repair. Randomized controlled trial. The Department of Paediatric Anaesthesia, Children Hospital, Pakistan Institute of Medical Sciences, Islamabad, from April to September 2006. Sixty children aged between 13-53 months coming for hypospadias repair were divided randomly into two groups A and B. A caudal block was performed immediately after induction of general anaesthesia. The patients in group A received 0.125% bupivacaine 1 ml/kg with tramadol 1 mg/kg body weight caudally. Group B patients received 0.25% bupivacaine 1 ml/kg body weight caudally. Anaesthesia was discontinued after completion of surgery. In the recovery area, ventilatory frequency and pain scores were recorded at 1 hourly interval for first 6 hours and then every 2 hours for next 6 hours postoperatively. A modified TPPPS [Toddler-Preschool Postoperative Pain Scale] was used to assess the pain. Episodes of vomiting, facial flush and pruritus were noted, if present. The duration of analgesia was significantly prolonged in group A patients [p-value=0.001]. A low frequency of postoperative vomiting was observed in both groups i.e. 10% in group A and 6.66% in group B [p-value=0.64]. No respiratory depression, flushing and pruritus were observed. Low dose combination of bupivacaine and tramadol, when administered caudally, had an additive effect and provided prolonged and effective postoperative analgesia with minimal side effects. The risk of toxicity from bupivacaine decreased when combined with tramadol in low doses