Modulation of the Inflammatory Response by Pre-emptive Administration of IMT504 Reduces Postoperative Pain in Rats and has Opioid-Sparing Effects.

Despite the available knowledge on underlying mechanisms and the development of several therapeutic strategies, optimal management of postoperative pain remains challenging. This preclinical study hypothesizes that, by promoting an anti-inflammatory scenario, pre-emptive administration of IMT504, a noncoding, non-CpG oligodeoxynucleotide with immune modulating properties, will reduce postincisional pain, also facilitating therapeutic opioid-sparing. Male adult Sprague-Dawley rats with unilateral hindpaw skin-muscle incision received pre-emptive (48 and 24 hours prior to surgery) or postoperative (6 hours after surgery) subcutaneous vehicle (saline) or IMT504. Various groups of rats were prepared for pain-like behavior analyses, including subgroups receiving morphine or naloxone, as well as for flow-cytometry or quantitative RT-PCR analyses of the spleen and hindpaws (for analysis of inflammatory phenotype). Compared to vehicle-treated rats, pre-emptive IMT504 significantly reduced mechanical allodynia by 6 hours after surgery, and accelerated recovery of basal responses from 72 hours after surgery and onwards. Cold allodynia was also reduced by IMT504. Postoperative administration of IMT504 resulted in similar positive effects on pain-like behavior. In IMT504-treated rats, 3 mg/kg morphine resulted in comparable blockade of mechanical allodynia as observed in vehicle-treated rats receiving 10 mg/kg morphine. IMT504 significantly increased hindpaw infiltration of mesenchymal stem cells, CD4+T and B cells, and caused upregulated or downregulated transcript expressions of interleukin-10 and interleukin-1ß, respectively. Also, IMT504 treatment targeted the spleen, with upregulated or downregulated transcript expressions, 6 hours after incision, of interleukin-10 and interleukin-1ß, respectively. Altogether, pre-emptive or postoperative IMT504 provides protection against postincisional pain, through participation of significant immunomodulatory actions, and exhibiting opioid-sparing effects. PERSPECTIVE: This preclinical study introduces the noncoding non-CpG oligodeoxynucleotide IMT504 as a novel modulator of postoperative pain and underlying inflammatory events. The opioid-sparing effects observed for IMT504 appear as a key feature that could contribute, in the future, to reducing opioid-related adverse events in patients undergoing surgical intervention.

The PPARγ agonist pioglitazone produces a female-predominant inhibition of hyperalgesia associated with surgical incision, peripheral nerve injury, and painful diabetic neuropathy.

Pioglitazone, an agonist at peroxisome proliferator-activated receptor gamma, is FDA-approved for the treatment of insulin resistance in type 2 diabetes. Numerous studies in male rodents suggest that pioglitazone inhibits inflammatory and neuropathic pain, but few included female subjects. To address this gap, we compared the effects of pioglitazone in both sexes in the intraplantar methylglyoxal model (MG) model of chemical pain and painful diabetic neuropathy (PDN), the plantar incision model (PIM) of postoperative pain, the spared nerve injury (SNI) model of traumatic nerve injury, and the ZDF rat and db/db mouse models of PDN. We administered pioglitazone by one-time intrathecal or intraperitoneal injection or by adding it to chow for 6 weeks, followed by measurement of hypersensitivity to non-noxious mechanical, noxious mechanical, heat, and/or cold stimuli. In all mouse models, injection of pioglitazone decreased pain-like behaviors with greater potency and/or efficacy in females as compared to males: heat and mechanical hypersensitivity in the MG model (0.1-10 mg/kg); mechanical hypersensitivity in the PIM model (10 µg); mechanical and cold hypersensitivity in the SNI model (100 mg/kg); and heat hypersensitivity in the db/db model (100 mg/kg). Furthermore, co-administration of low doses of morphine (1 mg/kg) and pioglitazone (10 mg/kg) decreased SNI-induced mechanical and cold hypersensitivity in female but not male mice. In the ZDF rat, pioglitazone (100 mg/kg) decreased heat and mechanical hypersensitivity with no sex difference. In the db/db model, pioglitazone had no effect when given into chow for 6 weeks at 0.3, 3 or 30 mg/kg doses. We conclude that females exhibit greater anti-hyperalgesic responses to pioglitazone in mouse models of chemical-induced nociception, postsurgical pain, neuropathic pain, and PDN. These findings set the stage for clinical trials to determine whether pioglitazone has analgesic properties across a broad spectrum of chronic pain conditions, particularly in women.

Dolor crónico posoperatorio: Una revisión necesaria de un problema ignorado / Chronic post-surgical pain: A necessary review for a disregarded problem

INTRODUCTION: Postoperative chronic pain (PCP) is defined as a discomfort that lasts more than expected or beyond 3 months after surgery. The recognition and study of this clinical entity has been gaining interest in the past few years. One of the main reasons is the great impact it can have on the quality of life of patients who suffer from it. OBJECTIVE: To describe the prevalence, risk factor and impact of PCP on patients subjected to different surgical procedures. MATERIALS AND METHODS: Search on MED- LINE/Pubmed, using the following terms: "chronic postsurgical pain", "chronic post operative pain", "chronic post operative pain", "chronic post surgical pain". Publications were then sieved using their title and abstract. RESULTS: Fifty-seven articles were analyzed. Ten to fifty percent of patients were reported as suffering PCP, with up to 10% incidence of severe pain. The main risk factors identified were the use of analgesics, pre-operative pain and type of surgery. Orthopedic surgery was highly associated with moderate to severe PCP within the first year. Twenty-one percent of patients referred PCP affected their quality of life and sleep; ability to carry out physical activity and return to work. CONCLUSION: The first approach to PCP is getting to know its impact and epidemiology. Surgical treatments can cause PCP, which will affect patient recovery and increase costs. Recognizing those patients at risk and establishing preventive management protocols could improve the quality of life of postsurgical patients.

INTRODUCCIÓN: El dolor crónico posoperatorio (DCPO) es aquel que aparece tras un procedimiento quirúrgico y se mantiene por más tiempo de lo esperado o más de tres meses luego de la cirugía. Es una entidad de reciente estudio y que tiene un gran impacto en la calidad de vida de los pacientes postoperados. OBJETIVO: Describir la prevalencia, factores de riesgo y el impacto del DCPO en pacientes sometidos a diferentes procedimientos quirúrgicos. MATERIAL Y MÉTODO: Se realizó una revisión de la literatura utilizando la base de datos MEDLINE/Pubmed. Los términos libres fueron "chronic postsurgical pain", "chronic postoperative pain", "chronic post operative pain", "chronic post surgical pain". Se realizó un cribado según título y resumen. RESULTADOS: Fueron analizados 57 artículos. De 10%-50% de los pacientes presentan DCPO y hasta 10% puede ser severo. El uso de analgésicos, presencia de dolor preoperatorio y especialidad quirúrgica han sido señalados como los principales factores de riesgo. La cirugía traumatológica aparece como la más asociada a DCPO moderado y severo a un año. Hasta 21% de los pacientes refieren que afecta su calidad de vida, el sueño, actividad física y reincorporación laboral. CONCLUSIÓN: El conocimiento de la epidemiología e impacto del DCPO es un primer acercamiento a este problema. Patologías de resolución quirúrgica pueden evolucionar con DCPO, afectando su recuperación y aumentando los costos que se desea contener. El reconocimiento de la población de riesgo y la instauración de protocolos preventivos pudiera mejorar la calidad de vida de los pacientes postoperados.

Impacto de la técnica anestésica en el dolor posoperatorio de cirugía reconstructiva mamaria / Impact of the anesthetic technique in postoperative pain in breast reconstructive surgery

OBJECTIVE: Our goal was to evaluate acute postoperative pain in patients undergoing breast reconstructive surgery with Deep Inferior Epigastric Perforator Artery (DIEP) flap technique. MATERIAL AND METHODS: A retrospective study was carried out in patients undergoing DIEP-flap breast reconstruction between January 2014 and December 2019. The main goal was the evaluation of acute postoperative pain through visual analogic pain scale (VAS) at rest (VASr) and movement (VASm) in the immediate postoperative period in post-anesthesia care unit (0h), at 24 h and at 48 h post-intervention and intravenous (IV) morphine con- sumption, depending on whether General Anesthesia (GA group) or Combined Anesthesia (CA group) was performed. Secon- dary outcomes were chronic pain incidence, perioperative complications, postoperative nausea and vomiting (PONV), reinterven- tion and readmission rate and lenght of hospital saty. RESULTS: Sixty seven patients were included, 24 in GA group and 43 in CA group. CA group showed better VASm values at 24 h postintervention (p = 0.01). Postoperative IV morphine continuous infusion was required for acute pain management in 10.4% of patients (25% in GA vs 2.3% in the CA group; p = 0.004). Chronic pain rate was 13.4% (25% in GA vs 7% in the CA group; p = 0.038). Patients with worse initial pain control (VASr > 3 at 0 h) showed a higher incidence of chronic pain (66.6% vs 9.6%; p = 0.008). GA group presented higher rate of postoperative complications (66.6% vs 34.9%; p = 0,012), as well reintervention rate (58.3% vs 30.2%; p = 0.025). A sub-analysis showed that of the 10 patients (5 in the AC and 5 in the AG group) who reported poor initial pain control (VASr > 3 at 0 h), those belonging to the AC group, the IV morphine requirements were lower at post-anesthesia care unit (2 (0-5) mg vs 16 (9.5-23) mg; p = 0.016) and throughout the hospitalization period (4 (0-6) vs 24 (17.5-49, 2); p = 0.008). CONCLUSIONS: Locorregional techniques could offer a better control of postoperative acute pain and a lower incidence of chronic pain, without assuming implying a higher risk of complications related to them in patients undergoing breast reconstructive surgery by DIEP flap technique.

OBJETIVO: El objetivo del estudio fue evaluar el dolor agudo posoperatorio en las pacientes sometidas a cirugía de reconstrucción mamaria mediante colgajo de la arteria perforante epigástrica inferior profunda (colgajo DIEP). MATERIAL Y MÉTODOS: Se revisaron retrospectivamente las pacientes intervenidas de reconstrucción mamaria con colgajo DIEP entre enero de 2014 y diciembre de 2019. El objetivo principal fue la valoración del dolor agudo posoperatorio mediante la escala visual analógica (EVA) en reposo (EVAr) y movimiento (EVAm) en el posoperatorio inmediato en la unidad de Reanimación (0 h), a las 24 h y a las 48 h post-intervención y el consumo de morfina endovenosa (ev), según si se realizó una Anestesia General (AG) o una Anestesia Combinada (AC). Los objetivos secundarios fueron: incidencia de dolor crónico posoperatorio, complicaciones peroperatorias, náuseas y vómitos posoperatorios (NVPO), tasa de reintervención y reingreso y estancia hospitalaria. RESULTADOS: Se incluyeron 67 pacientes, 24 en el grupo AG y 43 en el grupo AC. El grupo AC mostró un mejor control del dolor en movimiento a las 24 h (p = 0,01). Un 10,4% de las pacientes precisaron infusión de morfina endovenosa (ev) para control del dolor agudo posoperatorio en reposo (25% en el grupo AG vs 2,3% en el grupo AC; p = 0,004). La incidencia de dolor crónico fue del 13,4% (25% en el grupo AG vs 7% en el grupo AC; p = 0,038). Las pacientes con mal control inicial del dolor (EVAr > 3 a las 0 h) presentaron mayor incidencia de dolor crónico (66,6% vs 9,6%; p = 0,008). El grupo AG presentó mayor tasa de complicaciones posoperatorias (66,6% vs 34,9%; p = 0,012), así como tasa de reintervención (58,3% vs 30,2%; p = 0,025). Un subanálisis mostró que de las 10 pacientes (5 en el grupo AC y 5 en el grupo AG) que refirieron un mal control inicial del dolor (EVAr > 3 a las 0 h), las pertenecientes al grupo AC requirieron menos morfina ev en unidad de reanimación postanestésica (2 (0-5) mg vs 16 (9,5-23) mg; p = 0,016) y durante toda su hospitalización (4 (0-6) vs 24 (17,5-49,2); p = 0,008). CONCLUSIONES: Las técnicas locorregionales podrían ofrecer un mejor control del manejo del dolor agudo y una menor incidencia de dolor crónico, sin suponer un mayor riesgo de complicaciones relacionadas con ellos en pacientes sometidas a cirugía reconstructiva mamaria mediante técnica de colgajo DIEP.

Importancia del anestesiólogo en la prevención del dolor crónico / Importance of the anesthesiologist in the prevention of chronic pain

The development of chronic pain after surgery or persistent postoperative pain is a significant public health problem that affects between 10%-56% of patients undergoing surgical intervention. It produces great restrictions of mobility, limitation of daily activities, dependence on opioids, anxiety, depression, a great alteration of the quality of life and important legal and medical-economic consequences. There is a very close correlation between acute postoperative pain, and persistent postoperative pain. For this reason, pain must be treated effectively in its acute phase to reduce the incidence of chronic pain after surgery. There are risk factors that predispose to its appearance and that must be known by the anesthesiologist. In an individualized and meticulous pre-anesthetic consultation, these risk factors can be detected, as well as the presence of surgical procedures related to chronic pain, with the purpose of the therapeutic approach of the first ones if necessary, and a good planning of the anesthetic and analgesic technique, which reduces the participation of the second, in the chronicity of acute pain. The role of the anesthesiologist in the pre-anesthetic consultation is essential for the planning of preventive and multimodal analgesia that, together with other resources, should reduce the incidence of persistent postoperative pain.

El desarrollo del dolor crónico después de la cirugía o dolor posoperatorio persistente, es un problema de salud pública significativo que afecta entre el 10%-56% de los pacientes sometidos a una intervención quirúrgica. Produce grandes restricciones de la movilidad, limitación de las actividades de vida diaria, dependencia a los opioides, ansiedad, depresión, una gran alteración de la calidad de vida e importantes consecuencias legales y médico-económicas. Hay una correlación muy estrecha entre el dolor agudo posoperatorio, y el dolor posoperatorio persistente. Por esa razón, el dolor debe ser tratado de manera eficaz en su fase aguda para disminuir la incidencia del dolor crónico posterior a la cirugía. Existen factores de riesgo que predisponen a su aparición y que deben ser conocidos por el anestesiólogo. En una consulta pre-anestésica individualizada y minuciosa, se podrán detectar estos factores de riesgo, como también la presencia de procedimientos quirúrgicos relacionados con el dolor crónico, con la finalidad del abordaje terapéutico de los primeros de ser necesario, y una buena planificación de la técnica anestésica y analgésica, que disminuya la participación de los segundos, en la cronicidad del dolor agudo. El rol del anestesiólogo en la consulta pre-anestésica, es fundamental para la planificación de la analgesia preventiva y multimodal que junto a otros recursos deberían disminuir la incidencia del dolor postoperatorio persistente.

Analgesia en cirugía abdominal laparoscópica / Analgesia in laparoscopic surgery

Resumen: El abordaje laparoscópico ha revolucionado la cirugía abdominal en los últimos 30 años, y ahora los cirujanos son capaces de realizar operaciones sin realizar grandes incisiones a la pared abdominal. Así como la colecistectomía, apendicectomía y los procedimientos tubo-ováricos fueron los abordajes iniciales, la laparoscopía ahora ha incrementado su aplicabilidad a procedimientos mayores como histerectomía, procedimientos bariátricos y varias resecciones gastrointestinales y urológicas de tipo oncológico. Los avances tecnológicos han generado el desarrollo de muchas variaciones sobre el abordaje laparoscópico «tradicional o estándar¼. Los aspectos en el cuidado perioperatorio multimodal fueron asignados para alcanzar una recuperación más rápida después del procedimiento quirúrgico. Esto dependerá del tipo de cirugía realizada, de factores propios del paciente y de la presencia de comorbilidades. La duración de la recuperación después de la cirugía laparoscópica dependerá del procedimiento realizado, pudiendo ser tan corta como de una a dos semanas en procedimientos de tipo ambulatorio (visita http://www.painoutmexico.com para obtener la versión completa del artículo y el diagrama de recomendaciones).

Abstract: Laparoscopy has revolutionized abdominal surgery over the past 30 years that enable surgeons to perform operations without making large abdominal incisions. As well as cholecystectomy, appendicectomy, and tubo-ovarian procedures, laparoscopy is now increasingly used for hysterectomy, bariatric procedures, and many gastrointestinal and urological cancer resections. Technological advances have resulted in the development of several variations on the «standard¼ laparoscopic approach. The multimodal perioperative care pathways were designed to achieve early recovery after surgical procedures. This depends upon the type of surgery that has been performed, and patient factors such as comorbidities. The duration of recovery after laparoscopic surgery depends on the procedure performed and can be as short as 1-2 weeks in day case procedures (visit http://www.painoutmexico.com to see the full article and recommendations).

Usos más frecuentes de Arnica montana / Most common uses of Arnica montana

Introducción: Arnica montana es una planta original de Europa central y meridional, cuya eficacia para aliviar el dolor postraumático y otras desviaciones de la salud ha sido demostrada, sin embargo, es limitado el conocimiento que tienen los profesionales de la salud sobre esta y sus efectos beneficiosos. Objetivos: contribuir con el proceso de perfeccionamiento de quienes incursionan en los tratamientos alternativos a partir de la recolección de información actualizada sobre Arnica montana. Métodos: se desarrolló una estrategia de búsqueda con los términos: homeopatía, ensayo clínico, meta-análisis, revisión sistemática, eficacia y seguridad combinados con Arnica montana. Se utilizaron las bases de datos MEDLINE, CUMED, Registro Cochrane de Ensayos Controlados y el registro especializado Cochrane de Medicina Complementaria, limitada a los artículos publicados entre los meses de enero de 2002 a junio de 2012. Conclusiones: la evaluación de la información disponible permite afirmar que este producto natural puede utilizarse de manera segura y eficaz para aliviar el dolor y reducir la inflamación postraumática y posquirúrgica en humanos

Introduction: Arnica montana is a plant native to Central and Southern Europe of proven effectiveness to relieve posttraumatic pain and other conditions. However, knowledge about this plant and its beneficial effects is scant among health professionals. Objectives: contribute to the professional development of those involved in alternative treatments by gathering updated information about Arnica montana. Methods: a search strategy was developed based on the following terms: homeopathy, clinical trial, meta-analysis, systematic review, effectiveness and safety, as combined with Arnica montana. Use was made of the databases MEDLINE and CUMED, as well as the Cochrane Central Register of Controlled Trials and the Cochrane Complementary Medicine Specialized Register, limited to articles published from January 2002 to June 2012. Conclusions: based on the evaluation of the information available, it may be stated that this natural product may be used both safely and effectively to relieve pain and reduce posttraumatic and postsurgical inflammation in humans

Treatment of localized post-traumatic neuropathic pain in scars with 5% lidocaine medicated plaster.

OBJECTIVE: To evaluate the use of 5% lidocaine medicated plaster (LMP) for treating painful scars resulting from burns or skin degloving. PATIENTS AND METHODS: This was a prospective, observational case series study in individuals with painful scars <70 cm(2) in area, caused by burns or skin degloving. The study included a structured questionnaire incorporating demographic variables, pain evaluation using the numeric rating scale (NRS), the DN4 questionnaire, and measurement of the painful surface area. Patients with open wounds in the painful skin or with severe psychiatric disease were excluded. RESULTS: Twenty-one men and eight women were studied, aged (mean + standard deviation) 41.4 ± 11.0 years, with painful scars located in the upper extremity (n = 9), lower extremity (n = 19), or trunk (n = 1). Eleven patients (37.9%) had an associated peripheral nerve lesion. The scars were caused by burns (n = 13), degloving (n = 7), and/or orthopedic surgery (n = 9). The duration of pain before starting treatment with lidocaine plaster was 9.7 ± 10.0 (median 6) months. The initial NRS was 6.66 ± 1.84 points, average painful area 23.0 ± 18.6 (median 15) cm(2), and DN4 score 4.7 ± 2.3 points. The duration of treatment with LMP was 13.9 ± 10.2 (median 11) weeks. After treatment, the NRS was reduced by 58.2% ± 27.8% to 2.72 ± 1.65. The average painful area was reduced by 72.4% ± 24.7% to 6.5 ± 8.6 (median 5) cm(2). Nineteen patients (69%) showed functional improvement following treatment. CONCLUSION: LMP was useful for treating painful scars with a neuropathic component, producing meaningful reductions in the intensity of pain and painful surface area. This is the first time that a decrease in the painful area has been demonstrated in neuropathic pain using topical therapy, and may reflect the disease-modifying potential of LMP.

Eficácia analgésica pós-operatória e ação anestésica adjuvante do cloridrato de tramadol utilizado localmente após exodontias de terceiros molares inferiores impactados / Efficacy of postoperative analgesia and adjuvant anesthetic action of local tramadol hydrochloride injection after impacted third molar extraction

Foi estudado o efeito analgésico e anestésico adjuvante do cloridrato de tramadol aplicado localmente, após extração do terceiro molar inferior impactado. Um total de 52 pacientes foi submetido à exodontia sob anestesia local (mepivacaína 2% 1:20 000 corbadrina), em estudo duplo-cego, dose única, cruzado, controlado por placebo. Pacientes e os lados dos procedimentos foram distribuídos aleatoriamente para receberem 2 ml de tramadol (100%) (grupo T) ou 2 ml de solução salina 0,9% (grupo P). Ambas as soluções foram injetadas na submucosa gengival e alvéolo, imediatamente após as cirurgias realizadas por um mesmo cirurgião. Impacção dental e quantidade anestésica foram pareadas. Dados do consumo e a hora de uso de analgésico de resgate (dipirona 500 mg) foram utilizados para avaliar o efeito analgésico de tramadol. Uma Escala Analógica Visual (EAV) de dor foi aplicada após término da anestesia, 4, 8, 24, 48 e 72 horas após cirurgia, com os dados submetidos ao teste de Wilcoxon (p < 0,05). Não houve diferença no bloqueio anestésico e efeitos adversos entre os grupos. O grupo T requisitou um número significativamente menor (p = 0,008) de comprimidos de dipirona durante o período de avaliação (3,37 ± 4,65) do que o grupo P (4,4 ± 3,71). O grupo T levou mais minutos para usar a dipirona após a primeira cirurgia (303,72 ± 416,01) do que o grupo P (185,4 ± 59,4) (p = 0,006). O grupo T apresentou menor média de dor na EAV após término da anestesia (3,55 ± 2,27) do que no grupo P (5,26 ± 2,49) (p = 0,001). O tramadol administrado localmente após exodontia de terceiros molares inferiores melhora a qualidade da analgesia pós-operatória, porém não prolonga a duração da anestesia local com mepivacaína.

The present study sought to assess the analgesic and adjuvant anesthetic effects of surgical site administration of tramadol hydrochloride immediately after extraction of impacted mandibular third molars. In this double-blind, placebo-controlled, singledose, crossover investigation, 52 patients underwent bilateral extraction of impacted mandibular third molars under local anesthesia (mepivacaine 2% with levonordefrin 1:20 000). Patients and procedures, by side of intervention, were randomly assigned to receive either 2 mL of tramadol (100%) (Group T, n = 52) or 2 mL of normal saline, 0.9% (Group P, n = 52). Medications were administered by submucosal injection at the level of the third molar immediately after surgery. All patients were operated on by the same surgeon; patients were paired for technical difficulty and amount of anesthetic solution. Use of supplementary analgesics (500 mg metamizole) and time to first postoperative use of a rescue drug were used to assess the analgesic effect of tramadol. Pain level on both sides (Group T and P) was recorded on a visual analog scale (VAS 010 cm) immediately after cessation of anesthetic effect and at 4, 8, 24, 48, and 72 hours postoperatively. Data were compared using the Wilcoxon test (p < 0.05). There was no difference in anesthetic blockade between groups. There were no differences in reported adverse effects. In the 72 hours following surgery, patients in group T took significantly fewer (p = 0.008) metamizole tablets (3.37 ± 4.65) than did those in group P (4.4 ± 3.71). Time to first dose of a rescue drug (in minutes) was longer in Group T (303.72 ± 416.01) than in Group P (185.4 ± 59.4) (p = 0.006). Tramadol reduced pain intensity values (VAS) significantly in Group T (3.55 ± 2.27) as compared to Group P (5.26 ± 2.49) after anesthetic effect had worn off (p = 0.001)...