Clinical Management of Chronic Pelvic Pain in Endometriosis Unresponsive to Conventional Therapy

Background: Although several treatments are currently available for chronic pelvic pain, 30–60% of patients do not respond to them. Therefore, these therapeutic options require a better understanding of the mechanisms underlying endometriosis-induced pain. This study focuses on pain management after failure of conventional therapy. Methods: We reviewed clinical data from 46 patients with endometriosis and chronic pelvic pain unresponsive to conventional therapies at Puerta de Hierro University Hospital Madrid, Spain from 2018 to 2021. Demographic data, clinical and exploratory findings, treatment received, and outcomes were collected. Results: Median age was 41.5 years, and median pain intensity was VAS: 7.8/10. Nociceptive pain and neuropathic pain were identified in 98% and 70% of patients, respectively. The most common symptom was abdominal pain (78.2%) followed by pain with sexual intercourse (65.2%), rectal pain (52.1%), and urologic pain (36.9%). A total of 43% of patients responded to treatment with neuromodulators. Combined therapies for myofascial pain syndrome, as well as treatment of visceral pain with inferior or superior hypogastric plexus blocks, proved to be very beneficial. S3 pulsed radiofrequency (PRF) plus inferior hypogastric plexus block or botulinum toxin enabled us to prolong response time by more than 3.5 months. Conclusion: Treatment of the unresponsive patient should be interdisciplinary. Depending on the history and exploratory findings, therapy should preferably be combined with neuromodulators, myofascial pain therapies, and S3 PRF plus inferior hypogastric plexus blockade.

Sex differences in pain-related behaviors and clinical progression of disease in mouse models of visceral pain

Previous studies have reported sex differences in irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) patients, including differences in visceral pain perception. Despite this, sex differences in behavioral manifestations of visceral pain and underlying pathology of the gastrointestinal tract have been largely understudied in preclinical research. In this study, we evaluated potential sex differences in spontaneous visceral nociceptive responses, referred abdominal hypersensitivity, disease progression and bowel pathology in mouse models of acute and persistent colon inflammation. Our experiments show that females exhibit more visceral nociceptive responses and referred abdominal hypersensitivity than males in the context of acute but not persistent colon inflammation. We further demonstrate that, following acute and persistent colon inflammation, visceral pain-related behavioral responses in females and males are distinct, with increases in licking of the abdomen only observed in females and increases in abdominal contractions only seen in males. During persistent colon inflammation, males exhibit worse disease progression than females, which is manifested as worse physical appearance and higher weight loss. However, no measurable sex differences were observed in persistent inflammation-induced bowel pathology, stool consistency or fecal blood. Overall, our findings demonstrate that visceral pain-related behaviors and disease progression in the context of acute and persistent colon inflammation are sex-dependent, highlighting the importance of considering sex as a biological variable in future mechanistic studies of visceral pain as well as in the development of diagnostics and therapeutic options for chronic gastrointestinal diseases.

Delta opioid receptors on nociceptive sensory neurons mediate peripheral endogenous analgesia in colitis

Background Inflammatory visceral pain is endogenously controlled by enkephalins locally released by mucosal CD4+ T lymphocytes in mice. The present study aimed at identifying opioid receptor(s) expressed on nociceptive sensory nerves involved in this peripheral opioid-mediated analgesia. Methods The peripheral analgesia associated with the accumulation of CD4+ T lymphocytes within the inflamed colonic mucosa was assessed in conditional knockout mice specifically deleted for either of the two opioid receptors for enkephalins (i.e., µ (MOR) and δ (DOR) receptors) in Nav1.8-expressing sensory neurons in the dextran sulfate sodium (DSS)-induced colitis model. Results Endogenous analgesia is lost in conditional knockout mice for DOR, but not MOR at the later phase of the DSS-induced colitis. The absence of either of the opioid receptors on sensory nerves had no impact on both the colitis severity and the rate of T lymphocytes infiltrating the inflamed colonic mucosa. Conclusion The key role of DOR on primary afferents in relieving intestinal inflammatory pain opens new therapeutic opportunities for peripherally restricted DOR analgesics to avoid most of the side effects associated with MOR-targeting drugs used in intestinal disorders.

Ultrasound-Guided Regional Analgesia for Post-Cesarean Pain

Pain management after a surgical intervention is one of the fundamental pillars for optimal patient recovery. In obstetric patients, this management may affect the mother and the newborn. The gold standard for analgesic management is the use of intrathecal morphine due to its long-lasting effect; however, adverse effects related to the use of opioids are evidenced, whether administered intrathecally or systemically in case of contraindication to the neuraxial approach or if a long-acting opioid is not available. Cesarean sections have been associated with moderate-to-severe postoperative pain. Multimodal analgesic management seeks to minimize the undesirable effects on the mother-newborn binomial in order to increase maternal satisfaction. The most studied regional blocks for this surgery are the transversus abdominis plane block and the ilioinguinal-iliohypogastric block, which shows contradictory evidence at the time of evaluate pain where there is no significant difference compared with intrathecal morphine, but there were fewer side effects with the TAP block group when assessing pruritus, nausea, and vomiting. Quadratus lumborum and erectus spinae plane block demonstrate its usefulness with better pain management compared with TAP block regardless of them having a higher level of complexity due to the visceral pain control; but there is no evidence with methodologic quality enough that demonstrates better outcomes compared with intrathecal morphine.

Analgesic Effects of Different κ-Receptor Agonists Used in Daytime Laparoscopic Cholecystectomy

Background. Comparing the effect of two different κ-receptor agonists, nalbuphine and oxycodone, and regular morphine in patients for prophylactic analgesia of acute pain after daytime laparoscopic cholecystectomy. Methods. One hundred and twenty-four patients undergoing laparoscopic cholecystectomy were randomly allocated to receive nalbuphine (group N), oxycodone (group O), and morphine (group M). The three groups were all given intravenous injection (iv.) of 0.15 mg/kg injection before incision and 0.05 mg/kg injection at the end of pneumoperitoneum. The Visual Analogue Scale (VAS) scores (incision, visceral, and shoulder) and Ramsay sedation scores at 1, 2, 4, 8, 12, 16, 20, and 24 hours after surgery, the time of extubation, the incidence of postoperative adverse events, the satisfaction of pain treatment, and the duration of stay after surgery were all recorded. Results. Compared with group M, the VAS scores of visceral pain at rest decreased in group N and group O at 1-8 h after surgery ( P < 0.05 ). The VAS scores of visceral pain at movement in group N decreased longer than those in group O ( P < 0.05 ). Compared with that of group M, the postoperative time in Ramsay sedation score of group O increased longer than that of group N ( P < 0.05 ). Compared with group N, patients had worse sleep quality in group O, longer length of stay in group M, and lower satisfaction in both groups. Conclusion. Compared with morphine, prophylactic use of the κ-receptor agonists, nalbuphine and oxycodone, during laparoscopic cholecystectomy can reduce postoperative visceral pain. Furthermore, the nalbuphine group had fewer adverse reactions, better analgesia, and better satisfaction.

Pathophysiological Role of Purinergic P2X Receptors in Digestive System Diseases

P2X receptors (P2XRs) are trimeric, non-selective cation channels activated by extracellular ATP and widely distributed in the digestive system. P2XRs have an important role in the physiological function of the digestive system, such as neurotransmission, ion transports, proliferation and apoptosis, muscle contraction, and relaxation. P2XRs can be involved in pain mechanisms both centrally and in the periphery and confirmed the association of P2XRs with visceral pain. In the periphery, ATP can be released as a result of tissue injury, visceral distension, or sympathetic activation and can excite nociceptive primary afferents by acting at homomeric P2X(3)R or heteromeric P2X(2/3)R. Thus, peripheral P2XRs, and homomeric P2X(3) and/or heteromeric P2X(2/3)R in particular, constitute attractive targets for analgesic drugs. Recently studies have shown that P2XRs have made significant advances in inflammation and cancer. P2X7R mediates NLRP3 inflammasome activation, cytokine and chemokine release, T lymphocyte survival and differentiation, transcription factor activation, and cell death. The P2X7R is a potent stimulant of inflammation and immunity and a promoter of cancer cell growth. This makes P2X7R an appealing target for anti-inflammatory and anti-cancer therapy. It is believed that with the further study of P2XRs and its subtypes, P2XRs and its specific antagonists will be expected to be widely used in the treatment of human digestive diseases in the future.

Evaluation of Analgesia Effect after Ultrasound-Guided Laparoscopic Renal Surgery

Kidney surgery involves placing the kidney in the iliac fossa of the lower abdomen on the right or left side. Studies have found that most kidney patients experience moderate to severe pain after surgery. The stress response caused by postoperative pain, especially visceral pain, not only aggravates the patient’s pain and irritability and aggravates the original complications but may also harm the early recovery of renal function and affect the survival of the kidney. Therefore, adequate postoperative analgesia for renal patients is essential. This paper combines ultrasound-guided laparoscopic technology to improve the postoperative analgesia effect of renal surgery and compares the data with experimental research methods. Through experimental research, it can be seen that the method proposed in this article has a certain effect, and ultrasound-guided laparoscopic technology can be used in follow-up clinical research to improve the analgesic effect of renal surgery.

Assessment Screening of Chest Pain in Primary Setting: A Review

Chest pain can be caused by a variety of illnesses, ranging from benign and self-limiting to significant or life-threatening. Before a doctor examines more benign reasons, a workup must focus on ruling out significant pathology. The words "dull," "deep," "pressure," and "squeezing" are commonly used to describe visceral discomfort. Visceral pain generally has a diffuse distribution pattern, making it difficult for the patient to pinpoint a precise location. chest discomfort accounts for 1.5 percent of all consultations in primary care. The age group 45 to 64 years has the highest prevalence of chest pain consultations. Patients with suspected Acute coronary syndrome (ACS) should be diagnosed and treated as soon as feasible. While most patients are sent to the hospital, an electrocardiogram (ECG) is the sole examination necessary in primary care. In this review we will be looking at chest pain incident in primary care, and also we’ll be making overview to the etiology and diagnosis of the disease.

Targeting GATA1 and p2x7r Locus Binding in Spinal Astrocytes Suppresses Chronic Visceral Pain by Promoting DNA Demethylation

Irritable bowel syndrome is a gastrointestinal disorder of unknown etiology characterized by widespread, chronic abdominal pain associated with altered bowel movements. Increasing amounts of evidence indicate that injury and inflammation during the neonatal period have long-term effects on tissue structure and function in the adult that may predispose to gastrointestinal diseases. In this study we aimed to investigate how the epigenetic regulation of DNA demethylation of the p2x7r locus guided by the transcription factor GATA binding protein 1 (GATA1) in spinal astrocytes affects chronic visceral pain in adult rats with neonatal colonic inflammation (NCI). The spinal GATA1 targeting to DNA demethylation of p2x7r locus in these rats was assessed by assessing GATA1 function with luciferase assay, chromatin immunoprecipitation, patch clamp, and interference in vitro and in vivo. In addition, a decoy oligodeoxynucleotide was designed and applied to determine the influence of GATA1 on the DNA methylation of a p2x7r CpG island. We showed that NCI caused the induction of GATA1, Ten-eleven translocation 3 (TET3), and purinergic receptors (P2X7Rs) in astrocytes of the spinal dorsal horn, and demonstrated that inhibiting these molecules markedly increased the pain threshold, inhibited the activation of astrocytes, and decreased the spinal sEPSC frequency. NCI also markedly demethylated the p2x7r locus in a manner dependent on the enhancement of both a GATA1–TET3 physical interaction and GATA1 binding at the p2x7r promoter. Importantly, we showed that demethylation of the p2x7r locus (and the attendant increase in P2X7R expression) was reversed upon knockdown of GATA1 or TET3 expression, and demonstrated that a decoy oligodeoxynucleotide that selectively blocked the GATA1 binding site increased the methylation of a CpG island in the p2x7r promoter. These results demonstrate that chronic visceral pain is mediated synergistically by GATA1 and TET3 via a DNA-demethylation mechanism that controls p2x7r transcription in spinal dorsal horn astrocytes, and provide a potential therapeutic strategy by targeting GATA1 and p2x7r locus binding.