Effect of Neurostimulation on Chronic Pancreatic Pain: A Systematic Review.

BACKGROUND: Chronic pancreatic pain is one of the most severe causes of visceral pain, and treatment response is often limited. Neurostimulation techniques have been investigated for chronic pain syndromes once there are pathophysiological reasons to believe that these methods activate descending pain inhibitory systems. Considering this, we designed this systematic literature review to investigate the evidence on neuromodulation techniques as a treatment for chronic pancreatic pain. MATERIALS AND METHODS: We performed a literature search using the databases MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase until April 2024. The included studies used neurostimulation techniques in participants with chronic pancreatic pain and reported pain-related outcomes, with a focus on pain scales and opioid intake. Two reviewers screened and extracted data, and a third reviewer resolved discrepancies. We assessed the risk of bias using the Jadad scale. The authors then grouped the findings by the target of the neurostimulation, cortex, spinal cord, or peripheral nerves; described the findings qualitatively in the results section, including qualitative data reported by the articles; and calculated effect sizes of pain-related outcomes. RESULTS: A total of 22 studies were included (7 randomized clinical trials [RCTs], 14 case series, and 1 survey), including a total of 257 clinical trial participants. The two outcomes most commonly reported were pain, measured by the visual analogue scale (VAS), numeric rating scale (NRS), and pressure pain threshold scores, and opioid intake. Two RCTs investigated repetitive transcranial magnetic stimulation (rTMS), showing a reduction of 36% (±16) (d = 2.25; 95% CI, 0.66-3.83) and 27.2% (±24.5%) (d = 2.594; 95% CI, 1.303-3.885) in VAS pain scale. In another clinical trial, transcranial direct-current stimulation (tDCS) and transcranial pulsed current stimulation were not observed to effect a significant reduction in VAS pain (χ2 = 5.87; p = 0.12). However, a complete remission was reported in one tDCS case. Spinal cord stimulation (SCS) and dorsal root ganglion stimulation were performed in a survey and 11 case series, showing major pain decrease and diminished opioid use in 90% of participants after successful implantation; most studies had follow-up periods of months to years. Two noninvasive vagal nerve stimulation (VNS) RCTs showed no significant pain reduction in pain thresholds or VAS (d = 0.916; 95% CI, -0.005 to 1.838; and d = 0.17; -0.86 to 1.20; p = 0.72; respectively). Splanchnic nerve stimulation in one case report showed complete pain reduction accompanied by discontinuation of oral morphine and fentanyl lozenges and a 95% decrease in fentanyl patch use. Two RCTs investigated transcutaneous electrical nerve stimulation (TENS). One found a significant pain reduction effect with the NRS (d = 1.481; 95% CI, 1.82-1.143), and decreased opioid use, while the other RCT did not show significant benefit. Additionally, one case report with TENS showed pain improvement that was not quantitatively measured. DISCUSSION: The neuromodulation techniques of rTMS and SCS showed the most consistent potential as a treatment method for chronic pancreatic pain. However, the studies have notable limitations, and SCS has had no clinical trials. For VNS, we have two RCTs that showed a non-statistically significant improvement; we believe that both studies had a lack of power issue and suggest a gap in the literature for new RCTs exploring this modality. Additionally, tDCS and TENS showed mixed results. Another important insight was that opioid intake decrease is a common trend among most studies included and that adverse effects were rarely reported. To further elucidate the potential of these neurostimulation techniques, we suggest the development of new clinical trials with larger samples and adequate sham controls.

Neuropancreatology: The Nervous System and Pain Management in Pancreatic Diseases.

The intricate network of the pancreatic nervous system plays a fundamental role in physiologic functions of the endocrine and exocrine pancreas. Several pancreatic diseases affect the normal functionality of the pancreatic nervous system. This chronic derangement leads to anatomical alterations, such as neural hypertrophy and increased nerve density. Perineural invasion is a prominent feature of pancreatic cancer, contributing to cancer progression and metastasis. Despite the fact that these pathogenic mechanisms are still incompletely studied and understood, the constant occurrence of these alterations highlights their importance in the pathophysiology of the pancreatic diseases. The occurrence of anatomical changes is strictly linked to the appearance of pain. Pancreatic pain has peculiar features, and its management is complex in clinical practice. In the present review, the evidence on lifestyle, pharmacological and interventional approaches for the management of pancreatic pain is presented. Analgesic therapy is the cornerstone of pain treatment. However, it is important to identify the individual characteristic of the patients and personalize the approach to pain management. Nevertheless, the incomplete efficacy of these strategies makes this field an area of unmet needs. The study of neuroplasticity is crucial to understand the mechanisms that regulate the pathophysiology of pancreatic diseases. Several trials testing new drugs with specific neuromodulatory effects are ongoing. However, further studies are needed to investigate crucial targets to develop novel therapies for the modulation of the nervous system and the prevention of complications of pancreatic diseases. This comprehensive review summarizes the importance of the nervous system in pancreatic diseases with a special focus on its anatomy and physiology, its pathophysiological features and clinical relevance in pancreatic disease, the treatment of pancreatic pain, and the identification of future trends of research.

Painless form of chronic pancreatitis - multicentre study.

BACKGROUND: The painless form of chronic pancreatitis is one of the rarer forms of the disease. While 80% to 90% of all chronic pancreatitis cases have abdominal pain as their clinical symptom, a smaller proportion of persons with chronic pancreatitis do not report typical pain. This form of the disease is often associated with exocrine and endocrine pancreatic insufficiency and weight loss, but the absence of pain symptoms may initially lead to misdiagnosis. METHODS: In a cohort of 257 people with chronic pancreatitis, the painless form was diagnosed in 30 individuals (11.6%), with an average age of 56 years and a predominance of men (71.4%). Thirty-eight percent were non-smokers and 47.6% of patients smoked up to 10 cigarettes per day. Alcohol intake of less than 40 g per day was reported by 61.9% of subjects. A quarter were moderately overweight, with a mean BMI of 26.5. Newly diagnosed diabetes mellitus had 25.7% of the subjects. RESULTS: A frequent finding was the demonstration of morphological changes, with calcifications found in 85,7% and dilatation of the pancreatic duct greater than 6.0 mm in 66%. A surprising finding was the presence of metabolic syndrome in 42.8% and the most frequent finding was the demonstration of decreased external pancreatic secretion (90%). CONCLUSION: Painless chronic pancreatitis is usually treated conservatively. We demonstrate a subset of 28 patients with painless chronic pancreatitis treated surgically. Most frequent indications were benign stenosis of the intrapancreatic bile duct and stenosis of the pancreatic duct. Although approximately 1 in 10 people with chronic pancreatitis present with a painless form of it, so that the form of the disease is described as rare, this does not change the fact that management of these people is still not optimal.

A comprehensive study of the abdominal ganglia part 3: An overview of the most commonly observed ganglion patterns.

Chronic pain from untreatable abdominal cancers or pancreatitis can severely decrease an individual's quality of life due to accompanying neuropathic pain, the most difficult pain mechanism to treat. Current treatment modalities focus on peripheral block or neurolysis procedures of the sympathetic ganglia in an attempt to curb the pain and improve quality of life. Reports indicated that these treatments are ineffective with patients either experiencing no relief or return the pain in a few weeks. The aim of this study was to investigate the location, macro- and microscopic morphology, and interconnections of the abdominal ganglia. The abdominal sympathetic ganglia of nine adult cadavers were investigated. The locations, morphology, interconnections, and microscopic structure were studied in 108 potential abdominal ganglia. Particular emphasis was placed on direct interconnectivity between the ganglia and histological morphology. A total of 100 ganglia were confirmed histologically to contain ganglion cells. The number and locations of most of the ganglia identified in our study does not correspond to that described by previous reports. Numerous interconnections between the different ganglia, as well as direct communications with the lumbar sympathetic chain ganglia were observed. The interconnections and presence of ganglion cells the nerves connecting the ganglia lead to the belief that the system should be considered as a unit and that pain fibers may be transmitted via alternative previously undiscovered pathways. If the pain treatments are to be reassessed with this information in mind, we believe that greater success could be achieved.

A comprehensive study of the abdominal ganglia part 2: Aorticorenal ganglia.

Investigation into reports of pain treatment for abdominal cancer and abdominal pain syndromes revealed the lack of human studies on some of the abdominal sympathetic ganglia. Recent studies on renal artery denervation therapy as treatment for resistant hypertension has made the aorticorenal ganglia of particular importance. The aim of this study was to investigate the location, morphology, interconnections, and histological nature of aorticorenal ganglia. We dissected nine abdominal cavities and harvested 37 aorticorenal ganglia. Hematoxylin and Eosin, and Masson's staining techniques were used to study the histological structure. Additionally, ganglia harvested from five individuals were stained with immunohistochemical techniques to test for tyrosine hydroxylase activity. All aorticorenal ganglia were located in proximity to the renal artery, and the majority were close to the vessel origin. Identification of multiple aorticorenal ganglia was the norm, and ranged from 2 to 4 on the left and 1 to 3 on the right. While the pattern of aorticorenal ganglia seemed to be unique in each individual case, the interconnections between these and other ganglia were vast. The aorticorenal ganglia shared direct connections with the celiac, gonadal, inferior mesenteric, and first lumbar sympathetic trunk ganglion. Contributions from the greater, lesser, and least thoracic splanchnic nerves were also observed. While the results of our study may not have direct clinical implications in isolation, the vast number of interconnections with the other abdominal ganglia may cause complications in procedures such as celiac ganglion block. In addition, aorticorenal innervation interruption may lead to hypotension.

A comprehensive study of the abdominal ganglia part 1: Celiac, phrenic and superior mesenteric ganglia.

INTRODUCTION: Patients with pancreatic cancer, chronic pancreatitis and other abdominal pain syndromes may develop debilitating pain throughout the course of their illness with little to no relief by most conventional methods. While some form of relief is experienced by patients, not all benefit from these procedures and side effects, while transitory in most cases are severe and often not expected. Our aim was therefore to investigate the anatomy surrounding the abdominal sympathetic ganglia, the target for the invasive procedures in an attempt to understand the variations in results. MATERIALS AND METHODS: The abdominal cavities of nine individuals were dissected and the ganglia investigated, harvested and histologically and immunochemical stained. RESULTS: The phrenic ganglion was found inconsistently and more often in the left than the right. If present it was located in association with the inferior phrenic artery and often connected to the celiac ganglion. The celiac ganglion was located anterior to the diaphragmatic crus on both sides and specifically posteromedial to the suprarenal gland and superior to the renal artery on the left. On the right it was located posterior to the suprarenal gland and inferior vena cava also superior to the renal vessels. The superior mesenteric ganglion was only positively identified in one individual and was located on the left lateral aspect of the superior mesenteric artery. CONCLUSION: The blockade procedures for treatment of pain are developed to target the area around the celiac artery where the ganglion is commonly described to be located. However, based on our results of its location and interconnections the ganglion is not located in the targeted area.

Diagnostics and therapy of chronic pancreatitis according to UEG guidelines.

Chronic pancreatitis is one of the diseases whose incidence is slightly increasing long-term. Apparently this is related to our current dietary habits and to the way of life in industrialized societies in general. In recent years, chronic pancreatitis has experienced greater diagnostic accuracy and reliability, although we are still unable to diagnose the early stages of the disease. In diagnostics, sophisticated imaging methods are in the forefront, and less frequent is the use of tests that assess the exocrine function of the gland. Non-invasive therapeutic approaches include dietary measures, including an absolute ban on alcohol. Drug therapy consists of the application of drugs containing pancreatic digestive enzymes and the treatment of pancreatic pain. The administration of capsules containing microparticles containing pancreatic enzymes, protected against inactivation of enzymes in an acidic gastric environment, is effective. In the treatment of pancreatic pain, we use a range of analgesic drugs, but abstinence from alcohol itself leads to a decrease in the frequency of pancreatic pain. Surgical therapy is very effective. Among other treatment methods include also endoscopic therapy. From the point of view of diagnosis and therapy, chronic pancreatitis is one of the conditions requiring a multidisciplinary approach. In this review article, we discuss the possibilities of diagnosis and treatment of chronic pancreatitis according to the current recommendations of UEG (United European Gastroenterology).

Analysis of lifestyle factors in patients with concomitant chronic pancreatitis and liver cirrhosis.

BACKGROUND & OBJECTIVES: Chronic pancreatitis (CP) and liver cirrhosis (LC) are common gastroenterological disorders but their co-incidence is considered to be rare. This study was designed to identify lifestyle factors that are associated with the development of concomitant LC in patients with CP. METHODS: In a retrospective case-control study between 2000 and 2005 122 patients with both CP and LC and 223 matched control patients with CP and no known liver disease were identified in 11 European university medical centers. Another 24 patients and 48 CP controls were identified in the period between 2006 and 2012. RESULTS: Alcoholism was most commonly regarded as aetiology for both CP (82.2%; 95% confidence interval (CI): 75.0-88.0%) and LC (79.5%; 95% CI: 72.0-85.7%) as compared to controls with CP only (68.6%; 95% CI: 62.7-74.1%). The preferred type of alcoholic beverage and pattern of alcohol intake were the only significant lifestyle factors in multivariate analysis. Frequency of alcohol intake (p = 0.105) and smoking status (p = 0.099) were not significant in bivariate analysis and dropped out of the multivariate model. Recurrent and chronic pancreatic pain was observed more often in patients with only CP, whereas gallstones were more common in individuals with both chronic disorders. CONCLUSIONS: These findings indicate that certain lifestyle factors might be important for the development of concomitant CP and LC. More studies will be needed to identify additional genetic and environmental factors underlying this association.

Macrophage-derived HMGB1 as a Pain Mediator in the Early Stage of Acute Pancreatitis in Mice: Targeting RAGE and CXCL12/CXCR4 Axis.

Extracellular high mobility group box 1 (HMGB1) activates the receptor for advanced glycation end products (RAGE) or Toll-like receptor 4 (TLR4) and forms a heterocomplex with CXCL12 that strongly activates CXCR4, promoting inflammatory and pain signals. In the present study, we investigated the role of HMGB1 in pancreatic pain accompanying cerulein-induced acute pancreatitis in mice. Abdominal referred hyperalgesia accompanying acute pancreatitis occurred within 1 h after 6 hourly injections of cerulein. The anti-HMGB1 neutralizing antibody or recombinant human soluble thrombomodulin (rhsTM), known to inactivate HMGB1, abolished the cerulein-induced referred hyperalgesia, but not pancreatitis itself. Plasma or pancreatic HMGB1 levels did not change, but macrophage infiltration into the pancreas occurred 1 h after cerulein treatment. Minocycline, a macrophage/microglia inhibitor, ethyl pyruvate that inhibits HMGB1 release from macrophages, or liposomal clodronate that depletes macrophages prevented the referred hyperalgesia, but not pancreatitis. Antagonists of RAGE or CXCR4, but not TLR4, strongly suppressed the cerulein-induced referred hyperalgesia, but not pancreatitis. Upregulation of RAGE, CXCR4 and CXCL12, but not TLR4, were detected in the pancreas 1 h after cerulein treatment. Our data suggest that HMGB1 regionally secreted by macrophages mediates pancreatic pain by targeting RAGE and CXCL12/CXCR4 axis in the early stage of acute pancreatitis.

Systematic Reviews Published in the April 2016 Issue of the Cochrane Library.

The Cochrane Library of Systematic Reviews is published quarterly as a DVD and monthly online ( http://www.thecochranelibrary.com ). The April 2016 issue (2nd DVD for 2016) contains 6875 complete reviews, 2417 protocols for reviews in production, and 36,600 short summaries of systematic reviews published in the general medical literature (this short summary database is no longer being updated). In addition, there are citations of 934,000 randomized controlled trials, and 15,700 cited papers in the Cochrane Methodology Register. The Health Technology Assessment database contains some 16,000 citations. One hundred and twenty-nine new reviews have been published in the previous 3 months, of which three have potential relevance for practitioners in pain and palliative medicine. The impact factor of the Cochrane Library stands at 5.939. Readers are encouraged to access the full report for any articles of interest, as only a brief commentary is provided.