Review Neuropathic Pain in Pancreatic Cancer: An Update of the Last Five Years Raffaele Pezzilli Potenza County Medical Association, 85100 Potenza, Italy; [email protected] or [email protected]; Tel.: +39-09711564229 Abstract: Pain is the main symptom of pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC). Pain in pancreatic cancer may be visceral, somatic or neuropathic in origin. Pain is produced by tissue damage, inflammation, ductal obstruction and infiltration. Visceral nociceptive signals caused by damage to the upper abdominal viscera are carried along sympathetic fibers, which travel to the celiac plexus nerves and ganglia, which are found at the T12-L2 vertebral levels, anterolateral to the aorta near the celiac trunk. From here, the signals are transmitted through the splanchnic nerves to the T5-T12 dorsal root ganglia and then on to the higher centers of the central nervous system. Somatic and neuropathic pain may arise from tumor extension into the surrounding peritoneum, retroperitoneum and bones and, in the latter case, into the nerves, such as the lumbosacral plexus. It should also be noted that other types of pain might arise because of therapeutic interventions, such as post-chemoradiation syndromes, which cause mucositis and enteritis. Management with non-steroidal anti-inflammatory agents and narcotics was the mainstay of therapy. In recent years, celiac plexus blocks and neurolysis, as well as intrathecal therapies have been used to control severe pain, at times resulting in a decreased need for drugs, avoiding their unwanted side effects. Pain may impair the patient’s quality of life, negatively affecting patient outcome and resulting in increased psychological stress. Even after recognizing the negative effect of cancer pain on patient overall health, studies have shown that cancer pain is still undertreated. This review focuses on neuropathic Citation: Pezzilli, R. Neuropathic pain, which is difficult to handle; thus, the most recent literature was reviewed in order to diagnose Pain in Pancreatic Cancer: An Update neuropathic pain and its management. of the Last Five Years. Gastroenterol. Insights 2021, 12, 302–309. https:// Keywords: pancreatic neoplasms; pain management; visceral pain; nociceptive pain; systematic review doi.org/10.3390/gastroent12030027 Academic Editor: Yasushi Sasaki Received: 31 May 2021 1. Introduction Accepted: 24 June 2021 Pain is the main symptom of pancreatic cancer (pancreatic ductal adenocarcinoma, Published: 25 June 2021 PDAC), affecting 75% of patients at the time of diagnosis and over 90% of those in ad- vanced stages [1]. This review focuses on neuropathic pain, which is difficult to handle; Publisher’s Note: MDPI stays neutral thus, the most recent literature was reviewed in order to diagnose neuropathic pain and with regard to jurisdictional claims in its management. published maps and institutional affil- 2. Pancreatic Pain Diagnosis and Treatment: What We Know iations. Pain in pancreatic cancer may be visceral, somatic or neuropathic in origin. Pain is produced by tissue damage, inflammation, ductal obstruction and infiltration. Visceral nociceptive signals caused by damage to the upper abdominal viscera are carried along sympathetic fibers that travel to the celiac plexus nerves and ganglia, which are found at the Copyright: © 2021 by the author. Licensee MDPI, Basel, Switzerland. T12-L2 vertebral levels [2,3], anterolateral to the aorta near the celiac trunk. From here, the This article is an open access article signals are transmitted through the splanchnic nerves to the T5-T12 dorsal root ganglia and distributed under the terms and then on to the higher centers of the central nervous system. Somatic and neuropathic pain conditions of the Creative Commons may arise from tumor extension into the surrounding peritoneum, retroperitoneum and Attribution (CC BY) license (https:// bones and, in the latter case, into the nerves, such as the lumbosacral plexus. It should also creativecommons.org/licenses/by/ be noted that other types of pain may arise as a consequence of therapeutic interventions, 4.0/). such as post-chemoradiation syndromes, which cause mucositis and enteritis [4]. Gastroenterol. Insights 2021, 12, 302–309. https://doi.org/10.3390/gastroent12030027 https://www.mdpi.com/journal/gastroent Gastroenterol. Insights 2021, 12, FOR PEER REVIEW 2 pathic pain may arise from tumor extension into the surrounding peritoneum, retroperi- toneum and bones and, in the latter case, into the nerves, such as the lumbosacral plexus. It should also be noted that other types of pain may arise as a consequence of therapeutic interventions, such as post-chemoradiation syndromes, which cause mucositis and enter- itis [4]. Clinical examination should focus especially on the presence of two prominent Gastroenterol. Insights 2021, 12 303 symptoms: allodynia, which is a painful response to a normally innocuous stimulus, and hyperalgesia, which is an increased pain response to a normally painful stimulus [5]. There is no diagnostic gold standard for neuropathic pain, and so diagnosis is based on Clinical examination should focus especially on the presence of two prominent symp- clinical judgement; the elements of this process are to identify painful symptoms and a toms: allodynia, which is a painful response to a normally innocuous stimulus, and hyperalgesia,clinical which history is an increased that all pain match response a neuroanatomical to a normally painful pattern stimulus [6]. [5]. There is no diagnostic goldHistorically, standard management for neuropathic with pain, non-steroidal and so diagnosis anti-inflammatory is based on clinical agents and narcotics judgement;was the the elements mainstay of this of processtherapy. are In to recent identify years, painful celiac symptoms plexus blocks and a clinicaland neurolysis, splanch- history thatnicectomy all match a and neuroanatomical intrathecal therapies pattern [6 ].have been used to control severe pain, at times result- Historically,ing in managementa decreased withneed non-steroidal for drugs, avoiding anti-inflammatory their unwanted agents and side narcotics effects. Pain may impair was the mainstaythe patient’s of therapy. quality In recent of life years, (QoL), celiac negatively plexus blocks affecting and neurolysis, patient splanch-outcome and resulting in nicectomy andincreased intrathecal psychological therapies have stress. been usedEven to after control recognizing severe pain, the at times negative resulting effect of cancer pain in a decreased need for drugs, avoiding their unwanted side effects. Pain may impair on patient overall health, studies have shown that cancer pain is still undertreated [7]. the patient’s quality of life (QoL), negatively affecting patient outcome and resulting in increased psychological stress. Even after recognizing the negative effect of cancer pain on patient overall3. Literature health, studies Search have shown that cancer pain is still undertreated [7]. 3. Literature SearchA search on PubMed was carried out using the MESH terms pancreatic cancer and A searchpain, on which PubMed were was applied carried outto full using texts the of MESH papers terms published pancreatic in the cancer last and 5 years in the English pain, whichlanguage. were applied As toreported full texts in of Figure papers 1, published a total of in 244 the lastpapers 5 years were in the found. English Of these 244 papers, language. As50 reportedwere excluded in Figure 1because, a total ofthey 244 papersreported were data found. referring Of these to 244 topics papers, different 50 from those re- were excludedlated because to thethey aimreported of this study. data referring Of the to194 topics remaining different papers, from those 161 related were excluded because to the aimthey of this were study. case Of thereports, 194 remaining review articles papers, or 161 papers were excluded containing because no original they data. Thus, 33 were case reports,papers reviewwere finally articles selected. or papers Of containing these 33 pape no originalrs, 1 referred data. Thus, to the 33 pathophysiology papers of pain, were finally5 selected.to experimental Of these 33data papers, on animals, 1 referred 8 to to the pathophysiologywell-being of patients of pain, with 5 to pancreatic cancer experimentalpain data and on 19 animals, to the 8therapy to the well-being of neuropathic of patients pain. with pancreatic cancer pain and 19 to the therapy of neuropathic pain. Figure 1. PRISMA flowFigure chart 1. of PRISMA selected literature. flow chart of selected literature. 4. Experimental Studies of Neuropathic Pain 4. Experimental Studies of Neuropathic Pain From an anatomical point of view, genetically engineered mice have increasingly been used to study neuropathyFrom an andanatomical neural invasion point of due view, to pancreatic genetically cancer. engineered Saricaoglu mice and have increasingly coworkers showedbeen used that to nerve study trunks neuropathy in the mouse and pancreas neural were inva exclusivelysion due to located pancreatic around cancer. Saricaoglu the intrapancreaticand coworkers lymphoid showed structure that and nerve vessels, trunks and analyzed in the mouse the density pancreas of the were nerve exclusively located trunks, particularlyaround ofthe the intrapancreatic sensory nerves, lymphoid which was higheststructure in theand pancreatic vessels, headand analyzed [8]. the density of From a functional point of view, Han et al. tested the potential influence of