Pancreatic Cancer Related Pain: Review of Pathophysiology and Intrathecal Drug Delivery Systems for Pain Management

Abstract

BACKGROUND: Pancreatic cancer (PC) is one of the most lethal cancers and is the eleventh most common cancer worldwide. This disease is characterized by an often-fatal evolution and a high burden of symptoms, particularly pain. Several studies have demonstrated that pancreatic cancer patients have a high prevalence of pain, with up to 82% of patients reporting pain, often requiring systemic strong opioids as mainstay treatment. This comprehensive review of pancreatic cancer related pain (PCRP), focuses on current mechanisms that lead to pain including regional invasion processes, as well as the local secretion of factors that sensitize nociceptive nerves. OBJECTIVE: Our objective was to conduct a review of PCRP and provide updates on intrathecal drug delivery in PC therapeutic recommendations. STUDY DESIGN: We used a narrative review design. We present a novel perspective in the field of pain research by converging data from intrathecal drug delivery trials with previous elements of molecular pain research in PCRP. METHODS: The literature review relating to PCRP pathophysiology and intrathecal drug delivery systems (IDDS) was done with searches of English, French, and Spanish abstracts, using PubMed, Dynamed, EMBASE, SciELO, Uptodate, Google Scholar, and manual searches of the bibliographies of known primary and review articles from IDDS inception until August 2020. Different search strings based on MESH terms were used including: pain, chronic pain, cancer pain, prevalence, pathophysiology, pancreatic cancer, analgesia, invasive pain procedures, celiac plexus neurolysis, pancreatic neuropathy, intrathecal drug delivery, or a combination of these terms. A narrative review based on these sources was prepared. RESULTS: This paper reviews aspects related to pancreatic adenocarcinoma and PCRP prevalence and focuses on recent developments in pathophysiology with IDDS as a pain management strategy. We summarize the best available evidence regarding intrathecal therapy (IT) for PCRP management; 18 studies of IDDS including at least 236 PC patients are analyzed. LIMITATIONS: Some limitations include: IDDS studies heterogeneity regarding disease stage, patient population, and technical aspects, such as catheter placement and treatment regimen, do not allow integration of studies. CONCLUSION: This review analyzes both past and current literature with a critical analysis of findings and respective recommendations. Most studies of IDDS in PCRP evaluate outcomes on pain using one-dimensional pain scales, such as VAS. Other relevant results, such as performance status or quality of life, are not frequently reported. Burden of disease variables, such as cancer stage, location, and comorbidities, like depression and systemic analgesia co-prescription, are usually not presented in these studies. In the same way, most studies do not precisely inform IDDS titration and IT medication. These factors make integration of IDDS in PC studies difficult. Future studies regarding impact of IDDS on pain control on quality of life, in this particular population, may help clinicians in deciding the optimal time and approach for IDDS. The studies should report data on particular disease, comorbidities, and treatment regimens. KEY WORDS: Adenocarcinoma, cancer pain, pain, pancreatic carcinoma, pancreatic neoplasms, pain management, physiopathology, prevalence

Comparison of regional arterial chemotherapy and systemic intravenous chemotherapy for advanced pancreatic cancer: a systematic review and meta-analysis

“…Pain in advanced pancreatic cancer seriously affects the quality of the patients' life; 82% of pancreatic cancer patients will be affected by cancer pain. [33] The commonly used analgesic methods in clinical practice are opioids, however, drug resistance often occurs. Endoscopic ultrasound-guided celiac plexus neurolysis is also a method to treat pancreatic cancer pain, but its clinical effect is not satisfactory.…”

High-rate breakthrough cancer pain and tumour characteristics – literature review and case series

“…Patients with pancreatic cancer reported high intensity cancer pain and severe interference with activities of daily living. [67][68][69] The most common sites of metastatic disease are peritoneum, liver and lung. 69 Abdominal pain is usually referred to as lower mid-back pain and is accompanied by weight loss and sometimes jaundice.…”

“…[67][68][69] The most common sites of metastatic disease are peritoneum, liver and lung. 69 Abdominal pain is usually referred to as lower mid-back pain and is accompanied by weight loss and sometimes jaundice. Local pain may be related to intraluminal activation of pancreatic enzymes and malignant obstruction and distention of the pancreatobiliary tree, whereas anterior mass progression may cause small bowel distension and severe abdominal or intestinal colic pain, usually accompanied by nausea and vomiting.…”

“…Local pain may be related to intraluminal activation of pancreatic enzymes and malignant obstruction and distention of the pancreatobiliary tree, whereas anterior mass progression may cause small bowel distension and severe abdominal or intestinal colic pain, usually accompanied by nausea and vomiting. 69 Involvement of the peritoneum, abdominal wall, retroperitoneal tissues, and both intrapancreatic and extra pancreatic nerve plexuses, including the celiac plexus, determines mixed nociceptive and neuropathic pain. 1,66,69 Despite the World Health Organization guidelines regarding mild-to-moderate cancer pain treatment, only 40-49.6% of patients with pain due to pancreatic cancer receive a combination of opioids, adjuvant analgesic drugs and TIRF as the first choice for the treatment of unpredictable and rapid-onset BTcP.…”

“…69 Involvement of the peritoneum, abdominal wall, retroperitoneal tissues, and both intrapancreatic and extra pancreatic nerve plexuses, including the celiac plexus, determines mixed nociceptive and neuropathic pain. 1,66,69 Despite the World Health Organization guidelines regarding mild-to-moderate cancer pain treatment, only 40-49.6% of patients with pain due to pancreatic cancer receive a combination of opioids, adjuvant analgesic drugs and TIRF as the first choice for the treatment of unpredictable and rapid-onset BTcP. 41…”