Abdominal pain is the hallmark symptom of chronic pancreatitis (CP), affecting more than 80% of patients, is associated with lower quality of life and is difficult to treat for several reasons (1). First, there are no accurate diagnostic tests that enable clinicians to differentiate between highly prevalent functional gastrointestinal disorders (2) and early CP (3,4). Second, the characteristics of pain in patients with different visceral diseases cannot differentiate between these conditions because visceral pain is characteristically diffuse, often referred to somatic structures, and can be accompanied by autonomic symptoms (e.g., sweating, changes in heart rate) (5). Third, our limited understanding of the pathophysiology of pain in CP results in highly variable and unpredictable long-term pain relief with current treatments that largely center on opioid analgesics and invasive procedures such as endoscopy and surgery. Fourth, there is a lack of targeted therapies based on an assessment of the pain system and comorbidities in the individual patient.
Increasing data show that pain in CP arises from chronic inflammation of the pancreas resulting in changes in the characteristics of intrapancreatic nerves, which cause increased nociceptive barrage from the primary sensory afferents into the spinal cord and brain. This will result in chronic sensitization and neuroplasticity of the nervous system, where pain becomes relatively independent of the original source (6). However, this fails to explain why approximately 10% of all CP patients have no history of pain (7) (i.e., primary painless CP) and, importantly, why the characteristics of pain including intensity, pattern, and location differ among patients. One potential explanation may be that the pain network is different between patients with CP due to the changes in the conductive properties of the primary nociceptive afferents through genetic variants affecting neurotransmitter receptors (8) and ion channels (9). For example, loss-of-function variants in voltage-gated sodium channels (e.g., SCN10A) have recently been implicated in hypoalgesic inflammatory bowel disease (10). Another possibility is whether psychiatric comorbidities modify the pain response in CP. CP pain may be governed by inflammation and tissue damage early in the course of disease but, over time, pain intensity becomes less associated with nociception and more with emotional and psychosocial factors. Although data are lacking in CP, a functional neuroimaging study of brain regions involved in acute vs chronic back pain showed that pain networks transformed from reward in patients with acute pain to reward and emotion over a 1-year period (11).
Pain and psychiatric conditions clearly overlap because previous neurochemical and neuroimaging studies have shown an association between brain regions involved in processing nociception, emotions, and cognition (12,13). Similar changes in these regions of the brain on functional imaging have been noted in patients with painful visceral disorders including irritable bowel syndrome (14), ulcerative colitis (15), and CP (16) as well as psychiatric conditions including depression, anxiety, and posttraumatic stress disorder (PTSD) (17,18). What remains unclear is whether there is simply an association or directional causality between pain and these psychiatric conditions. Recognizing the limitations of assessing psychiatric comorbidity through clinical questionnaires, recent studies have attempted to determine whether variants in genes associated with susceptibility to different psychiatric conditions are associated with visceral pain (19). The first study to evaluate the association between genetic susceptibility to psychiatric condition and painful CP found 15 depression-associated single nucleotide polymorphisms (SNPs) that are significantly associated with a constant-severe pain phenotype (20). Three of these SNPs are associated with a higher likelihood of responsiveness to antidepressant drugs based on pharmacogenomic studies, which suggests a potential role for these drugs in patients with painful CP (21).
In this issue of The American Journal of Gastroenterology, Dunbar et al. (22) evaluated patients with CP and recurrent acute pancreatitis (RAP) from the North American Pancreatitis Study II (NAPS2) to determine whether there are associations between pain and SNPs related to anxiety and/or PTSD. The patients were classified into 3 pain phenotypes categories: constant, severe, and constant-severe pain. All these pain phenotypes were significantly associated with lower mean age and quality of life scores. A total of 13 anxiety and/or PTSD SNPs were found to be significantly associated with an increased or decreased risk of pain in patients with RAP and CP (odds ratios between 0.2 and 3.83) when compared with the presence or absence (case or control, respectively) of specific pain phenotypes. These anxiety and/or PTSD SNPs lie within genes that regulate dopamine and other pathways, including the hypothalamic–pituitary–adrenal axis, and cell–cell interactions. The cell–cell interaction gene catenin delta 2 (CTNND2) showed significant associations across all pain categories in patients with CP and RAP. CTNND2 interacts with glutamate receptors in neurons, is involved in emotion and learning (23), and has been associated with depression (20) and anxiety (24).
In addition to limitations raised by the authors, which included small sample size, lack of patients with non-European ancestry, and lack of psychiatric phenotyping, it is important to highlight that NAPS2 was a cross-sectional study and pain phenotypes were based on a one-time assessment of pain in patients with a chronic condition. Therefore, it was not possible to evaluate for changes in pain intensity and pattern and the impact of treatment. The lack of control patients with primary painless CP and those with anxiety and/or PTSD SNPs without CP is also an important limitation. Finally, given that our knowledge of the genetic basis of psychiatric comorbidities is incomplete, the probability that any given SNP found through a genome-wide association study is truly relevant is low, leading to poor data reproducibility. This is clinically highlighted by the finding that only 7% of individuals develop PTSD, but 50%–85% of Americans experience a traumatic event during their lifetimes (25). In this context, genetic testing may seem unnecessary as PTSD is primarily understood in terms of prior exposure to a traumatic event and relevant environmental factors (e.g., alcohol use, smoking, etc). Nonetheless, genetic studies are an early but essential step toward clarifying the complex association between pain and psychiatric conditions.
Pain is a complex disorder similar to many diseases where there is interplay between disease, genetics, and environmental factors. Clinicians are not used to thinking of a symptom as a complex disorder and largely focus on morphologic findings to explain and treat chronic pain. Furthermore, current pain assessment tools focus on patient pain perception, primarily intensity, without proper incorporation of suffering and pain behaviors (26). Future studies using multidisciplinary evaluation and treatment for those with genetic susceptibility to or overt clinical manifestations of psychiatric illness may help achieve greater pain relief in patients with CP and other painful visceral disorders.
CONFLICTS OF INTEREST
Guarantor of the article: Vikesh K. Singh, MD, MSc.
Specific author contributions: Drafting the article: M.F.; critical revision of the article: A.M.D. and V.K.S.
Financial support: None to report.
Potential competing interests: V.K.S. is a consultant for AbbVie and Nestlé Health Science, medical advisory board participant for Envara, and receives grant support from Orgenesis, Theraly, and AbbVie. The remaining authors disclose no conflicts.
1. Singh VK, Drewes AM. Medical management of pain in chronic pancreatitis. Dig Dis Sci 2017;62:1721–8.
2. Sperber AD, Bangdiwala SI, Drossman DA, et al. Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome Foundation Global Study. Gastroenterology 2021;160:99–114.e3.
3. Hashimoto S, Futagami S, Yamawaki H, et al. Epigastric pain syndrome accompanying pancreatic enzyme abnormalities was overlapped with early chronic pancreatitis using endosonography. J Clin Biochem Nutr 2017;61:140–5.
4. Larino-Noia J, de la Iglesia D, Iglesias-Garcia J, et al. Morphological and functional changes of chronic pancreatitis in patients with dyspepsia: A prospective, observational, cross-sectional study. Pancreatology 2018;18:280–5.
5. Drewes AM, Olesen AE, Farmer AD, et al. Gastrointestinal pain. Nat Rev Dis Primers 2020;6:1–7.
6. Olesen SS, Krauss T, Demir IE, et al. Towards a neurobiological understanding of pain in chronic pancreatitis: Mechanisms and implications for treatment. Pain Rep 2017;2:e625.
7. Amodio A, De Marchi G, de Pretis N, et al. Painless chronic pancreatitis. Dig Liver Dis 2020;52:1333–7.
8. Pereira V, Goudet C. Emerging trends in pain modulation by metabotropic glutamate receptors. Front Mol Neurosci 2019;11:464.
9. Hockley JR, Gonzalez-Cano R, McMurray S, et al. Visceral and somatic pain modalities reveal NaV 1.7-independent visceral nociceptive pathways. J Physiol 2017;595:2661–79.
10. Gonzalez-Lopez E, Imamura Kawasawa Y, Walter V, et al. Homozygosity for the SCN10A polymorphism rs6795970 is associated with hypoalgesic inflammatory bowel disease phenotype. Front Med (Lausanne) 2018;5:324.
11. Hashmi JA, Baliki MN, Huang L, et al. Shape shifting pain: Chronification of back pain shifts brain representation from nociceptive to emotional circuits. Brain 2013;136:2751–68.
12. Yoshimura S, Okamoto Y, Onoda K, et al. Cognitive behavioral therapy for depression changes medial prefrontal and ventral anterior cingulate cortex activity associated with self-referential processing. Soc Cogn Affect Neurosci 2014;9:487–93.
13. Hou Q, Wang C, Hou C, et al. Individual differences in pain sensitivity in drug-naive patients with major depressive disorder: An fMRI study. Brain Imaging Behav 2021;15:1335–43.
14. Blankstein U, Chen J, Diamant NE, et al. Altered brain structure in irritable bowel syndrome: Potential contributions of pre-existing and disease-driven factors. Gastroenterology 2010;138:1783–9.
15. Turkiewicz J, Bhatt RR, Wang H, et al. Altered brain structural connectivity in patients with longstanding gut inflammation is correlated with psychological symptoms and disease duration. Neuroimage Clin 2021;30:102613.
16. Frokjaer JB, Bouwense SA, Olesen SS, et al. Reduced cortical thickness of brain areas involved in pain processing in patients with chronic pancreatitis. Clin Gastroenterol Hepatol 2012;10(8):434–8.e1.
17. Hong JY, Labus JS, Jiang Z, et al. Regional neuroplastic brain changes in patients with chronic inflammatory and non-inflammatory visceral pain. PLoS One 2014;9:e84564.
18. Kropf E, Syan SK, Minuzzi L, et al. From anatomy to function: The role of the somatosensory cortex in emotional regulation. Braz J Psychiatry 2019;41:261–9.
19. Fadgyas-Stanculete M, Buga AM, Popa-Wagner A, et al. The relationship between irritable bowel syndrome and psychiatric disorders: From molecular changes to clinical manifestations. J Mol Psychiatry 2014;2(4):4. eCollection 2014.
20. Dunbar E, Greer PJ, Melhem N, et al. Constant-severe pain in chronic pancreatitis is associated with genetic loci for major depression in the NAPS2 cohort. J Gastroenterol 2020;55:1000–9.
21. Buniello A, MacArthur JAL, Cerezo M, et al. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res 2019;47:D1005–12.
22. Dunbar EK, Greer PJ, Amann ST, et al. Pain experience in pancreatitis: Strong association of genetic risk loci for anxiety and PTSD in patients with severe, constant, and constant-severe pain. Am J Gastroenterol 2021;116(10):2128–36.
23. Lu Q, Aguilar BJ, Li M, et al. Genetic alterations of delta-catenin/NPRAP/Neurojungin (CTNND2): Functional implications in complex human diseases. Hum Genet 2016;135:1107–16.
24. Nivard MG, Mbarek H, Hottenga JJ, et al. Further confirmation of the association between anxiety and CTNND2: Replication in humans. Genes Brain Behav 2014;13:195–201.
25. Kessler RC, Wang PS. The descriptive epidemiology of commonly occurring mental disorders in the United States. Annu Rev Public Health 2008;29:115–29.
26. Drewes AM, Bellin MD, Besselink MG, et al. Assessment of pain associated with chronic pancreatitis: An international consensus guideline. Pancreatology 2021;20:1045–55.