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References 459

Downloaded from https://onlinelibrary.wiley.com/doi/ by Universität Bern, Wiley Online Library on [22/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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38 Garg PK. Antioxidants for chronic pancreatitis: reasons

for disappointing results despite sound principles. Gastroenterology 2013;144:e19–20.

39 Talukdar R, Lakhtakia S, Nageshwar Reddy D etal.

Ameliorating effect of antioxidants and pregabalin combination in pain recurrence after ductal clearance in chronic pancreatitis: results of a randomized, double blind, placebo-

controlled trial. J Gastroenterol Hepatol

2016;31:1654–1662.

40 Ahmed Ali U, Jens S, Busch ORC etal. Antioxidants for

pain in chronic pancreatitis. Cochrane Database Syst Rev 2014:CD008945.

41 Mohta S, Singh N, Gunjan D etal. Systematic review and

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analysis: is there any role for antioxidant therapy for

pain in chronic pancreatitis. JGH Open 2021;5:329–336.

42 Rustagi T, Njei B. Antioxidant therapy for pain reduction

in patients with chronic pancreatitis: a systematic review and meta-

43 Zhou D, Wang W, Cheng X etal. Antioxidant therapy for

analysis. Pancreas 2015;44:812–818.

patients with chronic pancreatitis: a systematic review and meta-

analysis. Clin Nutr 2015;34:627–634.

460

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Pain Mechanisms inChronic Pancreatitis

Pierluigi Di Sebastiano

Department of Innovative Technologies in Medicine & Dentistry, University D’Annunzio Medical School, Chieti, Italy

Division of Surgical Oncology, Clinica Pierangeli, Pescara, Italy

General Surgery Unit, “F. Renzetti” Hospital, Lanciano, Italy

1,2

, Fabio Francesco di Mola

1,2

, Tommaso Grottola2, and Rossana Percario

Introduction

Pancreatitis is a complex, multifactorial pathology that involves the pancreatic gland. Two main types of pancreatitis are known: acute and chronic pancreatitis. Chronic pancreatitis (CP) is the step following an acute injury, which determines irreversible modifications to parenchymal structure, leading in turn to exocrine and endocrine insufficiency. To sum up this concept, a definition was coined: “chronic pancreatitis is a pathologic fibro- inflammatory syndrome of the pancreas in individuals with genetic, environmental and/or other risk factors who develop persistent pathologic responses to parenchymal injury or stress” [1]. It is estimated that incidence of newly diagnosed CP ranges from 4 to 12 per 100,000 persons per year; male:female ratio is 1.5:1, and age at diagnosis is 35–55 years[2,3]. Alcohol abuse is a primary cause of pancreatitis (about 70% of cases). A miscellanea of other causes, among them cystic fibrosis tumor, pancreatic resection, congenital abnormalities, autoimmune, and genetic, are responsible for 10% of pancreatitis, while the etiology remains unclear for the remaining 20%[4,5]. Chronic inflammation of the pancreas is characterized by a series of histologic modifications, according to the “twoinflammation, due to the various etiologies mentioned above, determines injury to the pancreatic parenchyma. Sustained inflammation of the pancreas leads to activation of a profibrotic cascade, which replaces endocrine and exocrine cells and determines loss of function[6]. The clinical signs and symptoms of acute pancreatitis, in decreasing order of frequency, are: abdominal pain,

hit model”: acute

weight loss, steatorrhea, malabsorption, history of alcohol abuse, history of recurrent pancreatitis. Pain is the first symptom, which is reported by patients in almost 75% of cases and it persists in 85–97% of cases [7]. Three typical pain profiles have been described: (i)acute intense pain associated with repeated episodes of acute pancreatitis (acinar necrosis) in the early stage; (ii) a spontaneous lasting pain relief in association with severe pancreatic dysfunction in the late stage of uncomplicated chronic pancreatitis; and (iii) a persistent severe pain (or frequent recurrent episodes of pain) usually in association with local complications such as pseudocysts, ductal hypertension, or extrapancreatic complications such as partial obstruction of the common bile duct, peptic ulcer, and opiate addiction[8]. Timing of evolution of pain and of the pathology is impossible to predict at the time of onset[9], but it is calculated that it takes about 18 years from onset of the pathology to complete destruction of pancreatic parenchyma (burnout), which leads to a paradoxical decrease of clinical pain[7].

The main difficulty in diagnosing chronic pancreatic pain is the assessment of its entity. With the aim of providing a standardized measure of this symptom, several instruments have been validated: one- dimensional scales that use numeric (usually 0 to 10), verbal, or visual descriptors to quantify pain or the degree of pain relief [8]; and multidimensional scales that measure aspects of pain (intensity, nature and location, impact of paint on mood or activity level)[10].

Figure58.1 presents a graphical synthesis from suspect clinical findings to proposed treatment.

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

Clinical suspicion of chronic pancreatitis

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Laboratory blood tests and

contrast-enhanced CT scan

Pathogenesis 461

Confirmed

diagnosis

Yes

Accurate etiology research and avoidance of

Medical management: diet, analgesic non-opioid/

Yes

Continuing medical

management

smoking and alcohol

opioid drugs, pancreatic enzymes

Good pain

relief

MRI and endoscopic US

Confirmed

diagnosis

Endoscopic

management

Consider other diagnostic

hypothesis

Yes

Continuing medical

management

Figure58.1 Algorithm for chronic pancreatitis.

Pathogenesis

Pathogenesis of pancreatic pain is still incompletely understood. First theories emerged at the beginning of the nineteenth century during comparative studies in relation to stones in salivary and biliary ducts[11]. Three levels of pain interest are proposed: extrapancreatic, intrapancreatic, and central.

Good pain

relief

Surgical treatment

Extrapancreatic Pain

Bile duct and duodenal stenosis due to extensive pancreatic fibrosis and inflammation have been considered extrapancreatic causes of pain[12]. Becker and Mischke described a pathologic condition named “groove pancreatitis” in 19.5% of 600 patients with CP[13]. This is characterized by the formation of a scar plate between the head of the pancreas and the duodenum. The scar

Pain Mechanisms inChronic Pancreatitis

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462

complications are determined by the topography: disturbance in the motility of the duodenum, stenosis of the duodenum, and tubular stenosis of the common bile duct, occasionally leading to obstructive jaundice. These alterations have been suggested to be responsible for several symptoms present in CP and for postprandial pain due to compression of nerves and ganglia located between the pancreatic head and the duodenum[14].

Intrapancreatic Pain

Authors have identified several possible causes of intrapancreatic (or pancreatic) pain that can act together: ductal hypertension, parenchymal hypertension, parenchymal ischemia, pseudocysts, autoimmune disease, and neural remodeling.

Ductal Hypertension

Many investigators have related the origin of pain to increased pressure in pancreatic ducts due to strictures or stones [15]. It is calculated that normal pressure in the main pancreatic duct is between 7 and 15 mmHg, while in cases of CP, ductal pressure increases to 20–80 mmHg[16]. In ductal hypertension, alcohol plays an important etiopathogenetic role. Alcohol promotes lithiasis, which, in turn, promotes inflammation, which leads to strictures [17]. The “ductal hypertension hypothesis” as an explanation for pain in CP is supported by observations that decompression of a dilated pancreatic duct or pseudocyst frequently relieves pain[18]. Clinical trials have shown that relief from pain might be achieved by eliminating stones and strictures (surgery) or by reducing secretion (octreotide and somatostatine) [19]; however, it has been estimated that around 30% of the patients treated with decompressive surgery experience recurrent attacks of pain[20]. Conversely, some authors found no relationship between pain score and pancreatic pressure, although the intrapancreatic pressure was positively correlated with ductal changes, and they concluded that pancreatic parenchymal pressure is not closely related to pain in CP[21].

Interstitial Hypertension

According to this theory, pain is induced when increased pancreatic ductal and parenchymal pressure produce a compartment syndrome that causes ischemia[22]. This hypothesis is supported by experimental studies [23] which show increased interstitial pressure correlates with decreased blood flow in a feline model of CP. These abnormalities were reversed by surgical incision of the gland and draining the pancreatic duct, but were affected minimally by stenting the pancreatic duct. This would suggest that incision of the gland may be more important

in relieving pain than ductal drainage. In addition, different studies[24,25] revealed that the degree of pancreatic fibrosis has no significant influence on pain generation since no correlation between the degree of fibrosis and intensity of pain could be demonstrated.

Ischemia

According to this theory, vascular resistance is augmented due to fibrosis, which may lead to hypoperfusion of the parenchyma. In a feline study, it was demonstrated that pancreatic perfusion in case of chronic inflammation is decreased by 40%[26].

Pseudocysts

Pseudocysts can cause intense pain in patients with CP. In the majority of cases (60%) treatment with octreotide results in a reduction in size and the eventual disappearance of the pseudocysts together with reduction of pain[27]. Enlargement of pseudocysts, causing compression of adjacent structures, might be a mechanism for pain generation.

Autoimmune Disease

Several authors have described patients with CP associated with autoimmune diseases. Sarles etal.[28] described a type of CP that might be caused by an autoimmune mechanism and termed it “primary inflammatory sclerosis of the pancreas.” Yoshida and colleagues[29] reported a similar case and proposed that pancreatitis with these characteristics has to be considered as autoimmune pancreatitis. Current accepted terminology for this condition is lymphoplasmacytic sclerosing pancreatitis or autoimmune pancreatitis[30]. Pain is often associated with this type of inflammation although the genesis of this clinical symptom has not yet been investigated.

Neural Remodeling

Neurogenic inflammation as a result of pancreatic inflammation and neural remodeling has recently been linked to both acute and chronic pancreatitis. Neurogenic inflammation encompasses a series of vascular and nonvascular inflammatory responses, triggered by the activation of primary sensory neurons (C- or Aδ- type nerve fibers) and the subsequent release of inflammatory neuropeptides, including substance P (SP) and calcitonin gene- related peptide (CGRP), and has been validated in human as well as in animal models of acute and chronic pancreatic damage [31,32]. Pancreatic and central changes can be distinguished.

Pancreatic Changes

Keith etal. suggested initially that neural and perineural alterations might be important in pain pathogenesis in CP [33]. They concluded that pain severity correlated

Pathogenesis 463

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with the duration of alcohol consumption, pancreatic calcification, and the percentage of eosinophils in perineural inflammatory cell infiltrates, but not with duct dilatation. A subsequent study demonstrated an increase in both number and diameter of pancreatic nerve fibers in the course of CP [34]. In tissue specimens from patients with chronic pancreatitis, foci of chronic inflammatory cells were often found surrounding pancreatic nerves (called pancreatic neuritis), which by electron microscopic analysis exhibit a damaged perineurium and invasion by lymphocytes. The changed pattern of intrinsic and possibly extrinsic innervation of the pancreas in CP suggested that there could be an upregulation of neuropeptides that usually populate those enlarged nerves. In fact, a further study[35] showed that there were striking changes in peptidergic nerves in CP. The changes consisted of an intensification of immunostaining for CGRP and PS in numerous nerve fibers. Because both of these peptides are generally regarded as pain neurotransmitters, these findings provided evidence for direct involvement of pancreatic nerves in the long- lasting pain syndrome in CP. Later reports[30,36] revealed that the presence of growth- associated protein- 43 (GAP- 43), an established marker of neuronal plasticity, directly correlated with the pain scores in patients with CP. GAP- 43 is a neuronal protein known to be involved in the development of axonal growth cones and presynaptic terminals, and mRNA and protein levels of GAP- 43 are increased after neuronal lesions. In the chronically inflamed human pancreas, enzymatic and double fluorescence immunohistochemistry reveals a significant expression of GAP- 43 in the majority of pancreatic nerve fibers. These immunohistochemical findings correlated with clinical and pathological findings in patients with CP, including the parenchyma–fibrosis ratio and the degree of perineural immune cell infiltration. Furthermore, a strong relationship with individual pain scores was present. The infiltration of pancreatic nerves by immune cells is significantly related to pain intensity, whereas pain scores do not correlate with the degree of pancreatic fibrosis or with the duration of the disease. The demonstration of a direct relationship between the degree of perineural inflammation and the clinical pain syndrome strongly supports the hypothesis of “neuroimmune interaction” as an important, if not predominant, factor in pain generation in patients with CP.

An interesting question concerns the mechanisms that contribute to the enlargement of pancreatic nerves. A recent study analyzed the expression of nerve growth factor (NGF) and one of its receptors (TrkA) in patients with CP[32]. NGF belongs to the neurotrophin family and plays a role in neuroblast proliferation and neuronal maturation, affecting neuronal phenotype and maintaining neuronal survival. NGF signaling is

mediated via binding high- and low- affinity receptors. TrkA is present in dorsal root and peripheral ganglia cells of primary sensory nerves, and is involved in signal transduction of noxious stimuli and tissue injury. Inflammation results in an elevation of NGF levels in different diseases. Interestingly, NGF may itself have cytokine- like functions; it can modify mast cell, macrophage, and B- cell functions, but may also activate TrkA located on sensory and sympathetic nerve fibers innervating the site of inflammation, thus modulating neuroimmune interactions. In CP tissue samples NGF and TrkA mRNA expressions are markedly increased and enhanced in pancreatic nerves and ganglia. Comparison of the molecular findings with clinical parameters revealed a significant relationship between NGF mRNA levels and pancreatic fibrosis and acinar cell damage, and between TrkA mRNA levels and pain intensity. These findings indicate that the NGF/TrkA pathway is activated in CP and that this activation might influence nerve growth and the pain syndrome, most probably by modulating the sensitivity of NGFindependent primary sensory neurons through increasing channel and receptor expression [32]. Similar results showing positive correlation with pain intensity and frequency in patients with CP were reported for brain- derived neurotrophic factor gene expression, a member of the neurotrophin family [37]. In addition, upregulated NGF might influence the pain syndrome in CP patients by regulating transcription and synthesis of SP and CGRP, as well as through the release of histamine. The neuropeptide SP is the main tachykinin involved in neural transmission of sensory information, smooth muscle contraction, nociception, sexual behavior, and possibly wound healing and tissue regeneration [38,39]. SP has wide- ranging functional effects, including the crosstalk between nervous and immune systems by acting through its specific neurokinin- 1 receptor (NK- 1R). A recent report by Shrikande et al. [40] demonstrated a significant correlation between NK-

1R and clinical–pathologic findings in patients with CP. In CP samples, NK- 1R mRNA expression and protein were localized mainly in nerves, ganglia, blood vessels, inflammatory cells, and occasionally in fibroblasts. A significant relationship between NK1R mRNA levels and intensity, frequency, and duration of pain in CP patients was reported. The expression of NK- 1R in inflammatory cells and blood vessels also points to crosstalk between immunoreactive PS nerves and inflammatory cells and blood vessels, and further supports the existence of a neuroimmune interaction that probably influences the pain syndrome and chronic inflammatory changes in CP. In addition, a recent study demonstrated that PS mRNA expression levels were higher in CP tissues compared with controls, whereas

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464

neprilysin (NEP) mRNA levels showed no significant differences between CP patients and healthy subjects. In CP patients, PS serum levels correlated with those in tissues, and after surgical resection SP serum levels were reduced compared to preoperative values. Failure of NEP to overexpress in CP tissues was associated with significant miR- 128a overexpression, suggesting that in an PS/NEP- mediated pathway NEP fails to provide adequate surveillance of SP levels and this failure of NEP might be microRNA associated[41]. The exact mechanisms involved in the interaction between inflammatory cells and nerves and ganglia— neuroimmune crosstalk— are not yet fully clarified. Different cytokines have been shown to interact with SP in various paradigms for pain and inflammation. SP directly stimulates the release of interleukin 8 (IL- 8) from macrophages.

8 release generates hyperalgesia by stimulation of

ILpostganglionic sympathetic neurons. A significant increase of IL- 8 mRNA was reported in CP tissue samples[42]. IL- 8was present mainly in macrophages surrounding the enlarged pancreatic nerves, in remaining acinar cells, and often in ductal cells. IL- 8mRNA expression was positively correlated with the inflammatory score and the presence of ductal metaplasia in CP tissue samples. The reported findings in the literature on the interaction of SP and IL- 8, in combination with what has been reported in CP, suggests that the increased mRNA expression of IL- 8in CP could in part be mediated by SP released from sensory pancreatic nerves. In addition, the release of IL- 8 from the remaining exocrine pancreatic parenchyma suggests the fascinating hypothesis of an intrinsic maintenance of the inflammatory response after the initial damage to the pancreatic gland, thus sustaining progression and evolution of the disease. In addition, in a rat model it was found that repeated caerulein stimulation causes experimental pancreatitis that is mediated in part by stimulation of vanilloid receptor type 1 (VR1) on primary sensory neurons, resulting in endogenous SP release [43]. These results were confirmed in human pancreas[44]. In fact, an activation of the VR1in pancreatic tissues from patients with pancreatic cancer and CP is known. This increase was correlated with pain score in those patients. The release of PS and Na+/K+ATPase (NKA) from primary afferent (sensory) nerve

endings to various stimuli is now considered to be induced by activation of the capsaicin (vanilloid) receptor (VR1).

Central Involvement

Patients with CP have lower thresholds to pain in response to deep abdominal palpation than healthy individuals (reflecting secondary referred hyperalgesia in the musculature)[45]. Furthermore, the area of referred pain is expanded in patients with CP who are subject to experimental electrical stimulation of viscera with changes in evoked potentials in the brain[46–48]; these data have also been confirmed by magnetic resonance imaging. These patients report hyposensitivity to cutaneous stimulation, probably as a result of altered descending inhibitory influences on spinal nociceptive neurons[49] and hyperalgesia to rectosigmoid stimulation, accompanied by impairment in diffuse noxious inhibitory control, a phenomenon that reflects descending central inhibition of pain, thought to be a countermeasure to noxious stimulation[50]. Central sensitization is associated with reduced efficacy of invasive endoscopic and surgical treatments directed at the pancreas [51]. In contrast to the previous sentences, many patients with continuous pain do not have structural complications or evidence of inflammation: this could be the case of a neuropathic pain[52].

Conclusion

Pain is the most frequent clinical feature in patients with chronic pancreatitis. Many components are responsible for pain at intrapancreatic, extrapancreatic, or central nervous system level, with different expression in relation to the individual patient, nociceptive level, and comorbidities. There is a complex network among neuropeptides, immune cells, cytokines, and NGF. Neuropeptides released from the enteric nervous system and their spatial relationship with inflammatory cells play a key role in pancreatic pain. A fuller knowledge of the physiopathology of pain may lead to a complete and effective medical and surgical treatment of chronic pancreatitis and its manifestations.

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Pain Management inChronic Pancreatitis

Louise Kuhlmann, Søren S. Olesen, and Asbjørn M. Drewes

Centre for Pancreatic Diseases & Mech- Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark

467

Introduction

Abdominal pain is the most common symptom in chronic pancreatitis (CP), and it remains a clinical challenge. Pain affects about 90% of patients along the course of the disease and can present in various forms[1,2]. The classical description of pancreatic pain is a constant, dull, epigastric pain that radiates to the back and is worsened by intake of high- fat foods [3]. Intensity can present in forms ranging from a barely noticeable sensation to immense, continuous pain. Some patients experience episodes of severe abdominal pain, whereas others experience a daily aching pain that may be exacerbated by acute flares[3]. Pain pattern has traditionally been looked at as either type A pain (intermittent pain with pain- free intervals in- between) or type B pain (constant pain with or without exacerbations) as described by Ammann et al. [4], but recent research concluded that several shifts between pain patterns can occur during the course of the disease [5]. Regardless of the type of presentation, pancreatic pain highly affects quality of life and is a risk factor for hospitalizations[6,7]. In an examination of 540 American CP patients in the NAPS2 (North American Pancreatitis Study 2) cohort, most patients reported at least one hospitalization in the last year, 25% were on disability benefits, and there was no association between the duration of the disease and pain severity[1].

Pathophysiology

Pain in CP is poorly understood, and the underlying mechanisms are still debated. However, generally, it is agreed that pancreatic pain has elements of nociceptive

pain, obstructive factors, and neuropathic/neuroplastic pain[3,8].

Nociception is the process whereby the sensory nervous system encodes noxious stimulations. It involves the activation of specific neural processes leading to an action potential that forwards the signal through the dorsal horn of the spinal cord and through ascending pathways to the limbic, thalamic, and cortical regions of the brain. Nociception can lead to the perception of pain, but as outlined below, pain is a subjective experience including affective and cognitive components, together with suffering and changes in behavior.

It is hypothesized that ductal and mechanical alterations can cause pain, especially ductal obstructions and local inflammatory masses. However, radiological findings are not correlated with pain severity[3,9], and postoperative long- term pain relief is dependent on many other factors[10].

The perception of pain is generally induced by tissue injury, but the neural structures can become sensitized over time. Sensitization will induce a greater neural response to noxious stimulations and increase the sensation of pain, leading to hyperalgesia. Sensitization can occur both peripherally in the primary nociceptors and centrally at the spinal level or higher levels, including the brain[11].

In CP, continuous inflammation can cause the pancreatic nerve fibers to convey signals to the brain, which is perceived as pain. The inflammation will cause the pancreatic tissue to break down, and the nerves can then be exposed to toxins and chemicals, leading to nerve hypertrophy, an increase in density, and an increased number of nerve endings[12]. These findings correlate with pain intensity and support the theory of neuropathic pain[13]. In such cases, spontaneous firing from the damaged

Pain Management inChronic Pancreatitis

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nerves and central sensitization, and lack of normal inhibition can amplify the pain.

Pancreatic nociception seems to be affected significantly in CP, where increased excitability is linked to an upregulation of several molecules, including the vanilloid receptor TRPV1, calcitonin gene- related peptide (CGRP), nerve growth factor (NGF), and the proteaseactivated receptor 2 (PAR- 2) [8]. This upregulation is believed to drive neural sensitization, starting peripherally and progressing centrally.

Pain in CP can also be secondary, related to complications of CP and treatment[14]. For example, CP patients are at increased risk of developing peptic ulcers and bacterial overgrowth in the small intestines. Furthermore, the analgesic treatment, especially opioid treatment, may result in severe side effects that can increase pain, including constipation and opioid- induced hyperalgesia. All of these complications need to be addressed appropriately to reduce pain.

Pancreatic pain does, however, comprise more than just nociception and pain intensity. Cognitive dimensions of pain include how the patient perceives him/herself in pain and predispositions for coping with pain, including temper and personality traits. Affective dimensions include depression and anxiety, which affect pain processing and the perception of pain. Finally, behavioral dimensions, such as grimacing, crying, and limping, can induce empathy in relatives and secondarily increase pain behavior. However, this negative spiral can ultimately also increase pain perception[15].

This multifactorial nature needs to be taken into account when managing pain in CP. However, patients differ with respect to pathophysiology, genetic and social factors, etc., and treatment should be tailored to the individual rather than a one- size- fits- all approach[16].

Pain Assessment

The clinician should always start with a thorough pain assessment to guide treatment. Pain intensity, pain pattern, factors that provoke or worsen pain can be important when determining which mechanisms are involved in the development of pain. In addition, this information can be used when evaluating whether the pain is nociceptive or neuropathic. Evaluation should include questions on pain intensity and characteristic features, pain interference on physical and emotional functioning, and quality of life assessment[17]. For details, the reader is referred to a recent guideline paper in pain assessment of CP[14]. Unfortunately, pain assessment tools developed specifically for CP have proven to be either dominated by unidimensionality, lack of validity and reliability testing, or poor coverage [18]. For

example, the Izbicki pain score developed for CP has been used in several studies, although it has never been formally validated [19,20]. Other pain questionnaires such as the Brief Pain Inventory have also been used extensively in CP and it is validated for nonmalignant pain; however, it lacks focus on features characteristic of pancreatic pain[21]. As a result, the COMprehensive Pain Assessment Tool (COMPAT) has been developed to include all core dimensions of pain and aspects specific to CP[22]. In addition, a short- form was recently developed to increase the clinical usability, comprising five pain dimensions to characterize pancreatic pain, including pain severity, pain pattern, factors provoking pain, qualitative pain assessment, and spreading pain. It has been validated and tested to be reliable in three centers in Denmark, New Zealand, and the United States[23].

As many pain assessment questionnaires do not include quality of life assessment, they can be accompanied by questionnaires such as, for example, the European Organisation for Research and Treatment of Cancer (EORTC) questionnaire for quality of life assessment[24].

Besides pain assessment tools, quantitative sensory testing (QST) has been examined as a diagnostic test for assessing somatosensory function in CP. QST is a method for determining how patients respond to painful stimulations. For example, a QST technique called the Pancreatic QST (P- QST) protocol uses bedside pressure testing, repetitive stimulations, and conditioned pain modulation testing to evaluate the nociceptive responses indirectly [25]. Studies using P- QST have phenotyped patients based on pain patterns and correlate increasing widespread hypersensitivity with pain intensity, pain interference, and quality of life[26]. In addition, neurophysiological examinations, including P- QST, can be used to guide treatment according to the presence of segmental hyperalgesia and deficient descending pain inhibition[27]. However, these methods are only available in the most advanced laboratories and are still considered research tools.

Noninterventional Pain Treatment

Pain management should start with optimizing lifestyle factors. Alcohol consumption is a significant risk factor for the development of acute-in-chronic pancreatitis. It has also been linked to the occurrence of severe pain[9]. Likewise, smoking is related to pancreatic pain as there is an increased risk of pain with an increasing number of daily cigarettes[9]. Therefore, abstinence from alcohol and smoking is an important part of hindering the progression of chronic pain and acute flares into chronic pain. It can be supported

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