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Appendix:Recommendations from the Working Group for the International Consensus Guidelines for Chronic Pancreatitis in collaboration with the International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society and European Pancreatic Club

Asbjørn M Drewes1, Stefan A W Bouwense2, Claudia M Campbell3, Güralp O Ceyhan4, Myriam Delhaye5, Ihsan Ekin Demir4, Pramod K Garg6, Harry van Goor2, Christopher Halloran7, Shuiji Isaji8, John P Neoptolemos7, Søren S Olesen1, Tonya Palermo9, Pankaj Jay Pasricha10, Andrea Sheel7, Tooru Shimosegawa11, Eva Szigethy12, David C Whitcomb13 & Dhiraj Yadav13, for the Working group for the International (IAP – APA – JPS – EPC) Consensus Guidelines for Chronic Pancreatitis

1. Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark2. Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands 3. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, USA4. Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany 5. Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium 6. Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India7. Institute of Translational Medicine, University of Liverpool, United Kingdom8. Department of Surgery, Mie University Graduate School of Medicine, Japan9. Seattle Children's Hospital Research Institute, Washington School of Medicine, USA10. Center for Neurogastroenterology, Johns Hopkins University School of Medicine, Baltimore, USA11. Department of Gastroenterology. Tohoku University Graduate School of Medicine, Japan12. Visceral Inflammation and Pain Center, Division of Gastroenterology, University of Pittsburgh and UPMC, Pittsburgh, Pennsylvania, USA13. Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and UPMC, Pittsburgh, Pennsylvania, USA

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Dhiraj Yadav and Claudia M Campbell

Q1. What is the natural history and burden of pain in chronic pancreatitis (in relation to treatment)?

Abdominal pain is the most frequent symptom of CP. However, the severity, temporal nature, and natural history of pain is highly variable (Quality assessment: moderate, recommendation: strong)

While variation in disease estimates exist, the prevalence of CP has been approximated at ~50/100,000 population(1). Abdominal pain, alone or during episode(s) of acute pancreatitis, is the most common symptom of CP. Patients typically describe their pain as a dull, sharp or nagging sensation in the upper abdomen, which can radiate to the back, and often presents after or worsened by food intake. In well conducted natural history studies, pain was observed as the initial presentation in ~75% of patients(2), and present during the clinical course in 85-97%(2–5). The prevalence of pain is influenced by demographic factors and etiology. Patients with early onset-disease and those with alcohol etiology are more likely to have pain when compared with patients who have late-onset idiopathic chronic pancreatitis(2,3).

Pain experience in an individual patient varies widely during the clinical course of disease. For example, in a multicenter cross-sectional study of 518 chronic pancreatitis patients of all etiologies, no, mild-moderate, and severe pain in the preceding year was reported by 15.6%, 17.6% and 66.8% patients respectively. Among patients with pain, 38% reported intermittent pain, and 62% constant pain. Among those with constant pain, only 7% experienced constant severe pain that did not change over time(6). Interestingly, the duration of disease did not influence the pain experience(7). During longitudinal follow-up of 207 patients with alcoholic chronic pancreatitis, two patterns of pain were observed – type A and type B(8). Type A pain was described as episodes, which could last for up to 10 days at a time with pain free intervals lasting up to several months. Type B pain was described as prolonged periods of persistent or recurring pain with no pain free intervals, often requiring repeated hospitalizations. Patients who had only type A pain (44%) were managed medically, while those with type B pain (56%) underwent surgical intervention to achieve pain relief followed by either pain free intervals or a change of pattern to Type A pain(8). A similar empiric analysis has not been conducted in patients with non-alcoholic etiologies, but it is likely that the natural course in these patients also has similar variability in pain patterns during the clinical course.

Whether and what fraction of patients achieve a complete and lasting pain-free status during the course of disease remains a matter of debate. According to the burn-out hypothesis, irrespective of the type of treatment received, a majority of patients with chronic pancreatitis achieve lasting pain-free status during the clinical course(3,8). This claim, however, has not

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been substantiated by others, mainly due to persistence of pain symptoms in a significant fraction of patients with ongoing pain even after 10 or more years of disease(9). The prevalence of pain seems to decrease with progression of morphological (e.g. calcifications) and functional changes (e.g. endocrine and exocrine insufficiency), however, this does not guarantee a transition to pain-free status(3,5,8).

Continued alcohol consumption is linked with disease progression(10), and increases the frequency of pain episodes in patients with established chronic pancreatitis(11). Although no empiric data specifically associates tobacco smoking to the pain experience, given the role of tobacco in disease progression(12), it is conceivable that it may have an indirect and negative effect on pain.

The underlying mechanisms responsible for producing pain in chronic pancreatitis are unclear. Pain could be related to status of the pancreas (e.g. acute or chronic inflammation, pancreatic ductal obstruction from stones and/or stricture), peripancreatic structures (e.g. common bile duct stricture, gastric outlet or duodenal obstruction) or local complications (e.g. pseudocyst). In a subset, no obvious structural cause is apparent. Similar to other pain conditions, little association exists between pain report and morphological characteristics in chronic pancreatitis patients(6). Thus, other factors clearly play a role in individual patient’s pain experience. Studies to systematically evaluate risk factors for the development of pain and examination of pain course and patterns are warranted. Such work may lead to the formulation of novel treatments that could potentially be deployed proactively to intervene for patients suffering with painful chronic pancreatitis.

Naturally, CP is a major burden for the patients and it is regarded the most severe complication to the disease. Accordingly, both pain intensity and the frequency of pain attacks have been shown to reduce life quality in patients with CP(7,13). A recent large study, using SF12 questionnaire, found pain to be the single most important predictor of quality of life in CP. When compared with patients with no pain, those with constant pain had a 5 (in the absence of severe pain) or 10-point (in the presence of severe pain) reduction in physical, and 7-point reduction in mental quality of life (a difference of 3 or more points is clinically relevant) (14).

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Pankaj Jay Pasricha, Søren Schou Olesen and Eva Szigethy

Q2. Are there different types of pain in CP and what does it mean for treatment?Pain in CP remains poorly understood and inadequately correlated with neurobiological mechanisms. By definition, CP is characterized by inflammation but unlike other inflammatory disorders, there is a paucity of therapeutic attempts targeting this particular aspect of pathophysiology. On the other hand, there are striking changes in structure and function in both the peripheral and central nervous system in this condition, lending plausibility to a maladaptive state that includes both neuropathic and dysfunctional pain. In the absence of effective anti-inflammatory approaches, it is clearly important to focus on the alteration of function that accompanies these changes in the nociceptive system as a potential therapeutic target. (Quality assessment: low; Recommendation: strong; Agreement: strong)

Pain in chronic pancreatitis is difficult to manage for multiple reasons as described several times in this position paper. A significant factor in this regard is the heterogeneous and multiplex nature of pain, representing different drivers (anatomical, inflammatory, primary neurobiological, psychosocial), locations (peripheral, central), and confounding factors (pharmacological dependence and aggravation). This chapter will attempt to provide a classification based on the etiopathogenesis of pain in the hope that it will provide the basis of more rational approach to treatment.

General biological categories of painAs reviewed by Woolf, pain can be classified broadly in terms of utility to the living being as either being adaptive/protective or maladaptive/pathological(15). Adaptive pain serves the organism by helping it to avoid harm from environmental or internal insults. Thus pain in response to a prick or contact with a hot object warns us of the possibility of serious injury and is the purest manifestation of the “nociceptive” response. In the clinical context, the most common form of pain can also be considered adaptive occurring in response to tissue injury of various origins (mechanical, chemical, infectious, immunological etc.), with accompanying inflammation that results in hypersensitivity (sensitization) of the nociceptive system. Such a pain is also adaptive in that it either results in seeking attention for it or causes avoidance of physical contact/movement that could interfere with healing and/or aggravate the injury.

The other broad category of pain can be considered maladaptive, in that it does not serve a useful purpose, as it is no longer linked to ongoing injury or pain in the relevant tissue. Instead, the pain is believed to result from either damage (neuropathy) or dysfunction to the nociceptive system itself, which is now behaving “pathologically” (hence the name).

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Clinical patterns of pain in chronic pancreatitis An early approach to classifying pain in chronic alcoholic pancreatitis was made by Amman et al based on the clinical pattern in a cohort of 207 patients followed prospectively with both surgical and conservative management(8). “A-type pain” pattern, with one or more discrete episodes of pain interspersed with pain-free intervals of several months to years, was observed in all patients in their series. Slightly less than half (44%) of patients also had “B-type pain” described as persistent (i.e. daily) pain over prolonged periods of time and/or closely clustered exacerbations of severe pain, with the typical case having severe pain 2 or more days per week for at least 2 months and requiring repeated hospitalizations in most instances.

A more recent study by the North American Pancreatic Study (NAPS) group also studied a prospectively followed cohort of 414 patients of mixed etiology (nearly half of whom were thought to be alcoholic in etiology) and attempted to classify pain according to temporal and severity criteria, and correlate these with quality of life, resource utilization and pain-associated complications(7). Although their parsing of pain categories was more nuanced, it appears that alcohol, tobacco use as well as most meaningful clinical outcomes including quality of life were best predicted when “intermittent” (about 45% of patients) versus “constant” pain were compared, thus echoing the earlier binary classification. However, it should be pointed out the descriptions in these two papers are not strictly comparable: the NAPS2 data is more based on patient recall of their pain pattern at a single time point whereas the study by Amman et al gathered this information by longitudinal observation of their patients.

Pattern of pain CP and correspondence with putative neurobiological causesInflammatory PainIt is intuitively appealing to suggest that a significant, if not major, type of pain in CP is inflammatory in nature, whether or not associated with mechanical/space-occupying lesions such as ductal dilation or pseudocysts. However, a more rigorous analysis would require consideration of the following issues before coming to a final conclusion:

1. Biological plausibility. Dolor (pain) is a cardinal feature of inflammation and the biological and clinical evidence linking the two is incontrovertible in general. The development of animal models to study pain in CP has also shown that inflammatory pain in CP is mechanistically generally similar to other chronic inflammatory conditions. The expression of numerous algogenic factors is altered in experimental models as well as in human pancreatic specimens obtained from patients with CP upon surgery. These molecules include NGF and its high affinity receptor (TrkA)(16,17), TRPV1(18), as well as SP and its receptor, NK-1(16,19,20), CGRP(19), BDNF(21) as well as other neurotrophic factors such as artemin and its receptor GFR3(22). Elevated levels of PGE2 have recently been found in the pancreatic secretions of

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patients with early CP who have significant pain but no clear structural abnormalities(23). Some but not all of these have been shown to correlate with pain severity (also see below), although causation is not proven. Nevertheless, these studies have been very valuable in supporting and strengthening evolving theories on the neural pathogenesis of pain in chronic pancreatitis, in keeping with what we have learnt from animal models(24).

2. Coincidence between inflammatory and painful exacerbations in time. If this was true, it would follow that the “intermittent” episodes of pain observed in patients correspond to a “flare” of inflammation. Many of these patients are hospitalized for “pancreatitis” during such episodes so such a connection is certainly plausible, although the literature does not actually provide evidence of correlation with established biomarkers of inflammation. With persistent pain patterns, the association with inflammation is even more controversial. In their paper, Amman et al state that, type B pain was thought to most often result from a potentially correctible cause - pseudocysts (54%), obstructive cholestasis (24%) and “presumptive ductal hypertension” (14%), with prompt relief by a drainage procedure(8). However, these results probably reflected the surgical bias in their series, as they have not been borne out by others. In a large prospective cohort study conducted by the NAPS2 consortium, there was no correlation between temporal pattern and the presence or absence of radiological evidence of inflammation or obstructive pathology. Indeed, many patients with CP but no pain had similar findings than those with pain(7).

3. Correlation between severity of inflammation and painThere are two lines of evidence on this subject, with seemingly conflicting results. The first comes from careful histological examination of pancreatic specimens from patients with CP showing correlation between the expression of several inflammatory biomarkers or cell types with pain. Immune cells are abundantly found in CP and their products including cytokines such as IL-8 and chemokines such as fractalkine are strongly implicated in neural responses and correlate with pain intensity in humans(25,26). Mast cells are also increased in chronic pancreatitis in humans(27) and patients with painful CP demonstrated a 3.5-fold increase in pancreatic mast cells as compared with those with painless CP(28). On the other hand, and in contrast to the earlier studies by Amman et al(8), the largest prospective study to date using modern radiological techniques found no evidence that either pain severity or temporal pattern correlates with inflammatory changes on imaging(6). Other smaller studies also provide support for the contention that morphological changes do not correlate with pain(29).

4. Attenuation of pain with lessening of inflammation by natural history, medical or surgical intervention. A recurring controversy in the field has been whether pain in CP recedes. In the study by Amman et al, pain patterns were more evident early in the course of the disease and with time both apparently gradually dissipated. Hence, more

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than 80% of patients with alcoholic pancreatitis were pain-free 10 years after the onset with the same proportion of patients also exhibiting severe pancreatic insufficiency; at this stage about 50% were diabetic, presumably reflecting endocrine failure(8). This has led this group to champion the so-called “burn-out” theory for pain in CP; however no evidence exists that it is actually the inflammation that is burnt out instead of just functional pancreatic parenchyma. Further, others have refuted this, most convincingly by the NAPS2 study, which showed that neither pain pattern nor severity changed with the duration of the disease, albeit based on patient recall data(7).

Another way to approach this relationship is to examine “therapeutic trials” with interventions directed primarily at inflammation. Unfortunately, there is a paucity of such interventions with anti-oxidants being the most studied class of agents, under the reasonable assumption that this will be associated with a reduction in inflammation. A Cochrane review of 12 such studies concluded that there was a slight reduction in the intensity of pain but no change in the proportion of patients that were pain free, thus making it difficult to draw a firm conclusion(30).

It is much more difficult to use surgical or endoscopic approaches in this way as determining any effect of putative reduction in inflammation from these interventions would be seriously flawed by the presence of multiple and complicated confounding factors. Even so, there have been no studies that directly examine the relationship between the degree of inflammation found at pancreatectomy and subsequent pain relief (although there are several descriptions relating this to pre-surgical pain status, as described above).

Neuropathic and Dysfunctional PainEvidence from animal models has provided convincing evidence that CP results in hypersensitivity of pain responses to pancreatic stimulation, associated with impressive sensitization of the primary nociceptive neuron with specific electrophysiological and molecular changes (such as a reduction in the IA current and changes in the expression of TRPV1, neuropeptides and other factors). These appear to be driven by factors in the milieu of CP such as NGF and more recently, TGF(24,31). Animal models also suggest a component of central sensitization including potential roles for spinal glial activation and descending inhibitory pathways facilitated by the rostral ventromedial medulla (RVM)(32–34).

Corresponding evidence for humans with CP is also beginning to emerge. Patients with severe CP have lower pain and expanded pain referral areas thresholds than patients with moderate CP or healthy volunteers, as measured by pressure and electric stimuli in selected dermatomes, reflecting somatic hyperalgesia and allodynia, which

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is a reflection of spinal sensitization(35,36). Alterations in descending inhibitory influences on spinal nociceptive neurons have been inferred based on changes in sensation at remote sites(35–38). (Electroencephalograpy (EEG) in patients with CP show functional changes suggesting a maladaptive pain response(36,39–41). In addition to functional changes, there are also morphological effects of CP on the nervous system. This is best demonstrated by the changes in neural density, hypertrophy and both peri- and endo-neural inflammatory infiltration in resected clinical specimens(42). The CNS may also be affected as seen by microstructural changes in cingulate and prefrontal cortices. Remarkably, there were differences in brain imaging between patients with episodic versus continuous pain as well as overall correlations between MRI findings and pain scores(43).

“Mechanical” causes of pain.In some cases of chronic pancreatitis, pain may likely be due to large space occupying lesions such as pseudocysts or cancers, or ductal obstruction from strictures or stones. Presumably this kind of pain results from activation of mechanosenstive nociceptive nerves and may represent another primary mechanism in some instances. More often, however, these lesions trigger or exacerbate pain on a background of a nociceptive system that has been sensitized by inflammatory or neuropathic mechanisms as discussed above.

Conclusions, Perspective and Future DirectionsPain in CP remains poorly studied and inadequately correlated with neurobiological mechanisms. By definition CP is characterized by inflammation but unlike other inflammatory disorders, there is a paucity of therapeutic attempts targeting this particular aspect of pathophysiology, rendering it difficult to understand how much it contributes to pain. On the other hand, there are striking changes in structure and function in both the peripheral and central nervous system in this condition, lending plausibility to a maladaptive state that includes both neuropathic and dysfunctional pain. In the absence of effective anti-inflammatory approaches, it is clearly important to focus on the alteration of function that accompanies these changes in the nociceptive system as a potential therapeutic target.

Pain is a complex and multifactorial phenomenon that affects every aspect of a patients’ life, including emotional, social and physical functioning, and correlates with quality of life in CP(13). Because patients with CP have not been systematically followed using a comprehensive and multidisciplinary approach, it is important to gain an understanding of each of these components, particularly as each has been shown to have relevance in other chronically painful conditions. This is best accomplished by a longitudinal multi-center registry that prospectively studies the outcomes of medical and surgical care of patients with

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CP, identifies biomarkers for inflammation and provides correlation with histological and molecular changes in pancreatic tissue. Of particular interest are questions that emphasize persistent pain, flare-ups and disability. Such an approach will increase our understanding of the etiology of pain in CP, allow the identification of “high-risk” subgroups for testing medical, surgical, and possibly psychosocial treatment in future clinical trials, and ultimately increase our ability to personalize treatment to the individual’s risk and clinical profile.

Claudia M Campbell and Pankaj Jay Pasricha

Q3. Which methods are available to assess pancreatic pain and its response to treatment? Assessment of pain in CP follows the guidelines for other types of chronic pain, where the multidimensional nature of symptom presentation is taken into consideration. Only a few instruments have been validated for subjective pain assessment in CP; however, several appropriate measures exist despite not being rigorously validated in this population. (Quality assessment: moderate; Recommendation: strong; Agreement: strong)

Pain is complex in nature and interacts with multiple systems, thus systematic, frequent multidimensional pain assessment is required to determine the most efficacious treatment plan, and evaluate effects for patients presenting with pain(44,45). As in many idiopathic pain conditions, CP pain is challenging to assess and treat in, for example perceived pain severity may be completely unrelated to observed physical manifestations or symptoms. Given that individual differences in the development, course, and sequelae of a given pain condition are broad, and that observable physical pathology (e.g., duct dilation, atrophy, calcifications) correlates minimally with pain-related symptomatology(6), other factors must play a role in either facilitating or protecting against the experience of long-term, disabling pain. In addition to pain intensity, which is the only routinely reported outcome in most previous CP studies, assessment of a number of qualities describing the dimensions and characteristics of pain is crucial, including documenting functional impairment and quality of life(46). These dimensions are described briefly below along with comments on different scales and frequently used questionnaires that can be used during pain assessment. Additional, somewhat more objective, methods for visualizing or assessing pain are also included along with a discussion of complicating factors and barriers to effective pain management.

Pain Dimensions for assessment:CP patients often describe their pain as severe, unremitting, exacerbated by eating and sometimes associated with post-prandial nausea and vomiting(47). Patients also frequently report breakthrough pain or enhanced pain during a “flare-up” which is sudden, unexpected and more intense than their baseline chronic pain level. Both of these distinct pain types should be assessed with regard to the following qualities.

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Etiology of pain (with respect to onset of symptoms). While diagnoses based on etiology is the current standard in chronic pain, some have suggested that a better approach to assessment, diagnosis, and treatment may be to identify the pathophysiologic mechanisms that “account” for a patient's pain and to then use these mechanisms as the basis for selecting the most appropriate approach to treatment(48,49). While the pathophysiology of CP is unclear, the individual etiology may hint at specific mechanisms and a potential course. Pain duration and chronicity should be evaluated by assessment of the onset and progression of pain over time. It may or may not coincide with the onset of other CP symptoms. Categorizing the pain into intermittent acute, continuous or combined might be appropriate. If the pain has persisted for greater than three months it is considered chronic(50) . As for breakthrough pain, duration may be more limited and time locked to meals, stress, alcohol intake, elimination, etc. A large CP study, conducted approximately five years ago, found that the temporal nature of pain was a more influential determinant of healthcare utilization and health-related QOL when compared to pain severity(7). Early diagnosis and treatment is important in CP, as repeated episodes of inflammation may produce irreversible damage, and pain relief may be less effective the longer the disorder is left untreated.Pain Intensity is subjective in nature and may vary strongly from person to person as a function of individual differences in pain sensitivity, activity level, diet, substance use, coping strategies, and the severity of the underlying disease, among other factors, many of which are likely yet unknown factors that may vary by the individual. Typically, intensity is queried on a 0-10 numerical pain rating scale where 0 = “no pain” and 10 = “the worst pain you can imagine”(51). Disease severity, different, but related to pain intensity is most commonly categorized in CP based on the Cambridge Classification system which divides CP into five severity groups based on morphological changes of the main pancreatic duct and its side branches based on ERCP, ultrasound and CT(52). A more recent classification of CP incorporates risk factors into a categorization schedule, not specifically linked to severity. TIGAR-O evaluates and categorizes CP into toxic-metabolic, idiopathic, genetic, autoimmune, recurrent and severe acute pancreatitis or obstructive(53).The Quality of pain, a subjective description provided by the patient, may hint at the type of pain they are experiencing. For example, pain described as burning, “pins and needles” feeling, etc. may be indicative of neuropathic pain, which may be under evaluated/treated in CP patients(47). Pain described as squeezing, pressure, cramping, distention, dull, deep, and stretching is usually visceral in origin. Visceral pain is most commonly recognized in CP patients, with pain that emanates from the viscera, is diffuse and difficult to localize and involves intense motor and autonomic reactions. It is also important to evaluate both the severity and quality of pain not only at rest or during a crisis, but to query these dimensions having the participant reference when they are standing, laying down, during movement, when using the bathroom and on palpation of the abdomen.Associated/Aggravating/Alleviating factors. Frequently diarrhea, nausea and vomiting accompany pain in CP, particularly breakthrough pain. Understanding what symptoms are

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associated with pain and when they occur in relation to pain, and what factors make it worse or improve it may bring insight into appropriate treatment recommendations. For example, if dietary, or other lifestyle factors play a role in aggravating symptoms, these would be a good place to start. Avoiding alcohol consumption, smoking and reducing fatty food consumption may all improve pain in CP (see treatment sections within these guidelines). Stress and anxiety frequently impact pain and patients who experience this connection may benefit from stress-reduction strategies or psychological interventions aimed at reducing such qualities. Similarly, factors that reduce pain should be queried, such as application of heat, relaxation, distraction, etc. as they could potentially be applied early in a flare.If alcohol issues are noted, it is warranted to delve deeper into the specifics of alcohol use, given the association between alcohol consumption and CP. If current alcohol use is endorsed or suspected, conducting a CAGE questionnaire (asking 1) have you felt the need to Cut down on your drinking?; 2) Have people Annoyed you by criticizing your drinking?; 3) Have you ever felt Guilty about drinking?; 4) Have you ever felt the need for an “Eye-opener” – a drink first thing in the morning to steady your nerves or get rid of a hangover) may aid in screening for problematic drinking behaviour. Mood is another important factor to consider and assess in CP. CP patients endorse significant difficulties in mood, social and emotional functioning. Depressive symptoms have been related to participants' reports of increased pain and decreased quality of life, with recent work suggesting that greater than half of CP patients may score above the cutoff for clinically significant depressive symptomology(54), which potentially warrants psychological evaluation and treatment. Of interest, they also found that clinically significant depression was strongly associated with greater pain severity and reduced physical and mental quality of life. While stress is a well-documented factor in flare ups, little research has focused on the role of anxiety or its relationship to pain or quality of life in CP. Pain catastrophizing, a negative cognitive and affective processes related to pain, characterized by helplessness, magnification and rumination about pain symptoms, is a risk factor for long-term pain and disproportionately-negative sequelae of pain (e.g., high levels of physical disability or healthcare costs)(55) in a variety of clinical pain conditions. Catastrophizing has been implicated as an etiologic or prognostic factor in a number of persistent pain(56–61), higher pain and disability following surgery(62–65), longer recovery times(66), and less improvement in pain(67). Thus, catastrophizing may well be an important prognostic factor in CP, but a dearth of information exists in regards to catastrophizing in CP patients.The impact on quality of life is also important to evaluate and is clearly important in patients with CP(13,68). Inquiring about changes in appetite, physical activity, relationships, family functioning/functioning within the household, sexual functioning, irritability, sleep, anxiety, anger, depression and concentration will aid in understanding the pain experience in each individual. A number of these factors have bidirectional relationships with pain which could represent modifiable risk factors that could be improved and reduce pain. Sleep for example, is well known to be disturbed by pain, but recent work also identifies sleep as an independent

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modulator of pain perception; thus disturbed sleep could exacerbate the following day’s pain creating a vicious cycle(69,70). In order to evaluate the impact of pain on patients’ quality of life, the EORTC QLQ-C30 and QLZQ-PAN26 questionnaires have been formally examined and validated for CP patients(71).

Central SensitizationPain processing occurs in the central nervous system, where nociceptive input can be inhibited or facilitated and which can undergo both functional and structural plasticity(72). When plasticity results in amplification of pain, this central sensitization (CS) represents a rewiring that can include inhibition of descending pain modulation and/or changes in connectivity(73), including changes to forebrain circuits involved in emotion and cognition(74). Central sensitization is implicated as a mechanism of pain chronification (transition from acute to chronic pain), amplification, and maintenance in a number of chronic pain conditions(73). In humans, CS manifests as hyperalgesia, allodynia, and spreading of pain and can be reliably assessed in laboratory studies through application of noxious stimuli (see below)(73). A growing literature implicates central sensitization in CP. Repeated and prolonged pain attacks influence the central nervous system and have been shown to alter brain regions in CP(36). This may be one reason that abdominal imaging or other physiological findings do not correspond with the reported level of pain(6). It may also factor in to why pain persists in approximately 30% of patients even after total pancreatectomy(75,76).

Types of assessmentSubjective verbal reports of either a single- or multi-dimensional scale are most common for pain assessment. However, additional methods for evaluating pain, and pain sensitivity are being increasingly employed in CP patients. While single-dimensional verbal reports of pain severity are the norm in the literature, a number of questionnaires have been developed for a more comprehensive pain assessment. For example, the WILDA (words to describe pain, intensity, location, duration, aggravating/alleviating factors)(77) pain assessment tool may be useful to aid in this assessment. A commonly used measure in CP, the Izbicki pain score was developed to capture some of the aforementioned dimensions of pain and provide a surrogate score based on the pain attack frequency, pain intensity score (VAS), analgesic use, and duration of disease-related inability to work(78). It has, however, never been strictly validated in patients with CP. Future work should consider truly validating this measure in a large sample, particularly since it has become the default pain assessment measure in CP.

Subjective Verbal Reports One-dimensional scales (usually pain intensity)

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One-dimension scales assess a single element of pain, but provide allow for a simple and fast method for patients to self-report the subjectively experienced intensity of their pain. Use of such scales is appropriate in settings of acute pain when the etiology is clear; however, they can oversimplify the pain experience(79).These scales use numeric (often 0-10), verbal (eg, mild, severe or other verbal descriptors like discomforting, excruciating…) or visual (pictures of faces, most typically used with children or the cognitively impaired) descriptors to quantify pain or the degree of pain relief. Numerical scales, such as the visual analogue scale (VAS), are commonly applied to assess the intensity of pain in CP patients, but should be combined with a standardized registration of the pain pattern in time including the frequency of pain exacerbations(7).Multidimensional scales Multidimensional scales measure several of the above overviewed aspects of pain, including its intensity, nature and location, and in some cases, pain’s impact on mood or activity level/physical functioning. Evaluating these variables is integral in overall pain assessment and management. Multidimensional scales are valuable in complex or persistent acute or chronic pain cases when intensity needs to be assessed as well as other factors such as quality of life, social support, interference with activities of daily living, and mood. The Brief Pain Inventory (BPI) is one such scale that is commonly used with chronic pain patients and relatively quick. It quantifies pain intensity as well as mood, ability to work, relationships, sleep, enjoyment of life, and the effect of pain on general activity. The BPI also has the ability to evaluate the progress of a patient with a progressive disease and provides an opportunity to evaluate improvement or decline in the assessed domains. BPI scores were recently correlated with quality of life in CP patients, not surprisingly suggesting that the more severe one’s pain, the worse their quality of life(13).The McGill Pain Questionnaire is another commonly used survey that assesses three aspects of the pain experience, including sensory, affective, and evaluative dimensions. These components are subdivided into subclasses that represent varying degrees of pain. Seicean and colleauges(80) note that the McGill is a more appropriate pain assessment measure that unidimensional numeric scales alone in CP patients.

Quantitative Sensory Testing (QST)Despite tremendous individual differences in clinical outcomes among patients with pancreatitis and the experience of almost daily pain (in approximately 55% of patients(24)), very little is currently known about pain phenotypes in pancreatitis and how these phenotypes predict clinical outcomes. Pain sensitivity and CS can be reliably assessed and quantified in the laboratory using quantitative sensory testing (QST)(73). These calibrated and standardized methods for delivering noxious stimuli under controlled conditions(81) are reflective of clinical conditions, as subjects who rate QST stimuli as most painful(82,83), or show heightened CS(84,85) report the most frequent, disabling clinical pain. QST often assess pain thresholds, which has been shown to be stable over time in CP(86), although more

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sophisticated, dynamic psychophysical techniques have the potential to more directly assess CNS pain-modulatory processes(87). Since incoming nociceptive input is actively regulated at multiple levels of the neuraxis, from spinal cord to cortex(88,89), it is important to understand individual differences in CNS pain-facilitatory and pain-inhibitory processes, which maps on to pain chronification and the variability reported among chronic pain patients(90). Participants who rate such calibrated noxious stimuli as most painful(82,83), who show the greatest CNS sensitizability(84) and the least endogenous pain inhibition(85), report the most frequent, disabling daily pain complaints (e.g., headaches, backaches, etc.). Such pain-sensitive individuals (i.e., lower pain threshold, higher pain ratings of standardized noxious stimuli) also obtain the least benefits following multidisciplinary treatment for chronic pain(91), experience enhanced acute postoperative pain in a number of surgical procedures(92–99), are at risk for developing chronic pain following surgery(100,101), and derive reduced analgesic effects from opioids(102). QST, along with other mechanistic-based techniques in CP patients was recently reviewed by Bouwense and colleagues(103); we refer the reader to their work for a more comprehensive overview.  CP patients have documented hypoalgesia to visceral and somatic stimulation from tonic and phasic mechanical stimuli compared to healthy controls(104), hypersensitivity to mechanical stimulation of the skin(105), and higher cortical activity than controls in specific bands when the esophagus is electrically stimulated to pain threshold, suggesting involvement of neuropathic pain mechanisms(106). Central sensitization in CP was hypothesized and examined using QST over a decade ago(37) and has received additional attention, evaluation and documentation through assessment of conditioned pain modulation and widespread pain(36,38), pain facilitation and referred pain to electrical stimulation(105), repeated electrical stimulation to the skin (reflective of pain facilitation)(104), as well as positive trials of pharmaceutical treatments known to impact central sensitization(107–109). For example, QST, being frequently employed to evaluate treatment responses, evaluated among CP patients, was found to elicit increased electrical pain detection and tolerance, as well as pressure pain tolerance following a three-week course of pregabalin as compared to placebo, suggesting inhibitory effects of the hyperalgesic spreading component of central sensitization(108). Additionally, oxycodone was found to be more effective than placebo and morphine on mechanically and thermally evoked pain stimulation as well as oesophageal heat pain(110). A particularly elegant study recently found that QST responses were able to predict the analgesic efficacy of pregabalin in CP patients(107) with solid classification accuracy (84%).

Biomarkers for pancreatic pain and pain severitySeveral studies from the same group of investigators suggest a correlation between inflammatory, neuropathological and expression of certain biological factors and severity of pain(111). However, this is based on access to resected pancreatic tissue and so is not a practical biomarker. On the other hand, there is some promise in analysing pancreatic juice

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obtained at endoscopy for cytokines and small molecules- elevated levels of PGE2 have recently been found in the pancreatic secretions of patients with early chronic pancreatitis who have significant pain but no clear structural abnormalities(23). Further studies are needed to validate this and other molecules in a broad spectrum of patients. Finally, there are several CNS markers that may be affected in CP and perhaps provide a so-called biomarker for pain in this condition. Electroencephalograpy (EEG) in patients with CP show functional changes suggesting a maladaptive pain response(39–41). The CNS may also be affected as seen by microstructural changes in cingulate and prefrontal cortices with differences noted in brain imaging between patients with episodic versus continuous pain as well as overall correlations between MRI findings and pain scores(68).

ConclusionsOngoing, comprehensive and multidimensional pain assessment is integral in CP and the factors overviewed here would be appropriate measures to include in such an evaluation. These variables and assessment of the type of pain a CP patient is experiencing (visceral, neuropathic, central, etc. and any overlap) may aid in treatment planning. While an in-depth and thorough QST assessment may not be realistic for everyday clinical use in CP patients, brief, mobile “bedside” assessments are available for classifying patients with other chronic pain conditions(112–114) and may be useful in CP. Such assessment has the potential to aid in a mechanistic approach to personalized treatment and the tracking of tangible outcomes.

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Eva Szigethy & Pramod Kumar Garg

Q4. What is the role of smoking and alcohol on pain treatment in CP Abstinence from alcohol and smoking, in addition to adequate treatment, should be strongly advised in patients with CP (Quality assessment: moderate (alcohol) to weak (smoking); Recommendation: strong; Agreement: strong)

Alcohol: Pain is the most common symptom in chronic alcohol- related pancreatitis. While high alcohol intake is a risk factor for pancreatitis, this relationship relative to acute and chronic pancreatitis has recently been established. In a meta-analysis of 7 association studies with 157,026 participants and 3618 cases of pancreatitis(115), the dose-response relationship between average volume of alcohol intake and chronic pancreatitis was monotonic in both men and women and for acute pancreatitis in men. The relationship was highly significant, but non-linear for acute pancreatitis in women. Compared to abstinence, there was a significant reduction of risk of acute pancreatitis in women below a threshold dose of 40g per day, but not for men. Alcohol consumption at a higher daily dose increased the risk of any type of pancreatitis. Recurrence of pancreatitis is high among patients with alcohol related acute pancreatitis. In a study of 562 patients in Finland the recurrence rate was 46% over 1-20 years(116). Similarly, 37–48% recurrence rates have been reported in other studies(117,118). Prospective studies evaluating the effects of cessation on chronic pain are lacking, but even in the absence of a direct causal relationship with CP-related pain, the health risks of alcohol use, including acceleration of disease progression, still makes abstinence advisable.

For treatment of alcohol-related pancreatitis, abstinence from alcohol is associated with reduction in frequency of recurrence of pancreatitis. In a prospective observational study, patients with first attack of alcoholic acute pancreatitis were followed-up for 2 years; out of 51 patients, 13 who remained abstinent at 2 years had no recurrence compared with compared with 17 patients with continued alcohol consumption(119). In a randomized controlled trial, 120 with alcohol-associated AP were randomized either to repeated intervention or initial intervention only for alcohol abstinence. Alcohol abstinence in the repeated intervention group resulted in significant reduction in recurrence of pancreatitis (9 vs. 20 episodes)(120). The authors followed up these patients to study the long-term outcome of patients who abstained. Of the 118 patients, 18 who remained abstinent had no further attack of pancreatitis during a mean follow-up of mean 5 years, compared to 34% of the 100 non-abstinent patients who had at least one recurrence during the follow-up(121). Pharmacological treatment is often necessary to ensure that the patients refrain from alcohol intake. Benzodiazepines remain the gold standard to reduce symptoms of alcohol withdrawal including seizures and delirium tremens(122,123). Long-term use of benzodiazepines carry the risk of abuse, addiction and liver toxicity. Mood stabilizers such as carbamazepine are

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safe and efficacious in treating moderate symptoms of alcohol withdrawal(123,124). It is important that severe withdrawal be treated in a hospital setting or facility where 24-hour monitoring is available for delirium tremens or seizures. Only three medications have FDA-approval to treat alcohol dependence; naltrexone, acamprosate and disulfiram. Naltrexone has strong support in reducing relapse in alcoholics(125), while acamprosate has shown efficacy in some(126) but not all trials(127). More recent research has found that functional genetic polymorphisms may predict who does and does not respond to treatment such as naltrexone for alcohol dependence(128). One large-scale study evaluated the efficacy of pharmacological (naltrexone versus acamprosate versus both and/or placebos in combination with medical management with or without behavioral therapy for alcohol dependence(127,129). Previous medical management of alcohol dependence and either behavioral therapy, naltrexone, or both was associated with significantly higher reduction of drinking and abstinence evaluated over 68 weeks. No combination had better efficacy in reducing drinking than naltrexone or behavioral therapy alone in the presence of medical management. No significant effects were found with acamprosate. Placebo pills had a positive effect in this study above that of behavioral therapy alone. While disulfiram has been widely used, there is no clear clinical trial data supporting positive outcomes(130). Other classes of psychotropic medications have been investigated but results are inconclusive(131). Limited data on use of selective serotonergic medications showed these may help with treating comorbid psychiatric conditions such as mood and anxiety disorders but not alcohol dependence directly. The identification and treatment of frequent psychiatric comorbidities associated with alcohol dependence is critical(132,133). Treatment-naïve active alcoholics had a greater number of psychiatric symptoms than normal controls, but less than treated alcoholics with long-term abstinence and highlights the importance of identifying subsyndromal psychopathology even when alcohol dependence has been treated(134). Non-pharmacological treatments have also been widely used. Several psychosocial interventions have shown significant behavioral change in patients with alcohol dependence including cognitive behavioral therapy (CBT), alcohol behavior coupled therapy, 12-step therapist facilitated treatments, and motivational interviewing and support the recommendation of some type of drug counseling to assist patients in remission(135,136). A systematic review included 13 studies with psychosocial interventions in inducing or maintaining abstinence from alcohol in patients with chronic liver disease. Combined CBT, motivational enhancement therapy, and comprehensive medical care increased alcohol abstinence and combined CBT plus medical management reduced recidivism(137). Mutual help and self-help organizations such as Alcoholics Anonymous can be helpful for many patients to provide support for recovery and facilitate the formation of new social connections but are not considered formal treatment and have not been extensively studied as part of randomized controlled trials(138).

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Tobacco: Several studies have shown that smoking tobacco, particularly cigarettes increased the risk for developing both acute(139,140) and chronic pancreatitis(141–143) and this relative risk is dose-dependent. While cigarette smoking is often present in alcohol abuse, studies showing smoking as an independent predictive factor are emerging(139,144–146). Prospective studies evaluating the effects of smoking cessation on chronic pain are lacking, but smoking was associated with the chronification of pain in other pain syndromes(147). As for alcohol use the health risks of smoking, including acceleration of disease progression, still makes abstinence advisable. Unfortunately, chronic pain has been associated with greater challenges in smoking cessation (148,149). More than 80% of patients with alcoholic chronic pancreatitis are smokers and smoking potentiates alcohol toxicity in dose-dependent way(142). Cigarette smoking has been shown to accelerate the progression of alcoholic pancreatitis, with appearance of calcifications, and diabetes and this effect was independent of amount of alcohol consumption(150). The exact mechanisms by which tobacco metabolites affect the pancreas are unknown. Substances from smoking which have been considered as causal agents include tobacco-specific metabolites such as NNK and nitrosamines as well as nicotine specific metabolites such as NNN and DEN(142). One hypothesis is that nicotine results in high levels of intracellular calcium release which causes cytotoxicity(151). Pharmacological treatment: Logically, smoking cessation should be a strong recommendation for patients with chronic pancreatitis. Although cessation of smoking has been shown to reduce the risk of developing pancreatitis(152), no study has evaluated the effect of smoking cessation on pain in patients with CP. Given that nicotine is addicting, several medications can help with cravings such as bupropion, which can also be safely combined with nicotine replacement therapies if necessary. In a recent double blind parallel group, bupropion plus naltrexone outperformed bupropion plus placebo in smoking abstinence at 7 weeks but not 6 months(153). Varenicline, a partial nicotine agonist, has been shown to enhance smoking abstinence through reduction of smoking compared to placebo(154). Varenicline together with nicotine replacement therapy enhance early and medium-term smoking cessation but did not outperform nicotine replacement in the longer-term(155). Varenicline can also help with cravings and reduction in overall alcohol consumption in some(156) but not all(157) studies and thus can be an option for patients with both alcohol and tobacco addiction. A recent systematic review supported the combination of bupropion and varenicline for greater efficacy than varenicline monotherapy for smoking cessation(158). Clonidine and nortriptyline are considered second line symptoms to reduce nicotine withdrawal as the results are inconsistent. In a review of Cochrane reviews of pharmacotherapy for smoking cessation through 2012, 267 studies involving 101,804 participants were identified(159). Nicotine replacement, bupropion, varenicline, and cytisine, another partial nicotine receptor agonist, had the greatest evidence for improving the chances of quitting. Non-pharmacological treatment: Cognitive behavioral therapy (CBT) combined with smoking cessation medications can be effective in smokers who are motivated to quit(160). Mindfulness-based therapy may help with recovery from smoking relapse(161). Other

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behavioral interventions that have shown promise are self-help groups, hypnosis, and motivational interviewing techniques delivered by trained behavioral specialists(162).

Pramod Kumar Garg & Eva Szigethy

Q5. Do enzymes and antioxidants influence pain in CP? Pancreatic enzyme therapy with high protease content may be tried as an initial treatment for pain relief in patients with CP. Furthermore; combination of antioxidants in sufficient dosages should be included in the armamentarium of pain treatments (Quality assessment: moderate; Recommendation: strong; Agreement: weak)

Role of Pancreatic Enzyme Supplementation on Pain Relief in Chronic PancreatitisPancreatic enzymes have been used for relief of pain in patients with chronic pancreatitis (CP). The pathophysiological basis of using pancreatic enzymes is related to a possible negative feedback loop involving cholecystokinin that regulates pancreatic exocrine secretion (163). Intraduodenal infusion of trypsin decreases pancreatic exocrine secretion through suppression of cholecystokinin (CCK)(164,165), but other studies have not shown that such a negative feedback mechanism operates. It is believed that nutrients stimulate release of cholecystokinin releasing factor (CRF) from the duodenum upon physiological delivery of chyme into the duodenum. The CRF releases cholecystokinin, which stimulates pancreatic secretion. Theoretically, the pancreatic enzymes degrade CRF thus limiting the release of cholecystokinin and subsequently decrease pancreatic secretion completing a negative feedback loop. A reduction in pancreatic enzymes in patients with CP therefore increases cholecystokinin release and pancreatic secretion. This may increase intraductal pressure in patients with CP who have ductal obstruction due to calculi or stricture and contributes to pain. Thus, the rationale of giving pancreatic enzymes for pain relief is that adequate enzymes will degrade CRF, decrease cholecystokinin release and thus reduce pancreatic secretion. There are many concerns with such a hypothesis. First, the negative feedback loop is not fully understood well or confirmed. Second, increased pancreatic secretion in patients with CP is counterintuitive because there is significant functional impairment in them. Third, increased intraductal pressure is but one of the mechanisms of pancreatic pain and not widely accepted. Fourth, enzyme supplementation has not been conclusively shown to decrease pancreatic secretion and reduce intraductal pressure as hypothesized. Six randomized clinical trials (RCTs) have been reported on the effect of pancreatic enzymes in pain relief. In a review of these(166), pain relief using pancreatic enzymes as tablets was noted in two trials(167,168) and no benefit was noted in 4 trials that used acid-protected capsule forms of enzyme replacement(169–172). The reason could be that the acid-protected form of pancreatic enzymes was not released in the duodenum and, therefore, could not

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activate the proposed negative feedback mechanism. Pancreatic enzyme supplements have shown most benefit for patients with small pancreatic duct disease, idiopathic pancreatitis and among women. These trials were conducted in 1980s and 1990s and have had certain methodological issues such as small sample size, heterogeneous patient population, variability in enzyme preparations, differences in outcome measures, and lack of standardized pain measuring tools. Despite these concerns, pancreatic enzymes are widely prescribed to patients with CP in the hope that at least some benefit may be derived. If enzyme therapy is tried in clinical practice as an initial treatment modality, the preparations of pancreatic enzymes should be uncoated, contain large amounts of proteases (>25,000 USP units per tablet) and be given in a dosage of four to eight tablets four times a day. In addition to the negative feedback regulation of pancreatic secretion, the other putative benefits of enzymes are – (i) better digestion of food leading to physiological ileal brake and help to regain intestinal motility as the ileal brake is a regulatory physiological feedback mediated by delivery of nutrients into the distal ileum, which inhibits gastric emptying and proximal small intestinal motility(173,174). Ileal brake is mediated by peptide YY via vagal pathway(175). It has been shown that patients with CP particularly those with exocrine insufficiency have abnormal digestive and interdigestive antroduodenal motility, which is corrected by pancreatic enzyme supplementation(176). Alteration of ileal brake with abnormal intestinal motility may lead to abdominal pain, discomfort, postprandial bloating and fullness. These symptoms may be relieved by enzyme supplementation. (ii) Treat sub-clinical maldigestion and thus help regain weight. (iii) contribute to a better glycemic control in those with diabetes.

Antioxidants may also be helpful in pain treatment. Normally, cells are in a state of redox homeostasis that means that the free radicals (FR) or reactive oxygen species (ROS) generated during the respiratory cycle are scavenged by the antioxidants. Oxidative stress (OS) refers to an imbalance between pro-oxidants and antioxidants with increased free radical formation(177). Either an increased production of ROS or a deficient antioxidant capacity of the cell may lead to OS. Increased FR production may occur due to exogenous sources such as pollutants, xenobiotics, smoking etc. or endogenously through respiratory burst. Mild oxidative stress is countered by cellular responses. If, however, ROS production is increased excessively, the antioxidant capacity may be overwhelmed resulting in OS. Pathological effects of ROS include lipid peroxidation, alteration in redox-sensitive signaling pathways, inflammation, and cell injury. Severe oxidative stress can even cause cell death.OS as a mechanism of inflammation in CP has been shown for the past 30 years. Many studies have shown increased OS and deficient antioxidant capacity in patients with CP(178–182). Consequent to the understanding that OS might be related to chronic inflammation in patients with CP who have an inadequate antioxidant status, antioxidant supplementation has been used to ameliorate OS and relieve pain in patients with CP. A study from Manchester, UK was the pioneer study. Uden et al(183) used a combination of dietary antioxidants (600 μg organic selenium, 9000 IU β -carotene, 0.54 g vitamin C, 270 IU

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vitamin E and 2 g methionine) and showed significant pain relief in patients with recurrent acute and chronic pancreatitis. In an observational study, Whiteley et al.(184) studied the effect of micronutrient supplementation in 103 patients with CP and showed that 75 patients remained pain free during a follow-up period of 9 years. There have been a total of 10 RCTs on the role of antioxidants in patients with CP. In a study of 36 patients by Kirk et al(185), significant improvement in the quality of life and pain was observed. A large, randomized, placebo-controlled trial showed that pain was significantly reduced during 6-month therapy and the benefit was evident as early as 3 months(186). A recent RCT had shown that antioxidants were ineffective in patients with predominantly alcohol induced CP(187). However, several shortcomings of the study such as improper patient selection, continued alcohol intake and smoking, opiate dependence, failed endoscopic/surgical therapy etc. limited the generalizability of the study(188,189). Recent meta-analyses have shown beneficial effect of antioxidants in patients with CP(30,190). Another systematic review and meta-analysis showed that antioxidants may help ameliorate pain in patients with CP(191). This analysis included 9 RCTs with 390 patients were included. A combination of antioxidants (selenium, β-carotene, vitamin C, vitamin E, and methionine) showed significant pain relief while studies with single antioxidant therapy showed no significant pain relief. The latest RCT has shown that a combination of pregabalin and antioxidants for 2 months followed by only antioxidants for 4 months resulted in significant pain relief in patients with CP who had recurrence of pain after ductal clearance by endotherapy or surgery(192). Finally, a recent observational study has shown that long-term pain relief may be obtained with optimized medical therapy including antioxidants in patients with CP(193). Overall, except for one RCT(187), all studies have shown significant pain relief with a combination of antioxidants in patients with CP.

Figure 1: Modified version of the WHO analgesic pain ladder. At level 1 treatment with non-opioids such as paracetamol and non-steroidal anti-inflammatory drugs will be initiated with or without adjuvants. If pain increases or persists level 2 treatment will be initiated. Level 2 treatment include opioids for mild or moderate pain with or without adjuvants. If pain still persists or increases, level 3 treatment may be initiated. Level 3 treatment includes opioids for moderate or severe pain with or without non-opioids and/or adjuvants. Laxatives shall always be considered when opioids are used.

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Asbjørn Mohr Drewes, Søren Schou Olesen & Eva Szigethy

Q6. Which analgesics are recommended for pain in chronic pancreatitis?Currently the standard guideline for analgesic therapy in CP follows the principles of the “pain relief ladder” provided by the World Health Organization (WHO) adjusted to the pain characteristics of this condition (Quality assessment: moderate; Recommendation: strong; Agreement: strong)

The individual experience and manifestation of pain is influenced by a complex series of interactions involving sensory, pathophysiological, affective, socio-cultural, behavioural and cognitive elements(194). Hence, there is always more to analgesia than analgesics, but pharmacological treatment is still the mainstay of pain treatment in CP(195). Of note, the absorption of drugs can potentially be difficult to predict due to e.g., changes in the intestinal pH, ischemia and bacterial overgrowth in patients with CP. Until now only one study has studied these patients. Despite a normal absorption of pregabalin was found there is an unmet need for further studies in more complicated molecules(196). Pharmacokinetics can also be changed in patients having problems with intake of tablets, and patch formulations with slow absorption of analgesics may be considered. Currently the standard guidelines for analgesic therapy in CP follow the principles of the “pain relief ladder” provided by the World Health Organization (WHO). This principle, which was originally launched for cancer pain treatment, is based on the serial introduction of drugs with increasing analgesic potency. This approach enables a simple stepwise escalation of drugs with increasing analgesic potency (level I-III) until pain relief is obtained, with simultaneous monitoring and handling of side effects (figure 1)(197). In the following the analgesics most used are described, and where possible special studies and precautions for CP are highlighted:

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Simple analgesics are used as a cornerstone in pain treatment and paracetamol is the preferred level I drug due to its limited side effects. It must be used with caution in patients with concomitant liver impairment or severe malnutrition, but otherwise there are no major restrictions. The non-steroidal anti-inflammatory drugs (NSAIDs) should in general be avoided due to their gastrointestinal toxicity (198). This may especially be relevant in CP as patients are already predisposed to peptic ulcer and have decreased duodenal pH due to insufficient buffering with bicarbonate(199). Nonetheless, NSAIDs are very effective in selected patients and may be used for short-term treatments (weeks). The variability in gastrointestinal and cardiac toxicity should be taken into consideration and proton pump inhibitors are normally co-prescribed. In clinical practice level 1 analgesic`s are often insufficient to alleviate pain as monotherapy, but it is important to maintain their use when more potent analgesics are considered.

Adjuvant analgesics are a heterogeneous group of drugs initially developed for indications other than pain and include antidepressants, anticonvulsants including the gabapentoids as well as anxiolytics. Although adjuvant analgesics have been widely used in the clinic to treat pain in CP, only the gabapentoid, pregabalin, has been investigated in a placebo controlled randomized trial titrated to 300-600 mg BID. In the short-term, it was found to induce a moderate pain relief with relatively limited side effects when used as an adjuvant analgesic in combination with the patients usual analgesic medication (200). Further, a reduction in opioid dose in the short-term may be seen although longer-term studies are needed(201).

Anti-depressive drugs are widely used for pain treatment and although no data exist in CP, their positive effect in patients with neuropathic pain (thought to be prevalent in CP) makes them attractive(202). Tricyclic antidepressants (TCA), selective serotonin reuptake Inhibitors (SSRI) and serotonin–norepinephrine reuptake inhibitors (SNRI) have been used successfully in functional gastrointestinal disorders. It is, however, unclear if they all have direct analgesic effects versus indirect benefit by reducing anxiety and depression(203). On the other hand, TCAs appear to have analgesic and neuromodulatory properties that are unrelated to their psychotropic effects(204,205). It is important to start at very low doses and titrate slowly over weeks as side effects such as cardiovascular can be dose-limiting(206). It should be noted that there are major differences in receptor properties and analgesic mechanisms between the different TCA and SSRI/SNRIs and therefore an individual approach is necessary. Due to the sedative effects a single dose at night-time may be preferable. Unfortunately, clinical experience indicates that the side effect profile often makes them less suitable in patients with CP. For further reading, see Törnblom et al. 2015(207) and Scottish Intercollegiate Guidelines Network(207).

Opioid analgesics are indispensable for the management of pain(208), but therapy should only be initiated when more simple strategies have failed following a reasonable trial

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period(209). Opioids are highly effective and safe analgesics and their appropriate use by competent clinicians is a crucial element in modern pain management. However, treatment is often complicated by severe adverse effects and may lead to addiction. Furthermore, some opioids like codeine, tramadol and morphine are contraindicated or require prolonged dose intervals in patients with severe renal and hepatic insufficiency, which is not uncommon in CP. While not studied in CP, patients who have chronic pain and opioid use disorders may benefit from partial opioid antagonists such as buprenorphine, though randomized controlled trials are not available(210,211). Opioids should not be used in isolation, but form part of a multi-faceted strategy that includes all necessary adjuvant analgesics, non-drug interventions, psychological support and rehabilitation. There are enormous variations in opioid use across the globe, and even within close regions major variations are observed(212). This is based partly on local traditions, partly on regulatory matters and to some degree by “opiophobia” and will not be the discussed further in this section. As opioid use seems to be a necessary step to dampen pain in many patients with CP it is mandatory that pancreatologists understand the complexity of opioid treatment, or alternatively treat patients in close collaboration with dedicated pain specialists. Of note, all patients must be fully educated on the proposed therapeutic strategy and informed about the risks for addiction and side effects especially opioid induced bowel dysfunction, emesis and affection of the central nervous system. In some cases the pain increases despite increased dose and in such situations opioid induced bowel dysfunction or opioid induced hyperalgesia (narcotic bowel syndrome) should be suspected as it may mimic the pain in CP. For details, see Drewes et al. 2016 and Drossman and Szigethy 2014(213,214). Treatment may include increased use of laxatives, opioid antagonists with restricted effect on the gut, tapentadol or in case of hyperalgesia tapering of opioids(214,215). Patients on long-term opioid therapy must be kept under close clinical surveillance and it shall be stressed that only about 25% of patients benefit from treatment. After 6 months of opioid therapy, a dose reduction (or “drug holiday”) should be considered and discussed with the patients(212,216). For further information the reader is referred to e.g. Dowell et al. 2016)(216)Codeine is a weak opioid in level II analgesia, but it is metabolized to morphine and therefore associated with the same spectrum of opioid-related side effects as seen for stronger opioids. Tramadol possesses both a weak opioid agonist activity along with an effect on noradrenaline and serotonin uptake(217). Tramadol is often the preferred level II analgesia and was shown to be superior to morphine in patients with CP, with fewer gastrointestinal side effects for the same level of analgesia (218). Level III analgesia comprises the group of strong opioids such as morphine, which are widely used for pain in CP. Most clinical available opioids have their activity at the μ-receptor, but preclinical and experimental studies suggest that activation of the κ-receptor (another opioid receptor activated by e.g. oxycodone) may also be important in visceral pain including pain in CP(110,219,220). Hence, oxycodone may posses an advantage over conventional opioids for pain treatment in CP, but head-to-head comparisons in clinical studies with long-term follow-up are not yet available. Transdermal administration (plaster

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formulation) of opioids is not recommended as first line opioid therapy for CP, but should be reserved to patients having trouble with tablet ingestion. Hence, in an open label randomized crossover trial, transdermal fentanyl plaster was compared to sustained release morphine tablets. No significant differences were found for pain control or patients’ preference or quality of life, while 44% of patients treated with fentanyl plaster reported side effects mainly as a rash at application site (221)There is marked inter-individual variability in responsiveness to different opioids, and in circumstances where an individual patient fails to achieve satisfactory pain control and/or they are troubled by unacceptable side effects, a trial of an alternative opioid is indicated. Opioid rotation may be difficult and for guidelines the reader is referred to(212). In patients with a severe and debilitating pain pattern, a more aggressive top-down approach using opioids combined with adjuvant analgesics as first line therapy may be recommended to control pain(217).

In some patients unconventional treatment with drugs such as ketamine is beneficial. Ketamine, an N-methyl-D-aspartate receptor antagonist, is used not only for anaesthesia, but also as a potent analgesic in acute and chronic pain as well as an antihyperalgesic used to reduce central sensitization(222). Multiple studies have consistently produced positive results regarding the use of ketamine in chronic pain patients with central sensitization and hyperalgesia and it thus comprises an interesting remedy to revert reduce central sensitization and its associated hyperalgesia in CP. This was supported by a double-blinded crossover trial designed to evaluate the effect of ketamine infusion on experimental hyperalgesia associated with CP(109). However, there are several limitations with the drug due to the side effects, which may be rather severe with longer-term negative consequences, and a current prospective clinical trial is awaited to establish its role in the management of painful CP(223).Experimental and clinical evidence suggest a key role for nerve growth factor (NGF) in the generation and maintenance of a wide range of pain states. Consequently, drug discovery efforts have resulted in several humanized anti-NGF monoclonal antibodies that have entered clinical trials as potential analgesics(224). NGF is up-regulated in patients with CP and is known to play a pivotal role in the process of peripheral sensitization. Therefore NGF-antagonism may also be effective for pain relief in these patients and in other visceral pain syndromes where up-regulation of NGF is assumed to mediate pain(225).Somastotatin-analogue inhibits pancreatic secretion by blocking CCK and secretin release and also by a direct inhibitory effect on acinar cells. These effects may theoretically alleviate pain through reduction of pancreatic ductal pressure and by lowering the central effects of CCK. There are conflicting data about the efficacy of somastotatin-analogues for pain in CP. While early pilot series of octreotide showed an effect on pain control, this effect could not be confirmed in later randomized controlled trials(226). Other drugs such as for example clonidine (centrally acting α2 adrenergic agonist), quetiepine (second generation antipsychotic) and neurokinin-1 receptor (NK-1R) antagonists have all demonstrated

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analgesic efficacy and may be used in selected patients(227). It may also be indicated to use benzodiazepines, anti-psychotics or cannabinoids in difficult cases although it should be stressed that no data in CP are not yet available to document their use.

Figure 2: Suggested algorithm for pharmacological treatment (grey boxes) of pain in chronic pancreatitis. “Autonomic” pain is defined as a primary pain type that is not related to local complications such as pseudocysts or obvious duct strictures and stones. In most cases, combination therapies are necessary. Treatment with antidepressives is guided by psychological evaluation including assessment of catastrophizing, depression etc. In case gabapentinoids are considered we use evaluation of the ration between segmental and generalised hyperalgesia (see text). Of note, treatment with gabapentinoids, TCA, SNRI (or SSRI in selected cases) should be titrated slowly until sufficient effect or intolerable adverse effects occur. Treatment shall be individualised due to major differences in receptor properties and analgesic mechanisms between patients. NSAIDs are normally not indicated and should be used carefully. Opioids shall be avoided if possible due to the major side effects on the gastrointestinal tract etc., but in severe pain they may be prescribed for limited periods and the physician shall always be aware of opioid induced bowel dysfunction and hyperalgesia (narcotic bowel). The timing of surgery is up to discussion (please see Q11) and is placed in the bottom of this algorithm mainly dealing with medical therapy.“Plus sign” indicate sufficient/satisfactory effect. “Minus sign” indicate insufficient effectESWL: extracorporal shock wave lithotrypsyPCM: paracetamolNSAID: non-steroidal anti-inflammatory drugs TCA: tricyclic antidepressivesSNRI: serotonin-noradrenalin reuptake inhibitorsSSRI: selective serotonin reuptake inhibitorsOIBD: opioid induced bowel dysfunction

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In practice pain treatment is mainly guided by evidence from somatic pain studies together with individual experience and traditions. However, the variability in phenotypic presentation of different pain syndromes is found to be greater between patients than between different pain syndromes, indicating that mechanistic etiologies are based on the individual rather than the level of disease (228). In figure 2 an example of a treatment algorithm used at Centre for Pancreatic Diseases, Aalborg University Hospital, Denmark is shown. A multidisciplinary approach is suggested both for evaluation and treatment of patients. This includes neurophysiological and psychological testing whereby specific pain mechanisms and psychiatric comorbidity are detected and rational treatment can be initiated. For example segmental hyperalgesia of the epigastric skin area (pancreatic viscerotome), detected by quantitative sensory testing, may serve as a clinical marker of central sensitization and predict the response to gabapentinoids(107). The tests are partly described in Q3 where more references can be found. Also, up to 40% of chronic pain patients are depressed and identification of mood disorders may identify patients where adjuvant therapy with antidepressants are particular beneficial (see section about psychological treatment). In addition, it is of outmost importance to identify secondary causes for pain (e.g. peptic ulcers or pseudocysts) as these are often easy to diagnose and treat, and secondary causes of pain should always be considered when the patient is experiencing an exacerbation in pain symptoms. The multidisciplinary approach to pain in CP, although typically used in centers dedicated for pancreatic pain therapy, may also be used in less specialized settings to guide pharmacotherapy in difficult cases. Over the past few decades, significant progress has been made in our understanding of the basic science of pain and the effect of analgesics. Non-invasive human methods using methods such as quantitative sensory testing, immunohistochemistry, neurophysiological evaluation, and assessment of brain function with electrophysiological methods and imaging

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have provided greater insights into the mechanisms of pain in CP and may lead to the development of more specific and effective therapies that may be individualized to fit the characteristics of the individual patient(217,229). Until then we are left with the guidelines outlined above. However, treatment should always be individualized and preferably initiated and monitored by expert pancreatologists due to the complexity of pain and complications to CP that always needs to be considered and treated appropriately.

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Myriam Delhaye, Shuiji Isaji and Stefan A W Bouwense

Q7. Is endoscopical therapy effective for pain treatment in CP?The best candidates for successful treatment of painful CP with first-line endoscopical therapy are middle-aged patients with distal obstruction of the main pancreatic duct (single stone and/or single stricture in the head of the pancreas) and in the early stage of the disease, that means as soon as possible after the first pain attack. Endoscopical therapy can be combined with Extracorporeal Shock Wave Lithotripsy (ESWL) in the presence of large (> 4 mm) obstructive stone(s) located in the pancreatic head, and with ductal stenting in the presence of a single main pancreatic duct stricture that induces a markedly dilated duct. (Quality assessment: moderate; Recommendation: strong; Agreement: conditional)

Endoscopical therapy (ET) in painful chronic pancreatitis (CP) is based on the rationale that pain is related to an outflow obstruction of the main pancreatic duct (MPD) due to stricture(s) or pancreatic intraductal stone(s).Therefore ET is indicated for selected patients with both:1. persistent (continuous or recurrent) pain related to CP after failed conservative pain

management;2. outflow obstruction of the MPD (i.e. MPD dilatation 5 mm), secondary to ductal

stricture(s) and/or stone(s) amenable to ET.Retrospective/observational studies: According to a multicenter study of > 1,000 patients who had been selected for ET of painful CP, MPD obstruction was caused by pancreatic stone(s) alone, ductal stricture(s) alone and a combination of stone(s) and stricture(s) in 18%, 47%, and 32% of cases respectively(230).ERCP can achieve MPD drainage by pancreatic sphincterotomy of the major and/or minor papilla, by temporarily stent insertion in the case of dominant stricture in the head of the pancreas, or by pancreatic stone extraction, usually after fragmentation with ESWL. The effectiveness of ET is usually the result of these combined procedures, all of these aimed to restore drainage of the MPD. With this approach 79% - 85% of patients experienced complete or partial pain relief in the short-term (follow-up (FU) < 2 years) (Tables 1 and 1S, all Tables appear after Q8), 76% - 94% in the medium-term (FU 2 – 5 years) (Tables 2 and 2S) and 66% - 96% in the long-term (FU > 5 years) (Tables 3 and 3S). Endoscopic MPD drainage yielded similar results in the different categories of patients (stone(s) alone, ductal stricture(s) alone and both stone(s) and stricture(s)), with 51% (523 / 1018) of patients having no pain at all at a mean FU of 4.9 years (intention-to-treat analysis)(230).Several independent series from different parts of the world have reported the long-term outcome (FU 24 months) after endoscopic therapy ( ESWL for 60% of patients) in a total of 1657 patients (Tables 4 and 4s). Complete or partial pain relief was reported on an

30

average in 78% (43% - 85%) of patients and surgery was avoided in 80% (74% - 96%) of patients (1265 / 1580) in studies where this data was available (Tables 4 and 4S).These studies are relatively homogeneous regarding baseline characteristics of included patients (mostly middle-aged men with pain, recurrent or continuous, alcohol abuse as main etiology of CP, average duration of disease prior to ET around 3 – 5 years, severe CP with endocrine / exocrine insufficiency at baseline around 30%) (Tables 1 to 4).However, the quality of evidence of reported results remains low in most of these retrospective observational non-randomized studies, with heterogeneity mainly in the use of unstandardized pain relief assessment, in the duration of follow-up and in the sample size, with no comparative analysis with a control group. Moreover, the retrospective design of a study may overestimate the treatment success rate.Randomized studies: Only two randomized controlled trial (RCT) were included in two Cochrane reviews published in 2012 and 2015(231) comparing ET and surgery. They included in the ET arm, only 19 patients for the highest quality RCT(232) and 36 patients in the other one(233).In the first RCT(232), in addition to the very small sample size of the study, the overall technical success rate of ET was only 53% (maybe because ESWL and ET were not performed by the same team in the same hospital, maybe because duration of pancreatic duct stenting was limited to a 27 weeks duration) as compared to 80% (1638 / 2040) (52% - 100%) in 8 studies with comparable patients (Table 2).Pain relief assessment, based on 6 measures of the Izbicki pain score during the first 2 years after ET was reported as complete or partial in only 32% of patients (6/19).In the second RCT(233), the ET was suboptimal also as ESWL and repeated ET in case of recurrent pain were not applied. Indeed, recurrent pain attacks after ET occurred in approximately one third of patients, and was usually related to stone migration or recurrence, progressive stricturing of the MPD or pancreatic stent obstruction or dislodgment(234). All these situations could be further managed successfully by endoscopy ESWL with a similar response rate as that for initial therapy(235). Contrary to surgery, patient’s age as well as severe co-morbidities occurring in CP such as portal hypertension are not risk factors for ET-related morbidity and mortality. Indeed, advanced age, severe co-morbidities, portal hypertension with vascular collaterals is relative or absolute contraindications for this type of surgery. Therefore, patients included in the ET group in both RCT were likely to have a poor outcome because the technical success of ET was poor(232) and the optimal ET was not performed(232,233)(233).Stenting: In 6 retrospective case series(236–241) with FU 24 months, including a total of 450 patients, pain improvement was reported in 67% (301 / 450, ranging from 43% to 74% in intention-to-treat analysis) after single plastic stent removal.In the largest study(239) after a median stenting duration of 23 months, 62% of patients maintained satisfactory pain control without pancreatic stent replacement during a median

31

time of 27 months. The majority of pain recurrences, requiring a new period of pancreatic stenting occurred during the first year following stent removal (79%) with almost all (97%) having relapsed by 24 months. Consequently, if a patient remains stable during the first year after stent removal, subsequent relapse and need for re-stenting are less likely.Results of multiple plastic stenting were reported in a single study that included 19 patients(242). A median number of 3 simultaneous stents were left in place during 7 months. At a mean FU of 38 months following stents removal, 84% (16/19) of the patients remained free of pain.For refractory MPD stricture, the temporary insertion of fully-covered self-expandable metallic stent (FC-SEMS) could be an option (Table 5). While uncovered and partially covered SEMS have provided disappointing results(243), 4 recent studies(244–247) have reported pain improvement in 53/61 patients (87%) but with a short FU after stent removal.Interestingly, a recent systematic review suggested that FC SEMS provide similar good results as multiple plastic stents(248).Factors predicting favorable clinical outcome after ET ESWL have been identified:1. Immediate pain relief or improvement after ET was significantly associated with technical

success (successful decompression of the MPD as suggested by a decrease in MPD diameter or a complete / partial duct clearance) and a low frequency of pain attacks before ET(249–252) (Table 1).

2. Medium-term clinical improvement correlated with low-frequency of pain attacks before treatment (Type A pain pattern according to Ammann RW et al(8)), short duration of disease before treatment, and absence of MPD stricture(236,251,253,254) (Tables 2 and 4). Note that in the RCT from Cahen et al(232), Type A pain pattern was recorded in only 37% of the patients randomized in the ET group and 16/19 (84%) presented with a MPD stricture.

3. Long-term clinical success was associated with a short duration of disease before treatment, absence of ongoing smoking at the end of FU, a shorter duration of ET and a lower number of ERCP procedures(255,256). Other prognostic factors for pain relapse during FU were identified in the study by Tadenuma et al(234), i.e. incomplete MPD stones removal after ET and the presence of MPD stricture (Table 3).

Taking into account all these above data, an algorithm is suggested for selection of good candidates for first-line limited trial of ET ESWL (Figure 3). If clinical success could be obtained with 5 endoscopic interventions, the patient will probably achieve long-term favorable outcome. The cut-off of 5 intervention is based on a study by Ali et al (257) They found that more pain relief after surgery was observed in patients who had 5 or fewer endoscopic treatments prior to surgery with an OR of 2.5 (95% CI, 1.1-6.3; p=0.04)). In this study, the multivariable analysis identified 3 independent risk factors for pain relief after surgery. These were pain duration of 3 years or less, no preoperative use of opioids and 5 or less endoscopic procedures prior to surgery. The authors tested also the cut-off of 3 endoscopic treatments with a statistically significant difference in the univariate analysis, but only the cut-off of 5 remained significant in the multivariate analysis. They proposed that the

Figure 3: The first step for the management of pain in patients with chronic pancreatitis should be to make a correct diagnosis based on clinical history and imaging procedures, and to exclude alternative diseases or complications that could induce pain not related to pancreatic ductal obstruction by stones and/or strictures.The second step should be to select the appropriate candidates for endoscopy (see the text for the definition of best candidates for endoscopical treatment with or without ESWL) and to treat such good candidates early in the disease course (within the first 2 to 3 years after symptom onset), with a limited number (< or = 5) of endoscopic interventions. If no persistent pain relief was obtained after a limited trial of endoscopic treatments +/- ESWL, that means that other factors than increased pancreatic ductal pressure could be involved in the pain syndrome and for these patients no further attempts at drainage should be proposed. In these patients or if the patient is not a candidate for endoscopy or in case of technical failure of endoscopy, medical treatment could be tried. Surgery and alternative options could also be proposed if no persistent pain relief was obtained after endoscopy, in case of limited effect of medical treatment.

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success of endoscopy should be determined in 5 or less endoscopic interventions to optimize outcome of future surgery. If endoscopy does not provide persistent pain relief, then surgery should be considered. Otherwise as observed in 18% of long-term followed patients after ET + ESWL(255), other factors than increased pancreatic ductal pressure could be involved in the pain syndrome and, for these patients, no further attempts at drainage should be proposed.

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Christopher Halloran, Myriam Delhaye Q8. Is ESWL effective for pain treatment in CP?In patients with uncomplicated painful calcified CP, ESWL alone is a safe and effective treatment. Best candidates for benefiting from initial first-line ESWL are patients with obstructive calcifications, > 4 mm confined to the head of pancreas. Combining systematic endoscopical therapy with ESWL adds to the cost of patient care, at the same time not probably improving the outcome of pancreatic pain (Quality assessment: moderate, Recommendation strong; Agreement: conditional).

ESWL for pancreatic stones is indicated for patients with all of the following:1. recurrent attacks of pancreatic pain;2. marked changes in the pancreatic ductal system i.e. dilated main pancreatic duct3. obstructing ductal stones (minimal diameter: 2 – 5 mm, calcified or radiolucent)(258)

Regardless of the method of shock waves generation (electrohydraulic, electromagnetic, piezoelectric) ESWL provides high rates of stones fragmentation (average of 91% ranging from 54 to 100%)(258).ESWL was proven useful for treating chronic pancreatitis (CP) related pain in a meta-analysis(259) that included a total of 588 patients from 16 studies. It was concluded from this analysis that ESWL effectively relieves MPD obstruction and alleviates pain in chronic calcifying pancreatitis most often in combination with endoscopic therapy (ET). The mean effect size (weighted correlation coefficient) on pain at follow-up (FU) was 0.62 0.7, with homogeneity reported for effect size between series.A most recent meta-analysis regarding the success of ESWL in chronic calcific pancreatitis management reviewed data from 27 studies including 3189 patients(260).The pooled proportion of patients with absence of pain at FU was 53% (95%, CI 51 – 55) and mild to moderate pain at FU was 33% (95%, CI 31 – 36).Narcotic use was decreased in 80% (95% CI, 77 – 82) of the pooled proportion of patients. Surgery was required in 4.4% (95% CI, 4 – 5) of the pooled proportion for various reasons, mainly for inadequate pain control with ESWL. Limitations of this meta-analysis are acknowledged i.e. the varying etiologies of CP, the wide range of FU periods among various

34

studies, the ESWL equipment varied among the studies, the pain score not universal and mainly the absence of control arm in all studies.In a prospective randomized study that compared ESWL alone with ESWL combined with endoscopy(261), including 55 patients with uncomplicated painful CP (no pseudocyst, no bile duct stricture) and calcifications > 4 mm obstructing the MPD, there was no evidence that the combination of endoscopy and ESWL was better than ESWL alone for the prevention of pain.Indeed ESWL alone (n=26) provided similar results than ESWL plus ET (n=29) in terms of decreasing number of pain episodes after trial intervention compared to baseline. Moreover, complete pain relief, 2 years after treatment, was achieved in 62% and 55%, respectively (p=NS).ESWL alone was also reported as a first-line treatment of calcified pancreatic stones in three non-randomized Japanese studies(262–264) (Table 6). Interestingly, the proportion of patients treated by ESWL alone in one large study was 57% (318 / 555)(263).Among 552 patients who underwent ESWL alone and included in these three studies, complete spontaneous MPD clearance was obtained in 63% (345 / 552, range 49% - 75%). In the study by Inui et al(263) the spontaneous ductal clearance after ESWL alone was not significantly different from that observed in the whole series (70% vs 73%). On the other hand, the ductal clearance rates were 49% after ESWL alone and 74% after ESWL ET in the study by Suzuki et al(264).Factors associated with complete stone clearance included the presence of a single stone vs. multiple stones(234,265) the absence of a MPD stricture(234) and a lower density of stones (< 820 Hounsfield units)(266).In the study by Ohara et al(262), a high rate of complete or partial pain relief (24/32, 75%) was obtained after ESWL alone over a mean FU of 44 months. This could be explained by the selection of patients without severe MPD stricture (in 22 out of 32 patients) and with good residual exocrine pancreatic function (only 2 patients (6%) presented steatorrhea) in this study.After treatment with ESWL (alone or combined with endoscopic drainage), most of the patients who experienced pain relapses developed them during the first two years following treatment(251,255,261). Interestingly, after treatment with ESWL alone, need for ERCP for pain relapses has been reported in only 3/32 (9%)(262) and in 8/26 (31%)(261) patients during FU.Pain relapse occurred significantly more frequently in patients with incomplete removal of stones after the initial therapy (ET ESWL) (HR, 3.7; p=0.007) and in those with a MPD stricture (HR, 3.4, p=0.02). Both factors were significant risk factors for pain relapse on multivariate analysis(234).Other factors independently associated with long-term ( 2 years) pain relief that could be taken into consideration for the selection of the best candidates for ESWL ET are a short disease duration prior to treatment, a low frequency of pain attacks before treatment, a

35

complete ductal stone clearance, the absence of MPD stricture and discontinuation of alcohol and tobacco during FU(234,240,251,255).

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Table 1 : ESWL + Endoscopy – Short term FU < 2 y

Author (year) (ref)

Design Population Intervention Outcome Comments

Delhaye (1992)(249)

Prospective observational

123 patients:81%

men, 80% OH

Age: 44.8 y Duration of

disease: 4.5 y Severe CP: 94% Pain: 87%

(Type A: 81%)

FU: 14 m Diabetes: 35% Steatorrhea: 28%

ESWL, EPSPancreating stenting: 39%Technical success: 90%(111 / 123 MPD )Complete MPD clearance: 59%(72 / 123)

Pain relief assessmentPain free interval

Complete pain relief: 40/88

Partial pain relief: 35/88

Complete or partial pain relief: 85%

Surgery: 8%

Recurrent pain more frequent when no decrease in MPD

LOE  : moderate

Schneider (1994)(267)

Retrospective observational

50 patients78% men, 66% OH

Age: 45 y Duration of

disease: 4.8 y Severe CP: -- Pain: 100%

(Type A: 72%)

ESWL, EPSPancreating stenting: 26%Technical success: 100%(50 / 50 complete or partial MPD clearance)Complete MPD clearance: 60%

Pain relief assessment pain frequency

Complete pain relief: 24/39 = 62%

Partial pain relief: 7/39 = 18%

Complete or partial

No predictive factor of pain relief

37

FU: 20 m Diabetes: 38% Steatorrhea: 14%

(30 / 50) pain relief: 79% Surgery: 12%

LOE  : low

38

Brand (2000)(252)

Prospective observational

48 patients73% men, 64% OH

Age: 51 y Duration of

disease: 69 m Severe CP: 92% Pain: 98%

(Type A: 67%)

FU: 7 m (n=38) Diabetes: 33% Steatorrhea: --

EPS (n=48)ESWL (n=48)Pancreating stenting: 56%Technical success: --(complete : 60%; complete MPD clearance: 44%)

Pain relief assessmentIzbicki pain score improved

Complete pain relief: 17/38 = 45%

Partial pain relief: 14/38 = 37%

Complete or partial pain relief: 82%

Improvement of pain score correlated with in MPD (r = 0.37, p<0.05)

Improvement of pain score associated with non-alcoholic CP (RR 1.4, 95% CI 1.1 - 1.8)

LOE  : low

Karasawa (2002)(268)

Retrospective 24 patients79% men, 71% OH

Age: 53 y Duration of

disease: 4.4 y Severe CP: -- Pain: 83%

(20/24) FU: 12 m Diabetes: 50% Steatorrhea: --

ESWL alone (n=10)ESWL + Endoscopy (n=14)Technical success: 79%(complete : 19/24; complete MPD clearance: 13/24 = 54%)

Pain relief assessment: NA

Immediate pain reliefComplete: 19/20 = 95%

Sustained pain relief at 12 m

Complete: 11/24 = 46%

No factor identified for predicting stone(s) disintegration

LOE  : very low

Tandan Prospective 1006 patients ESWL (n = 1006) Pain relief

39

(2010)(269) observational 66% men, 8% OH

Age: -- Duration of

disease: 1.7 y Severe CP: 100% Pain: 100% FU: 6 m Diabetes: 32% Steatorrhea: 7%

EPS (n = 938)Pancreatic stenting(n = 542, 54%)Duration of pancreatic stenting: 6 mTechnical success: 93% (complete or partial ductal clearance)Complete MPD clearance: 76%

assessment VAS analgesic use/m

Complete pain relief: 326/846 = 39%

Complete or partial pain relief: 711/846 = 84%

Surgery: 38/846 = 4.5%

LOE  : moderate

Milovic (2011)(270)

Prospective 32 patients75% men, 81% OH

Age: 48 y Duration of

disease: -- Severe CP: 100% Pain: 100% FU: 6-9 m Diabetes: -- Steatorrhea: --

ESWL (n=32)Pancreatic stenting: 19/32 (59%)Technical success: 100%(decompression of the MPD)Complete MPD clearance: 41%

Pain relief assessment5-point Likert scale pain score

Immediate pain relief: 24/32 = 75%

At 6-9 m after ET, improvement in pain score: 28/32 = 88%

Complete pain relief: 17/32 = 53%

Improvement of pain score not associated with complete MPD clearance

LOE: low

Kawaguchi retrospective 66 patients ESWL: 41/66 = 62% Pain relief In patients with

40

(2013)(271) 86% men, 88% OH

Age: 59 y Duration of

disease: - Severe CP: 100% Pain: 100% FU: ND Diabetes: -- Steatorrhea: --

Pancreatic duct stenting: 51/66 = 77%Technical success: 61/66 = 92%

assessment: NA

Complete pain relief: 60/66 = 91%

Partial pain relief: 5/66 = 7%

Complete or partial pain relief: 98%

only stones

Lower number of procedures

Fewer patients who required at least 1 y of treatment

LOE: very low

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Table 1S= ESWL + Endoscopy – Short term FU < 2 y – Studies 50 patients

Author (year) (ref)

Design Number of patients

Complete or partial pain relief

FU (months)

Comments (LOE)

Delhaye (1992)(249)

Prospective 123 85% (75 / 88)ITT: 75 / 123 = 61%

14 Recurrent pain more frequent when no decrease in MPD

LOE: moderate

Schneider (1994)(267)

Retrospective 50 79% (31 / 39)ITT: 31 / 50 = 62%

20 --

LOE: low

Tandan (2010) (269)

Prospective 1006 84% (711 / 846)ITT: 711 / 1006 = 71%

6 --

LOE: moderate

Total 1179 84% (79 - 85)ITT: 817 / 1179 = 69%

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Table 2 : ESWL + Endoscopy – Medium term FU 2 – 5 y

Author (year) (ref)

Design Population Intervention Outcome Comments

Sauerbruch (1992)(250)

Retrospective observational

24 patients:83% men,

63% OH

Age: 46 y Duration of

disease: 5 y Severe CP: -- Pain: 100% FU: 24 m Diabetes: -- Steatorrhea: --

ESWL, EPSPancreating stenting: 8%Technical success: 67%Complete MPD clearance: 42%(10 / 24)

Pain relief assessment pain frequency/m

Complete pain relief: 12/24

Partial pain relief: 8/24 Complete or partial

pain relief: 83% Surgery: 8%

Pain relief more often in patients with complete stone clearance (9/10 vs 3/14)No statistical analysis

LOE  : low

Costamagna (1997)(272)

Prospective observational

35 patients:89% men,

83% OH

Age: 46.3 y Duration of

disease: 3.3 y Severe CP: 95% Pain: 100% FU (n=32): 26.8 m Diabetes: 37% Steatorrhea: 11%

ESWL (n=35)EPS (n=34)Pancreating stenting: 51%Technical success: 86%( MPD )Complete MPD clearance: 74%

Pain relief assessment: NA

Complete pain relief: 23/32 = 72%

LOE  : low

Adamek Retrospective 80 patients: ESWL (n=80) Pain relief No association

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(1999)(265) observational 78% men, 75% OH

Age: -- Duration of

disease: -- Severe CP: -- Pain: 100% FU: 40 m Diabetes: 26% Steatorrhea: 24%

Pancreating stenting: NATechnical success: 43/80 = 54%(complete or partial MPD clearance + pancreatic stenting)

assessment: NA

Complete or partial pain relief: 61/80 = 76%

No analgesia: 43/80 = 54%

Surgery: 8/80 = 10%

between clinical improvement and technical success

LOE  : low

Farnbacher (2002)(235)

Retrospective observational

125 patients:81% men,

66% OH

Age: 48 y Duration of

disease: 5.9 y Severe CP: -- Pain: 86%

(Type A: 72%)

FU (n=84): 29 m Diabetes: -- Steatorrhea: --

ESWL (n=114)Pancreatic stenting (n=70)Technical success: 85% (106/125)Complete MPD clearance: 64/125 = 51%

Pain relief assessment: NA

Immediate pain reliefComplete: 94/101 = 93%

Sustained pain reliefComplete: 40/84 = 48%

Surgery: 15/114 = 13%

No association between relapse of pain (44/84) and

Continued consumption of alcohol

Complete vs partial MPD clearance

LOE: low

Kozarek Retrospective 40 patients: ESWL (n=40) Pain relief

44

(2002)(273) observational 53% men, 58% OH

Age: 53 y Duration of

disease: 5.9 y Severe CP: -- Pain: 100% FU: 2.4 y Diabetes: -- Steatorrhea: 10%

EPS (n=40) assessment VAS yearly hospitalizations narcotic medication monthly

Complete or partial pain relief: 32/40 = 80%

Surgery: 20%

LOE: low

Inui (2005)(263)

Retrospective multicenter: 11 centers

555 patients:84% men,

77% OH

Age: 52.5 y Duration of

disease: -- Severe CP: -- Pain: 85% FU (n=504): 44.3 m Diabetes: -- Steatorrhea: --

ESWL alone: n=318 ESWL + Endoscopy:

n=237Technical success: --Complete MPD clearance: 403/555 = 73%

Pain relief assessment: NA

Complete or partial pain relief: 382/504 = 76%

Surgery: 22/504 = 4%

LOE: low

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Cahen (2007)(232)

Prospective randomized controlled trial

39 patients 19 ET

58% men, 37% OH

Age: 52 y Duration of disease:

16 m Severe CP: 100% Pain: 100%

(Type A: 37%)

FU: 2 y Diabetes: 21% Steatorrhea: 68%

19 endoscopy / 20 surgery16 ESWL (84%)EPSPancreatic stenting: 16/19 = 84%Median duration of stenting: 6.2 mComplete MPD clearance: 16/18 = 89%Technical success: 53%

Pain relief assessmentIzbicki pain score at 6 w, 3, 6, 12, 18, 24 m

Complete pain relief: 3/19 = 16%

Partial pain relief: 3/19 = 16%

Complete or partial pain relief: 32%

Surgery: 4/19 = 21%

Low technical success rate (53%)

Low duration of pancreatic stenting (6.2 m)

ESWL and ET performed in different hospitals

LOE: high

Dumonceau (2007)(261)

Prospective randomized controlled trial

29 patients72% men,

69% OH

Age: 49 y Duration of disease:

-- Severe CP: 100% Pain: 100%

(Type A: 66%)

FU: 4.2 y Diabetes: 14%

ESWL: n=29Pancreatic stenting: 13/29 = 45%Technical success: NA

Pain relief assessment:- VAS (intensity)- number of pain episodes/y

Complete pain relief At 2 y: 55%: 16/29 At 4.2 y: 55%: 16/29

Need for ERCP: 18/29 = 62%

Factor independently associated with absence of pain relapse (whole series)

- Location of obstructive calcification in the head of pancreas (p=0.013)

Treatment costs per patient 3 times

46

Steatorrhea: -- Need for ESWL: 7/29 = 24%

Need for surgery: 3/29 = 10%

higher in the group ESWL + endoscopy compared to ESWL alone

LOE: high

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Hirota (2011)(274)

Retrospective 34 patients74% men,

50% OH

Age: 54.8 y Duration of

disease: -- Severe CP: 100% Pain: 100% FU: 3.4 y Diabetes: -- Steatorrhea: --

EPSESWL (n=21)Pancreatic stenting (n=34)Duration of pancreatic stenting 3.2 m (n=19) 27.0 m (n=15)

Pain relief assessment: NA

Incidence rate of pain (AP)

0.21 (n=34) 0.11 (n=19) 0.37 (n=15)

Surgery: 6/34 = 18%LOE: low

Seven (2012)(256)

Retrospective cross-sectional study

120 patients43% men,

54% OH

Age: 52 y Duration of disease

(n=215): 63 m Severe CP: -- Pain: 100% FU: 4.3 y Diabetes: 18% Steatorrhea: 53%

EPS (n=120)ESWL (n=120)Pancreatic stenting (114/120 = 95%)Technical success: NA

Pain relief assessment VAS (1 – 10) narcotic medication

Complete pain relief: 60/12 = 50%

Partial pain relief: 42/120 = 35%

Complete or partial pain relief: 85%

narcotic medication: 69/91 = 76%

Stop narcotic medication: 58%

FU 4 y (n=55)

Factors predicting improvement in narcotic pain medication use

Smokers who quit smoking after ESWL (95% vs 67%, p=0.014)

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(mean FU: 7.5 y)Need for ESWL: 16/55 = 29%Need for ERCP: 46/55 = 84%Need for surgery: 9/55 = 16%

LOE: moderate

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Suzuki (2013)(264)

Retrospective multicenter: 34 centers

916 patients86% men,

74% OH

Age: -- Duration of

disease: -- Severe CP: -- Pain: -- FU: 3.5 y Diabetes: -- Steatorrhea: --

ESWL (n=457)Endoscopy alone (n=83)ESWL alone (n=202)Surgery (n=135)Complete MPD clearance: 74%

Pain relief assessment: NA

Early complete or partial pain relief

After ESWL: 91% After endoscopy: 96% After surgery: 99%

Recurrent pain (most frequently within 3 y)

After ESWL: 18% After endoscopy: 8% After surgery: 5%

Need for surgery after ESWL/endoscopy: 10/540 = 1.9%

LOE: low

Tandam (2013)(275)

Retrospective analysis of a prospective database

636 patients364 FU 2 – 5 y272 FU > 5 y

65% men, 0% OH

Age: -- Duration of

disease: -- Severe CP: --

EPS (n=636)ESWL (n=636)Pancreatic stenting: 347/636 = 55%Complete MPD clearance: 78%Technical success: 100% (complete or

Pain relief assessment- VAS score (0 – 10)- number of analgesics- hospitalizations for pain

Complete pain relief:

50

Pain: 100% FU: 2 - 5 y Diabetes: 24% Steatorrhea: 8%

partial MPD clearance) 250/364 = 69% Partial pain relief:

93/364 = 26% Complete or partial

pain relief: 94% Surgery: 56/636 = 9%

LOE: moderate

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Ohyama (2015)(266)

Consecutive case series

128 patients77% men,

66% OH

Age: 51.4 y Duration of disease:

-- Severe CP: -- Pain: 100% FU: 3.5 y Diabetes: 22% Steatorrhea: --

EPSESWLPancreatic stenting: 14/128 = 11%Duration of stenting: 1 yComplete MPD clearance: 66/128 = 52%

Pain relief assessment4-grade scale

Immediate pain relief: 115/128 = 90%

Pain relief in complete MPD clearance: 61/66 = 92%

Pain relief in incomplete ductal clearance: 54/62 = 87%

Surgery: 1/128 = 0.8%

Pain relapse occurred at an early date in patients with incomplete duct clearance (39 m vs 84 m)

LOE: low

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Table 2S= ESWL + Endoscopy – Medium term FU 2 - 5 y – Studies 50 patients

Author (year) (ref)

Design Number of patients

Complete or partial pain relief

FU (months)

Comments (LOE)

Adamek (1999)(265)

Retrospective 80 76% (61 / 80)Complete 54% (43 / 80)

40 --

LOE: low

Farnbacher (2002)(235)

Retrospective 125 Complete: 48% (40 / 84)ITT: 40 / 125 = 32%

29 --

LOE: low

Inui (2005)(263)

Retrospective 555 76% (382 / 504)ITT: 382 / 555 = 69%

44 LOE: low

Seven (2012) (256)

Retrospective 120 85% (102 / 120)Complete: 50% (60 / 120)

52 Factors predicting improvement in narcotic pain medication use

Smokers who quit smoking

LOE: moderate

Suzuki (2013)(264)

Retrospective 916 After ESWL: 91%After Endoscopy: 96%

42 LOE: low

53

Tandan (2013)(275)

Retrospective 636N = 364; FU: 2 – 5 y

94% (343 / 364)Complete: 69% (250 / 364)

24 – 60 LOE: moderate

Ohyama (2015)(266)

Prospective 128 Immediate pain relief: 90% (115 / 128)

42 Pain relapse occurred at an early date in patients with incomplete duct clearanceLOE: low

Total 2288 Complete: 48 – 69%Complete or partial: 76 – 94%

54

Table 3 : ESWL + Endoscopy – Long term FU > 5 y

Author (year) (ref)

Design Population Intervention Outcome Comments

Delhaye (2004)(255)

Retrospective 56 patients:82% men,

68% OH

Age: 44 y Duration of

disease: 5 y Severe CP: 100% Pain: 100%

(Type A: 55%)

FU: 14.4 y Diabetes: 29% Steatorrhea: 29%

EPS: n=56ESWL: n=56Pancreating stenting: 48%Technical success: 86%(complete or partial MPD clearance + MPD )ET completed: 61%Mean treatment duration: 28.7 mET ongoing: 18%

Pain relief assessment number of hospitalizations for pain during FU

Complete clinical success

(no hospitalization): 17/56 = 30%

Partial clinical success(1 – 5 hospitalisation): 20/56 = 36%

Complete or partial clinical success: 66%

Surgery: 12/56 = 21%

Long-term clinical success associated with:

shorter duration of disease before ET

absence of ongoing smoking

shorter duration of ET

lower number of ERCP procedures

LOE  : low

Tadenuma (2005)(234)

Retrospective 117 patients:73% men,

68% OH

Age: 48 y Duration of

disease: --

ESWL (n=117)Endoscopy (n=65)Complete MPD clearance: 65/117 = 56%

Pain relief assessment4-grade scale: none, mild, moderate, severePain relief (none or

mild): 49/70 = 70%

Prognostic factors for pain relapse

Incomplete MPD stones removal after initial ET; HR

55

Severe CP: -- Pain: 100% FU (n=70): 77.5 m Diabetes: 36%

(25/70)

Steatorrhea: --

At 3 y after ET: 57/70 = 81% At 5 y after ET: 35/42 = 83% At 10 y after ET: 13/13 = 100%

Surgery: 1/70 = 1.4%

3.7, p=0.0067

MPD stricture; HR 3.4, p=0.018

LOE  : low

56

Cahen (2011)(276)

Prospective randomized controlled trial

39 patients 19 ET

58% men, 37% OH

Age: 52 y Duration of

disease: 16 m Severe CP: 100% Pain: 100%

(Type A: 37%)

FU (n=16): 7.1 y Diabetes: 21% Steatorrhea: 68%

19 ET / 20 surgery

At 7.1 y 31 remaining patients (7 †, 1 lost)16 ET / 15 surgery

ESWL (16/19)Pancreating stenting (16/19)Median duration of stenting: 9.2 m

Pain relief assessmentIzbicki pain score

Complete pain relief: 4/16 = 25%

Partial pain relief: 2/16 = 13%

Complete or partial pain relief: 6/16 = 38%

Surgery: 9/19 = 47%

Only 2/9 patients operated were completely free of pain after surgery (22%)This suggests that pain in these 7/16 patients (44%) was not related to MPD obstruction

LOE  : high

Tandan (2013)(275)

Retrospective analysis of a prospective database

636 patients:272 FU > 5 y

65% men, 0% OH

Age: -- Duration of

disease: -- Severe CP: -- Pain: 100% Diabetes: 24%

EPS (n=636)ESWL (n=636)Pancreatic stenting: 370/636 = 58%Complete MPD clearance: 76%Technical success: 100% (complete or partial MPD clearance)

Pain relief assessment- VAS score (0 – 10)- number of analgesics- hospitalization for pain

Complete pain relief: 60%

LOE: moderate

57

Steatorrhea: 8% Complete or partial pain relief: 96%

Surgery: 56/636 = 9%

58

Table 3S= ESWL + Endoscopy – Long term FU > 5 y – Studies 50 patients

Author (year) (ref)

Design Number of patients

Complete or partial pain relief

FU (months)

Comments (LOE)

Delhaye (2004)(255)

Retrospective 56 66%Complete: 30%

173 Long-term clinical success associated with

Shorter duration of disease Absence of ongoing smoking Shorter duration of ET Lower number of ERCP

procedures

LOE: low

Tadenuma (2005)(234)

Retrospective 70 70% 78 Prognostic factors of pain relapse

Incomplete MPD clearance MPD stricture

LOE: moderate

Tandan (2013)(275)

Retrospective 272 96% > 60 LOE: moderate

59

Total 398 87% (66 – 96)

60

Table 4 : Endoscopy “alone” (+ ESWL 60% of population) *with FU 24 m

Author (year) (ref)

Design Population Intervention Outcome Comments

Binmoeller* (1995)(236)

Retrospective observational

93 patients:70% men,

66% OH

Age: 49 y Duration of

disease: 5.6 y Severe CP: -- Pain: 100% FU: 4.9 y Diabetes: 17% Steatorrhea: 9%

EPSPancreatic stenting: 100% (single plastic)ESWL: 34/93 = 37%

Mean duration of stenting: 15.7 m

Mean FU after stent removal: 3.8 y

Definitive stent removal: 49/93 = 53%

Pain relief assessment severity / frequency of pain

Pain relief at 6 m- complete

46/93 = 49%- partial 23/93 = 25%

Complete or partial pain relief: at 4.9 y: 60/93 = 65%

Surgery: 24/93 = 26%

Predictive factor associated with long-term response

Duration of disease 7.0 y in non-responders vs 4.1 y in responders

No statistical analysis

LOE  : very low

Ponchon (1995)(277)

Prospective standardized protocol

23 patients:96% men,

100% OH

Age: 47 y Duration of

disease: -- Severe CP: -- Pain: 100%

EPSPancreatic stenting: 100%(single plastic)ESWL: 0%

Mean duration of stenting: 6 m

Mean FU after stent

Pain relief assessment severity of pain, analgesics

complete pain relief: 8/23 = 35%

partial pain relief: 13/23 = 57%

Stopped analgesic use associated with in MPD by 2 mm (US)

61

(Type A: 61%)

FU: 14 m Diabetes: -- Steatorrhea: --

removal: 14 m Definitive stent

removal: 100%

Complete or partial pain relief: 92%

Stopped analgesic use: 17/23 = 74%

Surgery: 3/23 = 13%LOE  : low

62

Smits* (1995)(237)

Retrospective observational

51 patients69% men,

61% OH

Age: 45 y Duration of

disease: 28.5 m Severe CP: -- Pain: 100% FU: 34 m Diabetes: -- Steatorrhea: --

EPS (n=31)Pancreatic stenting (n=49)(single, plastic)ESWL (n=3): 6%

Median duration of stenting: 6.3 m

Median FU after stent removal: 28.5 m

Definitive stent removal: 31/49 = 63%

Pain relief assessment compared with the 6 m prior pancreatic stenting < 50% of pain < 50% of analgesic use < 50% of hospitalizationPain relief during stenting (n=49)

Complete: 20/49 = 41%

Partial: 20/49 = 41% Complete or partial:

82%Pain relief after stent removal (n=31)

Complete: 12/31 = 39%Partial: 10/31 = 32%Complete or partial: 71%

Surgery: 6/51 = 12%

No predictive factor of clinical improvement after pancreatic stenting

LOE  : low

63

64

Dumonceau (1996)(251)

Retrospective observational

70 patients90% men, 80% OH

Age: 47 y Duration of

disease: 4.8 y Severe CP: -- Pain: 90%

(Type A: 31/56=55%)

FU: < 2 y Diabetes: 37% Steatorrhea: 43%

EPS (n=70)ESWL (n=41): 59%Pancreating stenting: 0%Technical success: 75%(complete or partial MPD clearance)Complete MPD clearance: 50%

Pain relief assessmentIntensity of pain graded on a 10-point scale (VAS)Immediate pain relief(n=56 patients with pain at admission)

Complete 41/56 = 73%

Partial 12/56 = 22%

Complete or partial: 95%

Pain relief during 2 y FU(n = 46)

Complete 25/46 = 54%

Partial 21/46 = 46%

Complete or partial: 100%

Factors associated with immediate pain relief

MPD clearance (p<0.01) (complete or partial)

Low frequency of pain attacks (< 2 in the

2 prior months) (p<0.05)

Factors associated with sustained pain relief during 2 y FU

Earlier treatment after onset of CP (p<0.005)

Low frequency of pain attacks (< 2

during 2 m before ET) (p<0.05)

Absence of MPD stricture (p<0.05)

LOE  : low

65

Rösch* (2002)(230)

Retrospective multicenter (8 centers)

1018 patients:71% men,

72% OH

Age: 50 y Duration of

disease: -- Severe CP: -- Pain: 100%

(Type A: 73%)

FU: 4.9 y Diabetes: 23% Steatorrhea: 37%

EPS: 92%ESWL: 26%Pancreatic stenting: 57%Technical success: 88%Complete MPD clearance: 64%Completed ET: 599/758 = 79%Ongoing ET: 159/758 = 21%

Pain relief assessment intensity of pain (no, weak, moderate, strong)

complete pain relief: 66%

partial pan relief: 19% Complete or partial

pain relief: 85% Surgery: 238/1018 =

23%

No difference in pain relief in patients with different ductal pathologies (i.e. strictures vs stones)

Trend for higher pain relief in patients with initial technical success (p=0.06)

LOE: moderate

66

Dite* (2003)(233)

Prospective randomized study

140 patients:85%

men, 88% OH

Age: 41.7 y72 randomized36 ET / 36 surgery68 non randomized28 ET / 40 surgery

FU: 5 y Pain: 100% Diabetes: 22%

ET: n=64EPS: n=64Pancreatic stenting: 33/64 = 52%ESWL: 0%

Mean duration of stenting: 16 m

Technical success: 62/64 = 97%

Surgery: n=76- Resection 80%- Drainage: 20%

Pain relief assessment- Melzack scoreComplete or partial pain relief after ET at 5 y FU 65% (n=64) (R + NR) 61% (n=36) (R)

High risk of bias- pseudo-randomization- unconcealed allocation- lack of baseline characteristics- lack of ITT analysis- not powered- lack of optimal ET(no ESWL, no repeated ERCP)

LOE: moderate

Vitale* (2004)(238)

Retrospective analysis of a prospective database

89 patients:47% men

Age: 48 y Pain: 100% FU (n=75): 43 m

Pancreatic stenting(single plastic)

Mean duration of stenting: 5.3 m

Pain relief assessment- pain intensity score (1 – 10)

Pain reduction: 62/75 = 83%

Reduction in analgesic

LOE: low

67

medication: 35/75 = 47%

Surgery: 11/89 = 12%Eleftheriadis* (2005)(239)

retrospective 100 patients:75%

men, 77% OH

Age: 49 y Duration of

disease: 3 y Severe CP: 86% Pain: 100% FU: 69 m FU after stent

removal: 27 m Diabetes: 18% Steatorrhea: 24%

EPS, ESWL (n=51)Pancreatic stenting(single plastic)

Median duration of pancreatic stenting: 23 m

Pain relief assessment: NA

Complete or partial pain relief: 62/100 = 62% at 27 m after stent removal, without pancreatic stent replacement

Re-stenting within the first year of FU: 30% at a median time of 5.5 m after stent removal

Re-stenting at the end of FU: 38%

Surgery: 4%

79% of pain relapse during the first year after stent removal97% had relapsed by 24 mPredictive factor for pancreatic re-stenting (n=30) within 1 y of stent removal: presence of PD (n=21) (12/21 vs 18/79, p=0.002)

LOE: moderate

Costamagna* (2006)(242)

Prospective observational

19 patients:84%

men, 58% OH

Age:45 y Duration of

disease: --

Pancreatic stenting: 100%(multiple plastic)ESWL: 6/19 = 32%

Mean duration of stenting: 7 m

Pain relief assessment: NAComplete pain relief: 16/19 = 84%

68

Severe CP: -- Pain: -- FU: 38 m Diabetes: -- Steatorrhea: --

LOE: low

Ishihara (2006)(278)

NA 20 patients:90%

men, 95% OH

Age: 52.4 y Duration of

disease: -- Severe CP: -- Pain: -- FU after stent

removal: 10.5 m Diabetes: -- Steatorrhea: --

Pancreatic stenting: n=20EPSESWL: 9/20 = 45%

Mean duration of stent patency: 12 m

Pain relief assessment4-grade scale: none, mild, moderate, severePain relief (none,

mild) after stent removal: 18/20 = 90%

LOE: low

Farnbacher* (2006)(240)

Retrospective 98 patients:86%

men, 73% OH

Age: 49 y Duration of

disease: -- Severe CP: 88% Pain: 89%

(Type A: 68%)

FU after stent

EPS (n=76)Pancreatic stenting (single plastic): n=98ESWL (n=60)

Mean duration of pancreatic stenting: 10 m

Pain relief assessmentVAS (intensity)

Complete pain relief: 53/96

Partial pain relief: 22/96

Complete or partial: 75/96 = 78%

Re-stenting: 17/96 =

69

removal: 3.8 y (n=57)

Diabetes: -- Steatorrhea: --

18% Surgery: 22/96 = 23%

LOE: low

70

Weber* (2007)(241)

Prospective observational

19 patients:63% men,

74% OH

Age: 54 y Duration of disease:

3 y Severe CP: 100% Pain: 100%

(Type A: 58%)

FU: 2 y Diabetes: 26% Steatorrhea: 5%

EPS: n=19Pancreatic stenting: n=17(single plastic)ESWL: n=5 (26%)Technical success: 17/19 = 89%)

Mean duration of stenting: 5.6 m

Pain relief assessment- VAS (intensity 0 – 10)- in pain medicationComplete or partial pain relief at 1 y: 14/19 = 74% at 2 y: 11/19 = 58% LOE: low

Rutter* (2010)(279)

Retrospective comparative

292 patients 150 ET:

70% men, 53% OH

Age: 51.3 y Duration of disease:

-- Severe CP: -- Pain: 28%

(81/292) FU: 2.8 y Diabetes: -- Steatorrhea: --

Endoscopy: n=150Pancreatic and/or bile duct stenting: n=60EPS: n=66

Surgery: n=99 Conservative: n=43

Technical success: --

Relapse-free interval: 4.8 7.0 m (for endoscopy group)

LOE: very low

71

72

Clarke* (2012)(253)

Retrospective analysis of a prospective database

85 patients:51% men,

41% OH

Age: 41 y Duration of

disease: -- Severe CP: -- Pain: 72%

(Type A: 58%)

FU (n=63): 4.8 y Diabetes: 8% Steatorrhea: 21%

ET in 71 patientsEPS: n=43 (61%)ESWL: n=6 (8%)Pancreatic stenting: n=53 (75%)Technical success complete or partial: 60/70 = 86%

Pain relief assessment- frequency of pain- discontinuation of narcotic medicationsClinical success (n=55)Complete: 23/55 = 42%Partial: 5/55 = 9%Complete or partial clinical success: 51%

Factors associated with long-term clinical response to ET (n=28 vs n=27)

Less constant pain: 21% vs 52%, p=0.031

Less daily narcotics: 14% vs 56%, p=0.001

Shorter duration between onset of CP and start of ET: 4 m vs 40 m, p=0.017

No association with specific baseline morphologic characteristics

LOE: low

Weber* (2013)(280)

Prospective observational case series

19 patients:63% men,

74% OH

Age: 54 y Duration of

Pancreatic stenting: n=17(single plastic)ESWL: n=5 (26%)Technical success:

Pain relief assessment- VAS (intensity 0 – 10)

73

disease: 3 y Severe CP: 100% Pain: 100%

(Type A: 58%)

FU: up to 5 y Diabetes: 26% Steatorrhea: 5%

17/19 = 89%

Mean duration of stenting: 5.6 m

- in pain medication

Complete or partial pain relief

at 5 y: 8/19 = 42%

Surgery: 3/19 = 16%LOE: very low

74

He* (2014)(254)

prospective 360 patients:89 stage I M-ANNHEIM classification

72% men, 38% OH

Age: -- Duration of

disease: -- Severe CP: 36/89 =

40% Mild CP: 32/89 =

36% Pain: -- FU (n=83): 24 m Diabetes: 0% Steatorrhea: 0%

ESWL: 0%EPSStone extraction: 36/89 = 40%Pancreatic stenting: 76/89 = 87% (single plastic)Technical success: NA

Mean duration of pancreatic stenting: 11 m

Pain relief assessmentIzbicki pain score before ET, at 24 mComplete pain relief: 54/83 = 65%Partial pain relief: 18/83 = 22%Complete or partial pain relief: 87%

Surgery: 4/89 = 4%

Mild CP in 36% of patients (i.e. no abnormality of the MPD) but 87% of pancreatic stenting to treat MPD stricture!Better clinical results if early treatment (before pancreatic endocrine/exocrine insufficiency)?

LOE: low

75

Table 4S= Endoscopy ESWL ( 50%) Studies 50 patients and FU 24 m

Author (year) (ref)

Design Number of patients

Complete or partial pain relief

FU (months)

Comments (LOE)

Binmoeller (1995)(236)

Retrospective 93 65% (60 / 93) 59 Predictive factor of long-term response

Shorter duration of disease

LOE: very low

Smits (1995)(237)

Retrospective 51 43% (22 / 51) 34 LOE: low

Rösch (2002)(230)

Retrospective 1018 85% (865 / 1018) 59 LOE: moderate

Dite (2003)(233)

Prospective partially randomized

64 66% (42 / 64) 60 LOE: moderate

Vitale (2004)(238)

Retrospective 89 70% (62 / 89) 43 LOE: low

Eleftheriadis (2005)(239)

Retrospective 100 62% (62 /100) 69 LOE: moderate

Farnbacher (2006)(240)

Retrospective 98 77% (75 / 98) 46 LOE: low

76

Rutter (2010)(279)

Retrospective 150 ND 34 LOE: very low

Clarke (2012)(253)

Retrospective 55 51% (28 / 55) 58 Predictive factor of long-term response

Less constant pain Less daily narcotics Shorter duration of disease

LOE: low

He (2014)(254)

Prospective 89 81% (72 / 89) 24 LOE: low

Total 1657 78% (43 – 85)(1288 / 1657)

77

Table 5 : SEMS in MPD for CP

Author (year) (ref)

Design Population Intervention Outcome Comments

Eisendrath (1999)(243)

Retrospective observational

38 patients:89% OH

Age:42 y (n=20)38 y (n=18)

Duration of disease: --

Severe CP: -- Pain: -- FU (n=20): 70 m Diabetes: -- Steatorrhea: --

UC- SEMS: n=20PC (n=9) / FC (n=9) - SEMS

Technical success: 20/20 = 100% 16/18 = 89% (migration)

Pain relief assessment: NA

Immediate pain relief 20/20 = 100% 16/16 = 100%

Sustained pain relief at 2 y

3/20 = 15% 4/16 = 25%

Surgery: 2/38 = 5%

LOE  : low

Park (2008)(244)

Prospective pilot study

13 patients:69% men,

62% OH

Age: 51 y Duration of

disease: -- Severe CP: -- Pain: 100% FU after stent

FC – SEMS (Niti D-type)

Duration of stenting: 2 m

Technical success: 100%

Pain relief assessment: NA

No pain relapse during the 5 m FU after stent removal

78

removal: 5 m Diabetes: -- Steatorrhea: --

LOE  : low

79

Sauer (2008)(245)

Prospective pilot study

6 patients67% men,

67% OH

Age: 55 y Duration of disease:

-- Severe CP: -- Pain: 100% FU: -- Diabetes: -- Steatorrhea: --

FC- SEMS (Viabil)

EPS: 6/6, ESWL: 4/6

Technical success: 100%

Stent removal: 5/6 (1 pancreatic cancer)

Duration of stenting: 3 m

Pain relief assessment- VAS before, 4 w after stent placement, 4 w after stent removal

Complete pain relief: 2/5

Recurrent symptomatic MPD stricture: 3/5

Pain score improved: 4/6 (67%)

LOE  : low

Moon (2010)(246)

prospective 32 patients:84% men,

59% OH

Age: 48 y Duration of disease:

-- Severe CP: -- Pain: -- FU after stent

removal: 5 m Diabetes: -- Steatorrhea: --

FC – SEMS (Niti-S,

bumpy type), EPSESWL: 19/32 = 59%

Technical success: 100%

Duration of stenting: 3 m

Pain relief assessment: NA

Recurrent symptomatic stricture: 3/32 = 9%

Complete pain relief: 27/32 = 84%

Surgery: 1/32 = 3%

LOE: low

Giacino (2012)(247)

Case series 10 patients:80% men,

EPS Pain relief

80

60% OH

Age: 55.7 y Duration of disease:

-- Severe CP: 100% Pain: 100% FU after stent

removal: 20 m Diabetes: -- Steatorrhea: --

FC – SEMS(1 biliary WST, 9 biliary WFX)

Technical success: 100%

Duration of stenting: 5.7 m

assessment: NA

Complete pain relief: 6/10 = 60%

Partial pain relief: 3/10 = 30%

Complete or partial pain relief: 90%

Surgery: 0% LOE: low

Table 6 : ESWL alone

Author (year) (ref)

Design Population Intervention Outcome Comments

Ohara (1996)(262)

Prospective observational

32 patients:88% men,

88% OH

Age: 57 y Duration of

disease: -- Severe CP: -- Pain: 88% FU: 44 m Diabetes: -- Steatorrhea: 6%

ESWL alone (n=32)Pancreatic stenting: 0%Technical success: 79% (15/19)( MPD )Complete MPD clearance: 24/32 = 75%

Pain relief assessment frequency

Complete pain relief: 22/28 = 79%

Partial pain relief: 2/28 = 7%

Complete or partial pain relief: 86%

Need for ERCP: 3/32 = 9%

Severe MPD stricture: 10/32 = 31%Steatorrhea: 2/32 = 6%No statistical analysis

LOE  : low

81

Need for surgery: 1/32 = 3%

Inui (2005)(263)

Retrospective multicenter: 11 centers

555 patients:84% men,

77% OH

Age: 52.5 y Duration of

disease: -- Severe CP: -- Pain: 85% FU (n=504): 44.3 m Diabetes: -- Steatorrhea: --

ESWL alone: n=318 Spontaneous stone

clearance: 222/318 = 70%

No separate outcome for patients treated by ESWL alone

LOE  : low

82

Dumonceau (2007)(261)

Prospective randomized trial

26 patients85% men,

73% OH

Age: 51.8 y Duration of

disease: -- Severe CP: 100% Pain: 100%

(Type A: 62%)

FU: 4.3 y Diabetes: 23% Steatorrhea: --

ESWL alone: n=26

Technical success: NA

Pain relief assessment- VAS (intensity)- number of pain episodes/y

Complete pain relief- at 2 y: 16/26 = 62%- during whole FU at 4.3 y: 15/26 = 58%

Need for ERCP: 8/26 = 31%

Need for ESWL: 7/26 = 27%

Need for surgery: 1/26 = 4%

Factor independently associated with absence of pain relapse (whole series)

- Location of obstructive calcification in the head of pancreas (p=0.013)

Treatment costs per patient 3 times lower in the group ESWL alone compared to ESWL + endoscopy

LOE  : high

Suzuki (2013)(264)

Retrospective multicenter: 34 centers

202 patients ESWL aloneComplete MPD clearance: 49%

No separate outcome for patients treated by ESWL alone

LOE: very low

83

List of Abbreviations in the Tables

ESWL : extracorporeal shockwave lithotripsy

FU : follow-up

y : year

ref : reference

CP : chronic pancreatitis

OH : alcohol etiology of chronic pancreatitis

EPS : endoscopic pancreatic sphincterotomy

MPD : main pancreatic duct

: diameter

VAS : visual analogue scale

LOE : level of evidence

very low: < 100 patients, retrospective, no assessment of pain relief, no statistical analysis

Low: < 100 patients, retrospective or prospective, subjective or objective pain relief assessment

Moderate: 100 patients, retrospective or prospective, objective pain relief assessment

High: RCT, 100 patients, prospective, objective pain relief assessment, identification of

significant predictive factor of pain relief

: stone(s) fragmentation

NA : not available

m: month

ND: not determined

ITT: Intention To Treat analysis

ET: Endoscopical therapy

AP: acute pancreatitis

†: dead

US: ultrasonography

R: randomized

NR: non randomized

PD: pancreas divisum

UC-SEMS: uncovered self expandable metal stent

PC-SEMS: partially covered expandable metal stent

84

FC-SEMS: fully covered expandable metal stent

85

Harry van Goor, Tonya M Palermo & Eva Szigethy

Q9. Are other treatments (neurolytical, psychological, ect.) effective for pain management in CP?Neurolytical interventions can be used in selected patients with painful CP who have failed endoscopic and surgical treatment. Thoracoscopic splanchnic denervation is more effective regarding long-term pain relief in patients who are not in chronic opioid treatment. Behavioral interventions should be part of the multidisciplinary approach in CP pain particularly when patients experience psychological impact of pain and quality of life has decreased. Early intervention in children may be particularly important.(Quality assessment: low, recommendation: strong; Agreement: conditional)

This chapter comprises two different types of pain treatment in CP, nerve ablation (neurolytic) and psychological or psychiatric intervention. Consequences of CP in children and psychological treatments are addressed in a separate paragraph to create awareness for this small but underexposed group of patients with chronic pain. Overall the evidence of these types of treatments regarding pain relief is low due to lack of good quality trials. Neurolytic interventionsNeurolytical treatments of patients with chronic pancreatitis pain are generally implemented when other medical treatments have failed and patients are referred to pain specialist teams. Treatment is only recommended in patients not responding to conventional analgesics and/or having severe side effects of medication, in patients who have no pathology suitable for surgery or endoscopy or are not willing to undergo these treatments. Commonly this is done at a late disease stage when patients have suffered longstanding intractable pain, despite numerous treatments and are desperately seeking pain relief (‘last resort’). As a result, studies of nerve ablation interventions are predominantly done in populations of patients with severe chronic pancreatitis pain, are heterogenous, include fairly low quality trials, and often fail to demonstrate a long term beneficial effect. Finally, as a sham arm has never been used it is not known whether the effects are a result of the intervention per se or reflects the natural course of the disease.Neurolytical treatments can be at different levels of the visceral afferent system; celiac plexus block (percutaneous fluoroscopy or CT guided), surgical, endoscopic ultrasound (EUS) assisted), splanchnic nerve ablation (surgical, percutaneous). Other treatment (although not neurolytical) are stimulation of central parts in the brain (spinal cord and transcranial magnetic resonance (TMS) stimulation).Several techniques for percutaneous celiac plexus blockade have been described(281) but pain relief only lasts for several weeks to months and in about half of patients with no long term

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benefits. EUS-guided celiac plexus blockade was effective in alleviating abdominal pain in 51.46% of patients based on a systematic review of 6 studies comprising a total of 221 patients(282). Although endoscopic ultrasonore guided plexus block was superior to percutaneous CT guided block in 2 RCTs regarding duration of pain relief, long term pain relief was insufficient or not investigated(283). Furthermore, there is a risk for side effects such as postural hypotension and diarrhea. After a short-lived period of use, endoscopic ultrasonore guided celiac plexus block is nowadays rarely applied.Thoracoscopic splanchnicectomy was first described as minimally invasive therapy for pain in 1994(284) and has been researched by several groups in the world since then; however, to date no RCT has been done. In a recent review of sixteen studies with 484 patients with thoracoscopic splanchnicectomy and a minimum follow-up of 12 months, a median of 49% of patients were free of opioids at end of follow-up(283). Similar to pancreatic surgery for chronic pancreatitis, preoperative opioid use and duration of disease and pain seem to impair long term results probably due to central sensitization(285). Splanchnicectomy early in the disease course and before opioids are started could be an attractive alternative to early pancreatic surgery, but this needs to be further researched in a trial. Even less invasive is percutaneous splanchnic nerve radiofrequency ablation. Only retrospective small series are reported with good effects, however, for a short period(286). Advantage of this technique is the possibility to repeat the ablation without much morbidity.There are only a few retrospective studies of spinal cord stimulation and case reports in transcranial magnetic stimulation (TMS) in chronic pancreatitis(287,288). Pain relief for more than a year was achieved in 66 percent of patients with severe chronic pancreatitis who had spinal cord stimulation. Drawback of the procedure is the invasiveness and potential for implant infection(287). Repetitive TMS holds promise for treating depression in chronic pancreatitis patients with a possible concurrent pain relieving effect, but this needs to be investigated in more homogenous groups of patients and with validated techniques. Psychological/psychiatric interventionsPain in CP is multi-determined and underlying etiology is not well delineated though features of nociceptive, visceral, neuropathic and central mechanisms have been implicated. In other disease populations, chronic non-cancer pain is associated with depression-anxiety spectrum disorders(289–291) and substance misuse or abuse(292,293), which if unaddressed, can further complicate treatment of pain. Post-traumatic stress disorder is also associated with chronic pain (294,295). Consistent with common psychosocial impact experienced by other patients with chronic pain, patients with CP also report high rates of depression, substance use, and poor quality of life(54,296,297). Severe chronic pancreatitis pain is also associated with declines in cognitive performance (e.g psychomotor performance, memory, and executive functions)(298);

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the co-occurrence of depressive symptoms, sleep disturbance, opioid use, and history of alcohol abuse also predicted cognitive decline. There are a paucity of studies examining the effects of psychological interventions for CP patients. In other chronic pain conditions and gastrointestinal disorders, psychological interventions have shown to be efficacious in reducing chronic pain and pain impact(299,300). Behavioral interventions with the most support for chronic pain include cognitive behavioral therapy (CBT), acceptance therapy, mindfulness approaches, and hypnosis(301–304). There is also growing evidence supporting the neurobiological processes involving the brain-gut axis which increasingly accepted as mediating the effects of psychological interventions(305).In one study of 311 CP patients captured during inpatient admissions, a collaborative interdisciplinary treatment program, which included psychological and psychiatric interventions, was associated with reduced healthcare costs(306). The psychological care included comprehensive psychosocial evaluations about the pain experience, depression, anxiety, post-traumatic stress disorder, substance use/misuse, coping styles, past psychiatric treatment, social support and educational/vocational achievement. Personalized psychological interventions included behavioral approaches to pain management (relaxation, guided imagery), biofeedback, hypnosis, and various psychotherapy modalities (acceptance-based, CBT, brief dynamic, and interpersonal). Psychiatric intervention included psychotropic medications targeting depression and anxiety, optimization of non-opioid pain medications (e.g., gabapentin, SSRI/SNRI, analgesics), screening for and treatment of addiction including buprenorphine/naloxone) and opioid tapers. The study, however did not have a comparison group and did not include standardized treatment protocols, thus it is not possible to attribute cost reduction directly to behavioral interventions.Chronic opioid management is often necessary for residual pain, which increases the risk of addiction and misuse(307,308). Identification of risk factors for opioid addiction is critical(309). In one study, clinical risks for opioid misuse in patients with chronic nonalcoholic pancreatitis included depression, poor quality of life and alcohol use(297). Behavioral intervention and psychosocial resources are critical to prevent or treat opioid misuse and dependence in patients with CP(310). A strong empathic doctor-patient relationship is also key. Successful opioid detoxification strategies have also been demonstrated, though recidivism was high at 6 months(311).

Children with CP painChildren with CP represent an important subgroup who experiences frequent pancreatitis-related abdominal pain(312), reduced quality of life and significant problems with fatigue(313). Similar to the impact of chronic pain in other pediatric chronic conditions, children with chronic CP also have severe disease burden, high health care utilization and costs(314). Moreover, children also

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experience the functional impact of CP on their ability to attend school. In one study, 70% of children with CP indicated one or more missed days of school in the past month due to chronic pancreatitis and one-third of children had missed 3 or more days of school in the most recent month(315). Additional research is critically needed to understand the epidemiology of chronic pancreatitis pain in children, risk factors for chronic pain and poor quality of life, and treatment approaches that may improve pain and quality of life for children. Longitudinal research will be particularly informative for understanding trajectories of pain into adulthood. Because CP pain and its impact have only recently been recognized in the pediatric population, there are no studies of neurolytical or psychological treatments conducted to date. Psychological treatments for other forms of pediatric chronic pain, including abdominal pain, are well studied and have promising effects. Treatments have included predominantly cognitive-behavioral interventions such as pain education, relaxation training, pain-specific cognitive therapy, and behavioral activation. Social learning theories have also guided treatment in children where intervention strategies focus on modifying parent behavior that may inadvertently reinforce maladaptive coping (such as teaching parents to reward activity participation like attending school). In the most recent systematic review of the efficacy of RCTs of psychological therapies for a range of pediatric chronic pain conditions including abdominal pain(316), moderate effects on pain and small effects on reducing disability were found at post-treatment. Unfortunately, even when effective psychological treatments are developed major barriers exist for families to access specialized pediatric pain services due to the geographical distance that separates most families from pediatric pain specialists. Very limited clinical resources are available to treat pediatric chronic pain and this shortage of treatment centers(317) has been identified as a major barrier contributing to an unmet clinical need. Availability of information and communication technology has expanded opportunities for reaching families remotely. An emerging evidence base now exists for internet-delivered psychological interventions for chronic pain in both adult and pediatric populations(318–320), with patients showing improvements in pain and disability. A major priority in treatment of chronic pancreatitis pain is to develop and evaluate low-cost psychological treatments to reduce pain and improve quality of life both for children and adults.

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Güralp O Ceyhan, Harry van Goor and Stefan A W Bouwense

Q10. What is the optimal surgical approach to relief pain in chronic pancreatitis Depending on the morphological changes of the pancreas and pain processing status a (partially) resection, decompression of the pancreatic duct or combined intervention can be performed to reduce pain. Long-term effects are variable, however success rates up to 80% have been reported. The emerging role of total pancreatectomy as initial surgical treatment looks promising but needs further investigation (Quality assessment: moderate; Recommendation: strong; Agreement: conditional)

Four groups of pathophysiological mechanisms have been suggested to cause pain in chronic pancreatitis: 1) inflammation of the pancreas; 2) increased intrapancreatic pressure within the parenchyma and/or pancreatic duct, causing tissue ischemia; 3) (late) pancreatic and extrapancreatic complications (e.g. pseudocysts, portal thrombosis, bile duct/duodenal strictures and peptic ulcers) and 4) alterations indicative of nerve damage, e.g. increased number and diameter of pancreatic nerves, and inflammation of perineural sheathes have been described in chronic pancreatitis together with changes in the central nervous system (peripheral and central sensitization)(42,103,199,321,322). How these different pathophysiological mechanisms exactly cause pain in chronic pancreatitis and which correct time point for surgerical procedures is most appropriate are still under debate. In many centres invasive treatment is recommended in patients where pain cannot be controlled without the use of opioids and endoscopic interventions have failed or are not indicated. Although long-term results of surgery are promising, most of studies to date are observational or only compare different invasive procedures. Question if surgery, when performed early, is better than opioid treatment or early endoscopy cannot be answered till now. The different studies have also compared surgical techniques or surgery vs. Endoscopy, and as no studies have used a sham control the natural history of disease and placebo effects have not been taken into consideration and data must be interpreted causiously. Surgical options for pain are classified into three categories: a) decompression (focusing on ductal hypertension), b) resection (focusing on inflammatory masses and stones in the pancreatic head) and c) mixed techniques. In the 1950s, Puestow and Gillesby developed a technique combining a longitudinal opening of the pancreatic duct and an anastomosis to the small intestine with a pancreatic left resection which is still applied nowadays for pancreatic stones and pseudocysts. Another technique by Partington and Rochelle is a modificaton of this procedure with an extended opening of the pancreatic duct and a preservation of the pancreatic tail. Surgical procedures for painful CP aim at the resection of the pancreatic inflammatory mass, such as (1) the standard Kausch-Whipple procedure with resection of the pancreatic head, gallbladder, duodenum, and gastric antrum, (2)

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the Traverso-Longmire procedure, a pylorus-preserving pancreaticoduodenectomy, (3) the Beger procedure, a resection of the pancreatic head that preserves the duodenum and intrapancreatic bile duct by subtotally excising the head and uncinate process, (4) the Frey procedure, a variation of the Beger procedure that combines longitudinal pancreaticojejunostomy with a local pancreatic head excision without transection of the pancreas above the portal vein, (5) the Berne/Farkas technique, a partial resection of the pancreatic head without a lateral pancreaticojejunostomy that avoids the transection of the pancreas above the portal vein and combines the advantages of the Beger and Frey operations. Depending on pathology and location, other organ-preserving procedures include (6) the “V-shape excision“ of the ventral pancreas, (7) the middle segmental pancreatic resection, (8) the pancreatic left resection or (9) total pancreatectomy.

Data on early surgical intervention might be associated with improved postoperative pain relief compared to delayed surgery after repeated endoscopic interventions(323). A randomized trial on early surgery compared to the ‚normal’ step-up approach (medication, followed by endoscopy and finally surgery when needed) has nearly finished and will provide us with data on the timing of surgery in chronic pancreatitis(324). In several randomized controlled trials, tailored organ-sparing procedures, such as the Beger or Frey procedures, have been found to be superior to the classic Whipple or the pylorus-preserving Whipple procedure in regard to pain relief (75%) and morbidity (20%)(325,326). In addition, independent randomized trials revealed that the Frey procedure provides a better quality of life, while the pylorus-preserving pancreaticoduodenectomy and the Frey procedure were found effective in long term pain relief (82-100%) and morbidity (17%)(327,328). Long-term follow-up showed comparable pain control and pancreatic function between both procedures, while survival rates were superior after the Frey procedure. In a prospective, randomized trial on different techniques of duodenum-preserving pancreatic head resection, the Beger and the Frey procedures were found to be equally safe and effective in pain relief(329). About ten years later, a long-term follow-up showed no difference in pain control within the two groups(330). In addition, a controlled, prospective, randomized study on the evaluation of the Beger and Berne procedures for CP showed the Berne technique to provide significantly shorter operation times and hospital stays, while the quality of life was found to be similar(331). However, ten-year follow-up did not show any differences in patient-relevant outcome parameters between the Beger and Berne procedures(332). In a randomized trial on pylorus-preserving and duodenum-preserving pancreatic head resections, both types of resections were found to be equally effective in pain relief and quality of life without differences in exocrine or endocrine pancreatic function(326). An indication for total pancreatectomy (with/without islet autotransplantation) is to palliate pain, especially after diabetes mellitus has developed. If performed early the clinical results of total pancreatectomy on pain relief look promising. Further trials are needed to provide high grade evidence on timing and efficacy of this procedure(333,334).

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Important phenomenon in chronic pain disorders like chronic pancreatitis is the change in central nervous system pain processing like peripheral and central sensitization. When sensitization is present painful stimuli become more painful and endoscopic and/or surgical therapy has a higher risk of failure. Factors that are relevant in developing sensitization are duration of the disease, age, pain history and previous invasive treatment(103).

In summary, surgery has to be tailored to the needs of patients and should be problem-oriented and preferably organ-sparing, and performed after thorough evaluation in an interdisciplinary setting in a high-volume center with expertise in pancreatic surgery. The success of surgery (or other invasive treatments) depends on the cause of pain and the nervous sytem status of processes painful stimuli (e.g. peripheral and central sensitization)(103,285,335). In this context, the pain processing status needs to be taken into account decising for surgery and the indication of surgery should be considered early once symptoms are unambiguous and opioids are needed. With regards to the surgical method, the duodenum-preserving pancreatic head resections (including Beger, Frey, and Berne procedures) have been shown to be superior to the classic Whipple procedure, while Frey, Beger and Berne procedures have similar results when being compared to each other. Thus, the choice of procedure should be determined by other factors, such as the presence of secondary complications of pancreatitis, intra-operative findings and individual experience of the surgeon(336).

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Ihsan Ekin Demir and Güralp O Ceyhan

Q11. When is the optimal time for surgery in painful CP?Current evidence on the timing of surgery for painful CP suggests a beneficial role for early surgery, i.e. 1) within the first 2 to 3 years after diagnosis or symptom onset, 2) for patients who had equal to or fewer than 5 endoscopic procedures, and 3) for patients who have not yet required opioid analgesics for medical pain treatment (Quality assessment: low; Recommendation: weak; Agreement: strong).

Pain, when refractory to medical treatment, represents one of the leading indications for surgery on patients with chronic pancreatitis (CP). Depending on the morphology of the pancreatic duct and the extent of inflammatory alterations in the pancreatic head, pancreatic drainage or resection procedures can be performed. For either type of surgery, high rates of postoperative pain relief of around 60-90% has been reported in numerous studies(337–339), including randomized controlled trials (RCTs)(232). Despite this effectiveness of surgery in the treatment of CP-associated pain, the time when a patient is referred to surgery, and the time point when a medical treatment is assumed to have “failed”, varies extensively between centers. Due its technical complexity and its perceived potential mortality/morbidity, pancreatic surgery does still not find frequent use for patients with a long-history of CP-associated pain. However, in the largest series, the overall mortality and morbidity after surgery for CP has been reported to lie only around 1% and 20-30%, respectively(338). Despite these acceptable figures, CP patients with severe pain requiring opioid analgesics are rarely referred to surgery in the first years after diagnosis. Rather, endoscopic measures are applied, yet evidence for the effectiveness of endoscopic interventions in the early phase of CP with regard to short or long-term pain relief, is, when compared to surgery, weaker(340), for detailed information see the endoscopy section.Currently, although there are no prospective controlled studies that specifically addressed the timing of surgery for painful CP, increasing amount of evidence suggests that surgery should be considered early for better pain outcomes. In a systematic review that analyzed the role of timing, Yang et al. found that the definition of “early” versus “late” was variable between eligible studies(323). Still, the concordant finding from 11 studies was that early surgery was associated with a greater probability to attain postoperative pain relief (RR=1.67, 95% CI: 1.09-2.56, p=0.02)(323). Moreover, in the meta-analysis of two studies, early surgery was associated with an increased likelihood of “complete” postoperative pain relief. In these two studies, early surgery was performed within the first 21 months after symptom onset (Cahen et al., 2007), or within 5 years of clinical disease(233). In a retrospective series, preoperative duration of CP for greater than 3 years tended to results in higher postoperative pain persistence rates (43% vs. 37%)(337). Clarke et al. reported somewhat better rates of pain relief after surgery for CP within

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54 months versus for 87 months after diagnosis(253). In a recent institutional retrospective study from the USA including 66 patients, Yang et al. calculated the optimal cutoff point for preoperative CP duration to reach best possible pain relief after surgery, and found 26.5 months or less after diagnosis to yield the best outcome(341). Furthermore, they identified shorter duration of CP before surgery as a predictor of pain-free status and reduced postoperative opioid use(341).Beyond the duration of CP, preoperative opioid use, or the frequency of endoscopic interventions also seems to influence the postoperative pain relief rates. Alexakis et al. analyzed the characteristics of 112 CP patients who underwent surgery, and found longer duration of pain and CP-associated symptoms among patients who were on opioids prior to surgery(342). During the first 24 months of follow-up, patients who had been on opioids preoperatively had greater pain scores after surgery than patients who had not previously used opioid analgesics(342). A similar observation was made by Ahmed Ali et al. who evaluated 266 CP patients in a cohort study from five academic centers with a 5-year follow-up(257). Here, they found that surgery within three years of pain onset was independently associated with more pain relief. Moreover, pain relief was more common among patients who were not taking opioids preoperatively(257). Interestingly, there was also a correlation between the frequency of previous endoscopic interventions and postoperative pain relief, since five or more endoscopic interventions resulted in less frequent pain relief among CP patients(257). In another cohort study with 55 patients from the UK, Terrace et al. analyzed the impact of pancreatic drainage surgery (longitudinal pancreatico-jejunostomy) with Frey’s procedure (that involves coring of the pancreatic head)(343). Here, there were comparable reductions rates in analgesia requirement, but patients who were not on opiods were likely to be pain-free after surgery than patients who had required opioids(343).As also underlined by the recent Cochrane Review on the comparison of endoscopy versus surgery in the management of painful CP(231), the three RCTs on this topic collectively demonstrate that surgery is superior to endoscopy with regard to pain relief both at middle-term (2-5 years) or long-term (>5 years) follow-up(232,233,344). Furthermore, early surgery was proposed to provide better pain relief and pancreatic function when compared to a conservative approach, yet based on the results of a single, old RCT with a small cohort and absent sample size calculation(231,344).

Figure 4: Timing of surgery in chronic pancreatitis Surgery is increasingly considered to be more effective for treating pain in CP, if considered early, i.e. within the 2-3 years after diagnosis, and if only a limited number of endoscopic therapy attempts (max. 3) have been made. Later surgery, i.e. after three years of diagnosis, may not provide the same degree of effectiveness in pain relief as early surgery.

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Collectively, current evidence on the timing of surgery for painful CP suggests a beneficial role for early surgery, i.e. 1) within the first 2 to 3 years after diagnosis or symptom onset, 2) for patients who had equal to or fewer than 5 endoscopic procedures, and 3) for patients who have not yet required opioid analgesics for medical pain treatment (Figure 4). These recommendations still need to evaluated in the context of novel, better designed RCTs comparing surgery with other measures in the early phase of CP. Encouragingly, the Dutch Chronic Pancreatitis Registry (CARE) has already collected detailed records on the pain and other characteristics of 1,218 patients from 33 hospitals and is likely to provide a solid basis for the role of early surgery in the management of painful CP. Moreover, the ESCAPE trial (“Early surgery versus optimal current step-up practice for chronic pancreatitis”), which is currently recruiting, represents the most current RCT that will yield important results toward answering

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the question on the timing of surgery for CP(324). In this study, the investigators reported that patients with a dilated pancreatic duct (≥5 mm) and moderate pain and/or frequent flare-ups are going to be monitored for randomization criteria (e.g. need for opioid analgesics)(324). Even though this requirement for opioid analgetics represents a potential confounder that may mask the potential beneficial effects of surgery for these patients, this study is still likely to allow a comparison between the duration of the disease and the benefit from surgery versus medical step-up treatment. Until the advent of its results and further well-designed RCTs, early surgery should be assumed to be the superior option in the management of painful CP. However, this recommendation of early surgery, i.e. drainage (e.g. Puestow) or resection (Beger, Frey or Büchler), does not hold for total pancreatectomy with islet auto-transplantation (TPIAT), since this procedure is currently recommended for CP patients with severe impairment of quality of life and for those who are already on opioid analgesics(345). Whether also this more invasive procedure (that has a higher risk of postoperative diabetes) should be considered at an earlier phase of painful CP is a matter of current and future investigation. Finally, more work is needed to establish the etiology of pain and if possible tailor the type of surgery accordingly. Hence, surgery may not be sufficiently beneficial in patients where the pain has a strong neurogenic origin(346). Although no solid evidence from human studies is available, it is plausible that such neuropathy may increase over time and thus justify the role of early surgery. In patients with obstruction of the duct system, surgery may play an even more prominent role, and timing can be decisive for the outcome. Hence, studies that explore pain mechanisms in CP further are still very much needed.

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Ihsan Ekin Demir, Shuji Isaji

Q 12. How to manage pain "relapse" after surgery or endoscopy for painful CP?Current evidence suggests that the first step for the management of pain relapse should be exclusion of obstructing stones or strictured anastomosis via imaging, followed by a limited number endoscopic interventions, and early consideration of re-surgery to achieve pain control (Quality assessment: weak; Recommendation: strong; Agreement: weak).

The management of pain in CP includes medical (medication-based), endoscopic, or surgical arms. Among these, surgery has been traditionally reserved for cases that are refractory to medical or endoscopic treatment and proposed as last resort within a “step-up” approach. Recent data, though, indicate that surgery performed at an earlier phase of CP, i.e. within the first three years of symptom onset, or prior to numerous endoscopic interventions, may yield clearly better pain relief than late surgery(323,257). After any type of surgery or intervention, though, pain relapse in CP is not uncommon. Indeed, even after the most radical and effective type of intervention, i.e. surgery, the long-term (5-year) pain-freeness lies around 50 to 60% in the largest series(337–339). This figure means that half to 40% of all CP patients who underwent surgery for painful CP are eventually going to develop pain relapse. A recent study showed high readmission rates at 30 and 90 days after surgery for CP (including duodenum reserving pancreatic head resection or pancreaticoduodenectomy), reaching 33% at 30 days and 40.5% at 90 days, mainly due to inadequate pain control(347). In the medical literature, the management of these cases of pain relapse either after surgery or even endoscopy has not been sufficiently addressed, and high-quality studies are lacking.After endoscopy, some studies with potential selection or publication bias have reported that persistent pain relief after endoscopic treatment (including endoscopic sphincterotomy, dilatation of the pancreatic duct, and stent placement) reached 57% at the five-year follow-up(280). For patients with pancreas divisum who underwent endotherapy, the response rate, i.e. complete or partial relief rate was reported to be 69.4% and to be comparable to that after surgery (74.9%)(348). In a long-term prospective controlled study, Seza et al. performed extracorporeal shock-wave lithotripsy (ESWL) or endoscopic basket extraction of pancreatic stones, followed by stenting or not (control) of the main pancreatic duct(349). The recurrence rates were 15% in the stented vs. 50% in the control group at the five-year follow-up(349). In a randomized controlled trial comparing ESWL in combination with endoscopy with ESWL alone, Dumonceau et al. reported 38% pain relapse after ESWL alone and 45% pain relapse after ESWL combined with endoscopy(261), rendering the benefit from additional endoscopy after ESWL questionable. In the largest retrospective cohort (n=636) of ESWL reported in the literature, 68.7% of the patients were pain-free, 25.4% had mild-to-moderate pain, and 5.5% had severe pain at 2 to 5 years of follow-up. In the long-term group (longer than 60 months follow-up), 60.3% had no pain, 35.7% had mild or moderate episodes of pain, and 4.04%severe pain(275). Overall, these results point

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out that in well-selected cases, endoscopic interventions may result in around 60% complete pain relief rates in the subsequent five years after the intervention.However, there seems to be no consensus on the management of pain relapse in CP patients who underwent previous endoscopic interventions. In a retrospective study with 100 CP patients, only 38 (38%) of CP patients who had underwent endoscopic stenting required re-stenting within the 69-month follow-up period, and these patients were ultimately referred to surgery (pancreatico-jejuonstomy)(239). In their retrospective series with 14 patients, Weber et al. had 6 patients who did not respond to endoscopic therapy, and 4 of these patients were treated using repeated stent therapy or analgesic/medical treatment(280). Only 2 of the 6 patients were referred to surgery. However, the rationale for the choice of three different strategies in these three pairs of patients was not delineated in the study(280). In a similar study, the investigators reported pain relapse in 5 out of 17 CP patients (stage III according to Cambridge classification) within the first two years after stent removal, and they speculated that repeated stenting may be an option for these relapse cases(241). In a recent randomized, double blind, placebo-controlled trial, the 87 narcotic-naïve CP patients with pain relapse after endoscopic ductal clearance received either antioxidant-pregabalin combination therapy (n=42) or matching placebo (n=45) for 2 months followed by open-label antioxidants for the next 4 months in both groups(192). In the treatment arm, the combined antioxidant-pregabalin therapy resulted in reduced pain scores, higher frequency of pain resolution, and reduced number of painful days when compared to placebo(192). The pain reduction was further persistent at 6 months in the treatment group(192). Therefore, after endoscopic interventions, the evidence for recommending a certain type of therapy for pain relapse is yet quite immature. However, it seems that endoscopy may provide adequate pain relief in selected cases, and patients with pain relapse may benefit from few additional sessions of repeat interventions like stenting, or subsequent medical treatment via antioxidants together with pregabalin. The caveat behind these observations is that all these studies with pain relapse after endoscopy did not include a study arm of patients who were referred to surgery after pain relapse. In fact, previous endoscopic stenting was not identified to be a risk factor for more or recurrent pain after surgery (pancreatico-jejunostomy)(350).Lack of sufficient evidence for concrete recommendations for managing pain relapse in CP also holds true for the post-surgery pain relapse. In a series with 39 patients who developed pain relapse after surgery (resection or drainage operation) from a pool of 316 patients, Howard et al. found that revision of pancreatico-jejunostomy enabled pain relief in 67% of the patients, whereas partial resections such as duodenum-preserving pancreatic head resection, pancreaticoduodenectomy, or distal pancreatectomy achieved pain relief in <50% of the patients(351). In a long-term follow-up series (10-year follow-up), Talamini et al. also identified pancreatico-jejunostomy to significantly correlate to a smaller annual number of pain relapses(352). In another case series, Markowitz et al. performed different types of salvage operations on 13 CP patients who previously had pancreatico-jejunostomy(353). These operations included distal pancreatectomy, extension of the pancreaticojejunostomy and

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choledochojejunostomy, biliary stenting followed by choledochojejunostomy, and pancreatico-duodenectomy(353). Ten of the 13 patients experience considerable or even excellent pain relief (353). Hence, the type of surgery to be chosen for a re-operation on a CP patient with relapse may vary, depending on the pancreatic morphology. In all cases, it is crucial to first exclude more simple reasons for therapy failure such as obvious stricture of anastomosis, or obstructing stones in the pancreatic or bile duct(354), that can possibly be removed by endotherapy interventions. Furthermore, it should be considered that a salvage operation for pain relapse may end up in a total pancreatectomy, which, in patients with predictably low postoperative compliance, would impose a major problem due to the unavoidable postoperative diabetes mellitus. In patients with pain relapse after pancreatic surgery, surgeons should consider that any kind of subsequent treatment may be subject to failure due to the intra- and extrapancreatic neuropathic alterations that may be irreversible(202)(355). In any case, relapse-free intervals were reported to be longer after surgery for CP when compared to endoscopic treatment(279).

In conclusion, pain relapse after surgical or endoscopic treatment of CP is a frequent and clinically very relevant problem. Current evidence suggests that the first step for the management of pain relapse should be exclusion of obstructing stones or strictured anastomosis via imaging, followed by a limited number endoscopic interventions, and early consideration of re-surgery to achieve pain control. This should be supported by an adequate pain therapy (see pharmacological pain treatment section), figure 5. Studies that address the management of pain relapse after surgery for CP, and that contain endoscopic and surgical intervention arms in a randomized, controlled setting are eagerly awaited.

Figure 5: Management of pain relapse in chronic pancreatitis after surgery or endoscopy. Even after surgery for CP (e.g. duodenum-preserving pancreatic head resection or drainage operations), repeat surgery can be a viable and effective option to treat pain relapse. Prior to surgery, though, obstructing stones or anastomotic strictures should be evaluated on imaging and interdisciplinarily whether they can be addressed in an endoscopic intervention. Salvage surgery for pain relapse in CP can in most cases be organ-sparing. In cases where organ-sparing procedures are not possible, total pancreatectomy can be effective option, yet at the cost of postoperative diabetes.

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Christopher Halloran and Dhiraj Yadav

Q13. What are the indications for referral to a specialist centre for further investigation of pain?

All patients with presumed or established diagnoses of CP should be routinely referred to specialist pancreatic centers for investigation and treatment of their pain (quality assessment moderate; Recommendation: strong; Agreement: strong).

1. Treatment of CP is challenging. It is vital that a systematic and robust approach is employed. Patients with pain from presumed CP require stepwise evaluation. Many patients are not referred in a timely fashion to specialist pancreatic or pain services until their pain progressively worsens or has become recalcitrant. The only evidence for benefit of referral comes from “general” advice regarding referral to chronic pain service’s:

a. Referral should be considered when non-specialist management is failing, chronic pain is poorly controlled, there is significant distress, and/or where specific specialist intervention or assessment is considered.

b. A systematic review of observational studies concluded that longer delays between specialist referral and specialist consultation result in poorer health and pain management by the time of this consultation. This deterioration starts as early as five weeks from referral and there is consensus that a delay of longer than six months is medically unacceptable(356).

c. No RCT evidence was found that early or late initiation of specific treatments or early or late specialist referral influences outcome in patients with chronic pain.

2. It should be considered whether patients with presumed or established diagnoses of chronic pancreatitis should be referred to specialist pancreatic centers not only for metabolic management, but also for assessment of type of pain (neuropathic/nociceptive/mixed), severity, functional impact and context. This includes not only assessment of chronic pancreatic pain vs. chronic non-pancreatic abdominal pain, but also the requirement in such patients to assess their overall pancreatic disease and to make appropriate management plans. Most importantly to diagnose whether:

a. Primary pancreatic pathology is responsible for the pain.b. Complications of chronic pancreatitis are responsible for the pain.

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c. Differentiate between a treatable pancreatic conditions as cause of the pain vs. a chronic pain syndrome without pancreatic disease vs. an alternate diagnosis.

References1. Yadav D, Lowenfels AB. The Epidemiology of Pancreatitis and Pancreatic Cancer.

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