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Pain management in chronic pancreatitis

Andrén-Sandberg, Åkea,b; Hoem, Dagb; Gislason, Hjörturb

European Journal of Gastroenterology & Hepatology: September 2002 - Volume 14 - Issue 9 - p 957-970
Review in Depth

aQueen Silvia's Hospital for Children, Sahlgrenska University Hospital, Gothenburg, Sweden; and bDepartment of Surgery, Haukeland University Hospital, Bergen, Norway

Correspondence to Dr Åke Andrén-Sandberg, Queen Silvia's Hospital, Sahlgrenska University Hospital, SE-416 85 Gothenburg, Sweden Tel: +46 73 6889323; fax: +46 31 210859; e-mail: ake.andren-sandberg@vgregion.se

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Introduction

Chronic pancreatitis is a disease characterized by a painful progressive destruction of the pancreatic gland [1]. Even though other symptoms may occur pain is the predominant symptom both from the point of view of the patient and of his or her doctor. For an important part of the patient population the pain is so severe that all a patient's waking hours are devoted to pain control, and the quality of life is low in every respect. Although much has been done to improve our understanding of the pathophysiology of chronic pancreatitis, there is still no therapy that counteracts the inflammatory process of the disease. As patients with chronic pancreatitis can, at best, be only symptom free, but never cured, the treatment continues to be directed against symptoms and complications, of which pain is the most dominant. The management of symptoms should therefore be of prime concern in most patients with chronic pancreatitis.

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Type of pain and its evolution

Different pain patterns have been described for patients with chronic pancreatitis. However, the pain is most often localized to the upper part of the abdomen and is spread over a large part of the abdomen. It is usual that the pain radiates to the back, and is frequently nocturnal. Patients often present with intermittent pain that ranges from mild to moderate to severe. It is often described as deep, penetrating and debilitating, and it may increase after a meal. Postprandial pain may contribute to weight loss by voluntary fasting not to provoke pain – increasing the negative effects of malabsorption due to exocrine insufficiency [2]. Moreover, the pattern of pain changes with time, being recurrent and intermittent in the initial stages of the typical disease, later usually to become more or less persistent. Still, it is characteristic for the pain of chronic pancreatitis that it may vary not only between patients but also in the same person from time to time [3].

At least 85% of patients with chronic pancreatitis will develop pain at some time during the course of their disease. The exact rate depends on definition and the method of recruitment of patients [4,5]. The frequency, severity, and other characteristics of pain in chronic pancreatitis have a major impact on its management: no treatment or medical and surgical interventions.

The aetiology of chronic pancreatitis cannot be determined from the pain profile, but painless courses of the disease are rare in alcoholic chronic pancreatitis (< 10% of cases), whereas the painless state is more frequent in the late-onset type of idiopathic chronic pancreatitis and in tropical chronic pancreatitis. In these cases, the disease is diagnosed only when exocrine or endocrine insufficiency have become symptomatic by steatorrhoea or overt diabetes [6–10].

In the early stages of chronic pancreatitis there is usually normal exocrine and endocrine function, and no calcifications. In the late stages of the disease, however, there are usually steatorrhoea, exocrine insufficiency, and diabetes; endocrine insufficiency and calcifications, but only moderate or no pain. This has been explained by the Swiss pancreatologist R. Amman as ‘the burn out paradox', indicating that, in the long run, there will be little exocrine pancreatic tissue left and then there is no basis for inflammation or increased intrapancreatic pressure, i.e. no pain [6–8]. If pain appears in the late stage disease, it may usually be due to local complications. Despite that, in the Zürich series of patients with chronic pancreatitis there may be uncomplicated courses with recurrent pain and long, pain free intervals. There may also be a complicated course with constant pain or frequent attacks of pain without longer, pain free intervals. However, there are also opponents to the Amman theories [9], and obviously there are also patients with severe pain after many years of chronic pancreatitis [1].

So, in chronic pancreatitis, pain tends to precede symptoms of diabetes and malabsorption by many years [11]. When pancreatic exocrine insufficiency becomes symptomatic the discomfort associated with fat and carbohydrate malabsorption may further limit food intake. Therefore, pain should be treated aggressively, not only to improve the quality of life in these patients, but also to prevent excessive weight loss. Also, the diabetic state may negatively influence the building of strength, and should therefore be adequately treated [12].

It is important to note that there are no proven associations between imaging findings or function test results on the one hand and the presence or intensity of pancreatic pain on the other [1,2,6,9,13]. Therefore assessment of pain in chronic pancreatitis has to be done primarily on clinical grounds, i.e. the patient's description of pain and the consumption of analgesics and the social functioning, and the information obtained from imaging and function tests must be correlated with great care.

The pain pattern, and its treatment, has also been correlated to the histological picture of the parenchyma. Although surgical approaches to ‘large duct’ chronic pancreatitis have been quite successful [4,5], patients with persisting pain from ‘small duct’ chronic pancreatitis have historically been a difficult group to manage. Medical therapy in this latter group has often been either inconclusive or ineffectual, and narcotic addiction is common. Surgical approaches have fared little better, with extensive ablations of pancreatic parenchyma either failing to relieve pain or leading to brittle diabetes, marginal ulceration, and serious malnutrition. Therefore, the histological picture, and the size of the ducts on morphological examinations, e.g. endoscopic retrograde pancreatography with or without x-ray of the bile duct and computed tomography scan, is of importance when treating the pain in patients with chronic pancreatitis, even if it is probably the same type of chronic inflammation as the ‘large duct’ disease.

Several additional factors interfere with the major commonly accepted factors, leading to a multifactorial definition, or rather description, of pancreatic pain and mechanisms of pain. A further obstacle is that the pain is difficult to interpret due to psychological factors, including addiction to alcohol and narcotics [2,14]. Therefore, the large number of studies on pain in chronic pancreatitis have conflicting results and are difficult to interpret. Furthermore, symptoms have often been assessed in rather rough categories, such as mild, moderate or severe. For example, after duct drainage combined with distal pancreatectomy, Morrow et al. [15] reported patients as asymptomatic, having occasional pain, or having no improvement. Mannell et al. [16] used a four-tiered system for pain assessment: excellent (no pain), good (better), fair (nil, better), or poor (same pain or worse) to assess the results of a variety of operations. Narcotic intake was not mentioned as part of the assessment. Russel [17] also used a four-tiered system to assess pain – none, minimal, moderate, or severe – in studying the results of preservation of the duodenum in total pancreatectomy compared with those of standard pancreaticoduodenectomy. However, he used a separate scale for assessing use of analgesics: no, minor, and moderate use of narcotics. He found no difference in pain relief between the results of the two operations. He noted that 13 (34%) of the 32 still had severe pain after duodenum preserving total pancreatectomy, and that six required major analgesics.

A thorough evaluation of the multidimentional construct ‘quality of life’ is missing in most studies. To draw valid conclusions, it will be necessary for future studies to relate the pain pattern and profile to all important variables, such as aetiology, onset of diagnostic criteria, stage of chronic pancreatitis, structural alterations, pancreatic function, possible alcohol abuse and use of narcotics, and maybe other factors.

The description and definitions of pain are primarily aimed at therapy for each individual patient with chronic pancreatitis. They are used secondarily for quality assessment of groups of patients. However, the concept of treatment in an individual patient must generally be established without a preoperative histological specimen and often with limited radiological information. Therefore, the decision making between pharmacological treatment, resection or decompensation, or other options for the treatment of pain in chronic pancreatitis must be based mostly on the medical history of each patient. It is then important for the doctor to consider what might be the most likely pathological origin of the pain.

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Pain in alcohol related pancreatitis

In up to 30% of the patients no distinct aetiology of the pancreatitis can be demonstrated in the Western countries most often cited in the literature [18]. However, most patients presenting with chronic pancreatitis in Europe, the United States, and South Africa will have alcohol related disease [19], and there are indications that this type of disease is increasing [20].

At the present state of knowledge, most interesting data on the natural course of pain in alcoholic chronic pancreatitis derive from the Zürich series [6–8]. Pain is the most prominent clinical feature in approximately 90% of patients with alcoholic chronic pancreatitis, and its natural cause has a major impact on a recently proposed, clinically based, staging system [21]. Patients with early onset idiopathic chronic pancreatitis usually live longer through a long period of severe pain but slowly develop morphological and functional pancreatic damage, whereas patients with late onset idiopathic chronic pancreatitis have a mild and painless course [7,10]. The most severe pain episodes are observed in the early stages of alcoholic chronic pancreatitis, often before the disease has been documented clinically.

As mentioned before, in advanced alcoholic chronic pancreatitis pain might vanish spontaneously due to lack of functional parenchyma in patients without local complications, whereas severe pain in advanced stages is often associated with local complications. However, this pattern has been challenged by others [9] who found few patients in whom the pain decreased pain with time. Also, pain of extra-pancreatic origin must also be taken into account (e.g. gallbladder disease, peptic ulcer), as these diseases are common in a population that drinks alcohol and smokes cigarettes, and most often eats a diet that is high in fat and low in protein.

In alcoholic chronic pancreatitis, cessation of alcohol abuse is said to have an impact on the natural course of the disease. Although impairment of pancreatic function also progresses after cessation in most patients, the progress has been shown to be slower and less severe [6,22,23]. It has been repeatedly shown that pain relief is more frequent in those who have stopped drinking or abstain from alcohol for long periods [23–26]. Most often it can be calculated that, in about 50% of patients, cessation of alcohol abuse is accompanied by a decreased severity of pain [27,28]. Therefore, doctors treating patients with chronic pancreatitis should spend considerable time convincing them of the importance of total alcohol abstinence. However, it must be admitted that there are studies in which the results show no beneficial effects of abstinence [29,30]. This discrepancy may, at least partly, reflect a failure to differentiate alcohol induced and idiopathic pancreatitis. Contrary to what has been shown about alcohol intake [23–26], there are no trials in which a relevant correlation between dietary measures and the occurrence of pain has been demonstrated.

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Pain mechanisms

Upper abdominal pain is the most common symptom in the clinical course of chronic pancreatitis. Although several different concepts of pain generation in chronic pancreatitis have been postulated during the past few decades, the mechanisms underlying the generation and perpetuation of the chronic pain is still insufficiently known and none of them can completely explain the pain in this disease. Present hypotheses include acute inflammation of the pancreas, increased pressure within the pancreatic ductal system and parenchyma, neuritis, recurrent ischaemia of the parenchyma, and intra-pancreatic causes such as acute pseudocysts and extra-pancreatic causes such as common bile duct or duodenal stenosis [31–33]. The relative contribution of inflammation, obstruction, neuritis and scarring to the pathogenesis of pain is still unclear and may vary from patient to patient.

If the cause of pain in chronic pancreatitis is due to the sequence of acute focal inflammation, necrosis and scar formation, this may explain transitory pain attacks of several days’ duration. If we accept this hypothesis, it also means that pain reflects dynamic events within the gland rather than static situations, i.e. it is the formation of a scar that hurts and not the scar tissue itself; it is the expansion, dilatation of the duct or a pseudocyst that hurts and not the dilated duct or cyst itself.

Pain in chronic pancreatitis may also be caused by complications of chronic pancreatitis such as pancreatic duct strictures (obstruction), pancreatic duct stones (obstruction), pseudocysts with vascular involvement leading to haemosuccus pancreaticus (obstruction), pancreatic abscesses, ascites, bile duct stenosis with cholestasis, duodenal stenosis and maldigestion (bacterial overgrowth, meteorism). The increased pressure from pseudocysts and other masses may contribute as well. In German speaking Europe, in particular, inflammatory tumours of the pancreatic head are not uncommon in alcoholics. The masses lead to local displacement of other organs, stenosis of the pancreatic and common bile duct, and alterations and occlusions of neighbouring arterial and venous blood vessels. The reasons why the appearance of the disease is mainly localized to some countries are not known at present. However, it is probable that these processes also may contribute to pain.

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Increased ductal and interstitial pressure

Post-inflammatory scaring of the pancreatic main and side duct may cause strictures, calculi or increased viscosity of pancreatic juice, all resulting in increased ductal and interstitial pressure with local ischaemia and acidosis that generates pain. For a long time, obstruction of the pancreatic duct system was seen as the major factor in the pathogenesis of chronic pancreatitis. However, the relationship between morphological changes, ductal pressures and pain has repeatedly been shown to be very variable, and other factors must be implicated [34]. An increased intracystic pressure may be assumed when a pseudocyst communicate with a stenotic duct. On the other hand, painless courses of the same anatomical abnormalities are also seen [35,36].

One of the first groups to document the intrapancreatic pressure was Ebbehöj and co-workers, who recorded pancreatic tissue pressure during surgery. They found higher values in pancreatitis patients than in control subjects. After surgical ductal drainage, a significant drop in tissue pressure was seen [37]. It is interesting to note that they were able to follow the patients’ postoperative pancreatic tissue pressures, after having developed a technique for percutaneous measurements guided by ultrasonography. In patients with recurrent pain after one year, the pressure again was increased, whereas those who remained pain free continued to have normal values [38]. Further support for tissue hypertension was given by Jalleh et al., who hypothesized that pain could be associated with a situation similar to that in a compartment syndrome in other sites, in that they found different pressures in different parts of the gland [39]. Bradley showed increased ductal pain in painful pancreatitis compared to a control group [40]. The findings were supported by Sato et al., who, in an intraoperative study, found elevation of ductal perfusion and residual pressure in patients with chronic pancreatitis, compared with observations in control subjects who had had surgery for gastric cancer [41]. Similarly, Madsen and Winkler reported high ductal pressure, measured intraoperatively in patients with chronic pancreatitis [42].

In an endoscopy study, Okazaki and co-workers confirmed these findings and demonstrated a statistically significant increase of the ductal pressure in chronic pancreatitis patients with pain, compared with that seen in a group of patients with painless disease [43]. Intraductal pressure as assessed by ERCP ranged between 10 and 16 mmHg in patients without pancreatic disease and between 18 and 48 mmHg in patients with a dilated pancreatic duct. However, pain patterns and profiles were not assessed in detail in these studies [40,42–44]. Pancreatic parenchymal pressure assessed at surgery ranged between 3 and 11 mmHg in control subjects and between 17 and 21 mmHg in patients with chronic pancreatitis. Following pancreaticojejunostomy or pseudocystojejunostomy, increased pancreatic pressure fell to control values, which was associated with the relief of pain in 12 out of 14 patients [45,46]. Although these data indicate that increased intraductal or parenchymal pressure is associated with pain in chronic pancreatitis, the pathological mechanism by which increased pressure causes pain is not clear.

With this theoretical background it is not surprising that, for a long time, the treatment of pain in chronic pancreatitis was generally directed to surgical decompression of the duct and that endoscopy now seems to be a tempting alternative.

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Pancreatic neuritis

A more recent pain concept in chronic pancreatitis concerns direct alterations of pancreatic nerves as one of the major pathophysiological events of pain generation [47–50]. It has been reported that phenotypic modification of primary sensory neurons may play a role in the production of persisting pain [51]. Autodigestion with tissue necrosis and both pancreatic and peripancreatic inflammation in the earlier stages changes the focal release and uptake of mediators in the peptidergic nerves and could be an important cause of pain. Previous studies in chronic pancreatitis revealed that pancreatic nerves are preferentially retained while exocrine pancreatic parenchyma atrophies and degenerates and is replaced by fibrosis. Moreover, in chronic pancreatitis compared with normal pancreas, the number and the diameter of pancreatic nerves are significantly increased, according to Bockman, and analysis of neuroplasticity markers gives evidence that they actively grow [47,49]. Büchler et al. [48] found that the pattern of intrinsic and possibly extrinsic innervation of the pancreas is changed in chronic pancreatitis. This leads to a differential expression of neuropeptides such as substance P and vasoactive intestinal peptide (VIP) in the chronically inflamed pancreas. Moreover, Nelson and co-workers [52] have shown that changes in levels of methionine–enkephalin correlates with pain, and it has been found that immune cell infiltration and growth associated protein 43 (GAP-43), a marker of neuroplasticity in enlarged pancreatic nerves and pancreatic neurons, expression correlate with pain in chronic pancreatitis [49]. In addition, electron microscopy examinations revealed that the perineurium of these nerves is partially destroyed to a different extent, indicating a barrier loss between nerve fibres and bioactive material in the perineural space [13]. Bockman et al. have put forward a concept they call ‘pancreatitis associated neuritis’ [13,18], which implies a comparative increase in the number of sensory nerves in inflammatory pancreatic tissue together with round cell infiltration and a striking disintegration of the perineurium. The loss of function of the perineural barrier may allow an influx of inflammatory mediators or active pancreatic enzymes that could act directly on the nerve cells. In fact, they have found the neuropeptides substance P and calcitonin gene related peptide (CGRP) within sensory nerves in pancreatic tissue with damage of the perineural sheet [47,50].

Based on the hypothesis that this neural inflammation is an important pathological mechanism of pain, resection of inflammatory tissue is proposed as the treatment of choice. It can be speculated that these two mechanisms – increased pancreatic tissue pressure and neuritis – could work together. High tissue fluid pressure would then facilitate influx of pain mediators into the nerves and result in more long-standing pain.

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Pancreatic ischaemia

There is evidence that pancreatic ischaemia may occur in an experimental model of chronic pancreatitis [53] giving decreased pancreatic blood flow, ischaemia and local changes in parenchymal pH. During ischaemia xanthine oxidase becomes activated which leads to the generation of toxic oxygen metabolites which may contribute to pain in chronic pancreatitis. However, a xanthine oxidase inhibiting substance, allopurinol, did not reduce pain in a randomized, two period, crossover, clinical trial [54].

The evidence that free-radical production is increased in patients with chronic pancreatitis is derived from the observations that patients with pancreatitis have induction of the hepatic and pancreatic mono-oxygenases and that their bile contains high levels of free-radical oxidation products. The cytochrome P450 system of mono-oxygenases is intimately involved in the metabolism of lipophilic substrates such as hydrocarbons [55]. The enzymes generate oxygen free-radicals from molecular oxygen and use them to metabolize their substrates by controlled release of superoxide, and its dismutation product hydrogen peroxide. Upon the action of exogenous agents, the activities of cytochromes P450 increase as part of a protective mechanism. This defence mechanism can be detrimental if antioxidant stores are depleted, and if agents that undergo P450 metabolism (e.g. hydrocarbons) are given concomitantly.

A case–control study [56] of patients with chronic pancreatitis has shown that they have increased susceptibility to hydrocarbon exposure, in particular diesel exhaust fumes, compared to control subjects. These environmental chemicals would act in a manner similar to alcohol and induce cytochromes P450. Several studies have shown that the cytochrome P450 enzyme system is induced in patients suffering from chronic pancreatitis [57–60]. Foster et al. [57] employed immunohistochemistry using antibodies raised against four phase I enzymes (metabolism) and one phase II enzyme (conjugation). They found that both hepatic and pancreatic biopsy specimens from patients with chronic pancreatitis and pancreatic carcinoma showed enhanced staining for cytochrome P450 compared to the staining observed in the control biopsies. Of note was the observation of cytochrome P450 induction in the islets of Langerhans. Evidence indicating interference in the induction of the cytochrome P450 enzyme family is derived from theophylline clearance studies in patients with chronic pancreatitis. In one study [58] it was found that a theophylline clearance was significantly higher in patients with idiopathic and alcohol related chronic pancreatitis compared to controls. In another study [59] it was found that patients taking long-term anticonvulsants, known inducers of the cytochrome P450 enzyme system, had similar levels of enzyme induction as those with chronic pancreatitis but without epilepsy.

A comparison of the composition of secretin stimulated bile from patients with pancreatic disease with that of controls revealed that patients with pancreatic disease had higher levels of free-radical oxidation products [61]. It was also found [62] that patients with chronic pancreatitis had significantly greater bile concentrations of 9 cis,11 trans-linoleic acid, conjugated dienes and ultraviolet fluorescence products compared to controls. Following the indications for a beneficial role of antioxidants in chronic pancreatitis, with the potential reduction in morbidity and the financial savings of administering global antioxidant therapy to all patients with chronic pancreatitis, an audit of 103 patients treated with antioxidant therapy revealed that at follow-up of up to 9 years, 75 were pain free, 27 had substantial reduction in their pain, and only seven required surgery (psuedocyst drainage in six) [63].

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Pharmacological treatment

Analgesic drugs are still the most commonly adopted method for pain relief. The drugs include paracetamol, dextropropoxyphene, prednisolone, non-steroidal anti-inflammatory drugs, tricyclic antidepressants or narcotic analgesics given orally or rectally, and opioids, which can also be administered subcutaneously or intrathecally [64]. A problem is that due to the chronic nature of the pain many patients subsequently become addicted to heavy narcotics. A major concept in prescribing is therefore to divide the analgesic treatment into three stages [3,21,30,65], the principal drug at each stage being paracetamol, dextropropoxyphene and morphine, respectively, and never to proceed to the next step without minute consideration of the short and long-term effects of the escalation. It should, however, be admitted that the dextropropoxyphene step has recently been questioned due to the not so obvious, but sometimes fatal, side effects of the drug.

Although the use of analgesic drugs is necessary in the majority of patients with chronic pancreatitis, there are no controlled trials assessing this treatment modality. However, most patients with chronic pancreatitis do not seek the help of a doctor until they have a pain that requires treatment with analgesics. The pain relieving drugs preferably should be taken before meals to prevent the postprandial exacerbation of pain. Initially, non-narcotic agents like paracetamol should be used and their effects maximized by increasing dose strength or frequency before switching to stronger alternatives. Time intervals and doses of drug application must be adapted to the individual pain pattern, but it is important that analgesics are always prescribed on a time contingent basis, because round the clock medications are more effective and may decrease the total daily amount of drug required. Although reluctance to use narcotic agents is advisable, such treatment should not be withheld if the treatment would otherwise not lead to adequate pain control [3,30], despite the risk that alcohol addiction changes to narcotic addiction. Adjuvant analgesic drugs like antidepressants are often helpful for a dose reduction of analgesics.

There are also four studies supporting the pain relieving effect of oral enzyme preparations in a proportion of patients with chronic pancreatitis [66–69], but also studies questioning that a negative feed-back in the proximal small bowel inhibit pancreatic secretion [70]. However, it might be worthwhile to give patients a therapeutic trial of enzyme supplements for 1 or 2 months, provided that a preparation known to increase intraduodenal trypsin activity is used [71]. Probably the application of pancreatic enzymes for the treatment of pain is also reasonable on the assumption of compensated malabsorption with flatulence, meteorism and bowel movement, which can be rather painful. The pain should be re-evaluated after 1 or 2 months, and enzyme supplementation stopped in the case of treatment failure. Sometimes H2 blockers or omeprazole are effective as a further adjunct, particularly as it has been reported that patients with chronic pancreatitis have increased duodenal acidity and risk of ulcer formation [29].

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Endoscopic procedures

If decompression of the pancreatic duct is all that is needed in a majority of the patients with chronic pancreatitis it is tempting to try endoscopic procedures that are less demanding for both the patient and the doctor. However, it should be remembered that surgical sphincterotomy and sphincteroplasty already has proved to be less efficient [72,73], and that these procedures are hardly ever used nowadays. This might be due to the fact that it is unusual to find uniform dilatation of the pancreatic duct system resulting from localized obstruction at the orifice of the main duct [64,74]. More recently, however, a number of endoscopic series have evolved which suggest an acceptable complication rate, particularly if undertaken in conjunction with stent placement or stone extraction.

Endocscopic stone extraction has been tried with and without mechanical lithotripsy, extracorporeal shock wave lithotripsy (ESWL), laser lithotripsy and with or without leaving a stent through the pancreatic duct orifice. Only placement of endoprostheses in the pancreatic duct are reported to give pain reduction in obstructive chronic pancreatitis [24] but stent occlusion and migration appear to be relatively common. With all modalities taken together it is usual to find a report of 80–90% complete stone clearance and good immediate pain relief [75]. However, the long-term results in a larger series are not that impressive so far. In a Belgian study Delhaye et al. [76] found that, of 123 patients, only 60% experienced complete or partial pain relief during 14 months follow-up. Whether this is a good result, with 60% pain free after a cheap procedure with few complications compared to open surgery, or a bad result, with only 60% of the patients pain free patients compared with the usual 80–90% after pylorus preserving pancreaticoduodenectomy (PPPD) [77] or the duodenum preserving operation according to Beger et al. [78], can be discussed. So far there have not been any randomized studies made between endoscopic and surgical procedures, and as long as the endoscopists have not yet put the final touches to their techniques or defined the indications for their procedures, it may not be fair to carry out randomized trials. At present the endoscopic approach to patients with chronic pancreatitis is still ‘promising'. It seems to be more useful in preventing relapsing attacks of pancreatitis as opposed to helping those with chronic pain [79], and may be it can be used as an adjunct to choose the right patients for lateral pancreatojejunostomy: if the patient is doing well with a stent, which has to be removed and changed at certain intervals, he/she will probably also do well with open surgery.

Pancreatic duct stents may be inserted in patients with proximal pancreatic duct stenosis and pain, with good short-term but with still variable long-term results. Within a follow-up period of up to 5 years, uncontrolled studies have reported symptom relief in 74–96% of patients and upon complete cessation of pain in 45–96% of patients [80,81]. Extracorporeal shock wave lithotripsy of pancreatic calculi is applied in patients with pancreatic duct stones and intermittent pain. The procedure may be combined with endoscopic sphincterotomy and extraction of calculi after one or several shock wave lithotripsy treatments. The results are still variable, ranging between symptomatic improvement in 37–83% of patients and complete pain relief in 41–79% of patients [76,82,83]. However, it must be remembered that chronic pancreatitis is not the same as stones in the pancreatic duct, to be compared with bile duct stones or uretherolithiasis, but is a disease primarily of the pancreatic parenchyma. Therefore it is not probable that endoscopy could be a real alternative for more than a minority of these patients. But if this subset of patients can be well defined, important progress has been made in the management of chronic pancreatitis.

In patients with pancreas divisum, a lesser papillotomy with intermittent stenting is an option when recurrent attacks of pancreatitis or signs of chronic obstructive pancreatitis are documented in the dorsal pancreas. Studies comparing resectional or operative drainage procedures to lesser papillotomy and stenting in pancreas divisum are not available.

Endoscopically placed biliary stents are also inserted for the subacute treatment of extrahepatic cholestasis secondary to common bile duct obstruction in chronic pancreatitis. In cases of acute cholangitis, at least the sphincterotomy is essential. The early results of endoscopic stenting of the strictured bile duct in chronic pancreatitis are convincing, whereas long-term results in patients with significant stenosis of the common bile duct probably are better when an operative procedure is subsequently performed.

In pancreatic pseudocysts, percutaneous punctures are performed for diagnostic purposes and in large pseudocysts also for therapeutic purposes, but long-term results are unfavourable. Internal drainage may be performed by endoscopic sphincterotomy and pancreatic duct stenting when a communication between the pseudocysts and the main duct exist; otherwise, an endoscopic pseudocystogastrostomy or pseudocystoduodenostomy is increasingly being performed [84,85]. The results with regard to pain seems to be equal – open surgery, endoscopically stenting or percutaneous procedures – which means that the easiest way in the individual patient should be favoured.

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Decompression procedures

Surgical decompression of the obstructed main pancreatic duct was for a long time the ‘gold standard’ against which other therapies should be measured [86]. Drainage operations are today most often carried out as a side to side pancreaticojejunostomy as this preserves pancreatic parenchyma. Longitudinal pancreaticojejunostomy according to Puestow and Gillesby [87] or Partington and Rochell [88], i.e. the duct of Wirsung opened from the tail of the pancreas to the duodenum and anastomosed to the side of the jejunum, has been one of the techniques that has been used most often [5]. The procedure is based on the concept that ductal obstruction leads to distension and that this in turn gives rise to pain and should thus be favoured only if the duct is widened. Theoretically, any measure that improves drainage, either by improving flow into the duodenum or by allowing flow into the jejunum or stomach, might be expected to relieve pain. Pancreatic decompression results in immediate and lasting pain relief in a high proportion (80–90%) of patients with non-alcoholic chronic pancreatitis [89], which is higher than most often reported in patients with alcoholic pancreatitis, where pain relief averaged 60% [16]. This result is similar to that reported by Sato et al., who found that over a mean period of 9 years only 56% of patients with alcoholic pancreatitis had good results after surgery, compared to 83% of those who had non-alcoholic pancreatitis [90]. Although early good results have also been reported after a lateral pancreaticojejunostomy in patients with alcoholic pancreatitis, when these patients are followed for 5 years only 38–60% of them continue to be pain free [90]. On the other hand, Brinton et al., in a study of 39 patients who underwent lateral pancreaticojejunostomy, did not find any correlation between the pain relief in alcoholic patients and those who were not alcoholic; but the mean duration of follow-up was not specified in their paper [91]. In a study of 145 patients with chronic calcified pancreatitis Amman and co-workers found that 85% had spontaneous and lasting relief of pain at a mean duration of 5 years after onset [6] and Nealon and Thompson [92], after a well designed study, reported that pain relief was achieved in 74 of 87 patients after standard longitudinal pancreaticojejunostomy in an average follow-up of 48 months.

Prinz and Greenlee [93] separated patients according to pain relief into three similar categories: complete, substantial and none, but did not include narcotics intake in the assessment. Eighty per cent of their patients had complete or substantial pain relief after lateral pancreaticojejunostomy, with an average follow-up of 8 years. There was no explanation of how the pain assessment was performed (e.g. patient interview or questionnaire). Neither a pain scale, nor a quality of life assessment was used. During follow-up of patients after a longitudinal pancreaticojejunostomy, Bradley [94] categorized patients’ status as good, fair or poor on the basis of communication with the patient, or referring physician, or by questionnaire. Fair was defined as decreased pain ‘not requiring narcotics'; poor was defined as ‘continuing to require narcotics'. Bradley's results, perhaps as a consequence of including narcotics as a criteria in pain assessment, gave a less optimistic picture of patient outcome than did those of Prinze and Greenlee [93]: only 28% of their patients had good results, 38% had fair, and 34% had poor results after an average follow-up of 6 years.

With a technique for intraoperative as well as percutaneous measurement of pancreatic fluid pressure Danish investigators found a close correlation between tissue pressure and pain in patients who underwent drainage operations for chronic pancreatitis. Postoperative reduction in pressure was followed by relief of pain whereas in patients with recurrent pain the pressure rose again [38]. However, there are also a number of studies casting doubt on the relationship between pain in chronic pancreatitis and intrapancreatic pressure [95]. One problem with the evaluation of the results of the operations are the different definitions of pain relief and the different follow-up times [14], but in spite of that it is obvious that not all patients will be pain free after technically well performed drainage operations [95]. It is widely accepted that the prospects for pain relief are poor if the pancreatic duct is not dilated, but even so, not all patients will experience pain relief [14,64]. About 30% of patients with chronic pancreatitis fail to obtain long lasting relief of pain [96,97]. The current experience is that if obstructed parts of the pancreatic duct are left undrained the operation will fail to relieve pain, but provided this is not the case there is little evidence to favour one operative procedure rather than another.

Although it has been shown that operative drainage of the pancreatic duct delays both endocrine and exocrine functional impairment in patients with chronic pancreatitis [98], the insulin requirement seems to be unchanged for a long time [90].

It should also be mentioned that there are numerous variations of the previously mentioned operations, the most interesting was described by Frey et al. [99,100]. Frey combined a coring out of the pancreatic head with a lateral pancreaticojejunostomy. In his own series of patients the pain relief after 5 years follow-up was complete or improved in 87% of cases, which is at least as good as any other procedure described so far. There is also one randomized series of patients comparing the techniques of Beger and Frey [100–104] where no difference in the decrease of pain was found but there was less postoperative morbidity after the Frey method. However, long follow-up of a more substantial series of patients operated upon by independent surgeons is still lacking, which makes this method a good alternative so far, but not more.

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Resections

The therapeutic principle of resection is based on the assumption that pain in chronic pancreatitis is predominantly caused by inflammation with qualitative and quantitative changes of nerve fibres. In the German speaking countries pancreatic resections have been put forward during the last decade for pain relief in chronic pancreatitis, especially in patients with normal sized ducts and masses of the head of the pancreas. According to German authors nearly 30% of patients with chronic pancreatitis develop inflammatory enlargement of the pancreatic head with subsequent obstruction of the pancreatic duct, and sometimes also of the common bile duct and duodenum. In these cases a pancreaticoduodenectomy, ‘Whipple procedure', has been the procedure of choice for a long time as they provide reasonably effective pain relief. These resections, however, give an immediate postoperative morbidity and long-term morbidity from insulin dependent diabetes mellitus; an increase in the incidence of diabetes from about 20% preoperatively to about 60% in the years that follow [103]. Also, postgastrectomy sequelae detract significantly from the overall quality of life. However, the long-term mortality rate and quality of life after this procedure in patients with chronic pancreatitis has not always been encouraging, and in some studies disappointing [86].

To correct these problems, the original type of pancreaticoduodenectomy has been substituted by the pylorus preserving pancreaticoduodenectomy (PPPD) [77] and the ‘Beger procedure’ [102–104]. The techniques of standard ‘Whipple’ and PPPD are basically the same, except for the treatment of the antrum, pylorus and duodenum. The latter procedure, made popular by Traverso and Longmire [77], hoped to preserve the normal gastric functions and give unimpaired nutrition and prevent bile reflux gastritis. The more conservative procedure of Beger et al. [78] resects the pancreatic head pathology but preserves all extrapancreatic organs including the duodenum. There have been two randomized trials comparing these two procedures [98,101] showing after 6 months follow-up that patients operated on according to Beger exhibited less pain. Moreover, they had a better preservation of insulin secretion and glucose tolerance, and more stable weight. The good results were also confirmed in a prospective study of 298 patients with chronic pancreatitis operated the same way [102]. It should be noted the low in-hospital mortality in this series (1%). These data suggest that in chronic pancreatitis as little as possible of extrapancreatic organs should be removed, which seems logical. However, the limited number of patients and lack of long-term follow-up preclude any definite conclusions as yet concerning the exact method to be recommended.

The duodenum preserving resection of the head of the pancreas has been shown to be associated with a 5 year interval of pain relief of up to 85% [101–104] in a selected subgroup of patients. Izbicki et al. [101], in comparing the results of duodenum preserving resection of the head of the pancreas with those of local resection of the head of the pancreas, used a visual analogue pain scale, noted the frequency of pain attacks, narcotics usage, and ability to work. These elements were combined into a pain score defined as the sum of the rank values of the four criteria divided by 4. No details of the narcotics assessment or what was meant by ‘frequency of attacks of pain’ were provided, but, in summary, the duodenum preserving procedure was recommended by Izbicki et al.

Morel et al. [105] reported on 20 patients with chronic pancreatitis treated with pancreaticoduodenectomy. Of eight patients observed for follow-up for an average of 8 years, four had recurrent, moderate, intermittent abdominal pain, but no mention was made of narcotics usage. Traverso and Kozarek [106] reported the results of pylorus preserving Whipple procedure for complications of chronic pancreatitis in 28 patients with a mean follow-up of 27 months. All patients were interviewed for follow-up, and 88% were reported to be pain free. No patient required re-operation for chronic pancreatitis. Narcotics usage was not described in the postoperative follow-up, although 12% of the patients continued to have enough pain to require pain medication.

Gall et al. [107] reported on results of pancreaticoduodenectomy with Etibloc occlusion of the duct system of the preserved distal remnant in 289 patients. Slightly more than half of the patients were completely pain free, and 35% had occasional complications. ‘Minor complaints', which occurred frequently but significantly less often than they did before surgery, were voiced by 11% of the patients. Two patients continued to have pain as severe as that experienced before surgery. The follow-up period averaged 6 years. The pain relief induced by pancreaticoduodenectomy was said to be constant and permanent.

Russel [17] in studying the results of preservation of the duodenum in total pancreatectomy compared with those of standard pancreaticoduodenectomy found no difference in pain relief between the results of the two operations. He noted that 13 (34%) of the 32 still had severe pain after duodenum preserving total pancreatectomy, and that six required major analgesics.

Distal pancreatectomy [108] has a very limited role in management of pain, and only in patients with non-dilated pancreatic duct and pseudocyst involving the tail of the pancreas does this procedure seem to be associated with a good outcome [109]. Keith et al. [110], in analysing results of 80% distal pancreatectomy and pancreaticoduodenectomy and total pancreatectomy, documented the codeine equivalent required by the patients after an average follow-up of 5 years, 9 years, and 6 years, respectively. Four of five patients, after pancreaticoduodenectomy, required narcotics, whereas 13 of 32 patients had complete pain relief after 80% distal pancreatectomy. No mention was made of the method of pain assessment.

In conclusion, today it is obvious that in patients in whom the ducts are not dilated resection should be considered if there is severe pain due to chronic pancreatitis. The ‘Beger procedure’ may be advocated, but if the surgeon is not familiar with that technique a pylorus preserving pancreaticoduodenectomy will probably do just as well.

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Sympatectomy

The make-up of nerves in the pancreas includes sympathetic, parasympathetic, sensory and motor fibres. The sensory fibres mediating pain are conducted towards the central nervous system, without synapse through the coeliac plexus, and the splanchnic nerves, to enter the thoracic spinal cord [111]. The cell bodies of these neurons are located in the dorsal root. The sympathetic innervation of the pancreas, including the nerves mediating pain, leaves from cells in tractus intermediolateralis in the spinal cord from Th 5 to Th 11. The sympathetic fibres are led to the sympathetic chain and further by the nervus splanchnicus major (from Th 5 to Th 10) and one or more nervi splanchnici minor (from Th 9 to Th 11) to synapses in prevertebral abdominal plexa, at first hand the coeliac ganglion. The postganglionic fibres pass along the arteries of the liver and spleen and the superior mesenteric artery into pancreatic tissue. Some sympathetic axons run directly to the pancreas without intra-abdominal synapses, mainly from the lower portion of the sympathetic chain (which partly may explain the limitation of pain control after surgical coeliacectomy). From a theoretical point of view the pain can be inhibited by cutting the nerve fibres anywhere along these paths. The procedure most often tried is chemical blockage of the coeliacus ganglion, and a newer alternative is thoracoscopic splanchnicectomy.

The coeliacus block can be done during laparotomy (not taken into account here) or percutaneously, usually from the back. The placement of the injection can be done simply by using anatomical landmarks or by checking the position by fluoroscopy, scout X-ray films, ultrasonography, computed tomography, or at angiography. A nerve block with 25 ml of 50% alcohol on each side should be preceded by a positive diagnostic block with long acting local anaesthesia, carried out at least 1 day earlier. The method aims at blockage of the splanchnic nerves before they reach the coeliac plexus rather than blockage of more than a part of the coeliac plexus itself. There are several different ways to ascertain that the needle tips and the fluid injected are in the right place. The site of the needle can be documented with scout films [112]. Theoretically more appealing, is to guide the injections of local anaesthetics (and later neurolytica) with fluoroscopy and contrast media in the injected fluid [113–115].

In 1990, in a critical review, Sharfman and Walsh [116] analysed data from 15 series published between 1964 and 1983, including 480 patients, on coeliac plexus blocking in pancreatic patients. At least a satisfactory response to the procedure was reported in 87% of the patients. The authors claimed, however, that there were major deficiencies in the reporting of the results. Taken together, it seems as if the results of coeliac block has been rather unpredictable, and as the pain tended to recur within about 3 months [64] the indication for this procedure is at present limited.

As the pain fibres run in the sympathetic chain, pain stimuli can be overcome from within the thoracic cavity where the chain lies immediately subpleural in a wave-like disposition over the ribs in the posterior mediastinum. A variety of approaches to splanchnicectomy have been used in the past. Mallet-Guy was apparently the first person to attempt any form of denervation of the pancreas in patients with chronic pancreatitis. Using a retroperiotoneal approach, he performed unilateral left splanchnicectomy in 1942 with successful relief of pain. By 1950 he was able to report successful results in 84% of 37 patients followed for 1 year or more [117] and in 1983 he reported on his expanded series of 215 patients with chronic pancreatitis who had undergone left splanchnicectomy and coeliac ganglionectomy. In 217 patients who had been followed for 5 years or more, relief of pain was observed in 88% [118]. Despite this, in 1983, White reported only a 20% success rate in relieving chronic pancreatic pain with left splanchnicectomy and coeliac ganglionectomy with the same technique [119].

These nerves are also identified easily at thoracoscopy. Thoracoscopic splanchnicectomy may be performed bilaterally under general anaesthesia using double-lumen endothraceal intubation. In a series of 30 patients treated in Lund, only two ports were used on each side: one optical cannula (10.0 mm) and another 5.5 mm operating cannula. A small hole in the pleura on each side of a splanchnic nerve, 10 mm from the sympathetic chain, was burnt with the hook and the nerves were then cut off completely so that the ends were seen to be well retracted from each other. In uncomplicated cases the patients were discharged from the hospital the day after the operation. Satisfactory stable pain relief was obtained from the first week after surgery to a median follow-up time of 18 months. All but one patient reported clearly reduced pain, but only about 20% of individuals reported immediate complete pain relief. It may be concluded that thoracoscopic splanchnicectomy appears promising as a relatively simple treatment for severe chronic pancreatic pain [65,120].

A different approach to pancreatic denervation was suggested by Yoshioka and Wakabayashi in 1958 [121]. After studying the neuroanatomy of postganglionic nerve fibres travelling from the coeliac ganglion to pancreatic parenchyma they recommended a selective bilateral neurectomy of the fibres entering the pancreas from the right and left ganglia. They reported that 35 of 36 patients with chronic pancreatitis experienced ‘excellent’ results from this challenging technique. Little or no additional information concerning these patients was provided. In a modification of this selective parenchymal sympatectomy, Hiraoka et al. [122] extended the Yoshioka procedure to include more extensive denervation of the body and tail by completely freeing the pancreas from its retroperitoneal attachments. Successful relief of pain was achieved in both patients undergoing this modified procedure.

Since the splanchnic nerves are thought to carry most, if not all, of the sympathetic pain afferent from the pancreatic parenchyma [123] it is not surprising that splanchnicectomy relieves pain in patients with chronic pancreatitis. Rather, it is the failure of splanchnicectomy to completely relieve pain that is remarkable. A plausible explanation for suboptimal pain response from splanchnicectomy might be that some elements of pain in chronic pancreatitis are mediated by somatic nerve pathways. As all surgeons dealing with chronic pancreatitis know, the disease process often extends beyond the boundaries of the gland to involve part of the retroperitoneum. Pain arising from chronic inflammation of the parietal tissues is true somatic exteroceptive pain, whose pathway is through the spinal nerves to the dorsal root ganglion, and then to the lateral spinothalamic tract. In support of this theory of mixed sympathetic and somatic involvement in some patients with chronic pancreatitis was the observation of Bradley et al. [4] that during testing with epidural analgesia in some patients with chronic pancreatitis there was some decrease of pain after sympathetic blockade but total anaesthesia required a full somatic block.

Moreover, the well-recognized failure of even total pancreatectomy to provide pain relief to some patients might be explained by somatic nerve involvement superimposed on sympathetic pain. If combined sympathetic and somatic nerve involvement is common in patients with chronic pancreatitis, an operation could be designed to add appropriate somatic denervation to the splanchnicectomy. Another explanation for the frequent absence of total analgesia after splanchnicectomy might be that pancreatic pain afferents are present in mixed nerves, thereby bypassing the coeliac ganglia and the splanchnic nerves. Although it is known that such fibres exist [4], their relative importance in the neurophysiology of pancreatic pain is unknown.

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Pain in pancreatic cancer in chronic pancreatitis

In the paper by Sharma and co-workers [89] 7% of the patients died from disseminated cancer. In all forms of pancreatitis there appears to be a cellular dysfunction, glandular destruction, and presumably increased cell turnover which has been suggested as a potential precursor of cancer in many organs. The excess risk of pancreatic cancer that has been documented in epidemiological studies in patients with various types of pancreatitis, also in ‘tropical pancreatitis', is consistent with this hypothesis. The uncertainties in epidemiological studies, notwithstanding, the existence of a clear association between pancreatitis and the subsequent risk of pancreatic cancer is found too often to be only randomized [124,125].

However, pancreatic cancer must always be ruled out, at the latest preoperatively, in all patients undergoing surgery for chronic pancreatitis. Abdominal pain in patients with chronic pancreatitis may have another source than the pancreatitis!

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Evaluation of treatment options

Patients with established chronic pancreatitis do not present with a uniform pattern for the stage of the disease (early or late), the extrapancreatic, secondary symptomatology or the morphological features. This also influences the pattern of pain and the outcome of the attempts of management not only of the symptoms but of the patient as a whole. The major goal of new treatment modalities in a benign disease like chronic pancreatitis must be an improvement of the patient's quality of life, which is a multidimensional condition. There are various studies in which pain or even quality of life has been assessed before and after surgical treatment of chronic pancreatitis [64,101,104,105,126–129]. Some of the studies have randomly compared the outcome of two different operative procedures [101,105].

A growing number of options are now available for managing the pain problems in chronic pancreatitis, including pharmacological, endoscopic and surgical methods. To compare the efficacy of different treatments, it is necessary to have a baseline inventory of the patient's general health status. Specifically it should be determined whether the patient's pancreatitis is caused by the use of alcohol or has some non-alcohol related cause, addiction to narcotics, and whether the patient has exocrine and endocrine insufficiency, weight loss, pain and grade of pain, and a record of emergency department visits and hospital admissions. It should be noted that alcohol and narcotics addiction has an unfavourable impact on longevity and pain relief, especially if their use is continued after treatment [130]. Pain in chronic pancreatitis must always be adapted to the individual situation, and this refers especially to specific complications of the disease. At present, decision making often depends not only on the individual case but also on the knowledge and experience of the doctors available and on concommittant health hazards. Pain is the cardinal symptom of chronic pancreatitis [1], but is most often contemporary with alcoholism, which together is the most difficult part to treat. For some patients with chronic pancreatitis pain is so severe that no other things matter. It is so severe that a consistent, reproducible standard of assessing pain status and quality of life is not possible to compare reliably over time or between individuals or groups: the patients are able to give any answer they think fit the situation, just to overcome the mistrust they experience. Therefore, the assessment of the individual's pain, which from an intellectual point of view is the only real pain, may or may not be handled with one surgical procedure with another, but it is just as difficult to compare results of pharmacological, endoscopic and other treatments that are locally available.

Even in the most recent literature on chronic pancreatitis, there is an absence of a consensus on a standard method for assessing pain relief and improved quality of life [92–94,100,108–110,131–133]. In the absence of a standard method for assessing pain relief and improved quality of life [93–94,100,108–110,131–133] Lankisch and Andrén-Sandberg have given guidelines about which items should be assessed in follow-up of patients treated for chronic pancreatitis [14]. Another suggestion is to use the EORTC QLQ-30 [134]. This questionnaire consists of a core with 30 generally applicable items and includes a functional scale; a working ability scale; a general symptom scale: scales on cognitive, emotional social functioning; a financial strain scale; a global quality of life scale etc. This may be used with its pancreas specific part, PAN-26 [134–136], which is under evaluation not only for pancreatic cancer but also for chronic pancreatitis.

The natural history of the disease may be characterized by spontaneous exacerbations and remissions, so there can be great variations in the pain course. The use of additive narcotics before and after surgery may obscure the severity of the pain and confuse attempts at comparison. Further, the classification of patients undergoing surgery or other interventions for pain control into groups according to ‘success’ and ‘failure’ is clearly inadequate and fails to provide reproducible, believable data. The need for a standard method of pain assessment to evaluate the efficacy of any therapy in chronic pancreatitis is more pressing than ever, because there are now a growing number of options for treating the suffering patients. In the absence of a standardized system of assessing pain relief and quality of life, it is virtually impossible to compare these operative procedures with other types of management. It is only by having a common yardstick that we can determine which is the most efficacious way of providing pain relief and maintaining a reasonable quality of life in patients with intractable pain from chronic pancreatitis. It is obvious that long-term results in chronic pancreatitis come from an appraisal of the individual's situation and that the treatment must be tailored to the patient as well as to the disease. The prognosis also depends on the attitude of the patient and may depend more on drinking habits than on the medical and surgical effects of major operations.

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Summary and options for the future

The principal prerequisite to keep the surgical frequency low is to have a good personal contact with the patient on a regular basis, and to try to reach an agreement for cooperation between the chosen doctor and the patient. This may be hard if the patient is addicted to drugs or has severe alcohol problems, but in such cases it makes no difference which medical or surgical management method is chosen, as the end result will be just as bad. However, if the patient has confidence in the doctor's management overall, he or she will be able to withstand more pain without escalating the analgesics, and the treatment can be seen from a long-term perspective. Therefore, the continuity in the patient–doctor relationship is of the utmost importance in these patients. An established relationship between the patient and the surgeon, not only with the general practitioner or gastroenterologist, for a long time before surgery is also of importance. Maybe, also, a patient's knowledge that he or she can have a pain relieving operation quickly, if really needed, may postpone the actual time for the operation.

However, there are also patients who certainly need surgical intervention in chronic pancreatitis. A borderline is crossed if the patient needs morphine on a regular basis. After a renewed work-up of the patient to avoid missing a pancreatic pseudocyst, a duodenal ulcer, gallbladder disease or other extrapancreatic pathological process, a thoracoscopic splanchnicectomy or percutaneous coeliac plexus block should be considered as an alternative to resective procedures in most cases as the results are good enough and the procedure does not preclude other interventions later on if needed. If pain relief is not achieved open surgery would be considered, and, if the right prerequisites are present, a longitudinal pancreaticojejunostomy would be the first choice.

For the remaining patients resections could be performed with low morbidity and without mortality today. Today, there are seven published randomized trials of surgical treatment: four comparing surgical techniques [99,101,137,138] and three examining individual aspects of surgical treatment such as gastric emptying delay [139–141].

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