The Natural History of Pain in Alcoholic Chronic Pancreatitis

Transcription

1 GASTROENTEROLOGY 1999;116: LIVER, PANCREAS, AND BILIARY TRACT The Natural History of Pain in Alcoholic Chronic Pancreatitis RUDOLF W. AMMANN, BEAT MUELLHAUPT, and ZURICH PANCREATITIS STUDY GROUP Division of Gastroenterology, Department of Medicine, University Hospital, Zurich, Switzerland See editorial on page Background & Aims: The pain pattern of chronic pancreatitis (CP) and its surgical implications are discussed. The aim of this study was to (1) define typical pain patterns, (2) correlate pain patterns with the presumptive causes of the pain, and (3) compare the natural history of patients treated conservatively or surgically with respect to pain relief, pancreatic dysfunction, and clinical outcome. Methods: A cohort in this prospective long-term study included 207 patients with alcoholic CP (91 without and 116 with surgery for pain relief). A clinically based staging system was applied to characterize pain in the evolution from onset to end-stage CP. Results: Average duration of CP was 17 years. In early-stage CP, episodes of recurrent (acute) pancreatitis predominated. Chronic pain was typically associated with local complications (mainly pseudocysts, 84 of 155; 54%), relieved definitely by a single (drainage) procedure in approximately two thirds of patients. Additional surgery was required for late pain recurrence in 39 patients (34%), primarily symptomatic cholestasis (18 of 39; 46%). All patients achieved complete pain relief in advanced CP. Conclusions: In our experience, relief of chronic pain regularly follows selective surgery tailored to the presumptive pain cause or occurs spontaneously in uncomplicated advanced CP. Chronic pancreatitis (CP) is a multifaceted disease characterized chronologically by an early stage of recurrent clinical acute pancreatitis and a late stage dominated by steatorrhea, diabetes, and/or pancreatic calcification. 1,2 There is a subgroup of primarily painless, predominantly idiopathic ( senile ) CP, 3,4 which becomes clinically apparent only when symptoms typical of end-stage CP appear. A large amount of conflicting data on pain in CP has been published in the last 2 3 decades. Most experts assume that the pain of CP, in contrast to that of acute pancreatitis, is typically chronic and caused by a single mechanism. 5,6 This clinically relevant issue has not been resolved because (1) CP is not a clinically well-defined entity, (2) the underlying mechanism of pain induction in CP is unclear and, (3) the long-term pain profile in the evolution of CP with and without surgical intervention is poorly defined. According to the current literature, 27% 67% of patients with alcoholic CP (ACP) experience chronic pain severe enough to warrant surgical intervention. 2,7 11 The choice of surgical procedure (drainage vs. resection) and its efficacy in relieving pain and maintaining pancreatic function are debated. 12,13 This issue has been difficult to resolve, particularly because in most series insufficient data are provided on the relationship of the pain pattern to the many pertinent variables, e.g., classification and staging of CP, particularly the presumptive cause of pain. 2,12 14 Therefore, data from different centers are difficult to compare. This report is based on the prospective study of a large mixed medical-surgical patient series with a follow-up of up to 35 years from the onset of illness. Special attention was paid to using a clearly defined terminology and to assessing the presumptive cause of pain in each pain episode. The main purpose of the study was to (1) characterize and classify the types of pain; (2) try to assess whether different types of pain may be related to events in the natural history of the disease process, e.g., local complications, early and late stage of ACP; and (3) characterize the pain profile in ACP in patients with and without surgery. The study focused on the pain pattern and its surgical implications to clarify some misinterpretations of our experience 13,15,16 concerning indication for surgery for pain relief in ACP. 2 Materials and Methods Definitions The diagnosis of ACP was based on a typical history of recurrent clinical acute pancreatitis; a daily alcohol intake of Abbreviations used in this paper: ACP, alcoholic chronic pancreatitis; CP, chronic pancreatitis; LPJ, longitudinal pancreaticojejunostomy by the American Gastroenterological Association /99/$10.00

2 May 1999 PAIN AND SURGERY IN CHRONIC PANCREATITIS g for at least 5 years; and one or more of the following: pancreatic calcifications, moderate to marked ductal lesions (Cambridge criteria), severe pancreatic exocrine insufficiency (pancreatic steatorrhea), and typical pancreatic histology. 17 We defined duration of the disease as the time between onset of ACP (first documented episode of pancreatitis) and either the cutoff date of the study (December 1996), the last personal contact, or death. All patients were prospectively observed from entry (equal to first assessment of exocrine function with or without first consultation in our Gastrointestinal Division) until the last follow-up contact. The course of the disease from onset to entry was analyzed from hospital records. Two typical pain patterns were identified. Type A pain pattern, typically observed in acute relapsing pancreatitis, is short-lived pain episodes usually lasting 10 days and separated by long pain-free intervals of several months to 1 year. Such intermittent pain episodes may either be severe, requiring hospitalization, or mild and transient (1 2 days), manageable by the patient with short-term intake of nonnarcotic analgesics (Figure 1). Virtually all patients with an A-type pain pattern had to be hospitalized at least once for severe clinical acute pancreatitis. Type B pain is characterized by prolonged periods of persistent (daily) pain and/or clusters of recurrent severe pain exacerbations (Figure 1). Typically severe pain occurred for 2 or more days per week for at least 2 months. All patients with Figure 1. Schematic representation of the two typical pain patterns in ACP. A-type pain pattern is characterized by short (usually 10 days) relapsing pain episodes separated by pain-free intervals of several months to 1 year. The intermittent pain episodes may either be severe, requiring hospitalization (H) (as is typical for acute pancreatitis), or mild and transient, manageable by the patient with short-term intake of nonnarcotic analgesics. B-type pain is characterized by prolonged periods of either persistent (daily) and/or clusters of recurrent severe pain exacerbations. Typically severe pain occurs 2 or more days per week for at least 2 months and requires repeated hospitalizations in most instances. B-type pain were hospitalized at least once for severe pain. B-type pain periods may follow an A-type pain episode, a condition often designated as smoldering or protracted (acute) pancreatitis 18,19 or may be interspersed between recurrent A-type pain episodes. Persistent pain relief was assumed in patients with recurrent pancreatitis after a pain-free interval of 2 years. Nonspecific dyspeptic symptoms of the flatulent type without pain (or need of analgesic therapy) were not considered equivalent to pancreatitis pain. A major reason for unexplained complaints of constant pain is narcotic addiction, which was investigated in close collaboration with the family doctor. Such patients were excluded from the present analysis because narcotic addiction jeopardizes the assessment of pancreatitis-associated pain. 2,13 16 The following structural abnormalities were assigned as the presumptive cause of B-type pain: (1) pseudocysts 2,20 ; (2) symptomatic cholestasis, i.e., pain associated with prolonged cholestasis caused by typical partial outlet obstruction of the common bile duct with bile duct dilatation (no pseudocysts) and prompt pain relief after bile duct drainage operation; and (3) symptomatic large-duct CP (presumptive high ductal pressure), i.e., pain associated by dilated main pancreatic duct with or without ductal stones (no cysts, no cholestasis), only minor or no exocrine insufficiency, and prompt pain relief after ductal drainage surgery. Two stages in the evolution of CP are distinguished: (1) early-stage CP, i.e., no calcification and only minor or no exocrine insufficiency; and (2) late-stage CP, i.e., with calcification and/or persistent exocrine insufficiency. 17 Study Design and Patients Since 1963 all cooperative patients with suspected ACP attending one of the large hospitals in our area (medical or surgical units) were studied prospectively in our Gastrointestinal Division according to a protocol outlined by us previously. 2 The visits at yearly intervals included a history of pain, hospitalization, alcohol intake, drug use, maximum/minimum body weight before and during ACP, clinical examination, routine laboratory tests, pancreatic function tests (serum amylase, lipase, fecal chymotrypsin test, 2 postprandial blood glucose, and glycosylated hemoglobin), and plain radiography of the pancreatic area in three projections. Additional studies (sonography, computerized tomography, endoscopic retrograde cholangiopancreatography endoscopy, and fecal fat studies) were performed when indicated. The regular yearly follow-up studies were supervised personally by the senior author. All patients with suspected ACP, fulfilling the criteria of CP cited above during follow-up, were included in the study. All hospital, surgical, and histopathologic records (autopsy reports and death certificates) of each patient were reviewed. Since 1963, 290 patients with proven ACP were included in the study. The following three categories of patients were excluded from the present analysis: subjects with primary painless ACP (n 24; because of undefined onset of ACP); subjects with a duration of ACP 6 years (n 49; mainly dropout, n 25; death, n 22); and subjects with continued

3 1134 AMMANN ET AL. GASTROENTEROLOGY Vol. 116, No. 5 narcotic addiction (n 10, 9 of whom had underwent pancreatic surgery). In our experience, ACP accounts for about 70% of all patients with CP; the rest is etiologically classified as idiopathic (about 24%) or due to rare causes (6%). 2,21 The present study includes 207 patients: 116 underwent surgery for B-type pain (surgical series), representing a total of 1984 patient years from the onset of illness. Fifty-six of the 116 patients died ( years from the onset), 6 patients were lost to follow-up ( years from onset), and 54 of the 116 patients are alive. An average 15.4 recorded hospital visits per patient (ambulatory control studies and/or records from medical or surgical hospitalizations; range, 2 28) were available. In the nonsurgical series (n 91; total of 1533 patient years from onset), 54 patients died ( years from onset), 4 patients were lost to follow-up ( years from onset), and 33 patients are alive. An average 18.7 recorded hospital visits per patient (range, 1 23) were available. The fecal chymotrypsin test was performed at yearly intervals an average of 11 times (range, 4 27) per patient in the surgical series of 54 living patients. In the 33 living nonsurgical patients, this test was performed an average of 9.6 times (range, 1 21) per patient. Methods of pancreatic surgery have not changed substantially over the last 3 decades in our hospitals. The indication for surgery was usually determined by our medical-surgical team (94 of the 116 patients entered our study at the time of or before surgery). Longitudinal pancreaticojejunostomy (LPJ) and/or a cyst drainage were the most common surgical procedures. Distal pancreatectomy was mainly performed for pseudocysts of the pancreatic tail (with or without splenic vein thrombosis). A resection of the pancreatic head was performed in 4 cases. A biliary drainage procedure (predominantly a hepaticojejunostomy) was performed in patients with persistent cholestasis. In some patients, LPJ was combined (prophylactically) with a biliary drainage procedure simply on the basis of a morphological narrowing of the distal bile duct (no cholestasis). For further technical details, see Ammann et al. 2 Statistics The statistical analysis for unpaired, nonparametric data was performed with either the Mann Whitney or the t test. A P value of 0.05 was considered statistically significant. The Kaplan Meier method was used to estimate the time-free interval probabilities of the disease characteristics within the surgical and nonsurgical group. Results Clinical data of the 207 patients with ACP are shown in Table 1. The sex and age distribution were similar in the surgical and nonsurgical series with a high male predominance. The high rate of calcific ACP in the series (87%) is considered to be related to the long follow-up observation time and the frequent evaluations. The average duration of ACP was approximately 17 years in both groups. The postoperative follow-up of the surgical series was 12.7 years (Table 1). Table 1. Relevant Clinical Data Surgical group (n 116) Nonsurgical group (n 91) P Age ( yr at onset) a NS Sex (M/F) b 103/13 86/5 NS Calcifications (yes/no) b 104/12 76/15 NS Duration of ACP ( yr from onset) a NS Death during follow-up b 56 (48) 54 (59) NS Persistent complete alcohol abstinence 17 (15) 10 (11) NS Postoperative follow-up ( yr ) a ACP not (yet) proven at surgery b 56 (48) a Values are mean SD. b Values are number of patients with percentage in parentheses, if indicated. Types of Pain and Hospitalizations The frequency of hospitalization for A-type pain was comparable in the nonsurgical and surgical series (Table 2). However, the total number of annual hospitalizations for A- and B-type pain was significantly higher in the surgical series (Table 2). Interestingly, the mean duration of the initial period of pain from onset to pain relief was identical in both subgroups (Table 2). In the nonsurgical series, an exploratory (diagnostic) laparotomy was performed in early-stage CP in 15 patients (16.5%), primarily for acute abdomen (n 11) or suspicion of cancer (n 4). The corresponding figures in the 9 patients of the surgical group are 5 and 4 patients, respectively. All diagnostic laparotomies except one were performed before 1978, before introduction of the modern imaging techniques. Indication and Operative Procedure in the Surgical Series Indication and type of surgery are summarized in Table 3. Two thirds of the procedures were performed for Table 2. Types of Pain and Hospitalization Duration of initial phase of pain from onset to relief ( yr ) Surgical group a (n 116) (5.0/0.5 14) Hospitalization b Type A pain (2.0/0 13) Type B pain (1.0 3) Total annual hospitalizations during initial phase with pain (types A B) b (0.7/0 3) a Values are means SE (median/range). b Number of hospitalizations required for pain. Nonsurgical group a (n 91) P (5.0/1 13) NS NS (2.0/0 9) (0.3/0 1.8)

4 May 1999 PAIN AND SURGERY IN CHRONIC PANCREATITIS 1135 Table 3. Surgical Procedures and Their Indications at First Surgical Procedure (n 116) Presumptive pain cause D LPJ Surgical procedure LP Whipple HJ Total n(%) Time of surgery after onset of illness ( yr ) Cysts (66.4) High ductal pressure 3 a (13.8) Cholestasis, no cysts 2 a b (16.3) Miscellaneous 4 (3.5) D, cyst drainage, mostly cystojejunostomy; LP, left pancreatectomy; HJ, hepaticojejunostomy. a Surgical spincterotomy. b Cholestatic jaundice without pain; n 2. B-type pain associated with pseudocysts (n 77), primarily in early-stage ACP. Less than 14% of patients (n 16) underwent surgery for symptomatic large-duct CP (i.e., presumptive high ductal pressure; no cysts, no cholestasis), and about 16% underwent the first for B-type pain accompanied by persistent cholestasis (without pseudocysts), typically found in late-stage ACP. The cumulative rate of surgical interventions in relation to the evolution of ACP from onset is outlined in Figure 2. The data indicate that the first surgical procedure for B-type pain was performed in 75% of patients within 6 years from onset. Thus, the first procedure was performed in about 50% in early-stage ACP (Table 1). The diameter of pseudocysts, documented adequately in 59 patients, was approximately 5 cm in 9 (15.2%), 6 14 cm in 40 (67.8%), and 15 cm in 10 patients (16.9%). The cysts were predominantly extrapancreatic and postnecrotic in origin, based on macroscopic and/or microscopic assessment. In the nonsurgical series, pseudocysts were observed in 9 patients (9.9%); these predominantly small cysts ( 5 cm in 7 patients) resolved spontaneously. The spontaneous rupture of a larger cyst into the stomach was documented in 1 patient by a barium meal and gastroscopy. Postoperative Pain Recurrences Pain recurrences occurred postoperatively in 65 patients. A second surgical procedure for B-type pain was performed in 39 of the patients. No second procedure was necessary in the remaining 26 patients with recurrence of A-type pain (episodes of pancreatitis, n 16; peptic ulcer, n 5; pseudocysts, n 2; and hepatic or peripancreatic abscesses managed with conservative therapy, n 3). Surgical procedures and their indications are outlined in Table 4. Hepaticojejunostomy for persistent cholestasis and/or jaundice or cholangitis was the most frequent second surgical procedure (n 18; 46.2%) in late-stage ACP (Table 4). B-type pain was judged to be caused by pseudocysts in 7 additional patients and presumably by ductal hypertension in 5 patients (Table 4). Peripancreatic (n 4) or hepatic (n 4) abscesses developed in 8 patients, 3 of them treated conservatively. 22 Four miscellaneous cases were managed by an appropriate procedure (Table 4). The second surgical intervention became necessary only after a long interval ( 8 years from onset in 50% or years after the first procedure) (Figure 2). The incidence of second surgery was similar after the three major surgical procedures: 30% after cyst drainage, 34% after LPJ, and 40% Table 4. Surgical Procedures and Their Indications at Second Surgical Procedure (n 39) Presumptive pain cause D LPJ Surgical procedure LP Whipple HJ Total n(%) Time of surgery after onset of illness ( yr ) Cysts (18) Abscess 5 5 (13) High ductal pressure (13) Cholestasis, no cysts a (46) Miscellaneous b 4 (10) Figure 2. Cumulative rate of surgery in relation to onset of ACP. The first surgical procedure ( ) for severe pain was necessary in 116 patients, mainly in early-stage ACP (in 75% 6 years after onset). A second procedure ( ) for severe pain recurrences was necessary in 39 patients (34%) years after the first procedure. D, cyst drainage, mostly cystojejunostomy; LP, left pancreatectomy; HJ, hepaticojejunostomy. a Cholestatic jaundice without pain; n 3. b Splenectomy, n 1; gastrojejunostomy, n 2; cicatricial hernia, n 1.

5 1136 AMMANN ET AL. GASTROENTEROLOGY Vol. 116, No. 5 Figure 3. Probability of remaining free from pain recurrence for nonsurgical ( ) and surgical (...)patients. after left pancreatectomy/whipple procedure. Thus, the first surgery was successful in achieving lasting pain relief in 70% (cyst drainage), 66% (LPJ), and 60% (left pancreatectomy/whipple procedure), respectively. Only 1 patient needed a third surgical procedure (hepaticojejunostomy, 19 years from onset). Pain Relief in The Surgical and Nonsurgical Series The interval between the onset of ACP and the realization of pain relief in the surgical and the nonsurgical series is shown in Figure 3. The curves are virtually parallel: pain relief was obtained in 50% within 6 years and in 80% within 10 years from onset of illness. The data are based on the first pain-free period for 2 years (see Materials and Methods, exclusion of late B-type pain recurrence). Complete (permanent) pain relief was documented in the nonsurgical series for an average of 11 years and in the surgical series for an average of 10.9 years after the first and for 6.8 years after the second procedure (Table 5). Figure 4. Probability of remaining free of exocrine insufficiency for nonsurgical ( ) and surgical (...)patients.afecalchymotrypsin value of 120 µg/g is indicative of normal exocrine function. Pancreatic Dysfunction and Pancreatic Calcification The progression of exocrine and endocrine insufficiency in relationship to the evolution of ACP is outlined in Figures 4 and 5 for the surgical and nonsurgical series. The curves in both groups are virtually parallel. The incidence of exocrine insufficiency was approximately 55% at 6 years from onset and 80% at 10 years in both groups. Overt diabetes (i.e., with need of oral hypoglycemic agents or insulin) was observed in about 20% at 6 years and in nearly 50% at 10 years from onset in both groups. Pancreatic calcification was noted in both groups in approximately 30% at 6 years and in 70% at 10 years (Figure 6). Table 5. Lasting Pain Relief: From Last Pain Episode to Last Contact Duration of pain remission ( yr ) Total Mean SD Range Nonsurgical series Surgical series First procedure Second procedure 37 a a One patient died postoperatively; 1 patient had pain relief for 2 years. Figure 5. Probability of remaining free of diabetes mellitus for nonsurgical ( ) and surgical (...) patients.

6 May 1999 PAIN AND SURGERY IN CHRONIC PANCREATITIS 1137 Table 6. Alcohol Abuse and Outcome Alcohol abuse Discontinued Continued or reduced Patients, n (%) 155 (75) 52 (25) Surgical series (%) 86 (74) 31 (26) Nonsurgical series (%) 69 (76) 21 (24) Duration of ACP ( yr ) a Death, n (%) 105 (67) 12 (23) Surgical series 54 (90) 6 (10) Nonsurgical series 51 (89) 6 (11) Unemployment, n (%) 51 (76) 16 (24) Surgical series 27 (75) 9 (25) Nonsurgical series 24 (77) 7 (23) a Mean SD. Figure 6. Probability of remaining free of calcification for nonsurgical ( ) and surgical (...)patients. Alcohol Consumption and Clinical Outcome Alcohol consumption and clinical outcome (pain, mortality, invalidity, and body weight) were assessed. Persistent total alcohol abstinence after onset of ACP was rare in both groups (Table 1). A reduced alcohol intake was reported by 12.1% of patients. However, 75% of the patients reported continued, mainly unchanged alcohol consumption (Table 6). The mortality was not statistically different in the surgical vs. nonsurgical series (Table 1). The death rate was, however, almost three times higher in the subgroup with continued alcohol abuse than the subgroup with reduced or ceased alcohol intake (Table 6). Overall survival data cannot be provided because 83 of 290 patients of our cohort of ACP were excluded from the present analysis for various reasons (see Study Design and Patients). A reduced employment capacity (0% 50%) combined with social support services was observed in 33.6% of patients with late-stage ACP in the surgical series ( years from onset) and in 27.4% of patients in the nonsurgical series ( years from onset). In the subgroup with continued alcohol abuse, the rate of marked physical impairment was three times higher than in the subgroup with reduced or absent alcohol intake (Table 6). Considerable fluctuations of body weight were observed (Figure 7). In early-stage ACP, a marked weight loss was observed in both groups, probably due to pain (Figure 7B). In the intermediate phase (average, 10.3 years from onset), a considerable weight gain occurred, probably as a result of pain relief (Figure 7C). However, a marked weight loss was noted between the premorbid maximum and the final body weight, probably related to a combination of factors, including diabetes and/or steatorrhea (Figure 7D). Discussion The clinical pain pattern of CP is generally characterized as chronic and usually requiring surgical intervention for relief. 5,6 Unfortunately, most reports provide insufficient descriptive data on the clinical pain pattern and its relation to the presumptive pain cause. 13,23 Therefore, data from different centers on pain characteristics and their therapeutic implications are difficult to compare. This report summarizes our prospective long-term experience assessing the pain profile in a mixed medical- Figure 7. Changes in body weight (in kg 95% confidence interval) from (A) onset to (D) final weight at the end of follow-up. An initial weight loss occurred in the early phase (A and B: P in surgical and nonsurgical series), probably related to pain (B). A transient weight gain is noted in an intermediate phase, probably primarily due to arrest of pain (C) (B and C, P in surgical and nonsurgical series). In advanced or end-stage ACP, a marked weight loss occurred, probably related to diabetes and/or steatorrhea (D) (C and D: P in surgical and nonsurgical series). There was no significant difference in weight between the surgical and nonsurgical series at any stage of the disease., Nonsurgical;, surgical.

7 1138 AMMANN ET AL. GASTROENTEROLOGY Vol. 116, No. 5 surgical series during evolution from onset to end-stage ACP. A clinically based staging system was applied, and special attention was paid to relating the pain pattern to the presumptive cause of pain in each pain episode. All 207 patients experienced one or several A-type pain attacks, which in most patients required at least one hospitalization because of severe pain. Ninety-one patients (44%) never had B-type pain (nonsurgical series). In the surgical series (n 116; 56%), at least one period of B-type pain with the need for surgery was interspersed in the course of recurrent A-type pain episodes. The allocation of patients to a surgical and a nonsurgical series might introduce a bias. On the basis of clinical data, particularly age and sex distribution, incidence of calcific ACP, and duration of ACP, both groups are comparable without apparent evidence of a bias. Obviously, the surgical series represents a selection of patients with severe pain. Unfortunately, there is no standardized definition for severe pain in ACP, and a pain score system, based on the long-term use of narcotics, as often used in surgical series, jeopardizes the assessment of pancreatitisrelated pain. 2,12 14 Furthermore, a pain score may be applied for chronic continuous pain, e.g., cancer, whereas the pain pattern in CP shows typically intermittent pain episodes of variable severity. Therefore, the pain profile in our series was characterized by three clinically defined variables: frequency, duration, and severity of pain episodes (with or without need for hospitalization). Patients with a long-term use of narcotics were excluded from our study (n 10). Recurrent episodes of A-type and/or B-type pain occurred predominantly in early-stage ACP, as noted previously. 1,2,7,13 Recurrent bouts of pain occurred on average for 5.5 years from onset to pain relief both in the surgical and nonsurgical series. The only difference was the significantly higher annual rate of hospitalizations required in the surgical series during the initial painful phase of ACP (Table 2). The issue of pain in CP has been reviewed. 6,13,23 26 B-type pain in our series was typically associated with local complications and was regularly relieved by surgical correction of the complication. The three main causes of B-type pain (first and second surgery, n 155) were pseudocysts (n 84; 54.2%), cholestasis (n 37; 23.9%), and presumptive ductal hypertension (n 21; 13.5%). The pseudocysts were usually large ( 6 cmin 85%) and extrapancreatic and typically postnecrotic in origin, as discussed previously. 20,26 Small pseudocysts ( 5 cm in 78%) were observed in 9 patients in the nonsurgical series (9.9%); these cysts disappeared spontaneously without surgical intervention. Presumptive ductal hypertension as major cause of chronic B-type pain in CP has probably been overestimated in the past 25 and was a rare indication for surgery in our series (13.5%). No reliable, noninvasive routine method for direct assessment of ductal (tissue) pressure is available, and therefore the issue of pain in relation to ductal pressure is controversial. 13,25 The interpretation of ductal hypertension as a causative factor of pain in CP is often based on the presence of ductal dilatation alone. In contrast, in the present study, symptomatic large-duct CP was diagnosed, only in patients with a preserved exocrine function, as observed previously. 2,21,27 Most experts probably agree that anatomic abnormalities per se do not predict whether a patient will be symptomatic with pain, 6,13,25 and severe ductal changes are commonly observed in advanced painless CP. The controversy on the relationship between pain and exocrine function with respect to ductal hypertension (ductal dilatation and/or stones) has not been resolved mainly because data on the exocrine function as an important variable are usually not provided. Further studies on this clinically relevant issue are mandatory. Persistent cholestasis, most often accompanied by B-type pain, was a common indication for surgery (23.9%), typically in late-stage ACP. The opinions are divided as to the role of partial bile duct obstruction in the production of pain in ACP. 25 Compression of the bile duct assessed by cholangiography is observed in up to 63% of advanced painless ACP. 28 However, ductal dilatation accompanied by pain (symptomatic cholestasis) is observed only in about 21% 30% of patients with CP. 25 Prompt pain relief after biliary drainage supports the notion that symptomatic cholestasis was probably the only cause of pain in these patients. Late B-type pain recurrence was observed in the surgical group in 39 patients (33.6%) compared with 4.9% 58% in other series. 13,29 33 B-type pain recurrences were typically associated with local complications, as noted above. Surgical procedures in ACP are palliative, and therefore it is not surprising that many patients experienced a recurrence of pain later, some of them requiring surgical reintervention. 13 Nonsurgical series are best suited to evaluating the pain profile during the evolution from early- to late-stage ACP. In our experience, lasting relief of A-type pain is a natural phenomenon in advanced uncomplicated ACP, i.e., in medical series and after appropriate drainage surgery of complicated ACP. The burnout hypothesis of ACP, first proposed 25 years ago by our group 2 and supported by other experts, 27 is still controversial. In fact, lasting pain relief has been observed irrespective of marked exocrine insufficiency in early-stage ACP after alcohol abstinence 13,23,25 as well as in some patients with nonprogressive ACP (with preserved exocrine function)

8 May 1999 PAIN AND SURGERY IN CHRONIC PANCREATITIS 1139 after multiple episodes of alcoholic pancreatitis despite continued alcohol intake. 34 The spontaneous cessation of recurrent pancreatitis despite well-preserved pancreatic function has been noted in some patients with nonalcoholic CP. 4 These exceptions to the rule remain to be clarified. We found no evidence in our study that surgery may delay the development of pancreatic insufficiency in ACP as postulated recently. 35 On the other hand, the progression of pancreatic dysfunction was virtually identical in the two series, supporting the notion that drainage procedures, as performed primarily in the present series, do not significantly affect the natural evolution of ACP. Alcohol abuse, in contrast to the use of narcotics, has no influence on the pain profile once the patient has reached advanced ACP. 2,27 However, the mortality rate and late-stage incapacity was three times higher in patients with continued alcohol abuse than in the subgroup with reduced alcohol intake or abstinence. These figures suggest that continued alcohol abuse rather than persistent pain plays a major negative role in the outcome of ACP. Survival data of our series of CP patients have been reported for ACP with or without surgery 2 and for ACP vs. nonalcoholic CP. 2,16 The cumulative survival in ACP averaged 50% at 20 years from onset, both in surgical and nonsurgical subgroups. 2 The data of the present study are not suitable for a survival analysis because many patients (n 83) were excluded for various reasons (see Study Design and Patients). Weight gain is often cited as evidence of success of pain-relieving surgery. In the present study, weight loss showed a biphasic curve with peaks in early- and end-stage ACP, interrupted by a transient weight gain, both in the surgical and nonsurgical series. The transient weight gain, on average 10.2 years after onset, is probably related to relief of pain. In both subgroups, however, the mean body weight later stabilized at a much lower level than the premorbid weight, probably because of diabetes and/or steatorrhea. Therefore, weight loss in ACP is probably multifactorial and intermittent rather than steadily progressive as suggested. 36 Additional studies on the relationship between pain and weight loss in CP are indicated, particularly because resectional surgery, usually considered to yield better results of pain relief, is accompanied by an increased risk of severe pancreatic dysfunction. 13 This may have an important impact on the patient s weight and nutritional status in the long-term evolution of ACP. In conclusion, we present a clinically based staging system of pain in ACP during the evolution from onset to end-stage disease. The data indicate that complete (permanent) pain relief regularly occurs in late-stage ACP either after selective surgical correction of local complications or spontaneously in uncomplicated ACP. Multicenter studies, based on a standardized protocol, are suggested to further define a common concept on pain mechanisms and to develop a rational strategy for surgical intervention. References 1. Comfort MW, Gambill EE, Baggenstoss AH. Chronic relapsing pancreatitis: a study of 29 cases without associated disease of the biliary or gastro-intestinal tract. Gastroenterology 1946;6: , Ammann RW, Akovbiantz A, Largiadèr F, Schüler G. Course and outcome of chronic pancreatitis. Longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology 1984; 82: Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP. 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