AGA technical review: Treatment of pain in chronic pancreatitis☆

Article Outline

• Abstract
• Methodology
• Medical treatment
  • Nonspecific supportive treatment
  • Suppression of pancreatic secretion
    • Inhibition of gastric acid secretion
    • Pancreatic enzymes
    • Octreotide
• Nerve block
• Reduction of oxidative stress
• Endoscopic treatment
• Surgical treatment
  • Decompression/drainage operations
  • Resection procedures
  • Surgical denervation
• Conclusion
• Acknowledgements
• References
• Copyright

Abstract 

This literature review and the recommendations therein were prepared for the American Gastroenterological Association Clinical Practice and Practice Economics Committee. Following external review, the paper was approved by the Committee on March 8, 1998.

GASTROENTEROLOGY 1998;115:765-776

Chronic pancreatitis comprises a spectrum of pancreatic disorders that range across a subclinical morphological derangement, intermittent inflammatory flares, chronic persistent pain, fibrotic obstruction of structures adjacent to the pancreas (bile duct, duodenum, and portal-mesenteric and splenic veins), and end-stage exocrine/endocrine failure. It is a disease with various causes (overwhelmingly alcohol abuse in the United States but also duct obstruction from tumors and strictures, hypercalcemia, hyperlipidemia, genetic mutations, and perhaps dietary or other environmental aberrations) and, in a substantial number of cases, no currently identifiable predisposing factor. Some investigators believe that the accumulated parenchymal injury from repeated attacks of acute pancreatitis may result in a form of chronic pancreatitis, although the prevailing opinion is that acute pancreatitis such as induced by passage of a gallstone is both pathogenetically and morphologically different from chronic pancreatitis. The onset of symptoms may be in childhood, after a decade of exposure to the inciting toxin, or late in life. The peak presentation occurs in patients in their middle years, ages 35 to 55.

The morphological and histological changes that characterize the disease are also extremely variable. Although the sobriquet pancreatitis implies inflammation, acute inflammatory changes are usually episodic and often absent. Fibrosis and some chronic inflammatory cell infiltration are the hallmarks of the disease.¹ Calcifications (stones), which are intraluminal precipitates of calcium carbonate and proteinaceous secretions, occur in roughly half of the patients, more often in alcoholic than in idiopathic chronic pancreatitis and usually in a late stage of the disease,² although the latter may not be a reliable observation.³ The pancreatic ducts, especially the main duct, may progressively dilate or become irregularly constricted by fibrotic encasement. It is believed that the pancreatic ducts may seem normal at pancreatography in some cases, perhaps early in the disease, despite severe symptoms of pain.⁴, ⁵, ⁶ In late stages, imaging tests that show pancreatic calcifications, dilated irregularly distorted pancreatic ducts, changes in gland texture, or pseudocysts and functional deficits in fat absorption or glucose intolerance can leave little doubt to the process. In other cases, any and all of these findings may be subtle, absent, or conflicting. Safe percutaneous biopsy is generally not feasible or reliable, and adequate tissue or histological confirmation is available only in patients subjected to surgical excision. A system of stratification or subgrouping of patients by morphological or functional criteria has never been agreed upon.⁷ As a consequence, the basis for inclusion of patients in trials of therapy are inconsistent and in some instances questionable.

Pain, by far the most common and recalcitrant indication for medical treatment, is not only difficult to quantify, but the assessment of its significance and impact is often clouded by addiction to alcohol and narcotic analgesics as well as by the personality disorders underlying these dependencies. Just as the disease has different causes and different morphological expression, pain in chronic pancreatitis is a highly variable phenomenon: intermittent, frequent, or persistent; mild, moderate, severe, or absent; increasing or decreasing over time. The mechanism of pain in chronic pancreatitis is incompletely understood and perhaps multifactorial, including inflammation, duct obstruction, high pancreatic tissue pressure (compartment syndrome),⁸ fibrotic encasement of sensory nerves, and a neuropathy characterized by both increased numbers and sizes of intrapancreatic sensory nerves and by inflammatory injury to the nerve sheaths allowing exposure of the neural elements to toxic substances.⁹, ¹⁰ The view that chronic pain will subside in a substantial number of patients with or without organ failure as the disease progresses to the point of organ failure (burnout)¹¹ has been widely accepted, but that process may take an unpredictable number of years or may never occur. Some studies suggest that the likelihood of spontaneous pain relief is low.¹²

It should not be surprising in view of this array of uncertainties that treatment of chronic pancreatitis has been strategically haphazard, ill-directed, too often unsuccessful, and controversial. Adding to the controversy are an array of treatment options that can be provided by primary care physicians, gastroenterologists, interventional endoscopists, and surgeons. Despite the new tools of imaging and accessing the pancreas in the last two decades (ultrasonography, endoscopic ultrasonography, computerized tomography [CT], magnetic resonance cholangiopancreatography, endoscopic cholangiopancreatography, stenting of the bile duct and pancreatic duct, and fine-needle aspiration), no consensus has emerged, and most reports are either anecdotal or collected experiences of a single approach.

It is the purpose of this technical review to focus principally on the treatment of pain in chronic pancreatitis when there is no obvious abnormality to remedy. Pseudocysts and obstruction of the bile duct, duodenum, and major peripancreatic veins will be considered only in association or in passing inasmuch as the rationale for treating these entities is better defined and agreed upon. Management of diabetes or steatorrhea per se will not be discussed. The differential diagnosis from cancer of the pancreas is of self-evident importance but is outside the scope of this analysis.

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Methodology 

The literature on treatment of pain in chronic pancreatitis is replete with and characterized by retrospective collections of patients who were subjected to treatment determined by interest in applying a certain method and evaluating, usually in vague subjective terms, whether that treatment worked. Whereas the benchmark for assessing effectiveness of treatment in clinical studies is the performance of a randomized, prospective, double-blind, placebo-controlled trial, few studies of the treatment of pain in chronic pancreatitis have embraced this standard.

For this technical review we have focused on selected articles published in high-quality refereed journals during the past 15 years. We have included data published in abstract form only when the information is new, important, and evaluable but unavailable in a more complete version. Before selecting studies for inclusion, we have determined the criteria that we felt to be essential for the evaluation of pain before treatment (Table 1) and criteria for evaluating the methodology of the study and reporting of results (Table 2). We then chose 22 articles on medical (nonsurgical) therapy published between 1984 and 1997 that best met the predetermined criteria. To exemplify the shortcomings of even these “best” studies, we then reanalyzed each according to those same criteria and tabulated how well each performed.

Table 1. Criteria for the evaluation of pain

Table 2. Criteria for methodology of the study and reporting of results

For the pretreatment evaluation of pain (Table 3), only 4 of the 22 articles provided information regarding the evaluation of addiction to narcotics, 4 provided measures of quality of life, and 10 included adequate information regarding the duration of pain dating back to the first episode. Regarding the 14 criteria for methodology (Table 4), 6 provided information regarding the continued consumption of alcohol, 7 provided a formal assessment of pain at the onset of treatment, 9 provided information on the existence of diabetes and 11 on steatorrhea, 10 were blinded, and only 12 were prospective.

Table 3. Evaluation of the use of defined criteria from table 1 to evaluate pain in studies of chronic pancreatitis and its nonsurgical treatment

NOTE. Each column lists the numbers of articles using the stated criterion.

Data from references 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 31, 32, 33, 34, 35, 36, 41, 42, 43, 85.

Table 4. Evaluation of the use of defined criteria from table 2 for methodology and reporting used in medical studies of chronic pancreatitis and its nonsurgical treatment

NOTE. Each column lists the numbers of reports in which these criteria are present or evaluable.

Data from references 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 31, 32, 33, 34, 35, 36, 41, 42, 43, 85, and 85.

Tables 5 and 6 show a derivation of the same criteria applied to the description of preoperative pain in studies of patients chosen for surgical treatment. These studies were culled from the surgical literature using the same predetermined criteria. In addition, a pain evaluation score (PES) was derived for these tables by allocating one point for each criterion met. It again shows the deficiencies of the best available studies. Only 2 studies contained a formal quality-of-life assessment. Only 3 of 22 nonsurgical studies and 6 of 15 surgical studies required an evaluation period of at least 1 year after treatment. Only 3 were randomized between treatment options, and only 1 compared surgical with nonsurgical treatment.

Table 5. Surgical drainage operations

Table 6. Surgical resection procedures

DPRPH, duodenum-preserving resection of pancreatic head; FBS, fasting blood sugar; PPW, pylorus-preserving Whipple.

As a consequence, we were required to use less stringent criteria for the selection of our database while still attempting to extract the analyses most likely to provide evaluable information.

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Medical treatment 

Options for medical treatment are listed in Table 7.

Table 7. Potential medical methods of treating pain in chronic pancreatitis

Expectant (nonspecific) therapy

Analgesics

Antidepressants

Decrease intrapancreatic pressure

Suppress secretion

Proton pump inhibitor or H2-blocking agents

Pancreatic enzymes

Octreotide

Relieve obstruction

Stents

Elimination of pancreatic stones

Modify neural transmission

Reduce oxidative stress

Antioxidant therapy

Allopurinol

Nonspecific supportive treatment 

Most patients with chronic pancreatitis have their pain treated with analgesics on an episodic or continuing basis, and most never come to the perceived need for surgical treatment. Obviously supportive therapy is directed at treating the concurrent symptoms, or the induced narcotic addiction, and not the underlying factors in pain causation. The remainder of this analysis will be directed at those factors.

There may be significant psychiatric, psychosocial, or psychosomatic contributions to the pain syndrome in these patients. Although acknowledging the difficulty in assessing the contribution of such components, many physicians and surgeons use antidepressant medications as adjuncts to therapy. The benefits are anecdotal and variable in any individual experience and have never been rigorously assessed. It has been suggested, principally by Ammann et al.,¹¹ that the natural path of chronic pancreatitis is toward progressive glandular insufficiency and calcification, and with the eventual burnout would come spontaneous remission of pain. Others have questioned whether that conservative strategy is acceptable; because of the uncertainty regarding the duration, pain must be endured until burnout or whether pain relief would ever occur.¹², ¹³ A recent revisitation to this concept¹⁴ found that the severity and frequency of pain decreased in patients with either idiopathic or alcoholic pancreatitis followed for a median of at least 12 years; 64%–77% of patients improved, but the magnitude of the improvement (i.e., decrease vs. disappearance of pain) is not given. In contrast to the study cited above,¹¹ the remission of pain occurred independently of pancreatic calcification and the appearance of exocrine or endocrine insufficiency. This group, along with some others, has called attention to the subsets of chronic pancreatitis (alcoholic vs. nonalcoholic; early vs. late onset) with differences in natural history that may impact the outcomes of studies with mixed populations.

Lankisch et al.¹² confirmed a significant reduction in pain over time but found that more than 50% of patients followed for a median of 9 years still had significant pain after 10 years of observation. Although alcoholics were slightly more likely to experience pain relief than nonalcoholics with the appearance of exocrine failure, 54% of alcoholics and 73% of nonalcoholics still experienced attacks of pain despite exocrine insufficiency requiring enzyme replacement, and there was no pain reduction with the development of severe endocrine insufficiency. Although reports of the effect of abstinence from alcohol have varied, this same group¹⁵ found no greater likelihood of pain relief with abstinence.

We conclude that a strategy of waiting for spontaneous pain relief is not reliable and may be unreasonable advice for the patient with persistent or frequent severe pain. Most studies do not describe pain in a detailed or quantitative fashion and standards have not been validated. Pending such future investigations, the judgments made about appropriate therapeutic response to pain remain just that: judgmental.

Suppression of pancreatic secretion 

Inhibition of acid secretion with H₂-receptor blocking agents or a proton pump inhibitor will lead to a higher duodenal pH and may therefore reduce a stimulus-driving pancreatic secretion. In theory these changes could decrease pancreatic pain, but thus far no studies have systematically addressed this therapeutic approach or shown it to be effective. Nonetheless, this approach is widely tried, perhaps because it is relatively easy and safe.

The presumed mechanism for pain relief after the administration of oral pancreatic enzymes is thought to involve negative feedback inhibition of the pancreas. A cholecystokinin (CCK)-releasing peptide in the duodenum is normally denatured by pancreatic trypsin. In chronic pancreatitis, damage to acinar cells results in decreased secretion of pancreatic trypsin and consequently insufficient denaturing of the CCK-releasing peptide. This in turn allows an increased release of CCK, which causes pancreatic pain by mechanisms that are unclear but presumably relate to an increase in pancreatic enzyme output. When pancreatic enzymes are administered orally, there is more complete denaturing of the CCK-releasing peptide, thereby diminishing the release of CCK.¹⁶, ¹⁷

A total of 6 randomized prospective double-blind studies involving 193 patients have been published on the effectiveness of pancreatic enzymes in relieving pain in chronic pancreatitis, 5 in refereed journals,¹⁸, ¹⁹, ²⁰, ²¹, ²² and 1 in abstract form.²³ Two trials using an enzyme preparation in tablet form¹⁸, ¹⁹ reported benefit. Four studies using an enzyme preparation in capsule form reported ineffectiveness of pancreatic enzyme therapy.²⁰, ²¹, ²², ²³ The heterogeneous composition of the patient populations with regard to the fraction with alcoholic vs. nonalcoholic pathogenesis make direct comparison of the studies difficult and may have influenced the outcomes in part. Most of these studies provided neither information regarding duration and character of pain nor a measure of quality-of-life. In addition, although blinded and prospective, a formal assessment of pain at the onset of the study was not provided in any of these reports. The importance of a randomized, prospective double-blind format for a study is illustrated in 2 reports. In 1 study²² that lasted 8 months, 6 of 26 patients who had been experiencing recurrent pancreatic pain did not experience any pain attacks over the entire study period. In all patients, regardless of whether pancreatic enzymes or a placebo were given in the first 4 months, there was an overall reduction in cumulative pain score with time. In a second study,²³ patients who received pancreatic enzymes and those who received placebo both experienced relief of pain when compared with the preintervention control.

One reason for ineffectiveness in 4 of the 6 studies has been attributed to the use of enzyme preparations in capsule form. Although the feedback mechanism is sited in the duodenum, it is possible that encapsulated enzymes may not be released until they reach the jejunum. However, there has been documentation that the enzymes used in capsule form in 2 of the 4 studies are in fact released in the duodenum and presumably would be available to inhibit stimulation of pancreatic enzymes.

The role of oral pancreatic enzymes in reducing pain in chronic pancreatitis therefore remains unclear. Additional studies are required to establish the effectiveness of this modality of treatment and to define whether certain subsets (chronic vs. intermittent pain, patients with or without exocrine insufficiency, alcoholic vs. idiopathic pancreatitis, minimal vs. extensive pancreatic duct changes) are more likely to benefit from enzyme therapy than others.

In a randomized, prospective, double-blind, placebo-controlled study conducted in Europe, octreotide (100 μg subcutaneously [SC] every 8 hours) administered to 10 patients for only 3 days was no more effective than placebo in relieving pain in chronic pancreatitis.²⁴ Although this study did provide a formal assessment of pain at the onset and was randomized and prospective, the medication was administered for only a very brief period of time. In a second study,²⁵ octreotide (100 μg SC every 8 hours for 3 weeks) administered to 6 patients in a nonblinded fashion provided relief of pain in some but not all patients. In a third study,²⁶ octreotide was administered to 84 patients for 4 weeks in a randomized, prospective, double-blind trial and showed a trend toward benefit at the highest dosage used (200 μg SC every 8 hours). However, this effect did not reach statistical significance in this dose-ranging study. The longevity of the possible benefit was not determined. Also, octreotide injections are painful, expensive, and at times poorly tolerated by some patients. Until further randomized prospective trials are performed, octreotide cannot be recommended for general use.

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Nerve block 

Although widely used, there have been relatively few formally reported experiences with nerve blocks for long-term therapy of chronic pancreatitis.²⁷, ²⁸, ²⁹ Leung et al.,²⁹ who studied the use of celiac block with alcohol, reported that 11 of 13 cancer patients had complete pain relief initially but only 12 of 23 with chronic pancreatitis had complete analgesia, whereas 6 had partial relief. The mean pain-free period achieved in chronic pancreatitis patients was only 2 months and the longest was only 4 months. Repeated blocks were not effective. Because of possible concerns about potential irreversible nerve injury (including very rare anecdotes of paraplegia) from neurolytic agents, principally alcohol as used for treatment of cancer pain, injection of steroids into the celiac plexus has been recommended instead.²⁸ In 1 study, steroid injection provided relief of pain (lasting 2 months) in only 4 of 16 patients.²⁷ Eleven of the 12 patients who did not obtain relief were narcotic dependent, whereas none of the 4 who obtained relief were narcotic dependent. This finding emphasizes the complexity of treating pain in a population of patients with chemical dependencies and other abnormal illness behavior. In another report,³⁰ which investigated the mode of delivering the nerve block, only 2 of 8 patients with a CT-guided celiac plexus block experienced relief of pain compared with 6 of 14 who were treated by endoscopic ultrasonography-guided celiac plexus block with 10 mL of bupivacaine 0.25% followed by (40 mg) 3 mL of triamcinolone injected into both sides of the celiac plexus. The benefit from endoscopic ultrasonography–guided celiac plexus block seemed to persist longer than CT-guided block. Additional studies are clearly needed to validate these results.

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Reduction of oxidative stress 

There have been 2 reports on measures to relieve oxidative stress in the pancreas in an effort to improve pain in chronic pancreatitis. In one study,³¹ 20 patients with chronic pancreatitis were given antioxidant therapy (600 μg of organic selenium, 9000 IU of β-carotene, 0.54 g of vitamin C, 270 IU of vitamin E, and 2 g of methionine daily) in a double-blind, dummy crossover trial that lasted 30 weeks. Patients were enrolled if they had at least two documented attacks of pain in the previous year and/or if they had consistent pain thought attributable to chronic pancreatitis. Six of the 20 patients experienced an attack of pancreatitis while on placebo compared with none while on active medication. It was not stated whether the 6 patients who developed an attack had been experiencing intermittent or persistent pain. Of some concern is the fact that the patient population seemed to be quite heterogeneous: 5 patients were described as having recurrent acute pancreatitis rather than chronic pancreatitis; 4 underwent endoscopic retrograde cholangiopancreatography (ERCP) that showed no abnormalities or only minimal changes in side branches; and 2 documented abdominal pain in their diaries but did not present themselves for clinical evaluation. Additional studies will be required to evaluate the role of antioxidant therapy to relieve pain of chronic pancreatitis. In a second study,³² allopurinol, which is believed to reduce oxidative stress by inhibiting xanthine oxidase and thereby preventing the formation of oxygen-derived free radicals, was given to 13 patients with pain occurring at least three times each week. This was a randomized, double-blind, two-period crossover trial. Allopurinol was not effective in reducing pain or improving activities of daily living. On the basis of these 2 published studies, there is insufficient evidence to endorse either direct antioxidant therapy or indirect blockade by allopurinol for the purposes of relieving pain in chronic pancreatitis.

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Endoscopic treatment 

Endoscopists have shown that they can overcome pancreatic duct obstruction caused by ampullary stenosis, strictures, or stones. However, there have been no published validated guidelines for defining significant obstruction, and methodology for assessing patients before treatment and judging the efficacy of treatment has been inadequate (Table 1, Table 4). Because any intervention carries finite risk, guidelines are needed to quantify the need for an intervention. For the present, such decisions are based partially on subjective judgments that include assessment of the need for long-term narcotic therapy, marked diminution of the quality of life because of intractable pain, or major nutritional consequences of pain. When major pain episodes cannot be controlled by acceptable maintenance analgesics, intervals of narcotics, or reasonable and brief periodic hospitalizations, a trial of interventional therapy can be justified.

There have been numerous reports suggesting that the endoscopic placement of stents within the pancreatic duct relieves recurrent or persistent pain associated with chronic pancreatitis in the majority of patients.³³ Among 3 recent studies involving stent therapy in 98 patients, at times associated with other interventional therapies such as lithotripsy and/or sphincterotomy,³⁴, ³⁵, ³⁶ 2 studies³⁴, ³⁶ reported amelioration of pain and 1 did not.³⁵ Of particular note was the fact that none of the 3 studies was blinded, prospective, or provided a formal assessment of pain before the initiation of the study. Also, none of the studies indicates the characteristics of the optimal candidates for stent therapy. The possible benefits conferred by pancreatic duct stenting also need to be balanced against the risk of causing damage to the duct and complicating the course of the disease. Two recent studies³⁷, ³⁸ emphasized that 50%–80% of patients who have polyethylene stents placed in the pancreatic duct for even a relatively short time (1–8 weeks) suffer significant ductal and parenchymal injury. Smith et al.³⁷ noted that complete resolution of the injury occurred in only 64% of patients after removal of the stents. Notwithstanding enthusiasm among some interventional endoscopists for stent therapy for relief of pain in chronic pancreatitis, additional studies are required to validate the treatment tactic. Until further information is available, prolonged stenting of the pancreatic duct should be used only in centers with a focus on pancreatic disease and in the setting of a clinical trial.

In addition to stenting, a variety of methods have been applied to eliminate intraductal pancreatic stones, including lithotripsy and pancreatic duct sphincterotomy with extraction by catheter techniques.³³ Marked improvement in pain has been reported with use of these techniques, and this improvement has apparently correlated with resolution of pathological pancreatic duct dilation. In 6 recent studies using lithotripsy and/or stone extraction,³⁹, ⁴⁰, ⁴¹, ⁴², ⁴³, ⁴⁴ a total of 328 patients were treated. Of particular note is that only 1 of these studies was prospective, none were blinded, and none provided a formal assessment of pain before the onset of the study. Kozarek and Traverso⁴⁵ have analyzed collected experiences and indicate that the likelihood of symptomatic improvement with combination endotherapy is reported to be 50%–85% at 15–25 months. Successful pain relief has been correlated anecdotally with stone removal and subsequent decrease in diameter of the pancreatic duct. As a rule, the focus is on stones in the main duct and the morbidity of side-branch stones has not been defined.

The claims for the efficacy of stone removal for pain relief should be considered in the context of the observations that the presence or absence of stones does not necessarily correlate with the existence of pain. In the absence of randomized prospective trials comparing stone ablation either with placebo or with surgical decompression, it is difficult to assess the anecdotal results of pancreatic stone removal. It will also be important to determine whether removal of stones is cost-effective. In summary, although studies using removal of stones have provided some encouraging observations, substantiation is awaited.

Endoscopic drainage of pseudocysts into the stomach and duodenum is now widely practiced and often effective. This literature was not evaluated.

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Surgical treatment 

Efforts to treat the pain of chronic pancreatitis by surgical means began in earnest in the 1950s with transduodenal sphincteroplasty and with caudal pancreatojejunostomy (the DuVal procedure), both of which gave variable and usually poor results, perhaps only helping some of those patients with true recurrent acute pancreatitis.⁴⁶, ⁴⁷ A more extensive drainage procedure, lateral pancreatojejunostomy, described by Puestow and Gillesby⁴⁸ and subsequently modified by Partington and Rochelle,⁴⁹ was applied to the subset of patients with dilated main pancreatic duct and became the first surgical treatment widely considered to be effective for pain in this disease. At that time, however, its application was hampered because there was no way to determine preoperatively if a patient with chronic pancreatitis had the dilated ducts required for this procedure because neither ERCP or CT were available until the 1970s. Thus, at exploration an intraoperative pancreatogram was used to select who would be candidates for lateral pancreatojejunostomy. In those without dilated ducts, the remaining options were to perform a sphincteroplasty (which was largely abandoned because of its failure) or to do nothing further. In the 1960s, surgeons began performing pancreatic resections for chronic pancreatitis, initially distal pancreatectomies (with poor results) and later distal subtotal (95%) resections, which were relatively more effective for pain but rendered most patients diabetic.⁵⁰ Proximal resections of the head of the pancreas (i.e., Whipple procedures) were not widely applied until the 1980s, when the associated operative morbidity and mortality fell quite substantially.⁵¹, ⁵², ⁵³, ⁵⁴

Like most surgical procedures currently in use, those for chronic pancreatitis gradually became part of the armamentarium without undergoing rigorous testing and were never compared against medical treatment or no treatment. The vast majority of patients are still operated on when they continue to have intractable pain despite medical treatment. There are very few controlled trials in the surgical literature on this disease. Surgical options include decompression/drainage operations, pancreatic resections, and denervation procedures. As with endoscopic interventional therapy, objective transferable criteria for the need for surgical intervention have not been developed or agreed upon.

Decompression/drainage operations 

These operations are predicated upon the presence of a widely dilated main pancreatic duct (generally taken as >6–7 mm) and the presumption that the dilated ducts imply an abnormally high pressure in the duct system⁵⁵ and in the pancreatic parenchyma.⁵⁵, ⁵⁶ The operation most commonly performed is a variant of the Puestow procedure, which is actually the Partington–Rochelle modification (lateral pancreaticojejunostomy).⁴⁹

From the many published series, we have selected 5,⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹, ⁶⁰ either because of the large number of patients studied and the adequate duration of follow-up evaluation, or because of the better quality of pain assessment (Table 5). These (and other) series find that short-term pain relief is achieved in about 80% of patients and that the operation can be performed with a very low morbidity and mortality (0%–5%). Series with long-term follow-up show that pain not uncommonly recurs as time goes by, perhaps related to progression of the pancreatic injury and fibrosis. Pain relief persists for more than 2 years in only 60% of patients.⁵⁸, ⁶¹ Strategies for salvage in patients with persistent or recurrent pain after drainage procedures include reperforming or extending the pancreatojejunostomy and resection procedures.⁶² Twenty-five percent to 66% of patients undergoing pancreatic duct drainage procedures require concomitant biliary or gastric drainage because of functionally significant obstruction of the bile duct or duodenum.⁶³, ⁶⁴ Biliary or duodenal strictures have been reported to be more likely in patients with large-duct disease than in their counterparts without dilated ducts.⁶⁴

The series by Ebbehoj et al.,⁵⁶ although modest in number, is particularly interesting because it shows a correlation between the magnitude of pain and intrapancreatic pressure. These investigators measured pancreatic pressure by a percutaneously placed needle preoperatively, postoperatively, and 1 year after pancreatic duct drainage. Patients whose pressure decreased after surgery and remained low were pain free, whereas those with recurrent pain had increased pressure.

The only reported attempt made to compare pancreatic duct drainage with no intervention in the management of pain is that of Nealon and Thompson.⁶⁵ In a series of 143 patients with well-documented chronic pancreatitis, 85% of the 87 patients who were treated by pancreatic duct decompression achieved pain relief, whereas pain abated spontaneously in only 1.3% of the 56 nonoperated patients. The study was not randomized, however, and the principal criterion to determine candidacy for the operation was the presence of a dilated pancreatic duct. Thus, what the study actually reports is the outcome of pancreatojejunostomy in patients with dilated ducts vs. the natural history of patients with chronic pancreatitis and no duct dilation. The study also found that deterioration of pancreatic function was slower in their patients with dilated ducts than in those with small ducts. Although this effect was ascribed by the investigators to the protection or relief afforded by the surgical drainage procedure, the cause and effect relationship is uncertain because of the differences in the patient population.

The consensus, albeit based on evidence from collected experiences, states that pancreatic duct decompression via lateral pancreatojejunostomy (a Puestow-type operation) can be accomplished with low associated morbidity and mortality and that pain relief will be achieved in the majority of patients, often quite completely. For most experienced pancreatic surgeons, it is the preferred surgical treatment option in patients whose main pancreatic duct measures 6 mm or more because of its simplicity, safety, and benefits, including the advantage that remaining pancreatic tissue and function are at least not compromised further by loss from resection.

Drainage of pancreatic pseudocysts provides another form of pancreatic decompression in conjunction and even in continuity with a lateral pancreatojejunostomy when the main duct is also dilated. Up to 39% of patients undergoing lateral pancreaticojejunostomy have evidence of pseudocyst disease at the time of surgery.⁶⁶ Pseudocysts are found in about 25% of patients with chronic pancreatitis and have a much lower rate of spontaneous resolution than those that are a consequence of an attack of acute pancreatitis.⁶⁶, ⁶⁷, ⁶⁸ They can be the source of pain indistinguishable from that of the underlying chronic pancreatitis. In 1 study, surgical drainage resulted in complete short-term pain relief in 96% of 55 patients, and 53% remained pain free after a median follow-up of 11 years.⁶⁸ Endoscopic drainage of pseudocysts into the stomach or duodenum may be an alternative, especially in patients who do not have associated duct dilation.

Resection procedures 

Patients with pain whose ducts are not dilated are not considered candidates for drainage procedures by most pancreatic surgeons. This is due in part to technical difficulties of creating and maintaining patency of the anastomosis to a small duct buried in fibrous and inflamed parenchyma. The failure rate (as measured by inability to reduce pain) is thought to be unacceptably high when the main pancreatic duct is <6 mm in diameter. In patients with small ducts, the surgical alternative has been pancreatic resection. We have selected 2 series each on the use of the Whipple procedure or pylorus-preserving pancreaticoduodenectomy, distal pancreatectomy, and total pancreatectomy and 2 on the duodenum-preserving resection of the pancreatic head (Table 6). The only randomized trials comparing two resection procedures in chronic pancreatitis (duodenum-preserving resection of the pancreatic head vs. pylorus-preserving Whipple resection or vs. a more limited excision of part of the pancreatic head) are also included in Table 6.⁷⁷, ⁷⁸

These (and many other studies that were not included) show that distal pancreatectomy alone has poor results unless the disease is largely confined to the body and tail of the gland, e.g., with an occlusion of the midpancreatic duct or with a pseudocyst in the tail. By contrast, resection of the pancreatic head by either a conventional or pylorus-preserving pancreaticoduodenectomy will provide pain relief in up to 85% of patients, even if the disease extends into the distal pancreas. The 2 series on total pancreatectomy, notable in that pain relief is still not obtained in all patients, underscore the complexities of managing patients with long-standing pain, who frequently have personality disorders and chemical dependencies. Total pancreatectomy is usually reserved as a last resort following a failed partial pancreatic resection.

The duodenum-preserving resection of the pancreatic head has been used mostly in a few European centers.⁷⁵, ⁷⁶ The procedure seems to be more demanding technically than the Whipple operation and has similar results for pain relief. The purported benefits of better postoperative nutritional status and glucose control in the duodenum-preserving procedure were addressed in 2 randomized trials.⁷⁷, ⁷⁹ Unfortunately, the short follow-up, the inordinately low incidence of pain relief in patients with the pylorus-preserving operation, and the lack of a blinded observer to evaluate results weaken the first study.⁷⁷ In the second, pain outcomes are not given and the stated advantages of more rapid convalescence and better nutritional and endocrine status are insignificant.⁷⁹ Frey and Amikura have recently reported a surgical modification that combines removing part of the anterior segment of the pancreatic head with longitudinal duct anastomosis to the jejunum.⁸⁰ A randomized trial⁷⁸ found little difference between the Frey procedure and the duodenum-preserving resection of the pancreatic head as described by Beger and Buchler.⁷⁵

Resection of pancreatic tissue results in the loss of some exocrine and endocrine function and increases the possibility or hastens the onset of fat malabsorption and diabetes. Whereas only 20% of normal pancreatic tissue is required for clinically adequate function, the pancreas already damaged by chronic pancreatitis may have substantially reduced reserves even before resection. Because of the complete lack of insulin and glucagon after total pancreatectomy, a very brittle diabetes may ensue and can be the source of considerable morbidity and even mortality. In an attempt to lessen these adversities, autotransplantation of either part of the organ⁸¹ or of islet tissue⁸² has been described. In the latter study, Farney et al. obtained insulin independence in 20% of 24 patients at a mean follow-up of 5.5 years. At this time the technical problems of islet or whole organ transplantation have not been sufficiently solved to consider these approaches more than experimental.

Almost all series on pancreatic resection and even some of those drainage procedures show that a proportion of patients (up to 15% in some series) thought to have chronic pancreatitis will be found to have pancreatic cancer,¹¹, ¹⁵, ⁶², ⁷² and it has recently been shown that a chronic pancreatitis is in fact a small but real risk factor in promoting the development of cancer.⁸³ This is an important consideration to keep in mind during the diagnostic work-up and choice of operation. The morphology of the pancreas by CT imaging and by cholangiopancreatography may fail to discriminate between cancer and chronic pancreatitis. A long or sharply marginated pancreatic duct stricture and a marked elevation of serum carbohydrate antigen 19-9 are suggestive, but either may be absent and neither is reliable. Cytological confirmation by fine-needle aspiration is helpful when positive (80%–90%), but the true diagnosis may become known only with resection. This consideration in some cases may determine the treatment strategy.

Noteworthy in recent years has been the very low operative morbidity and mortality of pancreatic resection, which may be one reason for the larger numbers of patients with benign disease being referred for surgical treatment. In a recent series of 231 pancreatic resections, the most frequent indication being chronic pancreatitis, the operative mortality was 0.4%.⁵⁴ McLeod et al.⁸⁴ studied the morbidity of the Whipple operation. Although the study focussed on resections for neoplasms, the observations pertain as well to those for chronic pancreatitis and show satisfactory digestion, weight maintenance, and activity level in the great majority of patients. A study of quality of life after pancreatic resections found that diabetes and its complications had the greatest negative influence on everyday well-being.⁸⁵

Surgical denervation 

Most of the sensory nerves returning from the pancreas pass through the celiac ganglion and splanchnic nerves. It is hypothesized that interruption of these fibers may lessen pain. Mallet-Guy⁸⁶ reported an extensive experience with 215 patients over 30 years whose principal treatment for pain was by sensory denervation. These patients first underwent abdominal exploration to document the absence of pancreatic ductal dilation or pseudocysts and to correct any associated biliary pathology; this was immediately followed by resection of the greater splanchnic nerve and celiac ganglion through a left translumbar approach. Although excellent long-term results are reported (90% of patients were pain-free, with 60% followed for more than 5 years), the heterogeneity of the patient population and the simultaneous use of biliary diversion procedures in many cases precludes meaningful conclusions. This treatment has not been widely accepted.

In a more recent experience, Stone and Chauvin reported on 15 patients with chronic pancreatitis who had previous unsuccessful operative procedures for pain.⁸⁷ Denervation was accomplished with a transthoracic left splanchnicectomy with concomitant vagotomy, and all 15 patients had immediate pain control. Five later suffered recurrent pain but were successfully treated with a right splanchnicectomy. The long-term outcomes are not known.

The advent of thoracoscopic surgery has made this procedure more attractive, and a few small series have reported its feasibility and early results.⁸⁸, ⁸⁹ Maher et al. recently reported on 15 patients with chronic pancreatitis, mostly idiopathic, with chronic pain measured by visual analogue pain scale.⁹⁰ Unilateral thoracoscopic splanchnic nerve resection in 8 patients and bilateral in 7 patients resulted in significant decreases in pain frequency and intensity, as well as in narcotic consumption. Overall, 80% of patients had good results or were improved, with a mean follow-up of 16 months. A controlled trial comparing this procedure to other surgical options or to medical treatment is needed. Of note, pancreaticoduodenectomy and duodenum-preserving resection of the pancreatic head may well confer pain relief at least in part through denervation.

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Conclusion 

This review of medical and surgical treatment of patients with pain due to chronic pancreatitis indicates, at least to the authors, that a reliable database for making sound judgments and recommendations is lacking in most areas. The methods of evaluating patients and reporting results are inconstant and inadequate,⁹¹ in large part due to the variability of the pathological anatomy and natural history, the multiple potential influences on outcome, and the lack of agreed-upon objective criteria for pain measurement. To add to the difficulty, there are few well-defined prospective trials of therapy, either in comparison with no therapy or with competing therapy. As a consequence, the current state of the art is just that: dependence on art (experience and judgment) and perhaps philosophy rather than science. While there have been positive anecdotal reports and institutional experiences, no nonsurgical therapy has been validated by a prospective trial or reproducibly been proven effective. Similarly, surgical treatments seem to be effective for some patients, but there is no consensus regarding the criteria for patient selection or the choice of operation.

In the absence of data we conclude that the first line of therapy for pain in chronic pancreatitis should be noninjurious. Reasonable levels of analgesics for maintenance or episodic exacerbations are acceptable on a chronic basis. Antidepressant therapy may be helpful in some cases. High-dose pancreatic enzyme therapy carries no risk and may be helpful to some patients. Pain that significantly reduces the quality of life or ability to carry on normal social and work functions, especially if it requires long-term narcotics, may indicate the need to consider interventional therapy.

Endoscopic stents and lithotripsy should be considered with the same caution as surgical procedures. We agree with those endoscopists who advise that such treatments should for the present be conducted under the auspices of studies. Nerve ablation, whether by percutaneous, endoscopic, or surgical means, must still be considered unproven and ineffective for long-term pain control.

Surgical treatment should be considered for the minority of patients with intolerable and continuing pain unresponsive to medical measures. Current consensus among surgeons is that a drainage operation (i.e., lateral pancreaticojejunostomy) is safest and most likely to be effective in patients with a main pancreatic duct >6 mm in diameter. Patients with smaller pancreatic ducts may benefit from resection of the pancreatic head.

This Technical Review has been endorsed in principle by the American Association for the Study of Liver Disease and the American College of Gastroenterology.

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Acknowledgements 

The Clinical Practice and Practice Economics Committee acknowledges the following individuals whose critiques of this review paper provided valuable guidance to authors: Richard Kozarek, M.D., Eugene DiMagno, M.D., and Chung Owyang, M.D.

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