Scott Bolesta and Patricia A. Montgomery
KEY CONCEPTS
ACUTE PANCREATITIS
Factors that can contribute to acute pancreatitis should be corrected, including discontinuation of medications that could be potential causes.
Patients with acute pancreatitis without the systemic inflammatory response syndrome should receive aggressive fluid replacement, but goal-directed therapy has not been defined.
Patients with severe acute pancreatitis and the systemic inflammatory response syndrome require early and aggressive IV fluid resuscitation and should be managed similarly to patients with sepsis.
Parenteral opioid analgesics are used to control abdominal pain associated with acute pancreatitis.
The only definitive indication for antibiotic use in acute pancreatitis is to treat known or suspected infection.
CHRONIC PANCREATITIS
Chronic pain, malabsorption with resultant steatorrhea, and diabetes mellitus are the hallmark complications and symptoms of chronic pancreatitis.
Pain from chronic pancreatitis can initially be treated with nonopioid analgesics, but opioids will eventually be required as the disease progresses.
Reduction in dietary fat intake and pancreatic enzyme supplementation are the primary treatments for malabsorption due to chronic pancreatitis.
Enteric-coated pancreatic enzyme supplements are the preferred dosage form in the treatment of malabsorption and steatorrhea due to chronic pancreatitis.
The addition of an antisecretory agent to pancreatic enzyme supplementation may increase the effectiveness of enzyme therapy for malabsorption and steatorrhea due to chronic pancreatitis.
Pancreatitis is inflammation of the pancreas with variable involvement of regional tissues or remote organ systems.1,2 Acute pancreatitis is characterized by severe pain in the upper abdomen and elevations of pancreatic enzymes in the blood.2 In the majority of patients, acute pancreatitis is a mild, self-limiting disease that resolves spontaneously without complications. Approximately 20% of adults with acute pancreatitis have a severe course, and 10% to 30% of those with severe acute pancreatitis die.1,2 Severe pancreatitis with either organ failure or infected necrosis is associated with a mortality of approximately 30% and it increases when both are present.3 Although exocrine and endocrine pancreatic functions may remain impaired for variable periods after an attack, acute pancreatitis usually does not progress to chronic pancreatitis.4
Chronic pancreatitis is characterized by long-standing inflammation that eventually leads to a loss of pancreatic exocrine and endocrine functions.4–6 It is a progressive disease that often goes unnoticed for many years. Usually patients first present with complaints of chronic abdominal pain. Later in the disease process malabsorption with resultant steatorrhea occurs. This leads to malnutrition and weight loss. Finally, patients develop diabetes mellitus due to a loss of pancreatic endocrine function.4,5
EPIDEMIOLOGY
The prevalence of pancreatitis varies widely with geographic, etiologic (e.g., alcohol consumption), environmental, and genetic factors. Hospitalizations for acute pancreatitis have increased in the United States, most likely related to an increase in gallstones in association with obesity.7 Admission rates for acute pancreatitis are approximately 40 per 100,000 per year in the United States.7 Approximately 6 per 100,000 population will develop chronic pancreatitis with a peak incidence between ages 35 and 54 and about 85% of cases occurring in men.6 However, this incidence may be underestimated due to diagnostic difficulties and various classification systems. Also, the prevalence of chronic pancreatitis varies widely based on geographic location.4,6 Hospitalization for chronic pancreatitis has also doubled in the past decade with black patients being almost two to three times as likely to be hospitalized for chronic pancreatitis than for alcoholic cirrhosis.6
PANCREATIC EXOCRINE PHYSIOLOGY
The pancreas possesses both endocrine and exocrine functions. The islets of Langerhans, which contain the cells of the endocrine pancreas, secrete insulin, glucagon, somatostatin, and other polypeptide hormones. The exocrine pancreas is composed of acini and ductules that secrete about 2.5 L/day of isotonic fluid that contains water, electrolytes, and pancreatic enzymes necessary for digestion. Bicarbonate and other electrolytes are secreted primarily by the centroacinar (ductular) cells in order to neutralize gastric acid. Pancreatic juice is delivered to the duodenum via the pancreatic ducts (Fig. 25-1) where the alkaline secretion neutralizes gastric acid and provides an appropriate pH for maintaining the activity of pancreatic enzymes.8
FIGURE 25-1 Anatomic structure of the pancreas and biliary tract.
The major pancreatic exocrine enzyme groups are as follows:
1. Amylolytic: amylase
2. Lipolytic: lipase, procolipase, prophospholipase A2, and carboxylesterase
3. Proteolytic: trypsinogen, chymotrypsinogen, procarboxy-peptidase, and proelastase
4. Nucleolytic: ribonuclease and deoxyribonuclease
5. Other: trypsin inhibitor
Amylase is responsible for digestion of starches and glycogen through hydrolysis. The lipolytic enzymes break down triglycerides, cholesterol, and other fats in the digestive tract. Specifically, lipase hydrolyzes triglycerides into fatty acids and monoglycerides. Colipase and bile acids facilitate this process by allowing lipase to act on the hydrophobic surface of fat droplets in the mainly hydrophilic environment. Phospholipase A2 and carboxylesterase continue to break down fatty acids, cholesterol, monoglycerides, and other products of fat digestion. Proteolytic enzymes digest proteins into oligopeptides and free amino acids, while nucleases break down nucleic acids.8,9
The production of proteolytic enzymes in the pancreas occurs in a manner that prevents self-digestion of the pancreas. These enzymes are synthesized within the acinar cells and secreted into the duodenum as zymogens (inactive enzymes). Enterokinase secreted by the duodenal mucosa converts trypsinogen to trypsin, which then activates all other proteolytic zymogens along with procolipase and prophospholipase A2. Thus, two important mechanisms protect the pancreas from the potential degradative action of its own digestive enzymes. First, the synthesis of proteolytic enzymes as zymogens requires extrapancreatic activation by trypsin. Second, pancreatic juice contains a low concentration of trypsin inhibitor, which inactivates any autocatalytically formed trypsin within the pancreas. Proteolytic activity of trypsin in the intestinal lumen is not inhibited because the concentration of trypsin inhibitor is minimal. Lipase, amylase, ribonuclease, and deoxyribonuclease are secreted by the acinar cells in their active form.8
The regulation of exocrine pancreatic secretion is a complex interplay of neurohormonal feedback with three distinct phases. The first phase is the cephalic phase where the sight, smell, and taste of food produce pancreatic enzyme secretion through stimulus of the vagus nerve. Vasoactive intestinal peptide (VIP) and gastrin-releasing peptide (GRP) released from efferent vagus nerve terminals bind to receptors on the acinar cells stimulating enzyme release.8 Water and bicarbonate are also released from ductal cells due to VIP stimulation. The gastric phase occurs due to gastric distension from food entering the stomach. This results primarily in secretion of digestive enzymes from the pancreas. Once chyme enters the duodenum, the intestinal phase begins. The chyme causes secretin to be released from the duodenal mucosa when its pH is less than 4.5. Secretin results in water and bicarbonate secretion from the pancreas, which is necessary since lipolytic enzymes are inactivated at a pH below 5.9 Digestive enzymes are released from the pancreas due to the presence of fatty acids, peptides, amino acids, and glucose in the duodenum.8
The feedback mechanism for continued release of pancreatic enzymes involves the hormone cholecystokinin (CCK). When products of fat, protein, and starch digestion enter the upper small intestine, they stimulate release of CCK from I cells into the blood. Elevated levels of CCK in the serum activate a vagovagal reflex causing further release of VIP and GRP, leading to enhanced pancreatic enzyme secretion. Inhibition of this feedback loop is thought to be due to trypsin. After digestion is complete, unoccupied trypsin is thought to inhibit the release of CCK.8 A more in-depth discussion of pancreatic physiology can be found elsewhere.8
ACUTE PANCREATITIS
Acute pancreatitis varies from mild to severe disease. The morphologic appearance of the pancreas and surrounding tissue ranges from interstitial edema and inflammatory cells (interstitial pancreatitis) to pancreatic and extrapancreatic necrosis (necrotizing pancreatitis). Necrotizing pancreatitis has a higher risk of infection, organ failure, and mortality.10,11 The rupture of blood vessels within or around the pancreas can also lead to a collection of blood in the retroperitoneal space.
Etiology
Table 25-1 lists the etiologic risk factors associated with acute pancreatitis. Obstruction caused by gallstones is the most common cause of acute pancreatitis and alcohol abuse the second; together they account for 70% to 80% of all cases of acute pancreatitis.6 Genetic and autoimmune causes of acute pancreatitis have been identified.14 Most of the remaining cases are idiopathic.2 Acute pancreatitis can occur as a result of an endoscopic retrograde cholangiopancreatography (ERCP) procedure and is more common following therapeutic ERCP than diagnostic, with overall rates of 1.6% to 5.4% and 0.4% to 5.4%, respectively. High-risk populations may have rates of acute pancreatitis as high as 15%.15 Cigarette smoking appears to increase the risk of pancreatitis, especially in alcohol-related disease.16 Pregnancy is not considered a cause of acute pancreatitis; however, pregnant women develop pancreatitis as a result of a coincident process, most commonly cholelithiasis. In pediatric patients, the common etiologies are systemic illness, biliary disease, trauma, and medications.17
TABLE 25-1 Etiologic Risk Factors Associated with Acute Pancreatitis
Medications
Drug-induced acute pancreatitis should be suspected when other causes have been excluded and there is a temporal relationship with the initiation of a medication that has been implicated as a cause. The percentage of acute pancreatitis cases caused by medications is reported to be 0.1 to 2.18 Most information on drug-induced acute pancreatitis is obtained from case reports, which do not provide reliable information on incidence. The most convincing case reports involve recurrence on rechallenge; however, rechallenge is rare, occurring only when alternative therapy is not available. When evaluating case reports, clinicians should review data supporting the diagnosis of acute pancreatitis, attempts to rule out other causes, and the onset of acute pancreatitis in relation to drug therapy. Further complicating the evaluation of some reports is that certain patient populations may have an increased risk of pancreatitis.
Proton pump inhibitors and histamine2-receptor antagonists may be initiated in response to early symptoms of unrecognized pancreatitis and may confound the association between the drug and the disease. However, a retrospective cohort study does not support an association between acute pancreatitis and proton pump inhibitors or histamine2-receptor antagonists.19 Medications that alter serum lipid concentrations, such as propofol and tamoxifen, are associated with pancreatitis from hyperlipidemia.20,21 In contrast, a meta-analysis of lipid-lowering therapies found that statins were associated with a decreased number of acute pancreatitis cases.22 Pancreatitis was not a stated end point of any of the trials included and there are numerous case reports of apparent drug-induced pancreatitis with statins. There is a higher incidence of drug-induced acute pancreatitis in U.S. patients with human immunodeficiency virus (HIV) treated with antiretroviral therapy.23 However, there was no increase in acute pancreatitis associated with antiretroviral use in a well-controlled trial including data from 33,742 person-years.24Medications used in the treatment of inflammatory bowel disease and type II diabetes mellitus have also been associated with a higher incidence of drug-induced acute pancreatitis.25,26 In addition, patients with diabetes mellitus may also have an inherent increased risk of acute pancreatitis. The commonly prescribed medication metformin is associated with acute pancreatitis at toxic serum concentrations.27 There have also been case reports of acute pancreatitis in patients receiving some of the newer antihyperglycemic agents, including the dipeptidyl peptidase-4 (DPP-4) inhibitors, sitagliptin, linagliptin, and vildagliptin, and the glucagon-like peptide-1 (GLP-1) receptor agonists, exenatide and liraglutide.18 Exenatide and liraglutide continue to account for a substantial percentage of drug-induced pancreatitis reported to the U.S. FDA.28
The onset of drug-induced pancreatitis after initiation of medications ranges from a few months to several years, with a median of 5 weeks; onset after rechallenge can occur within hours. The onset may differ according to the mechanism. Clinicians should be especially suspicious of drug-induced acute pancreatitis in high-risk patients, such as those receiving immunomodulating drugs or who have HIV infection, the elderly, or those with diabetes mellitus.18
Mechanisms of drug-induced pancreatitis are not clearly defined but may fall into several general categories, including direct toxic effects of the drug or its metabolites, hypersensitivity, drug-induced hypertriglyceridemia, and alterations of cellular function in the pancreas and pancreatic duct.26 Once the process is initiated, disease severity is determined by the propagation of proinflammatory mediators. Although acute pancreatitis is an infrequent complication of drug therapy, it is prudent to withdraw medication when an association is suspected.
Numerous drugs are believed to cause acute pancreatitis, but ethical and practical considerations prevent rechallenge with suspected agents. Table 25-2 lists specific agents associated with acute pancreatitis based on known association. Class I (definite association) implies a temporal relationship of drug administration to abdominal pain and hyperamylasemia in at least 20 reported cases with at least one positive response to rechallenge with the offending agent. Class II medications are implicated in more than 10, but less than 20, reported cases of acute pancreatitis and suggest a probable association. Class III includes medications with a possible association, defined as fewer than 10 published cases or unpublished reports in pharmaceutical or FDA files. Table 25-2 only includes selected class III medications. A comprehensive list of class III drugs can be found elsewhere.33
TABLE 25-2 Medications Associated with Acute Pancreatitis
Pathophysiology
The pathophysiology of acute pancreatitis is based on events that initiate injury and secondary events that establish and perpetuate the injury (Fig. 25-2). Alcohol abuse and gallstones cause different initial insults to the pancreas. However, acute pancreatitis of any etiology has long been thought to result from the premature activation of trypsinogen to trypsin within the pancreas, leading to activation of other digestive enzymes and autodigestion of the gland.2The lysosomal proteinase, cathepsin B, and intracellular calcium may be involved in the activation of trypsinogen as well as decreased activity of trypsin inhibitor.34 Genetic abnormalities in pathways that protect the pancreas from autodigestion also play a pathophysiologic role in the development of some forms of acute pancreatitis, and may be the differentiating factor in the minority of alcoholics who develop disease.35
FIGURE 25-2 Pathophysiology of acute pancreatitis: initiating and secondary events. (IL-1β, interleukin-1β; IL-6, interleukin-6; IL-8, interleukin-8; PAF, platelet-activating factor; TNF-α, tumor necrosis factor-α.)
In addition to increased production, activated enzymes are retained in the acinar cells in higher concentrations than normal.36 Activated pancreatic enzymes released into the pancreas and surrounding tissues produce damage and necrosis to the pancreatic tissue, the surrounding fat, the vascular endothelium, and adjacent structures. Lipase damages the fat cells, producing noxious substances that cause further pancreatic and peripancreatic injury. The release of cytokines by acinar cells directly causes their injury and enhances the inflammatory response.34 Injured acinar cells liberate chemoattractants that recruit neutrophils, macrophages, and other cells to the area of inflammation. These immune responses cause a systemic inflammatory response syndrome (SIRS). Vascular damage and ischemia causes the release of kinins, which makes capillary walls permeable and promotes tissue edema. The release of damaging oxygen-free radicals appears to correlate with the severity of pancreatic injury.10 Finally, pancreatic infection may result from increased intestinal permeability and translocation of colonic bacteria.35
Complications
Early complications are a result of fluid losses and SIRS. Hypotension results from hypovolemia, hypoalbuminemia, the release of kinins, and sepsis. Even patients with mild disease have significant fluid losses. Renal complications are usually caused by hypovolemia. The most common systemic complication of acute pancreatitis is respiratory failure.1 GI bleeding occurs secondary to numerous causes including rupture of a pseudocyst. Severe acute pancreatitis is also associated with confusion and coma.
Local complications—including acute fluid collection, pancreatic necrosis, infection, abscess (collection of pus in or adjacent to the pancreas), and pseudocyst—develop approximately 3 to 4 weeks after the initial attack. Pancreatic infections occur in 15% to 30% of those with pancreatic necrosis and are usually secondary infections of necrotic tissue.7 Pancreatic ascites occurs when pancreatic secretions spread throughout the peritoneal cavity. Systemic complications include cardiovascular, renal, pulmonary, metabolic, hemorrhagic, and CNS abnormalities.10 Long-term complications include glucose intolerance and recurrence of acute pancreatitis.37
Clinical Presentation
Signs and Symptoms
The clinical presentation of acute pancreatitis varies depending on the severity of the inflammatory process and whether damage is confined to the pancreas or involves local and systemic complications (Table 25-3).7
TABLE 25-3 Presentation and Diagnosis of Acute Pancreatitis
Diagnosis
Most guidelines agree that the diagnosis should be made within 48 hours based on characteristic abdominal pain and amylase, lipase, or both that are elevated to at least three times the upper limit of normal. Lipase is more sensitive and specific than amylase and is preferred. Contrast-enhanced computed tomography (CECT) of the abdomen may be used to confirm the diagnosis, including in patients with amylase or lipase that is not three times the upper limit of normal. Some guidelines consider ultrasonography to be an acceptable alternative to CECT.1,10,41 However, it is best used to ascertain the presence of gallstones. The diagnosis of acute pancreatitis should also be considered when evaluating patients with SIRS (see Table 25-3).10,41,42 For further information on laboratory tests and abdominal imaging, refer to Table 25-3.
Prediction of Disease Severity Prediction of severity of acute pancreatitis is useful for decisions involving the need for aggressive treatment, including admission to an intensive care unit. The risk for severe acute pancreatitis should be assessed on admission and on an ongoing basis.10,11 Several scoring systems have been developed to assess the likelihood of severe disease (Table 25-4). However, development and validation of such systems remains an ongoing area of research. Scoring systems are developed based on retrospectively identified associations between clinical and laboratory findings and morbidity and mortality.1,43,44 Many are too complicated for bedside use or rely on measurements that are not widely available. Some scoring systems have not been validated in prospective trials or have poor predictive ability.
TABLE 25-4 Prognostic Indicators for Severe Acute Pancreatitis
The first scoring system developed for pancreatitis was the Ranson’s criteria. It assesses 11 variables that must be monitored at the time of admission and during the initial 48 hours of hospitalization.10 Severe acute pancreatitis is characterized by three or more criteria. While still used by many clinicians, the Ranson’s score does not correlate well with disease severity. The Atlanta scoring system was developed based on consensus opinions; it consolidates clinical indicators, organ failure, and local complications to provide an ongoing assessment of disease severity.7
The Acute Physiology and Chronic Health Evaluation II (APACHE II) system uses 12 indicators of physiologic and biochemical function, age, and previous health status to predict mortality in critically ill patients, but it is not specific to pancreatitis. The APACHE II score is calculated within the first 24 hours and is considered among the best predictors of severity on admission. A score greater than or equal to 8 points is associated with an increased risk of organ failure and mortality.10 Other scoring systems include the Bedside Index of Severity in Acute Pancreatitis (BISAP), the Harmless Acute Pancreatitis Score (HAPS), and a computer-based tool using blood urea nitrogen (BUN), pleural effusion, and serum calcium. SIRS criteria alone are sensitive for predicting organ failure and death, but are not specific to severe acute pancreatitis.1,44
Clinical Course and Prognosis
The clinical course of acute pancreatitis varies from a mild transitory disorder to a severe necrotizing disease. Mild acute pancreatitis is self-limiting and subsides spontaneously within 3 to 5 days. Mortality is influenced by etiology, as idiopathic and postoperative acute pancreatitis have higher rates than gallstone- or alcohol-related disease. First and second occurrences also carry a higher mortality than subsequent episodes. Mortality increases with unfavorable early prognostic signs, local complications, and organ failure. Persistent organ failure is a greater risk than transient organ failure.3 Severe pancreatitis with either organ failure or infected necrosis is associated with a mortality of approximately 30%, which increases when both are present.3 Death during the first few days results from SIRS and multiorgan failure. When death occurs after this period, it is usually a result of infected necrosis, pancreatic abscess, and sepsis.10
TREATMENT
Acute Pancreatitis
Desired Outcome
Treatment of acute pancreatitis is aimed at relieving abdominal pain and nausea, replacing fluids, correcting electrolyte, glucose, and lipid abnormalities, minimizing systemic complications, and preventing pancreatic necrosis and infection. Management varies depending on the severity of the attack (Fig. 25-3). Patients with mild acute pancreatitis respond very well to the initiation of supportive care and the reduction of pancreatic secretions. Patients with severe acute pancreatitis should be treated aggressively and monitored closely.
FIGURE 25-3 Algorithm of guidelines for evaluation and treatment of acute pancreatitis. (ERCP, endoscopic retrograde cholangiopancreatography.)
General Approach to Treatment
All patients with acute pancreatitis should receive supportive care, including IV fluid resuscitation, adequate nutrition, and effective relief of pain and nausea. The use of nasogastric aspiration offers no clear advantage in patients with mild acute pancreatitis, but it is beneficial in patients with profound pain, severe disease, paralytic ileus, and intractable vomiting.10 Patients predicted to follow a severe course will require treatment of cardiovascular, respiratory, renal, and metabolic complications.1 Aggressive fluid resuscitation is essential to correct intravascular volume depletion.45 Patients with pancreatitis and SIRS should be treated according to SIRS guidelines. IV potassium, calcium, and magnesium are used to correct electrolyte deficiency states. Insulin is used to treat hyperglycemia. Local complications resolve as the inflammatory process subsides. However, patients with necrotizing pancreatitis may require antibiotics and surgical intervention.10 Medications listed in Table 25-2 should be discontinued if possible 
.
Nonpharmacologic Therapy
Nonpharmacologic therapy includes ERCP for removal of any underlying biliary tract stones, surgery, and nutritional support. Surgery is indicated in patients with pancreatic pseudocyst or abscess or to drain the pancreatic bed if hemorrhagic or necrotic material is present. The need for admission to an intensive care unit should also be addressed. Advances in minimally invasive surgical techniques are changing practice with respect to timing and approach to managing infected necrotizing pancreatitis, and may help lower the risk of mortality in the most critical patients.2,11,46,47
Nutrition and Probiotics
Nutritional support plays an important role in the management of patients with mild or severe disease as acute pancreatitis creates a catabolic state that promotes nutritional depletion. This can impair recovery, increase the risk of complications, and prolong hospitalization.48,49 Patients with mild acute pancreatitis can begin oral feeding when bowel sounds have returned and pain has resolved.7 In severe or complicated disease, nutritional deficits develop rapidly and are complicated by tissue necrosis, organ failure, and surgery. Nutritional support should begin when it is anticipated that oral nutrition will be withheld for more than 1 week.50 In the past, there was concern that enteral feeding stimulated pancreatic enzyme secretion and exacerbated the underlying disease. However, a Cochrane Collaboration review that included eight randomized controlled trials found that enteral nutrition results in decreased morality, multiple organ failure, and need for surgical intervention compared with parenteral nutrition.50Possible mechanisms for this include protection of the gut barrier and prevention of colonization with pathogenic bacteria, both of which may prevent translocation of bacteria and infection.11 Therefore, the enteral route is preferred over the parenteral in patients with severe acute pancreatitis provided that it can be tolerated. Ongoing trials are addressing some remaining issues such as the optimal timing to initiate enteral feeding and the safety of the nasogastric route as compared with nasojejunal. If enteral feeding is not possible or if the patient is unable to obtain sufficient nutrients, total parenteral nutrition should be implemented before protein and calorie depletion become advanced. IV lipids should not be withheld unless the serum triglyceride concentration is greater than 500 mg/dL (5.65 mmol/L).10
Clinical trials do not support the use of probiotics in the treatment of acute pancreatitis as they have not shown a benefit. One prospective randomized trial in patients with predicted severe acute pancreatitis showed an increase in mortality with probiotics compared with placebo.51
Pharmacologic Therapy
Recommendations
Patients with acute pancreatitis often require IV antiemetics for nausea. Those with severe acute pancreatitis should be treated with antisecretory agents to prevent stress-related mucosal bleeding. Patients also require appropriate fluid resuscitation and pain management, but there is controversy surrounding both of these therapies. Octreotide has been studied as a specific therapy in severe acute pancreatitis, but its efficacy remains uncertain (see Fig. 25-3). Prophylactic antibiotics used to be widely used, but clinical trials have failed to identify a group of patients that benefit from this therapy.
Fluid Resuscitation
Vasodilation from the inflammatory response, vomiting, and nasogastric suction contribute to hypovolemia and fluid and electrolyte abnormalities, thus necessitating replacement. Evidence for the benefit of adequate fluid resuscitation comes from observational studies demonstrating an associated increase in morbidity and mortality with failure to improve laboratory indicators of hemoconcentration (i.e., hematocrit and BUN). There are no large randomized trials to provide specific recommendations. Guidelines call for rapid replacement of fluid, without details on rate or type of fluid 
.
Observational studies have identified both benefit (decreased mortality and organ failure) and harm (abdominal compartment syndrome) associated with early aggressive fluid administration. Most studies have compared standard therapy with aggressive fluid therapy over the first 24 hours retrospectively. One trial found that administration during the first 24 hours of at least one third the cumulative volume given over the first 72 hours was associated with a decrease in mortality.52 A similar trial found a decrease in SIRS, organ failure at 72 hours, and length of stay in patients who received more fluid during the first 24-hour period than subsequent 24-hour periods.53 In contrast, another study found that patients who received more than 3.1 L of fluid during the first 24 hours had higher rates of persistent organ failure, respiratory failure, and renal failure than those who received smaller volumes.54 In a prospective, randomized trial, goal-directed fluid replacement therapy of 3 mL/kg/h for the first 20 hours did not result in a reduction in SIRS or C-reactive protein (CRP).55 Replacement at rates of 10 to 15 mL/kg/h was associated with more abdominal compartment syndrome, mechanical ventilation, and sepsis in the first 2 weeks following presentation than standard therapy in another trial.56
Interpretation of these trials is complicated by the likelihood that sicker patients were given larger volumes of fluid. Studies of fluid resuscitation in acute pancreatitis suggest that some patients may not require aggressive fluid resuscitation, while others may require gradual fluid administration. For example, those with reduced cardiac reserve may do better if fluid is replaced over 72 hours rather than 24 to 48 hours.57
In addition to questions about the rate and volume of fluid that should be administered to patients with acute pancreatitis, there is also debate regarding which fluid is most appropriate. A small randomized trial found that goal-directed resuscitation with lactated Ringer’s produced a reduction in SIRS and CRP at 24 hours compared with normal saline.55 The study protocol used aggressive replacement with a bolus of 20 mL/kg of lactated Ringer’s followed by 150 to 300 mL/h for the first 24 hours. If patients responded to this therapy as assessed by BUN, the rate could be reduced to 2 mL/kg/h. Patients with SIRS or sepsis should be resuscitated according to sepsis guidelines .58
Clinical Controversy…
Aggressive fluid resuscitation is generally recommended, but adequate studies on the volume and type of fluid have not been conducted. Excessive rates of administration have been associated with increased mortality in retrospective trials. Use of lactated Ringer’s solution may be preferred over normal saline.
Relief of Abdominal Pain
Parenteral opioid analgesics are used to control abdominal pain associated with acute pancreatitis . The most important factors to consider in selecting an analgesic are efficacy and safety. Although the administration of some opioids is associated with mild and transient increases in serum amylase and lipase, these effects are not deleterious to the patient. There is no agent that is preferred over others. Traditionally, treatment was initiated with parenteral meperidine (50 to 100 mg every 3 to 4 hours) because it did not significantly alter the function of the sphincter of Oddi (see Fig. 25-1), thereby worsening the disease course.59 However, meperidine is not recommended as a first-line agent because of the risk of adverse effects and dosing limitations. As a result, many hospitals have either restricted or eliminated the use of meperidine. Active metabolites of meperidine accumulate with kidney dysfunction and may cause seizures or psychosis. Other opiate analgesics should be used for initial analgesia in patients with severe pain from acute pancreatitis.
Parenteral morphine is often recommended for pain control because it provides a longer duration of pain relief than meperidine with less risk of seizures. Although morphine increases biliary pressure, there is no evidence to indicate that it is contraindicated for use in acute pancreatitis as no studies have compared clinical outcomes of acute pancreatitis using various analgesics.59 Patient-controlled analgesia should be considered in patients who require frequent opioid dosing (e.g., every 2 to 3 hours). Dosing of pain medications should be monitored carefully and adjusted daily. There is no evidence that antisecretory agents, such as histamine2-receptor antagonists or proton pump inhibitors, prevent an exacerbation of abdominal pain.60
Limitation of Systemic Complications and Prevention of Pancreatic Necrosis
Agents may be used to limit disease progression by either directly or indirectly reducing pancreatic secretion, inhibiting the action of circulating inflammatory mediators, or increasing pancreatic microcirculation, but there is currently no specific therapy for acute pancreatitis. The use of parenteral histamine2-receptor antagonists or proton pump inhibitors does not improve the overall outcome of patients with acute pancreatitis.7 The platelet-activating factor inhibitor antagonist, lexipafant, was not effective in preventing organ failure in acute pancreatitis.61 Clinical studies with protease inhibitors such as aprotinin, gabexate, and nafamostat have failed to show consistent benefit in acute pancreatitis, and their use is not supported by guidelines.7,10,41,42,62 None of these agents is currently available in the United States. Somatostatin and its synthetic analog octreotide are potent inhibitors of pancreatic enzyme secretion and have been used to interrupt the inflammatory process. Several studies and a metaanalysis that evaluated the efficacy of somatostatin and octreotide suggest a slight trend toward benefit in patients with severe pancreatitis.10,63 Limitations of these studies include small numbers of patients, no placebo, and inclusion of patients with mild disease. There are insufficient data to support the routine use of somatostatin or octreotide in the treatment of acute pancreatitis and guidelines do not recommend their use.42
Prevention of Infection
Prophylactic antibiotics do not offer any benefit in cases of mild acute pancreatitis or when there is no necrosis. Use of antibiotics in patients with severe acute pancreatic necrosis (with or without the presence of pancreatic necrosis), but without infection, is not currently supported by randomized controlled trials.
Antibiotic prophylaxis in early clinical trials showed no benefit, but these studies were limited due to inclusion of patients with a wide range of disease severity and insufficient enrollment of patients with severe necrotizing pancreatitis. In addition, they used ampicillin, which does not penetrate well into pancreatic tissue.64 Imipenem–cilastatin, metronidazole, cefotaxime, piperacillin, mezlocillin, ofloxacin, and ciprofloxacin all achieve satisfactory bactericidal tissue concentrations, whereas aminoglycosides have poor penetration.64–66 However, the importance of antibiotic penetration into pancreatic tissue has been debated, as it is the peripancreatic retroperitoneal necrotic fat and debris, not the pancreas itself, that becomes infected.
Several randomized clinical trials have compared antibiotic prophylaxis with no prophylaxis in patients with acute necrotizing pancreatitis with varying results. A meta-analysis found that prophylactic antibiotics do not reduce infected necrosis or mortality.64 In addition, overuse of antibiotics increases microbial resistance. Currently, use of antibiotics in necrotizing pancreatitis is only recommended in the presence of known or suspected infection . Once infection develops in the patient with necrotic acute pancreatitis, surgical debridement is required.
Because the source of bacterial contamination is most likely the colon, the choice of antibiotic for infected pancreatitis should be broad-spectrum, covering the range of enteric aerobic gram-negative bacilli and anaerobic microorganisms. Treatment should be initiated within the first 48 hours and continued for 2 to 3 weeks. Imipenem–cilastatin (500 mg orally every 8 hours) has been widely used because of its good penetration into the pancreas and one positive prophylaxis study.67 However, it has been replaced on many hospital formularies by one of the newer carbapenems (such as meropenem). Fluoroquinolones, such as ciprofloxacin or levofloxacin, combined with metronidazole should be considered for penicillin-allergic patients.66
Selective digestive tract decontamination uses oral minimally absorbed antibiotics, including polymyxin E, tobramycin, and amphotericin B, to eradicate bacteria in the intestinal flora, thereby reducing translocation.66,68 This alternative may be of benefit in reducing the risk of pancreatic infection, but randomized controlled trials in patients with acute pancreatitis are needed to confirm its effectiveness when compared with parenteral antibiotic prophylaxis.66
Post-ERCP Pancreatitis
The clinical characteristics of post-ERCP pancreatitis are similar to those of acute pancreatitis from other causes. In most cases the disease course is mild and resolves in several days. Pretreatment with octreotide, corticosteroids, calcium channel blockers, allopurinol, natural β-carotene, and aprotinin has been disappointing.69,70 Some benefit has been demonstrated with somatostatin, diclofenac suppositories, and gabexate.71,72 Indomethacin suppositories decreased the incidence of post-ERCP pancreatitis by 46% in a population at increased risk.73 This therapy was not associated with an increase in bleeding or renal failure. However, patients at increased risk for adverse effects from nonsteroidal antiinflammatory drugs (NSAIDs) were excluded. To date, there have not been any studies to evaluate the cost-effectiveness of prophylactic therapy.74,75
CHRONIC PANCREATITIS
Chronic pancreatitis results from long-standing pancreatic inflammation resulting in irreversible destruction of pancreatic tissue with fibrin deposition, leading to a loss of exocrine and endocrine functions.4–6It has four different stages beginning with a preclinical inflammatory stage where patients remain asymptomatic or have indistinguishable symptoms.6 In the second stage patients present with acute attacks that often resemble those of acute pancreatitis. The third stage consists of episodes of intermittent or constant abdominal pain. Finally, in the burnout stage patients present with diminished or absent pain, but develop malabsorption syndrome due to loss of pancreatic exocrine function and diabetes mellitus from loss of endocrine function.
Etiology
Chronic alcohol consumption, especially heavy drinking, remains the leading cause of chronic pancreatitis in Western society, accounting for approximately 70% to 80% of cases.6,76 Generally, consumption of ≥150 g/day of alcohol for ≥15 years poses a significant risk of chronic pancreatitis.77,78 Twenty percent of the remaining cases can be classified as idiopathic, while 10% are due to rare causes, such as autoimmune, hereditary, and tropical pancreatitis.6,79Various genetic alterations have also been associated with the occurrence of chronic pancreatitis, including mutations of the cationic trypsinogen (PRSS1), serine protease inhibitor Kazal type 1 (SPINK1), and the cystic fibrosis transmembrane conductance regulator (CFTR) genes.77,79 There is also a demonstrated risk of chronic pancreatitis with cigarette smoking that appears to be dose-dependent and may contribute to mortality from chronic pancreatitis.76,80–84 A proposed classification system called the M-ANNHEIM classification takes into account the various risk factors for chronic pancreatitis (Table 25-5).85
TABLE 25-5 M-ANNHEIM Classification of Risk Factors for Chronic Pancreatitis
Pathophysiology
Although the exact mechanism for the pathogenesis of chronic pancreatitis is unknown, several theories have been proposed. The oxidative stress theory proposes that the pancreas is exposed to by-products of mixed-function oxidases that lead to an inflammatory reaction.77,79 Increased activity of hepatic and pancreatic oxidases may be due to increased exposure to substrates (e.g., fat), inducers (e.g., alcohol), or other substances. A comparison of serum oxidative markers in chronic pancreatitis patients versus healthy volunteers supports this theory.86 A toxic-metabolic theory focuses on alcohol as a primary causative agent where by-products of its metabolism in the pancreas lead to lipid accumulation in acinar cells and eventual fatty degeneration of the pancreas.77 Ductal obstruction theories state that alcohol leads to obstruction of pancreatic ductals secondary to increased protein deposition and stone formation. This leads to scarring of ductal epithelial cells, which potentiates further obstruction and eventually results in acinar atrophy and fibrin deposition. The final major theory suggests that periductular necrosis from repeated episodes of acute pancreatitis eventually leads to ductal obstruction and stone formation with subsequent acinar atrophy and fibrosis.
Regardless of the pathophysiologic mechanism, several pieces of evidence now point to activation of pancreatic stellate cells as the cause of fibrin deposition in chronic pancreatitis. Various toxins, oxidative stress, and inflammatory mediators activate pancreatic stellate cells.77,87 Cellular signaling pathways involved in this activation are modulated by hydroxymethylglutaryl-coenzyme A reductases and peroxisome proliferator–activated receptor-αnuclear receptors.88 As an example, exposure of the pancreas to alcohol and its metabolites leads to the production of various mediators and proinflammatory cytokines, especially tumor necrosis factor-α and interleukin-1 and -6.87,88These then activate pancreatic stellate cells that initiate fibrinogenesis. Other mediators generated by the stellate cells themselves perpetuate continued stellate cell activation.
The pathogenesis of pain in chronic pancreatitis has long been thought to be the result of increased pancreatic parenchymal pressure from obstruction, inflammation, and necrosis.89,90 A neurogenic mechanism may also be responsible. Continued activation of trypsin not only damages afferent neurons but also has effects on sensory pain receptors within the pancreas.89 Changes also occur within the CNS that further contribute to the neurogenic mechanism of pain.89,91 This was demonstrated in a study that compared electroencephalogram recordings from chronic pancreatitis patients and healthy volunteers.92Therefore, compression of pancreatic nerve fibers after a meal along with continuous firing of peripheral and central neurons may explain the burning and shooting pain of chronic pancreatitis.91
Clinical Presentation
Chronic pain, malabsorption with resultant steatorrhea, and diabetes mellitus are the hallmark complications and symptoms of chronic pancreatitis . Although abdominal pain is the most common symptom at any stage, patients may present with various signs and symptoms depending on the stage of the disease. A more comprehensive list of the common signs and symptoms is presented in Table 25-6.
TABLE 25-6 Signs, Symptoms and Diagnosis of Chronic Pancreatitis
Diagnosis
The diagnosis of chronic pancreatitis is based primarily on presenting signs and symptoms in combination with either imaging or pancreatic function studies (Table 25-6). Although histology would be the best diagnostic test, it is difficult and risky to perform and is generally not recommended.77 Therefore, testing usually begins with noninvasive and inexpensive studies such as serum trypsinogen, fecal elastase, mixed triglyceride breath test, and abdominal ultrasonography.4,94,95 However, these tests are usually only useful in advanced disease.4 Magnetic resonance cholangiopancreatography or computed tomography (CT) may be used next. The most sensitive studies are the secretin and CCK stimulation tests for exocrine pancreatic insufficiency.5,77,79 Performing these studies is uncomfortable for patients and they are not widely available, so they are usually reserved to rule out chronic pancreatitis if imaging studies are nondiagnostic.4,5 The gold standard invasive study is ERCP.5,79 However, due to the risks associated with this procedure, endoscopic ultrasonography (EUS) has become an accepted alternative for the diagnosis of chronic pancreatitis.5,79
Clinical Course and Prognosis
The clinical course of chronic pancreatitis depends on the etiology. The median age at onset is as early as 10 years for hereditary chronic pancreatitis, whereas alcoholic and late-onset idiopathic chronic pancreatitis have median onsets of 36 and 62 years, respectively.96 Exocrine insufficiency, which occurs when lipase secretion is less than 10% of normal,4,79 develops about 5 years after diagnosis in alcoholic chronic pancreatitis and 22 years in hereditary chronic pancreatitis. Diabetes mellitus has been shown to occur about 8 years after diagnosis of alcoholic chronic pancreatitis and up to 27 years after diagnosis of early onset idiopathic chronic pancreatitis. Resolution of pain from pancreatic burnout tends to coincide with exocrine insufficiency.
The life expectancy of patients with chronic pancreatitis is shorter than that of the general population. The 10-year survival rate is approximately 70%, while the 20-year rate is 45%.6 However, death in patients with chronic pancreatitis most commonly results from cardiovascular disease, infection, or malignancy rather than from the disease itself.6,96 One of the most significant complications of long-standing disease is pancreatic cancer. Patients with alcoholic chronic pancreatitis are 15 times as likely as the general population to develop pancreatic cancer, while 40% of those with hereditary chronic pancreatitis may be diagnosed.6,79
TREATMENT
Chronic Pancreatitis
Desired Outcome
The major goals in the treatment of uncomplicated chronic pancreatitis are relief of abdominal pain, treatment of the associated complications of malabsorption and diabetes mellitus, and improvement in quality of life. Secondary goals include treating associated disorders such as depression and malnutrition.
General Approach to Treatment
Treatment of chronic pancreatitis and its complications involves various nonpharmacologic and pharmacologic interventions. Lifestyle modifications should include abstinence from alcohol and smoking cessation.5,79 Also, patients with steatorrhea may need to eat smaller, more frequent meals and reduce dietary fat intake.4,5 The majority of patients require analgesics and pancreatic enzyme supplementation.5,79 Pain can initially be controlled with medications, but may require more aggressive medical and surgical therapies as the disease progresses. Patients with malabsorption require pancreatic enzymes to reduce steatorrhea and maintain adequate nutrient absorption.5,79 An antisecretory agent may be added to the regimen when enzymes alone provide an inadequate reduction in steatorrhea.4,5,79
Nonpharmacologic Therapy
In addition to medical management, the treatment of chronic pancreatitis includes both lifestyle and dietary modifications. Patients should be counseled to abstain from alcohol use, and smoking cessation should be advocated. It is unclear if cessation of alcohol use reduces pain in patients with alcoholic chronic pancreatitis, but its use hastens disease progression.4 Smoking has been associated with an increased mortality in patients with chronic pancreatitis.82Patients with steatorrhea should be counseled to eat small and frequent meals.97 A reduction in dietary fat is not needed routinely, but a decrease to 0.5 g/kg/day is recommended for those whose symptoms are uncontrolled with enzyme supplementation. Patients who do not consume adequate calories from their normal diet may be given whole protein or peptide-based oral nutritional supplements. Supplementation with medium-chain triglycerides, which do not require lipolysis, should be considered for patients with steatorrhea who are unable to gain weight. Complete enteral nutrition is recommended for patients who cannot consume adequate calories, have continued weight loss, experience complications, or require surgery. A jejunal feeding tube is the recommended route for administration of enteral nutrition in chronic pancreatitis patients; it increases patient weight and decreases abdominal pain and opioid use.97
Invasive procedures and surgery are primarily used to treat uncontrolled pain and the associated complications of chronic pancreatitis. Stents placed via ERCP may be used to treat pancreatic duct strictures in order to relieve parenchymal pressure and reduce pain.90,98 Extracorporeal shock wave lithotripsy can be used to break up pancreatic stones with ultrasonic vibration prior to removal by ERCP.90,98 However, combining these procedures to treat pain provides no additional benefit and increases cost.99 Blockade of pain signals through the celiac plexus may be achieved utilizing EUS.90,98,100,101 The various complications of chronic pancreatitis that can be treated endoscopically include common bile duct strictures, duodenal obstructions, and pancreatic pseudocysts.98 Various surgical techniques including total pancreatectomy may also be used to relieve pain associated with chronic pancreatitis.5,90,102Surgery is more effective at relieving pain than endoscopic procedures, but these trials have a number of limitations.103,104 Finally, total pancreatectomy with transplantation of pancreatic islet cells to reduce the need for exogenous insulin is a possible option for the treatment of pain due to chronic pancreatitis.105,106
Pharmacologic Therapy
General Recommendations
Pharmacologic therapy of chronic pancreatitis is aimed at controlling pain, treating malabsorption and associated steatorrhea, and controlling diabetes mellitus. Once other causes have been excluded, nonopioid analgesics should be tried initially for pain management (Fig. 25-4).4,5 Patients unresponsive to nonopioid analgesics may be given a trial of pancreatic enzyme supplements prior to adding opioids.4,90 If these measures fail, an oral opioid should be added to the drug regimen. Opioids administered by nonoral routes should be reserved for patients who cannot take oral medications or whose pain is unresponsive to oral opioids. Additional agents may be considered for added pain control and disorders associated with chronic pancreatitis.
FIGURE 25-4 Algorithm for the treatment of abdominal pain in chronic pancreatitis. (ERCP, endoscopic retrograde cholangiopancreatography.)
FIGURE 25-5 Algorithm for the treatment of malabsorption and steatorrhea in chronic pancreatitis. (H2RA, histamine2-receptor antagonist; PPI, proton pump inhibitor.)
Most patients with malabsorption will require a modification in diet along with pancreatic enzyme supplementation in order to achieve adequate nutritional status and reduction in steatorrhea (Fig. 25-5). An antisecretory agent should be added to the regimen when there is an inadequate response to enzyme therapy alone.4 If these measures are ineffective, documentation of the diagnosis and exclusion of other diseases should be undertaken. Exogenous insulin is the primary pharmacologic agent used in the treatment of diabetes mellitus associated with chronic pancreatitis.4 However, some patients may have favorable results with the use of oral agents for control of blood glucose.
Relief of Chronic Abdominal Pain
Analgesics Pain from chronic pancreatitis can initially be treated with nonopioid analgesics, but opioids will eventually be required as the disease progresses 
. Therapy should begin with acetaminophen or NSAIDs (Table 25-7).4,5 Regimens should be individualized and should begin with the lowest effective dose. The dosage regimen should be maximized before adding or substituting agents. Analgesics should be scheduled around the clock rather than as needed in order to maximize efficacy. Also, scheduling short-acting analgesics prior to meals should help decrease postprandial pain. When nonopioid analgesics fail to control pain, low-potency opioids (e.g., hydrocodone) should be added to the regimen (see Table 25-7). Tramadol has also been used successfully to treat pain in patients with chronic pancreatitis, but at a higher dose than that approved in the United States.4 Severe pain unresponsive to these therapies necessitates the use of opiate analgesics. Although opioids carry about a 10% to 30% risk of addiction in this population, their use should not be withheld.4 Unless contraindicated, oral opioids should be used before parenteral, transdermal, or other dosage forms. Although oxycodone was found to relieve pain better than morphine in a study of simulated chronic pancreatitis pain, adequate trials comparing agents have not been conducted.107Therefore, the choice of agent should be based on cost, compliance, and avoidance of adverse drug events (e.g., allergic reactions).
TABLE 25-7 Recommendations for the Pharmacologic Treatment of Chronic Pancreatitis
Pancreatic Enzymes Although pancreatic enzymes are primarily used to treat malabsorption associated with chronic pancreatitis, they are also used to treat pain from the disease. Relief of pain using pancreatic enzymes is thought to be due to their ability to break down CCK.4,9,77,90 Normally, the release of CCK, which causes an increase in pancreatic secretion, is inhibited by trypsin. However, there is a decrease in the production of trypsin in patients with chronic pancreatitis. This leads to a loss of negative feedback on the release of CCK and thus an increase in pain due to unabated pancreatic secretion. The proteases in pancreatic enzyme supplements are thought to act as substitutes for endogenous trypsin, leading to a decrease in CCK release.
Despite this intuitive mechanism, mixed results have been found from trials investigating pancreatic enzyme supplements for the treatment of pain from chronic pancreatitis. This may be due to the differences between the various enzyme formulations used in the trials as well as the small number of subjects enrolled.4,9,90 A Cochrane Collaborative review found no beneficial effect on pain relief.108 However, trials that used non–enteric-coated enzyme formulations have demonstrated a benefit in the treatment of pain.4,9,90 It is thought that enteric-coated formulations may not release enough proteases in the duodenum to inhibit CCK release. A trial of non–enteric-coated enzyme supplements may be used for patients with less advanced disease before more aggressive therapy was considered.4,9 An alternative is to administer an enteric-coated product with an antisecretory agent in order to increase the amount of proteases available in the duodenum from these products (Table 25-7). However, no studies have been conducted using such a regimen for the treatment of pain from chronic pancreatitis.
Other Agents Various adjunctive agents are also used in patients experiencing pain from chronic pancreatitis. Selective serotonin reuptake inhibitors and tricyclic antidepressants are used both for treating the concomitant depression that often occurs in patients with chronic pancreatitis and for their potential effects on pain (see Table 25-7).4,90 Gabapentin has been used as an adjunct to opioids.4 Pregabalin also significantly decreases maximum and average daily pain scores when combined with other analgesics in patients with chronic pancreatitis.109 Limited evidence supports these therapies, but their use in this patient population is not uncommon. Octreotide and allopurinol have also been studied for the treatment of chronic pancreatitis pain, but the evidence does not support their use.4,90 There is evidence showing that patients with chronic pancreatitis have increased oxidative stress, and the use of antioxidants, such as selenium, vitamins C and E, and β-carotene, has demonstrated some benefit in relieving pain and improving quality of life in these patients.110–112
Treatment of Malabsorption
Pancreatic enzyme supplementation and reduction in dietary fat intake are the primary treatments for malabsorption due to chronic pancreatitis 
. Treatment should begin when steatorrhea is documented and persistent weight loss occurs despite initial dietary modifications. The combination of pancreatic enzymes and a reduction in dietary fat enhances the patient’s nutritional status and reduces steatorrhea. Malabsorption is minimized if the concentration of lipase delivered to the duodenum with supplementation is about 10% of normal pancreatic output.4 This requires that 25,000 to 40,000 units of lipase be administered with each meal (Table 25-7).9 In many cases the lipase dose will need to be increased due to insufficient lipolytic activity, but doses greater than 75,000 units per meal are not recommended.
There is little evidence regarding the optimal dosage form and administration of pancreatic enzyme supplements. Most studies have compared them with placebo rather than other enzyme products, and used quantitation of fat absorption or elimination as a primary measure of efficacy rather than weight gain.113 Although they have been shown to improve fat absorption, they may not completely eliminate steatorrhea.113,114 However, they improve the quality of life of patients with chronic pancreatitis.115 Since most exogenous lipase is rapidly and irreversibly destroyed at low intragastric pH, enteric-coated products are preferred for the treatment of malabsorption and steatorrhea . The enteric coating only dissolves at a pH greater than 5.5, which allows a sufficient quantity of enzymes to remain intact until dissolution of the coating in the duodenum.9 However, enzymes must also be emptied from the stomach into the duodenum at the same rate and time as ingested food. The size of the enteric-coated enzyme preparation influences the rate of enzyme delivery to the duodenum.4,9 Likewise, the administration time relevant to a meal influences the timing of enzyme delivery. Products that contain enzymes in small enteric-coated microspheres or minimicrospheres are often the best products because they are thought to mix effectively with chyme, thus leaving the stomach at a similar rate.9 Also, the optimal administration time of enzymes containing minimicrospheres appears to be either with a meal or just after.4,116
Despite enzyme therapy, patients may continue to have steatorrhea and fail to gain sufficient weight. Compliance should be assessed in these patients as the number of capsules required with each meal can lead to noncompliance. Alternative products with higher lipase content can be tried in order to reduce the number of capsules needed. If this fails, the dose of lipase should be increased. Finally, addition of an antisecretory agent may be tried to increase the availability of active enzymes in the duodenum.117
Pancreatic Enzyme Supplements Until recently none of the pancreatic enzyme supplements were approved by the FDA because they predated enactment of the Food, Drug, and Cosmetic Act of 1938. Since the FDA announced in 2004 that all products would have to seek approval, six products have been approved. Only two of these products are specifically approved for exocrine pancreatic insufficiency associated with chronic pancreatitis.118,119 Dosage forms of approved products include regular-release tablets, enteric-coated beads, bicarbonate-buffered enteric-coated microspheres, enteric-coated minimicrospheres, and enteric-coated minitablets or microtablets encased in a cellulose or gelatin capsule (Table 25-8). Enzymes are easily administered to patients able to swallow the capsules or their contents. However, administration to patients with enteral feeding tubes presents a challenge. Products containing microspheres may be administered through feeding tubes in an applesauce or apple juice mixture.9 Clinicians must be aware, however, that available products are not equivalent and should consider this before substituting products in patients who require administration through a nonoral route.
TABLE 25-8 Commercially Available Pancreatic Enzyme (Pancrelipase) Preparations
Adverse reactions from pancreatic enzyme supplements are generally benign. High doses can lead to nausea, diarrhea, and intestinal upset.9 One of the more serious adverse effects of these products is fibrosing colonopathy. It occurs when the enzymes cause deposition of fibrin in the colon leading to colonic stricture. This reaction is uncommon and has been reported mostly in children with cystic fibrosis who received high doses of enzymes for prolonged periods.9 Certain enteric coatings may specifically invoke this reaction. Another concern with pancreatic enzymes is the risk of possible viral infection due to contamination of these porcine-derived products.120 Finally, pancreatic enzymes have been associated with deficiencies in fat-soluble vitamins, and appropriate monitoring and supplementation, especially of vitamin D, should be instituted.4,79
Clinical Controversy…
Since the evidence supporting the use of pancreatic enzyme supplements for treating pain associated with chronic pancreatitis is not overwhelming, clinicians debate over their use for this purpose. Often the decision to use enzyme supplements for the treatment of pain comes from clinical experience and the knowledge that their use carries minimal risk of adverse effects.
Adjuncts to Enzyme Therapy The addition of a histamine2-receptor antagonist or proton pump inhibitor to pancreatic enzyme supplementation may increase the effectiveness of enzyme therapy for malabsorption and steatorrhea 
. The beneficial effects of these agents result from an increase in gastric and duodenal pH.9,79 This is thought to result in an increase in the amount of active enzymes available in the duodenum. Traditionally, their use has been advocated with non–enteric-coated enzyme products.4,9 In fact, the only non–enteric-coated formulation currently approved by the FDA is indicated for administration with a proton pump inhibitor.119 However, evidence shows that their use in combination with enteric-coated preparations results in similar efficacy between standard and low-dose enzyme regimens.117
PERSONALIZED PHARMACOTHERAPY
Some cases of drug-induced pancreatitis are associated with elevated concentrations of the causative medications, and it is possible that genetic differences in drug metabolism contribute to this. A pharmacogenetic analysis was performed in one case of drug-induced pancreatitis that was associated with high concentrations of clozapine.121 However, the patient was not found to have any genetic variants that would affect the metabolism of clozapine.
Although several genetic variations have been associated with the occurrence of chronic pancreatitis, variation in response to therapy related to these factors has not been studied. One cautionary note regarding pancreatic enzyme supplements is that they are all porcine-derived and thus contain purines. Therefore, they may increase uric acid levels and should be used cautiously in patients prone to the effects of hyperuricemia. This would include patients with a history of gout, impaired kidney function, and known hyperuricemia. One physiologic parameter affecting the efficacy of pancreatic enzyme supplements is GI transit. Non–enteric-coated formulations are preferred for patients with rapid gastrojejunal transit secondary to pancreatectomy associated with partial gastrectomy or vagotomy and gastroenteroscopy. These patients have hyposecretion of gastric acid and enteric-coated formulations would not be released early enough in the small intestine to confer a beneficial effect.9
EVALUATION OF THERAPEUTIC OUTCOMES
Acute Pancreatitis
Hydration status, serum electrolytes, pain control, and nutritional status should be assessed periodically in patients with mild acute pancreatitis, depending on the degree of abdominal pain and fluid loss. Patients with severe acute pancreatitis should receive intensive care and close monitoring of vital signs, fluid and electrolyte status, white blood cell count, blood glucose, lactate dehydrogenase, aspartate aminotransferase, serum albumin, hematocrit, BUN, serum creatinine, and international normalized ratio. Continuous hemodynamic and arterial blood gas monitoring is essential. Serum lipase, amylase, and bilirubin require less frequent monitoring. The patient should also be monitored for signs of infection, relief of abdominal pain, and adequate nutritional status. Severity of disease and patient response should be assessed using an evidence-based method, for example, APACHE II.
Chronic Pancreatitis
The severity and frequency of abdominal pain should be assessed periodically in patients with chronic pancreatitis using a standardized scale in order to determine the efficacy of pain therapy. Patients receiving opioids should be prescribed laxatives on an as-needed or scheduled basis and be monitored for constipation. Patients receiving pancreatic enzymes for malabsorption should have their weight and stool frequency and consistency monitored periodically. More objective assessments of fecal fat content, such as the 13C-mixed triglyceride breath test, can be utilized, but are usually unnecessary and impractical in general clinical practice.4,109,122 Blood glucose must be closely monitored in patients with diabetes mellitus, and those with long-standing disease should receive appropriate monitoring for nephropathy, retinopathy, and neuropathy.4
ABBREVIATIONS
REFERENCES
1. Anand N, Park JH, Wu BU. Modern management of acute pancreatitis. Gastroenterol Clin North Am 2012;41(1):1–8.
2. Lippi G, Valentino M, Cervellin G. Laboratory diagnosis of acute pancreatitis: In search of the Holy Grail. Crit Rev Clin Lab Sci 2012;49(1):18–31.
3. Petrov MS, Shanbhag S, Chakraborty M, Phillips AR, Windsor JA. Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute pancreatitis. Gastroenterology 2010;139(3):813–820.
4. Forsmark CE. Chronic pancreatitis. In: Feldman M, Friedman LS, Brandt LJ, eds. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management, 9th ed. Philadelphia: Saunders, 2010:985–1016.
5. Nair RJ, Lawler L, Miller MR. Chronic pancreatitis. Am Fam Physician 2007;76(11):1679–1688.
6. Spanier BW, Dijkgraaf MG, Bruno MJ. Epidemiology, aetiology and outcome of acute and chronic pancreatitis: An update. Best Pract Res Clin Gastroenterol 2008;22(1):45–63.
7. Lowenfels AB, Maisonneuve P, Sullivan T. The changing character of acute pancreatitis: Epidemiology, etiology, and prognosis. Curr Gastroenterol Rep 2009;11(2):97–103.
8. Pandol SJ. Pancreatic secretion. In: Feldman M, Friedman LS, Brandt LJ, eds. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management, 9th ed. Philadelphia: Saunders, 2010:921–930.
9. Ferrone M, Raimondo M, Scolapio JS. Pancreatic enzyme pharmacotherapy. Pharmacotherapy 2007;27(6):910–920.
10. Forsmark CE, Baillie J. AGA Institute technical review on acute pancreatitis. Gastroenterology 2007;132(5): 2022–2044.
11. Talukdar R, Swaroop VS. Early management of severe acute pancreatitis. Curr Gastroenterol Rep 2011;13(2):123–130.
12. Baran B, Karaca C, Soyer OM, et al. Acute pancreatitis associated with H1N1 influenza during 2009 pandemic: A case report. Clin Res Hepatol Gastroenterol 2012;36(4): e69–e70.
13. Lee JK, Enns R. Review of idiopathic pancreatitis. World J Gastroenterol 2007;13(47):6296–6313.
14. Finkelberg DL, Sahani D, Deshpande V, Brugge WR. Autoimmune pancreatitis. N Engl J Med 2006;355(25):2670–2676.
15. Feurer ME, Adler DG. Post-ERCP pancreatitis: Review of current preventive strategies. Curr Opin Gastroenterol 2012;28(3):280–286.
16. Morton C, Klatsky AL, Udaltsova N. Smoking, coffee, and pancreatitis. Am J Gastroenterol 2004;99(4):731–738.
17. Lowe ME, Greer JB. Pancreatitis in children and adolescents. Curr Gastroenterol Rep 2008;10(2):128–135.
18. Nitsche C, Maertin S, Scheiber J, Ritter CA, Lerch MM, Mayerle J. Drug-induced pancreatitis. Curr Gastroenterol Rep 2012;14(2):131–138.
19. Eland IA, Alvarez CH, Stricker BH, Rodriguez LA. The risk of acute pancreatitis associated with acid-suppressing drugs. Br J Clin Pharmacol 2000;49(5):473–478.
20. Lin HH, Hsu CH, Chao YC. Tamoxifen-induced severe acute pancreatitis: A case report. Dig Dis Sci 2004;49(6):997–999.
21. Devlin JW, Lau AK, Tanios MA. Propofol-associated hypertriglyceridemia and pancreatitis in the intensive care unit: An analysis of frequency and risk factors. Pharmacotherapy 2005;25(10):1348–1352.
22. Preiss D. Lipid-modifying therapies and risk of pancreatitis: A meta-analysis. JAMA. 2012;308(8):804–811.
23. Fessel J, Hurley LB. Incidence of pancreatitis in HIV-infected patients: Comment on findings in EuroSIDA cohort. AIDS 2008;22(1):145–147.
24. Smith CJ, Olsen CH, Mocroft A, et al. The role of antiretroviral therapy in the incidence of pancreatitis in HIV-positive individuals in the EuroSIDA study. AIDS 2008;22(1):47–56.
25. Dhir R, Brown DK, Olden KW. Drug-induced pancreatitis: A practical review. Drugs Today (Barc) 2007;43(7):499–507.
26. Balani AR, Grendell JH. Drug-induced pancreatitis: Incidence, management and prevention. Drug Saf 2008;31(10):823–837.
27. Mallick S. Metformin induced acute pancreatitis precipitated by renal failure. Postgrad Med J 2004;80(942):239–240.
28. Institute for Safe Medication Practices. QuarterWatch 2011 annual report: An estimated 2 to 4 million drug-induced serious injuries in 2011. ISMP Medication Safety Alert! Acute Care 2012;17(11):1–3.
29. Knezevich E, Crnic T, Kershaw S, Drincic A. Liraglutide-associated acute pancreatitis. Am J Health Syst Pharm 2012;69(5):386–389.
30. Bain SC, Stephens JW. Exenatide and pancreatitis: An update. Expert Opin Drug Saf 2008;7(6):643–644.
31. Ahmad SR, Swann J. Exenatide and rare adverse events. N Engl J Med 2008;358(18):1970–1971.
32. U.S. Food and Drug Administration. Information for Healthcare Professionals—Acute Pancreatitis and Sitagliptin (Marketed as Januvia and Janumet). September 25, 2009, http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm183764.htm.
33. Trivedi CD, Pitchumoni CS. Drug-induced pancreatitis: An update. J Clin Gastroenterol 2005;39(8):709–716.
34. Criddle DN, McLaughlin E, Murphy JA, Petersen OH, Sutton R. The pancreas misled: Signals to pancreatitis. Pancreatology 2007;7(5–6):436–446.
35. Vonlaufen A, Wilson JS, Apte MV. Molecular mechanisms of pancreatitis: Current opinion. J Gastroenterol Hepatol 2008;23(9):1339–1348.
36. Gorelick F. Pancreatic protease-activated receptors: Friend and foe. Gut 2007;56(7):901–902.
37. Sand J, Nordback I. Acute pancreatitis: Risk of recurrence and late consequences of the disease. Nat Rev Gastroenterol Hepatol 2009;6(8):470–477.
38. Balthazar EJ. Staging of acute pancreatitis. Radiol Clin North Am 2002;40(6):1199–1209.
39. Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol 2006;101(10):2379–2400.
40. Mofidi R, Patil PV, Suttie SA, Parks RW. Risk assessment in acute pancreatitis. Br J Surg 2009;96(2):137–150.
41. Pezzilli R, Uomo G, Zerbi A, et al. Diagnosis and treatment of acute pancreatitis: The position statement of the Italian Association for the study of the pancreas. Dig Liver Dis 2008;40(10):803–808.
42. Working Party of the British Society of Gastroenterology, Association of Surgeons of Great Britain and Ireland, Pancreatic Society of Great Britain and Ireland, Association of Upper GI Surgeons of Great Britain and Ireland. UK guidelines for the management of acute pancreatitis. Gut 2005;54(Suppl 3):iii1–iii9.
43. Wu BU. Prognosis in acute pancreatitis. Can Med Assoc J 2011;183(6):673–677.
44. Vege SS, Gardner TB, Chari ST, et al. Low mortality and high morbidity in severe acute pancreatitis without organ failure: A case for revising the Atlanta classification to include “moderately severe acute pancreatitis”. Am J Gastroenterol 2009;104(3):710–715.
45. Gardner TB, Vege SS, Pearson RK, Chari ST. Fluid resuscitation in acute pancreatitis. Clin Gastroenterol Hepatol 2008;6(10):1070–1076.
46. Bakker OJ, van Santvoort HC, van Brunschot S, et al. Endoscopic transgastric vs surgical necrosectomy for infected necrotizing pancreatitis. JAMA 2012;307(10): 1053–1061.
47. Falor AE, de Virgilio C, Stabile BE, et al. Early laparoscopic cholecystectomy for mild gallstone pancreatitis: Time for a paradigm shift. Arch Surg 2012;1–5.
48. McClave SA, Chang WK, Dhaliwal R, Heyland DK. Nutrition support in acute pancreatitis: A systematic review of the literature. J Parenter Enteral Nutr 2006;30(2): 143–156.
49. Meier RF, Beglinger C. Nutrition in pancreatic diseases. Best Pract Res Clin Gastroenterol 2006;20(3):507–529.
50. Al-Omran M, Albalawi ZH, Tashkandi MF, Al-Ansary LA. Enteral versus parenteral nutrition for acute pancreatitis. Cochrane Database Syst Rev 2010;(1):CD002837.
51. Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: A randomised, double-blind, placebo-controlled trial. Lancet 2008;371(9613):651–659.
52. Gardner TB, Vege SS, Chari ST, et al. Faster rate of initial fluid resuscitation in severe acute pancreatitis diminishes in-hospital mortality. Pancreatology 2009;9(6):770–776.
53. Warndorf MG, Kurtzman JT, Bartel MJ, et al. Early fluid resuscitation reduces morbidity among patients with acute pancreatitis. Clin Gastroenterol Hepatol 2011;9(8):705–709.
54. de-Madaria E, Soler-Sala G, Sanchez-Paya J, et al. Influence of fluid therapy on the prognosis of acute pancreatitis: A prospective cohort study. Am J Gastroenterol 2011;106(10):1843–1850.
55. Wu BU, Hwang JQ, Gardner TH, et al. Lactated Ringer’s solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol 2011;9(8):710–717.
56. Mao EQ, Tang YQ, Fei J, et al. Fluid therapy for severe acute pancreatitis in acute response stage. Chin Med J (Engl) 2009;122(2):169–173.
57. Trikudanathan G, Navaneethan U, Vege SS. Current controversies in fluid resuscitation in acute pancreatitis: A systematic review. Pancreas 2012;41(6):827–834.
58. Nasr JY, Papachristou GI. Early fluid resuscitation in acute pancreatitis: A lot more than just fluids. Clin Gastroenterol Hepatol 2011;9(8):633–634.
59. Thompson DR. Narcotic analgesic effects on the sphincter of Oddi: A review of the data and therapeutic implications in treating pancreatitis. Am J Gastroenterol 2001;96(4): 1266–1272.
60. Banks PA. Practice guidelines in acute pancreatitis. Am J Gastroenterol 1997;92(3):377–386.
61. Johnson CD, Kingsnorth AN, Imrie CW, et al. Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis. Gut 2001;48(1):62–69.
62. Kitagawa M, Hayakawa T. Antiproteases in the treatment of acute pancreatitis. J Pancreas 2007;8(4 Suppl):518–525.
63. Andriulli A, Leandro G, Clemente R, et al. Meta-analysis of somatostatin, octreotide and gabexate mesilate in the therapy of acute pancreatitis. Aliment Pharmacol Ther 1998;12(3):237–245.
64. Bai Y, Gao J, Zou DW, Li ZS. Prophylactic antibiotics cannot reduce infected pancreatic necrosis and mortality in acute necrotizing pancreatitis: Evidence from a meta-analysis of randomized controlled trials. Am J Gastroenterol 2008;103(1):104–110.
65. Buchler M, Malfertheiner P, Friess H, et al. Human pancreatic tissue concentration of bactericidal antibiotics. Gastroenterology 1992;103(6):1902–1908.
66. Lankisch PG, Lerch MM. The role of antibiotic prophylaxis in the treatment of acute pancreatitis. J Clin Gastroenterol 2006;40(2):149–155.
67. Rokke O, Harbitz TB, Liljedal J, et al. Early treatment of severe pancreatitis with imipenem: A prospective randomized clinical trial. Scand J Gastroenterol 2007;42(6): 771–776.
68. Luiten EJ, Bruining HA. Antimicrobial prophylaxis in acute pancreatitis: Selective decontamination versus antibiotics. Baillieres Best Pract Res Clin Gastroenterol 1999;13(2): 317–330.
69. Poon RT, Fan ST. Antisecretory agents for prevention of post-ERCP pancreatitis: Rationale for use and clinical results. J Pancreas 2003;4(1):33–40.
70. Lavy A, Karban A, Suissa A, Yassin K, Hermesh I, Ben-Amotz A. Natural beta-carotene for the prevention of post-ERCP pancreatitis. Pancreas 2004;29(2):e45–e50.
71. Murray B, Carter R, Imrie C, Evans S, O’Suilleabhain C. Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography. Gastroenterology 2003;124(7):1786–1791.
72. Hoogerwerf WA. Pharmacological management of pancreatitis. Curr Opin Pharmacol 2005;5(6):578–582.
73. Elmunzer BJ, Scheiman JM, Lehman GA, et al. A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. New Engl J Med 2012;366(15): 1414–1422.
74. Bai Y, Gao J, Zou DW, Li ZS. Prophylactic octreotide administration does not prevent post-endoscopic retrograde cholangiopancreatography pancreatitis: A meta-analysis of randomized controlled trials. Pancreas 2008;37(3): 241–246.
75. Zheng M, Chen Y, Bai J, Xin Y, Pan X, Zhao L. Meta-analysis of prophylactic allopurinol use in post-endoscopic retrograde cholangiopancreatography pancreatitis. Pancreas 2008;37(3):247–253.
76. Yadav D, Hawes RH, Brand RE, et al. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med 2009;169(11):1035–1045.
77. Braganza JM, Lee SH, McCloy RF, McMahon MJ. Chronic pancreatitis. Lancet 2011;377(9772):1184–1197.
78. Balakrishnan V, Unnikrishnan AG, Thomas V, et al. Chronic pancreatitis. A prospective nationwide study of 1,086 subjects from India. J Pancreas 2008;9(5):593–600.
79. Tattersall SJ, Apte MV, Wilson JS. A fire inside: Current concepts in chronic pancreatitis. Intern Med J 2008;38(7):592–598.
80. Maisonneuve P, Lowenfels AB, Mullhaupt B, et al. Cigarette smoking accelerates progression of alcoholic chronic pancreatitis. Gut 2005;54(4):510–514.
81. Maisonneuve P, Frulloni L, Mullhaupt B, et al. Impact of smoking on patients with idiopathic chronic pancreatitis. Pancreas 2006;33(2):163–168.
82. Seicean A, Tantau M, Grigorescu M, Mocan T, Seicean R, Pop T. Mortality risk factors in chronic pancreatitis. J Gastrointestin Liver Dis 2006;15(1):21–26.
83. Tolstrup JS, Kristiansen L, Becker U, Gronbaek M. Smoking and risk of acute and chronic pancreatitis among women and men: A population-based cohort study. Arch Intern Med 2009;169(6):603–609.
84. Andriulli A, Botteri E, Almasio PL, Vantini I, Uomo G, Maisonneuve P. Smoking as a cofactor for causation of chronic pancreatitis: A meta-analysis. Pancreas 2010;39(8): 1205–1210.
85. Schneider A, Löhr JM, Singer MV. The M-ANNHEIM classification of chronic pancreatitis: Introduction of a unifying classification system based on a review of previous classifications of the disease. J Gastroenterol 2007;42(2): 101–119.
86. Verlaan M, Roelofs HM, van-Schaik A, et al. Assessment of oxidative stress in chronic pancreatitis patients. World J Gastroenterol 2006;12(35):5705–5710.
87. Talukdar R, Tandon RK. Pancreatic stellate cells: New target in the treatment of chronic pancreatitis. J Gastroenterol Hepatol 2008;23(1):34–41.
88. Talukdar R, Saikia N, Singal DK, Tandon R. Chronic pancreatitis: Evolving paradigms. Pancreatology 2006;6(5): 440–449.
89. Anaparthy R, Pasricha PJ. Pain and chronic pancreatitis: Is it the plumbing or the wiring? Curr Gastroenterol Rep 2008;10(2):101–106.
90. Gachago C, Draganov PV. Pain management in chronic pancreatitis. World J Gastroenterol 2008;14(20):3137–3148.
91. Drewes AM, Krarup AL, Detlefsen S, Malmstrom ML, Dimcevski G, Funch-Jensen P. Pain in chronic pancreatitis: The role of neuropathic pain mechanisms. Gut 2008;57(11): 1616–1627.
92. Drewes AM, Gratkowski M, Sami SA, Dimcevski G, Funch-Jensen P, Arendt-Nielsen L. Is the pain in chronic pancreatitis of neuropathic origin? Support from EEG studies during experimental pain. World J Gastroenterol 2008;14(25):4020–4027.
93. Chen WX, Zhang WF, Li B, et al. Clinical manifestations of patients with chronic pancreatitis. Hepatobiliary Pancreat Dis Int 2006;5(1):133–137.
94. Sun DY, Jiang YB, Rong L, Jin SJ, Xie WZ. Clinical application of 13C-Hiolein breath test in assessing pancreatic exocrine insufficiency. Hepatobiliary Pancreat Dis Int 2003; 2(3):449–452.
95. Conwell DL, Banks PA. Chronic pancreatitis. Curr Opin Gastroenterol 2008;24(5):586–590.
96. Mullhaupt B, Truninger K, Ammann R. Impact of etiology on the painful early stage of chronic pancreatitis: A long-term prospective study. Z Gastroenterol 2005;43(12):1293–1301.
97. Grant JP. Nutritional support in acute and chronic pancreatitis. Surg Clin North Am 2011;91(4):805–820.
98. Kowalczyk LM, Draganov PV. Endoscopic therapy for chronic pancreatitis: Technical success, clinical outcomes, and complications. Curr Gastroenterol Rep 2009;11(2): 111–118.
99. Dumonceau JM, Costamagna G, Tringali A, et al. Treatment for painful calcified chronic pancreatitis: Extracorporeal shock wave lithotripsy versus endoscopic treatment: A randomised controlled trial. Gut 2007;56(4):545–552.
100. Puli SR, Reddy JB, Bechtold ML, Antillon MR, Brugge WR. EUS-guided celiac plexus neurolysis for pain due to chronic pancreatitis or pancreatic cancer pain: A meta-analysis and systematic review. Dig Dis Sci 2009;54(11):2330–2337.
101. Kaufman M, Singh G, Das S, et al. Efficacy of endoscopic ultrasound-guided celiac plexus block and celiac plexus neurolysis for managing abdominal pain associated with chronic pancreatitis and pancreatic cancer. J Clin Gastroenterol 2010;44(2):127–134.
102. Deviere J, Bell RH Jr, Beger HG, Traverso LW. Treatment of chronic pancreatitis with endotherapy or surgery: Critical review of randomized control trials. J Gastrointest Surg 2008;12(4):640–644.
103. Cahen DL, Gouma DJ, Nio Y, et al. Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis. N Engl J Med 2007;356(7):676–684.
104. Ahmed AU, Pahlplatz JM, Nealon WH, van Goor H, Gooszen HG, Boermeester MA. Endoscopic or surgical intervention for painful obstructive chronic pancreatitis. Cochrane Database Syst Rev 2012;1:CD007884.
105. Garcea G, Weaver J, Phillips J, et al. Total pancreatectomy with and without islet cell transplantation for chronic pancreatitis: A series of 85 consecutive patients. Pancreas 2009;38(1):1–7.
106. Bramis K, Gordon-Weeks AN, Friend PJ, et al. Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis. Br J Surg 2012;99(6):761–766.
107. Staahl C, Dimcevski G, Andersen SD, et al. Differential effect of opioids in patients with chronic pancreatitis: An experimental pain study. Scand J Gastroenterol 2007;42(3): 383–390.
108. Shafiq N, Rana S, Bhasin D, et al. Pancreatic enzymes for chronic pancreatitis. Cochrane Database Syst Rev 2009;(4):CD006302.
109. Olesen SS, Bouwense SA, Wilder-Smith OH, van Goor H, Drewes AM. Pregabalin reduces pain in patients with chronic pancreatitis in a randomized, controlled trial. Gastroenterology 2011;141(2):536–543.
110. Bhardwaj P, Garg PK, Maulik SK, Saraya A, Tandon RK, Acharya SK. A randomized controlled trial of antioxidant supplementation for pain relief in patients with chronic pancreatitis. Gastroenterology 2009;136(1):149–159.
111. Shah NS, Makin AJ, Sheen AJ, Siriwardena AK. Quality of life assessment in patients with chronic pancreatitis receiving antioxidant therapy. World J Gastroenterol 2010;16(32):4066–4071.
112. Grigsby B, Rodriguez-Rilo H, Khan K. Antioxidants and chronic pancreatitis: Theory of oxidative stress and trials of antioxidant therapy. Dig Dis Sci 2012;57(4):835–841.
113. Waljee AK, Dimagno MJ, Wu BU, Schoenfeld PS, Conwell DL. Systematic review: Pancreatic enzyme treatment of malabsorption associated with chronic pancreatitis. Aliment Pharmacol Ther 2009;29(3):235–246.
114. Safdi M, Bekal PK, Martin S, Saeed ZA, Burton F, Toskes PP. The effects of oral pancreatic enzymes (Creon 10 capsule) on steatorrhea: A multicenter, placebo-controlled, parallel group trial in subjects with chronic pancreatitis. Pancreas 2006;33(2):156–162.
115. Czako L, Takacs T, Hegyi P, et al. Quality of life assessment after pancreatic enzyme replacement therapy in chronic pancreatitis. Can J Gastroenterol 2003;17(10):597–603.
116. Dominguez-Munoz JE, Iglesias-Garcia J, Iglesias-Rey M, Figueiras A, Vilarino-Insua M. Effect of the administration schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: A randomized, three-way crossover study. Aliment Pharmacol Ther 2005;21(8):993–1000.
117. Vecht J, Symersky T, Lamers CB, Masclee AA. Efficacy of lower than standard doses of pancreatic enzyme supplementation therapy during acid inhibition in patients with pancreatic exocrine insufficiency. J Clin Gastroenterol 2006;40(8):721–725.
118. Creon (pancrelipase) [package insert]. North Chicago, IL: Abbott Laboratories, 2011.
119. Viokace (pancrelipase) [package insert]. Birmingham, AL: Aptalis Pharma US Inc, 2012.
120. Traynor K. First FDA-approved pancrelipase product may mark new era for providers, patients. Am J Health Syst Pharm 2009;66(12):1066, 1068.
121. Sani G, Kotzalidis GD, Simonetti A, et al. Development of asymptomatic pancreatitis with paradoxically high serum clozapine levels in a patient with schizophrenia and the CYP1A2*1F/1F genotype. J Clin Psychopharmacol 2010;30(6):737–739.
122. Dominguez-Munoz JE, Iglesias-Garcia J, Vilarino-Insua M, Iglesias-Rey M. 13C-mixed triglyceride breath test to assess oral enzyme substitution therapy in patients with chronic pancreatitis. Clin Gastroenterol Hepatol 2007;5(4):484–488.