US Pharm. 2009;34(8):26-35.
Alcohol abuse continues to be a major cause of morbidity and mortality in the United States. It results in more than 100,000 deaths and accumulates $185 billion in health care costs annually.1 In 2006, the National Household Survey on Drug Abuse reported that approximately 51.8% of Americans 12 years of age and older consumed alcohol, and of these, 1 out of 5 reported binge drinking, defined as having five or more drinks on one occasion, occurring at least within 30 days of the survey. It is well understood that chronic alcohol dependence negatively affects many organs in the human body. Among the common organs (liver, brain, heart), alcohol-induced pancreatitis is less prevalent and least understood, but it is known to be extremely painful and potentially fatal to the patient.1,2
The link between alcohol abuse and pancreatitis is relatively weak compared to that between alcohol and other well-defined and studied diseases such as liver cirrhosis. Nevertheless, a U.S. census in 1999 revealed that pancreatitis was the 235th leading cause of death, translating to 3,289 of 2.4 million fatalities. Of these, acute pancreatitis was responsible for 84%, with the remaining 16% attributed to chronic pancreatitis. Approximately 45% of the chronic pancreatitis deaths were correlated to alcohol abuse.2
It remains unclear why only 10% of alcohol abusers develop clinically relevant inflammation of the pancreas. It is hypothesized that certain individuals may be more susceptible to the disease then others. Of the proposed factors influencing pancreatitis development, the following have been identified as most relevant: diet, amount and type of alcohol consumed, race (African Americans have 2-3 times the likelihood of disease development), fat intolerance, smoking, and other environmental and genetic cofactors that are yet to be determined. Clinically, alcoholic pancreatitis has been defined as chronic pancreatitis associated with daily alcohol intake of ≥80 g/day (~8-10 standard drinks per day) for several years (average of 13-21 years).3 However, as previously mentioned, it is possible that alcohol alone may not be responsible for pancreatic cell damage; instead, it might act as a cofactor in the process of alcohol-induced pancreatitis.2-4
Although it was once thought that alcoholic pancreatitis is a chronic disease with acute exacerbations,5 recent evidence has indicated that repeated necroinflammation (inflammation of pancreatic tissue) during acute attacks leads to chronic pancreatic injury (acinar atrophy and fibrosis), ultimately resulting in endocrine and exocrine dysfunction.5,6 Although the association between alcohol abuse and pancreatitis has been confirmed, the pathophysiology continues to be under investigation with no defined explanation for the mechanism.4,5,7,8 Studies have been hindered by the difficulty in obtaining human pancreatic tissue for analysis, as well the minimal amount of appropriate animal models available specific for this disease.5 Despite this fact, in recent decades much research has been done and progress made in unveiling this not so well-defined phenomenon.
Previously, it was hypothesized that the effect of alcohol on the sphincter of Oddi, often referred to as the “sphincteric theory,” caused a reflux in the gallbladder and bile ducts, resulting in pancreatic damage.5 Inconsistent findings in several clinical trials have revealed that alcohol can both decrease and increase sphincter of Oddi activity in humans, shifting research away from this hypothesis.4 Despite the lack of strong clinical evidence supporting the sphincteric theory, it should be noted that a recent study confirmed that spasms of the sphincter of Oddi may be one of the contributory mechanisms that potentiate the decrease in pancreatic secretions.4
Over the past three decades, research has focused on examining the direct effect alcohol has on the clusters of secretory cells (acinar cells), the most abundant cells in the pancreas, responsible for the production of pancreatic juice containing digestive enzymes.5 It has been established that the pancreas, similar to the liver, is able to metabolize ethanol via both oxidative and nonoxidative pathways, producing acetaldehyde and fatty acid ethyl esters, respectively.4,7-9 The metabolic byproducts created during both of these processes have been linked to significant increases in both digestive and lysosomal enzymes, as well as to an increase in the contact between these enzymes. This is thought to lead to premature intracellular activation of digestive enzymes and results in autodigestion (predisposing the pancreas to the breakdown of its own enzymes) and necroinflammation.4-6 Repeated episodes of necroinflammation may trigger the activation of pancreatic stellate cells (PSCs), which in a normal pancreas are usually inactive and are a major source of extracellular matrix proteins that make up fibrous tissue, and thus have been found predominantly in areas of fibrosis. In addition, in vitro studies have demonstrated that PSCs can be activated directly by ethanol metabolism to acetaldehyde and during the subsequent production of oxidative stress. Continuous activation of PSCs will ultimately lead to chronic pancreatitis.4,5,7,8
Natural Progression and Clinical Manifestations
The onset of alcoholic pancreatitis usually occurs in men between the ages of 35 and 40 years. Initial presentation of alcoholic pancreatitis may take several years to surface and is induced by increase in alcohol consumption and duration of alcohol abuse.6 Commonly, symptoms associated with acute pancreatitis are relapsing upper abdominal pain (ranging in severity from mild to severe), nausea, vomiting, and loss of appetite.3,6,7,10 Pain may be relieved by bending over or lying on one side and is usually worsened by food intake.6,10 Mainly, acute pancreatitis is self-limiting and will resolve within a week.6,11 However, in rare cases mortality will occur in those patients with local complications and organ failure.6,11
Those patients who continue alcohol abuse will progress to develop chronic pancreatitis, which usually occurs 5 to 6 years after the presentation of initial symptoms.6 In contrast to acute pancreatitis, chronic pancreatitis is characterized by chronic, severe pain, calcification of pancreatic tissue, and exocrine and endocrine insufficiency.3,6,10 The pathophysiology of pain in chronic pancreatitis is not fully understood, and the duration of persistent pain is often unpredictable.3,6 It has been observed that with the progression of the disease, “pancreatic burnout” occurs with the onset of exocrine and endocrine insufficiency, and patients then achieve pain relief (mean time 4.5 years).3,6,7 Conflicting evidence suggests that this correlation does not exist, and further investigation is necessary to fully understand the process.6 Only about 10% of patients with chronic alcohol-induced pancreatitis present with endocrine and exocrine insufficiency without prior acute pancreatitis symptoms.3
Furthermore, chronic pancreatitis has been shown to lead to multiple comorbidities, including maldigestion, diabetes, and pancreatic cancer.12 The connection to the latter is less clear, since contributing factors such as smoking (alcohol abuse is strongly linked to tobacco abuse) and malnutrition can influence cancer development. Moreover, patients diagnosed with alcoholic pancreatitis will typically die within 20 years after the onset of the disease, with 1 out of 5 mortalities directly attributed to pancreatitis. The majority of the deaths will result from the effect of alcohol and/or tobacco on other organs.6,7
In addition to symptoms, diagnosis of pancreatitis is made when structural and functional abnormalities of the pancreas are noted. The gold standard of structural deformity was once thought to be the elevation of amylase (pancreatic enzyme that digests starch) levels in the blood.10 However, diagnosis has recently moved away from using this measure alone, and now an increase in both amylase and lipase (pancreatic enzyme that digests fats) three times above the normal limit is used to identify pancreatitis.6,7,10 In addition, computed tomography (CT) scans are commonly used to identify pseudocysts (pockets of digestive enzymes that accumulate in the pancreas after repeated attacks, often present in severe pancreatitis) and calcification.6,10 Magnetic resonance cholangiopancreatography (MRCP) is the newest imaging technique used for diagnosis, which provides exceptional cross-sectional images of the pancreas and will likely become the gold standard of diagnosing pancreatitis.7 One main indicator of pancreatic dysfunction is the presence of steatorrhea, which usually occurs with the development of exocrine dysfunction. Steatorrhea typically begins when the lipase secretion is less than 10% of normal and manifests as bulky, foul-smelling, and fatty stools that result from the malabsorption of fat. With the above in mind, it is understandable why pancreatitis presents with weight loss, as well the malabsorption of proteins and carbohydrates, which often leads to vitamin deficiency.3,6,7,10
Treatment of Acute Pancreatitis
Treatment of acute pancreatitis is patient specific and individualized based on the severity of symptoms.11 In the majority of cases, patients present with mild symptoms requiring mainly supportive care, such as bed rest, appropriate analgesia, abstinence from food intake, fluid replacement, and nasogastric suctioning (for patients presenting with nausea and vomiting). The goals of therapy are to prevent systemic complications, pancreatic necrosis, and infection.6,11,12
Nonpharmacologic Therapy (Nutritional Support)
In both mild and severe acute pancreatitis attacks, it is vital to ensure that the patient has adequate nutritional support. Pancreatitis attacks often create a catabolic state that potentiates the depletion of nutrients and also increases the risk for complications.11,12 In mild attacks, it is encouraged that once the patient reports pain resolution and bowel sounds are audible, oral feedings should be resumed. If in response to food the symptoms worsen, the feedings should be discontinued and attempted at a later time. In severe attacks, if it is anticipated that the patient will abstain from food for greater than 7 days, total parenteral nutrition (TPN) should be initiated.6,11,12
Recent debates over optimal means of nutrition delivery have created a controversy in treatment. It has been previously thought that delivering nutrients via the enteral route would further exacerbate symptoms of pancreatitis by stimulating pancreatic enzyme secretion. However, recent studies have shown that by delivering the nutrients directly into the jejunum, the gut can be avoided, preventing further enzyme secretion. Furthermore, the studies noted that patients receiving enteral feedings had a decrease in sepsis risk and improved maintenance of gut integrity, and also incurred lower hospital costs.6,11 Although numerous studies have revealed that enteral feedings are safe and as effective as TPN, larger multicenter trials are necessary prior to making enteral nutrition the standard of patient care.
Pain relief is the primary goal of therapy in acute pancreatitis. Analgesics, such as meperidine, morphine, and hydromorphone, are commonly used to achieve pain control. Previously, treatment with meperidine was considered a first-line option, mostly because other narcotics were thought to irritate the pancreas by increasing serum amylase and lipase levels, thereby worsening pancreatitis. Over the past several years, research has proven that the increase in the release of pancreatic enzymes during treatment with narcotics is minimal and does not typically affect progression of the disease.7 The use of meperidine, although still common, has diminished, likely due to the fact that this drug has a dosage ceiling, as well as an active metabolite that accumulates in renal insufficiency and is therefore contraindicated for use in renal failure patients. Both morphine and hydromorphone have been proven safe and effective analgesic options in acute pancreatitis, with a longer half-life than meperidine and no active metabolites.7
Secondary to pain control, the management of systemic complications, such as prevention of pancreatic necrosis, multi organ failure, and sepsis, are an integral part of treatment during an acute pancreatitis attack. Systemic complications may be diminished by adequate fluid resuscitation and supplemental support for vital organs such as the lungs, kidneys, heart, and liver. However, the method of prevention is a topic of controversy and is not yet well understood or defined, as is the disease itself.7
Multiple pharmacologic agents have been under investigation to diminish the progression of the disease by decreasing the secretion of pancreatic enzymes, as well as by attempting to limit the number of inflammatory mediators in circulation.7 Agents such as H2-receptor blockers, proton pump inhibitors (PPIs), corticosteroids, atropine, lexipafant, low-molecular-weight dextran, infliximab, and antioxidants have all proved to be either nonefficacious in decreasing mortality, or currently available data on them are inconclusive. In contrast, initiation of octreotide, an analogue of somatostatin, was found to improve pancreatic edema and shorten recovery time in a small, nonplacebo-controlled trial. Due to these limitations, additional clinical trials are necessary to evaluate the role of octreotide in the prevention of disease complications.7
In patients with severe, complicated, acute pancreatitis with confirmed pancreatic necrosis, the use of broad-spectrum antibiotics is mandated. Typically, treatment will be initiated with either imipenem-cilastatin or a fluoroquinolone plus metronidazole and continued for 10 to 14 days. These regimens have proven to decrease risk of sepsis and reduce rates of mortality. In those patients with acute pancreatitis without CT-proven necrosis, the use of prophylactic antibiotics is controversial and has been linked to resistant bacterial as well as fungal infections; therefore, their use is contraindicated.7
Treatment of Chronic Pancreatitis
Management of chronic pancreatitis is centered on the treatment of pain, maldigestion, and diabetesthree chief clinical features of the disease.
Abstinence from alcohol is the key factor in relieving abdominal pain associated with chronic pancreatitis. In addition, patients must adhere to a strict diet limiting intake of fat (50-75 g/day) and eat small, frequent meals (~6 per day) to decrease the amount of postprandial enzymes secreted from the pancreas. Surgical procedures such as subtotal pancreatectomy, decompression of the main pancreatic duct, and interruption of the splanchnic nerve aim to decrease intraductal or interstitial pancreatic pressure in those patients resistant to pain management with pharmacotherapy. Often, postsurgical pain relief is short lived, with only 50% to 60% of patients remaining pain free after 5 years.13
Pain: Appropriate pain management is the mainstay of therapy in chronic pancreatitis. Nonopioid analgesics such as acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line therapy and should be administered prior to each meal for prevention of postprandial pain.6,7 Because pain management with opioid analgesics is complicated by the difficulty in differentiating pain from narcotics addiction, prior to opioid initiation a trial of nonenteric-coated pancreatic enzymes plus a gastric acid suppressant (PPI or H2 blocker) may be warranted in patients in whom adequate pain management is not achieved with nonopioids; however, the efficacy of these agents is controversial.6,7 Severe pain, unresponsive to nonnarcotic analgesics, should be treated with opiate analgesics. Consideration should be given to coadministering nonnarcotic pain modulators such as selective serotonin reuptake inhibitors or tricyclic antidepressants to patients with depression and/or difficult-to-manage pain, since these agents have been shown to up-regulate the analgesic effect of narcotics.
Malabsorption: As previously discussed, a major complication of chronic pancreatitis is malabsorption, commonly resulting in steatorrhea. Although not all patients with steatorrhea require treatment, those patients who maintain a fat-restricted diet (~100 g per day) and are found to have more than 7 g of fat in their feces after a 24-hour collection are candidates for medical treatment. In such cases, the administration of pancreatic enzymes with each meal, as well as a further reduction of dietary fat intake (<25 g/meal), is indicated. To avoid the breakdown of the exogenous pancreatic enzymes by gastric acid, the enteric-coated formulation is preferred.6,7
Diabetes: Patients with type 2 diabetes induced by chronic pancreatitis have both insufficient insulin secretion and glucagon reserves. The combination of these two deficiencies puts the patient at greater risk for hypoglycemia then other patients with diabetes. Thus, the approach to treatment is often less aggressive, and oral agents are the initial choice of treatment. Life-threatening hypoglycemic episodes limit the use of insulin in such patients.3,12
The Pharmacist’s Role
Alcohol-induced pancreatitis is a complicated disease with many remaining unknowns. Because of such complexity, patients suffering from this disease greatly benefit from a multidisciplinary approach to treatment. Patients often need special attention from pain specialists, psychotherapists, and dieticians, as well as pharmacists. Primarily, patients receiving chronic therapy with narcotics should be evaluated for appropriate use of the medication with each refill, as well as educated about the commonly reported adverse affects such as constipation and respiratory suppression. Furthermore, patients with either acute or chronic pancreatitis must receive continuous counseling and education regarding the importance of eliminating alcohol use. Overall, pharmacists can play a vital role in helping patients identify primary signs and symptoms of the disease and also assist patients in making lifestyle modifications, which may prevent disease progression, lower hospital costs, and decrease incidents of morbidity and mortality.
1. Doering LP, Kennedy WK, Boothby LA. Substance-related disorders: alcohol, nicotine, and caffeine. In: DiPiro JT, Talbert RL, Yee CG, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: McGraw-Hill; 2008.
2. Dufour MC, Adamson MD. The epidemiology of alcohol-induced pancreatitis. Pancreas. 2003;27:286-290.
3. Schneider A, Singer MV. Alcoholic pancreatitis. Dig Dis. 2005;23:222-231.
4. Apte MV, Pirola RC, Wilson JS. Molecular mechanism of alcoholic pancreatitis. Dig Dis. 2005;23:232-240.
5. Vonlaufen A, Wilson JS, Pirola RC, Apte MV. Role of alcohol metabolism in chronic pancreatitis. Alcohol Res Health. 2007;30:48-54.
6. Apte MV, Wilson JS. Alcohol-induced pancreatic injury. Best Pract Res Clin Gastroenterol. 2003;17:593-612.
7. Apte MV, Wilson JS, Korsten MA. Alcohol-related pancreatic damage: mechanisms and treatment. Alcohol Health Res World. 1997;21:13-20.
8. Chowdhury P, Gupta P. Pathophysiology of alcoholic pancreatitis: an overview. World J Gastroenterol.
9. Purohit V, Russo D, Salin M, Brown R. Mechanism of alcoholic pancreatitis: introduction and summary of the symposium. Pancreas. 2003;27:281-285.
10. Acute pancreatitis. www.intelihealth.com. Accessed April 22, 2009.
11. Greenberger NF, Toskes PP. Acute and chronic pancreatitis. In: Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill; 2008.
12. Wolfe MM, Cohen S, Davis GL, et al, eds. Therapy of Digestive Disorders. Philadelphia, PA: WB Saunders; 2000:227-245.
13. Steer ML, Waxman I, Freedman S, et al. Chronic pancreatitis. N Engl J Med. 1995;332:1482-1490.
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