1. Top of page
  2. Summary
  3. Introduction
  4. Pathophysiology of pain in chronic pancreatitis
  5. Management of chronic pancreatitis pain
  6. Conclusions
  7. Acknowledgement
  8. References

Background  Pain in chronic pancreatitis chronic pancreatitis is a frustrating and challenging symptom for both the patient and clinician. It is the most frequent and most significant symptom. Many patients fail the currently available conservative options and require opiates or endoscopic/surgical therapy.

Aim  To highlight the pathophysiology and management of chronic pancreatitis pain, with an emphasis on recent developments and future directions.

Methods  Expert review, utilizing in addition a comprehensive search of PubMed utilizing the search terms chronic pancreatitis and pain, treatment or management and a manual search of recent conference abstracts for articles describing pain and chronic pancreatitis.

Results  Pancreatic pain is heterogenous in its manifestations and pathophysiology. First-line medical options include abstinence from alcohol and tobacco, pancreatic enzymes, adjunctive agents, antioxidants, and non-opiate or low potency opiate analgesics. Failure of these options is not unusual. More potent opiates, neurolysis and endoscopic and surgical options can be considered in selected patients, but this requires appropriate expertise. New and better options are needed. Future options could include new types of pancreatic enzymes, novel antinociceptive agents nerve growth factors, mast cell-directed therapy, treatments to limit fibrinogenesis and therapies directed at the central component of pain.

Conclusions  Chronic pancreatitis pain remains difficult to treat. An approach utilizing conservative medical therapies is appropriate, with more invasive therapies reserved for failure of this conservative approach. Treatment options will continue to improve with new and novel therapies on the horizon.


  1. Top of page
  2. Summary
  3. Introduction
  4. Pathophysiology of pain in chronic pancreatitis
  5. Management of chronic pancreatitis pain
  6. Conclusions
  7. Acknowledgement
  8. References

Chronic pancreatitis is a heterogeneous and complex disease. While we traditionally define acute pancreatitis as an event from which the pancreas recovers completely and chronic pancreatitis as a condition characterized by permanent and irreversible damage, this distinction is not accurate and the two conditions seem to be part of a single spectrum. Chronic pancreatitis often (perhaps always) evolves from episodes (clinical or subclinical) of acute pancreatic injury and the transition from acute to chronic pancreatitis may be subtle or even unrecognizable.

Pain may initially be episodic early in this process and the evolution and character of pain are highly variable. Pain may be intermittent, constant or continuous with superimposed acute flares. In some patients with chronic pancreatitis, pain can occur in discrete episodes with or without identifiable pancreatic inflammation (elevations in amylase and/or lipase with evidence of pancreatic or peripancreatic inflammation on abdominal computed tomography), with complete interval resolution. Others experience a chronic, daily, dull, epigastric ache, punctuated by severe exacerbations that may require hospitalization even in the absence of identifiable inflammation.

Pain may manifest in a multiplicity of forms, ranging from those patients with little or no pain to those with overwhelming, continuous and severe pain. The classic character of pain is a constant, severe, dull ache in the mid-epigastrium worsened by high-fat foods, which radiates between the shoulder blades and lasts for days at a time. This classic pain pattern is not universal, and the location, character and quality of pain can be quite variable. Generally, chronic pancreatitis is a condition that evolves slowly over time and pain may be a prominent early feature; at a time when the gland appears relatively normal on imaging studies and neither exocrine nor endocrine insufficiency has developed. Patients in this situation may have rather severe pain, but lack the features of pancreatic damage (structural or functional) that allow one to make a diagnosis of chronic pancreatitis using currently available diagnostic tests. In other words, patients lie on a spectrum ranging from very early painful disease (so called ‘minimal change’, or ‘small duct’ CP) with relatively preserved physiology to end stage disease with very little endocrine or exocrine function. In natural history studies, the progression from this early stage chronic pancreatitis to end stage disease with steatorrhoea and diabetes is about 20 years.1 The pain of chronic pancreatitis may remain stable, worsen or improve over this prolonged period of time. This may lead to a tendency during this time, on the part of patients and clinicians, towards complacency. This complacency may have been propagated by some studies that showed that the pain of chronic pancreatitis has a tendency to lessen with time;2–4hence, the adage that pain will probably ‘burn out’. Not all studies demonstrate this phenomenon, however, and it is not possible to predict in an individual patient if pain will diminish, remain stable or intensify over time. Most current theories of the pathophysiology of chronic pancreatitis postulate that repeated episodes of inflammation and pancreatic injury drive the process within the gland towards irreversible injury. This process is linked to peripheral and central nociceptive nerve sensitization, which play an important role in producing a chronic pain state that is self-perpetuating. Once the disease has advanced and these pathophysiological processes are firmly established, the management of pain becomes much less effective. It is therefore important to intervene as early as possible to prevent this progression, if possible, and complacency in management under the assumption that pain will ‘burn-out’ on its own is misguided.

The causes of chronic pancreatitis are diverse. While that is not the subject of this review, recognition of the cause of chronic pancreatitis in an individual is an important step in identifying possible interventions to reduce the progressive pancreatic damage and in that way mitigate, as much as possible, the pain of chronic pancreatitis. In the most common cause of chronic pancreatitis in the Western World, alcohol abuse, which accounts for 70% of cases, cessation of alcohol can slow the progression of disease5 and have some beneficial effect on pain.6–8 In chronic pancreatitis due to hypertriglyceridaemia, maintenance of triglycerides in a more normal range would be expected to reduce the chance of repeated painful attacks and ultimately the chance of chronic pancreatitis. In postnecrotic chronic pancreatitis due to severe gallstone pancreatitis, prevention of recurrent choledocholithiasis could minimize further damage to the pancreas. In all patients with recurrent pancreatitis, pancreatic duct strictures may occasionally develop and cause progressive injury to the upstream gland; recognition and management of this condition could mitigate the severity of pain. Patients with hypercalcaemia-induced pancreatitis due to hyperparathyroidism should be appropriately treated. In some causes of chronic pancreatitis, such as that due to genetic mutations, no specific therapy directed at the underlying cause may currently be possible. In all forms of chronic pancreatitis, however, it appears that smoking worsens the injury to the pancreas and may be enough, in and of itself, to cause chronic pancreatitis.9 Avoidance of tobacco would be expected therefore to have some long-term benefit on the pancreas outside the more obvious benefits of avoiding lung injury and lung cancer.

All these interventions have two important goals. The first is to reduce the recurrent injury to the pancreas. An acute episode of inflammation (acute pancreatitis) may or may not eventually lead to chronic pancreatitis. With repeated episodes, it becomes increasingly likely that the inflammatory milieu within the pancreas will shift towards chronic inflammation, with the activation of pancreatic stellate cells, fibrinogenesis and irreversible pancreatic damage.10–12 The second goal is one that seems very likely, but is not yet well established is that this reduction in pancreatic damage will ultimately be translated into a slowing of the natural history of disease, less exocrine and endocrine insufficiency and most importantly less severe abdominal pain.

Pathophysiology of pain in chronic pancreatitis

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathophysiology of pain in chronic pancreatitis
  5. Management of chronic pancreatitis pain
  6. Conclusions
  7. Acknowledgement
  8. References

The pathophysiology of the pain of chronic pancreatitis is incompletely characterized. Yet an understanding of the some of the mechanisms underlying the pain of chronic pancreatitis is useful to serve as a theoretical basis for current and future therapies. One of challenges in the study of chronic pancreatitis is the lack of an excellent animal model. There are fewer animal models of chronic pancreatitis than of acute pancreatitis and all have drawbacks, chiefly the fact that although fibrosis can be induced, acini tend to be preserved and remain relatively functional.13 Of course, the physiology of rat and mouse pancreas may be fundamentally quite different from that of our own. Models of pain in chronic pancreatitis are even more problematic. Only recently has one rat model been shown to demonstrate similar histology to human chronic pancreatitis, but assessment of pain in such a model is not straightforward or necessarily applicable to the human situation.14 Any interpretation of research on the pain of chronic pancreatitis must take these issues into consideration.

Ductal and mechanical mechanisms of pain

In the past, numerous hypotheses were offered for the development of pain in patients with chronic pancreatitis. Some patients were felt to have pain as a consequence of obstruction of a surrounding viscus (duodenum or bile duct), although the mechanism by which these would cause chronic pain is not entirely clear and in the case of bile duct obstruction, there is evidence to the contrary.15 Another frequent explanation was the development of a pseudocyst, which may very well cause pain if large, but most patients with painful chronic pancreatitis do not have pseudocysts. Pancreatic ductal obstruction was often invoked as a cause of pain, although the exact mechanism of pain was not well defined. It was suggested that pancreatic ductal obstruction (caused by a stricture or a stone) might cause extravasation of enzymes out the basolateral membrane of acinar cells or that it required hyperstimulation of the gland [due to high cholecystokinin (CCK) levels] in addition to the ductal stricture or stone. Others postulated high pressures within the gland or pancreatic duct and subsequent gland ischaemia as the driving mechanism. The use of antioxidants as a treatment of pain is based on an assumption of preventing the free radicals released by gland ischaemia from producing tissue damage. These hypotheses are not mutually exclusive. Feline models of chronic pancreatitis induced by pancreatic duct ligation have demonstrated increased parenchymal pressure with resultant decreased parenchymal pH, oxygen tension and blood flow.16 Stimulation of pancreatic secretion did not result in the expected increased blood flow in this model, mimicking a compartment syndrome. This study also found decreased gland pH in a few human patients undergoing surgery for chronic pancreatitis, but not in controls.17 One study in humans also showed high baseline pancreatic parenchymal pressures (median of 27 mmHg), which decreased with surgical drainage procedures. These investigators found a strong and significant correlation between pain scores and pressure readings.18–20

Other more recent studies have found increased parenchymal pressure in chronic pancreatitis in humans compared to controls but no relationship between pressure and pain.21 One study demonstrated a reduction in pancreatic ductal pressures after endoscopic stenting, but no correlation between pain and endoscopic intervention or pressure reduction was seen.22 Others have similarly found that many patients with normal pancreatic duct pressures at endoscopic retrograde cholangio-pancreatography (ERCP) still have chronic pain.23 Numerous studies have shown that there is no clear relationship between ductal anatomy (whether the duct is dilated or blocked) and pain.24

Neuropathic mechanisms of pain

The ‘plumbing’ problems described above in the main pancreatic duct have been postulated as one of the dominant causes of pain in chronic pancreatitis, which led naturally to ‘plumbing’ solutions to the problem (endoscopic and surgical duct decompression techniques). The hallmark of this type of pathophysiology would be a dilated pancreatic duct with an obstructing stone or stricture. These types of patients have been labelled as ‘big-duct’ chronic pancreatitis. Many patients with very painful chronic pancreatitis, however, do not have a dilated pancreatic duct and do not have a ductal stricture or stone. This group of patients is often labelled ‘small-duct’ or ‘minimal change’ chronic pancreatitis. This distinction has some utility in choosing therapy and will be discussed subsequently.

Another explanation for pain was suggested by observing that pancreatic nerves were abnormally large or injured in patients with chronic pancreatitis25 and that this nerve injury explained the pain without needing to invoke a coexistent ductal obstruction or elevated pressures. These historical explanations for pain are incomplete. Pain perception is a process involving both the primary nociceptive neuron as well as second and third order neurons in the spinal cord and central nervous system and the understanding of all types of chronic pain must be interpreted from this more complex perspective. Perhaps nowhere is this concept made more obvious by the not so infrequent patient who undergoes total pancreatectomy for painful chronic pancreatitis and yet who still has pain, in the absence of the pancreas! This certainly suggests a ‘wiring’ problem may be more important than the limited historical focus on a ‘plumbing’ problem.26

Neuroanatomy of the pancreas

The innervation of the pancreas is complex, involving both somatic–visceral and autonomic nerves. Painful stimuli, such as pressure, heat, acid or signals of cellular necrosis activate receptors on the dendrites of somatic–visceral nociceptive neurons in the pancreatic bed. One of the best studied receptors in this area is the transient receptor potential vanilloid 1 (TRPV1). This receptor integrates and transduces nociceptive stimuli. If the stimulus is sufficient, it produces depolarization. The signal passes cephalad along both unmyelinated C-fibres and small myelinated Aδ fibres, through the celiac plexus (though no synapse is made there) and are bundled together in the left and right greater splanchnic nerves through the sympathetic trunk ganglia (although again no synapse is made there) to the first nerve cell nucleus and cell body for the pancreatic somato-sensory system, located in the dorsal root ganglia of the spinal cord at levels T5–T9. Cell bodies of sensory neurons from the back and epigastric rectus abdominus muscles are also found there, which accounts for the pain of pancreatitis often referring to the thoracic back or epigastric region.27

Axons from these first order dorsal root ganglion cell bodies send projections in two distinct pathways. First, some of the axons project to the dorsal horn (grey matter) of the spinal cord and release glutamate, substance P (SP) and calcitonin gene-related peptide onto second order neurons within the dorsal horns via AMPA and NMDA receptors for glutamate and the NK-1 receptor for SP.14, 28 These second order neurons then project cephalad to the thalamus via the spinothalamic white matter columns in the spinal cord. Once at the thalamus, third order sensory neurons then project to the somatosensory cortex for cognitive integration of pain and the limbic system and hypothalamus for autonomic/affective integration of the pain. A second pathway for projections of some of the first order axons from the pancreas is that they also synapse within the same level of the spinal cord at the lateral horns of grey matter on sympathetic efferent cell bodies. These sympathetic efferent cell bodies in turn project down through the left and right greater splanchnic nerves to the celiac plexus, where they synapse with second order sympathetic neurons. Vagal afferents also carry noxious stimuli, especially stretch, from the pancreatic bed through the celiac plexus, although again no synapse is made. These afferents then travel with the rest of the vagus though the vagal trunks on the left and right of the oesophagus and through the neck to the base of the skull. At the jugular foramen, these neurons reach their first cell bodies, in the inferior (nodose) ganglion of the vagus and then project to second order neurons the cell bodies of which are located in the nucleus of the solitary tract and posterior nucleus of the vagus.

The noxious stimuli that account for neuronal stimulation of these various pathways also produce tissue and nerve damage in the pancreas. This tissue injury involves release of prostanoids, bradykinin, tachykinins, serotonin, growth factors and as yet uncharacterized mediators. The resulting damage may leave the sensory neurons hypersensitive to further stimulation, to either noxious (hyperalgesia) or non-noxious (allodynia) stimuli. Several interesting experiments support that the ‘gain’ of the sensory nervous system supplying the pancreatic bed is upregulated in the setting of pancreatic injury.

Sensitization of visceral nerves in chronic pancreatitis

One group has developed a rat model of chronic pancreatitis seen 3 weeks after intraductal administration of trinitrobenzene sulfonic acid (TNBS). Increased activity of dorsal root ganglia in TNBS rats is seen in this model compared to controls. In addition, a decreased Ia type potassium rectifier currents resulting in relatively depolarized resting state of these neurons is observed, which is a measure of nerve hypersensitivity. This was hypothesized to be due to the action of nerve growth factor (NGF) in chronic pancreatitis. Interestingly, other models of chronic pain such as colitis or cystitis do not illicit such a response.29 This same group found increased expression of TRPV1 in TNBS exposed rats, with dorsal root ganglia that demonstrated a fourfold increased response to capsaicin compared to control rats. Systemic administration of a TRPV1 antagonist decreased visceral pain behaviour and referred somatic hyperalgesia in TNBS rats, but not in controls.30 Thus TRPV1 may be an exciting new target for treating the pain of chronic pancreatitis.

Further evidence of neuronal up-regulation and hypersensitization in chronic pancreatitis pain has been found in humans. One study found an increased expression of growth-associated protein 43 (GAP-43, a nerve growth associated factor) in tissue specimens of patients with chronic pancreatitis and the level of expression correlated well with pain scores.31 Similar studies in surgical specimens from humans with chronic pancreatitis showed an increased expression of NGF and its receptor TrkA, also correlating well with pain scores.32 Similar results were seen with brain-derived neurotrophic factor.33

Interestingly, trypsin, a normal protease present within the pancreas, may cause activation and hypersensitivity of sensory neurons of the pancreas, independent of its injurious effects. Activated trypsin infused into the pancreatic duct of normal rats in sub-inflammatory concentrations can result in a nociceptive behavioural response, a dose-dependent activation of spinal neurons, and cause pain-induced behaviour that is mediated by the protease-activated receptor-2, (PAR-2) a family of G-protein-mediated receptors on the dendrites of sensory neurons.34 Similar experiments found that infusion of capsaicin into the pancreatic duct of rats caused an immediate visible pain response that mimicked that of trypsin. Injecting a peptide that activates PAR-2 in normal rats sensitizes dorsal root ganglion cells to the action of capsaicin and KCL in vivo and in vitro.35, 36

Another activator of PAR-2 is tryptase, a mast cell (cells that also release NGF) product, Mice that lack mast cells show less painful behaviour in response to experimentally induced chronic pancreatitis than controls. Furthermore, in a retrospective study of tissue specimens from patients with chronic pancreatitis, mast cells were increased 3.5-fold compared to controls.37 This exciting area needs to be explored in humans as several mast cell stabilizers exist and are already in use for systemic mastocytosis, such as Cromolyn sodium or in Europe, ketotifin.38 Besides chemical and neurotransmitter-mediated stimulation of dorsal root ganglia, pancreatic fibrosis itself may entrap and aggravate pancreatic sensory nerves.

Central mechanisms of pain

The central nervous system also changes in response to chronic pancreatitis pain and indeed in all forms of chronic pain. A recent study monitored EEG activity of patients with chronic pancreatitis undergoing electric stimulation of the oesophagus, stomach and duodenum. Increased areas of referred pain in chronic pancreatitis patients compared to controls and increased heterogeneity of the location of referred pain compared to controls were demonstrated.39 These findings are similar to those reported in patients with other types of neuropathic pain.40–42 There is evidence that magnetic brain stimulation43–46 can reduce the pain of chronic pancreatitis and other forms of chronic pain. This central nervous system reorganization and plasticity underlying the development of hyperalgesia and allodynia is likely a major factor in perpetuating the pain of chronic pancreatitis.

Other possible contributors to pain

Hormonal changes may also play a role in chronic pancreatitis pain. CCK levels are elevated threefold in some early chronic pancreatitis patients compared to controls.47, 48 Acting via the vagal nerve (and possibly the blood) CCK stimulates the pancreatic acini to secrete enzyme-rich pancreatic juice. In the setting of ductal obstruction, it is possible to imagine how pain could ensue from elevations in pressure and ischaemia. Not all patients with painful chronic pancreatitis have elevated levels of CCK, however. CCK could also cause pancreatic pain via direct action on the central nervous system. CCK receptors have been found in the area postrema of the medulla, also known as the vomiting centre.49 This centre lacks a blood–brain barrier. Consequently, neurons in this centre have direct access to CCK secreted into the blood. These neurons then project to pain centres, including the ventral tegmental area and areas responsible for emotional responses to pain, such as the locus ceruleus, limbic system and frontal cortex.50 However, there is currently no evidence as to whether blocking this central action of CCK has any influence on pancreatic pain.

In contrast, blocking CCK release in the duodenum may have some effect in attenuating pain. Oral supplementation with non-enteric coated, high protease enzymes that are active in the duodenum can degrade CCK-releasing factor and decrease CCK levels.51 This mechanism is postulated as the explanation for pain relief in some patients treated with enzyme therapy. Further evidence of a potential role of CCK in the pain of chronic pancreatitis comes from several interventional trials. In rat models of acute pancreatitis, CCK-A receptor antagonists decreased severity and pain.52–54 CCK antagonists may also decrease pain and severity of acute pancreatitis in humans.55 One placebo-controlled, randomized, multicentre trial in Japan of 207 chronic pancreatitis patients found that an oral CCK receptor antagonist significantly decreased pain compared to placebo, although the placebo response was 30%.56 Further research into CCK antagonists has been hampered by concerns over inducing pancreatic insufficiency and gallstones.

Pain in chronic pancreatitis is obviously complex (Table 1). This discussion of the multiple factors and pathways that may be involved in generating and perpetuating the pain of chronic pancreatitis serves to underscore the fact that no single mechanism is likely to be operative in all patients and hence no single therapy is likely to be effective in most or all patients. These observations do raise a potential list of new agents, which might be worthwhile testing in these patients.

Table 1.   Mechanisms of pain in chronic pancreatitis
Proposed mechanism of painSupporting data from animal models, humans or bothCurrent therapeutic option based on mechanismHypothetical therapeutic option based on mechanism
  1. TRPV-1, transient receptor potential vanilloid 1; PAR-2, protease-activated receptor-2; NGF, nerve growth factor; CGRP, calcitonin gene-related peptide; CCK, cholecystokinin.

Duodenal obstructionHumanSurgical bypass or endoscopic stent 
Bile duct obstructionHumanEndoscopic stent or surgery 
PseudocystHumanEndoscopic, surgical or percutaneous drainage 
Pancreatic duct obstruction by stone or strictureBothEndoscopic or surgical ductal decompression, lithotripsy 
Tissue hypertension and ischaemiaBothAntioxidants, endoscopic and surgical ductal decompression 
Intra-pancreatic nerve injuryBothCeliac plexus block or neurolysis, thoracoscopic splanchnicectomy 
Visceral nerve sensitizationBothTriclyclic antidepressants, selective serotonin re-uptake inhibitors, combined serotonin and noreopnephrine re-uptake inhibitors, α2δ inhibitorsTRPV-1 antagonists, PAR-2 antagonists, capsaicin, substance P or NK-1 antagonists, mast cell stabilizers, NGF antagonists, CGRP antagonists
Central nerve sensitizationBothTriclyclic antidepressants, selective serotonin re-uptake inhibitors, combined serotonin and norepinephrine re-uptake inhibitors, α2δ inhibitorsMagnetic brain stimulation
Elevations in CCKBothNon-enteric-coated pancreatic enzymesOctreotide, CCK antagonists

Management of chronic pancreatitis pain

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathophysiology of pain in chronic pancreatitis
  5. Management of chronic pancreatitis pain
  6. Conclusions
  7. Acknowledgement
  8. References

The approach to chronic pancreatitis pain first concentrates on making the correct diagnosis. This is not difficult in many patients with longstanding or advanced disease, as they usually have obvious structural damage to the pancreas visible on widely available tests such as computerized tomography (CT) or magnetic resonance imaging with magnetic resonance cholangiopancreatography. Making a correct diagnosis may be much more challenging and difficult in those with ‘small-duct’ chronic pancreatitis who by definition lack these obvious changes. In this setting, tests such as endoscopic ultrasonography and direct pancreatic function testing (e.g. secretin test) are usually used. These tests are more likely to be able to detect abnormalities in pancreatic structure or function at an earlier time point, but they may not be available to many clinicians. Although not the subject of this review, making a correct diagnosis is critical (Table 2). In our pancreas clinic, we frequently see patients with a chronic pain syndrome who have been incorrectly labelled as having chronic pancreatitis, who after further testing turn out to have a nonpancreatic source of pain. Treating this type of patient with therapies that may carry risk (chronic opiates, endoscopic or surgical therapy) is obviously not appropriate in the absence of a secure diagnosis.

Table 2.   Diagnosis of chronic pancreatitis
  1. MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreatography.

Diagnostic testPossible findings in ‘big-duct’ diseaseFindings in ‘small-duct disease’
Faecal elastaseUsually low (<100 μ/g of stool)Usually normal
Serum trypsinUsually low (<20 ng/mL)Usually normal
Abdominal ultrasonographyPancreatic atrophy, pancreatic duct dilation, pancreatic calcifications, pseudocystUsually normal
Computerized tomographyPancreatic atrophy, pancreatic duct dilation, pancreatic calcifications, pseudocystUsually normal or equivocal
MRI with MRCPPancreatic atrophy; pancreatic duct dilation, irregularity or stricture; pancreatic calcifications, pseudocystUsually normal or equivocal
Endoscopic ultrasonographyAbnormal (>4 features of chronic pancreatitis)May be abnormal
ERCPAbnormalNormal or minimally abnormal
Direct hormonal stimulation test (e.g. secretin test)AbnormalUsually abnormal

Once the diagnosis of chronic pancreatitis has been made, most patients are initiated on a trial of medical therapy. There are several important components of medical therapy. In those who drink alcohol, it is important to counsel against its use. Even if the disease is not due to alcohol, it is an appropriate recommendation to make as limiting any further damage to the gland is an important goal of medical therapy. In those with alcohol-induced chronic pancreatitis, cessation of alcohol slows the progression of disease and prolongs survival5 and relieves pain in some patients.6, 7 In addition to stopping alcohol, we strongly encourage patients to stop tobacco as there is mounting evidence that smoking is an important co-factor for chronic pancreatitis.11, 12

Most patients will require some analgesics for pain control. There is a risk of narcotic addiction in these patients, but the focus should be on pain improvement and not solely on the risk of dependence. We start with the least potent agent (usually tramadol or propoxyphene) and establish at the outset that the goal is significant improvement in pain but not necessarily complete absence of pain. Many patients will require more potent narcotics, although there is evidence that when used appropriately, tramadol can be equivalent to more potent agents with fewer negative effects on gut motility.57, 58 In those who require more potent narcotics, it is prudent to consider starting an adjunctive agent. These adjunctive agents have as their goal minimizing the dosage of narcotics required for pain control. They include tricyclic antidepressants, selective serotonin reuptake inhibitors, combined serotonin and norepinephrine reuptake inhibitors (duloxetine) and α2δ inhibitors (gabapentin or pregabalin). These agents have not been sufficiently studied to be able to determine if one or the other is superior in chronic pancreatitis, but they have all been used in a variety of chronic painful conditions and are often worth a therapeutic trial (Table 3).

Table 3.   Medical treatment of pain
AgentTypical starting dosageComments
Propoxyphene with acetaminophen (100 and 650 mg respectively)1–2 po q 8 hMaximum dose should not exceed 4 g of acetaminophen daily
Tramadol (50 mg)1–2 po q 8 hDo not exceed 400 mg daily
AntioxidantsTypical total daily dose might contain 500–1000 mg vitamin C, 250–300 IU vitamin E, 500–800 μg selenium, 2 gm methionine and 9000–10 000 IU β-carotene 
Tricyclic antidepressantsAmitryptyline: initiate at 25 mg po nocte, increase 25 mg/week as toleratedUsual maximum of 100–150 mg nocte. Variety of gastrointestinal, cardiac, neurological side effects at high dosage
Selective serotonin reuptake inhibitorsCitalopram, fluoxetine, sertraline, paroxetine and othersInitial dose and side effects vary with agent
Combined serotonin and norepinephrine re-uptake inhibitorsDuolexitine beginning at 20–40 mg daily, increase to 60 mg daily as toleratedSide effects rare, may cause nausea, vomiting and constipation
Pancreatic enzymesNon-enteric-coated enzymes only (e.g. Viokase-16 or equivalent at 4 pills with each meal and at night)Co-treat with H2-receptor antagonist or proton pump inhibitor to prevent degradation of enzymes by gastric acid
Octreotide50–100 μ SQ t.d.s., can increase to 200 μ SQ t.d.s.Data supporting effectiveness are very limited. May cause abdominal pain, gallstones

Medical therapy also often involves pancreatic enzyme therapy. The use of pancreatic enzymes to control pain has been the subject of several randomized trials and a meta-analysis. The basis of their use is the ability to degrade CCK-releasing factor in the duodenum and by doing so, lowering CCK levels and through this mechanism, reducing pain. Only non-enteric coated (i.e. tablet) formulations have this activity and studies using this type of enzymes have demonstrated improvement in pain.59, 60 In contrast, studies using enteric coated preparations (which are not active in the duodenum and hence cannot degrade CCK-releasing factor) have not shown similar results.61–63 One study that did show pain relief of enteric coated enzymes used a measurement of pain that included malabsorptive (such as bloating, gas or cramping), rather than more classic pancreatic abdominal pain.64 A meta-analysis65 combining these studies saw no effect of enzymes, although combining the two types of formulations in this analysis is probably not appropriate given the proposed mechanism of action. In our experience, enzyme therapy is most likely to be effective in those with ‘small-duct’ or ‘minimal change’ CP. In these patients particularly, we routinely attempt a trial with a high potency enzyme in tablet form (non-enteric-coated), along with a proton pump inhibitor to ensure that the enzymes survive into the duodenum. The dose is the equivalent of Viokase-16 (Axcan Pharma US, Inc., Birmingham, AL, USA), four tablets with meals and snacks, or q.d.s., if meals are skipped. A therapeutic trial should last at least 6 weeks. In patients with chronic relapsing pain (with discrete episodes of more severe pain), we also adjust the dose of enzymes during painful attacks – the equivalent of one tablet of Viokase-16 every 2 h while awake. This approach appears to allow some of our patients to prevent a flare from requiring hospitalization.

There are additional medical therapies for pain, but they are not well studied and their effectiveness is not known. One of these is antioxidants. The hypothesis of their use is the observation that free radicals may play a role in pancreatic injury. Numerous studies in animal models seem to support the potential efficacy of antioxidant therapy, but the results of human studies are inconclusive.66–70 Nonetheless, they appear to be risk-free and a trial of these agents is not unreasonable. A typical mixture would contain selenium, vitamin C, β-carotene, vitamin E and methionine.

A second medical therapy with insufficient data supporting its use is the agent octreotide, which is a synthetic somatostatin analogue. It is felt to work by suppressing CCK and secretin and hence by suppressing pancreatic secretion, although it may have other effects as well. In experimental models, octreotide has been shown to have anti-inflammatory properties, alter the cytokine milieu and protect pancreatic cells. Octreotide is available in two forms, short acting and depot-form given subcutaneously once a month. Several small studies have reached differing conclusions on its effectiveness in painful chronic pancreatitis. While pilot studies showed a trend in pain relief in advanced chronic pancreatitis71, 72 with an apparent dose response curve,73 other studies have not reached similar conclusions.74 In addition, most of these studies used octreotide in patients with ‘big-duct’ disease, so it is not known if the effect would be similar in ‘small duct’ chronic pancreatitis. We use the drug after other therapies have failed and in patients with few or no other options. In that setting, the short acting form is started first and titrated, at doses of 50–100 μg SQ thrice daily, escalating the dosage up to 200 μg t.i.d. If the patient achieves significant pain relief on the short acting form, we will convert to the long acting form. The long acting form only reaches steady state after 3 months, so the short acting form should be continued for at least 6 weeks (or somewhat after the second injection). The use of octreotide in chronic pancreatitis is controversial. It can also suppress the function of the islets of Langerhans. Depending on the patient, it can lead to either hypoglycaemia or lead to poorer glucose control in diabetics. In addition, it predisposes to biliary stasis. We maintain special vigilance for biliary stones in patients on octreotide. We attempt to reduce this risk with periodic holidays or with periodic use of pro-contractile agents such as macrolides.

In the patient who has failed medical management, one can consider options, which include nerve block, neurolysis, or endoscopic or surgical therapy. Endoscopic and surgical techniques are primarily used in those with a dilated pancreatic duct. These patients tend to be those with longstanding disease and most commonly alcohol-induced chronic pancreatitis. However, neurolysis can be performed irrespective of the size of the main pancreatic duct.

The most common target for nerve block or neurolysis is celiac ganglion. This can be performed with the intent of temporarily relieving pain (a nerve block injecting a combination of steroids and an anaesthetic) or with the intent of permanent neurolysis (injecting absolute alcohol). The procedure can be performed via CT-guided techniques, but techniques using EUS-guidance are safer and more effective. Celiac plexus nerve block by endoscopic ultrasound guidance may also last somewhat longer than percutaneous techniques.75 Although this technique is quite helpful in patients with pancreatic carcinoma, its use in chronic pancreatitis has been less utilized due to the often temporary effect of nerve block. Even when neurolysis is attempted with absolute alcohol, pain may not be permanently relieved, although experience with neurolysis in chronic pancreatitis is limited. In patients with painful chronic pancreatitis, based on small and uncontrolled studies, about half of patients undergoing nerve block will get significant pain relief. Unfortunately, pain relief is often transient, on average 2–4 months.76 Although the effect is transient, EUS-guided celiac plexus block may be used to provide a temporary respite from pain for patients who might benefit from this, and often to allow some temporary downward titration of narcotic analgesics. EUS-guided celiac plexus blocks are quite safe, but there are reports of paraplegia with repeated CT-guided celiac plexus neurolysis.

Another technique to achieve neurolysis is via sectioning of the splanchnic nerves. This can be performed with thoracosocopic, minimally invasive approaches. This can be performed unilaterally or bilaterally and the surgeon can usually gain access to the splanchnic nerve roots from T5 to T10. In short-term follow-up, pain is relieved in up to 80% of patients, but this falls to <50% with even short-term follow-up.77–79 The explanation for this decrease in efficacy may be because the splanchnic nerve roots may extend over up to 10 spinal segments (ganglia), which is far more than can be accessed by thoracoscopy. In addition, central mechanisms of pain may be present and cause pain recurrence by central rather than pancreatic mechanisms. The relatively poor long-term efficacy has led some centres to utilize this approach rarely, if at all.

Endoscopic therapy, in addition to EUS-guided celiac plexus block, is considered when pain continues despite medical therapy and in appropriately selected patients. Endoscopic therapy includes stenting or dilation of pancreatic duct strictures and removal of obstructing pancreatic duct stones. Proper selection of patients requires a detailed understanding of the individual patient’s pancreatic ductal anatomy. Stones can be removed if they are not too large (1 cm is probably the upper limit of size), are not tightly impacted, are relatively close to the tip of the working side-viewing duodenoscope (found in the head of the pancreas) and are not upstream from a stricture (i.e. there is not a stricture between the endoscope and the stone). Adding extracorporeal or intraductal lithotripsy to standard endoscopic techniques allows larger stones to be fragmented into pieces which can be extracted. These endoscopic techniques require substantial expertise.

In one large case series of 1018 patients treated with endoscopic techniques at eight different centres, pain improvement was seen in 65% at 2–12 years of follow-up.80 Over this same time period, one-quarter required surgery for failure of endoscopic therapy. These patients were selected based on an appropriate ductal anatomy, with a mixture of strictures and stones. Therapy required a median of 3 ERCPs, with a range of 1–25.

While lithotripsy may be required to fragment stones to the point that they can be extracted, there are some data that extracorporeal shock wave lithotripsy (ESWL) alone (without subsequent attempts at endoscopic stone extraction) may actually improve pain. In one recent randomized trial, 55 patients were randomized to ESWL alone or combined with endoscopy and stone extraction.81 After 2 years of follow-up, pain relief was equivalent. The explanation for these results is not clear; perhaps ESWL may have some effect on nociceptive neurons separate from its effect on stones.

Surgical therapy is also considered in those patients who fail medical therapy. The modified Puestow or lateral pancreaticojejunostomy is the most commonly performed procedure and is a relatively simple procedure with low morbidity and mortality. In this operation, the pancreatic duct is filleted from the anterior surface, ductal strictures are incised and pancreatic duct stones are removed. The longitudinal incision into the pancreatic duct is carried out from the body of the pancreas to as close to the duodenum as is easily accessible, and this is overlaid with a defunctionalized jejunal limb. This operation conserves the maximum amount of pancreatic tissue. This type of operation requires that the pancreatic duct is dilated enough that it is identifiable at surgery (usually a lower limit of 5–6 mm). Pain relief after this operation is very good, in the range of 80%.82–84 With long-term follow-up, this drops to about 50%.85–88

More complex operations for chronic pancreatitis pain usually involve some resection of the gland, in addition to ductal drainage. A number of variations have been developed, including the traditional pancreaticoduodenectomy (Whipple operation), a limited resection of the pancreatic head (Beger operation), a combined opening of the pancreatic duct and excavation of some of the pancreatic head (Frey operation) and variations of the above.89, 90 These operations involve some resection of the pancreatic head, often in addition to drainage of the pancreatic duct. There is a common although unsupported belief amongst surgeons that the pancreatic head may be the ‘pacemaker’ of the disease. In addition, in certain situations, resection of the head may be useful to treat concomitant duodenal or bile duct obstruction caused by enlargement and/or fibrosis in the head of the pancreas. These operations involving resection seem to have equivalent short-term pain relief, compared to a Puestow operation, but better long-term pain relief.91 These operations do have somewhat higher morbidity as well compared with simple drainage procedures. They are used as the primary surgical approach in some countries, but tend to be less utilized in the US. This is primarily because most US surgeons have not been trained in these techniques.

There have now been some randomized comparisons of endoscopic and surgical therapy for painful chronic pancreatitis. In the first study,92 72 patients were randomized to surgical or endoscopic therapy. Patients with pancreatic duct strictures or obstructing stones were included. Of 140 eligible patients, only 72 agreed to participate. The analysis of pain relief in the randomized groups showed the two approaches to be equivalent at 1 year of follow-up. At 5 years, pain relief was significantly better in the group randomized to surgery: 34% of the surgical group experienced complete absence of pain vs. 14% of the endoscopic group. Partial relief of pain was seen in 52% of the surgery group compared to 46% of the endoscopic group. The surgical group was also noted to have a statistically better outcome in body weight at the end of both 1 year and 5 years, without an increase in diabetes. This study has been criticized in that the endoscopic techniques were less than might be considered optimal (only half received a pancreatic stent, stone extraction was carried out in 23%) and the surgical therapy was perhaps more aggressive than might be typical (80% underwent resection including pancreatic head resections and only 20% had a simple drainage operation). Nonetheless, this study seemed to demonstrate superior durability for surgery. A second randomized trial reported on 39 patients randomized to endoscopic or surgical therapy.93 The endoscopic therapy in this study was more complex and included ESWL if needed and the use of larger calibre pancreatic duct stents. The surgical therapy was a lateral pancreaticojejunostomy (modified Puestow operation). The study was ended early after an interim analysis revealed the superiority of surgery over endoscopic therapy. At 24 months of follow-up, the surgical group had better quality of life and less pain (complete or partial pain relief in 75% of surgical patients, compared to 32% of endoscopic patients). This study has also been criticized due to the relatively short follow-up. While endoscopic therapy may still be preferable for many patients who wish to avoid surgery, we now notify patients of these study results and discuss the options in light of these studies. Many patients still choose endoscopic therapy first.

One surgical therapy which has not yet been discussed is total pancreatectomy, usually coupled with harvesting of islet cells and autotransplantation. This is a particularly attractive option in patients who have a high risk of pancreatic cancer, such as those with hereditary pancreatitis. Total pancreatectomy is available at only a few highly specialized pancreatic centres in the US. Pain relief is not universal with these procedures94 and up to 50% may still require narcotics at 1 year after these procedures. Proponents point out that having half of the most intractable chronic pancreatitis patients off of narcotics should be considered a clinically significant success. The risk of diabetes is largely dependent on the number of islets that can be harvested. Some patients do not require insulin therapy after total pancreatectomy with islet cell autotransplantation, but diabetes will occur in many of these patients and may be brittle and difficult to manage. The yield of islet cells available for autotransplantation may be improved if the patient has not previously undergone pancreatic surgery.95, 96 It is the rare patient with chronic pancreatitis, outside of those with cancer risk, who has such severe and intractable symptoms to consider this option.

In addition to these management options for pain, it is important to not forget that in a patient with chronic pancreatitis, pain may occur from a complication of the disease (pseudocyst, duodenal obstruction, superimposed carcinoma), an associated condition (in particular gastroparesis or narcotic bowel) or an unrelated coexistent disease. Several of these have specific therapy and are worth considering in all patients with chronic pancreatitis experiencing pain. In addition, one should not neglect the management of exocrine or endocrine insufficiency in these patients while focusing too intently on pain. The foregoing discussion also serves to illustrate that current options for managing pain are imperfect. In the future, new therapies may be able to take advantage in advances in our understanding of nociception and target molecules, receptors and mechanisms involved in pain perception.


  1. Top of page
  2. Summary
  3. Introduction
  4. Pathophysiology of pain in chronic pancreatitis
  5. Management of chronic pancreatitis pain
  6. Conclusions
  7. Acknowledgement
  8. References

The pain of chronic pancreatitis is a challenging clinical problem. Management begins with medical therapy directed both at relieving pain, but equally important, it is directed at preventing additional pancreatic injury. Failures of medical therapy may have endoscopic and surgical options, depending on the ductal anatomy and available expertise. As the understanding of the mechanisms of pain continues to evolve, future studies should be aimed at additional and hopefully more effective medical therapies.


  1. Top of page
  2. Summary
  3. Introduction
  4. Pathophysiology of pain in chronic pancreatitis
  5. Management of chronic pancreatitis pain
  6. Conclusions
  7. Acknowledgement
  8. References
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