Pain Management in Acute and Chronic Pancreatitis

INTRODUCTION

Pancreatitis is a rare disease characterised by pathologic swelling and inflammation of the pancreas.¹Erica Roth, Steven Kim. Pancreatitis. Available from http://www.healthline. th com/health/pancreatitis#Overview1 [Accessed on 24 June 2016].   Pancreatic damage occurs when the digestive enzymes are activated and begin attacking the pancreas. In very severe cases, pancreatitis can result in bleeding into the gland itself; serious tissue damage, infection and fluid collections may occur. Severe pancreatitis can result in damage to other vital organs such as the heart, lung and kidneys.²Cleveland Clinic. Pancreatitis, Acute & Chronic Overview. Available from:http://my.clevelandclinic.org/health/diseases_conditions/hic_Pancreatitis/th dd_overview [Accessed on 24 June 2016].  

DEFINITION AND CLASSIFICATION

According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), pancreatitis is broadly classified into two types:¹Erica Roth, Steven Kim. Pancreatitis. Available from http://www.healthline. th com/health/pancreatitis#Overview1 [Accessed on 24 June 2016].  

Acute Pancreatitis: Acute pancreatitis is an acute inflammatory process of the pancreas, usually accompanied by abdominal pain and elevations of serum pancreatic enzymes. It is a condition that arises suddenly and may be quite severe, although patients usually have a complete recovery. This syndrome is usually a discrete episode, which may cause varying degrees of injury to the pancreas and adjacent and distant organs. It may be classified as mild, moderate or severe based on physiological findings, laboratory values and radiological imaging.³Johns Hopkins Medicine Acute Pancreatitis. Available from http://www.hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/pancreas_biliary_tr th act/acute_pancreatitis.pdf [Accessed on 24 June 2016].  

According to the Atlanta classification, acute pancreatitis can be divided into two broad categories:⁴Vege SS. Management of acute pancreatitis. Available from http://www.upth todate.com/contents/management-of-acute-pancreatitis [Accessed on 24 June 2016].  

• Interstitial oedematous acute pancreatitis: It is characterised by acute inflammation of the pancreatic parenchyma and peripancreatic tissues but without recognisable tissue necrosis.
• Necrotising acute pancreatitis: It is characterised by inflammation associated with pancreatic parenchymal necrosis and/or peripancreatic necrosis.

Chronic Pancreatitis: Chronic pancreatitis is commonly defined as a continuing, chronic, inflammatory process of the pancreas, characterised by irreversible morphologic changes.⁵Huffman JL. Chronic Pancreatitis. Available from http://emedicine.medscth ape.com/article/181554-overview#showall [Accessed on 24 June 2016].  

It occurs when the pancreas becomes damaged by long-standing inflammation.⁶Freedman SD. Clinical manifestations and diagnosis of chronic pancreatitis in adults. Available from http://www.uptodate.com/contents/chronicpanth creatitis-beyond-the-basics [Accessed on 24 June 2016].   Chronic pancreatitis is characterised by recurrent episodes of abdominal pain associated with both exocrine and endocrine pancreatic failure and progressive atrophy of the pancreatic parenchyma.⁷Gheonea DI, Vilmann P, Saftoiu A, Ciurea T, Pirvu D, Lonescu M. The Differential Diagnosis of Chronic Pancreatitis. Curr Health Sci J. 2009 Jul-Sep;35(3): 159-164.  

CLINICAL PRESENTATION – PAIN

Pain is the commonest presentation in both acute and chronic pancreatitis apart from other clinical manifestations. As the name suggests- in acute pancreatitis- pain is sudden – moderate – to-severe in intensity and usually subsides over 48-72 hrs with subsidence of the pancreatic inflammation, whereas, in chronic pancreatitis the pain may be episodic or dull unrelenting hampering daily routine and in certain cases making the patients addicted to narcotic pain killers and occasionally making them contemplate suicide.

TREATMENT: PAIN MANAGEMENT

Acute Pancreatitis

Severe abdominal pain is a hallmark of acute pancreatitis (AP). AP-associated pain is often described as a deep and penetrating type of pain with acute onset and without any prodrome. The most common localisation of acute pain is the epigastric region. Pain in AP is often associated with nausea and vomiting. Physical examination yields a pronounced tenderness of the upper abdomen with guarding, which can occur in combination with other unspecific symptoms like fever or tachycardia.⁸Schorn S, Ceyhan GO, Tieftrunk E, Friess H, Demir IE. Pain Management in Acute Pancreatitis. Pancreapedia: Exocrine Pancreas Knowledge Base. 2015.DOI: 10.3998/panc.2015.15  

According to the modified Atlanta consensus guidelines, AP can be diagnosed if at least two of the following criteria are fulfilled:⁸Schorn S, Ceyhan GO, Tieftrunk E, Friess H, Demir IE. Pain Management in Acute Pancreatitis. Pancreapedia: Exocrine Pancreas Knowledge Base. 2015.DOI: 10.3998/panc.2015.15  

• The occurrence of abdominal pain that is characterised by an acute onset and radiates to the back.
• Serum pancreatic enzymes (lipase or amylase) elevated at least three-fold over the normal serum enzyme level.
• Characteristic findings of AP in imaging (contrast-enhanced CT, MR-Imaging, transabdominal ultrasound).

The successful treatment of patients with AP has three prerequisites:⁸Schorn S, Ceyhan GO, Tieftrunk E, Friess H, Demir IE. Pain Management in Acute Pancreatitis. Pancreapedia: Exocrine Pancreas Knowledge Base. 2015.DOI: 10.3998/panc.2015.15  

• An adequate and early fluid resuscitation
• Proper nutrition support
• An adequate pain management

Role of Medical Treatment in Pain Management during AP: According to the World Health Organisation (WHO) regimen, the pain treatment begins with low potent non-steroidal antiinflammatory drugs (NSAIDs), which may be sufficient in mild Dr. Jayanta Mukherjee MD, DM (Gastroenterology) ILS Hospital Kolkata or moderate pain due to AP and rises step by step up to highly potent NSAIDs alone or in combination with opioids, high doses of antibiotics for infected pancreatic necrosis and even to surgical or interventional procedures in cases of severe AP. Opioid analgesics may be considered an appropriate choice in the treatment of AP-associated pain and importantly, they decrease the need for supplementary analgesia (Figure 1).⁸Schorn S, Ceyhan GO, Tieftrunk E, Friess H, Demir IE. Pain Management in Acute Pancreatitis. Pancreapedia: Exocrine Pancreas Knowledge Base. 2015.DOI: 10.3998/panc.2015.15   Antispasmodics too can be used to relieve spasmodic pain.

Role of Nutrition in Pain Management during AP: AP-associated pain is potential pain exacerbation after ingestion of food or fluids. The right management of nutrition is strongly dependent on the severity of AP. Importantly in patients with mild-tomoderate AP, nasogastric feeding seems to be well tolerated and might reduce the intensity and the duration of abdominal pain, the need of pain medication and the risk of oral food intolerance.⁸Schorn S, Ceyhan GO, Tieftrunk E, Friess H, Demir IE. Pain Management in Acute Pancreatitis. Pancreapedia: Exocrine Pancreas Knowledge Base. 2015.DOI: 10.3998/panc.2015.15   Fluid resuscitation should be sufficient to maintain haemodynamic stability. A diet low in fat and high in protein and carbohydrates is recommended, especially in patients with steatorrhoea.⁵Huffman JL. Chronic Pancreatitis. Available from http://emedicine.medscth ape.com/article/181554-overview#showall [Accessed on 24 June 2016].  

Role of Endoscopic Retrograde cholangiopancreatography (ERCP) in Pain due to AP: Gallstones are the most common cause of AP. ERCP should only be used for clearance of proven bile duct stones especially in patients who suffer from severe AP, with clear evidence of cholangitis, in those who are poor candidates for cholecystectomy, in those who are postcholecystectomy and in those with strong evidence of persistent biliary obstructions. ERCP should be avoided in patients with low or intermediate suspicion of retracted bile duct stones.⁸Schorn S, Ceyhan GO, Tieftrunk E, Friess H, Demir IE. Pain Management in Acute Pancreatitis. Pancreapedia: Exocrine Pancreas Knowledge Base. 2015.DOI: 10.3998/panc.2015.15   During ERCP procedure duodenal peristalsis can make cannulation of the papilla and the necessary therapeutic procedures difficult. Use of directly acting antispasmodics, which are non-cholinergic in nature like Drotaverine hydrochloride shows good spasmolytic effect and reduces intubation and operation time. It can be taken as common drug before operation.

Role of Minimally-Invasive Necrosectomy and Decompressive Laparotomy in Pain due to AP: Traditionally, infected pancreatic necrosis as a result of AP was considered an indication for open surgical necrosectomy, but recently minimally invasive approaches like repetitive percutaneous drainage via largecaliber catheters, endoscopic transluminal necrosectomy, retroperitoneal approach with percutaneous insertion of endoscopic material and especially a “step-up approach” have emerged that could effectively limit local and systemic damage and thereby, without the need for open invasive surgery. AP-associated abdominal hypertension was defined by the World Society of Abdominal Compartment Syndrome (WSACS) as a “life-threatening sustained elevation of the intra-abdominal pressure (IAP) that is associated with new onset organ failure or acute worsening of existing organ failure”. It results from a combination of pancreatic and visceral oedema, acute peripancreatic fluid collections, capillary leakage, ascites and paralyticileus. An approach to deal with AP-associated abdominal hypertension was decom-pressive laparotomy.⁸Schorn S, Ceyhan GO, Tieftrunk E, Friess H, Demir IE. Pain Management in Acute Pancreatitis. Pancreapedia: Exocrine Pancreas Knowledge Base. 2015.DOI: 10.3998/panc.2015.15  

Novel Strategies of Pain Management in AP: A novel analgesic technique interacts with the nervous system with the pan-creatitis (Figure 2).⁸Schorn S, Ceyhan GO, Tieftrunk E, Friess H, Demir IE. Pain Management in Acute Pancreatitis. Pancreapedia: Exocrine Pancreas Knowledge Base. 2015.DOI: 10.3998/panc.2015.15  In a prospective single cohort study conducted by Bachmann et al., reports improvement in survival owing to thoracic epidural analgesia (TEA) in a porcine AP model that is based on the infusion of glycodesoxycholic acid into the pancreatic duct. Treatment with nitric oxide synthase (NOS) inhibitors or glycine reduced abdominal hyperalgesia and AP-associated histological alterations during AP by targeting on neuronal cells. Inhibitors of the proteinase-activated-receptor-2 (PAR2) or of the transient receptor potential vanilloid-1 (TRPV1) show beneficial effects in treating pain. Blockade of interleukin-6 (IL-6) signalling by an orally available, small-molecule IL-6 receptor inhibitor shows to diminish abdominal hyperalgesia during AP.⁸Schorn S, Ceyhan GO, Tieftrunk E, Friess H, Demir IE. Pain Management in Acute Pancreatitis. Pancreapedia: Exocrine Pancreas Knowledge Base. 2015.DOI: 10.3998/panc.2015.15  

CHRONIC PANCREATITIS

The frequency, severity and other characteristics of pain in chronic pancreatitis have a major impact on its management, the number of treatments and the choice between medical and surgical interventions. Possible mechanisms for pain include acute inflammation of the pancreas, increased pressure within the ductal system and parenchyma, neuritis, recurrent ischemia of the parenchyma; intrapancreatic causes such as acute pseudocysts and extrapancreatic causes such as common bile duct or duodenal stenosis.⁷Gheonea DI, Vilmann P, Saftoiu A, Ciurea T, Pirvu D, Lonescu M. The Differential Diagnosis of Chronic Pancreatitis. Curr Health Sci J. 2009 Jul-Sep;35(3): 159-164.  

Endoscopic Therapy: Endoscopic therapy aimed at decompressing an obstructed pancreatic duct can be associated with pain relief. Pancreatic duct stones can be fragmented by extracorporeal shock-wave lithotripsy (ESWL) and removed endoscopically after sphincterotomy of the pancreatic duct. The narrowing of the pancreatic ducts can block secretions from the pancreas, which leads to pain and inflammation of the pancreas. A stent is placed inside the pancreatic duct to hold it open. Stents relieves pain in patients with narrow pancreatic duct or pancreatic stones lodged in the duct.⁷Gheonea DI, Vilmann P, Saftoiu A, Ciurea T, Pirvu D, Lonescu M. The Differential Diagnosis of Chronic Pancreatitis. Curr Health Sci J. 2009 Jul-Sep;35(3): 159-164.  

Nerve Blockade: The endoscopic ultrasonography-guided celiac plexus block is safe and well tolerated. This approach tries to alleviate pain by modifying afferent sensory nerves in the celiac plexus, using anesthetize agents, which reduces inflammation.⁷Gheonea DI, Vilmann P, Saftoiu A, Ciurea T, Pirvu D, Lonescu M. The Differential Diagnosis of Chronic Pancreatitis. Curr Health Sci J. 2009 Jul-Sep;35(3): 159-164.  

Surgical Treatment: The choice of surgery depends on the clinical problem and the preoperative assessment of the abnormality. In general, the approach aims either to improve pancreatic duct drainage or to resect the diseased organ. Various surgeries are performed like;

• Pancreatic duct drainage/decompression: Pancreatic duct decompression via lateral pancreatojejunostomy is done in patients with a dilated duct.
• Pancreatic resection: If the disease is limited to the head of the pancreas, a conventional or pylorus-preserving pancreaticoduodenectomy can produce good results. Distal pancreatectomy is performed when the disease is largely confined to the body and tail of the gland.
• Total pancreatectomy followed by islet cell autotransplantation: It is a last resort following a failed partial pancreatic resection.
• Surgical denervation: Resection of the greater splanchnic nerve and celiac ganglion through a left translumbar approach results in significant decreases in pain frequency and intensity.⁷Gheonea DI, Vilmann P, Saftoiu A, Ciurea T, Pirvu D, Lonescu M. The Differential Diagnosis of Chronic Pancreatitis. Curr Health Sci J. 2009 Jul-Sep;35(3): 159-164.  

Behaviour Modification: Cessation of alcohol consumption and tobacco smoking are important.⁷Gheonea DI, Vilmann P, Saftoiu A, Ciurea T, Pirvu D, Lonescu M. The Differential Diagnosis of Chronic Pancreatitis. Curr Health Sci J. 2009 Jul-Sep;35(3): 159-164.  

Diet: Low fat and high protein and carbohydrates is recommended. Oral supplementation of enzymes is recommended.⁵Huffman JL. Chronic Pancreatitis. Available from http://emedicine.medscth ape.com/article/181554-overview#showall [Accessed on 24 June 2016].  ⁷Gheonea DI, Vilmann P, Saftoiu A, Ciurea T, Pirvu D, Lonescu M. The Differential Diagnosis of Chronic Pancreatitis. Curr Health Sci J. 2009 Jul-Sep;35(3): 159-164.  

Medical Therapy: The first line in pain management is the use of medical therapy. Medical therapy includes;⁷Gheonea DI, Vilmann P, Saftoiu A, Ciurea T, Pirvu D, Lonescu M. The Differential Diagnosis of Chronic Pancreatitis. Curr Health Sci J. 2009 Jul-Sep;35(3): 159-164.  

• Nonspecific supportive therapy: Analgesic drugs are still the most commonly adopted method for pain relief. (E.g. Hydrocodone and acetaminophen, Tramadol, Naproxen, D iclofenac,Ketorolac, Ibuprofen, Celecoxib, etc.)
• Pancreatic enzymes: The aim of an exogenous pancreatic enzyme supplements is to trigger a negative feedback inhibition. Pancrelipase assists in the digestion of protein, starch and fat. Uncoated pancrelipase is used to treat painful chronic pancreatitis. Nonenteric-coated products are used for pain caused by pancreatitis in combination with a proton pump inhibitor. The enteric-coated products may be used for restoration of digestion and absorption.
• Hormones: Cholecystokinin-receptor antagonists or somatostatin analogues, such as octreotide, works on the negative feedback inhibition as well as hypertension of the pancreatic duct due to outflow obstruction.
• Antioxidant therapy: Patients with chronic pancreatitis had significantly lower plasma concentrations of selenium, Vitamins A and E, betacarotene, xanthine, betacryptoxanthine and lycopene in comparison with patients with recurrent acute pancreatitis. Bhardwaj et al reported a decreased micronutrient intake (Vitamin E, riboflavin, choline, magnesium, copper, manganese and sulphur) in patients with chronic pancreatitis.
• Antidepressants and TCAs: In addition to alleviating coexistent depression, tricyclic antidepressants may ameliorate pain and potentiate the effects of opiates. (E.g. Clomipramine, Doxepin, Nortriptyline, Desipramine, etc.)⁵Huffman JL. Chronic Pancreatitis. Available from http://emedicine.medscth ape.com/article/181554-overview#showall [Accessed on 24 June 2016].  
• Antispasmodics: Antispasmodics suppresses muscle spasms. They are used for smooth muscle contraction (E.g., drotavarine, dicyclomine, hyoscyamine, mebeverine, etc.)

Drotavarine Hydrochloride: Drotaverine hydrochloride is a drug of choice in emergency abdominal pain of different aetiologies and spasm in patients with different gastrointestinal disorders. It is a phosphodiesterase-IV (PDE4) inhibitor. Since it does not mask the symptoms of the underlying disease it can be initiated for management of emergency abdominal pain even before the actual aetiological diagnosis is established.

Drotaverine may reduce abdominal pain and spasm in patients with different gastrointestinal disorders. Drotaverine has been shown to prevent the spasm of the sphincter of Oddi which may render it useful in the treatment of functional or organic pancreatic and biliary disorders/dyskinesia.

Parenteral administration of drotaverine ensures rapid and immediate relief from spasmodic pain. Administered intravenously the action commences in just 2 minutes. The onset of action with the i.m route is 5 minutes and 15 minutes on oral administration. Oral administration of drotaverine can be continued for further sustaining its effects. Drotaverine is devoid of the anticholinergic side effects like constipation, dry mouth, blurred vision, tachycardia etc. Among all the antispasmodics available, drotaverine is the safest as it can be safely administered in pregnancy, lactation, Benign Prostate Hyperplasia (BPH), elderly patients and patients suffering from Gastrointestinal Reflux Disease (GERD) and Glaucoma.⁹Pap A, Topa L, Balghe V, Szikszay E, Blasko G. Drotaverine examination of the impact of the papilla of Vater dyskinesia nutritious. Allerg. Diet. 3 (5-6),23-27., 1998.  

CONCLUSION

Abdominal pain is the earliest and a leading symptom of patients with AP. Novel studies also suggest that the severe abdominal pain in AP could also be effectively treated by thoracic epidural anesthesia owing to the improvement of pancreatic microcirculation and preservation of tissue architecture. Disruption of neurogenic inflammation in AP holds great promise as a novel analgesic and therapeutic strategy for AP, which yet needs to be tested in clinical early phase trials. Development of inhibitors directed against selected targets on pancreatic afferents is likely to open new paths toward more effective management of pain as an interdisciplinary challenge.

Pain is the most difficult to treat symptom of chronic pancreatitis. A step wise strategy is recommended starting with life style modifications such as alcohol abstinence and low fat diet, then moving to high dose non-coated pancreatic enzymes and oral analgesic therapy. In patients with dilated main pancreatic duct unresponsive to medical therapy, endoscopy or decompressive surgery should be considered. Patients with debilitating pain, non-dilated pancreatic duct and inflammatory masses may be candidates for resective surgery.

The role of pain modifying agents like antidepressants, antispasmodics, gabapentin, pregabalin, celiac plexus block, antioxidants, octreotide and total pancreatectomy with islet cell auto transplantation remains to be determined. An antispasmodics drug like drotaverine hydrochloride is an effective and safe pharmaceutical agent that results in rapid relief of spasms and emergency abdominal pain from any origin, without masking the signs and symptoms of the underlying disease.

REFERENCES

1. Erica Roth, Steven Kim. Pancreatitis. Available from http://www.healthline. th com/health/pancreatitis#Overview1 [Accessed on 24 June 2016].
2. Cleveland Clinic. Pancreatitis, Acute Chronic Overview. Available from:http://my.clevelandclinic.org/health/diseases_conditions/hic_Pancreatitis/th dd_overview [Accessed on 24 June 2016].
3. Johns Hopkins Medicine Acute Pancreatitis. Available from http://www.hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/pancreas_biliary_tr th act/acute_pancreatitis.pdf [Accessed on 24 June 2016].
4. Vege SS. Management of acute pancreatitis. Available from http://www.upth todate.com/contents/management-of-acute-pancreatitis [Accessed on 24 June 2016].
5. Huffman JL. Chronic Pancreatitis. Available from http://emedicine.medscth ape.com/article/181554-overview#showall [Accessed on 24 June 2016].
6. Freedman SD. Clinical manifestations and diagnosis of chronic pancreatitis in adults. Available from http://www.uptodate.com/contents/chronicpanth creatitis-beyond-the-basics [Accessed on 24 June 2016].
7. Gheonea DI, Vilmann P, Saftoiu A, Ciurea T, Pirvu D, Lonescu M. The Differential Diagnosis of Chronic Pancreatitis. Curr Health Sci J. 2009 Jul-Sep;35(3): 159-164.
8. Schorn S, Ceyhan GO, Tieftrunk E, Friess H, Demir IE. Pain Management in Acute Pancreatitis. Pancreapedia: Exocrine Pancreas Knowledge Base. 2015.DOI: 10.3998/panc.2015.15
9. Pap A, Topa L, Balghe V, Szikszay E, Blasko G. Drotaverine examination of the impact of the papilla of Vater dyskinesia nutritious. Allerg. Diet. 3 (5-6),23-27., 1998.