Effect of Non-enteric Coated Enzymes Substitution on Pain in Patients With Chronic Pancreatitis

Study Overview
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Brief Summary
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Pain in CP entails several independent yet overlapping mechanisms including oxidative stress-mediated parenchymal inflammation, pancreatic and central neuropathy and neuroplasticity. Medical modalities for long-term pain management includes antioxidants and neuromodulators. Pancreatic enzymes are also invariably used for pain management. CP with ductal obstruction and pain is treated with either endotherapy or drainage surgery. However, it has been observed that a substantially increasing proportion of patients experience pain recurrence as the duration of follow-up after endotherapy or surgery gets longer. Neural and dietary (proteins) stimuli activate CCK receptors in D1 & D2 which gives a positive feedback signal for pancreatic secretion. Once enzyme secretion starts, due to ductal and interstitial/tissue hypertension, nociception begins that results in pain. Blockade of the duodenal CCK receptors could inhibit the positive feedback loop, thereby reducing pancreatic secretion and resulting pain. Currently available enteric coated enzyme supplements are released throughout the small bowel and therefore may not be released sufficiently in the duodenum to effectively suppress the feedback loops. High doses of proteases ( 25k-30k) would be required to block the receptors, while most of the currently available preparations have higher lipase but not proteases. This led to the investigators' hypothesis that negative feedback of CCK by non enteric coated pancreatic enzymes could ameliorate pain in a more effective manner by NE-PERT.

Detailed Description
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Chronic pancreatitis (CP) is a fibro-inflammatory disorder of the pancreas characterized by progressive and irreversible damage. It manifests with abdominal pain and/or exocrine or endocrine insufficiency. Recurrent abdominal pain is the dominant clinical hallmark that mandates aggressive management. Pain in CP entails several independent yet overlapping mechanisms including oxidative stress-mediated parenchymal inflammation, pancreatic and central neuropathy and neuroplasticity. Medical modalities for long-term pain management includes antioxidants and neuromodulators. Pancreatic enzymes are also invariably used for pain management. CP with ductal obstruction and pain is treated with either endotherapy or drainage surgery. However, it has been observed that a substantially increasing proportion of patients experience pain recurrence as the duration of follow-up after endotherapy or surgery gets longer. It has been postulated that neural and dietary (proteins) stimuli activate CCK receptors in D1 & D2 which gives a positive feedback signal for pancreatic secretion. Once enzyme secretion from the pancreas begins, due to ductal and interstitial/tissue hypertension, nociception is initiated that results in pain. On this premise, the investigators hypothesized that blocking the duodenal CCK receptors could inhibit the positive feedback loop, thereby reducing pancreatic secretion and resulting pain. Earlier meta-analyses that evaluated the effect of pancreatic enzyme supplementation on pain reported that there were no overall benefits in pain management. All but two of those studies used enteric coated enzyme. Currently available enteric coated enzyme supplements are released throughout the small bowel and therefore may not be released sufficiently in the duodenum to effectively suppress the feedback loops. High doses of proteases ( 25k-30k) would be required to block the receptors, while most of the currently available preparations have higher lipase but not proteases. However, on subgroup analyses in the aforementioned meta-analyses, pain reduction was observed in the two studies that used non-enteric coated preparations. These studies were done several years earlier, had a small sample size, and had a cross over design. This formed that rationale of the investigators' current study to test the hypothesis using a statistically valid design with a higher sample size that would allow subgroup analyses, adjust for alternative pain mechanisms, and achieve a better effect size.

Official Title
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Effect of Non-enteric Coated Enzymes Substitution on Pain in Patients With Chronic Pancreatitis: a Double -Blinded Placebo Controlled Randomized Trial (NE-PERT Trial)

Conditions
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Pain, Chronic Pancreatitis

Intervention / Treatment
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* Drug: Non-enteric coated pancreatic enzyme preparation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic pancreatitis of at least 3 years At least 3 episodes of pain in the past 3 months Pain score of at least 3 on VAS (0-10) Age 18-60yrs Both genders Exclusion Criteria: Acute pancreatitis episode at the time of enrolment. Pancreatic cancer. Other chronic painful conditions. Active substance use (alcohol, smoking, smokeless tobacco, illicit drugs). Pregnancy and lactation. Inability to give informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NE PERT<br>Non-enteric coated pancreatic enzyme capsules containing 30,000U of protease will be provided three times a day along with food (breakfast, lunch and dinner) | Drug: Non-enteric coated pancreatic enzyme preparation<br>* The patients will be given a non-enteric coated pancreatic enzyme capsule containing 30000 U of protease thrice daily along with meals for 3 months.<br>* Other names: Placebo;|
| Placebo Comparator: Placebo<br>Similar appearing glucose capsules will be provided three times a day along with food (breakfast, lunch and dinner) | Drug: Non-enteric coated pancreatic enzyme preparation<br>* The patients will be given a non-enteric coated pancreatic enzyme capsule containing 30000 U of protease thrice daily along with meals for 3 months.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pain score | IZBICKI pain score will be used. Score ranges from 0-100, 100 indicating most severe. | 3 months | 
| Change in pain score | IZBICKI pain score will be used. Score ranges from 0-100, 100 indicating most severe. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in number of painful days | Number of days when the patient experienced pain | 3 months | 
| Change in number of painful days | Number of days when the patient experienced pain | 6 months | 
| Change in quality of life | Will be measured using the EORTC QLQ c30 with PAN28 tool. Score ranges from 0 to 100. 0 indicates worst for function scales, while 100 indicates worst for symptom scales. | 3 months | 
| Change in quality of life | Will be measured using the EORTC QLQ c30 with PAN28 tool. Score ranges from 0 to 100. 0 indicates worst for function scales, while 100 indicates worst for symptom scales. | 6 months | 
| Change in analgesic requirement | Number of analgesic tablets required will be recorded | 3 months | 
| Change in analgesic requirement | Number of analgesic tablets required will be recorded | 6 months | 
| Change in the number of hospitalization | Number of hospital admissions and days in hospital will be recorded | 3 months | 
| Change in the number of hospitalization | Number of hospital admissions and days in hospital will be recorded | 6 months |