Efficacy of pancreatic enzyme supplementation

ReferenceStudy type/Evidence levelNumber of patientsPatient characteristicsInterventionComparisonLength of follow-upOutcome measuresSource of funding
Delhaye M. Comparative evaluation of a high lipase pancreatic enzyme preparation and a standard pancreatic supplement for treating exocrine pancreatic insufficiency in chronic pancreatitis. European Journal of Gastroenterology & Hepatology. 1996; 8(7):699–703. Ref ID:4881+ randomized open crossover studyN=32
Completed study n=25

Drop out n=7
Inclusion criteria: patients with alcohol-related chronic pancreatitis.
Diagnosis of exocrine pancreatic insufficiency was based on steatorrhoea defined as a fat balance of more than 10g/day on a 100g fat intake without enzyme supplementation.

Exclusion criteria: patients allergic or hypersensitive to porcine protein, suffering from any other pathological condition, pregnant women, or patients continuously taking medications which could interfere with the study medications such as H2 antagonist, antacids, anti- diarrhoeals, sucralfate, carbenoxolone, bismuth compounds or antispasmodics.

Patient Characteristics:
Men/women: 24/1
Mean age (SE; range): 52.4 (1.7; 40–69) years
Weight: 63.6 ± 2.3 kg
Height: 171.7 ± 1.3 cm
Alcoholic pancreatitis: 23/25 (92%)
Idiopathic pancreatitis: 2/25 (8%)
Previous pancreatic surgery: 9/25 (36%)
Diabetic patients: 16/25 (64%)
Pancrease HL
3 capsules/day (high dose enteric-coated enzyme supplement: 25 000 European Pharmacopoeia Units (EPU) lipase, 22 500 EPU amylase, 1250 EPU protease per capsule).

*Study divided into 4 periods of 2 weeks, each one corresponding to a new treatment regimen:
  1. Pancrease HL 1 capsule/meal + omeprazole 20mg/day, 30 min before breakfast
  2. Creon 3 capsules/meal and omeprazole 20mg/day, 30 min before breakfast
  3. Pancrease HL 1 capsule/meal.
  4. Creon 3 capsules/meal
All patients were randomized to received the same 4 different treatment regimen but in varying orders:
ABCD n=7
BCDA n=8
CDAB n=3
DABC n=7

At the end of each 2 week period patients received a standard diet for 5 days (fixed daily intake 100g fat)

Stool collection was done at the last 3 days of the standard diet.
Creon
9 capsules/day (standard lipase dose enteric-coated enzyme supplement: 8000 EPU lipase, 9000 EPU amylase, 450 EPU protease per capsule.)

See intervention for details*
56 daysEfficacy: 72 hrs faecal fat, Stool frequency, odour, colour, and consistency, general wellbeing, abdominal pain and appetite. Safety: blood samples for renal and liver function and haematological parameters at day 0, 14, 28, 42 and 56Not reported
Effect Size
Outcomes
  1. Faecal Fat (g/100g):
    • A. Pancrease HL + omeprazole: 9.52 ± 0.71
    • B. Creon 3 + omeprazole: 9.14 ± 0.56
      -

      Significant reduction in faecal fat with the addition of an enzyme and omeprazole p=0.03

    • C. Pancrease HL: 10.68 ± 0.66
    • D. Creon 3: 10.26 ± 0.61
      -

      No significant reduction in faecal fat with the addition of an enzyme alone

    • There is no significant difference between the 2 pancreatic enzyme treatment groups for the mean values of faecal fat.
    • No significant change during the 4 treatment period (no results provided).
  2. Weight:
    • No significant change: Day 0: 63.6 ± 2.3 kg compared to 64.1 ± 2.2 kg at Day 56.
  3. Wellbeing score:
    • No significant change in wellbeing score during the 4 treatment periods (no data)
  4. Absorption:
    • Fat (%)
      -

      A: Pancrease + omperazole: 83.8 ± 2.4

      -

      B: Creon + omeprazole: 83.1 ± 3.3

      -

      C: Pancrease: 82.0 ± 2.0

      -

      D: Creon: 82.1 ± 2.3

      -

      No significant difference between different enzymes or with the addition of omeprazole.

    • -

      A: Pancrease + omperazole: 80.2 ± 1.9

      -

      B: Creon + omeprazole: 77.5 ± 2.7

      -

      C: Pancrease: 80.9 ± 1.5

      -

      D: Creon: 81.1 ± 1.8

      -

      No significant difference between different enzymes or with the addition of omeprazole.

Authors Conclusion:
‘The reduction in capsule number is cited in most cases as the main reason for preferring Pancreas HL.’
Vecht J. Efficacy of lower than standard doses of pancreatic enzyme. supplementation therapy during acid inhibition in patients with pancreatic exocrine insufficiency. Journal of Clinical Gastroenterology. 2006; 40(8):721–725. Ref ID: 20181+ Cross over studyN=16Inclusion criteria: patients with chronic pancreatitis and an exocrine insufficiency, defined as faecal fat excretion >10g/24hr. Pancreatic enzyme replacement had to be stopped at least 3 days before starting the study.
Exclusion criteria: not reported

Patient Characteristics:
Men/women: 13/3
Age (range): 53 ± 3 yrs (27–74)
Interval between diagnosis of chronic pancreatitis and entering study (range): 9 ± 2 yrs (4–20yrs)
Alcohol related chronic pancreatitis: 9/16 (56 %)
Pancreatic duct anomaly: 1/16 (6%)
Idiopathic: 6/16 (38%)
Previous pancreatic surgery: 4/16 (25%)
All patients were on pancreatic enzyme replacement therapy, mean: 4± 1 yrs.
Acid suppression use:
H2 receptor blockers: 2/16 (13%)
Proton pump inhibition: 6/16 (38%)
Treatment A: Omeprazole 60 mg + enteric-coated microspheres (Pancrease, 10,000 FIP lipase, tid) before meals

Pancrease dose was given as 2 capsules, each consisting of 5000 FIP IU lipase, 2900 FIP IU amylase and 330 FIP IU protease. These were given with 2 pancrease- placebo capsules.

Omeprazole 60 mg was ingested 30 mins before meals (3 capsules of 20 mg)
Treatment B: Omeprazole 60 mg with enteric-coated microspheres (Pancrease, 20,000 FIP lipase, tid) before meals.

Pancrease dose was given as 4 capsules (each capsule containing 5000 FIP IU lipase, 2900 FIP IU amylase and 330 FIP IU protease)

Omeprazole 60 mg was ingested 30 mins before meals (3 capsules of 20 mg)
45 daysFaecal parameters
Abdominal symptoms
Grant from Jansen Cilag.
Effect Size
Outcomes
  1. Faecal fat excretion:
Basal
(before treatment)
Treatment A (omeprazole + lipase 10,000 IU tid)Treatment B (omeprazole + lipase 20,000 IU tid)
Faecal fat excretion (g/24hrs)36.5 ± 8.417.9 ± 6.5 *18.3 ± 4.7 *
 *p<0.01 compared with basal value
    • Faecal fat excretion was not effected by whether a patient had previously been operated on or not.
  1. Abdominal symptoms:
    • Abdominal symptoms score included: abdominal pain, cramps, bloating and flatulence (0=no symptoms, 10= intolerable).
    • The change in symptom scores did not differ between patients who had been operated on and those that had not.
Basal
(before treatment)
Treatment A (omeprazole + lipase 10,000 IU tid)Treatment B (omeprazole + lipase 20,000 IU tid)
Abdominal symptoms (0–10)3.2 ± 0.51.3 ± 0.3*1.2 ± 0.3 *
*p<0.01 compared with basal value
3.

Wellbeing score (0–10):

Basal
(before treatment)
Treatment A (omeprazole + lipase 10,000 IU tid)Treatment B (omeprazole + lipase 20,000 IU tid)
Wellbeing score (0–10)4.9 ± 0.26.1 ± 0.2*6.2 ± 0.2*
*p<0.05 compared basal
4.

Fat absorption (%):

Basal
(before treatment)
Treatment A (omeprazole + lipase 10,000 IU tid)Treatment B (omeprazole +lipase 20,000 IU tid)
Fat absorption (%)49 ± 876 ± 7*75 ± 5*
  • Significant increase in fat absorption in both treatment groups compared to basal value, p<0.01*
Authors conclusion :
‘ During acid inhibition with 60 mg omeprazole, not only standard doses of 20,000 FIP IU lipase tid with meals but also lower doses of 10,000 FIP IU lipase significantly improve fat absorption by 50% and significantly and beneficially affect abdominal symptoms and general wellbeing.’
Van Hoozen CM, Peeke PG, Taubeneck M et al. Efficacy of enzyme supplementation after surgery for chronic pancreatitis. Pancreas. 1997; 14(2):174–180. Ref ID: 20101+ randomized crossover trialN=11Inclusion criteria: patients with a clinical diagnosis of chronic pancreatitis who underwent elective surgery (local resection longitudinal pancreaticojejunostomy) for relief of recurrent abdominal pain. The diagnosis of chronic pancreatitis was based on a compatible history and abnormal endoscopic retrograde pancreatography and CT of the pancreas and was confirmed in each instance by surgical and histopathological findings.
Exclusion criteria: subjects with a history of bowel resection, active cancer, chronic liver, or kidney disease or evidence of ongoing drug or alcohol abuse.
Patient characteristics:
Male/Female: 8/3
Age range: 33–62 yrs
History of chronic alcohol abuse: 11/11 (100%)
Concurrent cholethiasis: 1/11 (9%)
Concurrent haemochromatosis: 1/11 (%)
Recurrent abdominal pain as the major indication for surgery: 11/11 (100%)
Weight loss >10kg + diarrhoea +/or greasy stools prior to surgery: 6/11 (55%)
Pancreatic calcifications prior to surgery: 9/11 (82%)
Fasting hyperglycaemia prior to surgery: 5/11 (45%)
3 different time points:
  1. Initial baseline evaluations 3 weeks after surgery:
    DIET MODIFICATION:
    Including 1 week of adaptation to oral feeding (patients withdrawn from parenteral nutritional support and adapted to rountine hospital diet providing 30 kcal/kg ideal body weight, containing 35% of kcal as fat, 15–20% protein, and 44–55% carbohydrate).
  2. First 4 weeks after baseline measurements:
    All patients received pancreatin USP: each capsule containing 8,000 USP U of lipase, 13,000 USP U of protease, and 30,000 USP U of amylase in enteric-coated microspheres and minimicrospheres. The total daily dose of pancreatin was based on the initial daily faecal fat excretion and was divided among meals to provide 4, 7, 8, 11 or 12 capsules/day for patients whose daily faecal fat excretion exceeded 15 g and reached 30, 40, 50, 60 or 70g/day, respectively. Each patient also received an oral H2 blocker of gastric acid secretion in usual therapeutic dose range.
  3. After 4 weeks (4–8 week period):
    PANCREATIN OR PLACEBO:
    Tests of digestion and nutritional assessment were repeated in the outpatient clinic, and patients were then double- blind randomized to receive the same dose of pancreatin or placebo. At the end of the 8 weeks tests were repeated.
NA8 weeksAbsorption
Nitrogen
Weight
Vitamin and mineral levels
Abdominal pain
Grants from Solvay Pharmace uticals and the National Institutes of Health.
Effect Size
Outcomes:
  1. Weight:
    • Week 4–8: those randomized to receive pancreatin gained 3.6–5.5kg in body weight over the 8 week period compared to no weight gain in those randomized to placebo.
    • All patients reported decreased abdominal pain following surgery.
    • Pain scores (0=no pain, 5=worst ever pain):
      -

      Pain scores were similar and minimal prior to starting the 4–8 week period of the trial:

      -

      No changes in pain scores were reported between or within the groups during the 8 week follow up.

  2. Absorption (coefficient %):
Patients randomized to placebo for weeks 4–8 had significantly worse fat and total energy absorption than patients who continued to receive pancreatin, p<0.02.
Ramo OJ, Puolakkainen PA, Seppala K et al. Self-administration of enzyme substitution in the treatment of exocrine pancreatic insufficiency. Scandinavian Journal of Gastroenterology. 1989; 24(6):688–692. Ref ID: 4281 + Randomized crossover trialN=10Inclusion criteria:
  1. chronic pancreatitis verified by either histologically and/or with endoscopic retrograde pancreatography;
  2. persistent upper abdominal pain:
  3. continuous enzyme substitution necessary;
  4. bicarbonate output <6 mmol/l/30 min in the secretin test by duodenal intubation (normal value >15 mmol/l/30min)
  5. All patients stopped previous enzyme supplements 1 week befor entering the study.
Exclusion criteria: not reported

Patient Characteristics:
Male/female: 3/7
Mean age(range): 52.4 yrs (36–73 yrs)
Aetiology:
Chronic alcohol abuse: 9/10 (90%)
Idiopathic: 1/10 (10%)
Mean duration of disease: 8.2 ± 2.5 yrs
Insulin-dependant diabetics: 10/10 (100%)
Previous resection of the caudal part of the pancreas: 9/10 (90%)- performed 5.0 ± 1.7yrs earlier.
‘Regular dosage’
-

Pancrease- encapsulated enteric coated microspheric pancreatic enzyme (each capsule containing 4000 NFU lipase, 20,000 NFU amylase, 25,000 NF proteases)

-

dosage recommended by the manufacturer: 2 capsules at meals and 1 capsule with snacks.

After 4 weeks patients were examined, weighed and laboratory tests were performed and then changed to the ‘individual dosing/self administration’ dosing for 4 weeks.

All patients were told not to use any analgesics or alcohol during the study, but could follow a normal diet.
‘individual dosing/self administration’
-

Pancrease

-

Dosage given in accordance with the symptoms experienced to obtain maximum relief of symptoms.

After 4 weeks patients were examined, weighed and laboratory tests were performed and then changed to the ‘regular dosing’ for 4 weeks.

All patients were told not to use any analgesics or alcohol during the study, but could follow a normal diet.
8 weeksLaboratory markers
Weight
Bowel movements
Pain (0–3)
Sigrid Juselius Foundation (Star Oyy, Tampere, Finland and Cilag AB, Sollentuna, Sweden wh donated the pancrease)
Effect Size
Outcomes
The consumption of pancreatic enzyme (capsules/day) was significantly higher (p<0.001) during the self-administration of the pancrease:
-

Regular dosage: 5.0 ± 1.3

-

Individual dosing/self administration: 11.4 ± 2.4

  1. Weight:
    • There was no significant change in weight (kg) between the 2 groups:
      -

      Regular dosage: 62.8 ± 13.2

      -

      Individual dosing/self administration: 63.8 ± 13.2

  2. Pain score (0–3):
    • The pooled data on pain showed a significantly lower (p<0.05) pain score during the self-administration of pancrease:
      -

      Regular dosage: 2.2 ± 0.7

      -

      Individual dosing/self administration: 1.1 ± 0.7

    • The difference in pain scores did not reach significance in 3 of the patients in individual comparison, although there was a tendency towards a decrease of pain in these patients.
Authors’ Conclusion:
‘It might be useful to allow patients with chronic pancreatitis to try self-administration in the treatment of chronic pancreatitis to achieve optimal relief of symptoms.’
Gouerou H. Alipase versus nonenteric- coated enzymes in pancreatic insufficiency. A french multicenter crossover comparative study. International Journal of Pancreatology. 1989; 5 Suppl:45–50. Ref ID: 4981+ Open multi- centre crossover study (conducted in 16 centres in France.)N=35
Drop Out= 8/35 (23%)
Completed study: 27
Inclusion criteria: patients with pancreatic insufficiency and signs of chronic pancreatitis. The diagnosis of exocrine pancreatic insufficiency was based on steatorrhea >8g/24hrs without enzyme therapy, and chronic pancreatitis shown morphologically by pancreatic calcifications, abnormal cholangio-pancreato retrograde endoscopy or other histological signs. Patients may have had previous pancreatic surgery.
Exclusion criteria: patients who had acute attacks of pancreatitis within the last 15 days, gastric or duodenal ulcer, disease of the small intestine, previous enterectomy, hepatic insufficiency, cholestasis, or plans for surgery.
Patient Characteristics:
Group 1: (P then E) n=20

Pancrease- enteric coated microphere containing enzyme. 9 capsules/day

Patients received pancrease then Eurobiol for 21 days each.

Pancrease was started after a 10 day wash-out period.
Group 2: (E then P) n=15

Eurobiol- non-enteric coated enzyme. 3 vials/day.

Patients received eurobiol then pancrease for 21 days each.

Eurobiol was started after a 10 day wash-out period.
52 days (10 days washout, 2×21 dasfor each treatment)Steatorrhoea
Digestive symptoms: abdominal extension, pain
Drug acceptance
Adverse reactions
Not reported
Group 1Group 2
Sex M/F19/114/1
Age (yrs)50.5 (±9.8)47.2 (±11.4)
Weight (kg)57.0 (±9.0)57.9 (±12.3)
Pancreatitis due to alcoholism19/20 (95%)14/15 (93%)
Abdominal pain16/20 (80%)13/15 (87%)
Diabetes9/20 (56%)7/15 (54%)
Surgical operations85%53%
Steatorrhoea g/d25.8 (±31.8)20.3 (±15.1)
There were no statistically significant differences in baseline characteristics across groups.
Effect Size
Outcomes
  • Faecal fat excretion:
    -

    No significant difference in mean faecal fat between the 2 groups (mean ± SD) :

    • Pancrease: 13.9 ± 12.96 (2.2–52.1)
    • Eurobiol: 12.32 ± 9.48 (0–33.2)
    -

    Data of individual patients showed a wide variation in both drug groups;

    • After Pancrease: faecal fat excretion varied from 2.2–52.1 g/d
    • After Eurobiol: faecal fat excretion varied from 0–33.2 g/d
  • -

    No significant/borderline decrease in the number of patients (n=8) complaining of abdominal pain (p<0.10) (pancrease 14% vs. Eurobiol 86%)

Authors’ Conclusion:
‘Improvement in functional symptoms, improved taste, and ease of administration of Pancrease when compared to conventional enzymes leads to better patient compliance, which is the best guarantee of long-term drug efficacy.’
Lankisch PG, Lembcke B. Therapy of pancreatogenic steatorrhoea: does acid protection of pancreatic enzymes offer any advantage? Zeitschrift für Gastroenterologie. 1986; 24(12):753–757. Ref ID: 5071+ Randomized crossover trialN=8Inclusion criteria: patients with chronic pancreatitis diagnosed by typical case histories, abnormal secretin-pancreozymin test and/or histological investigation of the pancreas at operation. Patients’ daily fat intake was 100g and previous pancreatin supplementation was stopped 3 days prior to the study.
Exclusion criteria: not reported.
Patient Characteristics:
Male/Female: 7/1
Faecal fat excretion: >15g/day
Aetiology:
Alcohol related pancreatitis: 7/8 (88%)
Idiopathic: 1/8(13%)
Each patient received 1 of the following 3 regimens for 5 successive days:
  1. Pankreon 700 (6.3g/day: 252,000 FIP lipase/day): 3×3 dragees daily
  2. Pankreon 700 (6.3g/day: 252,000 FIP lipase/day): 3×3 dragees daily + cimetidine 300mg, 30 min prior to 3 main meals
  3. Kreon (5.4g/day: 180,000 FIP lipase/day): 3×6 capsules daily
NAFaecal weight
Faecal fat
8 daysNot reported
Effect Size
Outcomes:
  • Faecal Fat excretion(g/day):
    -

    Pankreon 700: non-significant mean reduction of 44% (33.5g/day)

    -

    Pankreon 700 + cimetidine: significant mean reduction of 60% (23.6 g/day) p<0.05

    -

    Kreon: significant mean reduction of 79% (12.6 g/day) p<0.05

    -

    Despite the mean reduction of faecal fat excretion during Pankreon + cimetidine and Kreon treatment, the individual daily faecal fat excretion was only normalized in 2 patients (2/8; 25%) both of whom were on the Kreon regimen.

Authors’ Conclusion:
‘ The new acid-protected pancreatin preparation Kreon has been shown to be an equally potent alternative for this therapeutic concept, and may possibly simplify treatment of excocrine pancreatic insufficiency n the presence of gastric hypersecretion.’
Isaksson G, Ihse I. Pain reduction by an oral pancreatic enzyme preparation in chronic pancreatitis. Digestive Diseases & Sciences. 1983; 28(2):97–102. Ref ID: 20141++ Double- blind crossoverN=19Patients with chronic pancreatitis

Diagnosis was based on low pancreatic isomylase in serum 10/19 patients, pathological findings at Lundh test in 12/12, calcification on x-ray 6/19, pathological ECRP findings in 14/14 investigated

Patient population: female:male 8:11, mean age 43 and 47 respectively.

10/11 male patients had alcohol- related pancreatitis

0/8 in female patients suspected alcohol etiology
PankreonPlaceboOne week per treatmentPain (patient on o to 100 mm analog scale and physician blind to written records)
Effect
Pancreatic enzyme vs placebo
Pain
15/19 had pain relief during the week on pancreatic enzyme treatment compared with placebo (no data; p<0.05)
Examiner rated pain was significantly lower when patients were on pancreratic enzyme compared with placebo (p<0.05)
The patient-rated mean pain score during the week was significantly lowers when patients were on enzyme supplementation compared with placebo (210 vs 120; p<0.01)
The examiner-rated mean pain score was significantly lower on pancreatic enzyme compared with placebo (32 vs 20; p<0.05)
The frequency of pain was significantly lower in patients on enzyme supplementation compared with placebo (score 1 to 4: 2.22±0.19 vs. 2.78± 0.2, P<0.05)
There was no significant difference in the number of analgesic tablets consumed when patients were on enzyme supplementation compared with placebo (7.8 vs 8.9; ns)

Side effects
‘Several patients stopped taking enzyme supplementation because of side effects’. No further details given.
Halgreen H, Thorsgaard P, Worning H. Symptomatic effect of pancreatic enzyme therapy in patients with chronic pancreatitis. Scandinavian Journal of Gastroenterology. 1986; 21(1):104–108. Ref ID: 3391+ Double- blind, crossoverN=20Patients with chronic painful pancreatitis

Chronic pancreatits with steatorrhea

Alcohol etiology N=4

Chronic pancreatitis without steatorrhoea

Alcohol etiology N=7

Chronic pancreatitis was verified by a reduced exocrine function and at least one of the following criteria: pancreatic calcifications, previous acute attacks of pancreatitis and/or typical abnormalities by endoscopic retrograde pancreatography

11 patients had severely reduced pancreatic function, with a meal- stimulated duodenal lipase concentration of less than 50 kU/l and a faecal fat excretion of more than 7 g/day.

9 patients had less severe reduction of the exocrine pancreatic function and a normal faecal fat excretion

Chronic pancreatitis with steatorrhea: age range 29 to 58 yrs, disease duration range 4 to 20 yrs, diabetes mellitus present N=6

Chronic pancreatitis without steatorrhoes: age range 32 to 58 yrs, disease duration range 3 to 10 yrs, diabetes melititus present N=1

Patients population
Pancreatic enzyme

Encapsulated enteric-coated microspheric enzymes

Pancreas

Lipase 4000 Nationak Forumulary Units

Amylase 20 000 NFU

25 000 Proteases NFU

2 capsules at meals, 1 capsule at snacks

Patients already on enzyme supplementation had it stopped two weeks prior to entering the study
Placebo4 week trial duration

2 and 4th weeks daily records of pain
Postprandial pain score, pain between meals, No. of pain attacks, analgesic consumption, subjective pain score, general well-beingCilag AB, Sollentuna, Sweden
Effect
Enzyme supplementation vs placebo
Pain
For patients with or without steatorrhea there were no significant differences when patients were on enzyme supplementation compared with placebo for:
Postprandial pain score: chronic pancreatitis with steatorrhoea (n=11) placebo 6.4, pancrease 4.6; chronic pancreatitis without steatorrhoea (n=9) placebo 2.5, pancrease 3.6 (ns; no p value)
pain between meals: chronic pancreatitis with steatorrhoea (n=11) placebo 7.4, pancrease 6.1; chronic pancreatitis without steatorrhoea (n=9) placebo 5.3, pancrease 6.0 (ns; no p value)
No. of pain attacks: chronic pancreatitis with steatorrhoea (n=11) placebo 20, pancrease 17; chronic pancreatitis without steatorrhoea (n=9) placebo 16, pancrease 19 (ns; no p value)
analgesic consumption; chronic pancreatitis with steatorrhoea (n=11) placebo 58, pancrease 49; chronic pancreatitis without steatorrhoea (n=9) placebo 48, pancrease 57 (ns; no p value)
subjective pain score: chronic pancreatitis with steatorrhoea (n=11) placebo 3.5, pancrease 2.6; chronic pancreatitis without steatorrhoea (n=9) placebo 1.5, pancrease 2.0 (ns; no p value)
general well-being: chronic pancreatitis with steatorrhoea (n=11) placebo 2.3, pancrease 1.7; chronic pancreatitis without steatorrhoea (n=9) placebo 1.7, pancrease 2.0 (ns; no p value)
Faecal fat g/day:
  1. Chronic pancreatitis with steatorrhoea (n=11):
    Placebo: 24.2; Pancrease: 10.4; P<0.01
  2. Chronic pancreatitis without steatorrhoea:
    Placebo: 2.3; Pancrease: 3.3; No significant difference (no data)
Mossner J, Secknus J, Meyer J et al. Treatment of pain with pancreatic extracts in chronic pancreatitis: Results of a prospective placebo- controlled multicenter trial. Digestion. 1992; 53(1–2):54–2. Ref ID: 20161+ multi- centre double blind crossover trialN=47

N=43 completers
Patients with chronic pancreatitis

Inclusion criteria: acute or chronic abdominal pain most likely due to chronic pancreatits, parenteral nutrition or intensive therapy not required, abnormlaties at ERCP or calcification or typical signs on CT/sonography, faecal fat below 30 g/day, duration not more than 30 months

Exclusion criteria included: history of gastric resections or vagotomy, history of pancreatic resections,

Patient population: 41 males, 6 females
Pancreatic enzyme

Acid-protected

Given at higher dosage than commonly used treatment

Panzytrat 20 000 capsules with microtablets 5 × 2 capsules/day

Lipase 20 000 Eur U
Amylase 18 000 Ph Eur E Proteases 1 000 ph Eur U

This dosage ensured the application of 10 000 Ph Eur U of proteases/day
Placebo28 daysPain (score 1 to 3)
Analgesic use Symptoms
Nordmark Arzneimittel, Uetersen, FRG
Effect
Pancreatic enzyme vs placebo
Faecal fat
There was no significant difference in faecal fat when patients were on enzyme supplementation compared with placebo at 14 days (11 vs 10 g/day; ns) or 28 days (11 vs 9 g/d; ns)

Pain
There was no significant difference in mean daily pain score at 14 days when patients were on enzyme supplementation compared to placebo (mean score 1.08± 0.87 vs 1.26± 0.89; ns)

There was no significant difference at 28 days for analgesic use when comparing patients on enzyme supplementation compared to placebo (no data; ns)

Symptoms
There was no significant difference for patients on enzyme supplementation compared with those on placebo for:
Diarrhoea (ns)
Nausea (ns)
Vomiting (ns)
Flatulence (ns)
O’Keefe SJ, Cariem AK, Levy M. The exacerbation of pancreatic endocrine dysfunction by potent pancreatic exocrine supplements in patients with chronic pancreatitis. Journal of Clinical Gastroenterology. 2001; 32(4):319–323. Ref ID: 20071+ Randomised, parallelN=29 intervention/treatment

N=40 (run-in period)
Adults with pancreatic insufficiency defined as presence of suppressed cholecystokinin-stimulated enzyme secretition or steatorrhea and to have to have typical signs of chronic pancreatitis

Alcohol etiology:
14/15 treatment

13/15 placebo

Exclusion criteria included gastroparesis with nausea and vomiting after large meals, malignant disease, current alcohol use

Patiebt population: Placebo Mean age 57.8*, Body weight 65.5 kg, decompression surgery 2/14, insulin diabetes 10/14*, oral diabetes 2/14, stool fat 44.3 g/d

Supplement group:
Mean age 49.1*, Body weight 57.2 kg, decompression surgery 7/15, insulin diabetes 5/15*, oral diabetes 1/15, stool fat 48/0 g/d

* denotes significant difference
Pancreatic enzyme supplementation: Creon

N=15

Mini-microspheres

Lipase 10 000 USP U/capsule

Amylase 33 200 U SP U/capsule

Protease 37,5000 USP U/capsule

Four capsules were given with each main meal and two with snacks = 16 capsules per day for 7 days

Run-in period consisting of a placebo, nonsupplemented, 7-day study to assess the degree of pancreatic malaborption followed by a 7-day observation period of standard pancreatic enzyme supplementation whilst awaiting the results of the absorption tests

Patients were asked to adhere to a standard diet of 12.6 MJ of energy per day for men and 10.5 MK/d for women consisting of 31% fat, 54% carbohydrate and 15% protein throughout the study periods
Placebo

N=14
7 days per treatmentSymptoms steatorrheaKali- Chemie Pharma Germany
Effect
Enzyme vs placebo
Symptoms
There was no significant difference between enzyme supplementation and placebo for:
Abdominal pain (ns)
Distention (ns)
Flactulance (ns)

Steatorrhea
Stool fat was significantly lower when patients were taking enzyme supplementation compared with placebo (20.3 ± 4.3 vs 48 ± 10.6 g/d; p=0.003)

Fat absorption:
Creon: 80.8 ± 3.8%
Placebo: 54.0 ± 9.7%
P=0.002
Slaff J, Jacobson D, Tillman CR. Protease- specific suppression of pancreatic exocrine secretion. Gastroenterology. 1984; 87(1):44–52. Ref ID: 4471+ Double- blind crossoverN=20Patients with well-established chronic pancreatitis (alcohol- induced) or idiopathic

N=10
Alcohol-induced

Each patients had an abnormal secretin test on at least two occasions (> 80 mEq/L normal)

12 patients had a normal fat excretion and a maximum bicarbonate on the secretin test of 63.67 mEq/L

8 patients had steatorrhea and a maximum bicarbonate of 42.75 mEq/L

Age range 31 to 65 yrs
Steatorrhea range 1.6 to 48.4 g/24 hr
Pancreatic enzme Ilozyme

6 tablets q.i.d

Pancreatic extract was stopped 2 weeks prior to investigation
Placebo60 days trial duration (30 days per treatment)Pain (score 1 to 4)
Daily analgesic requirements
Adria Inc., Columbus and National Institute of Health
Effect
Pancreatic enzyme vs placebo
Patients with mild to moderate impairments of exocrine function (maximum bicarbonate concentration in the secretin test between 50 and 80 mEq/L and normal faceal fat determination) had significantly more pain relief with enzyme supplementation than placebo (p<0.05, no data)
9/12 (75%) with mild to moderate disease experience pain relief with enzyme supplementation compared with 2/8 (205)% of patients with severe disease (steatorrhea)
For patients with mild to moderate disease the average daily pain score was significantly lower on enzyme supplementation compared with placebo (1.02 ± 0.39 vs. 3.4 ± 0.35, P<0.01)
In addition, the use of analgesics decreased by 40% in these 9 patients
Delchier JC, Vidon N, Saint MGM et al. Fate of orally ingested enzymes in pancreatic insufficiency: comparison of two pancreatic enzyme preparations. Alimentary Pharmacology & Therapeutics. 1991; 5(4):365–378. Ref ID: 1621+ Double blind, crossoverN=6Patients with severe pancreatic insufficiency secondary to chronic pancreatitis

N=5 history of chronic alcohol abuse before the onset of pancreatitis, N=1 familial chronic pancreatitis

Pancreatic insufficiency defined as: abnormal faecal fat excretion (> 7.0 g/24 hr on 100 g/day fat intake); b) a normal d-xylose absorption test; and c) the presence of at least one of the following clinical criteria: a marked abnormal BT-PABA test, radiological evidence of pancreatic calcifications or multiple strictures in the main pancreatic duct, or histological evidence of chronic pancreatitis on surgically resected tissue.

All three criteria were present in each patient

Mean disease duration 19 yrs (range 2 to 38 yrs). Four patients presented mild cholestatis and one had histologically proven cirrhosis. Insulin-dependent and non-insulin dependent diabetes mellitus were presented in 3 and 1 patient respectively.

At the time of the study all 6 patients had been taking pancreatic enzyme supplements for more than one year and were in stable metabolic condition
Eurobiol

Freeze-dried pig pancreas (1 dose = 5 g)

Eurobiol 25 000

Capsules containing 500 mg of pH-sensitive, enteric- coated pancreatin microtablets (1 dose = 2 capsules)

The meal was 490kcal 50% carbohydrate, 30% fat and 20% protein
Placebo

Powder of pork fillet (1 dose = 5 mg) and gelatine capsules containing 500 mg of enteric- coated microtablets of pork fillet
24 hr per treatmentFacecal fatLaboratoires Euroga (France)
Effect
Eurobiol vs Eurobiol 25 000 vs placebo
Faecal fat excretion
There was a significant difference in mean faecal fat excretion in g/24 hr between the treatments (32 ± 7.8 vs. 24 ± 1.5 vs. 42 ± 4.5 g/24 hr; p<0.05)
Eurobiol 25 000 was significantly different to placebo (p<0.05).
Daily faecal fat output was not normalised in any patient, regardless of the preparation used.
Schneider MU, Knoll RM, Domschke S et al. Pancreatic enzyme replacement therapy: comparative effects of conventional and enteric-coated microspheric pancreatin and acid- stable fungal enzyme preparations on steatorrhoea in chronic pancreatitis. Hepato- Gastroenterology. 1985; 32(2):97–102. Ref ID: 2161- open label crossover trialN=17Inclusion criteria: patients with alcoholic pancreatitis insufficiency as shown by the secretin- pancreozymin test, and considerable steatorrhoea (>15g total faecal fat excretion per day) as a sign of pancreatogenic maldigestion, were examined.
Exclusion criteria: patients with extra-pancreatic causes of steatorrhoea.
Patient Characteristics:
Previous Whipple’s procedure with intraoperative pancreatic duct occlusion (performed 3–8 months prior to entering study): 9/17 (53%)
Chronic pancreatitis + intact upper digestive tract: 8/17 (47%)
Group A: patients who had previously undergone Whipple’s procedure.

3 separate enzyme preparations were taken for 2 weeks each:
  1. Kreon-acid protected preparation. 10 capsules/day ( 100,000 U lipase, 100,000 U amylase, 6,500 U protease per capsule)
  2. Pankreon- conventional porcine preparation. 10 teaspoonfuls or 30g/day (360,000 U lipase, 270,000 U amylase, 24,000 U protease per capsule)
  3. Nortase- acid-stable fungal preparation. 10 capsules/day (75,000 U lipase, 100,000 U protease, 7,000 U amylase per capsule).
Prior to entering the study patients went for 5 days without pancreatic enzyme preparations, H2 antagonists or antacids. During the 3 treatment periods the diet of the patients was based on worked-out daily diet containing 100g fat/day and adequate carbohydrate and protein.
Group B: patients with intact upper digestive tract.

See Group A info.
47 daysStools/day
Stool weight
Weight
Faecal fat concentrations
Not reported
Effect:
  1. Weight
    • The mean increase in weight in response to 2 weeks of supplementation with Kreon was:
      -

      Group A: from 62.0 ± 9.9 to 64.3 ± 8.8 kg

      -

      Group B: from 60.1± 10.4 to 61.5 ± 10.5 kg

  2. Faecal Fat concentration
    • Group A:
      -

      A significant (p<0.01) reduction in faecal fat concentrations was found when using the conventional porcine preparation (Pankreon).

      -

      The acid stable fungal preparation (Nortase) led to a statistically non-significant mean reduction in faecal fat concentration. Although 2/8 (25%) of patients the preparation led to mormalization of faecal fat concentrations.

    • Group B:
      -

      There was no significant reduction in faecal fat seen when using the conventional porcine preparation (Pankreon).

      -

      The acid stable fungal preparation (Nortase) led to a statistically non-significant mean reduction in faecal fat concentration.

    • In both treatment groups all pancreatic enzyme preparations led to a significant reduction in total faecal fat excretion/day:
      -

      Group A (average): Kreon: 58% drop; Pankreon: 67% drop; Nortase: 54% drop

      -

      Group B (average): Kreon: 58% drop; Pankreon: 52% drop; Nortase: 46% drop

    • In treatment Group A the total faecal fat excretion/day was lowered to below the ‘indication threshold’ for enzyme replacement (15g faecal fat excretion/day) in 1 patient by Nortase and the Pankreon preparations.
    • In treatment Group B the total faecal fat excretion/day was lowered to below the ‘indication threshold’ for enzyme replacement (15g faecal fat excretion/day) in 2 patients by the Kreon preparation.
    • The difference in the reduction of total faecal fat excretion/day produced by various enzyme preparations were not statistically significant, either within the therapy groups (A or B) or in a direct comparison of the enzyme preparations with one another.
Authors’ Conclusion:
‘..the virtually identical lipase activities of an acid-protected porcine pancreatic enzyme preparation (Kreon) and an acid-stable fungal enzyme preparation (Nortase) produced largely the same effect as a conventional porcine pancreatic enzyme preparation (Pankreon) with four times as much lipase activity, in the treatment of severe pancreatogenic steatorrhoea.
Dutta SK, Tilley DK. The pH- sensitive enteric- coated pancreatic enzyme preparations: an evaluation of therapeutic efficacy in adult patients with pancreatic insufficiency. Journal of Clinical Gastroenterology. 1983; 5(1):51–54. Ref ID: 20121- crossover trialN=7Inclusion criteria: patients with pancreatic insufficiency diagnosed by:
  1. the presence of steatorrhoea (>7.0g/24 hrs faecal fat)
  2. an abnormal secretin test
  3. a normal d-xylose absorption test
Exclusion criteria: not reported.

Patient Characteristics:
Men/female: 7/0
Mean age (range):50 yrs (44–57)
Pancreatic insufficiency secondary to chronic alcoholic pancreatitis: 7/7(100%)
Previous pancreatic, biliary tract or gastrointestinal surgery: 0/7 (0%)
Insulin dependant diabetes: 3/7 (43%)
Patients received each of the 3 different regimes for 72 hrs each:
  1. Pancreatin: a conventional pancreatic enzyme preparation with low enzyme content (protease USP units 8743 ± 187; lipase USP units 684 ± 52) 10 tablets with each meal 3 times/day (3 tablets at beginning and end of meal and 4 tablets in the middle)
  2. Pancrease: enzyme preparation with pH sensitive coating (protease USP units 28000 ± 335; lipase USP units 4933 ± 140) 4 capsules with each meal, 3 times/day (1 capsule at the beginning and end of meal and 2 in the middle).
  3. Cotazym-S: enzyme preparation with pH sensitive coating with higher lipase concentration (protease USP units 28000 ± 298; lipase USP units 5712 ± 152) 4 capsules with each meal, 3 times/day (1 capsule at the beginning and end of meal and 2 in the middle).
All patients were given a 100g/day fat diet for 3 days with 72 hour faecal collection prior to starting any treatment.
NA12 daysFaecal fat excretion
Bowel movement
The Veterans Administration
Effect Size
Outcomes
  • Faecal fat excretion, g/24 hrs (mean ± SEM):
    -

    Untreated: 31.0 ± 4.0

    -

    Pancreatin: 19.0 ± 4.0

    -

    Pancrease: 13.0 ± 5.0

    -

    Cotazym-S: 9.0 ± 2.0

    -

    A trend to greater reduction of faecal fat with pH sensitive enteric coated pancreatic enzymes (Cotazym-S + Pancrease) did not reach statistical significance.

    -

    There was no difference between the 2 pH sensitive enteric coated pancreatic enzymes (Cotazym-S + Pancrease).

From: Evidence Tables

Cover of Alcohol Use Disorders
Alcohol Use Disorders: Diagnosis and Clinical Management of Alcohol-Related Physical Complications [Internet].
NICE Clinical Guidelines, No. 100.
National Clinical Guideline Centre (UK).
Copyright © 2010, National Clinical Guidelines Centre.

Apart from any fair dealing for the purposes of research or private study, criticism or review, as permitted under the Copyright, Designs and Patents Act, 1988, no part of this publication may be reproduced, stored or transmitted in any form or by any means, without the prior written permission of the publisher or, in the case of reprographic reproduction, in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK. Enquiries concerning reproduction outside the terms stated here should be sent to the publisher at the UK address printed on this page.

PubMed Health. A service of the National Library of Medicine, National Institutes of Health.