cochrane database of systematic reviews (reviews) || pancreatic enzymes for chronic pancreatitis

Pancreatic enzymes for chronic pancreatitis (Review)

Shafiq N, Rana S, Bhasin D, Pandhi P, Srivastava P, Sehmby SS, Kumar R, Malhotra S

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2010, Issue 11

http://www.thecochranelibrary.com

Pancreatic enzymes for chronic pancreatitis (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

11DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Pancreatic enzyme versus placebo, Outcome 1 Weight loss. . . . . . . . . . . 23

Analysis 1.2. Comparison 1 Pancreatic enzyme versus placebo, Outcome 2 Amount of faecal fat. . . . . . . . 24

Analysis 1.3. Comparison 1 Pancreatic enzyme versus placebo, Outcome 3 Quality of life scores. . . . . . . . 24

Analysis 3.1. Comparison 3 Different enzymatic preparations, Outcome 1 Amount of faecal fat. . . . . . . . 25

25APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iPancreatic enzymes for chronic pancreatitis (Review)


[Intervention Review]

Pancreatic enzymes for chronic pancreatitis

Nusrat Shafiq1, Surinder Rana2 , Deepak Bhasin2, Promila Pandhi1, Puja Srivastava3 , Surjit S Sehmby1, Raj Kumar4, Samir Malhotra1

1Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India. 2Department of Gas-

troenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India. 3Department of Internal Medicine, Post-

graduate Institute of Medical Education and Research, Chandigarh, India. 4Dr. Tulsidas Library, Postgraduate Institute of Medical

Education and Research, Chandigarh, India

Contact address: Samir Malhotra, Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandi-

garh, 160012, India. [email protected].

Editorial group: Cochrane Upper Gastrointestinal and Pancreatic Diseases Group.

Publication status and date: Edited (no change to conclusions), published in Issue 11, 2010.

Review content assessed as up-to-date: 16 June 2009.

Citation: Shafiq N, Rana S, Bhasin D, Pandhi P, Srivastava P, Sehmby SS, Kumar R, Malhotra S. Pancreatic enzymes for chronic

pancreatitis. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD006302. DOI: 10.1002/14651858.CD006302.pub2.


A B S T R A C T

Background

The efficacy of pancreatic enzymes in reducing pain and improving steatorrhoea is debatable and the evidence base for their utility

needs to be determined.

Objectives

To evaluate the efficacy of pancreatic enzymes in patients with chronic pancreatitis. The specific objectives were to compare the following:

1) pancreatic enzyme versus placebo; 2) different pancreatic enzyme preparations and 3) different dosage schedules of the enzyme

preparations. We evaluated the following outcomes: change in frequency of abdominal pain, duration of pain episodes, intensity of

pain, weight loss, steatorrhoea, faecal fat and quality of life.

Search methods

We devised a search strategy to detect all published and unpublished literature and the search included CENTRAL (The Cochrane

Library 2009, issue 1), MEDLINE (1965 to February 2009) and EMBASE (1974 to Feburary 2009). We handsearched reference lists

and published abstracts from conference proceedings to identify further relevant trials. The date of the last search was April 2009.

Selection criteria

Randomised controlled trials with or without blinding. We included abstracts or unpublished data if sufficient information was available.

Data collection and analysis

Two authors independently extracted and pooled the data pertinent to study outcomes. We combined continuous data using standardised

mean difference (SMD) with 95% confidence interval (CI) and calculated the odds ratio (OR) for dichotomous data (95% CI).

Main results

Ten trials, involving 361 participants, satisfied the inclusion criteria. All the trials were randomised; two had a parallel design while the

remainder had a cross-over design. Although some individual studies reported a beneficial effect of pancreatic enzyme over placebo in

improving pain, incidence of steatorrhoea and analgesic consumption, the results of the studies could not be pooled for these outcomes.

With the use of pancreatic enzymes, we observed a non-significant benefit for weight loss (kg) (SMD 0.06; 95% CI -0.23 to 0.34);

1Pancreatic enzymes for chronic pancreatitis (Review)


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a significant reduction in faecal fat (g/day) (SMD -1.03; 95% CI -1.60 to -0.46) and non-significant difference in subjects’ Clinical

Global Impression of Disease Symptom Scale (SMD -0.63; 95% CI -1.41 to 0.14). We found no significant benefit in reducing faecal

fat with any particular schedule of enzyme preparation or type of enzyme.

Another small study did not show any significant benefit of timing the administration of enzyme preparations in relation to meals on

faecal fat.

Authors’ conclusions

The role of pancreatic enzymes for abdominal pain, weight loss, steatorrhoea, analgesic use and quality of life in patients with chronic

pancreatitis remains equivocal. Good quality, adequately powered studies are much warranted.

P L A I N L A N G U A G E S U M M A R Y

Pancreatic enzymes for chronic pancreatitis

Chronic pancreatitis is a condition afflicting nearly 0.04% to 5% of the population worldwide. The disease presents as recurrent episodes

of abdominal pain, fatty stools and weight loss, or may be asymptomatic. Patients may develop complications over a variable period

of time. Medical treatment often involves prescription of pancreatic enzyme preparations for these patients. This practice is based on

studies which have shown the benefit of pancreatic enzymes on various outcomes such as abdominal pain, weight loss, analgesic use,

fatty stools and quality of life. However, a collective conclusion about the role of pancreatic enzymes in chronic pancreatitis patients

needs to be established from these studies. This systematic review aimed to collect all published and unpublished data on this subject

in order to evaluate whether pancreatic enzymes have any benefit on various parameters in chronic pancreatitis, to compare different

types of enzyme preparations and to evaluate whether different dosage schedules have any influence on the various outcomes. We

included 10 studies in the review. These studies had enrolled small numbers of patients. Though individual studies showed benefit of

varying degrees on the parameters mentioned above, we could not pool the results of these studies. With the evidence available so far,

no definitive conclusion can be drawn for the benefit of pancreatic enzymes in patients with chronic pancreatitis.

B A C K G R O U N D

Description of the condition

Chronic pancreatitis is known to afflict approximately 0.04% to

5% of the population worldwide (Owyang 1991). A regional vari-

ation has been noted in the prevalence of the condition with a

prevalence of 27.4 per 100,000 reported in Scandinavia and ap-

proximately one per 830 in the orient and India (Copenhagen

1981). The condition is associated with mortality rate that ap-

proaches 50% within 20 to 25 years (Steer 1995). Approximately

15% to 20% of patients die of complications associated with exac-

erbation of symptoms, which occurs from time to time, and most

of the remaining deaths are due to factors such as trauma, malnu-

trition, infection or tobacco abuse, which are frequently present in

patients with alcoholic pancreatitis (AGA 1998). Chronic pancre-

atitis is associated with diverse aetiologies such as alcohol intake,

obstructive lesions of the pancreatic duct, hyperparathyroidism

and autoimmunity (Bhadada 2007; Bhasin 2006; Greenberger

2005). The pathophysiology of the disease is multifactorial and

includes environmental, nutritional, chemical and genetic abnor-

malities (Behrman 2007). Approximately 20% to 30% of cases

may be idiopathic (Layer 1994) and in some heredity may play

a role (Etemad 2001). With the advent of new laboratory and

technological advances, it has been possible to reveal the aetiol-

ogy in 79% to 80% of patients who would previously have been

labelled as idiopathic pancreatitis (Lee 2007). Additionally, with

the identification of genetic mutations, a large number of these

cases would no longer be classified as idiopathic. After two ini-

tial reports of an increased incidence of cystic fibrosis transmem-

brance conductance regulator (CFTR) gene mutation in patients

with chronic pancreatitis, mutations in other genes such as serine

protease inhibitor (SPINK 1) and the protease serine 1 (PRSS1)

have been shown to be associated with chronic pancreatitis (Cohn

1998; Kiraly 2007; Whitcomb 1996; Witt 2005).

After a subclinical phase of variable duration, exocrine or en-

docrine insufficiency (or both) may appear. In most cases, both

exocrine and endocrine functions are lost (Steer 1995). Exocrine



insufficiency seen in chronic pancreatitis manifests as maldiges-

tion and malnutrition. A retrospective study has estimated a 30%

to 40% incidence of exocrine pancreatic insufficiency in patients

with chronic pancreatitis (Kalthoff 1984). It may develop soon af-

ter the onset of chronic pancreatitis or may take 25 years to evolve

(Layer 1994). The exocrine tissue may be destroyed because of

long-standing inflammation and fibrosis of the gland. Inadequate

delivery of bicarbonate to the duodenum and secondary inactiva-

tion of the enzyme and bile acids by gastric acids further aggravate

maldigestion. Other factors, such as poor oral intake, continuing

intake of alcohol, gastric dysmotility and mechanical outlet ob-

struction, may all aggravate the maldigestion (Bruno 1995). In

patients with extensive damage to the pancreas (< 10% of the ex-

ocrine function remaining), steatorrhoea (faecal loss of fat) and

azotorrhea (faecal loss of proteins) may occur (Greenberger 2005).

Pain is a common presenting feature (Steer 1995). It may be con-

tinuous or intermittent. In 10% to 20% of patients, pain may be

absent. In some patients fibrosis and scarring of pancreatic tissue

may ultimately lead to pancreatic burnout and spontaneous relief

of pain. The issue of pancreatic burnout, however, is debatable.

It is suggested that relief of pain in these cases may be due to pa-

tients getting used to pain or avoiding factors precipitating pain.

Several mechanisms, such as elevated intraductal pressure, neural

inflammation, neurohormonal changes, gastroparesis and increase

in cholecystokinin levels, have all been proposed as the likely cause

for the pain of pancreatitis (Ammann 1999). Pain may also be

due to other causes, such as pancreatic malabsorption, or steator-

rhoea, and could also be non-visceral (Ammann 1999). Biliary and

colonic strictures (Frey 1990) and the development of malignancy

(Hsu 2005 ) may also lead to pancreatic pain.

Patients may also present with diabetes, jaundice or malabsorp-

tion. The morphologic changes of chronic pancreatitis include

varying degrees of oedema, acute inflammation and necrosis, su-

perimposed on a background of chronic changes that include fi-

brosis, inflammation and loss of exocrine tissue. Ductal elements

may be dilated, and intraductal protein plugs, which may be calci-

fied, can be seen (Steer 1995). The condition is characterised by a

progressive loss of pancreatic parenchymal tissue (Kloppel 1992).

Description of the intervention

Therapy for patients with chronic pancreatitis is directed towards

three major problems - pain, malabsorption and complications of

pancreatitis, such as pseudocysts, fistulae and biliary obstruction.

Additionally, complications such as diabetes need to be managed

as they arise.

Though pancreatic enzyme supplements are the mainstay of treat-

ment for exocrine pancreatic insufficiency in chronic pancreati-

tis, other measures, like substitution of part of their fat intake by

medium chain triglycerides, may act as adjuvant treatments (Steer

1995).

Non-invasive approaches for management of pain include advis-

ing abstinence from alcohol or other causative agents and adminis-

tering analgesic medications. Minimally invasive procedures such

as nerve blocks and endoscopic decompression, or surgical tech-

niques like ductal decompression or side to side pancreaticoje-

junostomy, may prove helpful in ameliorating pain. In some cases

of intractable pain, partial surgical resection of the gland, such

as pylorus preserving pancreatectomy, duodenum preserving head

resection or tail resection, Frey procedure, side to side pancreati-

cojejunostomy and total pancreatectomy with or without islet cell

transplantation, may be undertaken (AGA 1998; Schnelldorfer

2008). However, these surgical procedures may be associated with

loss of exocrine and endocrine functions as well as complications

related to the procedure.

How the intervention might work

Diarrhoea and steatorrhoea show improvement with pancreatic

enzyme replacement. Lipase is the most important component of

pancreatic enzyme supplements. The enzyme replacement may

differ in the formulation (non-enteric coated or enteric coated mi-

crosphere preparations) or timing of administration (with food,

before or after food) (Bruno 1995). Enteric coated preparations

were developed in an attempt to protect pancreatin from acidic

inactivation by preventing liberation of enzymes at acidic pH of

the stomach. In the small intestine, where the pH is likely to rise

above a particular pH threshold, the enteric coat dissolves, releas-

ing the enzymes. Various enteric coated microsphere preparations

show marked differences in physical characteristics, such as total

enzyme content, particle size, lipase/protease ratio, pH threshold

of dissolution of the enteric coating, and the rate of enzyme re-

lease. There is a need to evaluate the differential efficacy of these

enzyme preparations (FDA 2004; Greenberger 1999). Addition-

ally, the dosing schedule of the enzymes may also influence the

clinical outcome and needs to be evaluated in a systematic review

(Dominguez 2005).

Normally, the release of cholecystokinin from specific intestinal

cells is regulated by a cholecystokinin-releasing peptide in the prox-

imal small intestine that is luminally active and trypsin-sensitive

(Sandberg 1989). Pancreatic enzymes are proposed to suppress the

release of cholecystokinin-releasing peptide by a negative feedback

mechanism. Pancreatic enzymes may produce a beneficial effect on

pain through this mechanism although other mechanisms such as

reduction in steatorrhoea may be important. Pancreatic enzymes

have been evaluated for their efficacy in relieving pain (Czack

2003; Halgreen 1986; Isaksson 1983; Larvin 1991; Malesci 1995;

Mossner 1992; Slaff 1984). The results of these studies are varied

and an earlier meta-analysis (Brown 1997) concludes no benefit

of pancreatic enzyme preparations over placebo in reducing pain

in patients with chronic pancreatitis. The parameter evaluated in

this meta-analysis was percentage of patients showing preference

for enzymes over placebo. No evaluation of visual analogue scales



of pain, analgesics used or frequency of episodes of pain was made

and few studies have subsequently investigated the role of pancre-

atic enzymes in reducing pain either as their primary objective or

a secondary objective.

Why it is important to do this review

The review aims to highlight the comparative efficacy of various

types of enzyme preparations in chronic pancreatitis. Additionally,

it will also evaluate the role of pancreatic enzymes in reducing

abdominal pain associated with chronic pancreatitis.

O B J E C T I V E S

To evaluate the efficacy of pancreatic enzymes in patients with

chronic pancreatitis.

Comparisons will be as follows.

1. Pancreatic enzyme versus placebo in changing the frequency

of abdominal pain, duration of pain episodes, intensity of pain,

weight loss, steatorrhoea, analgesic use and quality of life.

2. Different pancreatic enzyme preparations in changing the

frequency of abdominal pain, duration of pain episodes, intensity

of pain, weight loss, steatorrhoea, analgesic use and quality of life.

3. Different dosage schedules of enzyme preparations in

changing the frequency of abdominal pain, duration of pain

episodes, intensity of pain, weight loss, steatorrhoea, analgesic

use and quality of life.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Inclusion criteria

Randomised controlled trials, with or without blinding. We in-

cluded abstracts or unpublished data if sufficient information on

study design, characteristics of participants, interventions and out-

comes was available and if full information, as well as final results,

could be confirmed by contacting the first author.

Exclusion criteria

We excluded open, uncontrolled, observational studies from the

meta-analysis.

Types of participants

We included studies that evaluated patients with chronic pancre-

atitis in the meta-analysis. The criteria for the diagnosis of chronic

pancreatitis included in these studies were clinical grounds and

the presence of:

1. grade II to IV changes in the main pancreatic duct and the

branches of the main pancreatic duct at endoscopic retrograde

cholangiopancreatography (ERCP) as per the Cambridge

classification, or chronic pancreatitis diagnosed on magnetic

resonance cholangiopancreatography (MRCP) OR parenchymal

(gland atrophy, hyperechoic foci, hyperechoic stranding, cysts,

lobularity)/ductal (narrowing, dilation, irregularity, calculi, side

branch dilation, hyperechoic endoscopic walls) on endoscopic

ultrasonography (EUS);

2. pancreatic calcifications on plain film or and on computed

tomography (CT);

3. abnormalities at ultrasonography (US) scan; and

4. pancreatic insufficiency as diagnosed by one or more of the

following: the secretin-cerulein test, positive Lundh test, the

lipiodol test, faecal elastase less than 200 microgram/day or

chymotrypsin less than 20 U/gram.

It should be noted that the diagnostic criteria for chronic pancre-

atitis have undergone several revisions since they were first outlined

in 1963. Due to lack of consensus on the definition of chronic

pancreatitis, clinical investigators have used various definitions for

chronic pancreatitis (Etemad 2001).

Types of interventions

Orally administered pancreatic extract preparations (uncoated or

enteric coated microspheres).

Types of outcome measures

Primary outcomes

Change in subjective pain scores and amount of faecal fat for

evaluation of chronic pancreatic insufficiency.

Secondary outcomes

1. Change in frequency of abdominal pain

2. Change in duration of pain symptoms

3. Change in analgesic use

4. Change in weight loss

5. Change in incidence of steatorrhoea



6. Change in quality of life scores

Further, it was planned that the studies would be ordered by follow-

up times to see if there was any time trend in the above mentioned

outcomes, if sufficient data could be extracted.

Search methods for identification of studies

Electronic searches

We conducted a search to identify all published and unpublished

randomised controlled trials.

We identified trials by searching the following electronic databases:

the Cochrane Central Register of Controlled Trials (CENTRAL)

(The Cochrane Library 2009, issue 1), MEDLINE and EMBASE.

We handsearched reference lists from trials selected by electronic

searching to identify further relevant trials. We also handsearched

published abstracts from conference proceedings from the United

European Gastroenterology Week (published in Gut) and Diges-

tive Disease Week (published in Gastroenterology).

We constructed the search strategy for this review by using a com-

bination of MESH subject headings and text words relating to the

use of pancreatic enzymes for the treatment of chronic pancreati-

tis.

To identify randomised controlled trials, we combined the search

(Appendix 1) with the Cochrane highly sensitive search strategy

phases one, two and three as contained in the Cochrane Handbook

for Systematic Reviews of Interventions (Higgins 2005).

The date of the last search was 1 April 1009.

Searching other resources

We also searched the following web resources:

• http://www.controlledtrials.com;

• http://www.cancer.gov/cancerinformation;

• http://clinicaltrials.gov;

• http://www.eortc.be;

• http://www.swog.org;

• http://www.ctg.queensu.ca; and

• http://www.CenterWatch.com/.

In addition, we contacted members of the Cochrane UGPD

Group and experts in the field and asked them to provide details of

outstanding clinical trials and any relevant unpublished materials

Data collection and analysis

Selection of studies

In order to select studies for further assessment, two independent

authors scanned the title, abstract section and keywords of every

record retrieved. Full articles or abstracts providing sufficient in-

formation were taken into account for further assessment if the

information given suggested that the study satisfied the inclusion

criteria.

Data extraction and management

If there was any doubt regarding these criteria from the informa-

tion given in the title and abstract, we retrieved the full article for

clarification. If differences in opinion existed, we resolved these

by discussion. If no clarification was provided, we consulted the

review group editorial base. We extracted all the relevant data for

the review.

Two authors independently extracted details of study population,

interventions and outcomes using a standardised data extraction

form. This form included at least the following items:

• general information: title, authors, source, contact address,

country, published/unpublished, language and year of

publication, sponsor of trial;

• trial characteristics: design, duration/follow up and quality

assessment criteria as specified above;

• patients: inclusion and exclusion criteria, sample size,

baseline characteristics, similarity of groups at baseline,

withdrawals and losses to follow up;

• interventions: dose, route, duration of treatment,

concomitant medications;

• outcomes: number of pain episodes,visual analogue scores,

median, mean, standard deviation, number of analgesics used,

weight loss and faecal fat.

Additionally, we also presented weight loss and steatorrhoea as

binary data and calculated odds ratios wherever possible.

We developed a template data extraction form and tested this

in a pilot study. Two evaluators independently performed data

extraction and data entry in duplicate. We resolved differences in

data extraction by consensus with a third author, referring back to

the original article. If data were missing in a published report, the

review authors contacted the first author.

Assessment of risk of bias in included studies

Two authors independently assessed the risk of bias of the eligible

studies unblinded, with disagreements resolved by a third author

until consensus was obtained. We extracted data using an assess-

ment form designed for the topic of this review (Cochrane Hand-

book for Systematic Reviews of Interventions). We considered the

following criteria:

1. Was the allocation truly random?

2. Was the treatment allocation concealed?

3. Were the groups similar at baseline regarding the most

important prognostic factors?

4. Were the number of withdrawals, drop-outs and losses to

follow up in each group completely described?



http://www.controlledtrials.com



http://www.cancer.gov/cancerinformation




http://clinicaltrials.gov



http://www.eortc.be

http://www.eortc.be

http://www.eortc.be

http://www.swog.org

http://www.swog.org

http://www.swog.org

http://www.ctg.queensu.ca



http://www.CenterWatch.com/



5. Was the analysis done by intention-to-treat?

6. Were type and schedule of the follow up similar in the

comparison group?

Answers to these questions were categorised as:

• yes (a);

• no (b);

• unclear (c).

Based on these criteria, the studies were broadly subdivided into

the following three categories of quality:

A - all of the criteria met: low risk of bias;

B - all criteria of question 1, 2 and 3 met; one or more of criteria

4 to 6 not met;

C - question 1 met, one or more of questions 2 to 6 not met;

D - unclear: insufficient information given (in these cases, the first

author of the study was contacted).

We used this classification as the basis of a sensitivity analysis.

Measures of treatment effect

For continuous data we calculated the standardised mean differ-

ence (SMD). For binary outcomes, we calculated the odds ratio

(OR) and 95% confidence intervals (CIs) as relevant effect mea-

sures from the given data.

Unit of analysis issues

For the data obtained from cross-over trials, we planned to carry

out a paired analysis if possible, as this is the preferred method

of analysis. As these data were not available from any of the trials

included in the review, we used data presented in the original pa-

pers which were combined from both treatment and control arms

of the trials, thereby ignoring the cross-over design. We included

such data in the meta-analysis, which may be considered to be jus-

tified but unsatisfactory. This should be taken into account when

considering the results of this review.

Dealing with missing data

With regard to loss to follow up cases, only cases available for in-

tention-to-treat analysis were evaluated. We made an attempt to

contact the authors to obtain any missing data, such as standard

deviation, if this could not be calculated from the available infor-

mation in the report.

Assessment of heterogeneity

We planned to use the I2 statistic with a significance threshold of

alpha = 0.1 to test for heterogeneity. As per the protocol, if needed,

we planned to consider the following factors as possible sources of

heterogeneity:

• differences in baseline characteristics of the study patients;

• quality of studies;

• adjuvant therapy permitted versus no adjuvant therapy.

Assessment of reporting biases

For the assessment of publication bias, if sufficient data were avail-

able we planned to construct a funnel plot. However, in view of

the different endpoints used in the studies, none of which allowed

for the construction of funnel plot, this could not be undertaken.

Data synthesis

For continuous data, we calculated pooled standardised mean dif-

ference. We extracted the mean and standard deviation of each

group. We used these values to calculate the standardised mean

difference (SMD) with 95% confidence interval (CI). We planned

to pool the odds ratio (OR) of individual studies using a ran-

dom or fixed-effect model. No evaluable dichotomous outcomes

were available for analysis and hence the methods for evaluation

of dichotomous outcomes, as outlined in the protocol, were not

utilised. We used RevMan (RevMan 2008) for all statistical anal-

yses.

Subgroup analysis and investigation of heterogeneity

We planned a subgroup analysis for the following aetiological cat-

egories: alcohol-induced and idiopathic pancreatitis.

Sensitivity analysis

We also planned a sensitivity analysis in order to evaluate hetero-

geneity amongst the studies.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies; Characteristics of studies awaiting classification.

Results of the search

Ten studies met the criteria for inclusion in the review. These stud-

ies included a total of 361 patients. Six of these studies (Halgreen

1986; Larvin 1991; Malesci 1995; Mossner 1992; O’Keefe 2001;

Safdi 2006) compared enteric coated pancreatic enzyme prepa-

rations with placebo; one compared non-enteric coated granules

(Isaksson 1983); two studies (Delhaye 1996; Lankisch 1986) com-

pared different pancreatic enzyme preparations and one study eval-

uated the effect of administration schedule on the therapeutic effi-

cacy of oral enzyme supplementation (Dominguez-Munoz 2005).



The preparation of pancreatic enzymes used were different in the

various studies. While in one study non-enteric coated pancreatic

enzyme granules (Isaksson 1983) were used, in another (Mossner

1992) acid protected porcine pancreatic enzyme was used. Six

studies evaluated pancreatic microspheres (Dominguez-Munoz

2005; Halgreen 1986; Larvin 1991; Malesci 1995; O’Keefe 2001;

Safdi 2006). One study (Lankisch 1986) compared conventional

enzyme preparation with or without cimetidine and an acid-pro-

tected enzyme preparation. Another study (Delhaye 1996) com-

pared a conventional high lipase preparation with an equivalent

dose of enteric coated enzyme supplement.

Included studies

All studies were randomised, controlled studies, eight of which

were of cross-over design (Delhaye 1996; Dominguez-Munoz

2005; Halgreen 1986; Isaksson 1983; Lankisch 1986; Larvin

1991; Malesci 1995; Mossner 1992) and the remainder were par-

allel group studies (O’Keefe 2001; Safdi 2006). The duration of

follow up of the studies varied from five days to four months. In

all the studies a washout period was mentioned and was adequate

with respect to the duration of follow up.

Excluded studies

We excluded eleven studies because they were either non-ran-

domised or did not satisfy the inclusion criteria.

Risk of bias in included studies

A summary of the assessed risks of bias are provided in Figure 1

and Figure 2.

Figure 1. Methodological quality graph: review authors’ judgements about each methodological quality

item presented as percentages across all included studies.



Figure 2. Methodological quality summary: review authors’ judgements about each methodological quality

item for each included study.



Allocation

Allocation concealment was adequate in four studies (Dominguez-

Munoz 2005; Halgreen 1986; Isaksson 1983; Malesci 1995) but

was not clear in the remaining six studies (Delhaye 1996; Larvin

1991; Lankisch 1986; Mossner 1992; O’Keefe 2001; Safdi 2006).

Blinding

Seven studies were conducted in a double-blind manner (Halgreen

1986; Isaksson 1983; Lankisch 1986; Larvin 1991; Malesci 1995;

Mossner 1992; Safdi 2006) while two were open (Delhaye 1996;

Dominguez-Munoz 2005). In one study the authors mention hav-

ing used a matching placebo but the blinding status is not clearly

mentioned (O’Keefe 2001).

Incomplete outcome data

Number of drop-outs, withdrawals and loss to follow up were in-

completely described in all the studies. Analysis was carried out

by the intention-to-treat method in three studies (Dominguez-

Munoz 2005; Isaksson 1983; O’Keefe 2001) while it was not un-

dertaken in two (Mossner 1992; Safdi 2006) and it was not clear

in the remaining studies (Delhaye 1996; Halgreen 1986; Lankisch

1986; Larvin 1991; Malesci 1995). All the studies described the

results outlined in the methods sections. However, due to the un-

availability of standard deviations or other relevant data, we could

not pool the results for the majority of the outcomes. None of the

studies evaluated all of the outcomes

Selective reporting

It is possible that trials with statistically non-significant results

have not been reported. This could not be assessed as we could

not construct a funnel plot due to paucity of data

Other potential sources of bias

Type and schedule of administration was comparable between the

groups in all the studies except one (Lankisch 1986) in which the

aim of the study did not allow this assessment to be made. Thus,

while no study was category A, five studies (Dominguez-Munoz

2005; Isaksson 1983; Halgreen 1986; Malesci 1995; O’Keefe

2001) were classified as category B, while the rest were classified

as category C studies.

Effects of interventions

Comparison 01: Pancreatic enzyme compared with

placebo

The following outcomes were evaluated for this comparison:

01-Frequency of abdominal pain

We identified no study which reported the frequency of abdominal

pain.

02-Duration of pain episode

We identified no study which reported the duration of pain

episodes.

03-Intensity of pain

Two studies (Larvin 1991; Mossner 1992) were identified which

presented pain scores as mean and standard deviation. However,

the scales used for scoring of pain were different. In one study

(Mossner 1992) a 0 to 3 score was used and for the other (Larvin

1991) 0 to 5 scale was used. Due to the differences in the scale,

we did not pool the data for these studies. Three other studies also

reported intensity of pain scores. In one study (Halgreen 1986)

the pain score was categorized as 1 to 5 and only mean values

were given without standard deviation. In the other study (Malesci

1995) the results were expressed as median values, while in the

third study (Isaksson 1983) only the sum of scores was given.

These results could not be pooled.

In the study by Mossner et al, there was a non-significant improve-

ment in the pain scores with enzyme treatment (1.26 +/- 0.89) as

compared to placebo treatment (1.08 +/- 0.87) (Mossner 1992). In

the study by Larvin et al, the pain scores were significantly different

on treatment with enteric coated pancreatic microspheres (1.93

+/- 1.04) as compared to the placebo treatment (2.05 +/- 0.82)

(Larvin 1991). In the third study, the postprandial pain scores

between the two treatment periods (pancreatic enzyme (4.6) and

placebo (6.4)) were not significantly different (Halgreen 1986). In

the study done by Malesci et al, there was a significant reduction

in the cumulative pain score (median 95; range 0 to 1005, versus

134; 0 to 972; P < 0.05) in the treatment phase with pancreatic

enzyme as compared to the treatment phase with placebo (Malesci

1995). Isaksson et al, have also shown a significant improvement

in the pain score with pancreatic enzyme treatment as compared

to the placebo treatment (Isaksson 1983).

04-Analgesic use

Four studies reported analgesic use. However, in view of missing

SD values the data could not be tabulated. In the first of these stud-

ies (Isaksson 1983) analgesic consumption was shown to be de-

creased (7.8 tablets during the enzyme treatment period versus 8.9



tablets during the placebo treatment period). In the second study

(Halgreen 1986), analgesic consumption score was non-signifi-

cantly decreased in the enzyme treated group as compared to the

placebo group. The authors have presented the results for chronic

pancreatitis patients with and without steatorrhoea. In the former

group analgesic consumption score (stratified in accordance with

their potency from 1 to 4) was 49 in the pancreatic enzyme as

compared to 58 in the control; similarly figures for the patients

with chronic pancreatitis without steatorrhoea show the analgesic

consumption score was 57 in the pancreatic enzyme group and 48

in the placebo group. In the third study (Larvin 1991), mean daily

analgesic use was 51 mg during placebo and 45 mg during pan-

creatic enzyme treatment, the difference being statistically non-

significant. In the fourth study (Malesci 1995) the median score

of analgesic consumption, corrected for drug potency, was higher

although not statistically different, during enzyme therapy (12)

than during placebo (0).

05-Weight loss

Two studies (Isaksson 1983; Larvin 1991) including a total of 97

patients evaluated weight loss (kg). There was a greater weight

loss in the control as compared to the pancreatic enzyme treated

period; the difference being non-significant (SMD 0.06; 95% CI

-0.23 to 0.34).

06-Steatorrhoea

We identified no study which reported presence or absence of

steatorrhoea.

07-Amount of faecal fat

Four studies (Halgreen 1986; Mossner 1992; O’Keefe 2001; Safdi

2006) were identified which reported faecal fat in grams per day.

However, data for only two studies could be pooled. Pancre-

atic enzyme supplementation showed a significant decrease in the

amount of faecal fat (g/day) as compared to placebo (SMD -1.03;

95% CI -1.60 to -0.46). In the third study (Halgreen 1986), for the

chronic pancreatitis with steatorrhoea group, mean faecal weight

was shown to decrease significantly when treated with pancreatic

enzyme (10.4) as compared to the placebo-treated period (24.2).

In the subgroup of chronic pancreatis patients without steator-

rhoea, there was a non-significant increase in average faecal weight

(63) when treated with enzyme as compared to the period when

placebo was administered (58). However, since the authors did

not provide the SD values the results could not be tabulated. In

the fourth study (Mossner 1992), the findings for faecal fat have

only been represented graphically and no mean or standard values

could be obtained.

08-Change in quality of life scores

One study evaluated the effect of pancreatic enzyme supplemen-

tation on a Clinical Global Impression of Disease Symptoms Scale

as compared to placebo (Safdi 2006). After two weeks of the dou-

ble blind treatment phase, there was no significant difference in

subjects’ symptom scales (SMD -0.63; 95% CI -1.41 to 0.14).

The authors noted a statistically significant improvement in the

physician Clinical Global Impression of Disease Symptoms Scale

in the enzyme supplementation group as compared to placebo.

Comparison 02: Comparison of different dosage

schedules

In the only study (Dominguez-Munoz 2005) in which different

dosage schedules were compared, the outcomes of frequency of

abdominal pain, duration of pain episode, intensity of pain, anal-

gesic use, weight loss and changes in quality of life were not re-

ported. The authors were contacted to provide the pertinent data

in case they had been evaluated but not reported. However, as we

failed to obtain any response, we report the main outcome of 13

CO2 recovery in the breath test in the present review. Schedules

of drug administration in which pancreatic enzymes were supple-

mented just after meals or along with meals (one capsule before,

two during and one just after meals) were found to improve the

mean (SD) six-hour cumulative recovery rate of 13 CO2 (61.4%

(21.4) and 60.6% (21.8), respectively) as compared to the sched-

ule in which enzyme supplementation was done just before meals

(53.9% (20.3)). However, the difference was not statistically sig-

nificant.

Comparison 03: Comparison of different enzyme

preparations

Two studies were included in this category (Delhaye 1996;

Lankisch 1986).

01-Change in the incidence of steatorrhoea

One study (Lankisch 1986) compared a conventional pancreatic

enzyme preparation with an acid protected enzyme but presented

the data for effect on steatorrhoea in a format which could not be

utilised for the present analysis. The authors do report that there

was no significant difference between the periods when patients

received conventional pancreatic enzymes and when they received

the acid protected enzyme preparation.

The second study (Delhaye 1996) evaluated a high lipase (HL)

dose enteric coated enzyme supplement with a standard lipase

dose, enteric-coated enzyme supplement. While the HL prepa-

ration was given as a single capsule with each meal resulting in

25,000 U of lipase with each meal, the standard lipase preparation

contained 8000 U of lipase and was given as three capsules with

each meal. As a consequence, the enzymatic content of the two



preparations was almost similar. The authors noted no significant

difference in the amount of faecal fat with the two enzyme prepa-

rations (SMD 0.13; 95% CI -0.42 to 0.69).

D I S C U S S I O N

The majority of the studies included in this review used a cross-

over design. These studies included very small numbers of pa-

tients and only short-term follow-up data were available. The latest

study dates from 2006 and the earliest from 1983. The diagnostic

criteria for and management of chronic pancreatitis patients has

undergone some changes during this period. Moreover, the trials

varied widely in their reporting of the study findings. This could

be due to lack of standard format for reporting of clinical trials in

chronic pancreatitis. For example, the use of different scales for as-

sessment of pain precluded the pooling of data for this important

outcome. The authors of the studies were asked to provide the

data which could be incorporated in our analysis, however most

expressed their inability to provide these.

For the comparison of pancreatic enzyme versus placebo, all studies

except one (Isaksson 1983) used enteric coated pancreatic enzyme

preparations. The preparations also varied in their enzymatic con-

tents. Only one study (Isaksson 1983) compared a conventional

enzyme preparation with placebo. The concomitant medications

used in this analysis were not clearly outlined in the studies.

Only one study could be identified in which different dosage

schedules of pancreatic enzymes were evaluated (Dominguez-

Munoz 2005). The study was small and an intervention period

of one week for each dosage schedule cannot be considered as

adequate. Again, a single study was identified in which a com-

parison of conventional pancreatic enzyme preparations and acid

protected microspheres was made (Lankisch 1986). However, the

quality of this study, assessed as described above, was poor. It was

a small study conducted in eight patients and the outcomes of

faecal weight and faecal fat were not expressed in a format which

allowed these to be included in our review. The other important

outcomes, such as change in pain scores and analgesic use, were

not evaluated.

No clinical trial evaluated any long-term outcome. Moreover, qual-

ity of life was also evaluated in only one of the trials (Safdi 2006).

Though the effect of pancreatic enzyme replacement therapy on

quality of life in chronic pancreatitis patients was assessed in an-

other study (Czako 2002), it did not satisfy our inclusion criteria

so was excluded from the present analysis.

We could not undertake the subgroup analysis as planned. No

study had categorised the patients on the basis of aetiology. Since

the number of trials was small and very few outcomes could be

entered into RevMan, we did not carry out a sensitivity analysis

in order to check the robustness of study results. Further, we can-

not comment on publication bias. None of the parameters had a

sufficient number of studies for the data to be used to construct a

funnel plot.

A relative lack of standardised outcomes, primary or secondary,

prevented us from pooling the results of several outcomes. Again,

missing standard deviation or error values or 95% confidence in-

tervals in studies reflects upon the poor quality of data analysis.

In conclusion, no strong evidence exists for recommending pan-

creatic enzyme treatment for either the alleviation of pain or the

reduction of steatorrhoea in patients with chronic pancreatitis.

Further, no evidence exists for the effect of pancreatic enzymes on

quality of life. Lastly, from the available evidence it cannot be con-

clusively shown that any one of the enzyme preparations, enteric

or non-enteric coated, should be preferred over any other.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Based on this review, the use of pancreatic enzyme supplements

(enteric coated or non-enteric coated) is not of any benefit in

reducing the symptom of pain or steatorrhoea in patients with

chronic pancreatitis. Since no study evaluated long-term outcomes

or quality of life, the evidence for benefit of pancreatic enzyme

preparations on these parameters is also lacking.

Implications for research

There is a strong need for sufficiently powered, randomised clinical

trials comparing pancreatic enzymes with placebo, preferably with

government funding. Outcomes such as effect on pain scores (a

more comprehensive scoring system such as Izbicki could be used),

steatorrhoea, need for hospitalisation, development of complica-

tions and mortality need to be evaluated. Quality of life should be

a component of secondary outcomes. Based on clinically relevant

subgroups, stratified randomisation could be used in the study

design in order to enable subgroup analysis. Once the efficacy (or

otherwise) of pancreatic enzymes over placebo is established then

subsequent studies to compare different doses, formulations, or

both, should be carried out.

A C K N O W L E D G E M E N T S

We wish to acknowledge the help extended to us by the Cochrane

UGPD Group, especially Cathy Bennett for the continuous guid-

ance provided to us in the conduct of this review. We wish to

thank Rosemary Campbell-Blair, for helping us with the literature

search for this review.



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Delhaye 1996 {published data only}

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M. Comparative evaluation of a high lipase pancreatic

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Figueiras A, Vilarino-Insua M. Effect of the administration

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Isaksson 1983 {published data only}

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Lankisch 1986 {published data only}

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Larvin 1991 {published data only}

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Regan PT 1977 {published data only}

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Delhaye 1996

Methods Open, cross-over, prospective study

Participants Chronic pancreatitis with steatorrhoea

Interventions Pancrease HL (25,000 U lipase), 3 capsules/day, pancreatic enzyme containing micro-

spheres (8000 U lipase), 9 capsules/day, with or without omeprazole

Outcomes Faecal fat, protein and energy excretion

Notes Authors noted that use of omeprazole did not significantly alter the faecal fat, protein or

energy excretion

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Blinding?

All outcomes

No Not done

Incomplete outcome data addressed?

All outcomes

Yes Data presented for 25 out of 32 patietns as the

remaining patients did not complete the study

Free of selective reporting? Yes Yes

Free of other bias? Yes Possibility of bias due to lack of true intention to

treat analysis may be present

Dominguez-Munoz 2005

Methods Randomised, open, cross-over

Participants Severe chronic pancreatitis with steatorrhoea

Interventions Three different administration schedules of enteric coated microspheric enzyme prepa-

rations with 10,000 U lipase in each capsule. The 3 schedules were:

Schedule A: 4 capsules just before meals; Schedule B: 4 capsules just after meals; Schedule

C: 1 capsule just before meals, 2 during and 1 just after meals

Outcomes 6-hour cumulative recovery rate of 13 CO2 as measured by the 13C-MTG-breath test



Dominguez-Munoz 2005 (Continued)

Notes Each treatment schedule was administered for a week

Risk of bias


Allocation concealment? Yes The corresponding sequence was concealed until inter-

vention was assigned

Blinding?

All outcomes

Yes Double blind


All outcomes

Unclear Not required

Free of selective reporting? Yes

Halgreen 1986

Methods Randomised, double blind, cross-over

Participants Adult chronic pancreatitis patients

Interventions Encapsulated enteric-coated microspheric enzyme preparation containing 4000 National

Formulary Units (NFU) lipase, 20,000 NFU amylase and 25,000 NFU proteases or

placebo

Outcomes 1. Faecal fat (g/day)

2. Faecal weight (g/day)

3. Postprandial pain score

4. Subjective pain score

5. Analgesic consumption

Notes Results were stratified according to those with and without steatorrhoea. Patients were

followed up for a period of 4 weeks

Risk of bias



Blinding?

All outcomes

Yes Double blind


All outcomes

No Standard deviations or any other measure of

dispersion not mentioned for several outcomes



Halgreen 1986 (Continued)

Free of selective reporting? No Dropouts and withdrawals not mentioned

Free of other bias? Yes

Isaksson 1983



Interventions Conventional (non-enteric coated) pancreatic enzyme granules, 7.5 ml 5 times daily or

placebo

Outcomes 1. Body weight

2. Steatorrhoea

3. Pain scores

Notes For pain scores patients were stratified into good and poor responders. The total follow-

up period was 2 weeks

Risk of bias



Blinding?

All outcomes

Yes Double blind


All outcomes

Unclear Data for one patient was not included


Free of other bias? Unclear It is not clear if intention to treat analysis was

undertaken

Lankisch 1986

Methods Randomised, cross-over


Interventions 1. Conventional enzyme preparation, 3 x 3 dragees daily

2. Pankreon 700, 3 x 3 dragees daily, plus cimetidine 300 mg, 30 minutes prior to the 3 main meals

3. Kreon 3 x 6 capsules daily

Pancreatin (6.3 g/day for regimes 1 and 2; 5.4 g/day for regimen 3); lipase (252,000 FIP units/day for



Lankisch 1986 (Continued)

regimes 1 and 2;180,000 FIP units/day for regimen 3) were comparable

Outcomes 1. Faecal weight

2. Faecal fat

Notes The study compared different pancreatic enzyme preparations. The duration of follow up for each of the

treatment periods was 5 days

Risk of bias



Larvin 1991

Methods Randomised, cross-over

Participants Adult chronic pancreatitis patients without steatorrhoea

Interventions Enteric coated enzyme preparations (3 capsules, 4 times daily) or placebo

Outcomes 1. Pain severity score

2. Pain frequency/duration index

3. Rescue analgesic consumption

4. Weight loss

Notes The study results are available as abstracts only and detailed description of the study methodology could

not be obtained. The duration of follow up was for a period of 8 weeks

Risk of bias



Malesci 1995



Interventions Pancreatic extract (capsules of enteric coated microspheres, each capsule containing 34,

375 USP of protease, 13,000 USP units of lipase and 43, 570 units of amylase)

Outcomes 1. Patients’ record of pain on a 10 cm linear visual analogue scale which was scored from

1 to 4 on a metric basis



Malesci 1995 (Continued)

Notes Results were presented as median with range. The patients were followed up for a period

of 4 months

Risk of bias



Blinding?

All outcomes

Yes Double blind


All outcomes

Unclear Data for four patients was not included in the

final analysis

Free of other bias? No Intention to treat analysis was not undertaken

Mossner 1992



Interventions Acid protected pancreatic extract capsules given 5 x 2 capsules/day with each capsule

containing triacylglycerol lipase 20,000 Ph Eur U, amylase 18,000 Ph Eur U, proteases

1000 Ph Eur U

Outcomes 1. Pain score recorded on a 0 to 3 scale with 0 indicating no pain and 3 very severe pain

2. No of patients with possible acute relapse

3. Serum amylase and gamma-glutamyl transferase levels

4. Faecal fat excretion

Notes The total follow-up period was 2 weeks

Risk of bias



Blinding?

All outcomes

Yes Double blind


All outcomes

No




Mossner 1992 (Continued)

Free of other bias? Unclear Intention to treat analysis was not done

O’Keefe 2001

Methods Randomised, parallel group study

Participants Adult chronic pancreatitis patients with documented evidence of disturbed pancreatic exocrine function

Interventions Pancreatic enzyme containing mini-microspheres containing lipase 10,000 USP U, amylase 33,200 U

and proteases 37,500 USP U. 4 capsules were given with each full meal and 2 were given with snacks.

Matching placebo was given to the comparator arm

Outcomes Coefficient of fat and protein absorption, stool weight, stool fat excretion, stool nitrogen extent

Notes Statistically significant differences were noted for the baseline variables of age, body weight, body mass

index and diabetes in the 2 groups

Risk of bias



Blinding?

All outcomes

No



Safdi 2006

Methods Randomised, double blind, placebo-controlled, parallel group

Participants Adults with chronic pancreatitis and history of pancreatic exocrine insufficiency

Interventions Enteric coated minimicrospheres containing 10,000 U of lipase, 37,500 U of protease

and 33,200 U of amylase, administered as 4 capsules with each meal and 2 capsules with

snacks

Outcomes Coefficient of fat absorption, daily fat excretion, Clinical Global Impression of Disease

Scale

Notes The duration of double blind treatment was 2 weeks

Risk of bias



Safdi 2006 (Continued)



Blinding?

All outcomes

Yes Double blind


All outcomes

Yes



C-MTG = Radiocarbon Labelled Mixed Triglyceride Breath Test

FIP = Fungi Lipase International, units for measuring pancreatic enzyme activity

NFU = National Formulary Units

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Benini 1991 Non-randomised

Bruno 1998 Non-randomised

Czako 2002 Non-randomised

Gouerou 1989 Non-randomised

Madsen 2003 Non-randomised, different objectives

Marotta 1989 Non-randomised

Mizushima 2004 Does not satisfy inclusion criteria (comparison of healthy and chronic pancreatitis patients)

Pasquali C 1996 Non-randomised

Regan PT 1977 Non-randomised

Schneider 1985 Non-randomised

Tsujino 2005 Different drug (protease inhibitor)



(Continued)

Vecht J 2006 Protease inhibitor given with low and high dose of pancreatic enzyme supplementation

Characteristics of studies awaiting assessment [ordered by study ID]

Paris JC 1993

Methods Double blind, placebo-controlled trial

Participants Chronic alcoholic pancreatitis

Interventions Panzytrat 25,000, 2 capsules given 3 times daily or placebo for 7 days

Outcomes Panzytrat reduced steatorrhoea and stool weight

Notes The study will be assessed in detail in any future updates of the review if authors provide the requested information



D A T A A N D A N A L Y S E S

Comparison 1. Pancreatic enzyme versus placebo

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Weight loss 2 194 Std. Mean Difference (IV, Fixed, 95% CI) 0.06 [-0.23, 0.34]

2 Amount of faecal fat 2 55 Std. Mean Difference (IV, Fixed, 95% CI) -1.03 [-1.60, -0.46]

3 Quality of life scores 1 27 Std. Mean Difference (IV, Fixed, 95% CI) -0.63 [-1.41, 0.14]

Comparison 3. Different enzymatic preparations

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Amount of faecal fat 1 50 Std. Mean Difference (IV, Fixed, 95% CI) 0.13 [-0.42, 0.69]

Analysis 1.1. Comparison 1 Pancreatic enzyme versus placebo, Outcome 1 Weight loss.

Review: Pancreatic enzymes for chronic pancreatitis

Comparison: 1 Pancreatic enzyme versus placebo

Outcome: 1 Weight loss

Study or subgroup Pancreatic enzyme Placebo

Std.Mean

Difference Weight

Std.Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Isaksson 1983 19 62 (2.9) 19 61 (2.8) 19.3 % 0.34 [ -0.30, 0.98 ]

Larvin 1991 78 63 (14.2) 78 63.2 (14.3) 80.7 % -0.01 [ -0.33, 0.30 ]

Total (95% CI) 97 97 100.0 % 0.06 [ -0.23, 0.34 ]

Heterogeneity: Chi?? = 0.96, df = 1 (P = 0.33); I?? =0.0%

Test for overall effect: Z = 0.38 (P = 0.70)

Test for subgroup differences: Not applicable

-1 -0.5 0 0.5 1

Favours treatment Favours control



Analysis 1.2. Comparison 1 Pancreatic enzyme versus placebo, Outcome 2 Amount of faecal fat.



Outcome: 2 Amount of faecal fat

Study or subgroup Pancreatic enzyme Placebo

Std.Mean

Difference Weight

Std.Mean

Difference


O’Keefe 2001 15 20.3 (16.77) 14 48 (39.22) 54.7 % -0.90 [ -1.67, -0.13 ]

Safdi 2006 12 18.6 (14) 14 51.8 (34.78) 45.3 % -1.18 [ -2.02, -0.33 ]

Total (95% CI) 27 28 100.0 % -1.03 [ -1.60, -0.46 ]

Heterogeneity: Chi?? = 0.22, df = 1 (P = 0.64); I?? =0.0%



-2 -1 0 1 2


Analysis 1.3. Comparison 1 Pancreatic enzyme versus placebo, Outcome 3 Quality of life scores.



Outcome: 3 Quality of life scores

Study or subgroup Treatment Control

Std.Mean

Difference Weight

Std.Mean

Difference


Safdi 2006 13 1.5 (1.08) 14 2.1 (0.74) 100.0 % -0.63 [ -1.41, 0.14 ]

Total (95% CI) 13 14 100.0 % -0.63 [ -1.41, 0.14 ]

Heterogeneity: not applicable



-4 -2 0 2 4




Analysis 3.1. Comparison 3 Different enzymatic preparations, Outcome 1 Amount of faecal fat.


Comparison: 3 Different enzymatic preparations

Outcome: 1 Amount of faecal fat

Study or subgroup Experimental Control

Std.Mean

Difference Weight

Std.Mean

Difference


Delhaye 1996 25 10.68 (3.3) 25 10.26 (3.05) 100.0 % 0.13 [ -0.42, 0.69 ]

Total (95% CI) 25 25 100.0 % 0.13 [ -0.42, 0.69 ]

Heterogeneity: not applicable



-1 -0.5 0 0.5 1

Favours experimental Favours control

A P P E N D I C E S

Appendix 1. Search strategy

exp pancreatitis/

(chronic adj3 pancreatitis).tw.

or/30-31

(pancreatic adj2 enzyme$).tw.

32 and 33

29 and 34

W H A T ’ S N E W

Last assessed as up-to-date: 16 June 2009.

Date Event Description

21 September 2010 Amended Contact details updated.



H I S T O R Y

Protocol first published: Issue 1, 2007

Review first published: Issue 4, 2009

Date Event Description

12 December 2008 Amended Converted to new review format.

C O N T R I B U T I O N S O F A U T H O R S

Conceiving the review: Dr Samir Malhotra, Dr Nusrat Shafiq

Designing the review: Dr Nusrat Shafiq, Dr S. Malhotra

Co-ordinating the review: Prof P Pandhi, Prof DK Bhasin

Data collection for the review: Dr Nusrat Shafiq, Dr Surjit S Sehmby, Mr Raj Kumar

Designing search strategies: Rosemary Campbell-Blair.

Undertaking searches: Rosemary Campbell-Blair, Dr Nusrat Shafiq

Screening search results: Dr Nusrat Shafiq, Dr Puja Srivastava, Dr Surjit S Sehmby

Organising retrieval of papers: Mr Raj Kumar

Screening retrieved papers against inclusion criteria: Dr Nusrat Shafiq, Dr Puja Srivastava, Dr Surinder Rana

Appraising quality of papers: Dr Nusrat Shafiq, Dr Samir Malhotra, Dr Puja Srivastava

Extracting data from papers: Dr Nusrat Shafiq, Dr Samir Malhotra, Dr S.Sehmby

Writing to authors of papers for additional information: Dr Nusrat Shafiq

Providing additional data about papers: Mr Raj Kumar

Obtaining and screening data on unpublished studies: Dr Nusrat Shafiq

Data management for the review: Dr Nusrat Shafiq, Dr Samir Malhotra, Dr Surjit S Sehmby

Entering data into RevMan: Dr Nusrat Shafiq, Dr Samir Malhotra, Dr Puja Srivastava

Analysis of data: Dr Nusrat Shafiq, Dr Samir Malhotra

Interpretation of data: Dr Nusrat Shafiq, Dr Samir Malhotra

Providing a methodological perspective: Dr Nusrat Shafiq,Dr Samir Malhotra

Providing a clinical perspective: Prof DK Bhasin, Dr Surinder Rana, Dr Puja Srivastava

Providing a policy perspective: Dr Samir Malhotra, Prof P Pandhi, Prof DK Bhasin

Providing a consumer perspective: Prof P.Pandhi

Writing the review: Dr Nusrat Shafiq, Dr Samir Malhotra

Providing general advice on the review: Dr Nusrat Shafiq, Dr Samir Malhotra, Prof P.Pandhi, Prof DK Bhasin



D E C L A R A T I O N S O F I N T E R E S T

None declared.

S O U R C E S O F S U P P O R T

Internal sources

• Dept of Pharmacology, PGIMER, Chandigarh, India.

External sources

• No sources of support supplied

I N D E X T E R M S

Medical Subject Headings (MeSH)

Enzymes [∗therapeutic use]; Pancreas [∗enzymology]; Pancreatitis, Chronic [∗drug therapy]; Randomized Controlled Trials as Topic;

Steatorrhea [∗drug therapy]; Weight Loss

MeSH check words

Humans



cochrane database of systematic reviews (reviews) || pancreatic enzymes for chronic pancreatitis

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