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National Clinical Guideline Centre (UK). Alcohol Use Disorders: Diagnosis and Clinical Management of Alcohol-Related Physical Complications [Internet]. London: Royal College of Physicians (UK); 2010. (NICE Clinical Guidelines, No. 100.)

  • August 2019: Some glossary terms were updated by NICE, and the recommended alcohol units for men and women were updated in line with advice from the UK Chief Medical Officer.

August 2019: Some glossary terms were updated by NICE, and the recommended alcohol units for men and women were updated in line with advice from the UK Chief Medical Officer.

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Alcohol Use Disorders: Diagnosis and Clinical Management of Alcohol-Related Physical Complications [Internet].

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4Alcohol-related Pancreatitis

Prolonged hazardous drinking can result in progressive and irreversible damage to the pancreas gland. This occurs on the background of pancreatic inflammation, acinar atrophy and, ultimately, fibrosis and can result in significant exocrine and endocrine insufficiency. Some individuals may develop this condition with alcohol intakes as low as 20 g/day; others may need to drink in excess of 200 g/day before evidence of the disease develops; others may never develop this condition no matter how much they drink or for how long. In susceptible individuals the longer the duration of drinking the greater the risk of developing significant pathology.

Acute alcohol-related pancreatitis may present as an acute episode of abdominal pain, nausea and vomiting and in severe cases can be accompanied by profound metabolic abnormalities and circulatory collapse. These acute episodes may recur, often precipitated by an increase in alcohol intake. Complications such as narrowing of the common bile duct, localized leakage of pancreatic fluid and pancreatic exocrine and endocrine insufficiency may develop resulting in jaundice, pseudocyst formation, malabsorption and diabetes. In some individuals, however, the clinical course is insidious with progression to pancreatic insufficiency without acute inflammatory episodes.

The major clinical features of chronic pancreatitis are abdominal pain coupled with malabsorption/maldigestion and diabetes resulting from the exocrine and endocrine insufficiency. The stages and natural history of alcohol-related chronic pancreatitis have been difficult to characterize due to the fact that patients may present having suffered from symptoms for varying periods of time. In addition, the pancreas is rarely biopsied unless malignancy is suspected. Nevertheless, withdrawal of alcohol at an early stage may arrest the process and, even when the condition is established, may reduce the number of inflammatory episodes and allow for better control of both exocrine and endocrine insufficiencies.

4.1. Diagnosis of Chronic alcohol-related pancreatitis

4.1.1. Clinical Introduction

The diagnosis of chronic pancreatitis is based on relevant symptoms, imaging and the assessment of pancreatic function. Histological diagnosis requires a biopsy, which is rarely available. With specific treatments available for pancreatic pain and insufficiencies it is important to investigate appropriately and to confirm the diagnosis as early as possible in the pathogenic process.

The clinical question asked and upon which the literature was searched was:

”What is the diagnostic accuracy of abdominal ultrasound versus computed tomography (CT) for the diagnosis of alcohol-related chronic pancreatitis?”

4.1.2. Clinical methodological introduction

Three studies were identified that reported on the diagnostic accuracy of CT and abdominal ultrasound in patients with chronic pancreatitis 127; 128; 129. Papers were excluded if they reported on either CT or ultrasound but not both. None of the papers reported the results of patients with alcohol-related chronic pancreatitis separate from other aetiologies of chronic pancreatitis. The three studies varied with respect to the patient population and the ‘gold standard’ used for diagnosis. See Table 4-1 for further details. Note, the studies are likely to overestimate diagnostic accuracy due to incorporation bias. Incorporation bias occuured when the result of the index test is used in establishing the final diagnosis,

Table 4-1. Summary of included studies.

Table 4-1

Summary of included studies.

Level 1b+

4.1.3. Clinical evidence statements

Table 4-2 below summarises the results for the three studies

Table 4-2. Summary of results.

Table 4-2

Summary of results.

Level 1b+

4.1.4. Health economic methodological introduction

No relevant economic analysis was identified that assessed the cost-effectiveness of abdominal ultrasound and computed tomography scan for the diagnosis of alcohol-related chronic pancreatitis. The cost of the procedures in England and Wales were presented to the GDG.

4.1.5. Health economic evidence statements

In England and Wales, computed tomography scans (two areas with contrast) are approximately twice as expensive as ultrasound scans: the national average unit cost varies from £96 to £125 per procedure for computed tomography scans and from £45 to £64 per procedure for ultrasound scans 100.

We believe that in current practice, a patient would usually be offered a CT scan in specialist clinical practice (based on history and symptoms), but would more likely get an ultrasound in primary care due to easier access. Even though CT scans are more expensive they may well be cost-effective or even cost saving compared with ultrasound in patients where there is a high clinical suspicion since they are far more sensitive at diagnosing chronic pancreatitis and have a high level of specificity. However, this might require direct access to CT scans for primary care practices.

4.1.6. Evidence to recommendations

Before reviewing the evidence the GDG discussed the difficulty in writing guidance for the diagnosis of chronic alcohol-related pancreatitis. Chronic pancreatitis is characterised by progressive irreversible damage that ultimately results in both endocrine and exocrine insufficiency, and structural abnormality of the pancreas. The extent of each of these will vary between patients. The GDG concluded that no single test will give all of the information needed to make a diagnosis. Rather, an assessment of structure and function is required and this is reflected in the first recommendation.

When reviewing the evidence for ultrasound scan (USS) versus CT for the diagnosis of chronic pancreatitis, the GDG felt that there was an important differentiation to make: abdominal USS is a good first line test in patients with abdominal pain of unknown aetiology, however, if the history and symptoms suggest chronic pancreatitis, (if the index of suspicion is high), USS does not have comparable sensitivity and a CT should be the first line investigation. In addition, given the higher sensitivity of CT compared to USS and its high specificity, even being twice as expensive, the GDG believe that the use of CT in well selected patients is likely to be cost-effective (improving clinical outcomes and reducing the use of public resources). Finally, it was recognized by the GDG that if the clinical picture strongly suggests chronic pancreatitis and the USS does not, the patient will have a CT at some point. In addition, if chronic pancreatitis is suggested by an USS, the patient will also, ultimately, have a CT scan. Therefore, if the clinical picture is suggestive, it was felt that it was better to skip the USS and use CT as the first line imaging modality. This is reflected in the second recommendation.

4.1.7. Recommendations

R29.

To inform a diagnosis of chronic alcohol-related pancreatitis use a combination of:

  • the person’s symptoms
  • an imaging modality to determine pancreatic structure and
  • tests of pancreatic exocrine and endocrine function.
R30.

Use computed tomography as the first-line imaging modality for the diagnosis of chronic alcohol-related pancreatitis in people with a history and symptoms suggestive of chronic alcohol-related pancreatitis.

4.2. Diagnosis of acute alcohol-related pancreatitis

The comparison of diagnostic tools used to obtain a diagnosis of acute pancreatitis was included the scope of this guideline, however, as this is considered uncontroversial it was de-prioritised for literature review. The GDG refer readers to the publication issued by the UK working party on acute pancreatitis publication titled ‘UK guidelines for the management of pancreatitis’130 for further information in this area.

4.3. Pancreatic surgery versus endoscopic therapy for chronic alcohol-related pancreatitis

4.3.1. Clinical introduction

The most troublesome symptom of chronic alcohol-related pancreatitis is pain. This pain is usually epigastric and may radiate to the back and flanks. It can be intermittent or continuous, and may alleviate late in the natural history; possibly associated with the loss in pancreatic exocrine function. Patients with chronic pancreatitis may, in addition to the pain they experience intrinsic to the disease itself, also develop pain in association with episodes of acute pancreatitis, formation of pseudocysts or associated conditions such as peptic ulceration. However, it is the pain of chronic pancreatitis to which we refer in this guideline. In spite of the varying aetiologies of chronic pancreatitis, the presenting symptoms are the same. As such the evidence was taken from studies of all types of chronic pancreatitis.

It is important to encourage abstinence from alcohol in this patient population. Abstinence probably reduces the severity of the pain and improves the response to treatment. Typically, pain is managed with simple analgesics but the dosage and strength of these may need to be increased over time. Many patients require high doses of opiates to control pain at its worst. However there are now a number of interventional procedures that can also be used to treat pain in this population. These range from nerve block/destruction (coeliac plexus block and thoracoscopic splanchnicectomy) to pancreatic endotherapy and surgery.

It was the aim of the GDG to determine which of these interventional therapies was most effective in the management of pain in this patient population. In addition, they aimed to determine the most appropriate timing for these procedures and whether they were best performed early in the natural history or later, after, for instance, analgesic failure. The following clinical questions were asked and upon which the literature was searched:

  1. In patients with chronic alcohol-related pancreatitis, does early versus later referral for a) coeliac axis block b) transthoracic splanchnicectomy c) early referral for coeliac axis/plexus block versus transthoracic splanchnicectomy improve patient outcomes?
  2. In patients with chronic alcohol-related pancreatitis, what is the safety and efficacy of a) transthoracic splanchnicectomy compared with coeliac axis/plexus block? b) or either intervention compared to conservative management?
  3. In patients with chronic alcohol-related pancreatitis, does early versus later referral for a) endoscopic interventional procedures b) surgery c) early referral for surgery versus endoscopic interventional procedures improve patient outcomes?
  4. In patients with chronic alcohol-related pancreatitis, what is the safety and efficacy of endoscopic interventional procedures compared with surgery? Or either intervention compared with conservative management?

4.3.2. Clinical methodological introduction

The following studies were identified:

  • One paper incorporating two case-control studies comparing coeliac plexus block with splanchnicectomy 131.
    Level 2+
  • Two RCTs comparing surgery with endoscopic procedures 132,133
    Level 1+
  • Two prospective cohorts comparing surgery with conservative management (no surgery) 134,135
    Level 2+
  • One prospective case series comparing surgery with patients on opioids and one with those not on opioids (patients who are not on opioids are likely to be younger with a shorter duration of illness than those not on opioids and may therefore represent an early versus late surgery comparison) 136
    Level 2+

Coeliac plexus block versus splanchnicectomy

One study, based on two non-randomised, prospective, case control studies compared patients with chronic pancreatitis treated with neurolytic coeliac plexus block (NCPB) or videothorascopic splanchnicectomy (VERSUSPL) in both of which the control patients were managed conservatively 131. In both studies, the patient ‘chose the procedure according to their needs’. The two studies differed with respect to the quality of life measures used. A meta-analysis was performed on the data, but no details of heterogeneity were reported. Important methodological aspects of the study include:

  • Non-randomised design
  • the patients chose which intervention to undergo
  • small sample size
  • limited reporting of clinical and demographical variables at baseline
  • analyses did not including confounding variables or adjust for baseline differences

Level 2+

Surgery versus conservative management

Two prospective cohort studies compared patients with chronic pancreatitis who underwent surgery with patients who did not undergo surgery 135; 134. The studies differed with respect to patient population, surgical intervention and length of follow-up. Importantly, patients who underwent surgery may represent a more severe end of the disease spectrum than those who did not undergo surgery. In one study, disabling pain was present in all patients who were operated on, but in only 28/44 (64%) of patients who were not operated on 135. No details of any differences between patients who were operated on compared with those who were not were reported in the remaining study 134. One additional prospective cohort study compared patients who were on opioids prior to surgery with those who were not on opioids 136.

Level 2+

Surgery versus endoscopic therapy

Two RCTs were identified that compared surgery with endoscopic interventions 133,132. In the Dite study, 72 patients were randomised and an additional 68 patients chose whether to undergo surgery or endoscopic treatment. The two studies differed with respect to both interventions. In the Dite study, 80% of patients opting for surgery underwent resection. In the Cahen study, all patients underwent a drainage procedure. The Dite study tailored the surgery to the individual. In comparison to the Cahen study, the Dite study did not use shock-wave lithotripsy, cumulative stenting or repeated treatment after recurrence of symptoms

Level 1+

4.3.3. Clinical evidence statements

Coeliac plexus block versus splanchnicectomy

Pain and quality of life

Table 4-3 below shows that at eight-week follow-up both treatments reduced pain, but VERSUSPL was more effective than NCPB. Physical well-being and fatigue also improved with treatment compared to conservative management but with little difference between the two treatments. Note, the follow-up period was relatively short 131.

Table 4-3. Summary of results.

Table 4-3

Summary of results.

Level 2+

Opioid use

There was no statistical difference in the proportion of patients who underwent NCPB and VERSUSPL for:

  • Opioid withdrawal (8/18 (47%) versus 11/30 (36%); RR1.21; 95%CI 0.60 to 2.44; p=0.59)
  • Reduction in opioid dose (9/18 (53%) versus 14/30(45%); RR1.07; 95%CI 0.59 to 1.95; p=0.82)131
    Level 2+
Adverse events/complications

Orthostatic hypotension was observed for three days in 9/30 (30%) from the NCPB group and in 1/18 (5.5%) patients in the VERSUSPL group (RR5.40; 95%CI 0.74 to 39.17; p=0.10). Intermittent intercostal pain was treated with paracetamol for two weeks in 4/18 (22%) patients in the VERSUSPL group. In one of these, an intercostal nerve block was performed and in one patient a classic thoracotomy was performed due to massive adhesions (excluded from study) 131.

Level 2+

Mortality

No cases reported 131.

Level 2+

Surgery versus conservative management

Pain

One study reported a significant reduction in pain in patients who underwent surgery compared to those managed conservatively:

  • Disabling abdominal pain (28/44 (64%) versus 41/41 (100%); RR0.64; 95%CI 0.51 to 0.90; p<0.00001) 135.

A second study reported no significant difference in pain in the surgery group compared with the conservative management group:

  • pain disappeared or distinctly subsided immediately after operation in 62/70 (89%) patients with full documentation of the postoperative course: 40 had pain relief for a mean of 6.3 (± 4.5) years, but pain relapse occurred in 22 (36%) patients 1.6 ± 2 years after the operation. There was no significant difference in the pain course between operated and non-operated patients (p=0.61) 134
    Level 2+
Weight gain

One study reported on this outcome.

A significantly higher proportion of patients who underwent surgery compared with those who did not:

  • gained weight (25/30 [87%] versus 5/38 [13%]; RR6.33; 95CI 2.76 to 14.56; p<0.00001) and the mean weight gained was significantly higher (4.2 kg [1.4 to 12.7] versus 0.50 kg [−3.6 to 2.7]; p<0.05)135.
    Level 2+
Pancreatic function

At follow-up there was a significant difference between the surgery and no surgery groups for the proportion of patients who remained at the same grade of mild to moderate (sustained pancreatic function) (16/19 [84%] versus 7/24 [29%]; RR2.89; 95%CI 1.50 to 5.55; p=0.001) or who progressed to ‘severe’ (3/19 [16%]versus 17/24 [71%]; RR0.22; 95%CI 0.08 to 0.65; p=0.006) 135.

Level 2+

Mortality
  • One operative death occurred 135.
    Level 2+
  • Three patients died within eight weeks of surgery. Three further patients died of hypoglycaemia 134.
    Level 2+
Complications

Three patient had wound infections 135.

Level 2+

Surgery plus previous opioid use versus surgery with no previous opioid use

One prospective cohort reported on the outcomes of patients following pancreatic resection in patients with prior opioid use 136.

Level 3

Group differences

Patients not on opioids compared to those who were on opioids prior to surgery:

  • were significantly older (median 48 [18 to 79] versus 42 [21 to 63]; p=0.001)
  • were significantly older when the first symptoms appeared (median 43 [9 to 77] versus 35 [8 to 59] years; p=0.004)
  • had significantly fewer hospitalisations (median 3 [0 to 42] versus 10 [1 to 30]; p=0.001)
  • had a significantly shorter duration of symptoms (2 [0 to 40.5] versus 5.9 [0.1 to 22.1]; p=0.038)
  • significantly more patients in the opioid compared to the non-opioid group underwent one or more types of total pancreatectomy (21 [46%] versus 19 [14%]; p=0.0002).136
    Level 3
Pain

There was a significant difference in the non-opioid and opioid groups on the visual analogue scale (VAS) score preoperatively (median 7 [0 to 10] versus 9 [7 to 10]; p=0.001)and at 3 months (median 2 [0 to 7] versus 3 [0 to 9]; p=0.030). There were no significant differences at 12 (no data) or 24 months (no pain 57 versus 49%; not significant).136

Level 3

Complications

Patients on opioids experienced a significantly greater number of haemorrhages and early reoperation 136. See Table 4-4 below.

Table 4-4. Summary of results.

Table 4-4

Summary of results.

Level 3

Surgery versus endoscopy

One RCT reported that surgery was more effective than endoscopic treatment with respect to pain control, physical health and the number of procedures required. The mean difference between surgery and endoscopic interventions (adjusting for baseline differences) was 24 points out of 100 on the Izbicki pain score, representing no pain (surgery) or daily pain (endoscopic interventions) or taking no sick leave for pain (surgery) or being permanently unable to work (endoscopic interventions) 132. The results are summarised in Table 4-5 below.

Table 4-5. Summary of results.

Table 4-5

Summary of results.

Level 1++

Similarly, the study by Dite also reported a significant improvement in pain and increase in body weight associated with surgery compared with endoscopic procedures. The results are summarized in Table 4-6 below.

Table 4-6. Summary of results.

Table 4-6

Summary of results.

Level 1+

Complications

Endoscopic procedures

Two bleeding episodes, two cases of acute pancreatitis and one pancreatic abscess 133 were reported.

Level 1+

Surgery

Two cases of acute pancreatitis, two fistulas, one case of ileus and one case of anastomotic leakage. One patient underwent repeat surgery due to ileus and one patients for anastomotic leakage 133.

Level 1+

4.3.4. Health economic methodological introduction

No cost-effectiveness analysis was identified that assessed the treatment and the timing for treating people with alcohol-related chronic pancreatitis using coeliac access block, splanchnicectomy, endoscopic interventional procedures, or surgery.

In current medical practice in England and Wales, surgical and endoscopic interventions are available for patients with chronic pancreatitis and a dilated pancreatic duct. The clinical literature review included two RCTs comparing endoscopic and surgical interventions in this population of patients132,133. The findings of both RCTs showed that surgical drainage of the pancreatic duct was more effective than endoscopic drainage.

Surgical and endoscopic drainage of the pancreatic duct are interventions associated with extensive resource use and cost, and there is a lack of published health economic evidence to support the use of one or the other. For these reasons, we undertook our own economic evaluation comparing these two interventions (see 0 for the full analysis).

4.3.5. Health economic evidence statements

The objective of the economic analysis undertaken was to assess the cost-effectiveness of the surgical drainage of the pancreatic duct compared to the endoscopic drainage, for patients with chronic pancreatitis and an obstructed pancreatic duct in England and Wales.

This economic analysis was conducted mainly based on the Cahen 2007 study132, from an England and Wales NHS perspective, over a 24-month time horizon for the base-case analysis (median follow-up time in the Cahen trial). A lifetime horizon was used in the sensitivity analysis. The health outcome considered was Quality-Adjusted Life Year (QALY). An annual discount rate of 3.5% was applied to both costs and health outcomes incurred after one year.

In the Cahen study132, the EQ-5D questionnaire was completed by participants (unpublished). Data were collected for each arm at baseline, six weeks, three months, six months, 12 months, 18 months, and 24 months. The patient-level EQ-5D data from the trial was obtained and utility scores generated for both arms at every follow-up point using the UK tariff. As the baseline utility scores differed slightly between arms, it was controlled for utility score at baseline by applying linear regression. The utility scores were used to calculate QALYs (utility score * time-period) for the 24-month duration of the trial for the base-case analysis, and a lifetime horizon in sensitivity analyses. For the lifetime horizon, a constant utility score, post trail, was assumed for the endoscopy group (using the value at 24 months). No difference in utility score post-trial between the cohorts and therefore applied the constant utility score of the endoscopy group (value at 24 months) to the surgical cohort was assumed.

Costs considered in this analysis, taken from the Cahen trial132 for the first 24 months (Cahen trial follow-up), were related to therapeutic procedures (surgical drainage, endoscopic drainage, and lithotripsy sessions), diagnosis procedures, the treatment of complications, the treatment of exocrine insufficiency, and the conversion to surgical drainage for patients in the endoscopic arm in who the treatment failed. After 24-months, the same yearly cost was applied to patients in both the surgery and endoscopy groups, and was extrapolated from the observed resource usage from the Cahen trial.

In the Cahen 2007132 RCT, one death was reported in the endoscopy group (5%), which was not clearly related to the intervention. There were no deaths related to the interventions in the Dite 2003133 RCT. For the base-case analysis, we assumed no mortality in either group. From a review of clinical studies, the mortality related to surgical drainage was estimated to be 0.9%. It was decided to use a mortality rate related to surgery of 0.9% and an upper estimate of 2% in the sensitivity analysis. These mortality rates were applied to patients in the surgical group and to patients who converted to surgery in the endoscopic group, and were applied on the Cahen within-trial time horizon (24 months) and on a lifetime horizon.

Sensitivity analyses were performed to assess the robustness of the results to plausible variations in the model parameters. Five one-way sensitivity analyses were conducted, varying one parameter at a time from the base case: two were costing differently the diagnostic procedures; two were varying the ratio of patients who convert to surgery after failure of the endoscopic treatment using extreme values from a review of clinical studies; and one varied the length of hospital stay adjusting the amount of in-patient bed-days from the length of hospital stay included in the HRG-code cost to the amount reported by the Cahen study132. In addition, two-way sensitivity analyses were performed, concurrently using two extreme varying estimates from a review of clinical studies: the probability of stent-related complication (endoscopic group) and the rate of re-operation (surgical group). Four combinations were assessed. Finally, sensitivity analyses were conducted applying mortality rates to surgical drainage on the Cahen within-trial time horizon (24 months) and on a lifetime horizon.

The result of the base-case analysis was that surgical drainage of the pancreatic duct dominates endoscopic drainage (it was more effective and less costly – Table 4-7.). The sensitivity analysis showed that the surgical option remains dominant (cost-saving) in the majority of scenarios (Table 4-8 and Table 4-9). The results were sensitive to the proportion of patients in the endoscopy group who convert to surgical drainage when the endoscopic drainage failed. When patient conversion to surgery was less than 10%, surgical drainage was no longer cost-saving, but it was still highly cost-effective when compared with a threshold of £20,000 per QALY gained (£1,495 per QALY gained when the probability of conversion to surgery was 0% - Table 4-8). In addition, surgical drainage was no longer cost-saving when a lower complication rate was applied to endoscopy and a higher re-opearation rate was applied to surgery. Nevertheless, surgery was again highly cost-effective (£700 per QALY gained - Table 4-8). The base-case analysis, the analyses considering mortality rates related to surgical drainage, and all other sensitivity analyses showed very high probabilities of cost-effectiveness for surgical drainage compared to endoscopic drainage. The presented results reveal that surgical drainage is highly cost-effective compared to endoscopic drainage.

Table 4-7. Base-case analysis probabilistic results: Mean costs.

Table 4-7

Base-case analysis probabilistic results: Mean costs.

Table 4-8. Probabilistic results.

Table 4-8

Probabilistic results.

Table 4-9. Two-way sensitivity analysis.

Table 4-9

Two-way sensitivity analysis.

A 24-month time horizon was chosen for the base-case analysis as this was the period covered by the Cahen study132. It was judged that extrapolating the results of the Cahen trial would involve uncertainty and that the 24-month time horizon adequately captures the difference in economic and health outcomes between the compared interventions (keeping in mind that these treatments are undertaken for pain-control). The Cahen trial was stopped after an interim analysis on the basis of a significant difference in outcomes favouring surgery. This may have resulted in overestimating the health outcomes in favour of surgery.

The sensitivity analysis, varying the probability for conversion to surgery in the endoscopy group showed that surgical drainage was no longer cost-saving when patient conversion to surgery was less than 10%. However, even with a probability of conversion to surgery of 0% surgery was highly cost-effective with a cost of £1,495 per QALY gained. In addition, surgical drainage was no longer cost-saving when a lower complication rate was applied to endoscopy and a higher re-opearation rate was applied to surgery. Nevertheless, surgery was again highly cost-effective (£700 per QALY gained).

The sensitivity analysis adjusting the amount of in-patient bed-days from the length of hospital stay included in the HRG-code cost to the amount reported by the Cahen study132, showed low cost savings for surgery, with the probability that surgery is cost-saving being 48%. However. the probability that surgery is cost-effectiveness for this analysis was 98.8%. The Cahen study132 was conducted in the Netherlands, a country with a healthcare system and with practices in this area that may be different to the UK NHS. Therefore the base-case analysis using the HRG-code length of hospital stay is perhaps more relevant for estimating the cost impact on the UK NHS.

The sensitivity analysis applying mortality rates of 0.9% and 2% to surgical drainage showed cost-saving results with very high probabilities of cost-effectiveness. Furthermore, the probability that surgery is cost-effective was very high across all analyses, varying from 95.2% to 99.7%. This was due to the magnitude of the improvement in quality of life with surgical drainage compared to endoscopic drainage.

We have used medians to estimate means for some resource use outcomes, because they were the best available estimates as reported by Cahen 200719. In health economic assessments, the mean is the most informative measure for costing resource use, and provide information about the total cost that will be incurred by treating all patients, which is needed as the basis for healthcare policy decisions. The median in contrast describe a ‘typical’ cost for an individual137. The most costly interventions (surgical and endoscopic therapeutic procedures, and lithotripsy sessions) were costed using median estimates. Although, the mean estimates by Dite 2003133 for numbers of therapeutic procedures seem to be in agreement with Cahen 2007132 medians. Moreover, to be safe, we used conservative assumptions not favouring surgical drainage when costing lithotripsy sessions.

Finally, the results of the present study cannot be extrapolated to all patients with ductal obstruction due to chronic pancreatitis because patients with an inflammatory mass were excluded from the Cahen trial132.

4.3.6. From evidence to recommendations

The GDG recognised that it was not within their scope to determine the safety or efficacy of a specific surgical procedure for pain. Instead, they searched for evidence that would help determine whether there is benefit for referral for intervention rather than conservative management and when this should be done (either ‘early’, when the pain commences, or ‘late’ after conventional escalation of treatment along the analgesic ladder until this fails). More specifically, they attempted to determine whether there was evidence for preferring coeliac axis block over splanchnicectomy, if either is considered, and whether endoscopic procedures are better than surgery, if either of these is considered.

The GDG noted that without intervention, a proportion of patients will become relatively pain-free due to the natural history of the disease. However, there was concern that the proportion of patients who become pain-free without intervention may be overestimated.

The group discussed the likelihood that most patients with pain related to chronic pancreatitis are not referred for consideration for surgical or endoscopic procedures. A critical step in determining the optimal treatment is to determine whether the patient has large (obstructive) or small (non-obstructive) duct disease. It was agreed that this disease sub-stratification should be done as part of the routine assessment of these patients. The recommendations reflect this consideration by encouraging referral to a specialist centre for consideration of multidisciplinary assessment.

The evidence comparing splanchnicectomy to coeliac axis block was of poor quality and consisted of two case-control studies with small sample sizes. Due to the very limited evidence base, the GDG felt that they were unable to make any recommendations that would favour one intervention over the other.

There were two moderate-quality trials comparing surgery with conservative management. The GDG did not think these provide definitive information, but support the recommendation that patients should be referred for multidisciplinary assessment and consideration of surgery.

The literature comparing early to late surgery (before versus after long term opioid use) indicated that it was better to operate early thereby avoiding the possible problem of opioid dependence.

With regard to large (obstructive) duct disease, there were two RCTs comparing endoscopic against surgical intervention; one of moderate quality and one of high quality. The high-quality study was terminated early due to significantly improved outcomes associated with surgical intervention. This trial suggests that surgical treatment is optimal in this population. The GDG was, however, reluctant to recommend surgical therapy as the only option in these patients. There is a small, but definite mortality and some patients may do well with endoscopic therapy. On the other hand, endoscopic drainage involves more interventions than surgical drainage (median of 5 versus median of 1 according to the high quality study – Cahen 2007132). The cost-effectiveness analysis undertaken comparing surgical and endoscopic drainages in patients with large duct (obstructive) chronic pancreatitis showed that surgical drainage is highly cost-effective compared to endoscopic drainage. It was agreed that patients with large duct (obstructive) chronic pancreatitis should be offered surgery given that current evidence suggests better outcomes with surgery compared to endoscopy.

With regard to pain from small duct disease, there is considerable debate over the optimum management. Coeliac axis block, splanchnicectomy and surgery are available options. Surgery was considered more controversial than in the large duct disease population. In addition, the GDG was unable to determine from the evidence whether coeliac axis block or splanchnicectomy was better for pain relief in this population. The GDG felt that it is not possible to mandate these procedures based on the poor evidence available.

In current practice, patients with poorly controlled pain from small duct disease will get more analgesia in most places. The GDG recognise that coeliac axis block, splanchnicectomy and surgery should be considered when appropriative. The availability of this type of surgery is currently limited in England and Wales. The group did agreed on consensus that patients with severe symptoms should be consider for these procedures and offered them when appropriate. This is unlikely that the recommendation will have much impact on resource utilisation.

4.3.7. Recommendations

R31.

Refer people with pain from chronic alcohol-related pancreatitis to a specialist centre for multidisciplinary assessment.

R32.

Offer surgery, in preference to endoscopic therapy, to people with pain from large-duct (obstructive) chronic alcohol-related pancreatitis.

R33.

Offer coeliac axis block, splanchnicectomy or surgery to people with poorly controlled pain from small-duct (non-obstructive) chronic alcohol-related pancreatitis.

4.4. Prophylactic antibiotic treatment for acute alcohol-related pancreatitis

4.4.1. Clinical Introduction

Acute alcohol-related pancreatitis can present as a relatively mild syndrome which resolves spontaneously or as a severe illness with a high mortality. Acute necrotizing pancreatitis can be complicated by infection of the necrotic pancreatic tissue and this infection has an impact on morbidity and mortality. These infections are often bacterial. Whilst antibiotic treatment for acute infections is not debated amongst clinicians, the role of prophylactic antibiotics is; randomised trials of prophylactic antibiotics have been performed since the 1970s. In spite of this, there is variation in practice across the UK, presumably because of conflicting trial results.

The GDG sought to provide recommendations for the use of antibiotics in this condition and thus searched the literature to address the following clinical question:

In patients with acute alcohol-related pancreatitis, what is the safety and efficacy of prophylactic antibiotics versus placebo?

4.4.2. Clinical methodological introduction

For the comparison antibiotics versus placebo/no treatment, three RCTs on patients with acute mild pancreatitis were identified 138; 139; 140. These studies were performed before CT imaging was available. See table 4-10 below for the study characteristics.

Table 4-10. Study characteristics.

Table 4-10

Study characteristics.

Level 1+

For patients with acute severe pancreatitis, six RCTs were identified 141 142 143 144 145 146. Only papers that used CT to confirm the diagnosis of pancreatitis were included. One open label RCT was excluded due to study limitations 147. See table 4-11 below for study characteristics.

Table 4-11. Study characteristics.

Table 4-11

Study characteristics.

Level 1+

4.4.3. Clinical evidence statements

Mild pancreatitis

A summary of the results is presented in Table 4-12 below. There were no significant differences between the patients treated with antibiotics and those without in terms of mortality, length of hospitalisation, duration of elevated serum amylase or fever 138; 139; 140.

Table 4-12. Summary of results.

Table 4-12

Summary of results.

Level 1+

One study reported that a significantly greater proportion of patients treated with antibiotics experienced recurrent pancreatitis 138.

Level 1+

Complications

There were no significant differences in the number of serious complications reported in relation to antibiotic use. 138 139 140

Level 1+

Severe necrotising pancreatitis

Table 4-13 below summarises the results of the meta-analysis (all studies) for the RCTs on patients with severe acute pancreatitis. Refer to figures Figure 4-1, Figure 4-2, Figure 4-3, Figure 4-4, and Figure 4-5 for forest plots from the meta-analysis.

Table 4-13. Summary of results.

Table 4-13

Summary of results.

Figure 4-1. Antibiotics versus placebo, outcome: pancreatic infection.

Figure 4-1

Antibiotics versus placebo, outcome: pancreatic infection.

Figure 4-2. Antibiotics versus placebo, outcome: mortality.

Figure 4-2

Antibiotics versus placebo, outcome: mortality.

Figure 4-3. Antibiotics versus placebo, outcome: Non-pancreatic infection.

Figure 4-3

Antibiotics versus placebo, outcome: Non-pancreatic infection.

Figure 4-4. Antibiotics versus placebo, outcome: Surgical intervention.

Figure 4-4

Antibiotics versus placebo, outcome: Surgical intervention.

Figure 4-5. Antibiotics versus placebo, outcome: Length of stay.

Figure 4-5

Antibiotics versus placebo, outcome: Length of stay.

Summary of findings

Antibiotics versus placebo

Overall, prophylactic antibiotics compared to placebo were associated with a significant reduction in:

  • Mortality
  • Non-pancreatic infection

Level 1+

There were no significant differences between prophylactic antibiotics and placebo for:

  • Pancreatic infection
  • Surgical intervention
  • Length of stay

Level 1+

Carbapenem versus placebo

Carbapenem compared with placebo was associated with a significant reduction in:

  • non-pancreatic infection (moderate to high heterogeneity)

Level 1+

There are no significant differences between carbapenem and placebo for:

  • pancreatic infection
  • mortality
  • surgical intervention.

No data was reported for length of stay.

Level 1+

‘Other antibiotics’ versus placebo

‘Other antibiotics’ compared to placebo were associated with a significant reduction in:

  • mortality.

Level 1+

There was no significant difference between ‘other antibiotics’ and placebo for:

  • pancreatic infection
  • non-pancreatic infection
  • surgical intervention
  • length of stay.

Level 1+

4.4.4. Health economic methodological introduction

No relevant economic analysis was identified assessing the cost-effectiveness of prophylactic antibiotics for patients with acute alcohol-related pancreatitis. Costs and resource use information associated with the use of prophylactic antibiotics in patients with acute alcohol-related pancreatitis were presented to the GDG.

4.4.5. Health economic evidence statements

The main components of resource use associated with prophylactic antibiotic therapy for patients with acute alcohol-related pancreatitis are the treatment itself and the hospital stay. The treatment cost is high, varying from £200 to nearly £2000 when costing therapies used in clinical trials included from the clinical review41. For the hospitalisation cost, the clinical review showed that the length of hospital stay was not significantly reduced using prophylactic antibiotics either in patients with mild acute pancreatitis or in patients with severe acute pancreatitis.

4.4.6. From evidence to recommendations

The evidence for this clinical question is reported separately for mild and severe acute pancreatitis. There was variability in the definition of severe pancreatitis which makes it difficult to issue clear guidance based on the available evidence. In addition, the trials used different antibiotics for different durations.

Mild acute pancreatitis

The GDG considered the evidence for antibiotic treatment in mild acute alcohol-related pancreatitis. It was noted that the trials were over 30 years old and were performed before the advent of CT as a diagnostic and prognostic tool. All the trials used a short course of ampicillin. The clinical evidence did not support the use of antibiotics on the basis of the chosen outcomes.

Given that the evidence for antibiotics in mild pancreatitis was based on a single drug (ampicillin) the GDG found it difficult to make a recommendation based solely on the clinical evidence review. There was no health economic evidence available to influence the recommendation.

The GDG therefore agreed, by consensus, that antibiotics should not be given to patients with mild acute pancreatitis as no positive evidence for their use had been found. Patients should to be monitored to ensure that their condition does not progress from a mild to severe state, when the question of antibiotic use would be raised again.

Severe acute pancreatitis

The GDG considered the evidence for use of prophylactic antibiotics in severe acute pancreatitis. There was variability in the definition of severe pancreatitis and the trials used different antibiotics for different treatment durations. While a carbapenem was found to reduce non-pancreatic infections, it was ‘other antibiotics’ that were found to reduce mortality in the meta-analysis. At present there is no nationwide or European clinical consensus on this topic and the evidence reviewed was variable and is interpreted differently between centres in the UK. The GDG did not believe there was enough evidence to support a recommendation for offering antibiotics for acute alcohol-related pancreatitis.

4.4.7. Recommendations

R34.

Do not give prophylactic antibiotics to people with mild acute alcohol-related pancreatitis, unless otherwise indicated.

4.5. Nutritional support for acute alcohol-related pancreatitis

4.5.1. Clinical Introduction

Supportive care is the mainstay of treatment for acute pancreatitis. The timing and delivery of nutritional therapy is an important component of this care. There are three broad treatment options; withhold feeding, enteral nutrition (either oral or tube feeding) and parenteral nutrition. Each option has historically had periods of clinical favour. The supporters of withholding enteral feeding (or feeding nasojejunally) suggest that resting the pancreas avoids exocrine secretion and further pancreatic injury. Supporters of enteral feeding highlight the importance of maintaining nutritional intake and intestinal integrity, reducing bacterial translocation and thereby limiting the systemic inflammatory immune response.

Oral nutritional intake in pancreatitis, particularly if severe, is often limited by nausea so enteral feeding often implies either nasogastric or nasojejunal feeding. Parenteral feeding is generally given as total parenteral nutrition. Many trials have attempted to answer the question of which form of feeding is superior and results have been conflicting. By looking at all the evidence to date with regard to a wide variety of outcome measures from mortality to sepsis and multi-organ failure, the GDG aimed to provide guidance on the most clinical and cost-effective modality. The data are based on studies in patients with acute pancreatitis irrespective of aetiology.

The clinical question searched was:

‘In patients with acute alcohol-related pancreatitis, what is the safety and efficacy a) of nutritional supplementation vs no nutritional supplementation b) early (first 48 hours) versus late supplementation c) NJ versus NG) versus parenteral nutrition?’

In patients with acute alcohol-related pancreatitis, what is the safety and efficacy of:

  1. nutritional supplementation versus no supplementation
  2. early (first 48 hours) versus late supplementation
  3. enteral versus parenteral nutrition
  4. nasojejunal versus nasogastric feeding

4.5.2. Clinical methodological introduction

Studies were included that reported on the safety and efficacy of nutritional supplementation versus no supplementation; early (first 48 hours) versus late supplementation; enteral versus parenteral nutrition or nasojejunal versus nasogastric nutrition in patients with acute alcohol related pancreatitis. Outcomes of interest were mortality, length of hospitalisation, systemic inflammatory response syndrome (SIRS), multiple organ failure (MOF), operative intervention, infection and local complications (such as abscesses).

Fifteen studies were included in the review; thirteen RCTs 148–160 and two SRs 161,162 The results of the studies included in the SRs were reported separately if they included further outcomes of interest not covered by the SRs.

Outcomes reported were mortality, infection, length of stay, MOF, SIRS, pancreatic complications and operative interventions.

The studies were reported under the following categories:

  1. nutritional supplementation versus no supplementation (n=4)
  2. enteral versus parenteral nutrition (n=9)
  3. nasojejunal versus nasogastric (n=3)

No studies were found that directly compared early (first 48 hours) versus late supplementation. A more detailed summary of the included studies can be seen below.

Summary table of included studies.

Table

Summary table of included studies.

Limitations

  • The number of patients with alcohol related pancreatitis ranged from 11% 160 to 81% 149 across the studies, and was not reported in one of the SRs 161.
  • A number of the included studies were underpowered for outcomes of interest 153,154,157
  • One of the NJ versus NG studies 154 included patients with both mild and severe acute pancreatitis rather than severe acute pancreatitis which was the clinically relevant population selected

4.5.3. Clinical evidence statements

Nutritional support versus no nutritional support

Mortality

The systematic review 161 reported on the difference in mortality in those treated with:

  1. parenteral nutrition versus none (3 RCTs):
    • Parenteral nutrition resulted in a statistically significant 64% reduction in risk. Parenteral group 4/56; no nutrition group 13/57. RR0.36 (95% CI 0.13, 0.97) p=0.04 (no heterogeneity)
  2. enteral nutrition versus None (1 RCT):
    • Enteral nutrition resulted in a 78% reduction in risk. RR (95% CI): 0.22 (0.07–0.70) p= 0.01
    Level 1+

One other study reported on the difference in mortality between those treated with immediate oral refeeding (+ iv fluids when needed) versus fasting 150:

  • No deaths in either group.
    Level 1+
Infection

The systematic review 161 reported on the difference in infectious complications in those treated with:

  1. parenteral nutrition versus none (3 RCTs)
    • Parenteral nutrition resulted in a statistically non-significant increase of 36% in the risk of infectious complications. Parenteral group 8/49; no nutrition group 8/49; risk ratio 1.36 (95% CI 0.18–10.40) p=0.77 (moderate heterogeneity between study results).
  2. enteral nutrition versus none (1 RCT):
    • Risk reduced non-significantly by 44% with the use of enteral nutrition over no nutrition. RR (95% CI): 0.56 (0.07–4.32) p=0.58. This difference was probably non-significant due to the small sample size.

Level 1+

Length of stay (LOS)

Three studies reported on the differences in length of stay between those treated with nutritional support versus no nutritional support. See Table 4-14 for a summary of results.

Table 4-14. Summary of results.

Table 4-14

Summary of results.

Level 1+

Multi-organ failure (MOF)

One study reported on MOF in those treated with nutritional support versus no nutritional support, and showed no obvious benefit. See Table 4-15 for a summary of results.

Table 4-15. Summary of results.

Table 4-15

Summary of results.

Level 1+

Systemic inflammatory response syndrome (SIRS) (CRP, leukocytes)

One study reported on two markers of SIRS, CRP and leukocytes in those treated with immediate oral feeding versus fasting, and showed no obvious benefit. See Table 4-16 and Table 4-17 for a summary of results.

Table 4-16. a) CRP.

Table 4-16

a) CRP.

Table 4-17. b) leukocytes.

Table 4-17

b) leukocytes.

Level 1+

Pancreatic complications

One study 150 reported on this outcome for nutritional support versus no nutritional support and reported no complications such as necrosis, abscess or pseudocysts in either group.

Level 1+

Operative interventions

One study 150 reported on this outcome for nutritional support versus no nutritional support and reported no significant difference between groups concerning the number of interventions performed during hospital stay (cholecystectomy and endoscopic retrograde cholangiopancreatography)

  • Fasting 7/30 versus oral refeeding 6/29, p>0.30; RR 1.13 (95% CI 0.43, 2.96)

Level 1+

Enteral versus parenteral

Mortality

The SR 161 reported on the difference between in-hospital mortality in those treated with enteral versus parenteral nutrition (n=9 RCTs)

  • Enteral nutrition resulted in a non-significant 40% reduction in risk. Enteral group 16/191; parenteral group 34/213; risk ratio 0.60 (95% CI 0.32, 1.14) p=0.12. Heterogeneity explained by random variation.
    Level 1+
Infection

The SR 161 reported on the difference in infectious complications seen between those treated with enteral versus parenteral nutrition (n=10 RCTs).

  • Enteral nutrition resulted in a significant 59% reduction in risk compared to parenteral nutrition. Enteral group 33/204; parenteral group 89/226; RR0.41 (95% CI 0.30, 0.57) P<0.00001. Heterogeneity explained by random variation.
    Level 1+
Length of stay

Six of the studies reported on the difference in length of stay between those treated with enteral versus parenteral nutrition. A meta-analysis was performed on two of the studies 157,159 where adequate data were available. However due to 80% heterogeneity between the studies the results were reported separately. Overall, no difference was seen between the groups. See Table 4-18 for a summary of results.

Table 4-18. Summary of results.

Table 4-18

Summary of results.

Level 1+

Multi-organ failure (MOF)

Four studies reported on the difference in MOF between those treated with enteral versus parenteral nutrition. The results varied across the studies. However, most showed a non-significant difference across the groups favouring enteral feeding. See Table 4-19 for a summary of results.

Table 4-19. Summary of results.

Table 4-19

Summary of results.

Level 1+

Nasogastric (NG) versus nasojejunal (NJ) feeding

Mortality

One SR 162 reported on the difference in mortality in those treated with NG versus NJ nutrition.

Nasogastric feeding was associated with a non-significant reduction in the risk of death:

  • NG feeding: 10/43; NJ feeding 11/36; RR 0.77; 95% CI 0.37 to 1.62; p=0.50
    Level 1+
Infection (includes positive blood culture, tracheal aspirate, pancreatic aspirate and bile culture)

One study 153 reported on the infection rate in patients treated with NG versus NJ feeding. No significant difference was reported between the groups:

  • NJ group: 6/14 (43%); NG group: 7/16 (44%); P=0.467; RR 0.98 (95% CI 0.43, 2.23)
    Level 1+
Length of stay

Two studies 153,154 reported on length of stay in patients treated with NG versus NJ feeding. No significant difference was reported between the groups (see Table 4-20 for summary of results).

Table 4-20. Summary of results.

Table 4-20

Summary of results.

Level 1+

Operative interventions

One study 153 reported on the number of operative interventions in patients treated with NG versus NJ feeding. No significant difference was reported between the groups.

  • NJ group: 2/14; NG group: 1/16; RR 2.29 (95% CI 0.23, 22.59), p=0.48
    Level 1+

Summary

Nutritional supplementation versus no supplementation (n=3)

Nutritional supplementation resulted in a statistically significant reduction in:

  • Mortality (Parenteral versus none and enteral versus none) 161
  • Length of stay 150,158,160

Level 1+

Nutritional supplementation resulted in a statistically non-significant reduction in:

  • Infections (Enteral versus none) 161
  • SIRS 150
  • MOF 160
  • Operative interventions 150

Level 1+

Nutritional supplementation (parenteral versus none) resulted in a statistically non-significant increase in:

Level 1+

Enteral versus parenteral nutrition (n=9)

Enteral nutrition resulted in a statistically significant reduction in:

Level 1+

Enteral nutrition resulted in a statistically non-significant reduction in:

Level 1+

NJ versus NG (n=3)

NG feeding resulted a non-significant reduction in:

Level 1+

There was a statistically non-significant difference between NJ versus NG in:

  • Operative interventions 153
  • Length of stay 153
  • Infections 153

Level 1+

4.5.4. Health economic methodological introduction

No cost-effectiveness analysis was identified assessing nutritional supplementation in patients with acute alcohol-related pancreatitis. Three RCTs155,156,164 reporting a cost-comparison assessment of the use of enteral nutrition versus parenteral nutrition were selected and presented to the GDG.

4.5.5. Health economic evidence statements

Table 4-21 presents cost-comparison assessments of the use of enteral nutrition versus parenteral nutrition in patients with acute pancreatitis. One of the three assessments presented was conducted from a United Kingdom perspective 155, and the other two were conducted from the perspective of countries with a health-care system reasonably comparable to the NHS (Canada 164 and Greece 156). The three assessments concluded that the use of enteral nutrition is less costly than parenteral nutrition in patients with acute pancreatitis.

Table 4-21. Cost-comparison of enteral nutrition.

Table 4-21

Cost-comparison of enteral nutrition.

4.5.6. From evidence to recommendations

A significant reduction in mortality and length of stay was associated with provision of nutritional support either enterally or parenterally (compared to withholding feeding) and clearly supported a recommendation. Although there were no papers specifically comparing early to late feeding, the consensus of the GDG was that feeding should be initiated soon after admission.

The GDG discussed the route for providing nutritional support. They agreed that the evidence supports enteral feeding over parenteral feeding primarily due to a reduced incidence of infection and a reduced length of stay. This evidence reflects the clinical experience of the group. Enteral feeding is also associated with reduced cost.

When discussing the type of enteral tube feeding it was apparent that the evidence did not clearly favour any particular route (NG or ND or NJ). The GDG discussed whether a recommendation could reflect this and support the most practical and non-invasive option, but it was felt that the evidence was insufficient and that there may be other benefits that were not identified in the studies conducted to date. As such, it was decided that the best approach was to make a research recommendation to determine the optimal method of delivery for people with severe acute alcohol-pancreatitis.

4.5.7. Recommendations

R35.

Offer nutritional support20 to people with acute alcohol-related pancreatitis:

  • early (on diagnosis) and
  • by enteral tube feeding rather than parenterally where possible.

4.5.8. Research Recommendation

RR7.

What is the clinical and cost-effectiveness of nasogastric versus nasojejunal delivery of nutritional support to patients with acute severe alcohol-related pancreatitis?

4.6. Enzyme supplementation for chronic alcohol-related pancreatitis

4.6.1. Clinical introduction

Steatorrhoea and weight loss are features of chronic pancreatitis and arise because of the associated exocrine insufficiency. Steatorrhoea is caused by an increase in faecal fat due to a significant (usually over 90%) drop in pancreatic lipase production. Maldigestion of other nutrients can occur, but fat maldigestion is the first to become clinically relevant. Pancreatic enzymes are often prescribed for these manifestations of chronic pancreatitis, and once they have been started, they are often continued lifelong.

Pancreatic enzyme supplementation is also prescribed for the pain of chronic pancreatitis by some clinicians, on the basis that the exogenous enzymes may rest the pancreas and reduce endogenous enzyme production, thereby relieving the pain.

The GDG searched for evidence for the efficacy of enzyme supplementation for steatorrhoea, weight loss and pain in chronic pancreatitis. In addition, they wished to determine if there was a benefit of one formulation of enzymes over another.

Therefore the clinical question posed and upon which the literature was searched was:

In patients with chronic alcohol-related pancreatitis, what is the safety and efficacy of pancreatic enzyme supplementation versus placebo for a) steatorrhoea and weight gain b) abdominal pain, duration of pain episodes, intensity of pain and analgesic use for pancreatic exocrine insufficiency?

4.6.2. Clinical methodological introduction

Studies were included that reported on the safety and efficacy of pancreatic enzymes in patients with chronic pancreatitis (predominantly alcohol-related pancreatitis) that reported on the outcomes of steatorrhoea, weight gain, abdominal pain duration of pain episodes, intensity of pain, analgesic use, absorption and wellbeing score.

Twelve studies were included in the evidence review 165–176

Level 1+/1++

These studies were reported under the categories:

  • Enzyme versus placebo (N=7)
  • Enzyme versus enzyme (N=3)
  • Comparisons of different doses (N=2)

The studies, sample size (number of patients completing the study) and the quality rating are presented below:

Enzyme versus placebo

  • Van Hoozen 1997174 (N=11) 1+
  • Isaksson 1983165 (N=19) 1++
  • Halgreen 1986167 (N=20) 1+
  • Mossner172 1992 (N=43) 1+
  • O’Keefe 2001175 (N=29) 1+
  • Slaff 1984166 (N=20) 1+
  • Delchier 1991171 (N=6) 1+

Enzyme versus enzyme

  • Delhaye 1996173 (N=25) 1+
  • Gouerou 1989170 (N=20) 1+
  • Lankisch 1986170 (N=8) 1+

Comparison of different dose

  • Vecht 2006176 (N=16) 1+
  • Ramo 1989169 (N=10) 1+

Two studies were excluded from the review because they were of low quality with no reporting on randomisation, allocation concealment or blinding 177,178.

Level 1−

Eleven of the twelve studies were cross-over trials, however only two of these studies reported on a wash-out period between treatments 165,173. The overall quality of the studies was low, in nine studies the method of randomisation was poor or unclear 166,168–171,173–176; in nine studies allocation concealment was unclear 165–168,170,171,173,174,176 and in ten studies the method of blinding was unclear 166,168,170–176. Two studies also had high drop out rates, between 22–23% 170,173.

4.6.3. Clinical evidence statements

Steatorrhoea/ faecal fat

Placebo versus pancreatic enzyme

Four studies comparing a pancreatic enzyme preparation with placebo reported on change in faecal fat 167,171,175,179. Two studies reported a significant difference in faecal fat reduction when comparing pancreatic enzyme preparations with placebo 171,175. One study reported a significant reduction in faecal fat with enzyme preparation compared to placebo in patients with steatorrhoea 167. See Table 4-22 below.

Table 4-22. Summary of results.

Table 4-22

Summary of results.

Level 1+

One study used a symptom score to measure steatorrhoea and reported no significant difference between the placebo and pancreatic enzyme preparation 165.

Level 1++

Enzyme versus enzyme/Comparisons of different doses

Three studies comparing different pancreatic enzyme preparations reported on change in faecal fat 168,170,173. One study reported on change in faecal fat when looking at different dosing of pancrease 176. See Table 4-23 below.

Table 4-23. Summary of results.

Table 4-23

Summary of results.

Level 1+

Weight gain

Placebo versus pancreatic enzyme

Two studies which compared a pancreatic enzyme preparation with placebo reported on the outcome body weight. Patients 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 174.

Level 1+

Enzyme versus enzyme

One study comparing different pancreatic enzyme preparations reported on body weight. No significant change in body weight was seen between day 0 compared to day 56 at which point all the different enzyme preparations had been taken 173.

Level 1+

Comparisons of different doses

One study comparing regular dosing of a pancreatic enzyme (as recommended by the manufacturer) with individually administered dosing (symptom triggered) found no significant change in weight between the two dosing regimens 169.

Level 1+

Abdominal pain (duration of pain episodes, intensity of pain and analgesic use)

Placebo versus pancreatic enzyme

Six studies comparing pancreatic enzyme preparations with placebo reported on change in pain 165–167,172,174,175.

Level 1+

Three studies reported no significant change in pain scores between the placebo and pancreatic enzyme preparation 167,172,174.

Two studies reported an improvement in pain scores when using pancreatic enzyme supplementation compared with placebo 165,166:

  • Examiner rated pain was significantly lower when patients were on pancreatic enzyme compared with placebo (N=1)
  • The patient-rated mean pain score during the week was significantly lower when patients were on enzyme supplementation compared with placebo (N=1)
  • The examiner-rated mean pain score was significantly lower on pancreatic enzyme compared with placebo (N=1)
  • The frequency of pain was significantly lower in patients on enzyme supplementation compared with placebo (N=1)
  • For patients with mild to moderate disease the average daily pain score was significantly lower on enzyme supplementation compared with placebo (N=1).

Level 1+

Two studies saw a reduction in pain when comparing a pancreatic enzyme preparation to placebo 165,166 :

  • 15/19 had pain relief during the week on pancreatic enzyme treatment compared with placebo (N=1)
  • Patients with mild to moderate impairments of exocrine function (maximum bicarbonate concentration in the secretin test between 50 and 80 mEq/L and normal faecal fat determination) had significantly more pain relief with enzyme supplementation than placebo (N=1)
  • 75% with mild to moderate disease experienced pain relief with enzyme supplementation compared to 25% of patients with severe disease (steatorrhoea) (statistically non-significant difference) (N=1)

Level 1+

Two studies reported no significant change in abdominal pain when comparing placebo with a pancreatic enzyme preparation. 167,175.

Level 1+

Two studies reported no significant change in analgesic use when comparing placebo with a pancreatic enzyme preparation 167,172. However, one study reported a 40% reduction in the use of analgesics 166.

Level 1+

Enzyme versus enzyme

Two studies comparing different enzyme preparations found no significant change in pain 170,173.

Level 1+

Comparisons of different doses

One study comparing different doses of a pancreatic enzyme preparation reported a significant reduction in abdominal symptoms score with both doses compared to basal values (0–10).

Level 1+

One study reporting on different dosing regimes reported a significantly lower pain score during the self-administration of pancrease.

Level 1+

Wellbeing score

Placebo versus pancreatic enzyme

One study reported on patients’ general wellbeing and found no significant difference between the placebo and enzyme group, however no data were provided, so the exact difference could not be assessed 167.

Level 1+

Enzyme versus enzyme

One study reported on this outcome and found no significant change in wellbeing score during the four treatment periods, however no data was provided 173.

Level 1+

Comparisons of different doses

One study reported on this outcome and found a significant improvement in wellbeing score when using both doses of pancrease in comparison to basal values 176.

Level 1+

Absorption

Placebo versus pancreatic enzyme

Two studies comparing a pancreatic enzyme preparation with placebo reported results on the outcome absorption 174,175. Both studies reported a significant increase in fat absorption when taking the pancreatic enzyme preparation compared to placebo.

Level 1+

One study reported a non-significant improvement in carbohydrate and protein absorption when using a pancreatic enzyme preparation compared to placebo 174. However they did report a significant increase in total energy absorption when using a pancreatic enzyme preparation.

Level 1+

Enzyme versus enzyme

One study comparing different enzyme preparations reported on the change in fat and protein absorption. No significant difference in fat or protein absorption was found between different enzymes or with or without the addition of omeprazole 173.

Level 1+

Comparisons of different doses

One study reported difference in fat absorption when using different doses of a pancreatic enzyme preparation. They found a significant increase in fat absorption in both treatment groups (pancrease 10,000 and pancrease 20,000) compared to placebo.

Level 1+

Subgroup: Studies looking at pancreatic enzymes in combination with H2 blockers versus pancreatic enzymes alone

Steatorrhoea/faecal fat

One study 173 reporting fat excretion (g/day) saw no significant difference with the addition of omeprazole to pancrease or creon.

Level 1+

One study 168 reported a significant reduction in faecal fat with the addition of cimetidine or when using the pH sensitive enzyme preparation Kreon compared to a non-significant reduction with pankreon alone.

Level 1+

Weight gain

No results were reported on the difference with and without the addition of an H2 blocker.

Abdominal pain (duration of pain episodes, intensity of pain and analgesic use)

One study 173 reported no significant difference in the severity of abdominal pain with Creon or Pancrease HL with or without the addition of omeprazole.

Level 1+

Wellbeing score

One study 173 reported no significant difference in general wellbeing with Creon or Pancrease HL with or without the addition of omeprazole.

Level 1+

Absorption

One 173 reported no significant difference in percentage fat or protein absorption with Creon or Pancrease HL with or without the addition of omeprazole.

Level 1+

Limitations of evidence

The small sample size of most of these studies (range N=6–43) may have left the studies underpowered to detect a significant change in any of the reported outcomes. All of the studies were reporting on short-term use of pancreatic enzymes (24 hours to 30 days per treatment), which may not have allowed time for the enzymes to take full effect.

4.6.4. Health economic methodological introduction

No relevant economic analysis was identified assessing the cost-effectiveness of pancreatic enzyme supplementation in patients with alcohol-related pancreatitis. The cost of drugs used for pancreatic enzyme supplementation was presented to the GDG.

4.6.5. Health economic evidence statements

In NHS current medical practice, pancreatic enzyme supplementation is given to a large number of patients suffering from chronic alcohol-related pancreatitis, primarily as a means for controlling pain. The cost of treatment options are presented in Table 4-24.

Table 4-24. Pancreatic enzyme supplementation.

Table 4-24

Pancreatic enzyme supplementation.

4.6.6. From evidence to recommendations

The small sample size of most of these studies (range N=6–43) means that they may be underpowered to detect a significant change in any of the reported outcomes. All of the studies were reporting on short-term use of pancreatic enzymes (24 hours to 30 days per treatment), this may not have allowed time for the enzymes to produce a clinically significant effect.

A number of studies included dietary intervention (moderation of fat intake) and moderation of alcohol intake.

The studies in general showed a reduction in faecal fat in those patients on pancreatic enzyme supplementation. The GDG felt that this was important in terms of symptom control (steatorrhoea) and with regard to calorie and fat soluble vitamin absorption in the longer term. In spite of the short length of the studies, there was also some evidence for weight gain with enzyme supplementation to support their use.

The GDG felt that there was not sufficient evidence to support the use of enzyme supplements for pain related to chronic pancreatitis. While there may be patients with pain that require enzyme supplementation for other reasons, supplementation should not be used as a treatment for pain or in those patients with pain without steatorrhoea or weight loss. These patients should be managed with reference to the specific guidance on the management of pain associated with chronic pancreatitis (see Chapter 4.3). In addition, considering that enzyme supplementation is currently used mostly for pain control, the non-negligible cost of this treatment and the necessity to avoid unnecessary expenditure of public resources was highlighted. The GDG also noted that many patients in current practice need higher doses of enzyme supplementation than proposed in the BNF.

As there is no clinical evidence favouring one enzymatic preparation over another, the GDG felt that the choice of which one to prescribed should be based on cost. It was noted that acid suppression may be required in addition to enzyme supplementation when the ‘older’ formulations are used which are not microencapsulated. This would involve additional costs.

In summary, it was felt that there was sufficient evidence to recommend enzyme supplementation to improve nutritional status and steatorrhoea in patients with pancreatic exocrine insufficiency, but not for pain alone.

4.6.7. Recommendations

R36.

Offer pancreatic enzyme supplements to people with chronic alcohol-related pancreatitis who have symptoms of steatorrhoea and poor nutritional status due to exocrine pancreatic insufficiency.

R37.

Do not prescribe pancreatic enzyme supplements to people with chronic alcohol-related pancreatitis if pain is their only symptom.

Footnotes

19

Number of surgical and endoscopic therapeutic interventions; number of diagnostic interventions; total length of hospital stay; number of lithotripsy sessions.

20

See ‘Nutrition support in adults: oral nutrition support, enteral tube feeding and parenteral nutrition’. Clinical guideline 32 (2006). Available from www​.nice.org.uk/guidance/CG32

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.

Bookshelf ID: NBK65575

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