Article Text

Protocol
Analgesia for the treatment of acute pancreatitis: a protocol for a systematic review and network meta-analysis
  1. Sriya S Subramani1,
  2. Alaina C Berg2,
  3. Lee A Kral3,
  4. Mohammad Hassan Murad4,
  5. Abigail Smith5,
  6. Anna Evans Phillips6,
  7. Dhiraj Yadav6,
  8. Aliye Uc7,
  9. Aamer Imdad8
  1. 1 Stead Family Department of Pediatrics, The University of Iowa, Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USA
  2. 2 The University of Iowa, Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USA
  3. 3 Department of Anesthesia, The University of Iowa, Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USA
  4. 4 Department of Internal Medicine, Division of Public Health, Infectious Diseases and Occupational Medicine, Mayo Clinic, Rochester, Minnesota, USA
  5. 5 Health Science Library, SUNY Upstate Medical University, Syracuse, New York, USA
  6. 6 Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburg, Pittsburg, Pennsylvania, USA
  7. 7 Stead Family Department of Pediatrics, Radiation Oncology, Fraternal Order of Eagles Diabetes Research Center, The University of Iowa, Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USA
  8. 8 Stead Family Department of Pediatrics, Division of Gastroenterology, Hepatology, Pancreatology and Nutrition, The University of Iowa, Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USA
  1. Correspondence to Dr Aamer Imdad; aamer-imdad{at}uiowa.edu

Abstract

Introduction Gastrointestinal hospitalisations in the USA cause over US$130 billion in expenditures, and acute pancreatitis is a leading cause of these hospitalisations. Adequate pain control is one of the primary treatment goals for acute pancreatitis. Though opioids are commonly used for analgesia in these patients, there have been concerns about short-term and long-term side effects of using opioids. Recently, non-opioid medications have been studied to treat pain in patients with acute pancreatitis. This systematic review and network meta-analysis aims to assess the comparative efficacy of analgesic medication for non-severe, acute pancreatitis.

Methods and analysis We will search multiple electronic databases for randomised controlled trials that study pain management in patients with non-severe, acute pancreatitis. The intervention will be any analgesic for acute pancreatitis in the hospital setting. The comparison group will be patients who received a placebo or other active interventions for pain management. The primary outcomes of interest include pain scores and the need for supplementary analgesia. The secondary outcomes will be serious adverse events, local complications, progression to severe pancreatitis, transfer to the intensive care unit, length of hospitalisation, time to start enteral feeds, 30-day all-cause mortality and Quality of Life Scale scores. If sufficient homogeneity exists among included studies, the findings will be pooled using a traditional pairwise and network meta-analysis. The risk of bias in randomised control trials will be evaluated using the Cochrane Risk of Bias Tool 2.0. The Grading of Recommendations, Assessment, Development, and Evaluation approach will be used to report the certainty of evidence.

Ethics and dissemination This systematic review will not involve direct contact with human subjects. The findings of this review will be published in a peer-reviewed journal. They will give healthcare providers a better awareness of the optimal analgesic medication for pain treatment in non-severe, acute pancreatitis.

  • Pancreatic disease
  • Pain management
  • PAIN MANAGEMENT
  • Adult gastroenterology
  • Paediatric gastroenterology
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STRENGTHS AND LIMITATIONS OF THIS STUDY

  • This systematic review will evaluate all available evidence from randomised controlled trials to evaluate the effectiveness of analgesics for treating acute pancreatitis.

  • The statistical analysis will include the traditional pairwise meta-analysis and a network meta-analysis that will give insights into the comparative efficacy of interventions across the included studies.

  • We will use The Grading of Recommendations, Assessment, Development, and Evaluation criteria to report the certainty in the totality of the evidence for a given analgesic to treat acute pancreatitis.

  • We anticipate that some studies will include severe and non-severe acute pancreatitis patients and will try to obtain the disaggregated data for non-severe pancreatitis from the study authors; if disaggregated data are not available, we will include the study if more than 50% of the participants have non-severe, acute pancreatitis.

  • We anticipate that all the included studies may not report all the outcomes of interest in this review and that information required for the risk-of-bias assessment may not be available from some studies.

Introduction

Background

Acute pancreatitis is an inflammatory condition of the pancreas that can lead to local and systemic manifestations involving one or more organ systems. In adults, the most common causes of acute pancreatitis are gallstones and significant alcohol consumption; however, hypertriglyceridaemia, infection, trauma and a genetic predisposition can also contribute to the development of acute pancreatitis. Children with acute pancreatitis are commonly noted to have either anatomic abnormalities (particularly of the pancreatic or biliary tract), gallstones, genetic risk variants, or severe systemic disease or require medications that confer an increased risk of developing acute pancreatitis.1 2 Clinically, acute pancreatitis is characterised by at least two out of three of the following clinical findings: epigastric abdominal pain, elevated levels of serum pancreatic enzymes and inflammatory changes in the pancreas on various imaging modalities.3 4 In many instances, recurrent episodes of acute pancreatitis can lead to chronic pancreatitis, a continuing inflammatory disease of the pancreas that can lead to irreversible morphological changes and/or permanent loss of function.5

Patients with acute pancreatitis can be classified as having mild, moderate or severe disease. Mild, acute pancreatitis is characterised by evidence of pancreatitis and the absence of organ failure, local complications or systemic complications. Moderate acute pancreatitis is characterised by either no organ failure or transient organ failure that lasts no longer than 48 hours. Severe acute pancreatitis is characterised by organ failure lasting more than 48 hours.3 6

As of 2016, the global incidence of acute pancreatitis was 34 cases per 100 000 person years, while the incidence of deaths was 1.6 per 100 000 person years.7 In America, acute pancreatitis among privately insured and hospitalised adults is estimated at 111 cases per 100 000 persons. In American children, the incidence is about 12 cases per 100 000 persons.8 In 2015, gastrointestinal disease totalled US$135.9 billion in healthcare expenditures. As a leading cause of gastrointestinal hospitalisations in the USA, acute pancreatitis contributes significantly to this monetary burden.9 10 Hospitalisation costs associated with acute pancreatitis are about US$30 000 per person in the USA.11 About 80% of the patients admitted with acute pancreatitis have mild-to-moderate disease, and the rest have severe acute pancreatitis.3

Adequate pain control is one of the primary treatment goals for acute pancreatitis. There is no clearly defined first-line analgesic for patients hospitalised with acute pancreatitis in adult and paediatric populations.12 Opioids are commonly used for analgesia in patients hospitalised with acute pancreatitis. However, opioid use has the risk of adverse effects, including gastrointestinal intolerance, decrease in gastrointestinal motility and risk for potential dependence.13 More recently, non-opioid analgesics, including non-steroidal anti-inflammatory drugs and paracetamol (known as acetaminophen in the USA), have been studied for pain control in acute pancreatitis.14–16 Previous systematic reviews have assessed the efficacy of different analgesics17–19; however, these analyses are limited by pairwise analysis of two interventions at a time,17 19 and comparative effectiveness cannot be fully evaluated.17 20 The previous systematic reviews had additional limitations including no reporting of the overall certainty of the evidence,17 18 and inclusion of only pain outcomes and no other clinical or patient-reported outcomes.17 20 Furthermore, newer, randomised controlled trials have become available since the publication of the last systematic review.21 For these reasons, we aim to conduct an updated systematic review, in which we will include a network meta-analysis in addition to the traditional pairwise meta-analysis. Finally, we will report the certainty of the overall evidence for each analgesic intervention used in acute pancreatitis by using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.

Objective

To assess the comparative efficacy of analgesic medications in patients with non-severe acute pancreatitis.

Methods and analysis

We will follow the standard guidelines of Cochrane Collaboration and report the findings of the review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The protocol is registered at the International Prospective Register of Systematic Reviews website (ID: CRD42023477878). The study will start on 5 April 2024, and it will run through 30 July 2024.

Study type

We will include individual, and cluster randomised controlled trials. We will exclude observational studies such as cohort studies, case-control studies, case reports, case series, controlled before-and-after studies, interrupted time series and commentaries.

Population

We will consider studies that included adult and paediatric patients with non-severe, acute pancreatitis that require hospital admission. Acute pancreatitis will be defined based on the presence of at least two out of three of the following findings: epigastric abdominal pain, elevated levels of serum pancreatic enzymes and/or imaging evidence of pancreatic inflammation. Non-severe forms of acute pancreatitis will be defined as having the absence or transient (less than 48 hours) presence of organ failure, local pancreatic, or systemic complications.3 6 In sum, our definition embraces mild and moderate forms of acute pancreatitis. We will exclude studies that include patients diagnosed with chronic pancreatitis being managed in outpatient settings; however, we will include studies that address acute pancreatitis in patients with recurrent pancreatitis. We will exclude studies restricted to patients with severe pancreatitis because pain management is more complex in these patients and should be addressed in a separate review. We will, however, consider studies where both severe and non-severe cases of pancreatitis were included, and disaggregated data are available for non-severe pancreatitis patients. If the disaggregated data are not available, we will include the study if more than 50% of the patients had non-severe pancreatitis. We will do a sensitivity analysis to assess if the inclusion of such studies affects the results. We will exclude studies where patients had pancreatic cancer.

Intervention

We will assess all analgesic medications that aim to treat pain in patients with non-severe, acute pancreatitis, including opioid and non-opioid analgesics. We will only consider medications administered in the hospital setting. We will include medications irrespective of route of administration, dose, frequency, and duration. We will exclude studies that addressed non-pharmacological interventions such as acupuncture, massage and so on. Table 1 gives a list of commonly used medications for pain management in acute pancreatitis.

Table 1

Medications used to treat pain in patients with acute pancreatitis

Comparison

The comparison group may include a placebo or other active, pharmacological or non-pharmacological interventions to treat pain in acute pancreatitis.

Outcomes

Primary outcomes

  1. Pain score (continuous outcome).

  2. Need for supplementary analgesia (dichotomous outcome).

Secondary outcomes

  1. Number of patients with improved pain as defined by author (dichotomous outcome).

  2. Number of patients with controlled pain as defined by author (dichotomous outcome).

  3. Need for analgesia for breakthrough pain (number of breakthrough analgesia deliveries) (continuous outcome).

  4. Need for analgesia for breakthrough pain (amount of breakthrough analgesia delivered) (continuous outcome).

  5. Serious adverse events (dichotomous outcome).

  6. Non-serious, adverse events: nausea and vomiting (dichotomous outcome).

  7. Non-serious, adverse events: ileus (dichotomous outcome).

  8. Non-serious, adverse events: any cause (dichotomous outcome).

  9. Time to Enteral diet initiation (hours, continuous outcome).

  10. Local complications: peripancreatic fluid collection, peripancreatic/pancreatic necrosis, pancreatic pseudocyst (dichotomous outcome).

  11. Progression to severe pancreatitis (organ or organ system failure lasting >48 hours) (dichotomous outcome).

  12. Length (days) of hospitalisation (continuous outcome).

  13. 30-day all-cause mortality (dichotomous outcome).

  14. Quality-of-life scores (continuous outcome).

Need for supplementary analgesia will be defined as instances when the trial drug fails to relieve pain following the trial protocol. The need for analgesia for breakthrough pain will be defined as occurrences when the primary trial drug continued, and supplementary analgesia was used for breakthrough pain only. The serious adverse events will be defined based on the definitions of the US Food & Drug Administration. We will consider the adverse events per person and not the total number of adverse events per group.

Time of follow-up

For the primary outcomes, we will consider the time of follow-up at 48–96 hours of admission. For the secondary outcomes, we will use the information from the longest available follow-up.

Literature search

In conjunction with the review team, a medical librarian at our institution, the University of Iowa, will develop a comprehensive search strategy. The systematic literature search will be conducted in several databases, including PubMed, Embase, Cochrane Library, Cochrane Central Register of Controlled Trials, Scopus, Web of Science collections, Cumulative Index to Nursing and Allied Health and Global Index Medicus. The search strategies for PubMed and other databases are available in the online supplemental document. No studies will be excluded based on language, publication year, publication status (excepting retraction) or outcome. Additionally, the National Library of Medicine’s Clinical Trials database (ClinicalTrials.gov) will be used to identify active or unpublished studies. We will use the clinical trial registration number to find all studies published from a particular trial. Additional studies will be found through citation tracking of all included studies. The references of previously published, network studies will be reviewed for additional inclusion. We will also search for data presented at major gastrointestinal conferences (North American Society of Pediatric Gastroenterolgy, Hepatology and Nutrition (NASPGHAN), Euorpean Society of Pediatric Gastroenterolgy, Hepatology and Nutrition (ESPGHAN), Digestive Disease Week, PancreasFest, World Congress on Gastroenterology, American Pancreatic Association (APA)) and use grey literature by way of websites with content on pertinent projects (Investigator of the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE) Pediatric Pancreatitis Research Project, Swedish Pancreatitis Cohort, Dutch Pancreatitis Study Group). Finally, we will reach out to the experts in the field to ask for any known studies on analgesia control in acute pancreatitis.

Supplemental material

Data extraction and synthesis

Selection of studies

The studies from all the databases will be compiled in EndNote, and duplicates will be removed. Two authors will apply a three-phase approach to screen studies to select those to be used for end-phase data extraction; screening and end-phase data extraction will be done using the systematic review software, COVIDENCE V.2.0.22 The initial phase will involve screening titles and abstracts to identify eligible studies. Studies identified in the first phase will move to phase two for full-text review, which will lead to data extraction in the third and final phase. If studies are presented only in truncated format, we will reach out to authors to obtain complete study details; based on the amount of detail provided, authors will decide about inclusion based on available data. If studies are available in a language other than English, we will work to obtain an English text or use local translation resources. If multiple reports of the same study exist, they will be consolidated into a single study, with appropriate extraction from all reports.

Data extraction

Two authors will independently extract data from phase three studies and subsequently compare their findings. Any conflicts will be addressed with assistance from a senior author (AU). The following information will be extracted from each study: study authors, publication journal, study type, study site, study year, population characteristics (age, diagnosis, inclusion criteria, exclusion criteria), intervention characteristics (medication, dose, route, frequency, duration), control characteristics (placebo or medication dose, route, frequency, duration), outcomes and risk of bias. A draft of the data extraction sheet is available as a online supplemental document. Preference will be placed on data that require the least processing or conversion by authors and the least inference by reviewers, and we will aim to extract raw values (means, SD) as opposed to effect sizes. To avoid reviewer bias, we will have a predetermined order of preference for extracting outcomes when data are available in multiple formats. Preference will be placed on data that require the least manipulation by authors or inference by reviewers, and we will aim to extract raw values (means, SD) as opposed to effect sizes. For mortality data, we will give preference to denominators in the following order: number with definite outcome known, number randomised and time of follow-up.

Studies with missing data

Any missing data will be documented. If the authors report the imputed missing data, we will use the same. If no calculations are available for missing data, we will contact the study authors to request missing data. For continuous outcomes, if a study does not report a SD for a mean and cannot be calculated from the reported data, we will use an SD reported from a similar study for the same outcome. When possible, we will use the final values of a continuous outcome in our analysis. If final values are not provided, we will use a clinically appropriate difference or rate of change to calculate the final values. If the final values are not available for the difference between the start and end of the study, we will request this information from the authors. We will use the data based on intention-to-treat analysis (ITT) from randomised control trials. If ITT data are not provided, we will create an appropriate ITT analysis based on known outcomes and conduct a sensitivity analysis to assess the impact of the calculation.

Assessment of risk bias in included studies

The risk of bias in randomised control trials will be evaluated using the Cochrane Risk of Bias Tool (ROB V.2.0). This tool focuses on the risk-of-bias assessment in different aspects of study design, study execution and study reporting. Specifically, five domains will be addressed: bias during initial randomisation, bias due to deviation from intervention design, bias due to missing outcomes data, bias due to outcome measurement and bias during result selection and reporting. Possible risk-of-bias judgments are (1) low risk of bias, (2) some concerns for bias, or (3) high risk of bias.23 Risk-of-bias assessment for each study will be carried out independently by two authors, and a senior author will address disagreement.

Data synthesis

The findings from the included studies will be reported qualitatively and quantitively. Characteristics of the included studies and methodology will be summarised, and if the included studies are deemed to be homogenous by members of the research team, meta-analyses will be performed.24

We will first conduct an updated traditional pairwise meta-analysis that compares two interventions at a time, including an analysis of opioids versus non-opioids. We will consider network meta-analysis that compares multiple interventions via direct and indirect comparison if the research team members conclude that assumptions of transitivity and coherence hold true. Direct comparison summary estimates can be mathematically summated to transitively produce indirect comparisons between various analgesics across multiple randomised controlled trials if the interventions have a point of connectivity.25 The transitivity will be assessed based on study characteristics and the presence of an effect modifier. We will consider the following effect modifiers: age, gender and route of administration. The coherence assumption will be assessed by calculating a coherence factor. Data from each study will be extracted, with the effect size calculated for a given comparison. The treatment effect of analgesics for pain control shall be calculated using the mean difference or standardised mean difference for the continuous outcomes at a given follow-up. For the primary outcome of pain scores, we will consider the pain scores at the end of the follow-up. Dichotomous outcomes will be pooled to obtain a relative risk. Due to treatment variation across studies, we will use a random effect model for pairwise meta-analysis. Network meta-regression and subgroup analysis will be conducted to evaluate for any effect modifier that may influence the effect sizes of interventions within the network of network meta-analysis.24

We anticipate that all the studies may not report all the outcomes of interest in the desired format. For example, different studies may use different pain scales for pain scores. Even though the Visual Analogue Scale is the most commonly used scale for the assessment of pain, we will consider other scales that are used by primary studies and pool the data via standardised mean differences provided that the assumption of direction of effect is similar across the scales (eg, lower scores indicated better pain control). If all data for a continuous outcome are provided in the same scale, we will use mean difference for analysis; however, if data for a continuous outcome are provided in different scales, we will use standard mean difference for analysis.

The GRADE approach will be used to report the certainty of evidence for each pairwise comparison of interventions in the network meta-analysis.26–28 The GRADE approach is a comprehensive framework to assess the overall quality of the evidence for an outcome based on study design, risk of bias, heterogeneity of studies, directness of evidence, precision of effect estimates and publication bias. The approach to GRADE analysis of the network meta-analysis will be that we will rate the certainty of evidence for each of the pairwise analyses in a network separately, and both direct and indirect evidence (combined effect) will be considered for the same. The key considerations specific to ratings of evidence from a network meta-analysis include a differential approach to the consideration of imprecision in rating, taking into account the certainty of direct and indirect evidence to consider the implication of incoherence in the network, and pairwise analysis. The evidence quality for each pairwise analysis will be characterised as very low (little confidence in the effect estimate), low (limited confidence in the effect assessment), moderate (moderate confidence in the effect assessment), or high (high confidence in the effect assessment).26–28 We will use GRADEpro GDT software that will assist in the development of a summary of the findings table from the GRADE analysis.29 We will rate the quality of evidence for the following outcomes: pain score, need for supplementary analgesia (dichotomous outcome), length (days) of hospitalisation (continuous outcome), serious adverse events and quality-of-life scores.

We are interested in the totality of the evidence for analgesics used to treat acute non-severe pancreatitis. For the interpretation of data for a given analgesic, we will assess the benefits and adverse events. We will consider a minimal clinically important difference of 20% to establish non-inferiority versus superiority of an analgesic versus a control group in a pairwise analysis.

Subgroup analyses

  1. Age: paediatric (< 18 years of age) versus adult population.

  2. Route of administration.

  3. Aetiology of pancreatitis.

  4. Type of supplemental analgesia.

Sensitivity analysis

Choice of model (pairwise analysis): random versus fixed effect.

ETHICS AND DISSEMINATION

This is a systematic review and will not involve direct contact with human subjects. The findings of this review will be published in a peer-reviewed journal and will allow healthcare providers to better understand optimal analgesic medications for pain treatment in patients with non-severe acute pancreatitis.

Ethics statements

Patient consent for publication

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • Contributors SSS and AI wrote the first draft of the manuscript and edited the subsequent iterations. The study’s research question and design were conceived by AI and AU. AS and AI developed the search strategy. ACB developed the initial data extraction template. MHM, SSS, ACB and AI provided the support for methodology. AI, ACB, LAK, DY, AEP and AU supported the content being evaluated in the review. All authors contributed to the preparation of this manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.