==== Front Front Med (Lausanne) Front Med (Lausanne) Front. Med. Frontiers in Medicine 2296-858X Frontiers Media S.A. 10.3389/fmed.2021.782151 Medicine Systematic Review Pain Management in Acute Pancreatitis: A Systematic Review and Meta-Analysis of Randomised Controlled Trials Cai Wenhao 1 2 † Liu Fei 3 † Wen Yongjian 1 † Han Chenxia 1 Prasad Manya 4 Xia Qing 1 Singh Vikesh K. 5 Sutton Robert 2 Huang Wei 1 * 1Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China 2Liverpool Pancreatitis Research Group, Liverpool University Hospitals NHS Foundation Trust and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom 3Department of Anaesthesiology, Laboratory of Anaesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anaesthesiology, West China Hospital, Sichuan University, Chengdu, China 4Clinical Research and Epidemiology, Institute of Liver and Biliary Sciences, New Delhi, India 5Division of Gastroenterology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, United States Edited by: Giuseppe Losurdo, University of Bari Medical School, Italy Reviewed by: Jayanta Samanta, Post Graduate Institute of Medical Education and Research (PGIMER), India; Katherine N. Theken, University of Pennsylvania, United States *Correspondence: Wei Huang patricia87@example.net This article was submitted to Gastroenterology, a section of the journal Frontiers in Medicine †These authors have contributed equally to this work and share first authorship 17 12 2021 2021 8 78215123 9 2021 15 11 2021 Copyright © 2021 Cai, Liu, Wen, Han, Prasad, Xia, Singh, Sutton and Huang. 2021 Cai, Liu, Wen, Han, Prasad, Xia, Singh, Sutton and Huang https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Background: Pain management is an important priority in the treatment of acute pancreatitis (AP). Current evidence and guideline recommendations are inconsistent on the most effective analgesic protocol. This systematic review and meta-analysis of randomised controlled trials (RCTs) aimed to compare the safety and efficacy of analgesics for pain relief in AP. Methods: A literature search was performed to identify all RCTs assessing analgesics in patients with AP. The primary outcome was the number of participants who needed rescue analgesia. Study quality was assessed using Jadad score. Pooled odds ratios (ORs) or weighted mean differences (WMDs) with 95% confidence intervals (CI) were analysed using a random-effects model. Results: Twelve studies comprising 699 patients with AP (83% mild AP) were analysed. The tested analgesics significantly decreased the need for rescue analgesia (3 studies, OR.36, 95% CI 0.21 to 0.60) vs. placebo or conventional treatment. The analgesics also improved the pain score [Visual Analogue Scale (Δ-VAS)] at 24 h (WMD 18.46, 0.84 to 36.07) and by the 3rd to 7th days (WMD 11.57, 0.87 to 22.28). Opioids vs. non-opioids were associated with a decrease in the need for rescue analgesia (6 studies, OR 0.25, 95% CI 0.07 to 0.86, p = 0.03) but without significance in pain score. In subgroup analyses, opioids were similar to non-steroidal anti-inflammatory drugs (NSAIDs) regarding the primary outcome (4 studies, OR 0.56, 95% CI 0.24 to 1.32, p = 0.18). There were no significant differences in other clinical outcomes and rate of adverse events. Other studies, comparing epidural anaesthesia vs. patient-controlled analgesia and opioid (buprenorphine) vs. opioid (pethidine) did not show significant difference in primary outcome. Study quality issues significantly contributed to overall study heterogeneity. Conclusions: NSAIDs and opioids are equally effective in decreasing the need for rescue analgesia in patients with mild AP. The relative paucity of trials and high-quality data in this setting is notable and the optimal analgesic strategy for patients with moderately severe and severe AP still requires to be determined. pain management acute pancreatitis analgesics randomised-controlled trial meta-analysis ==== Body pmcIntroduction Pain is one of the most prevalent and costly health conditions. The estimated cost of pain in the United States was more than that of heart disease and cancer treatments, reaching $560 billion to $635 billion per year (1). Acute abdominal pain is the leading symptom and principal reason for hospital admission in patients with acute pancreatitis (AP). Acute pancreatitis (AP) is one of the most common gastrointestinal diseases with an increasing global incidence (2), for which there is no specific targeted therapy (3). According to the latest epidemiological investigation, aggregate annual health care cost of AP rose to $2.6 billion in the United States in 2014 (4) and £200 million in the United Kingdom (NHS). Abdominal pain not only serves as one of the diagnostic criteria (5), but also a prognostic factor (6), and is related to the length of hospital stay and other self-reported outcomes of patients with AP (7, 8). Nearly all patients with AP experienced abdominal pain which warrants prompt analgesia, and this is one of the main management priorities in the early management of AP (9). Some current practise guidelines have overlooked recommendations for pain management (10–14), while others provide a clear recommendation for pain assessment (15, 16), and best pharmacological options (15) (Table 1). No guidelines provide sufficient details regarding the type, dose, route, and frequency of analgesia administration. Table 1 Acute Pancreatitis (AP) guideline recommendations for pain management. AP guidelines Recommendations for pain management 2013 IAP/APA Evidence-based Guidelines for the Management of Acute Pancreatitis No recommendations 2013 American College of Gastroenterology Guideline: Management of Acute Pancreatitis No recommendations 2015 Japanese Guidelines for the Management of Acute Pancreatitis Recommendation: Pain associated with AP is severe and persistent, raising the need of sufficient pain control. (Strong recommendation, high-quality evidence) 2015 The Italian Association for the Study of the Pancreas: Consensus guidelines on severe acute pancreatitis No recommendations 2018 NICE guideline: pancreatitis No recommendations for pain management in acute pancreatitis 2018 American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis No recommendations 2019 WSES guidelines for the management of severe acute pancreatitis Recommendation: No evidence or recommendation about any restriction in pain medication is available. NSAIDs should be avoided in acute kidney injury. Epidural analgesia should be an alternative or an agonist with intravenous analgesia, in a multimodal approach. Patient-controlled analgesia should be integrated with every described strategy. (Strong recommendation, low-quality evidence) AP, acute pancreatitis; IAP, International Association of Pancreatology; APA, American Pancreatic Association; NICE, National Institute for Health and Care Excellence; WSES, World Society of Emergency Surgery; NSAID, non-steroidal anti-inflammatory drug. There are many pharmacological options, with opioids being the most frequently prescribed analgesics for pain relief of patients with AP. Since abdominal pain in AP is secondary to pancreatic parenchymal inflammation (17, 18), non-steroidal anti-inflammatory drugs (NSAIDs) that target the enzyme cyclooxygenase (COX) are often used (19, 20). Much less frequently, local anaesthetics (i.e., procaine and bupivacaine) and paracetamol (19–21) are used. A previous meta-analysis of only 5 studies (22) (227 participants) showed there was no significant difference between opioids vs. non-opioids (3 studies, 162 participants) regarding the need for rescue analgesia, pain intensity, clinical outcomes, and adverse events for pain relief of patients with AP. It is noted that opioid requirement during hospitalisation is strongly associated with more complications of this disease (23, 24) and there is the need for more evidence regarding the safety and efficacy of individual opioids in AP management. Further, a recent systematic review (25) demonstrated that NSAIDs reduced AP severity and mortality rate in animal models and patients. However, this review included studies that were of poor quality, the efficacy of NSAIDs for pain relief in this setting still needs to be addressed. Recently, thoracic epidural anaesthesia has been shown to significantly improve pancreatic microcirculation and splanchnic perfusion and reduce indices for multiple organ failure and mortality (26). There is the need to repeat a systematic review on this topic and it includes recent clinical studies of pain relief protocols in patients with AP to guide clinical management and trials. The aim of this systematic review and meta-analysis was to include recent randomised clinical trials (RCTs) to evaluate the safety and efficacy of analgesics in the management of pain in patients with AP. Methods The study was conducted following protocols of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) Statement (27). Literature Search Strategy A thorough literature search was carried out in the databases of Ovid Medline (PubMed), EMBASE, Science Citation Index Expanded, and Cochrane Library up to June 23, 2021. The detailed search strategy is shown in Appendix 1 (supplementary material). All RCTs investigating pain management in AP were collated. Reference lists of relevant reviews and other non-primary data sources regarding this context captured by the search strategy were also manually screened. Only publications in English were included. Relevant articles were manually reviewed by three investigators (W.C., F.L., and Y.W.). Study Selection Inclusion criteria for eligible studies were: (1) RCTs carried out in patients with AP; (2) treatment with opioids, NSAIDs, systemic, or epidural administration of local anaesthetics for abdominal pain; and (3) include at least one outcome measure for analysis. Non-RCTs, retrospective studies, reviews, abstracts, case reports/series, editorials, expert opinions, and non-English publications were excluded. Outcomes of Interest The primary outcome was the number of patients requiring rescue analgesia beyond the analgesic being tested during the observation time of the trial (thereafter called "need for rescue analgesia") (28). It is provided that a patient requesting rescue analgesic for multiple times is not counted more than once. This was chosen as the primary outcome because this was widely used in the trials, and it was considered more objective than the multiple patient-reported pain scoring systems. The rescue analgesia could be the same analgesic in the trial arm or a different analgesic. Secondary outcomes included change of pain score, all complications, mortality, length of hospital stay, and adverse event rate. Pain scores were converted to a 0–100 scale Visual Analogue Scale (VAS) from the 0–5 or 0–10 scales for pooled calculation, and their change (Δ-VAS) was assessed within 24 h, at 72 h, and/or on 3–7 d after randomisation. Any complication was defined as development of local complication (acute peripancreatic fluid collection, acute necrotic collection, walled-off necrosis, pancreatic pseudocyst, and vein thrombosis) (5), organ failure (acute respiratory failure, acute liver injury, acute kidney injury, and cardiovascular failure), and other complications (e.g., altered bowel function, ileus, ascites, and pleural effusion) that were not attributed to an adverse drug reaction. Data Collection Two authors (W.C. and Y.W.) independently extracted data from included studies using a standardised pro forma designed by a senior author (W.H.). These included: authors, year of publication, country, centre(s), sample size calculation, number of patients screened (analysed), patient baseline characteristics (age, gender, weight or body mass index, aetiology, disease severity), trial criteria, and process (time of pain to admission, inclusion and exclusion criteria, treatment details of all comparison groups, observation duration, assessment tool and frequency of pain, pain scores, frequency and dose of rescue analgesic, and outcome measures). Study Quality and Evidence Quality Assessment Two authors (W.C. and Y.W.) scored each included study by using the Jadad system (29) that assesses randomisation (0 or 1), double blinding (0, 1, or 2), recording of dropouts and/or withdrawals (0 or 1), and allocation concealment (0 or 1), with a score ≥ 3 indicative of high quality. The Grading of Recommendations, Assessment Development and Evaluations (GRADE) approach was used to assess the quality of the supporting evidence for selected outcomes using the GRADEpro software (https://gdt.gradepro.org). The quality of the evidence was classified as high, moderate, low, or very low based on consideration of the risk of bias, the directness of evidence, consistency, and precision of the estimates. Statistical Analysis Quantitative data were pooled by meta-analyses using RevMan 5.3.5 (Cochrane Collaboration; Oxford, UK). For dichotomous variables, pooled effect estimates were calculated using odds ratios (ORs) with 95% confidence intervals (c.i.). Means and SDs of continuous variables were used for meta-analysis and estimated when medians with ranges were given to generate weighted mean difference (WMD) with 95% c.i. (30). All probability (P) values were two-tailed, and a p < 0.05 was considered statistically significant. Heterogeneity was evaluated by Cochrane's Q statistic with P value. I2 values were used to quantify the degree of heterogeneity (I2 ≥ 50% or p < 0.1 indicative of high heterogeneity). A random effect model was employed to pool the overall effect estimate. Subgroup analyses of the primary outcome were conducted by separately analysing studies comparing the same type of analgesics. Sensitivity analysis of primary outcome was performed by restricting studies with high quality (Jadad ≥ 3), sample size ≥ 40, Western population, and by studies mainly including patients with mild AP. Statistical analysis of publication bias was performed using StatsDirect 3.0 (StatsDirect Ltd; Birkenhead, UK), and p values were generated from Begg-Mazumdar (31) and Egger (32) tests as p < 0.10 was also considered significant. Results Design and Quality Assessment of Included Studies A PRISMA flow diagram for study selection is shown in Figure 1. A total of 12 studies (33–44) were included. Study design and quality assessment are displayed in Table 2 and a detailed Jadad scoring is shown in Supplementary Table 1. Only one study (36) was conducted in multiple centres. Three studies (36, 37, 41) performed sample size calculation. Seven (33, 35, 36, 38, 41, 42, 44) and 5 studies (34, 37, 39, 40, 43) had Jadad score ≥ 3 and ≤ 2, respectively. Figure 1 Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram of article selection for the review. Table 2 Design and quality assessment of included studies. Refrences Country Comparison groups Centre Patient type Sample size calculation Jadad score Blamey et al. (33) UK Opioid (buprenorphine) vs. Opioid (pethidine) Single Consecutive No 3 Ebbehoj et al. (34) Denmark NSAID (indomethacin) vs. Placebo Single Consecutive No 2 Jakobs et al. (39) Germany Opioid (buprenorphine) vs. local anaesthetic (procaine, i.v.) Single Consecutive No 2 Stevens et al. (44) USA Opioid (TTS fentanyl) vs. Placebo Singe Consecutive No 5 Kahl et al. (40) Germany Opioid (pentazocine) vs. local anaesthetic (procaine, i.v.) Singe Non-consecutive No 2 Peiró et al. (43) Spain Opioid (morphine) vs. NSAID (metamizole) Single Non-consecutive No 2 Layer et al. (36) Germany Local anaesthetic (procaine, i.v.) vs. Placebo Multiple Consecutive Yes, difference of 20 VAS and SD of 24 points 4 Sadowski et al. (37) Switzerland Local anaesthetic (bupivacaine, PCEA) + Opioid (fentanyl, PCEA) vs. Opioid (fentanyl, PCIA) Single Non-consecutive Yes, to detect an OR of > 2.5 with a power of 80% (p < 0.05), 50 patients are needed 2 Gülen et al. (38) Turkey Opioid (tramadol) vs. NSAID (paracetamol) vs. NSAID (dexketoprofen) Single Consecutive No 4 Mahapatra et al. (42) India Opioid (pentazocine) vs. NSAID (diclofenac) Single Non-Consecutive No 4 Huang et al. (35) China NSAIDs (parecoxib + celecoxib) vs. Conventional treatment Single Consecutive No 3 Kumar et al. (41) India Opioid (tramadol) vs. NSAID (diclofenac) Single Consecutive Yes, difference of SD of 30 mm for VAS, considering 30% dropout, 46 patients are needed 5 NR, not reported; NSAID, non-steroidal anti-inflammatory drugs; TTS, transdermal therapeutic system; VAS, visual analogue scale; SD, standard deviation; PCEA, patient-controlled epidural anaesthesia; PCIA, patient-controlled intravenous analgesia; OR, odds ratio. Baseline Characteristics of Included Patients These data are shown in Supplementary Table 2. A total of 800 patients with AP were screened and 699 were analysed with age ranged from 23 to 86 years old. Gender was reported in 11 studies (34–44). Two studies (39, 40) reported the weight and 3 studies (35–37) reported body mass index. Ten studies (34–43) reported aetiology of AP. Regarding AP severity classification, 2 studies (38, 44) did not report data on AP severity, 2 studies (35, 37) reported substantial proportion of patients with severe AP, and the remaining 8 studies (33, 34, 36, 39–43) mainly included patients with mild AP. Pooled prevalence of mild AP was estimated to be 83% (478/577). Details of Trials These are listed in Table 3. Ten studies (33–41, 43) were used the VAS to assess pain intensity, with VAS (0–100) in 6 studies (36, 38–41, 43) and VAS (0–10) in 4 studies (33–35, 37). One study (44) employed verbal self-report scale (0–5) for pain assessment and one (42) did not score pain. Study duration ranged from.5 h to 7 days. Table 3 Details of trial criteria and process. Study Sample size Time of pain to admission Inclusion and exclusion criteria Intervention group Control group Observation time Pain assessment (tool and frequency) Rescue analgesia Outcome measures Blamey et al. (33) 32 NR NR Pethidine (100 mg, i.m.) Buprenorphine (0.3 mg, i.m.) 24 h VAS (0–10); baseline and 24 h after treatment Pethidine (100 mg, i.m.) VAS (0–10) Ebbehoj et al. (34) 30 NR NR Indomethacin (50 mg, rectal, twice/day) Placebo 168 h VAS (0–10); daily Opiates VAS (0–10); pain free days; number of rescue analgesic injections during 7 days treatment Jakobs et al. (39) 40 NR Included: Not specified; Excluded: Cardiac arrhythmias or previous severe arrhythmias, pregnancy, contradictions to anaesthetics Procaine (2 g/day, i.v.) Buprenorphine (0.3 mg bolus maintained with 2.4 mg per day, i.v.) 72 h VAS (0–100); 3 times a day Opiates VAS (0–100); need for rescue analgesia Stevens et al. (44) 32 NR Included: Pain ≥ 2 on verbal self-report scale (0–5); Excluded: Respiratory diseases, contradictions to anaesthetics Fentanyl (50 mg/h, TTS for 3 days) Placebo 72 h or discharged earlier McGill-Melzack Pain Q and verbal self-report scale (0–5); every 3 h Demerol (50–100 mg, every 3 h as needed for 3 days) Verbal self-report scale (0–5); total amount of fentanyl and Demerol Kahl et al. (40) 101 <72 h Included: Not specified; Excluded: Any analgesic prior to hospitalisation and pregnancy Pentazocine (30 mg/kg, i.v., every 6 h) Procaine (2 g/24 h, continuous i.v.) 96 h VAS (0–100); baseline, and twice daily Pentazocine VAS (0–100); total amount of pentazocine Peiró et al. (43) 16 <12 h Included: Not specified; Excluded: Advanced comorbidities, contradictions to anaesthetics Morphine (1%, 10 mg/4 h, s.c.) Metamizole (2 g/8 h, i.v. for 3 min) 48 h VAS (0–100); baseline and every 4 h Pethidine Pain free within 24 h (<15 mm VAS) Layer et al. (36) 44 NR Included: Not specified; Excluded: Advanced comorbidities, pregnancy, contradictions to anaesthetics Procaine (2 g/24 h, i.v.) Placebo 72 h or until pain free VAS (0–100); daily and after analgesic given Metamizole or buprenorphine Final change of pain intensity (delta VAS 72 h); need for rescue analgesia; response rate Sadowski et al. (37) 35 NR Included: Ranson ≥ 2 and/or CRP > 100 mg/l and/or necrotising AP; Excluded: Contradictions to anaesthetics Bupivacaine (0.1%, PCEA) + Fentanyl (2 μg/ml, PCEA) Fentanyl (10 μg/ml, PCIA) 72–120 h VAS (0–10); every 8 h Fentanyl PCIA VAS (0–10); pancreatic blood perfusion Gülen et al. (38) 90 <24 h Included: VAS > 40/100 mm Excluded: Taken NSAID <24 h, advanced comorbidities, trauma, contradictions to anaesthetics Tramadol (1 mg/kg in 100 ml saline, i.v., for 4–5 min) Paracetamol (1,000 mg, i.v., for 4–5 min) or dexketoprofen (50 mg/kg, i.v., for 4–5 min) 0.5 h VAS (0–100); baseline and 30 min after drug given Morphine Pain relief at 30 min; need for rescue analgesia Mahapatra et al. (42) 50 <7 days Included: Organ failure grade <2; Excluded: Comorbid coronary artery disease, altered sensorium, serum creatinine ≥ 1.5 mg/dl, paralytic ileus, chronic pancreatitis Pentazocine (30 mg, Q8h, i.v., for 24 h) Diclofenac (75 mg, Q8h, i.v., for 24 h) 40 h NR Fentanyl PCIA Dose of rescue analgesic; pain free period; total number of demands of the rescue analgesic Huang et al. (35) 188 <48 h Included: APACHE II ≥ 8; Excluded: AP due to trauma; drug allergy Conventional treatment Parecoxib (40 mg per day, p.o., for 3 days) and celecoxib (200 mg, twice daily, p.o., for 7 days) 72 h VAS (0–10); baseline and every 4 h during the first 3 days (50–100 mg, i.m.) VAS (0–10) Kumar et al. (41) 41 <72 h Included: Not specified; Excluded: Advanced comorbidities, pregnancy, contradictions to anaesthetics, lack of informed consent Diclofenac (1 mg/kg, i.v., over 5 min twice daily) Tramadol (1 mg/kg, i.v., over 5 min twice daily) 168 h VAS (0–100); assessed 1, 3, 6, 12 and 24 h after drug given, then every 6 h Morphine (0.06 mg/kg) after the first 1 h then (0.03 mg/kg) after another 30 min VAS after 1 h of drug administration and need for rescue analgesia NR, not reported; i.m., intramuscular; VAS, visual analogue scale; i.v., intravenous; TTS, transdermal therapeutic system; CRP, C-reactive protein; AP, acute pancreatitis; PCEA, patient-controlled epidural anaesthesia; PCIA, patient-controlled intravenous analgesia; NSAID, non-steroidal anti-inflammatory drug; APACHE II, Acute Physiology, Age and Chronic Health Evaluation II. In terms of pharmacological interventions, 4 studies compared analgesics with controls [3 studies with placebo, and one study (35) underwent the same treatments with intervention group without using tested analgesics], 6 studies compared opioids with non-opioids, one study (33) compared opioid with opioid, and one study (37) compared patient-controlled epidural analgesia (PCEA) with patient-controlled intravenous analgesia (PCIA). Rescue analgesics (the primary outcome) in all studies were opioids (4 pethidine, 2 opiates, 2 fentanyl, 2 morphine, 1 pentazocine, and 1 buprenorphine) and 1 study (36) also used metamizole as an alternative to buprenorphine. Results for Comparative Data That Cannot Be Quantitively Synthesised Opioid vs. Opioid Blamey et al. (33) compared the use of opioid (buprenorphine) with another opioid (pethidine) mostly in patients with mild AP (29/32, 90.6%), reporting no significant difference (both p ≥ 0.54) in the need for rescue analgesia and adverse events between these two opioids. PCEA vs. PICA Sadowski et al. (37) compared the PCEA (bupivacaine and fentanyl) with PCIA (fentanyl) in patients with predicted severe AP. While the authors found a decrease in absolute VAS value on the day of PCEA implementation vs. the PCIA regimen (1.6 ± 1.8 vs. 3.5 ± 2.2, p = 0.020) and day 10 (0.2 ± 0.4 vs. 2.33 ± 2.3, p = 0.034) from respective baselines (6.6 ± 3.4 vs. 7.31 ± 3.4, p = 0.572). There were no changes in Δ-VAS from randomisation at all designated time points (all p ≥ 0.13; data not shown). The PCEA regimen significantly improved the perfusion of the pancreas compared with the PCIA regimen (13/30, 43% vs. 2/27, 7%, p = 0.0025). Results of Meta-Analysis Data from 4 studies (34–36, 44) comparing analgesics with controls (placebo or conventional treatment) and 6 studies (38–43) comparing opioids with non-opioids were quantitatively synthesised for analysis. Results of the meta-analysis of primary outcome measure are presented in Figures 2, 3. All outcome measures are summarised in Table 4. Results of subgroup analysis are presented in Table 5. Figure 2 Forest plots of need for rescue analgesia in analgesics vs. controls. M-H, Mantel-Haenszel; CI, confidence interval; NSAIDs, non-steroidal anti-inflammatory drugs. Figure 3 Forest plots of need for rescue analgesia in opioids vs. non-opioids. M-H, Mantel-Haenszel; CI, confidence interval; NSAIDs, non-steroidal anti-inflammatory drugs. Table 4 Results of meta-analyses. Outcomes of interest No. of patients Effect estimate herogeneity No. of studies Experimental Control WMD/OR (95% CI) P -value I2 (%) P -value Analgesics vs. Controls Pain related outcome Need for rescue analgesia 580.537.1958 (0.21, 0.60) 0.0001 0 0.38 Initial VAS (0–100) 4 147 147 0.93 (-8.15, 10.01) 0.84 83 0.0006 Δ-VAS at 24 h 2 118 114 18.46 (0.84, 36.07) 0.04 94 <0.0001 Δ-VAS on 3–7d 3 132 130 11.57 (0.87, 22.28) 0.03 98 <0.00001 AP related outcome Any complication 2 118 114 0.36 (0.11, 1.16) 0.09 58 0.12 Mortality 580.537.1958 (0.22, 5.19) 0.94 0 0.45 Length of hospital stay (d) 2 110 110 −4.76 (-11.46, 1.95) 0.16 99 <0.00001 Opioids vs. Non-opioids Pain related outcome Need for rescue analgesia 580.537.1958 (0.07, 0.86) 0.03 68 0.005 Initial VAS (0–100) 5 129 159 3.28 (-0.07, 6.63) 0.06 34 0.18 Δ-VAS within 24 h 580.537.1958 (-18.10, 30.22) 0.62 98 <0.00001 AP related outcome Any complication 580.537.1958 (0.61, 2.20) 0.66 0 0.41 Local complication 2 32 34 0.62 (0.05, 7.80) 0.71 48 0.16 Organ failure 4 73 74 1.74 (0.41, 7.36) 0.45 39 0.19 Mortality 3 65 66 0.69 (0.11, 4.52) 0.70 0 0.56 Length of hospital stay (d) 2 44 46 −3.03 (-7.34, 1.28) 0.17 74 0.05 Drug safety outcome Adverse events 580.537.1958 (0.55, 4.21) 0.42 25 0.25 WMD, weighted mean difference; OR, odds ratio; CI, confidence interval; NSAID, non-steroidal anti-inflammatory drug; VAS, visual analogue scale; AP, acute pancreatitis. Table 5 Subgroup analysis of need for rescue analgesia. Outcomes of interest No. of patients Effect estimate Heterogeneity No. of studies Experimental Control WMD/OR (95% CI) P -value I2 (%) P -value Analgesics vs. Controls NSAIDs vs. Controls 580.537.1958 (0.06, 0.99) 0.05 45 0.18 Opioids vs. Non-opioids Opioids vs. NSAIDs 4 83 84 0.56 (0.24, 1.32) 0.18 0 0.90 Opioids vs. Local anaesthetics 2 70 71 0.02 (0.00, 0.08) <0.00001 0 0.81 WMD, weighted mean difference; OR, odds ratio; CI, confidence interval; NSAID, non-steroidal anti-inflammatory drug. Analgesics vs. Controls Three (34–36) (n = 262) out of the 4 included studies (34–36, 44) reported the primary outcome. The pooled results demonstrated that the use of analgesics significantly reduced the need for rescue analgesia (OR 0.36, 95% CI.0.21 to 0.60, p = 0.0001) without heterogeneity (I2 = 0) vs. controls. With comparable initial VAS scores in both groups (p = 0.84), the analgesic group significantly improved pain intensity (Δ-VAS) within 24 h [2 studies (35, 36), n = 232; WMD 18.46, 95% CI.0.84 to 36.07, p = 0.04] and 3 to 7 days [3 studies (34–36), n = 262; WMD 11.57, 95% CI 0.87 to 22.28, p = 0.03], albeit with high heterogeneity (both I2 ≥ 94%). There were no significant differences in terms of any complication, mortality, length of hospital stay, and adverse events (all p ≥ 0.09). Subgroup analysis of NSAIDs vs. controls still resulted in reduced need for rescue analgesia [2 studies (34, 35), n = 218; OR 0.25, 95% CI 0.06 to 0.99, p = 0.05] with low study of heterogeneity (45%). Opioids vs. Non-opioids All 6 studies (38–43) (n = 338) reported the primary outcome [1 (42) by personal communication]. The pooled results indicated that opioids significantly reduced the need for rescue analgesia compared with non-opioids (OR 0.25, 95% CI 0.07 to 0.86, p = 0.03) with high study heterogeneity (I2 = 68%). The initial pain score was slightly higher in opioids group than non-opioids group [5 studies (38–41, 43), n = 288; WMD 3.28, 95% CI−0.07 to 6.63, p = 0.06] and pooled data demonstrated no significant difference regarding the Δ-VAS within 24 h in these two groups [4 studies (38, 40, 41, 43), n = 248; WMD 6.06, 95% CI-18.10 to 30.22, p = 0.62] with high heterogeneity (I2 = 98%). The other clinical outcomes were not significantly different between these two groups (all p ≥ 0.17). In subgroup analysis, when restricting studies to those comparing opioids with NSAIDs, no significant difference in the need for rescue analgesia was observed [4 studies (38, 41–43), n = 167; OR 0.56, 95% CI 0.24 to 1.32, p = 0.18]. However, the primary results remained significant when comparing opioids with systemic use of local anaesthetics [2 studies (39, 40), n = 141; OR 0.02, 95% CI 0.00 to 0.08, p < 0.00001]. There was no study heterogeneity in both subgroup analyses (both I2 = 0). These results demonstrated that the superiority of opioids in opioids vs. non-opioids analysis was driven by the results of the opioids vs. local anaesthetics. Sensitivity Analysis The sensitivity analysis could only be performed for opioids vs. non-opioids (Supplementary Table 3). The primary results of the need for rescue analgesia became insignificant by only analysing studies of high quality (38, 41, 42) (3 studies, n = 181; OR 0.55, 95% CI 0.24 to 1.23, p = 0.14) with improved heterogeneity (68% to 0). The results were not affected by only including studies with sample size ≥ 40 (38–42), Western population (39, 40, 43), or by studies mainly including patients with mild AP and these had similar study heterogeneity. GRADE Assessment The GRADE could only be applied to the studies of opioids vs. non-opioids (Table 6). Moderate quality of evidence was rated for the need for rescue analgesia. Low quality of evidence was rated for other outcomes assessed including Δ-VAS within 24 h, any complication, length of hospital stay, and adverse events. Table 6 Grading of Recommendations, Assessment Development and Evaluations (GRADE) evidence profile and summary of findings: Opioids vs. Non-opioids. Certainty assessment No. of patients Effect Certainty Outcomes No. of studies Risk of bias Inconsistency Indirectness Imprecision Other considerations Opioid Non-opioid Relative (95% CI) Absolute (95% CI) Need for rescue analgesia 6 RCTs seriousb, c, e seriousd not serious not serious strong association 60/183 (32.8%) 110/185 (59.5%) OR 0.25 (0.07 to 0.86) 326 fewer per 1,000 (from 501 fewer to 37 fewer) ⊕⊕⊕◯ MODERATE ΔVAS within 24 h (follow up: 0.5 h to 24 h) 4 RCTs seriousb, c serious a, d not serious not serious none 109 139 - MD 6.06 higher (18.10 lower to 30.22 higher) ⊕⊕◯◯ LOW Any complication 5 RCTs seriousb, c, e serious d, f not serious not serious none 59/123 (48.0%) 59/125 (47.2%) OR 1.16 (0.61 to 2.20) 37 more per 1,000 (from 119 fewer to 191 more) ⊕⊕◯◯ LOW Length of hospital stay 2 RCTs seriouse seriousd not serious not serious none 42 46 - MD 3.03 lower (7.34 lower to 1.2 higher) ⊕⊕◯◯ LOW Adverse events 5 RCTs seriousb, c, e seriousd not serious not serious none 18/162 (11.1%) 14/165 (8.5%) OR 1.52 (0.55 to 4.21) 37 more per 1,000 (from 35 fewer to 191 more) ⊕⊕◯◯ LOW CI, confidence interval; RCT, randomised controlled trial; VAS, visual analogue scale; MD, mean difference; OR, odds ratio. a Variation of time points for pain scoring. b Unblinded of study by Kahl et al. (40). c Unblinded of study by Peiro et al. (43). d Variation of dose and approach for drug administration. e Unblinded of study by Jakobs et al. (39). f Definitions of complications of acute pancreatitis were not consistent across different studies. GRADE levels of quality of evidence: High, further research is very unlikely to change our confidence in the estimate of effect; Moderate, further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; Low, further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; Very low, any estimate of effect is very uncertain. Publication Bias There was no convincing evidence of publication bias for the primary outcome measure in opioids vs. non-opioids (Begg-Mazumdar and Egger: p > 0.1) by funnel plot analysis (Supplementary Figure 1). Discussion This systematic review and meta-analysis included 12 RCTs investigating analgesics for pain relief in AP and comprised a total of 699 patients, of whom 83% were mild cases. It was found that the use of analgesics was associated with reduced need for rescue analgesia and with pain score compared with controls. Unlike the previous meta-analysis (22) showing opioids were equivalent to non-opioids in decreasing the need for rescue analgesia, this meta-analysis found that opioids were superior to non-opioids in regards to the need for rescue analgesia but without significant differences in pain score, other clinical outcomes, and adverse events. It was found that NSAIDs and opioids were equally effective in decreasing the need for rescue analgesia in patients with AP, which was not the case for the systemic administration of local anaesthetics. The lack of heterogeneity in these two subgroups analyses makes the conclusion more convincing. Of the 4 RCTs that investigated the effects of analgesics in comparison with controls, 2 reported that NSAIDs reduced the need for rescue analgesia. Ebbehoj et al. (34) showed that indomethacin was effective for pain relief. In a most recent study, Huang et al. (35) demonstrated that parecoxib plus celecoxib (selective COX-2 inhibitors) was associated with significantly less meperidine injections, reduced pain score, systemic and local complications, length of hospital stay, and cost without evidence of adverse events. Indeed, NSAIDs (i.e., celecoxib) are strongly recommended by the EARS Society as a component of a multimodal analgesic strategy and have been shown to reduce PCIA morphine consumption after major surgery in patients without contraindications (45, 46). Overall, our findings support the use of NSAIDs (in the absence of acute kidney injury) for pain relief in AP which is not a feature in previous AP guidelines. Compared with the Cochrane database review conducted by Basurto et al. (22) in 2013 which included 5 RCTs with 227 participants, the current systematic review included 12 RCTs with 699 participants. For opioids vs. non-opioids, while Basurto et al. (22) did not show significance (3 studies with 162 patients, OR 0.41, 95% CI 0.14 to 1.19, p = 0.10), our results of an additional 3 RCTs favoured opioids over non-opioids (6 studies with 338 patients; OR 0.25, 95% CI 0.07 to 0.86, p = 0.03) in reducing the need for rescue analgesia. Subgroup analysis of 2 studies comparing opioids with procaine did not change the result of the primary outcome (OR 0.02, 95% CI 0.00 to 0.08, p < 0.00001), indicating opioids are a more effective analgesic than the systemic administration of procaine. The rationale for using procaine is because of its local analgesic effect and, possibly, its inhibitory effect on phospholipase A2 catalytic activity, which is an important enzyme involved in the early pathogenesis of AP (47). Therefore, systemic administration of local anaesthetics, mainly procaine, was already recommended as front-line analgesic in AP by consensus conferences in several European countries two decades ago (48, 49). Our results suggested that systemic use of local anaesthetics is not supported and, thus, its role in pain management in AP needs to be defined. Subgroup analysis of 4 studies between opioids and NSAIDs revealed there was no significant difference in the need for additional analgesic (OR 0.56, 95% CI 0.24 to 1.32, p = 0.18) without heterogeneity (I2 = 0), Δ-VAS, other clinical outcomes, and adverse events. Recently, a retrospective study conducted by Kim et al. (50) showed that opioid was associated with an increased risk of developing AP compared to NSAIDs (OR 2.64, 95% CI 1.54 to 4.52). It is reported that opioids can potentially cause AP in patients with a history of cholecystectomy due to its adverse effect of sphincter of Oddi constriction (50, 51). There are other effects of opioids including ileus, dysbiosis, opioid hyperalgesia, and others (22, 52). However, opioids have been overused for pain management in AP especially in North America where 92.5% of patients with AP received opioids for impatient pain management and 64.3% have been given opioids at discharge (53). On the other hand, the over prescription or prescription of opioids without adequate supervision has led to an alarming rise of opioid overdose-associated deaths (54). From 2013 to 2019, the synthetic opioid-associated death rate increased more than 10 folds, from 1.0 to 11.4 per 100,000 age-adjusted population in the United States (55). Therefore, based on the available evidence, it appears that NSAIDs are preferred over opioids as first line analgesia in patients with AP. Epidural analgesia is an essential component of most enhanced recovery after surgery (ERAS) pathways and is commonly used in major abdominal surgery, because it is associated with superior pain control (46). However, epidural analgesia is rarely used in patients with AP. Sasabuchi et al. (56) investigated 44,146 patients with AP in Japan between 2010 and 2013 and found that only 0.7% of patients received epidural analgesia for pain management. A large propensity score-matched retrospective observational study (57) of 1,003 patients conducted in 2018 demonstrated that the mortality of critically ill patients with AP who received epidural analgesia was significantly lower than those who did not. In our study, there was only one RCT focusing on PCEA vs. PCIA (37). It was clear that PCEA markedly improved pancreatic arterial perfusion over PCIA, and this finding is consistent with studies from experimental AP models (26) and with patients who are critically ill with AP (37). Meanwhile, a multi-centre RCT (58) is underway to elucidate the benefits of PCEA among critically ill patients with AP. PCEA is not currently recommended for patients with in mild and moderately severe AP because of potential adverse effects including catheter placement-related hypotension and epidural abscess, although at a relatively low incidence. More studies evaluating the safety and efficacy of epidural analgesia in patients with severe AP are warranted. In our study, we did not include studies assessing the analgesic effect of acupuncture on patients with AP as we focused on the pharmacological intervention. A systematic review and meta-analysis (59) have demonstrated that acupuncture was associated with significantly reduced abdominal pain (mean difference −0.87, 95% CI −1.01 to −0.73, p < 0.00001), improved gastrointestinal function, accelerated time of resuming to diets, and shortened the length of hospital stay without noticeable adverse events. However, most of these studies are published in Chinese and more rigorously designed RCTs are needed to confirm these findings. It is striking that there is not more level 1 evidence available to guide decision-making with optimised analgesic protocols in patients with AP. The evidence available from the 12 RCTs is limited by the quality and heterogeneity of included studies as shown by our sensitivity analysis. In order to minimise the impact of heterogeneity, the random-effects model was adopted in the quantitative analysis for all outcomes. The unblinding characteristic of some studies may influence the patient-reported outcomes including the scoring of pain. Moreover, the variation in drug administration route and dosages impacted the study outcomes and this is reflected in the low GRADE levels. For example, in opioids vs. non-opioids, Peiró et al. (43) utilised smaller doses of morphine subcutaneously while other studies administered greater doses of opioids by intravenous approach. This might also explain the differences between studies. Other aspects that impact the trial design and outcomes are differences in the timing of pain onset in relation to hospital admission or recruitment, admission pain intensity, and predicted severity. We chose the primary outcome to be "the need for rescue analgesia" as data were not available on opioid equivalent for the rescue analgesic in most studies. For future trials, there is also the need for standardised reporting of pain outcomes and inclusion the identification of objective biomarkers (electrophysiology, bioassay, omics, imaging, and behaviour) (54). The important finding from this study is that NSAIDs are as effective as opioids and opioids are more effective than systemic local anaesthetics on reducing the need for rescue analgesia in patients with mild AP. Epidural anaesthesia shows promise but will need further trials in patients with predicted severe AP before it can be recommended or adopted. Data Availability Statement The original contributions presented in the study are included in the article/Supplementary Materials, further inquiries can be directed to the corresponding authors. Author Contributions WC, FL, and YW are joint first authors of this article, undertook the statistical analysis, and interpreted data. WH conceived and designed the study. WC, FL, YW, and CH undertook the systematic literature search, acquisition of data, quality cheque, and risk of bias assessment. MP contributed to the design of statistical analysis. WC, FL, YW, and WH drafted the manuscript. WH and QX obtained funding and supervised the study. VS and RS had important intellectual input. All authors have approved the final version of manuscript before submission. Funding This project is supported by the National Nature Science Foundation of China (No. 82104598, CH; No. 81973632, WH). NZ-China Strategic Research Alliance 2016 Award (China: 2016YFE0101800, QX and WH). WC is funded by China Scholarship Council (No. 201806240274) and West China Hospital-Liverpool Clinician Scientist Development Award. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's Note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. The authors thank Dr. Kun Jiang (West China Hospital) for her assistance in preparation of this work. Supplementary Material The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.782151/full#supplementary-material Click here for additional data file. Click here for additional data file. ==== Refs References 1. Smith TJ Hillner BE . The cost of pain. JAMA Netw Open. (2019) 2 :e191532. 10.1001/jamanetworkopen.2019.1532 30951152 2. Xiao AY Tan ML Wu LM Asrani VM Windsor JA Yadav D . 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