Initial Pain Management in Pediatric Pancreatitis: Opioid vs. Non-Opioid (PATIENCE)

• ClinicalTrials.gov Identifier: NCT04291599
• Recruitment Status: Not yet recruiting
• First Posted: March 2, 2020
• Last Update Posted: December 10, 2020
• Sponsor: Boston Children's Hospital
• Collaborator: The National Pancreas Foundation
• Information provided by (Responsible Party): Amit Grover, Boston Children's Hospital

Study Description

Brief Summary:

This will be a phase 2, single-center, unblinded randomized controlled pilot trial of two arms comparing opioid-sparing analgesia to the current Boston Children's Hospital institutional practice which has been reported to predominantly include administration of opioids as a first-line analgesic to pediatric patients who present to the emergency department with a diagnosis of acute pancreatitis (AP). This is a pilot trial for which many outcomes have not previously been studied in the pediatric AP population. The focus of this investigation will be to investigate the magnitude and variability of effect sizes for designing a future multi-center, double-blinded randomized controlled trial.

Condition or disease	Intervention/treatment	Phase
Acute Pancreatitis	Drug: Ketorolac; Drug: Opioid	Phase 2

Detailed Description:

Acute pancreatitis (AP) is the most common pancreatic disease of childhood with an increasing incidence estimated at 13.2 cases in 100,000 children per year. Given the dearth of pediatric literature, most pediatric providers often rely on diagnostic, prognostic and treatment guidelines that have been derived from adults. This is problematic because adult therapeutic guidelines fail to consider the unique age-related responses and requirements of childhood. Pain management is one of the cornerstones in the treatment of pancreatitis, with abdominal pain being the most common presenting symptom of AP. Currently, there are no data on optimal pain management in pediatric AP. Older guidelines suggest that the "use of intravenous patient-controlled analgesia (PCA) is advantageous" as it allows the patient to self-administer opioids and strike a balance between analgesia and side effects. This requires cognitive maturity to understand how to use PCA and poses challenges for younger children, particularly infants and toddlers, as well as pediatric patients with developmental delay. It is particularly concerning that greater than 94% of surveyed pediatric practitioners would use morphine or related opioids as a first-line therapy in children with AP especially when there have been no studies examining the benefits/risks of opioid vs non-opioid analgesics or opioid-sparing therapies in pediatric AP. Furthermore, we recently reported a retrospective analysis demonstrating that opioids are prescribed far more frequently either alone or in combination with non-opioids (70%) than non-opioid alternatives alone (30%). Amongst all types of analgesia prescribed to children who presented to the BCH emergency department (ED) with acute pancreatitis, morphine was the most common. Further research in this area is imperative, particularly given the recent opioid epidemic. From a pediatric perspective, it has been demonstrated that adolescents are amongst those at risk for opioid abuse, thus there is an urgent need to determine whether opioids are necessary for the management of pain in this vulnerable population with AP.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This will be a phase 2, single-center, unblinded randomized controlled pilot trial of two arms comparing opioid-sparing analgesia to the current BCH institutional practice which has been reported to predominantly include administration of opioids as a first-line analgesic to pediatric patients who present to the emergency department with a diagnosis of acute pancreatitis.
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: Initial Pain Management in Pediatric Pancreatitis: Opioid vs. Non-Opioid
• Estimated Study Start Date: January 1, 2021
• Estimated Primary Completion Date: January 2022
• Estimated Study Completion Date: February 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Experimental Arm - Ketorolac (Opioid-Sparing); Patients assigned to this arm of the study will follow the standardized step-up approach to pain management per the hospital Evidenced Based Guideline (EBG). If analgesia is not obtained with first-line medications such as acetaminophen, the patient will be given the NSAID ketorolac intravenously every 6 hours at the standard weight-based dose throughout hospitalization. If the patient experiences continued pain, they (or their guardian/ caregiver) may request a rescue medication in the form of low-dose morphine (or an alternative opioid if allergic to morphine) at 0.025 mg/kg/dose every 4 hours.	Drug: Ketorolac; Subjects will be randomized to either receive opioid (standard of care) or opioid-sparing analgesia.; Other Name: Toradol
Active Comparator: Control Arm - Conventional Treatment/Standard of Hospital Care; Patients assigned to this arm of the study will be treated per institutional policy and procedural care as dictated by established hospital order sets and at the discretion of the provider. This may involve the step-up approach per the hospital EBG utilizing acetaminophen or ibuprofen as first-line agents; however, it remains at the discretion of the treating provider. The current standard of care for children presenting to the ED is based on prescribing order sets within the electronic medical record (EMR). Physicians in the BCH emergency department choose in an intermittently-prescribed manner, standard doses of analgesia including acetaminophen (Tylenol) or ibuprofen per the hospital EBG, as well as opioids (morphine, hydromorphone).	Drug: Opioid; Subjects will be randomized to either receive opioid (standard of care) or opioid-sparing analgesia; Other Name: Morphine, hydromorphone

Outcome Measures

Primary Outcome Measures :

1. Efficacy: amount of opioid analgesia (mg/kg/hr) from the time of enrollment until discharge home, transfer to the ICU, or initiation of PCA [ Time Frame: time of enrollment through study completion (approximately 5 days), or transfer to the ICU or initiation of PCA ]
   The primary endpoint for efficacy is the amount of opioid analgesia (mg/kg/hr) from the time of enrollment until discharge home, transfer to the ICU, or initiation of PCA.

Secondary Outcome Measures :

1. Safety: number of hours from the time of enrollment until discharge home, transfer to the ICU, or initiation of PCA [ Time Frame: time of enrollment through study completion (approximately 5 days), or transfer to the ICU or initiation of PCA ]
   The secondary endpoint for safety is defined as the total number of incident adverse events, grade 2 or higher, from the time of enrollment until discharge home, transfer to the ICU, or initiation of PCA.
2. Length of stay [ Time Frame: time of enrollment through study completion (approximately 5 days), or transfer to the ICU or initiation of PCA ]
   The secondary endpoint for length of stay is defined as the number of hours from the time of enrollment until discharge home, transfer to the ICU, or initiation of PCA.
3. Time to initiation of oral or enteral diet [ Time Frame: time of enrollment through study completion (approximately 5 days), or transfer to the ICU or initiation of PCA ]
   The secondary endpoint for time to initiation of oral or enteral diet is defined as the number of hours from the time of enrollment until first oral or enteral intake. The number of hours will be expressed to two decimal places to account for fractions of an hour.
4. Predefined Feasibility Outcomes to Assess Trial Success [ Time Frame: duration of trial, approximately 1 year from the start of enrollment ]
   The secondary endpoint for feasibility is defined as (1) ≥80% of eligible patients approached for consent during the trial, and (2) ≥20% of eligible patients randomized into the trial.
5. Pain resolution: pain scores [ Time Frame: time of enrollment through study completetion (approximately 5 days), or transfer to the ICU or initiation of PCA ]
   To compare pain resolution from time of enrollment throughout hospital stay by comparing pain scores in patients receiving opioid-sparing therapies to those receiving standard of care opioid analgesics.

Eligibility Criteria

• Ages Eligible for Study: up to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patients who present to the ED and are admitted to BCH with a diagnosis of acute pancreatitis or an acute bout of chronic pancreatitis based on INSPPIRE14 Criteria (Appendix 1)
2. Age ≤21 years
3. Patient weight ≥8 kg

Exclusion Criteria:

1. Allergy to morphine (and hydromorphone) or aspirin/NSAID
2. History of renal or hepatic insufficiency
3. History of peptic ulceration
4. History of bleeding diathesis
5. Pregnant females
6. Patients who have a documented history of substance abuse disorder or those who use opioids chronically
7. Patients admitted to the Intensive Care Unit (ICU)
8. Patients admitted via transfer to BCH from another hospital (ED or inpatient)
9. Patients who received intravenous opioid patient-controlled analgesia (PCA) in transit or during their ED admission.

Contacts and Locations

Contacts

Contact: Amit Grover, MB BCh BAO; 617-355-6058; Amit.Grover@childrens.harvard.edu

Contact: Shannon Manzi, PharmD; 617-355-2837; Shannon.Manzi@childrens.harvard.edu

Sponsors and Collaborators

Boston Children's Hospital

The National Pancreas Foundation

Investigators

• Principal Investigator: Amit Grover, MB BCh BAO; Boston Children's Hospital

More Information

Publications:

Banks PA, Freeman ML; Practice Parameters Committee of the American College of Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006 Oct;101(10):2379-400.

Grover AS, Mitchell PD, Manzi SF, Fox VL. Initial Pain Management in Pediatric Acute Pancreatitis: Opioid Versus Non-opioid. J Pediatr Gastroenterol Nutr. 2018 Feb;66(2):295-298. doi: 10.1097/MPG.0000000000001809.

Wu BU, Banks PA. Clinical management of patients with acute pancreatitis. Gastroenterology. 2013 Jun;144(6):1272-81. doi: 10.1053/j.gastro.2013.01.075. Review.

Forsmark CE, Baillie J; AGA Institute Clinical Practice and Economics Committee; AGA Institute Governing Board. AGA Institute technical review on acute pancreatitis. Gastroenterology. 2007 May;132(5):2022-44. Review.

Rudd RA, Seth P, David F, Scholl L. Increases in Drug and Opioid-Involved Overdose Deaths - United States, 2010-2015. MMWR Morb Mortal Wkly Rep. 2016 Dec 30;65(50-51):1445-1452. doi: 10.15585/mmwr.mm655051e1.

Munro HM, Walton SR, Malviya S, Merkel S, Voepel-Lewis T, Loder RT, Farley FA. Low-dose ketorolac improves analgesia and reduces morphine requirements following posterior spinal fusion in adolescents. Can J Anaesth. 2002 May;49(5):461-6.

Howard ML, Isaacs AN, Nisly SA. Continuous Infusion Nonsteroidal Anti-Inflammatory Drugs for Perioperative Pain Management. J Pharm Pract. 2018 Feb;31(1):66-81. doi: 10.1177/0897190016665539. Epub 2016 Aug 31. Review.

Hadland SE, Wood E, Levy S. How the paediatric workforce can address the opioid crisis. Lancet. 2016 Sep 24;388(10051):1260-1. doi: 10.1016/S0140-6736(16)31573-2.

Bai HX, Lowe ME, Husain SZ. What have we learned about acute pancreatitis in children? J Pediatr Gastroenterol Nutr. 2011 Mar;52(3):262-70. doi: 10.1097/MPG.0b013e3182061d75. Review.

Nydegger A, Heine RG, Ranuh R, Gegati-Levy R, Crameri J, Oliver MR. Changing incidence of acute pancreatitis: 10-year experience at the Royal Children's Hospital, Melbourne. J Gastroenterol Hepatol. 2007 Aug;22(8):1313-6. Epub 2007 Apr 19.

Morinville VD, Barmada MM, Lowe ME. Increasing incidence of acute pancreatitis at an American pediatric tertiary care center: is greater awareness among physicians responsible? Pancreas. 2010 Jan;39(1):5-8. doi: 10.1097/MPA.0b013e3181baac47.

Abu-El-Haija M, Lin TK, Palermo J. Update to the management of pediatric acute pancreatitis: highlighting areas in need of research. J Pediatr Gastroenterol Nutr. 2014 Jun;58(6):689-93. doi: 10.1097/MPG.0000000000000360. Review.

Miech R, Johnston L, O'Malley PM, Keyes KM, Heard K. Prescription Opioids in Adolescence and Future Opioid Misuse. Pediatrics. 2015 Nov;136(5):e1169-77. doi: 10.1542/peds.2015-1364.

Morinville VD, Husain SZ, Bai H, Barth B, Alhosh R, Durie PR, Freedman SD, Himes R, Lowe ME, Pohl J, Werlin S, Wilschanski M, Uc A; INSPPIRE Group. Definitions of pediatric pancreatitis and survey of present clinical practices. J Pediatr Gastroenterol Nutr. 2012 Sep;55(3):261-5. Erratum in: J Pediatr Gastroenterol Nutr. 2013 Apr;56(4):459. Abu-Al-Haija, Maisam [corrected to Abu-El-Haija, Maisam].

Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009 Apr;42(2):377-81. doi: 10.1016/j.jbi.2008.08.010. Epub 2008 Sep 30.

Cohen J. A power primer. Psychol Bull. 1992 Jul;112(1):155-9.

Huguet A, Stinson JN, McGrath PJ. Measurement of self-reported pain intensity in children and adolescents. J Psychosom Res. 2010 Apr;68(4):329-36. doi: 10.1016/j.jpsychores.2009.06.003. Epub 2009 Oct 2.

• Responsible Party: Amit Grover, Principal Investigator, Boston Children's Hospital
• ClinicalTrials.gov Identifier: NCT04291599
• Other Study ID Numbers: P00034168
• First Posted: March 2, 2020
• Last Update Posted: December 10, 2020
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Amit Grover, Boston Children's Hospital:

Pancreatitis

Additional relevant MeSH terms:

Pancreatitis; Pancreatic Diseases; Digestive System Diseases; Ketorolac; Morphine; Hydromorphone; Analgesics, Opioid; Narcotics; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action