Review

. 2018 Feb;159(2):193-205.

doi: 10.1097/j.pain.0000000000001104.

Clinical trial designs and models for analgesic medications for acute pain in neonates, infants, toddlers, children, and adolescents: ACTTION recommendations

Gary A Walco^{1

2}, Ernest A Kopecky^{3

4}, Steven J Weisman⁵, Jennifer Stinson⁶, Bonnie Stevens⁶, Paul J Desjardins⁷, Charles B Berde⁸, Elliot J Krane^{9

10}, Kanwaljeet J S Anand¹¹, Myron Yaster¹², Carlton D Dampier¹³, Robert H Dworkin¹⁴, Ian Gilron¹⁵, Anne M Lynn^{1

2}, Lynne G Maxwell¹⁶, Srinivasa Raja¹¹, Bernard Schachtel¹⁷, Dennis C Turk¹

Affiliations

¹ Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA.
² Department of Anesthesiology and Pain Medicine, Seattle Children's Hospital, Seattle, WA, USA.
³ Collegium Pharmaceutical, Inc., Canton, MA, USA.
⁴ Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, ON, Canada.
⁵ Departments of Anesthesiology and Pediatrics, Children's Hospital of Wisconsin, Milwaukee, WI, USA.
⁶ Department of Nursing Research, Hospital for Sick Children, Toronto, ON, Canada.
⁷ Pfizer Consumer Healthcare, New York, NY, USA.
⁸ Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, MA, USA.
⁹ Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Department of Anesthesiology, Perioperative and Pain Management, Stanford Children's Health, Palo Alto, CA, USA.
¹¹ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
¹² Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University Hospital, Baltimore, MD, USA.
¹³ Department of Pediatrics, Emory University, Atlanta, GA, USA.
¹⁴ Departments of Anesthesiology and Perioperative Medicine, Neurology, and Psychiatry, University of Rochester, Rochester, NY, USA.
¹⁵ Departments of Anesthesiology and Biomedical Sciences, Queen's University, Kingston, ON, Canada.
¹⁶ Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁷ Yale School of Public Health, New Haven, CT, USA.

PMID: 29140927
PMCID: PMC5949239
DOI: 10.1097/j.pain.0000000000001104

Review

Clinical trial designs and models for analgesic medications for acute pain in neonates, infants, toddlers, children, and adolescents: ACTTION recommendations

Gary A Walco et al. Pain. 2018 Feb.

. 2018 Feb;159(2):193-205.

doi: 10.1097/j.pain.0000000000001104.

Authors

Affiliations

¹ Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA.
² Department of Anesthesiology and Pain Medicine, Seattle Children's Hospital, Seattle, WA, USA.
³ Collegium Pharmaceutical, Inc., Canton, MA, USA.
⁴ Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, ON, Canada.
⁵ Departments of Anesthesiology and Pediatrics, Children's Hospital of Wisconsin, Milwaukee, WI, USA.
⁶ Department of Nursing Research, Hospital for Sick Children, Toronto, ON, Canada.
⁷ Pfizer Consumer Healthcare, New York, NY, USA.
⁸ Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, MA, USA.
⁹ Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Department of Anesthesiology, Perioperative and Pain Management, Stanford Children's Health, Palo Alto, CA, USA.
¹¹ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
¹² Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University Hospital, Baltimore, MD, USA.
¹³ Department of Pediatrics, Emory University, Atlanta, GA, USA.
¹⁴ Departments of Anesthesiology and Perioperative Medicine, Neurology, and Psychiatry, University of Rochester, Rochester, NY, USA.
¹⁵ Departments of Anesthesiology and Biomedical Sciences, Queen's University, Kingston, ON, Canada.
¹⁶ Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁷ Yale School of Public Health, New Haven, CT, USA.

PMID: 29140927
PMCID: PMC5949239
DOI: 10.1097/j.pain.0000000000001104

Abstract

Clinical trials to test the safety and efficacy of analgesics across all pediatric age cohorts are needed to avoid inappropriate extrapolation of adult data to children. However, the selection of acute pain models and trial design attributes to maximize assay sensitivity, by pediatric age cohort, remains problematic. Acute pain models used for drug treatment trials in adults are not directly applicable to the pediatric age cohorts-neonates, infants, toddlers, children, and adolescents. Developmental maturation of metabolic enzymes in infants and children must be taken into consideration when designing trials to test analgesic treatments for acute pain. Assessment tools based on the levels of cognitive maturation and behavioral repertoire must be selected as outcome measures. Models and designs of clinical trials of analgesic medications used in the treatment of acute pain in neonates, infants, toddlers, children, and adolescents were reviewed and discussed at an Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) Pediatric Pain Research Consortium consensus meeting. Based on extensive reviews and continuing discussions, the authors recommend a number of acute pain clinical trial models and design attributes that have the potential to improve the study of analgesic medications in pediatric populations. Recommendations are also provided regarding additional research needed to support the use of other acute pain models across pediatric age cohorts.

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Conflict of interest statement

The views expressed in this article are those of the authors, none of whom have financial conflicts of interest related to the specific issues discussed in this article. ACTTION has received research contracts, grants, or other revenue from the FDA, multiple pharmaceutical and device companies, philanthropy, and other sources. At the time of the consensus meeting on which this article is based, 2 of the authors were employed by companies that provided unrestricted grants to the University of Rochester Office of Continuing Professional Education to support the activities of ACTTION, including the consensus meeting; these companies were Collegium Pharmaceutical, Inc. and Purdue Pharma, LP.

Figures

**Figure 1**
Acute Pain Analgesic Trial Design Considerations: ACTTION Recommendations

See this image and copyright information in PMC

References

1. Adlard K. Examining the push-pull method of blood sampling from central venous access devices. J Pediatr Oncol Nurs. 2008;25:200–207. - PubMed
1. Allegaert K, Vanhaesebrouck S, Verbesselt R, van den Anker JN. In vivo glucuronidation activity of drugs in neonates: Extensive interindividual variability despite their young age. Ther Drug Monit. 2009;31:411–415. - PubMed
1. Anand KJ. Clinical importance of pain and stress in preterm neonates. Biol Neonate. 1998;73:1–9. - PubMed
1. Anand KJ, Aranda JV, Berde CB, Buckman S, Capparelli EV, Carlo W, Hummel P, Johnston CC, Lantos J, Tutag-Lehr V, Lynn AM, Maxwell LG, Oberlander TF, Raju TN, Soriano SG, Taddio A, Walco GA. Summary proceedings from the Neonatal Pain-Control Group. Pediatrics. 2006;117(Suppl 1):S9–S22. - PubMed
1. Anand KJ, Hall RW, Desai N, Shephard B, Bergqvist LL, Young TE, Boyle EM, Carbajal R, Bhutani VK, Moore MB, Kronsberg SS, Barton BA, NEOPAIN Trial Investigators Group Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet. 2004;363:1673–1682. - PubMed

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Clinical trial designs and models for analgesic medications for acute pain in neonates, infants, toddlers, children, and adolescents: ACTTION recommendations

Affiliations

Clinical trial designs and models for analgesic medications for acute pain in neonates, infants, toddlers, children, and adolescents: ACTTION recommendations

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical