Analgesic trials pose unique scientific, ethical, and practical challenges in pediatrics. Participants in a scientific workshop sponsored by the US Food and Drug Administration developed consensus on aspects of pediatric analgesic clinical trial design. The standard parallel-placebo analgesic trial design commonly used for adults has ethical and practical difficulties in pediatrics, due to the likelihood of subjects experiencing pain for extended periods of time. Immediate-rescue designs using opioid-sparing, rather than pain scores, as a primary outcome measure have been successfully used in pediatric analgesic efficacy trials. These designs maintain some of the scientific benefits of blinding, with some ethical and practical advantages over traditional designs. Preferred outcome measures were recommended for each age group. Acute pain trials are feasible for children undergoing surgery. Pharmacodynamic responses to opioids, local anesthetics, acetaminophen, and nonsteroidal antiinflammatory drugs appear substantially mature by age 2 years. There is currently no clear evidence for analgesic efficacy of acetaminophen or nonsteroidal antiinflammatory drugs in neonates or infants younger than 3 months of age. Small sample designs, including cross-over trials and N of 1 trials, for particular pediatric chronic pain conditions and for studies of pain and irritability in pediatric palliative care should be considered. Pediatric analgesic trials can be improved by using innovative study designs and outcome measures specific for children. Multicenter consortia will help to facilitate adequately powered pediatric analgesic trials.
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February 2012
Special Article|
February 01 2012
Pediatric Analgesic Clinical Trial Designs, Measures, and Extrapolation: Report of an FDA Scientific Workshop
Charles B. Berde, MD;
aDivision of Pain Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine, Children's Hospital, Boston, Boston, Massachusetts;
bHarvard Medical School, Boston, Massachusetts;
Address correspondence to Charles Berde, MD, PhD, Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Children’s Hospital, Boston, 333 Longwood Ave, 5th floor, Boston, MA 02115. E-mail: charles.berde@childrens.harvard.edu
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Gary A. Walco, PhD;
Gary A. Walco, PhD
cDepartment of Anesthesiology and Pain Medicine, Seattle Children's Hospital, Seattle, Washington;
dUniversity of Washington School of Medicine, Seattle, Washington;
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Elliot J. Krane, MD;
Elliot J. Krane, MD
eStanford University School of Medicine, Stanford, California;
fLucile Packard Children's Hospital, Stanford, California;
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K. J. S. Anand, MBBS;
K. J. S. Anand, MBBS
gDivision of Pediatric Critical Care Medicine, Le Bonheur Children's Hospital, Memphis, Tennessee;
hUniversity of Tennessee Health Science Center, Memphis, Tennessee;
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Jacob V. Aranda, MD;
Jacob V. Aranda, MD
iThe Children's Hospital of Brooklyn, State University of New York, New York, New York;
jPediatric Pharmacology Research Unit Network, Children's Hospital of Michigan, Detroit, Michigan;
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Kenneth D. Craig, PhD;
Kenneth D. Craig, PhD
kDepartment of Psychology, University of British Columbia, Vancouver, British Columbia, Canada;
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Carlton D. Dampier, MD;
Carlton D. Dampier, MD
lEmory University School of Medicine, Atlanta, Georgia;
mAtlanta Clinical Translational Science Institute, Atlanta, Georgia;
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Julia C. Finkel, MD;
Julia C. Finkel, MD
nDepartment of Anesthesiology George Washington University, Washington, District of Columbia;
oDivision of Anesthesiology and Pain Medicine, Children's National Medical Center, Washington, District of Columbia;
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Martin Grabois, MD;
Martin Grabois, MD
pBaylor College of Medicine, Houston, Texas;
qUniversity of Texas Health Science Center-Houston, Houston, Texas;
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Celeste Johnston, RN;
Celeste Johnston, RN
rSchool of Nursing, McGill University, Montreal, Canada;
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John Lantos, MD;
John Lantos, MD
sChildren's Mercy Bioethics Center, Children's Mercy Hospital, Kansas City, Missouri;
tUniversity of Missouri–Kansas City, Kansas City, Missouri
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Alyssa Lebel, MD;
Alyssa Lebel, MD
aDivision of Pain Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine, Children's Hospital, Boston, Boston, Massachusetts;
bHarvard Medical School, Boston, Massachusetts;
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Lynne G. Maxwell, MD;
Lynne G. Maxwell, MD
uDepartment of Anesthesiology and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;
vDepartment of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania;
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Patrick McGrath, OC;
Patrick McGrath, OC
wIWK Health Centre, Halifax, Nova Scotia, Canada;
xDalhousie University, Halifax, Nova Scotia, Canada;
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Timothy F. Oberlander, MD;
Timothy F. Oberlander, MD
yDivision of Developmental Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada;
zBC Children's Hospital, Vancouver, British Columbia, Canada;
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Laura E. Schanberg, MD;
Laura E. Schanberg, MD
aaDuke University Medical Center, Durham, North Carolina;
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Bonnie Stevens, RN;
Bonnie Stevens, RN
bbThe Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;
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Anna Taddio, BScPhm;
Anna Taddio, BScPhm
bbThe Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;
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Carl L. von Baeyer, PhD;
Carl L. von Baeyer, PhD
ccDepartment of Psychology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada;
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Myron Yaster, MD;
Myron Yaster, MD
ddDivision of Pediatric Anesthesiology, Department of Anesthesiology and Critical Care Medicine, Children's Medical and Surgical Center, The Johns Hopkins Hospital, Baltimore, Maryland; and
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William T. Zempsky, MD
William T. Zempsky, MD
eeDivision of Pain and Palliative Medicine, Connecticut Children's Medical Center, University of Connecticut School of Medicine, Hartford, Connecticut
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Address correspondence to Charles Berde, MD, PhD, Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Children’s Hospital, Boston, 333 Longwood Ave, 5th floor, Boston, MA 02115. E-mail: charles.berde@childrens.harvard.edu
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
Pediatrics (2012) 129 (2): 354–364.
Article history
Accepted:
October 26 2011
Citation
Charles B. Berde, Gary A. Walco, Elliot J. Krane, K. J. S. Anand, Jacob V. Aranda, Kenneth D. Craig, Carlton D. Dampier, Julia C. Finkel, Martin Grabois, Celeste Johnston, John Lantos, Alyssa Lebel, Lynne G. Maxwell, Patrick McGrath, Timothy F. Oberlander, Laura E. Schanberg, Bonnie Stevens, Anna Taddio, Carl L. von Baeyer, Myron Yaster, William T. Zempsky; Pediatric Analgesic Clinical Trial Designs, Measures, and Extrapolation: Report of an FDA Scientific Workshop. Pediatrics February 2012; 129 (2): 354–364. 10.1542/peds.2010-3591
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