Immediate rescue designs in pediatric analgesic trials: a systematic review and meta-analysis

Abstract

Background: Designing analgesic clinical trials in pediatrics requires a balance between scientific, ethical, and practical concerns. A previous consensus group recommended immediate rescue designs using opioid sparing as a surrogate measure of analgesic efficacy. The authors summarize the performance of rescue analgesic designs in pediatric trials of four commonly used classes of analgesics: opioids, nonsteroidal antiinflammatory drugs, acetaminophen, and local anesthetics.

Methods: MEDLINE, Embase, CINAHL, The Cochrane Library, and Web of science were searched in April 2013. The 85 studies selected were randomized or controlled clinical trials using immediate rescue paradigms in postoperative pain settings. A random-effects meta-analysis was used to synthesize predefined outcomes using Hedges' g. Difference between the means of the treatment arms were also expressed as a percentage of the corresponding value in the placebo group (placebo-treatment/placebo). Distributions of pain scores in study and control groups and relationships between opioid sparing and pain scores were examined.

Results: For each of the four study drug classes, significant opioid sparing was demonstrated in a majority of studies by one or more of the following endpoints: (1) total dose (milligram per kilogram per hour), (2) percentage of children requiring rescue medication, and (3) time to first rescue medication (minutes). Pain scores averaged 2.4/10 in study groups, 3.4/10 in control groups.

Conclusions: Opioid sparing is a feasible pragmatic endpoint for pediatric pain analgesic trials. This review serves to guide future research in pediatric analgesia trials, which could test whether some specific design features may improve assay sensitivity while minimizing the risk of unrelieved pain.

Figure 1

A. Typical time course of pain scores for a double-blind, parallel-group, placebo-controlled, active comparator analgesic trial. Note that in general, requirement for rescue analgesia result in termination of pain score in for that subject. B. Idealized time course of hourly rescue dosing of a short – acting opioid. C. Idealized time course of the pain. Note that, depending on the dosing schedule for rescue analgesics, in some trials of this design, pain scores remain lower in the active group than in the placebo group. VAS – Visual analog scale. (Taken from Berde et al. 2012, with permission).

Figure 2

Flow chart of literature search with summary of excluded and included studies.

Figure 3

Forest plot for opioids as study drug. Expressed as Hedges’ G score and 95% Confidence Intervals. Negative scores favors study drug over control. *Study included more than one active treatment arm.

Figure 4

Forest plot for nonsteroidal anti-inflammatory drugs as study drug. Expressed as Hedges’ G score and 95% Confidence Intervals. Negative scores favors study drug over control. *Study included more than one active treatment arm.

Figure 5

Forest plot for acetaminophen as study drug. Expressed as Hedges’ G score and 95% Confidence Intervals. Negative scores favors study drug over control. *Study included more than one active treatment arm.

Figure 6

Forest plot for local anesthetics as study drug. Expressed as Hedges’ G score and 95% Confidence Intervals. Negative scores favors study drug over control. *Study included more than one active treatment arm.

Figure 7

Efficacy – Burden relationship for nonsteroidal anti-inflammatory drugs as the study drug. A. Rescue opioid usage (mg/kg/h) as the outcome. B. Percentage requiring rescue medication as the outcome. C. Time to first rescue medication (minutes) as the outcome. Opioid Sparing: placebo— study/placebo.

Figure 8

Nonsteroidal antiinflammatory drugs as the study drug. A. Rescue opioid usage (mg/kg/h) as the outcome. B. Percentage requiring rescue medication as the outcome. C. Time to first rescue medication (minutes) as the outcome. Colorless circles indicate studies without pain scores.

Figure 9

Efficacy – Burden relationship for local anesthetics as the study drug. A. Rescue opioid usage (mg/kg/h) as the outcome. B. Percentage requiring rescue medication as the outcome. C. Time to first rescue medication (minutes) as the outcome. Opioid Sparing: placebo—study/placebo.

Figure 10

Local anesthetics as the study drug. A. Rescue opioid usage (mg/kg/h) as the outcome. B. Percentage requiring rescue medication as the outcome. C. Time to first rescue medication (minutes) as the outcome. Colorless circles indicate studies without pain scores.