Exploring the Interplay between Rescue Drugs, Data Imputation, and Study Outcomes: Conceptual Review and Qualitative Analysis of an Acute Pain Data Set

Abstract

In placebo-controlled acute surgical pain studies, provisions must be made for study subjects to receive adequate analgesic therapy. As such, most protocols allow study subjects to receive a pre-specified regimen of open-label analgesic drugs (rescue drugs) as needed. The selection of an appropriate rescue regimen is a critical experimental design choice. We hypothesized that a rescue regimen that is too liberal could lead to all study arms receiving similar levels of pain relief (thereby confounding experimental results), while a regimen that is too stringent could lead to a high subject dropout rate (giving rise to a preponderance of missing data). Despite the importance of rescue regimen as a study design feature, there exist no published review articles or meta-analysis focusing on the impact of rescue therapy on experimental outcomes. Therefore, when selecting a rescue regimen, researchers must rely on clinical factors (what analgesics do patients usually receive in similar surgical scenarios) and/or anecdotal evidence. In the following article, we attempt to bridge this gap by reviewing and discussing the experimental impacts of rescue therapy on a common acute surgical pain population: first metatarsal bunionectomy. The function of this analysis is to (1) create a framework for discussion and future exploration of rescue as a methodological study design feature, (2) discuss the interplay between data imputation techniques and rescue drugs, and (3) inform the readership regarding the impact of data imputation techniques on the validity of study conclusions. Our findings indicate that liberal rescue may degrade assay sensitivity, while stringent rescue may lead to unacceptably high dropout rates.

Keywords: Acute pain; Analgesia; Bunionectomy; Clinical trial design; Clinical trials; Data imputation; Missing data; Pain; Post-surgical pain; Postoperative pain; Rescue medication.

Fig. 1

Hypothetical data set illustrating different data imputation methods and their effects on SPID48 values. SPID48 summed pain intensity difference over 48 h after first dose of study medication

Fig. 2

Differential impacts of rescue drug potency on placebo vs. treatment study arm. mg milligram, SPID48 summed pain intensity difference in 48 h following first dose of study drug

Fig. 3

Balancing the amount and frequency of rescue medication is crucial in experimental design

Fig. 4

Comparison of SPID48 values [mean ± standard error (SE)] using no imputation or windowed imputation techniques. Data sets from five of seven articles included in this analysis; two remaining manuscripts did not provide windowed imputation data to allow for comparisons. Altman [1] and Jensen [41] used windowed baseline observation carried forward (6 h); Altman [14], Singla [31], and Singla [32] used windowed last observation carried forward (6 h). SPID48 summed pain intensity difference in 48 h following first dose of study drug