Uncontrolled pain: a call for better study design

Abstract

Studies assessing animal pain in veterinary research are often performed primarily for the benefit of animals. Frequently, the goal of these studies is to determine whether the analgesic effect of a novel treatment is clinically meaningful, and therefore has the capacity to improve the welfare of treated animals. To determine the treatment effect of a potential analgesic, control groups are necessary to allow comparison. There are negative control groups (where pain is unattenuated) and positive control groups (where pain is attenuated). Arising out of animal welfare concerns, there is growing reluctance to use negative control groups in pain studies. But for studies where pain is experimentally induced, the absence of a negative control group removes the opportunity to demonstrate that the study methods could differentiate a positive control intervention from doing nothing at all. For studies that are controlled by a single comparison group, the capacity to distinguish treatment effects from experimental noise is more difficult; especially considering that pain studies often involve small sample sizes, small and variable treatment effects, systematic error and use pain assessment measures that are unreliable. Due to these limitations, and with a focus on farm animals, we argue that many pain studies would be enhanced by the simultaneous inclusion of positive and negative control groups. This would help provide study-specific definitions of pain and pain attenuation, thereby permitting more reliable estimates of treatment effects. Adoption of our suggested refinements could improve animal welfare outcomes for millions of animals globally.

Keywords: analgesia; animal ethics; farm animals; randomized controlled trials; study design.

Figure 1

Pain studies may experimentally-induce pain or utilize pain that is already present. Examples or categories of each pain source are provided in italic font.

Figure 2

(A–D) Interpretations for hypothetical scenarios where the outcome measure of pain in the experimental group (represented as arrows to reflect confidence intervals) exceeds, is no different, or is below the confidence interval of the outcome measure of pain in the control group(s). Interpretations are included in grey text boxes that overlay each plot and are made in the context of whether the study has a negative control group only (plot A), a positive control group only (B), negative and positive control groups that have non-overlapping results (C), or negative and positive control groups with results that overlap (D). The confidence intervals are assumed to be constructed such if they do not overlap then this indicates a statistically significant difference.