Systematic review and meta-analysis of studies in which burrowing behaviour was assessed in rodent models of disease-associated persistent pain

Abstract

Burrowing behaviour is used to assess pain-associated behaviour in laboratory rodents. To gain insight into how models of diseaseassociated persistent pain and analgesics affect burrowing behaviour, we performed a systematic review and meta-analysis of studies that assessed burrowing behaviour. A systematic search in March 2020 and update in September 2020 was conducted in 4 databases. Study design characteristics and experimental data were extracted, followed by a random-effects meta-analysis. We explored the association between burrowing and monofilament-induced limb withdrawal. Dose response relationship was investigated for some analgesics. Forty-five studies were included in the meta-analysis, in which 16 model types and 14 drug classes were used. Most experiments used rat (79%) and male (72%) animals. Somatic inflammation and trauma-induced neuropathy models were associated with reduced burrowing behaviour. Analgesics (nonsteroidal anti-inflammatory drug and gabapentinoids) attenuated burrowing deficits in these models. Reporting of measures to reduce risk of bias was unclear except for randomisation which was high. There was not a correlation (R 2 5 0.1421) between burrowing and monofilament-induced limb withdrawal. Opioids, gabapentin, and naproxen showed reduced burrowing behaviour at high doses, whereas ibuprofen and celecoxib showed opposite trend. The findings indicate that burrowing could be used to assess pain-associated behaviour. We support the use of a portfolio of composite measures including spontaneous and stimulus-evoked tests. The information collected here could help in designing experiments involving burrowing assessment in models of disease-associated pain.

Improving Preclinical Development of Novel Interventions to Treat Pain: Insanity Is Doing the Same Thing Over and Over and Expecting Different Results

“…Because of these limitations of reflexive behaviors to assess pain and analgesia following interventions intended to mimic chronic pain, a variety of other methods have been explored, which reflect ethologically relevant behaviors that are impacted by inferred pain. These include burrowing, 12,21,22 thigmotaxis, [23][24][25][26][27][28] facial grimacing, 29 weight bearing, 30 gait analysis, 31 and conditioned place preference or avoidance. 32 However, these are commonly used by a small December 2022 • Volume 135 • Number 6 www.anesthesia-analgesia.org 1133 minority of laboratories and are rarely declared as primary outcomes over reflexive measures.…”

“…Systematic review and meta-analysis of preclinical studies can be a rich unbiased source of the data required to inform sample size calculations. [10][11][12][13] The use of appropriate sample sizes mitigates against the impact of underpowered studies, which have greater risks of generating false-positive results and exaggerating effect sizes. While there is an ethical imperative to use the minimal number of animals necessary in an experiment, it is also true that an underpowered experiment in which little faith can be placed in the results is equally unethical.…”

“…Systematic review and meta-analysis of experiments involving animal model experiments in pain research have clearly identified areas where rigor in internal validity must be improved in order that faith may be placed in the veracity of the results. [10][11][12][13] Although it should be again emphasized that this issue is widespread, it is by no means a unique feature of animal model-based research. For example, a systematic review of 341 publications using models of chemotherapy-induced neuropathy ascertained that only 51% of reports reported blinded assessment of outcome, 28% randomization to group, 18% animal exclusions, 2.1% the use of a sample size calculation, and just 1.5% reported allocation concealment.…”

A systematic review and meta-analysis of thigmotactic behaviour in the open field test in rodent models associated with persistent pain

“…We were also unable to ascertain differences in thigmotactic outcomes between strains because of the predominant use of Sprague-Dawley and Wistar rats and C57BL/6 mice. This issue of homogeneity in the rodent strain used for preclinical pain research has been observed in other systematic reviews [40][41][42]. Studies have shown that modification of behavioural outcomes caused by disease models associated with persistent pain is strain dependent [43][44][45].…”

“…We could not discern the influence of sex on thigmotactic outcomes because male animals were predominantly used. In other preclinical systematic reviews of pain, sex accounted for a significant proportion of the heterogeneity [40][41][42]48]. Women are clinically prone to be affected by chronic pain and tend to experience greater pain intensity than men [8].…”