Grimace scale, burrowing, and nest building for the assessment of post-surgical pain in mice and rats-A systematic review

Abstract

Several studies suggested an informative value of behavioral and grimace scale parameters for the detection of pain. However, the robustness and reliability of the parameters as well as the current extent of implementation are still largely unknown. In this study, we aimed to systematically analyze the current evidence-base of grimace scale, burrowing, and nest building for the assessment of post-surgical pain in mice and rats. The following platforms were searched for relevant articles: PubMed, Embase via Ovid, and Web of Science. Only full peer-reviewed studies that describe the grimace scale, burrowing, and/or nest building as pain parameters in the post-surgical phase in mice and/or rats were included. Information about the study design, animal characteristics, intervention characteristics, and outcome measures was extracted from identified publications. In total, 74 papers were included in this review. The majority of studies have been conducted in young adult C57BL/6J mice and Sprague Dawley and Wistar rats. While there is an apparent lack of information about young animals, some studies that analyzed the grimace scale in aged rats were identified. The majority of studies focused on laparotomy-associated pain. Only limited information is available about other types of surgical interventions. While an impact of surgery and an influence of analgesia were rather consistently reported in studies focusing on grimace scales, the number of studies that assessed respective effects was rather low for nest building and burrowing. Moreover, controversial findings were evident for the impact of analgesics on post-surgical nest building activity. Regarding analgesia, a monotherapeutic approach was identified in the vast majority of studies with non-steroidal anti-inflammatory (NSAID) drugs and opioids being most commonly used. In conclusion, most evidence exists for grimace scales, which were more frequently used to assess post-surgical pain in rodents than the other behavioral parameters. However, our findings also point to relevant knowledge gaps concerning the post-surgical application in different strains, age levels, and following different surgical procedures. Future efforts are also necessary to directly compare the sensitivity and robustness of different readout parameters applied for the assessment of nest building and burrowing activities.

Keywords: MGS; RGS; facial expression; home cage behavior; pain assessment; rodents.

Figure 1

Study selection.

Figure 2

Study characteristics, animal characteristics, and intervention characteristics for Mouse Grimace Scale (k = 18 studies) and Rat Grimace Scale (k = 29 studies). (A,B) Number of published studies using grimace scale for the assessment of post-surgical pain in mice (A) and rats (B) during the last decade. X-axis represents years. (C,E) Number of grimace scale studies in mice (C) and rats (E) using females, males, and both sexes. (D,F) Scored action units (AUs) in mice (D) and rats (F). All but whisker: all AUs were scored except of whisker change. Eyes, ears: narrowing of the eyes and ears changes were evaluated. (G,H) Type of intervention in mice (G) and rats (H). (I,K) Studies describing within-subject comparison in mice (I) and rats (K). The within-subject comparison revealed an influence of the surgical intervention in all mouse and all rat studies. (J,L) Studies describing between-subject comparison in mice (J) and rats (L). (M,N) Studies describing an analysis of the impact of an analgetic drug on MGS (M) or RGS (N) in comparison with a control group. The analysis revealed an influence in all rat studies.

Figure 3

Study characteristics, animal characteristics, intervention characteristics, and outcome characteristics for nest building in mice (k = 20 studies). (A) Number of published studies using nest building for the assessment of post-surgical pain in mice during the last decade. X-axis represents years. (B) Number of included nest building studies using females, males, and both sexes. (C) Type of intervention in mice. (D) Used nest building material in mice. (E) Reported nest building parameters in mice. (F) Studies describing within-subject comparison in mice. The within-subject comparison revealed an influence of the surgical intervention in all studies. (G) Studies describing between-subject comparison in mice. (H) Studies describing an analysis of the impact of an analgetic drug in comparison with a control group.

Figure 4

Study characteristics, animal characteristics, and intervention characteristics for burrowing in mice (k = 10 studies) and rats (k = 7 studies). (A,B) Number of published studies using burrowing for the assessment of post-surgical-pain in mice (A) and rats (B) during the last decade. X-axis represents years. (C,E) Number of burrowing studies in mice (C) and rats (E) using females, males, and both sexes. (D,F) Used burrowing material in mice (D) and rats (F). (G,H) Type of intervention in mice (G) and rats (H). (I,J) Reported burrowing parameter in mice (I) and rats (J). (K,M) Studies describing within-subject comparison in mice (K) and rats (M). The within-subject comparison revealed an influence of the surgical intervention in all mouse and all rat studies. (L,N) Studies describing between-subject comparison in mice (L) and rats (N). The between-subject comparison revealed an influence of the surgical intervention in all mouse studies. (O,P) Studies describing an analysis of the impact of an analgetic drug in comparison with a control group in mice (O) and rats (P). The analysis revealed an influence in all rat studies.

Figure 5

Type of analgesia in mice (k = 39 studies) and rats (k = 36 studies) combined for grimace, nest building and burrowing. (A) Type of analgesia used in mice. (B) Type of analgesia used in rats.

Figure 6

Risk of bias assessment for grimace scale (A), nest building (B), and burrowing (C). Mice and rats were pooled together per pain parameter. YES, scored a low risk of bias; NO, scored a high risk of bias; UNCLEAR, scored an unclear risk of bias; NA, not applicable; RoB item was not applicable as only one group was used in the study.