Cross-centre replication of suppressed burrowing behaviour as an ethologically relevant pain outcome measure in the rat: a prospective multicentre study

Rachel Wodarski, Ada Delaney, Camilla Ultenius, Rosie Morland, Nick Andrews, Catherine Baastrup, Luke A. Bryden, Ombretta Caspani, Thomas Christoph, Natalie J. Gardiner, Wenlong Huang, Jeffrey D. Kennedy, Suguru Koyama, Dominic Li, Marcin Ligocki, Annika Lindsten, Ian Machin, Anton Pekcec, Angela Robens, Sanziana M. Rotariu & 9 others Sabrina Voß, Marta Segerdahl, Carina Stenfors, Camilla I. Svensson, Rolf-Detlef Treede, Katsuhiro Uto, Kazumi Yamamoto, Kris Rutten, Andrew S. C. Rice

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Abstract

Burrowing, an ethologically relevant rodent behaviour, has been proposed as a novel outcome measure to assess the global impact of pain in rats. In a prospective multicentre study using male rats (Wistar, Sprague-Dawley), replication of suppressed burrowing behaviour in the complete Freund adjuvant (CFA)-induced model of inflammatory pain (unilateral, 1 mg/mL in 100 µL) was evaluated in 11 studies across 8 centres. Following a standard protocol, data from participating centres were collected centrally and analysed with a restricted maximum likelihood-based mixed model for repeated measures. The total population (TP-all animals allocated to treatment; n = 249) and a selected population (SP-TP animals burrowing over 500 g at baseline; n = 200) were analysed separately, assessing the effect of excluding "poor" burrowers. Mean baseline burrowing across studies was 1113 g (95% confidence interval: 1041-1185 g) for TP and 1329 g (1271-1387 g) for SP. Burrowing was significantly suppressed in the majority of studies 24 hours (7 studies/population) and 48 hours (7 TP, 6 SP) after CFA injections. Across all centres, significantly suppressed burrowing peaked 24 hours after CFA injections, with a burrowing deficit of -374 g (-479 to -269 g) for TP and -498 g (-609 to -386 g) for SP. This unique multicentre approach first provided high-quality evidence evaluating suppressed burrowing as robust and reproducible, supporting its use as tool to infer the global effect of pain on rodents. Second, our approach provided important informative value for the use of multicentre studies in the future.

Original languageEnglish
Pages (from-to)2350-2365
Number of pages16
JournalPain
Volume157
Issue number10
DOIs
Publication statusPublished - Oct 2016

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Freund's Adjuvant
Multicenter Studies
Outcome Assessment (Health Care)
Prospective Studies
TP 7
Pain
Rodentia
Population
Injections
Sprague Dawley Rats
Confidence Intervals
Therapeutics

Keywords

  • non-evoked pain
  • validation
  • reproducibility
  • preclinical controlled trials

Cite this

Cross-centre replication of suppressed burrowing behaviour as an ethologically relevant pain outcome measure in the rat : a prospective multicentre study. / Wodarski, Rachel; Delaney, Ada; Ultenius, Camilla; Morland, Rosie; Andrews, Nick; Baastrup, Catherine; Bryden, Luke A.; Caspani, Ombretta; Christoph, Thomas; Gardiner, Natalie J.; Huang, Wenlong; Kennedy, Jeffrey D.; Koyama, Suguru; Li, Dominic; Ligocki, Marcin; Lindsten, Annika; Machin, Ian; Pekcec, Anton; Robens, Angela; Rotariu, Sanziana M.; Voß, Sabrina; Segerdahl, Marta; Stenfors, Carina; Svensson, Camilla I.; Treede, Rolf-Detlef; Uto, Katsuhiro; Yamamoto, Kazumi; Rutten, Kris; Rice, Andrew S. C.

In: Pain, Vol. 157, No. 10, 10.2016, p. 2350-2365.

Research output: Contribution to journalArticle

Wodarski, R, Delaney, A, Ultenius, C, Morland, R, Andrews, N, Baastrup, C, Bryden, LA, Caspani, O, Christoph, T, Gardiner, NJ, Huang, W, Kennedy, JD, Koyama, S, Li, D, Ligocki, M, Lindsten, A, Machin, I, Pekcec, A, Robens, A, Rotariu, SM, Voß, S, Segerdahl, M, Stenfors, C, Svensson, CI, Treede, R-D, Uto, K, Yamamoto, K, Rutten, K & Rice, ASC 2016, 'Cross-centre replication of suppressed burrowing behaviour as an ethologically relevant pain outcome measure in the rat: a prospective multicentre study' Pain, vol. 157, no. 10, pp. 2350-2365. https://doi.org/10.1097/j.pain.0000000000000657
Wodarski, Rachel ; Delaney, Ada ; Ultenius, Camilla ; Morland, Rosie ; Andrews, Nick ; Baastrup, Catherine ; Bryden, Luke A. ; Caspani, Ombretta ; Christoph, Thomas ; Gardiner, Natalie J. ; Huang, Wenlong ; Kennedy, Jeffrey D. ; Koyama, Suguru ; Li, Dominic ; Ligocki, Marcin ; Lindsten, Annika ; Machin, Ian ; Pekcec, Anton ; Robens, Angela ; Rotariu, Sanziana M. ; Voß, Sabrina ; Segerdahl, Marta ; Stenfors, Carina ; Svensson, Camilla I. ; Treede, Rolf-Detlef ; Uto, Katsuhiro ; Yamamoto, Kazumi ; Rutten, Kris ; Rice, Andrew S. C. / Cross-centre replication of suppressed burrowing behaviour as an ethologically relevant pain outcome measure in the rat : a prospective multicentre study. In: Pain. 2016 ; Vol. 157, No. 10. pp. 2350-2365.
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T1 - Cross-centre replication of suppressed burrowing behaviour as an ethologically relevant pain outcome measure in the rat

T2 - a prospective multicentre study

AU - Wodarski, Rachel

AU - Delaney, Ada

AU - Ultenius, Camilla

AU - Morland, Rosie

AU - Andrews, Nick

AU - Baastrup, Catherine

AU - Bryden, Luke A.

AU - Caspani, Ombretta

AU - Christoph, Thomas

AU - Gardiner, Natalie J.

AU - Huang, Wenlong

AU - Kennedy, Jeffrey D.

AU - Koyama, Suguru

AU - Li, Dominic

AU - Ligocki, Marcin

AU - Lindsten, Annika

AU - Machin, Ian

AU - Pekcec, Anton

AU - Robens, Angela

AU - Rotariu, Sanziana M.

AU - Voß, Sabrina

AU - Segerdahl, Marta

AU - Stenfors, Carina

AU - Svensson, Camilla I.

AU - Treede, Rolf-Detlef

AU - Uto, Katsuhiro

AU - Yamamoto, Kazumi

AU - Rutten, Kris

AU - Rice, Andrew S. C.

N1 - Acknowledgements This Europain project has received support from the Innovative Medicines Initiative (IMI) Joint Undertaking (under grant agreement number 115007), resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/20072013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies in-kind contribution (see http://www.imieuropain.org/ for details). Eli Lilly and Company United Kingdom: We would like to thank Dr Gary Gilmour for his assistance in bringing forward this publication. Karolinska Institute: A. Delaney also received funding from Ulla & Gustaf af Ugglas Foundation; EU Project FP7-Health-2013-Innovation-1602919-2. Boehringer Ingelheim: We would like to thank Stacey Gould for technical assistance.

PY - 2016/10

Y1 - 2016/10

N2 - Burrowing, an ethologically relevant rodent behaviour, has been proposed as a novel outcome measure to assess the global impact of pain in rats. In a prospective multicentre study using male rats (Wistar, Sprague-Dawley), replication of suppressed burrowing behaviour in the complete Freund adjuvant (CFA)-induced model of inflammatory pain (unilateral, 1 mg/mL in 100 µL) was evaluated in 11 studies across 8 centres. Following a standard protocol, data from participating centres were collected centrally and analysed with a restricted maximum likelihood-based mixed model for repeated measures. The total population (TP-all animals allocated to treatment; n = 249) and a selected population (SP-TP animals burrowing over 500 g at baseline; n = 200) were analysed separately, assessing the effect of excluding "poor" burrowers. Mean baseline burrowing across studies was 1113 g (95% confidence interval: 1041-1185 g) for TP and 1329 g (1271-1387 g) for SP. Burrowing was significantly suppressed in the majority of studies 24 hours (7 studies/population) and 48 hours (7 TP, 6 SP) after CFA injections. Across all centres, significantly suppressed burrowing peaked 24 hours after CFA injections, with a burrowing deficit of -374 g (-479 to -269 g) for TP and -498 g (-609 to -386 g) for SP. This unique multicentre approach first provided high-quality evidence evaluating suppressed burrowing as robust and reproducible, supporting its use as tool to infer the global effect of pain on rodents. Second, our approach provided important informative value for the use of multicentre studies in the future.

AB - Burrowing, an ethologically relevant rodent behaviour, has been proposed as a novel outcome measure to assess the global impact of pain in rats. In a prospective multicentre study using male rats (Wistar, Sprague-Dawley), replication of suppressed burrowing behaviour in the complete Freund adjuvant (CFA)-induced model of inflammatory pain (unilateral, 1 mg/mL in 100 µL) was evaluated in 11 studies across 8 centres. Following a standard protocol, data from participating centres were collected centrally and analysed with a restricted maximum likelihood-based mixed model for repeated measures. The total population (TP-all animals allocated to treatment; n = 249) and a selected population (SP-TP animals burrowing over 500 g at baseline; n = 200) were analysed separately, assessing the effect of excluding "poor" burrowers. Mean baseline burrowing across studies was 1113 g (95% confidence interval: 1041-1185 g) for TP and 1329 g (1271-1387 g) for SP. Burrowing was significantly suppressed in the majority of studies 24 hours (7 studies/population) and 48 hours (7 TP, 6 SP) after CFA injections. Across all centres, significantly suppressed burrowing peaked 24 hours after CFA injections, with a burrowing deficit of -374 g (-479 to -269 g) for TP and -498 g (-609 to -386 g) for SP. This unique multicentre approach first provided high-quality evidence evaluating suppressed burrowing as robust and reproducible, supporting its use as tool to infer the global effect of pain on rodents. Second, our approach provided important informative value for the use of multicentre studies in the future.

KW - non-evoked pain

KW - validation

KW - reproducibility

KW - preclinical controlled trials

U2 - 10.1097/j.pain.0000000000000657

DO - 10.1097/j.pain.0000000000000657

M3 - Article

VL - 157

SP - 2350

EP - 2365

JO - Pain

JF - Pain

SN - 0304-3959

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ER -