The secondary outcome was the effect of local protocol variations on burrowing behaviour. Because of the nature of the study design, no statistical hypothesis testing was performed, and data are presented as observational findings only with descriptive statistics. Observations were made including all animals allocated to a treatment group (TP population), focusing on the 24-hour time point at which burrowing deficits were most pronounced. Data summarising burrowing behaviour at all time points by protocol variation can be found in the supplemental material (Supplemental digital content 3, http://links.lww.com/PAIN/A304). There seemed to be no strain difference between Wistar and Sprague-Dawley rats, but there was a tendency towards a more prominent CFA-associated burrowing deficit in animals of lower body weight. Burrowing deficits after CFA injection were also more noticeable when a substrate of smaller size was used (Fig. 6). An increased number of training sessions negatively affected burrowing behaviour in naive animals. In addition, when a larger amount of substrate was provided, the burrowing deficit was more pronounced. The sex of the experimenter also might have affected burrowing behaviour; increased burrowing behaviour was observed with a male experimenter in naive animals, whereas in contrast, a more pronounced burrowing deficit was present in CFA animals with a male experimenter (Supplemental digital content 4, http://links.lww.com/PAIN/A305). It should be noted that because the study was not designed to identify variables that affect burrowing outcome, confounding factors were identified, and observational data should be interpreted cautiously. In particular, animals were unevenly distributed across groups. An n = 4 was recorded for the naive group that underwent 3 training sessions and for the naive group that was tested by a male experimenter. Furthermore, sand as the burrowing substrate and provision of 2000 g of the substrate was only reported by one centre in one study each.
A prospective preclinical multicentre study across 8 laboratories assessed the reliability of CFA-associated suppressed burrowing in rats. Overall, reduced burrowing was partially replicated at 6 of the 8 participating centres with an element of variability between and within centres. The prospective multicentre approach was important in that it enabled the evaluation of variability of suppressed burrowing, and it could prove important for future studies aiming to identify the factors underlying such variability.
We showed prominent CFA-associated suppressed burrowing in 7 of 11 studies. Consistent with our results, CFA-associated suppression of behaviour previously has been shown in feeding behaviours,31,33,36 locomotion,21,30 and operant behaviours.18,69 Analysis of the combined data demonstrated that burrowing deficits peaked 24 hours after CFA injection, although with high variability between individual studies, but some studies show no suppression of burrowing. Notably, the original sample size calculation was based on a pilot study with a large effect size; however, across centres, burrowing deficits ranged from 1570 to 273 g. Therefore, some studies were underpowered using the originally estimated sample size. This could result in a reduced chance to detect a true effect. We have calculated sample size recommendations for a range of mean differences and SD (Supplemental digital content 5, http://links.lww.com/PAIN/A306) to provide guidance for future studies. Increasing the sample size of underpowered studies would result in a more accurate estimated effect size and could reduce variability within studies. Group allocation, time of assessment, laboratory ID, group-by-time interaction, and baseline burrowing-by-time interaction all significantly contributed to the heterogeneity across studies. Adjustment for laboratory ID showed a change from baseline similar to data without adjustment, demonstrating that suppression of burrowing is robust across laboratories, despite the variability in the effect size.
We also observed effects of local protocol variations on burrowing behaviour. No statistical analyses were performed on these observations, as the study was not designed to formally detect such effects. Confounding factors such as uneven distribution of animals across groups and variables reported only by one centre should be considered when interpreting the data. Observations made were reported both for transparency and to identify variability factors in burrowing behaviour meriting future study. Although strain differences have been reported for other outcome measures,8,42,63 in this study, no strain differences between Sprague-Dawley and Wistar rats were observed for suppressed burrowing. Animals with a lower body weight developed an increased burrowing deficit, whereas burrowing in sham or naive groups was unaffected. As all animals received the same volume and concentration of CFA, it may be that smaller animals received relatively more CFA per paw mass, resulting in a more severe inflammatory response leading to a larger burrowing deficit. The suppression of burrowing observed with a smaller amount of provided substrate is most likely due to the reduced amount of substrate available. In naive animals, we observed an increased burrowing deficit with male experimenters as compared with female experimenters or mixed experimenter teams. Because a male experimenter was only reported by one centre and only 4 rats were in this group, this result may be due to chance or a centre-specific effect. A study in mice showed that the experimenter's sex affects pain outcome measures in mice.67 Further studies are required to verify whether burrowing behaviour in rats is also affected by the experimenter's sex. Additional studies would be required to assess the impact of the substrate size and number of training sessions on burrowing, specifically whether a small sized substrate is superior to larger sized substrate and whether an increased number of training sessions reduces burrowing behaviour.
To assess the effect of excluding “poor” burrowers, we analysed the TP (all animals allocated to treatment groups) and an SP (all allocated animals that burrowed above 500 g at baseline), an approach adapted from the intention-to-treat and per-protocol analyses used in clinical trials.22 In both populations, the pattern of suppressed burrowing was comparable, which suggests that suppressed burrowing is a robust measure. Therefore, we recommend not to exclude “poor” burrowers. Excluding animals would increase variability, resulting in a less accurate effect size estimates. Exclusions could also result in attrition bias, an issue particularly important for studies using relatively small sample sizes.1,13,24
Adding nonevoked ethologically relevant outcome measures to assess the global impact of pain previously has been suggested as a potential means to improve translation.49,56,68,75 Development and validation of these measures is of key relevance, particularly as spontaneous pain, functioning, and quality of life are primary outcome measures in clinical trials. Suppression of burrowing reflects the global impact of purportedly pain-induced reduction of general “well-being”.27–29,74 Although suppressed burrowing is not a pain-specific test, treatment with known analgesics has been shown to attenuate decreased burrowing behaviour in various pain models, suggesting a pain-specific component.2,9,35,61,62 A limitation of our study was the lack of an independent validation of suppressed burrowing as indicative of a pain-specific outcome measure; it will be crucial to address the interdependence of this connection in future studies. Correlation with other nonevoked pain-related outcomes would be essential, particularly as a lack of correlation has been shown between burrowing performance and evoked mechanosensory thresholds in a neuropathic pain rat model,35 which suggests that suppressed burrowing may reflect a pain component not directly linked to sensory gain. Furthermore, pharmacological validation studies should be conducted, preferably informed by robust meta-analyses of clinical trials to guide both drug and dose selection.17,53 First, it should be demonstrated to what extent clinically efficacious drugs reverse suppression of burrowing. In the CFA model, ibuprofen has been shown to reverse suppressed burrowing, whereas gabapentin, which has a large body of evidence supporting efficacy in neuropathic, but not inflammatory, pain, is appropriately inefficacious,2,20,62 suggesting good pharmacologic sensitivity of suppressed burrowing. Second, compounds such as neurokinin 1 antagonists and cannabinoid 2 receptor agonists that have been shown to be efficacious in animal pain models measuring evoked endpoints but have failed in clinical trials48,65,75 should be tested to assess the degree of pain specificity of burrowing.
We chose the CFA model, as we expected a high likelihood of ongoing spontaneous pain.19,46,47 To validate suppressed burrowing as a pain-relevant outcome measure for neuropathic pain conditions, burrowing behaviour should be measured in a range of models. An important aspect of modelling neuropathic pain is gender generalizability. Animal studies use mainly male rodents, whereas clinical trials enrol both sexes.7 Importantly, sex differences in behavioural responses have been shown in rodents.15,42,66 As the primary interest of our study was to evaluate burrowing across centres and not establish the model's predictive validity as a pain outcome measure, only male rats were used. However, future validation studies should include female rats.
A multicentre approach for preclinical studies is very novel. Similar to clinical multicentre trials, the study design should be of a high standard, and results should be reported transparently. In this study, all participating centres followed a basic protocol that was previously reviewed and agreed upon by all parties; however, minor changes were permitted to pragmatically accommodate for local variations in laboratory practice and procedures. No detailed specifications were given regarding the scope of these changes, inevitably resulting in some degree of uncontrolled heterogeneity between studies. An external review of the protocol could have identified this issue before study start. Variations were also reported concerning bias reduction procedures. Although guidance on Good Laboratory Practice was given, there was variability between centres as to the extent to which such practice was followed, most notably as a result of constraints imposed by established local procedures. Future preclinical multicentre studies should not only provide Good Laboratory Practice training and validation but also establish an independent central monitor, similar to phase III clinical trials, to ensure protocol compliance and bias reduction.6 It should be noted that despite following bias reduction procedures, because of CFA-induced paw oedema, allocation concealment and blinding could not be maintained in all studies, potentially resulting in an overestimation of the effect size.12,13,64 As it was not possible to control for all model-specific factors, it is crucial to report data as transparently as possible to clearly highlight study limitations related to internal validity issues. In clinical trials, the near-universal implementation of the CONSORT reporting guidelines has noticeably improved reporting rigour and transparency.70 Although ARRIVE guidelines32,43 and other recommendations34,55,69 provide a similar framework for preclinical studies, they are not yet as well established as CONSORT4,32; however, a similar positive impact on preclinical studies is expected as these guidelines achieve broader acceptance and implementation. In this study, we reported according to ARRIVE guidelines and presented the data as transparently as possible. Recommendations for future studies, based on our practical experience, are summarised in Table 7. An audio abstract of this study is available in the supplemental material (Supplemental digital content 7, Audio, http://links.lww.com/PAIN/A310.)
In conclusion, our approach demonstrates how implementation of a multicentre study design to evaluate novel preclinical outcome measures can yield robust data and can help accelerate the validation of outcome measures, pain models, and pharmacological interventions. This hopefully may help inform the design and conduct of similar future multicentre studies.
The following authors are/were employees of the following companies at the time this study was undertaken: R. Wodarski, M. Ligocki, D. Li, and J. D. Kennedy: employees of Eli Lilly and Company; C. Ultenius and C. Stenfors: employees of Astra Zeneca; L. A. Bryden and A. Pekcec: employees of Boehringer Ingelheim; T. Christoph, A. Robens, and K. Rutten: employees of Grünenthal; K. Uto, S. Koyama, and K. Yamamoto: employees of Asahi Kasei; A. Lindsten and M. Segerdahl: employees of Lundbeck. Imperial College London: A. S.C. Rice also received research funding from Pfizer and Astellas. Heidelberg University: R.-D. Treede also received research funding from AbbVie, Astellas, and Boehringer Ingelheim. The other authors have no conflicts of interest to declare.
Joint first authors: R. Wodarski, A. Delaney, C. Ultenius, and R. Morland; Joint senior authors: K. Rutten and A. Rice.
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.
Supplemental Digital Content
Supplemental Digital Content associated with this article can be found online at http://links.lww.com/PAIN/A302, http://links.lww.com/PAIN/A303, http://links.lww.com/PAIN/A304, http://links.lww.com/PAIN/A305, http://links.lww.com/PAIN/A306, http://links.lww.com/PAIN/A307.
A supplemental video accompanying this article can be found online at http://links.lww.com/PAIN/A310.
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