Abstract
We report a systematic review and meta-analysis of research using animal models of chemotherapy-induced peripheral neuropathy (CIPN). We systematically searched 5 online databases in September 2012 and updated the search in November 2015 using machine learning and text mining to reduce the screening for inclusion workload and improve accuracy. For each comparison, we calculated a standardised mean difference (SMD) effect size, and then combined effects in a random-effects meta-analysis. We assessed the impact of study design factors and reporting of measures to reduce risks of bias. We present power analyses for the most frequently reported behavioural tests; 337 publications were included. Most studies (84%) used male animals only. The most frequently reported outcome measure was evoked limb withdrawal in response to mechanical monofilaments. There was modest reporting of measures to reduce risks of bias. The number of animals required to obtain 80% power with a significance level of 0.05 varied substantially across behavioural tests. In this comprehensive summary of the use of animal models of CIPN, we have identified areas in which the value of preclinical CIPN studies might be increased. Using both sexes of animals in the modelling of CIPN, ensuring that outcome measures align with those most relevant in the clinic, and the animal’s pain contextualised ethology will likely improve external validity. Measures to reduce risk of bias should be employed to increase the internal validity of studies. Different outcome measures have different statistical power, and this can refine our approaches in the modelling of CIPN.
Highlights
Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of many frequently used and effective cancer chemotherapeutic agents and is known to impair daily function and diminish quality of life [1]
Our aim is to provide a systematic overview of research in the field of in vivo animal modelling of chemotherapy-induced peripheral neuropathy (CIPN), with a focus on the reporting of pain-related behavioural outcome measures, to provide useful information for preclinical researchers wishing to improve the design of experiments and refine the in vivo modelling of painful neuropathy
In the updated search (November 2015), we identified a further 11,880 publications
Summary
Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of many frequently used and effective cancer chemotherapeutic agents and is known to impair daily function and diminish quality of life [1]. Used chemotherapeutic agents reported to cause neurotoxic effects include platinum derivatives, taxanes [2], vinca alkaloids, epothilones, and newer agents (e.g., thalidomide and bortezomib) [3]. Symptoms of sensory disturbance reported by patients include paraesthesiae, numbness or tingling, and, less frequently, pain and cold allodynia [4]. The acute form is a chemotherapy dose-related, and often dose-limiting, polyneuropathy, which in many cases resolves in patients once the chemotherapy ceases. In some patients, this will persist, with other patients only developing symptoms after treatment has finished. A chronic, often painful, distal sensory neuropathy is still present in 33% of patients 1 year after completion of treatment [5]. No preventive or curative disease modifying treatments exist, and there is a pressing need for more effective treatments [6]
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