Predictive validity of behavioural animal models for chronic pain

Abstract

Rodent models of chronic pain may elucidate pathophysiological mechanisms and identify potential drug targets, but whether they predict clinical efficacy of novel compounds is controversial. Several potential analgesics have failed in clinical trials, in spite of strong animal modelling support for efficacy, but there are also examples of successful modelling. Significant differences in how methods are implemented and results are reported means that a literature-based comparison between preclinical data and clinical trials will not reveal whether a particular model is generally predictive. Limited reports on negative outcomes prevents reliable estimate of specificity of any model. Animal models tend to be validated with standard analgesics and may be biased towards tractable pain mechanisms. But preclinical publications rarely contain drug exposure data, and drugs are usually given in high doses and as a single administration, which may lead to drug distribution and exposure deviating significantly from clinical conditions. The greatest challenge for predictive modelling is, however, the heterogeneity of the target patient populations, in terms of both symptoms and pharmacology, probably reflecting differences in pathophysiology. In well-controlled clinical trials, a majority of patients shows less than 50% reduction in pain. A model that responds well to current analgesics should therefore predict efficacy only in a subset of patients within a diagnostic group. It follows that successful translation requires several models for each indication, reflecting critical pathophysiological processes, combined with data linking exposure levels with effect on target.

Grid-climbing Behaviour as a Pain Measure for Cancer-induced Bone Pain and Neuropathic Pain

“…Despite affecting millions of people, chronic pain is generally insufficiently treated, leaving a large number of patients with inadequate pain-relief (2,3). The low success rate for development of new analgesic therapy has been linked to a poor translation from preclinical findings to clinical effects (4,5), which have led to extensive criticism of the predictive value of the animal models of chronic pain (5-7). However, animal models are currently the best available tool for testing the analgesic potential of new drugs.…”

Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs

“…It is increasingly being recognized that only a few new analgesics have entered the general market to be of use in pain patients (Berge, 2011). Of these, only one new target has been discovered: the gabapentinoids (Chizh et al, 2009).…”

Anti-allodynic Effects of Obtusifolin and Gluco-Obtusifolin against Inflammatory and Neuropathic Pain

“…Firstly, the formalin model, which is considered to be a pain model with very high predictive validity. 21) Formalin treatment produces a biphasic behavioral reaction with phases that resemble acute and tonic pain. 1,22) Central pain modulation occurs in the second phase of the formalin test, through a mechanism thought to involve the release of inflammatory mediators.…”