Design, study quality and evidence of analgesic efficacy in studies of drugs in models of OA pain: A systematic review and a meta-analysis

Objective: Studies using animal models are important in drug development, but often poorly predict treatment results in man. We investigated factors that may impact on the magnitude of the analgesic treatment effect in animal models of osteoarthritis (OA) pain. Design: Systematic review of studies that measured behavioural pain outcomes in small animal models of OA, and tested drugs which reduce OA pain in man. Standardised mean difference (SMD) and 95% confidence intervals (CIs) were calculated using random effects meta-analysis for selected models and drugs. Results: Most studies used rat models (42/50) and chemical methods of OA induction (39/50). Analgesic treatment effect (SMD) was most commonly measured between drug- and vehicle treated rats with knee OA. Meta-analysis was carried out for 102 such comparisons from 26 studies. The pooled SMD was 1.36 (95% CI=1.15-1.57). Non-steroidal anti-inflammatory drugs (NSAIDs) were associated with smaller SMDs than opioids ( z=-3.25, P=0.001). Grip strength gave larger SMDs than assessment of static weight bearing ( z=-4.60, P<0.001), mechanically-evoked pain ( z=-3.83, P=0.001) and movement-evoked pain ( z=-5.23, P<0.001), and SMDs for mechanically-evoked pain were larger than for movement-evoked pain ( z=-2.78, P=0.006). Studies that reported structural evaluation of OA phenotype were associated with smaller SMDs ( z=-2.45, P=0.014). Publication was significantly biased towards positive findings. Conclusion: Attention to study-level moderators and publication bias may improve the ability of research using animal models to predict whether analgesic agents will reduce arthritis pain in man.