Learned analgesic cue association and placebo analgesia in rats: an empirical assessment of an animal model and meta-analysis

Abstract

This thesis focuses on animal models of placebo analgesia. Placebo analgesia is the experience of reduced pain, or pain relief, without the delivery of a pain-relieving drug or actual reduction of the painful stimulus. Research into the underlying neuro-mechanisms of placebo analgesia have been limited by unreliable animal models of the effect and attempts to replicate human placebo testing paradigms in animals have had mixed outcomes. In many cases, a tolerance to analgesic has been observed instead. The project had two main aims. The first was to replicate a recent model of placebo analgesia. The second aim of the project was to conduct a meta-analysis of the existing published literature and determine the overall effect size of placebo analgesia in rodent models. Experiment 1 sought to replicate a previous model of rodent placebo analgesia. Results from experiment 1 did not support previous findings and showed no evidence for placebo analgesia in rodents. Experiment 2 was a second attempt to replicate a previous model of placebo analgesia. The second attempt adjusted the potential limitations from experiment 1 such as cue chamber intensity and re-ran the protocol using rodents of the same sex and strain as the original paper. Results from experiment 2 were similar to experiment 1 and did not support the hypotheses or provide any evidence for placebo analgesia in rodents. Experiment 3 used a simplified version of the behavioural conditioning methodology from experiments 1 and 2, but was modified to reduce handling stress, to increase the salience of the to-be-conditioned placebo cue, and to reduce stress-induced analgesia. Results from experiment 3 found no evidence for placebo analgesia in rodents was observed. The results from 45 studies across 21 papers were meta-analysed and showed a moderate effect size for placebo analgesia in rodents, and moderator analysis revealed that cue type was a significant factor in the development of the effect in rodents. Using a context cue box as the cue type was found to be the most effective approach to establishing placebo analgesia in rodents. The current research has highlighted the replicability problem in pre-clinical research and as such it is recommended that animal studies looking at placebo analgesia aim to include more methodological detail in their reporting, particularly in regard to cue type. A limitation of the current project was the exclusion of drug tolerance literature that results in nocebo responses. Future research should compare and contrast this body of work more closely with research into placebo analgesia in rodents.