Simultaneous Translation: What is Needed from Preclinical Science

A.H. Dickenson Dept. NPP Pharmacology, University College London, WC1E 6BT UK 

Pain signalling and modulatiory mechanisms in the CNS change following physiopathological events such as in the two broad major types of pain, neuropathic and inflammatory pain. There is a clear unmet need for either new drugs or better use of existing agents. Development of new drugs requires preclinical science but many feel let down when molecules fail in patients. However, many novel therapies have come from preclincal science.

There are mutiple pain mechanisms at various sites including peripheral and central sensitisation and so thoughtful application of animal models to integrated systems is essential.

Molecules may fail because they do not engage the target in humans, are used at too low a dose or trialled in the wrong patients where sensory phenotypes should have been applied. It is hard to gauge subtle side-effects such as confusion, dizziness etc in animals so failure as a result of side-effects might be expected. But failures based on efficacy are inexcusable. It is possible in animals and volunteers to produce peripheral and central sensitisation and integrity of descending controls can be gauged. Thus why are drugs not routinely tested on these measures in animals and in humans before the clinical trials?

Outcome measures in animal models are critical. Many use behaviour that relies on evoked withdrawal responses at only the pain threshold and ignore ongoing pain. Many drugs may modulate the pain threshold (often marginally) yet lack efficacy with stronger stimuli and so may fail in patients. I will expand on how in vivo electrophysiology can inform on neuronal responses to suprathreshold stimuli, reveals differential drug effects on different modalities and produces information that translates very well to humans.

Understanding mechanisms for pain enhancement should help to explain altered pain states in patients but also could lead to better use of treatments and novel therapies.