Conference on Analgesic Trials

Early proof-of-concept studies utilizing human experimental pain bio-markers may help profiling new analgesic or anti-inflammatory compounds and determine adequate doses. The challenge is to translate the animal experimental data on analgesic efficacy into a meaningful clinical context. The translation of animal data into humans and further into patients is problematic but a set of experimental human pain bio-markers have been developed helping this transition. The application of experimental pain stimuli to healthy volunteers can be performed under normal conditions, but also under semi-pathophysiological conditions where peripheral or central sensitization can been imposed experimentally. This area of human experimental pain research has advanced significantly over the last 20 years and is now a valuable tool in early drug development.

Human volunteer models may act as proxies for clinical conditions/symptoms and hence be used as surrogate models help predicting which patient population or pain mechanism will respond to the compound. Experimental pain bio-markers can tease out mechanistically which pain pathways and mechanisms are modulated by a given compound. Predictive human volunteer pain models and adequate derived bio-markers mimicking different conditions (e.g. inflammatory, neuropathic, musculoskeletal, visceral) and symptoms (e.g. hyperalgesia, allodynia, after-sensation) may optimize drug development and make Phase II and III studies much more cost effective.

The bio-markers derived from experimental models can be psychophysical, electrophysiological, imaging or bio-chemical. The psychophysical markers can be e.g. pain thresholds, threshold tracking, or stimulus response functions. Selected bio-markers can then be used to probe the effect a given compounds on particular mechanisms such as temporal summation, generalized hyperalgesia, long term potentiation, spread of pain, referred pain, or descending conditioning pain modulation (CPM).

The multi-modal, multi-tissue pain assessment paradigm for profile compounds can predict which patient population e.g. visceral pain should be selected for later clinical trials. More and more studies indicated the advantage of including experimental pain bio-markers in clinical phase I, II and III studies as they often are more sensitive than simple clinical pain measures and provide a valuable mechanistic understanding of the drug action.

 

The relationship between study endpoints and label claims will be discussed. Principles of good measurement and study design will be accompanied by examples from recently approved labels.

 

• A review of interventions designed to reduce the placebo response and their results
• A review of accuracy of pain reporting and its relationship to interoceptive accuracy and the placebo response
• Recommendations on addressing the placebo response in clinical trials

Osteoarthritis is one of the most common problems confronting most Western Societies and consumes a significant portion of the medical budgets of most countries around the world. Both progressive symptomatic and structural disease leads to both increased disability as well as increased mortality due either to therapy associated adverse events or to increased sedentary lives. The development of drugs to alter progression of the progressive disease is in the distant future; thus, the development of therapies to improve pain and function continue to be the mainstay of therapy. However, the studied patient populations are heterogeneous, the drugs are impressive only being adequate in alleviating pain, and it is unclear how short terms studies help to understand the chronic effects both in terms of durable efficacy as well as in terms of safety.

An opioid sparing label claim is an important commercial and scientific milestone that is highly sought after by drug developers. However, the regulatory hurdles associated with obtaining such a label claim can be daunting and confusing. Dr. Singla will discuss: (1) experimental designs that can detect clinically meaningful differences in opioid related symptom distress (2) regulatory requirements for the provision of an opioid sparing label claim and (3) relevant failures and successes in recently completed programs.