Lost but making progress--Where will new analgesic drugs come from?

Abstract

There is a critical need for effective new pharmacotherapies for pain. The paucity of new drugs successfully reaching the clinic calls for a reassessment of current analgesic drug discovery approaches. Many points early in the discovery process present significant hurdles, making it critical to exploit advances in pain neurobiology to increase the probability of success. In this review, we highlight approaches that are being pursued vigorously by the pain community for drug discovery, including innovative preclinical pain models, insights from genetics, mechanistic phenotyping of pain patients, development of biomarkers, and emerging insights into chronic pain as a disorder of both the periphery and the brain. Collaborative efforts between pharmaceutical, academic, and public entities to advance research in these areas promise to de-risk potential targets, stimulate investment, and speed evaluation and development of better pain therapies.

Fig. 1. Imaging in drug development

Brain imaging is useful for identifying and investigating various endpoints of translational significance in the preclinical phase of analgesic drug development.

Fig. 2. Chronic pain affects the brain

Damage to peripheral nerves (or to the CNS) can produce pain that is associated with ongoing plasticity of the brain. Such plasticity can reflect increased “centralization” of pain within specific (for example, emotional) circuits. Centralization of pain includes changes that are often associated with pain such as altered cognition and affect (depression or anxiety). Understanding the processes promoting such chronification of pain is critical for successful translation of pain therapies.

Fig. 3. Integrated translational programs

A concerted effort by different interested stakeholders (patients, academicians, and pharmaceutical companies) can produce more coherent and robust translation of pain therapies. Such efforts would provide a much-needed impetus to define pain phenotypes in animals and humans and to evaluate and develop new and better translational models.

Fig. 4. Relative proportion of chronic pain conditions as a medical burden to global society

Adapted with permission from (177).