The last five decades have witnessed enormous advances in our knowledge of mechanisms of pain. As a result, a myriad of potential pharmacological targets have been discovered that have given much hope to improve pain treatment. Unfortunately, despite these massive efforts, the condition of our patients has improved only minimally over the last decades.
A very low number of discovered potential drug targets in animal studies translate into the development of compounds that are tested in first humans studies ("phase 1 clinical trials"). Among this relatively few medications that are tested in phase 1 clinical trials, only 10% have a chance to survive the 4 phases that eventually lead to approval for clinical use, as shown by a recent study. In addition, the efficacy of the available treatments remains at best modest, with the majority of patients still suffering of substantial pain, disability, and psychosocial distress.
The reasons for the disconnect between progress in knowledge and benefit for patients are multiple. In this blog, I discuss the research pathway that leads from discoveries to availability of effective medications, and the perspective to revise this pathway.
From animals to humans
Basic research has relied on discovery of potential drug targets in animals and subsequent testing of drugs in humans. The obvious reason is the very limited ability to study in depth mechanisms of pain in humans. For instance, neurons of the spinal cord that elaborate and convey pain signals to the brain cannot be sampled and studied from patients with pain. The increasing evidence of substantial differences between the pain system of animals and humans explains in part the failure of medications that have been developed based on animal research. For instance, a recent study has found that neurons receiving the first pain input ("nociceptors") are very different in animals and humans (1). Therefore, medications that target those neurons and are developed based on findings in animals may not work in humans. Furthermore, pain is not a pure sensory experience, but is deeply embedded in emotional, social, cognitive, and affective dimensions. These dimensions cannot be reproduced in animal experiments.
Better: From humans to animals, and back to humans
A group of scientists has met and subsequently produced a position paper (2) that outlines a novel approach to drug discovery for pain treatment. We have indicated a pathway that involves advanced analysis of human tissues derived from organ donors or patients undergoing surgery, in which some tissues are discarded or disrupted as the result of surgery, as well as the analysis of substances from biological fluids such as the cerebrospinal fluid, blood and urine.
The findings would then be associated with advanced clinical characterization (phenotyping), to determine which findings are relevant to which specific clinical characteristics (for instance, pain with touch or with activity). This aspect is of utmost importance and has received little attention in the past. The pain experience has several facets, and varies extremely among patients, also within the same diagnosis. A promising perspective is to enlarge our measures beyond recordings of pain intensity to determine which molecular targets are relevant to which aspects of the pain experience. We have adopted this concept in a running project on neck pain, funded by the NIH, in which we are studying mechanism of neck pain aiming to identify novel pharmacological targets applicable to human pain (learn more here).
The next step of this research pathway would be the validation in animal studies, such as testing whether modifications of the pain pathways discovered in human studies determine changes in pain behaviors. After this step, medications that target the pathway would be tested in humans for safety and efficacy.
It is just a start, but a promising one.
1. Tavares-Ferreira D, Shiers S, Ray PR, Wangzhou A, Jeevakumar V, Sankaranarayanan I, Cervantes AM, Reese JC, Chamessian A, Copits BA, Dougherty PM, Gereau RWt, Burton MD, Dussor G, Price TJ. Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors. Sci Transl Med. 2022;14(632):eabj8186.
2. Renthal W, Chamessian A, Curatolo M, Davidson S, Burton M, Dib-Hajj S, Dougherty PM, Ebert AD, Gereau RW, Ghetti A, Gold MS, Hoben G, Menichella DM, Mercier P, Ray WZ, Salvemini D, Seal RP, Waxman S, Woolf CJ, Stucky CL, Price TJ. Human cells and networks of pain: Transforming pain target identification and therapeutic development. Neuron. 2021;109(9):1426-9.