Lessons learned in translating pain knowledge into practice

Abstract

Introduction: During the past 2 decades, basic research deciphering the underlying mechanisms of nociception and chronic pain was thought to finally step beyond opioids and nonsteroidals and provide patients with new analgesics. But apart from calcitonin gene-related peptide antagonists, nothing arrived in hands of clinicians.

Objectives: To present existing evidence of 3 representative target molecules in the development of novel pain treatment that, so far, did not result in approved drugs.

Methods: This Clinical Update aligns with the 2022 IASP Global Year Translating Pain Knowledge into Practice and selectively reviews best available evidence and practice.

Results: We highlight 3 targets: a ion channel, a neuronal growth factor, and a neuropeptide to explore why these drug targets have been dropped in clinical phase II-III trials. Antibodies to nerve growth factor had very good effects in musculoskeletal pain but resulted into more patients requiring joint replacements. Blockers of NaV1.7 were often not effective enough-at least if patients were not stratified. Blockers of neurokinin receptor were similarly not successful enough. In general, failure was most often to the result of a lack of effect and to a lesser extend because of unexpected severe side effects. However, all studies and trials lead to an enormous move in the scientific community to better preclinical models and testing as well as revised methods to molecularly phenotype and stratify patients.

Conclusion: All stakeholders in the process can help in the future: better preclinical studies, phenotyping and stratifying patients, and participation in clinical trials to move the discovery of analgesics forward.

Keywords: NGF; NK1R; Sodium channel; Translational pain medicine.

Figure 1.

Summary of reasons for failure for selected pathways and possible future direction of pain research to foster translation of pain knowledge into practice. Failure of analgesics in clinical trials can be attributed to 2 categories: lack of effect and unwanted side effects. Examples are given in the right column and explained in the main text. Many suggestions for the future have been made based on these observations—mainly to address the lack of effect. CCI, chronic constriction injury; CIPN, chemotherapy-induced neuropathy; CNS, central nervous system; DH, dorsal horn; DPN, diabetic polyneuropathy; DRG, dorsal root ganglion; FAAH, fatty acid amide hydrolase; IPSC, induced pluripotent stem cells; NaV1.7, voltage-gated sodium channel; NGF, nerve growth factor; RPOA, rapid progressing osteoarthritis; SNI, spared nerve injury; TRPA1, transient receptor potential ankyrin 1; TRPV1, transient receptor potential vanilloid 1.