Novel approaches for drug development against chronic primary pain: A systematic review

Abstract Chronic primary pain (CPP) persisting for more than 3 months, associated with significant emotional distress without any known underlying cause, is an unmet medical need. Traditional or adjuvant analgesics do not provide satisfactory pain relief for a great proportion of these patients. Therefore, identifying novel therapeutic targets and determining new treatments is important. In the present systematic review, we provide a comprehensive summary of Phases 1–3 clinical trials conducted between 01 January 2014 and 31 July 2024, available on clinicaltrials.gov , clinicaltrialsregister.eu and PubMed, concerning both original drug development approaches and repurposing for the important widespread and regional musculoskeletal CPP conditions fibromyalgia (FM), complex regional pain syndrome and chronic low back pain. Unfortunately, there has not been a breakthrough in the pharmacotherapy of these conditions. This may be related to (i) the unsuccessful approaches to reveal pathophysiological mechanisms and identifying novel targets, with the lack of appropriate preclinical animal models with translational relevance, and (ii) the heterogeneity of these patient populations with several co‐morbidities. Alongside innovative drug developmental concepts such as TRPA1 and the P2X7 purine receptor inhibition and somatostatin SST 4 receptor activation, most trials have focussed on repurposing antidepressants, antiepileptics, psychedelics, immune modulators, or suppressants. The most promising candidates have targeted cannabinoid, glutamate, GABAergic, neuroinflammatory and immune mechanisms, because several studies were initiated focussing on these pathways and proving their efficacy and safety. Only cannabidiol (CBD) and (es)ketamine have been tested for all three CPPs despite similar etiological factors and mechanisms related to stress‐pain interactions.