Circadian rhythm and cancer-related pain: a systematic review of preclinical and clinical evidence

Background Cancer-related pain and neuropathy are common complications that substantially affect quality of life. Circadian rhythms regulate biological processes involved in pain and treatment response; however, evidence linking circadian biology and treatment timing with cancer-related pain and neuropathy remains limited and heterogeneous, and the underlying mechanisms are incompletely understood. This systematic review aimed to evaluate these relationships and their potential biological mechanisms and clinical implications across clinical and preclinical studies. Methods PRISMA-guided systematic review was registered in PROSPERO (CRD420251174524). PubMed and Web of Science were searched for original human and preclinical studies published up to October 20, 2025. Eligible studies evaluated circadian rhythms, clock genes, or circadian-based treatment timing in relation to cancer- or treatment-related pain, neuropathy, or analgesic response. Direct pain-related and indirect neuropathy outcomes were synthesized separately. Risk of bias was assessed using JBI tools for human studies and SYRCLE for preclinical studies. Results Thirty-nine studies were included: 35 human (89.7%) and 4 preclinical studies (10.3%). Most populations included mixed cancer types (10/39, 25.6%). Cohort or observational studies represented 38.5% and clinical trials represented 28.2%, with 16/39 (41%) studies published between 2015 and 2025. Clinical findings were heterogeneous, with temporal variation reported for cancer-related pain and analgesic requirements, while chronotherapy studies suggested potential reductions in treatment-related neuropathy and neurotoxicity, representing indirect pain-related evidence. Potential mechanisms were reported or discussed in 15/35 (42.9%) human studies and were largely hypothesis-generating, involving HPA-axis/cortisol dysregulation, drug pharmacokinetics, and metabolism, inflammatory signaling, and circadian-regulatory pathways; direct clinical clock-gene evidence was limited to RORA . Four preclinical studies provided experimental evidence implicating clock genes ( PER2 , BMAL1 , and REV-ERBα/β ), oxidative stress, neuronal injury, drug metabolism, and neuroinflammatory (IL-6/LCN2) pathways. Methodological quality was limited, with high risk of bias in 10/15 (67%) cohort studies and 8/11 (73%) clinical trials and high or unclear risk across several preclinical domains. Conclusion Current evidence suggests a potential relationship between circadian biology and cancer- and treatment-related pain, analgesic response, and neuropathy. Clinical findings remain heterogeneous, human mechanistic evidence is predominantly hypothesis-generating, and experimental evidence remains limited. Prospective mechanistic studies are needed to support future circadian-informed approaches for cancer pain management. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251174524 , identifier CRD420251174524.