Body clock may shape cancer pain, but evidence remains thin, review finds

A systematic review of research on circadian rhythms and cancer-related pain has concluded that the body’s internal clock may genuinely influence how cancer pain, chemotherapy-induced neuropathy, and analgesic responses unfold across the day, but that the evidence base is still too heterogeneous and methodologically weak to support firm clinical conclusions. The review, led by Vivian Salama of West Virginia University and registered in PROSPERO (CRD420251174524), followed PRISMA guidelines and searched PubMed and Web of Science for original human and preclinical studies published up to October 20, 2025. Eligible studies had to evaluate circadian rhythms, clock genes, or circadian-based treatment timing in relation to cancer- or treatment-related pain, neuropathy, or analgesic response.

In total, 39 studies met the inclusion criteria: 35 human studies, accounting for 89.7 percent of the pool, and 4 preclinical studies, or 10.3 percent. Most populations involved mixed cancer types, reported in 10 of the 39 studies (25.6 percent). Cohort or observational designs made up 38.5 percent of the included work and clinical trials 28.2 percent, with 16 of 39 studies (41 percent) published between 2015 and 2025. The reviewers separated direct pain-related outcomes from indirect neuropathy outcomes, a distinction that matters because much of the chronotherapy literature concerns treatment-related neurotoxicity rather than pain itself.

On the clinical side, the findings were markedly heterogeneous. Several studies reported temporal variation in cancer-related pain and in analgesic requirements, consistent with the idea that pain intensity and the need for pain medication are not constant across the 24-hour cycle. Chronotherapy studies, which time drug administration to circadian phases, suggested potential reductions in treatment-related neuropathy and neurotoxicity, but the reviewers classified this as indirect pain-related evidence rather than direct demonstrations of pain relief. No single consistent pattern emerged across cancer types, drugs, or measurement approaches.

Mechanistic evidence from human studies was sparse and largely hypothesis-generating. Potential mechanisms were reported or discussed in 15 of the 35 human studies (42.9 percent), and the pathways invoked included dysregulation of the hypothalamic-pituitary-adrenal axis and cortisol rhythms, circadian variation in drug pharmacokinetics and metabolism, inflammatory signaling, and broader circadian-regulatory pathways. Direct clinical clock-gene evidence was limited to a single gene, RORA, underscoring how little human molecular data currently connect clock biology to cancer pain outcomes.

The four preclinical studies provided the review’s only experimental evidence, implicating specific clock genes, including PER2, BMAL1, and REV-ERBα/β, in processes relevant to pain and neuropathy. These animal and cell studies pointed to oxidative stress, neuronal injury, circadian variation in drug metabolism, and neuroinflammatory signaling through an IL-6/LCN2 pathway as candidate mechanisms. Such findings are mechanistically informative but cannot be extrapolated directly to clinical benefit in patients, and they represent a small fraction of the overall evidence base.

Methodological quality emerged as a central weakness. Using JBI tools for human studies and SYRCLE for preclinical studies, the reviewers found a high risk of bias in 10 of 15 cohort studies (67 percent) and in 8 of 11 clinical trials (73 percent), with high or unclear risk across several preclinical domains. This means the temporal associations and chronotherapy signals reported in the literature rest substantially on studies vulnerable to confounding, selection effects, and reporting limitations.

The authors conclude that current evidence suggests a potential relationship between circadian biology and cancer- and treatment-related pain, analgesic response, and neuropathy, while emphasizing that clinical findings remain heterogeneous, human mechanistic evidence is predominantly hypothesis-generating, and experimental evidence remains limited. They call for prospective mechanistic studies to support future circadian-informed approaches to cancer pain management. Until such studies are done, the review positions circadian biology as a promising but unproven dimension of cancer pain research rather than an established basis for treatment decisions.

Subject of Research: Circadian rhythm biology and cancer-related pain, neuropathy, and chronotherapy: a systematic review of preclinical and clinical evidence

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

Article References: Salama, V., Karunananthan, A., Pazin, J., Godinich, B. M., O’Connell, M., Wang, L., Knoth, J. C., Martinez, I., & Weed, S. A. (2026). Circadian rhythm and cancer-related pain: a systematic review of preclinical and clinical evidence. Frontiers in Pain Research, 7, Article 1875251. https://doi.org/10.3389/fpain.2026.1875251

Image Credits: AI Generated

DOI: 10.3389/fpain.2026.1875251

Keywords: cancer pain, circadian rhythm, chronotherapy, clock genes, neuropathy, neuroinflammation, opioids, systematic review, HPA axis, PER2, BMAL1, risk of bias