​Cracking the Code of Chronic Cancer Pain: The Immune System and Your Inner Clock   June 6th, 2023

Although there are more cancer survivors due to better treatment options, cancer survivors still face many challenges including chronic pain1,2. According to recent studies, approximately 40% of cancer survivors suffer from chronic pain which significantly impacts their quality of life1,3,4. Nowadays, scientists are investigating the underlying mechanisms so they can better understand the causes of chronic pain in order to improve pain management.

Recent insights suggest that the immune system plays a crucial role in the development and maintenance of chronic pain5. More specifically, the pro-inflammatory cytokine signaling between immune, neuro, and glial cells appears to play an essential role6-8. Whenever tissue damage or a nerve injury takes place, immune cells are recruited towards the invasion site to secrete pro-inflammatory cytokines such as IL-6 and TNF-α. Positive feedback loops amplify this immune response, whereas the release of anti-inflammatory cytokines such as IL-10 counteracts this to maintain homeostasis6,8. However, a dysregulation of the cytokine balance is hypothesized as a response to cancer treatment, leading to the development and maintenance of chronic cancer-related pain. This is supported by literature where there is evidence of animals9-11 suffering from chemotherapy-induced peripheral neuropathy and people suffering from chronic low back pain12 or fibromyalgia13.

Interestingly, the immune system is coordinated by our intern circadian clock meaning that variables of inflammatory processes can be distinguished throughout the day14. For instance, pain patients reported experiencing more stiffness or pain during the morning. This could perhaps be attributed to the peak of IL-6 levels in the morning, exacerbating inflammation and thus pain. This is in contrast to healthy individuals who experience a drop in IL-6 levels in the morning15.

Another interesting finding is that breast cancer survivors who prefer to wake up and go to sleep early, also known as having a morning chronotype, would be less vulnerable to experiencing pain compared to intermediate or late chronotypes. This preference characteristic has been shown to be protective against the development of chemotherapy-induced peripheral neuropathy16. This can be rationalized by considering that evening chronotypes are more predisposed to experience depressive and anxious states17. This is in line with the fact that chronic cancer-related pain is correlated with symptoms of depression and anxiety as indicated by previous research18.

In conclusion, inflammatory biomarkers such as cytokines could be useful in addition to self-reported pain measurements to understand the underlying mechanisms behind chronic cancer-related pain. However, taking circadian rhythmicity into account could be of added value.

Amber De Groote

Amber is a biomedical scientist and PhD researcher at the University of Antwerp. Her research focuses on biomarkers for chronic pain after breast cancer treatment.

2023 Pain in Motion

References and further reading:

1. Bennett MI, Kaasa S, Barke A, et al. The IASP classification of chronic pain for ICD-11: chronic cancer-related pain. Pain. Jan 2019;160(1):38-44.

2. Pachman DR, Barton DL, Swetz KM, et al. Troublesome symptoms in cancer survivors: fatigue, insomnia, neuropathy, and pain. J Clin Oncol. Oct 20 2012;30(30):3687-3696.

3. Morlion B, Coluzzi F, Aldington D, et al. Pain chronification: what should a non-pain medicine specialist know? Current Medical Research and Opinion. 2018;34(7):1169-1178.

4. van den Beuken-van Everdingen MH, Hochstenbach LM, Joosten EA, et al. Update on Prevalence of Pain in Patients With Cancer: Systematic Review and Meta-Analysis. J Pain Symptom Manage. Jun 2016;51(6):1070-1090 e1079.

5. Grace PM, Tawfik VL, Svensson CI, et al. The Neuroimmunology of Chronic Pain: From Rodents to Humans. Journal of Neuroscience. Feb 3 2021;41(5):855-865.

6. Austin PJ, Moalem-Taylor G. The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol. Dec 15 2010;229(1-2):26-50.

7. Jiang BC, Liu T, Gao YJ. Chemokines in chronic pain: cellular and molecular mechanisms and therapeutic potential. Pharmacol Ther. Aug 2020;212:107581.

8. Vanderwall AG, Milligan ED. Cytokines in Pain: Harnessing Endogenous Anti-Inflammatory Signaling for Improved Pain Management. Front Immunol. 2019;10:3009.

9. Al-Mazidi S, Alotaibi M, Nedjadi T, et al. Blocking of cytokines signalling attenuates evoked and spontaneous neuropathic pain behaviours in the paclitaxel rat model of chemotherapy-induced neuropathy. Eur J Pain. Apr 2018;22(4):810-821.

10. Janes K, Wahlman C, Little JW, et al. Spinal neuroimmune activation is independent of T-cell infiltration and attenuated by A(3) adenosine receptor agonists in a model of oxaliplatin-induced peripheral neuropathy. Brain Behavior and Immunity. Feb 2015;44:91-99.

11. Li YY, Li H, Liu ZL, et al. Activation of STAT3-mediated CXCL12 up-regulation in the dorsal root ganglion contributes to oxaliplatin-induced chronic pain. Mol Pain. Jan-Dec 2017;13:1744806917747425.

12. Canli K, Billens A, Van Oosterwijck J, et al. Systemic Cytokine Level Differences in Patients with Chronic Musculoskeletal Spinal Pain Compared to Healthy Controls and Its Association with Pain Severity: A Systematic Review. Pain Med. Dec 1 2022;23(12):1947-1964.

13. Peck MM, Maram R, Mohamed A, et al. The Influence of Pro-inflammatory Cytokines and Genetic Variants in the Development of Fibromyalgia: A Traditional Review. Cureus. Sep 6 2020;12(9):e10276.

14. Orozco-Solis R, Aguilar-Arnal L. Circadian Regulation of Immunity Through Epigenetic Mechanisms. Frontiers in Cellular and Infection Microbiology. Mar 13 2020;10

15. Nilsonne G, Lekander M, Akerstedt T, et al. Diurnal Variation of Circulating Interleukin-6 in Humans: A Meta-Analysis. PLoS One. 2016;11(11):e0165799.

16. Son KL, Jung D, Lee KM, et al. Morning Chronotype Decreases the Risk of Chemotherapy-Induced Peripheral Neuropathy in Women With Breast Cancer. J Korean Med Sci. Feb 7 2022;37(5):e34.

17. Zou H, Zhou H, Yan R, et al. Chronotype, circadian rhythm, and psychiatric disorders: Recent evidence and potential mechanisms. Front Neurosci. 2022;16:811771.

18. Moloney NA, Pocovi NC, Dylke ES, et al. Psychological Factors Are Associated with Pain at All Time Frames After Breast Cancer Surgery: A Systematic Review with Meta-Analyses. Pain Medicine. Apr 2021;22(4):915-947.