Chronic musculoskeletal pain remains a challenging condition to manage, not only because of its physical impact but also due to the significant role psychosocial factors, like stress, play in exacerbating the condition (Kang et al., 2023). Recent research has begun to highlight the potential of oxytocin, a hormone traditionally associated with childbirth and social bonding, in modulating both pain and stress, potentially offering new avenues for chronic pain management (Mekhael et al., 2023).
Oxytocin's influence on chronic pain is thought to be understood through its dual impact on (1) stress levels (and hence its indirect effects on pain via stress) and (2) direct modulation of pain physiology. Although acute stress can attenuate pain sensitivity in pain-free individuals, stress can also exacerbate (chronic) pain, thereby contributing to both the severity and persistence of pain conditions (Windle et al., 2004). Oxytocin appears to have a calming effect on the stress response by modulating the hypothalamic-pituitary-adrenal (HPA) axis, which is often dysregulated in patients with chronic pain (Nelson et al., 2021; Woda et al., 2016). So, by attenuating stress, oxytocin may indirectly modulate the effects of stress on pain (Jurek & Neumann, 2018).
Moreover, oxytocin's role in pain physiology extends beyond stress modulation. The hormone is thought to enhance the body’s endogenous analgesic systems, which are responsible for reducing pain perception. First, oxytocin has been shown to influence pain-related brain regions such as those responsible for processing the threat value and the meaning of pain, thereby potentially affecting pain perception and regulation (e.g. amygdala and anterior cingulate cortex) (Aygün et al., 2024; Kandić et al., 2021). Second, oxytocin's analgesic effects are also believed to result from its interaction with the central endogenous opioid system, as supported by various animal studies (Gu & Yu, 2007; Han & Yu, 2009). Third, oxytocin has been shown to reduce pain transmission at the spinal level by modulating inhibitory neurons (e.g., GABAergic interneurons), which limit nociceptive signalling (Xin et al., 2017).
These findings highlight oxytocin's multifaceted role in pain modulation; however, there is still limited understanding of how the endogenous oxytocinergic system functions in diverse chronic pain populations.
A recent systematic review and meta-analysis indicated that endogenous oxytocin levels are generally lower in people with chronic pain, which might suggest that the absence of oxytocin’s buffering role may contribute to the development and persistence of chronic pain. Yet the number of studies is limited, and the findings are still conflicting (Mekhael et al., 2023). Some studies even reported higher oxytocin levels in people with chronic migraine, while others, like studies on people with fibromyalgia, found no significant differences with pain-free controls, though identified more variability in oxytocin levels (Mekhael et al., 2023). The review by Mekhael et al., (2023) also found that while exogenous oxytocin administration did not significantly reduce overall pain intensity compared to placebo (yet only 3 studies were included), it did show promise in reducing pain sensitivity in specific conditions, such as back pain, abdominal pain, and migraines. The findings also suggest that individual factors, including sex and the specific type of chronic pain, may influence oxytocin's effectiveness, indicating the need for more targeted research (Mekhael et al., 2023).
Ongoing research at UGent, VUB and Tilburg University is set to further explore these avenues, investigating how oxytocin levels fluctuate in response to pain and stress in individuals with chronic pain conditions like low back pain and fibromyalgia. This research aims to uncover whether oxytocin could serve as a biomarker for pain vulnerability or as a predictor for the transition from (sub)acute to chronic pain. Such insights could lead to the development of new, oxytocin-centered therapeutic strategies, which could offer a novel holistic approach, targeting both the psychological and physiological components of pain.
Matthijs Moerkerke
2024Pain in Motion
References and further reading:
Aygün, O., Mohr, E., Duff, C., Matthew, S., & Schoenberg, P. (2024). Oxytocin Modulation in Mindfulness-Based Pain Management for Chronic Pain. Life 2024, Vol. 14, Page 253, 14(2), 253.
Gu, X. L., & Yu, L. C. (2007). Involvement of Opioid Receptors in Oxytocin-Induced Antinociception in the Nucleus Accumbens of Rats. The Journal of Pain, 8(1), 85–90.
Han, Y., & Yu, L. C. (2009). Involvement of oxytocin and its receptor in nociceptive modulation in the central nucleus of amygdala of rats. Neuroscience Letters, 454(1), 101–104.
Jurek, B., & Neumann, I. D. (2018). The oxytocin receptor: From intracellular signaling to behavior. Physiological Reviews, 98(3), 1805–1908.
Kandić, M., Moliadze, V., Andoh, J., Flor, H., & Nees, F. (2021). Brain Circuits Involved in the Development of Chronic Musculoskeletal Pain: Evidence From Non-invasive Brain Stimulation. Frontiers in Neurology, 12, 732034.
Kang, Y., Trewern, L., Jackman, J., McCartney, D., & Soni, A. (2023). Chronic pain: definitions and diagnosis. BMJ, 381.
Mekhael, A. A., Bent, J. E., Fawcett, J. M., Campbell, T. S., Aguirre-Camacho, A., Farrell, A., & Rash, J. A. (2023). Evaluating the efficacy of oxytocin for pain management: An updated systematic review and meta-analysis of randomized clinical trials and observational studies. Canadian Journal of Pain, 7(1).
Nelson, S., Bento, S., & Enlow, M. B. (2021). Biomarkers of Allostatic Load as Correlates of Impairment in Youth with Chronic Pain: An Initial Investigation. Children 2021, Vol. 8, Page 709, 8(8), 709.
Windle, R. J., Kershaw, Y. M., Shanks, N., Wood, S. A., Lightman, S. L., & Ingram, C. D. (2004). Oxytocin Attenuates Stress-Induced c-fos mRNA Expression in Specific Forebrain Regions Associated with Modulation of Hypothalamo–Pituitary–Adrenal Activity. Journal of Neuroscience, 24(12), 2974–2982.
Woda, A., Picard, P., & Dutheil, F. (2016). Dysfunctional stress responses in chronic pain. Psychoneuroendocrinology, 71, 127–135.
Xin, Q., Bai, B., & Liu, W. (2017). The analgesic effects of oxytocin in the peripheral and central nervous system. Neurochemistry International, 103, 57–64.
Review of Mekhael et al. (2023), free PDF available from:
https://www.tandfonline.com/doi/full/10.1080/24740527.2023.2191114#abstract
