Mechanism-Based Understanding of Chronic Pain in Internal Medicine: From Sensitization Pathways to Clinical Phenotypes
DOI:
https://doi.org/10.64784/126Keywords:
Chronic pain, central sensitization, peripheral sensitization, nociplastic pain, neuropathic pain, internal medicine, pain phenotyping, multisystem disease, pain modulation, interdisciplinary managementAbstract
ABSTRACT
Chronic pain represents a major challenge in internal medicine due to its persistent nature, heterogeneous presentation, and frequent dissociation from identifiable tissue damage. Contemporary evidence indicates that chronic pain should be conceptualized as a multisystem condition sustained by interacting mechanisms of peripheral sensitization, neuropathic remodeling, and central sensitization, rather than as a linear extension of acute nociception. This narrative integrative review synthesizes key findings from pain neuroscience, clinical research, and contemporary classification systems to examine how these mechanisms contribute to pain persistence, symptom amplification, and functional impairment. The analysis highlights the clinical relevance of pain phenotyping—nociceptive, neuropathic, nociplastic, and mixed—using observable clinical features commonly encountered in internal medicine practice. Patterns such as widespread pain, disproportionate symptom intensity, sleep disturbance, fatigue, cognitive complaints, and autonomic manifestations are discussed as indicators of central-dominant mechanisms. The review further explores how differential therapeutic responsiveness across phenotypes supports a mechanism-based approach to management, emphasizing the limitations of uniform analgesic strategies and the value of interdisciplinary care, including pharmacologic modulation, rehabilitation, and pain education. By integrating mechanistic understanding with diagnostic reasoning, this review provides an educational framework aimed at improving clinical decision-making in internal medicine. Recognizing chronic pain as a condition with modifiable neurobiological drivers supports more individualized, effective, and patient-centered care across diverse healthcare settings.
References
[1] A. V. Apkarian, J. A. Hashmi, and M. N. Baliki, “Pain and the brain: Chronic pain plasticity,” Pain, vol. 152, no. 3 Suppl, pp. S49–S64, 2011, doi: 10.1016/j.pain.2010.11.010.
[2] R. Baron, A. Binder, and G. Wasner, “Neuropathic pain: Diagnosis, pathophysiological mechanisms, and treatment,” The Lancet Neurology, vol. 9, no. 8, pp. 807–819, 2010, doi: 10.1016/S1474-4422(10)70143-5.
[3] D. L. Bennett et al., “The role of voltage-gated sodium channels in pain signaling,” Physiological Reviews, vol. 99, no. 2, pp. 1079–1151, 2019, doi: 10.1152/physrev.00052.2017.
[4] D. J. Clauw, “Fibromyalgia and related conditions,” Mayo Clinic Proceedings, vol. 90, no. 5, pp. 680–692, 2015, doi: 10.1016/j.mayocp.2015.03.014.
[5] D. J. Clauw et al., “Considering the potential for nociplastic pain,” Pain, vol. 161, no. 1, pp. 1–8, 2020, doi: 10.1097/j.pain.0000000000001656.
[6] M. Costigan, J. Scholz, and C. J. Woolf, “Neuropathic pain: A maladaptive response of the nervous system to damage,” Annual Review of Neuroscience, vol. 32, pp. 1–32, 2009, doi: 10.1146/annurev.neuro.051508.135531.
[7] H. Flor and D. C. Turk, “Chronic pain: An integrated biobehavioral approach,” The Lancet, vol. 377, no. 9784, pp. 2223–2234, 2011, doi: 10.1016/S0140-6736(11)60314-2.
[8] R. Gatchel, J. McGeary, M. McGeary, and D. Lippe, “Interdisciplinary chronic pain management,” American Psychologist, vol. 69, no. 2, pp. 119–130, 2014, doi: 10.1037/a0035514.
[9] S. E. Harte, R. E. Harris, and D. J. Clauw, “The neurobiology of central sensitization,” Journal of Applied Biobehavioral Research, vol. 23, no. 2, e12137, 2018, doi: 10.1111/jabr.12137.
[10] A. Latremoliere and C. J. Woolf, “Central sensitization: A generator of pain hypersensitivity,” Journal of Pain, vol. 10, no. 9, pp. 895–926, 2009, doi: 10.1016/j.jpain.2009.06.012.
[11] J. Loeser and R.-D. Treede, “The Kyoto protocol of IASP pain terminology,” Pain, vol. 137, no. 3, pp. 473–477, 2008, doi: 10.1016/j.pain.2008.04.025.
[12] G. L. Moseley and D. S. Butler, “Fifteen years of explaining pain,” Journal of Pain, vol. 16, no. 9, pp. 807–813, 2015, doi: 10.1016/j.jpain.2015.05.005.
[13] G. L. Moseley, “Reconciling pain neuroscience with clinical practice,” Physical Therapy, vol. 87, no. 4, pp. 452–461, 2007, doi: 10.2522/ptj.20060296.
[14] J. Nijs et al., “Treatment of central sensitization in patients with chronic pain,” Expert Opinion on Pharmacotherapy, vol. 15, no. 12, pp. 1671–1683, 2014, doi: 10.1517/14656566.2014.915924.
[15] M. H. Ossipov, G. O. Dussor, and F. Porreca, “Central modulation of pain,” Journal of Clinical Investigation, vol. 120, no. 11, pp. 3779–3787, 2010, doi: 10.1172/JCI43766.
[16] R.-D. Treede, W. Rief, A. Barke, Q. Aziz, M. I. Bennett, and R. Baron, “A classification of chronic pain for ICD-11,” Pain, vol. 156, no. 6, pp. 1003–1007, 2015, doi: 10.1097/j.pain.0000000000000160.
[17] R.-D. Treede et al., “Chronic pain as a symptom or a disease: The IASP Classification of Chronic Pain,” Pain, vol. 160, no. 1, pp. 19–27, 2019, doi: 10.1097/j.pain.0000000000001384.
[18] A. C. Vlaeyen and S. J. Linton, “Fear-avoidance and its consequences in chronic musculoskeletal pain,” Pain, vol. 85, no. 3, pp. 317–332, 2000, doi: 10.1016/S0304-3959(99)00242-0.
[19] D. J. Williams and C. Eccleston, “Psychological therapies for the management of chronic pain,” Pain, vol. 152, no. 8, pp. 1769–1777, 2011, doi: 10.1016/j.pain.2011.03.015.
[20] C. J. Woolf, “Central sensitization: Implications for the diagnosis and treatment of pain,” Pain, vol. 152, no. 3 Suppl, pp. S2–S15, 2011, doi: 10.1016/j.pain.2010.09.030.
