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Deciphering nociplastic pain: clinical features, risk factors and potential mechanisms

Nature Reviews Neurology (2024)Cite this article

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Abstract

Nociplastic pain is a mechanistic term used to describe pain that arises or is sustained by altered nociception, despite the absence of tissue damage. Although nociplastic pain has distinct pathophysiology from nociceptive and neuropathic pain, these pain mechanisms often coincide within individuals, which contributes to the intractability of chronic pain. Key symptoms of nociplastic pain include pain in multiple body regions, fatigue, sleep disturbances, cognitive dysfunction, depression and anxiety. Individuals with nociplastic pain are often diffusely tender — indicative of hyperalgesia and/or allodynia — and are often more sensitive than others to non-painful sensory stimuli such as lights, odours and noises. This Review summarizes the risk factors, clinical presentation and treatment of nociplastic pain, and describes how alterations in brain function and structure, immune processing and peripheral factors might contribute to the nociplastic pain phenotype. This article concludes with a discussion of two proposed subtypes of nociplastic pain that reflect distinct neurobiological features and treatment responsivity.

Key points

  • Nociplastic pain was recently endorsed as the third mechanistic descriptor of pain and is characterized by widespread body pain, often co-occurring with fatigue and altered sleep, cognition and mood, as well as multisensory hypersensitivity.

  • Nociplastic pain probably occurs on a continuum and can coexist with nociceptive and/or neuropathic pain.

  • Although the exact cause (or causes) of nociplastic pain remain unknown, female sex, early-life stressors, trauma, poor sleep, heightened somatic awareness and physical inactivity increase the risk for nociplastic pain.

  • Alterations in the central nervous system, particularly in brain regions situated within the default mode, salience and somatosensory networks, have been reported in many chronic pain conditions with nociplastic features.

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Fig. 1: Central nervous system-mediated features of nociplastic pain.
Fig. 2: Risk factors for nociplastic pain across the lifespan.
Fig. 3: The pathophysiology of nociplastic pain.
Fig. 4: Subtypes of nociplastic pain: top-down and bottom-up.

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Authors and Affiliations

  1. Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, USA

    Chelsea M. Kaplan, Andrew Schrepf, Daniel J. Clauw & Steven E. Harte

  2. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

    Eoin Kelleher

  3. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK

    Anushka Irani

  4. Division of Rheumatology, Mayo Clinic Florida, Jacksonville, FL, USA

    Anushka Irani

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  1. Chelsea M. Kaplan
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  5. Daniel J. Clauw
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The authors contributed equally to all aspects of the article.

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Correspondence to Chelsea M. Kaplan.

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Competing interests

D.J.C. has consulted for Aptinyx, Daiichi Sankyo, Intec, Lundbeck, Pfizer, Regeneron, Samumed, Teva, Theravance, Tonix, Virios and Zynerba; has received research funding from Aptinyx, Cerephex and Pfizer; and has been involved in litigation testifying against opioid manufacturers in the States of Oklahoma and Florida. S.E.H. has consulted for Aptinyx, Dana-Farber Cancer Institute, Indiana University Indianapolis, Memorial Sloan Kettering Cancer Center, University of North Carolina-Chapel Hill and Wayne State University; has received research funding from Aptinyx and Arbor Medical Innovations, LLC; and holds the following patents: EP2482716B1, US9307906B2, WO2011041683A2, CA2775775C, AU2010300372B2, US11701092B2, USD1010145S1, US20230077464A1 (pending), CN115720508A (pending), CA3177295A1 (pending) and EP4142583A1 (pending). All other authors declare no competing interests.

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International Association for the Study of Pain (IASP): https://www.iasp-pain.org/resources/terminology/#:~:Text=Pain%20that%20arises%20from%20altered,somatosensory%20system%20causing%20the%20pain.&Text=A%20stimulus%20that%20is%20damaging%20or%20threatens%20damage%20to%20normal%20tissues

Patient-Reported Outcomes Measurement Information System: https://www.healthmeasures.net/explore-measurement-systems/promis

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Kaplan, C.M., Kelleher, E., Irani, A. et al. Deciphering nociplastic pain: clinical features, risk factors and potential mechanisms. Nat Rev Neurol (2024). https://doi.org/10.1038/s41582-024-00966-8

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