On the Concept of Pain Chronicization: Clinical Observations and Neurobiological Inference

Abstract

Background

Pain chronicization is commonly used to describe the transition from acute to chronic pain driven by central mechanisms.

Objective

To reassess its clinical relevance by comparing neurobiological models with patient observation.

Methods

Conceptual analysis integrating experimental data and clinical experience. The analysis particularly considers animal models, human neuroimaging and ICD‑11 chronic pain categories.

Results

While central sensitization is well established experimentally, clinical observation rarely shows a clear transition from acute to chronic pain. Chronic pain is typically heterogeneous, discontinuous and influenced by multiple factors. Neuroimaging findings are largely associative and lack temporal and causal definition. The distinction between chronic primary and secondary pain is clinically useful but does not demonstrate a biological conversion.

Conclusion

Pain chronicization should be considered a theoretical construct rather than a clinically demonstrable process, and interpreted with caution in individual patients.

Introduction

Dear Editor, we have read with great interest the growing body of literature addressing the concept of pain chronicization and the role of central mechanisms in sustaining persistent pain. The shift away from purely lesion-based models has undoubtedly contributed to a more comprehensive understanding of pain and has helped legitimize the experience of patients in whom no clear peripheral pathology can be identified.¹ However, we would like to raise a methodological and clinical concern regarding the increasingly implicit assumption that pain chronicization represents a demonstrable and linear transition from acute to chronic pain in humans, analogous to what has been convincingly demonstrated in animal models.²

In our opinion the major gaps in this research area are the lack of longitudinal human evidence, reliance on cross‑sectional neuroimaging and the inferential use of classification systems.

In this perspective article we highlight these methodological gaps which can lead to substantial misunderstanding of chronic pain experience.

Discussion

From a clinical perspective, longitudinal observation of patients with pain suggests that such a transition is rarely identifiable as a coherent and continuous process.³ In everyday practice, acute pain most often resolves, while chronic pain frequently presents as a complex, discontinuous condition, shaped by multiple episodes, contextual factors, and evolving psychological meanings attributed to the pain experience. The transformation of a well-defined acute pain state into a chronic pain condition, in the strong causal sense implied by the term “chronicization”, is seldom directly observable. Neuroscientific models, particularly those derived from experimental animal studies, have provided compelling evidence for central sensitization and for the persistence of pain-related behaviors independent of ongoing peripheral nociceptive input.⁴ Nevertheless, the translational step from these models to the human condition remains inferential. In humans, experimental control over afferent input is inherently limited, and direct access to subjective pain experience is not universally possible. Two areas where the transition from acute to chronic pain has been epidemiologically demonstrated but without providing strong evidence of the mechanisms underlying this phenomenon are low back pain and chronic post-surgical pain.^3,5–10 Acute low back pain has a rate of chronicization up to 60%, common predictors of this transition are pre-existing pain, disability, negative affect, sleep disturbance, and catastrophizing.^8–10 All these factors are not biological in itself and often pre-existing, despite their epidemiological correlation they are not representative of biological model of chronicization. Chronic post-surgical pain is another common condition where acute pain becomes chronic. Its incidence is highly variable, depending on type of surgery and techniques, ranging from 5% to 85%.⁵ The proposed mechanisms underlying this transition (opioid induced hyperalgesia, central sensitization, imbalance between descending spinal facilitation and inhibition, NMDA receptors activation) have been demonstrated in animal studies but their role in humans remains controversial.⁷ In the pediatric setting it has been postulated that early exposure to pain experience can lead to the development of chronic pain in adult age. However, while numerous animal studies suggest nociceptive priming related to stressful/painful experiences in early life and maladaptive pain responses in later life, human studies are not conclusive.¹¹ Consequently, central neuroplastic changes observed in patients with chronic pain should be interpreted with caution, particularly when causal inferences are drawn. Neuroimaging studies have consistently demonstrated functional and structural alterations in cortical and subcortical networks associated with pain processing.¹² Yet, these findings are largely cross-sectional, lack pre-morbid baselines, and often demonstrate limited specificity with respect to pain, overlapping substantially with patterns observed in stress-related and affective disorders. Moreover, the partial reversibility of these changes following clinical improvement raises the possibility that they represent correlates or consequences of persistent pain rather than its primary cause.¹³ It should be emphasized that no reliable biomarker of the transition from acute to chronic pain has been validated in humans.^6,11 Similarly, the distinction introduced by ICD-11 between chronic secondary and chronic primary pain has clear clinical and classificatory value. Nonetheless, it risks being misconstrued as evidence of a biological transition, whereas in practice it more often reflects the limits of etiological explanation rather than a demonstrable change in underlying pathophysiology.¹⁴

Conclusion

We believe that framing pain chronicization as a universally applicable, mechanistically defined process may unintentionally obscure the heterogeneity of chronic pain conditions and overstate the current level of empirical support, particularly in humans. A more cautious interpretation would consider chronicization as a useful explanatory model—one that highlights potential mechanisms of pain maintenance—without reifying it as an established biological trajectory. Maintaining a clear distinction between experimentally supported mechanisms, inferential models, and clinical observation is essential to preserve both scientific rigor and clinical relevance. We submit that acknowledging the limits of the chronicization paradigm does not weaken pain research, but rather strengthens it by keeping theoretical constructs open to refinement and verification. We do believe that the concept of chronicization has its clinical significance and can be useful for clinicians, for example in structuring follow‑up, designing interventions targeting central mechanisms, or framing long‑term rehabilitation strategies. More accurate investigations on human mechanisms of long term persistent pain can lead to more precise interventions and better treatment for patients.

We hope that this perspective may contribute to an ongoing and constructive discussion within the pain and pain physician communities, but also within people with lived experiences of pain.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Michael E Schatman is a senior medical advisor for Apurano Pharma, outside the submitted work. Andrea Tinnirello reports Consulting fees from Avanos medical; Honoraria from Avanos medical, outside the submitted work. Laura Demartini reports Consulting fees from Boston Scientific, Abbott; Honoraria from Boston Scientific, Abbott; Meeting/travel support from Boston Scientific; Data safety/advisory board participation from Bosotin Scientific, Abbott, outside the submitted work. The authors report no other conflicts of interest in this work.