Uncertain Trajectories in Neuropathic Pain: Rethinking Treatment Response

Abstract

Chronic neuropathic pain remains one of the most elusive clinical challenges. Despite advances in pharmacology, neuroscience, and phenotypic characterisation, patient trajectories continue to be marked by profound heterogeneity. Some individuals improve, others stagnate, and a few even deteriorate—without a clear ability to anticipate these outcomes. In a context where mechanistic classifications of pain are beginning to show their limitations, and where nociplasticity is emerging as an integrative paradigm, it becomes urgent to reconsider how we evaluate clinical evolution in patients with neuropathic pain. The recent study by Moisset et al. offers an original perspective on this challenge: rather than assessing treatment response as a static endpoint, it proposes viewing it as a trajectory—a curve unfolding over time. This longitudinal approach, grounded in group-based trajectory modelling, enables the identification of evolutionary patterns that elude conventional analyses. It is not merely a question of how much a patient improves, but how, when, and under what circumstances that improvement occurs (Moisset et al. 2025).

The study is based on patients treated in multidisciplinary tertiary care centers, ensuring specialised assessment and structured follow-up. Through this approach, the authors identify three distinct clinical trajectories: one characterised by moderate pain that progressively decreases over time; another marked by persistent moderate pain with no significant change; and a third defined by severe pain that remains stable throughout the follow-up period. These trajectories are not interpreted as fixed response categories, but rather as dynamic expressions of the pain experience. Each poses different challenges in terms of monitoring, therapeutic adjustment, and clinical communication. This segmentation does not aim to label or oversimplify, but rather to offer a more sensitive lens through which to observe the evolution of pain. Nevertheless, it raises inevitable questions: how can these patterns be translated into concrete clinical decisions? Can we anticipate a patient's trajectory during consultation? And what tools do we need to do so without falling into reductionism?

Factors associated with more favourable outcomes—such as age, pain duration, baseline intensity, psychiatric comorbidities, and type of treatment—have been identified in previous studies, yet their predictive capacity remains limited. In practice, each patient's evolution challenges linear models and statistical expectations. Some improve unexpectedly, while others fail to respond despite all efforts. This compels us to ask whether we are truly measuring what matters. What variables are being left out of our algorithms? What role do social determinants, personal narratives, expectations, and the therapeutic relationship play?

Personalised medicine has become a therapeutic ideal, yet in the context of neuropathic pain, that ideal collides with the reality of diffuse pathophysiology, unpredictable treatment response, and a subjective experience that resists modelling. Interindividual variability compels us to rethink our diagnostic categories and pharmacological strategies. The mechanistic classification of pain—nociceptive, neuropathic, nociplastic—proves insufficient to capture clinical complexity. While mechanism-based approaches have been useful in guiding drug development, they have not translated into robust therapeutic algorithms. From this perspective, trajectory-based models may offer a meaningful dialogue with the nociplastic paradigm, as they capture not only pain intensity but also its temporal evolution, emotional burden, and functional impact. However, their implementation demands a profound transformation of the clinical approach—one that includes digital tools, targeted training, and a renewed sensitivity to the unfolding of suffering (Ablin 2024).

One of the most valuable contributions of the study by Moisset et al. is its implicit invitation to consider trajectories not only of pain, but also of suffering, functionality, and quality of life. Neuropathic pain is not a number on a scale—it is a lived experience that transforms, becomes chronic, and is redefined over time. There is an urgent need to incorporate multidimensional measures into clinical studies and routine care. Do we need to redefine what we mean by “response”? Is pain reduction sufficient, or should functional and emotional dimensions be included? What does “improvement” truly mean in the context of chronic pain? Clinical trials should systematically include aspects such as emotional impact, sleep, physical activity, social participation, and treatment satisfaction. This broader perspective would not only allow for a more accurate assessment of treatment response, but also prompt a deeper reflection on what it truly means to “improve” in the context of chronic pain (Dworkin et al. 2005). These questions challenge not only research frameworks, but also everyday clinical practice.

In parallel, other studies have attempted to correlate sensory profiles with pharmacological response, yielding mixed results. Attal et al. proposed a phenotypic classification based on quantitative sensory testing, with the aim of identifying subgroups more responsive to specific treatments. However, the clinical translation of these findings has been limited. Intraindividual variability, the influence of psychosocial factors, and the lack of reliable biomarkers continue to hinder therapeutic personalization (Attal et al. 2011). While the study by Moisset et al. does not rely on sensory phenotypes, its longitudinal approach could complement them by offering a temporal dimension that cross-sectional studies fail to capture.

In summary, the work by Moisset et al. offers a valuable contribution to the study of chronic neuropathic pain, while raising questions that warrant further investigation. Their analytical approach, though promising, requires validation and expansion to achieve genuine clinical utility. The identification of differentiated trajectories is an important step, but their integration into routine care will depend on additional studies that confirm their relevance and applicability. If validated, these models could reshape how we monitor, stratify, and support patients with chronic neuropathic pain.

Moisset, X., M. G. Pagé, B. Pereira, and M. Choinière. 2025. “Patient Subgroups and Predictors of Improvement in Chronic Neuropathic Pain: A Trajectory-Based Analysis,” European Journal of Pain 29, no. 10: e70137, https://doi.org/10.1002/ejp.70137.