In their position paper in this journal, Häuser and Kosek (2026) challenge the notion that fibromyalgia (FM) invariably represents a prototype of ‘pure’ nociplastic pain. They argue that nociplastic mechanisms often operate on a continuum rather than as discrete categories and question the strict exclusion of nociceptive or neuropathic components for diagnosis. We fully agree with this nuanced view. Nevertheless, FM remains a paradigmatic clinical exemplar of predominant nociplastic pain, defined by the IASP as pain arising from altered nociception without adequate explanation by nociceptive tissue damage or neuropathic lesions. Given the high comorbidity with major depressive disorder (MDD; pooled prevalence approximately 40%–55% according to recent meta-analyses), a relevant proportion of patients diagnosed with FM likely present a mixed or amplified phenotype in which MDD contributes significantly to the nociplastic features through affective, cognitive and neuroinflammatory pathways (Jafari et al. 2026). This commentary does not propose to redefine FM or to exclude MDD-comorbid cases from the diagnosis. Instead, we argue for phenotypic stratification within FM cohorts to better account for this heterogeneity and to extend the nociplastic pain debate initiated by Häuser and Kosek (2026). The clinical overlap is substantial: extreme fatigue, cognitive dysfunction (‘fibro-fog’), non-restorative sleep and anhedonia frequently coexist with widespread pain. Network and resting-state fMRI studies show shared neural signatures, such as disrupted insula-frontal and hippocampal-cingulate connectivity, associated with catastrophizing and affective dysregulation. Bidirectional Mendelian randomization studies yield mixed results—some indicate no clear unidirectional genetic causality from MDD to FM, while others suggest an elevated risk for myalgia-related disorders in depression—pointing toward shared genetic vulnerability or phenotype-specific effects (Wei et al. 2025). Chronology of symptoms onset: Widespread pain and tenderness clearly preceding the first major depressive episodes (by ≥ 6 months) versus pain symptoms emerging or markedly worsening in close temporal association with MDD episodes. Symptom predominance and severity: High Widespread Pain Index (WPI ≥ 7) and Symptom Severity Score (SSS ≥ 9) with relatively mild depressive symptoms (PHQ-9 < 10 or BDI-II < 14) versus prominent affective-cognitive symptoms (PHQ-9 ≥ 15 or BDI-II ≥ 20) with secondary widespread pain. Treatment response pattern: Limited or partial improvement of pain with antidepressants alone in FM-dominant cases versus substantial and concurrent improvement of both widespread pain and fatigue with antidepressant monotherapy (SNRIs, mirtazapine) in MDD-contributed cases. Objective sensitization measures (when available): Lowered pressure pain thresholds on algometry and high Central Sensitization Inventory (CSI) score with lower psychological distress versus high CSI score driven mainly by affective items (Pettersen et al. 2025). These criteria remain provisional and require prospective validation. This framework is intended as a pragmatic starting point to reduce heterogeneity rather than as definitive diagnostic categories. We emphasize that significant overlap exists between phenotypes and that the CSI correlates with both central sensitization and psychological distress, limiting its specificity. Nevertheless, systematic use of this framework combined with structured DSM-5/ICD-11 psychiatric assessment can improve phenotypic characterization in both clinical care and research settings. Routine structured psychiatric assessment (DSM-5/ICD-11) combined with validated tools such as the Central Sensitization Inventory (CSI), PHQ-9 or BDI-II and algometry is recommended at diagnosis, in line with EULAR recommendations. Superficial screening frequently misses primary or severe MDD. Several reports describe substantial or near-complete resolution of diffuse pain and fatigue with adequate thymoleptic antidepressant treatment, although underlying nociplastic features may persist or recur upon MDD relapse. Untreated moderate-to-severe MDD can heighten nociplastic sensitization and reduce response to purely nociception-targeted therapies. Failure to account for this MDD contribution introduces phenotypic heterogeneity in FM cohorts and may partly explain inconsistent replication of nociplastic-targeted interventions in randomized controlled trials (RCTs). We therefore recommend that structured depression screening become mandatory in future FM RCT protocols to improve cohort homogeneity and better isolate treatment effects in nociplastic-dominant subgroups. While currently unavailable in routine practice, advanced research tools such as resting-state fMRI (showing overlapping yet partly distinct patterns of insula-ACC and default-mode network connectivity) and multi-omics approaches hold promise for future objective stratification. These methods remain investigational and should not yet be considered clinical recommendations. In conclusion, FM retains full validity as a nociplastic pain syndrome underpinned by central sensitization, small-fibre pathology in subsets and neuroinflammatory processes—even when MDD significantly shapes or amplifies the phenotype. A meaningful subset of widespread nociplastic presentations may be driven or exacerbated by MDD-related mechanisms, particularly when affective features predominate or respond preferentially to antidepressants. By prioritizing careful clinical differentiation and systematic psychiatric assessment, the pain community can reduce heterogeneity in research, mitigate biases in RCTs, and personalize care. This phenotypic stratification framework extends the important debate opened by Häuser and Kosek (2026) and aligns with recent calls for integrated pain-psychiatry models.
Hugues Magne (Wed,) studied this question.