Warmth where there should be cold: an early sign of sensory loss?

Aims: This longitudinal study aimed to determine whether paradoxical heat sensation (PHS) is associated with somatosensory dysfunction and whether it can predict future thermal sensory loss or the development of diabetic polyneuropathy (DPN).

Methods: The study followed 420 individuals (263 with DPN, 62 with diabetes but no DPN, and 95 healthy controls) over a 5-year period. All participants underwent quantitative sensory testing (QST), nerve conduction studies (NCS), and skin biopsies to assess intraepidermal nerve fiber density (IENFD). PHS was assessed using the thermal sensory limen procedure from the original QST protocol and was defined as a warm or burning sensation during skin cooling.

Results: At baseline, PHS was more frequent in individuals with DPN than in controls (51% vs 32%, p=0.001) but there was no difference between people with diabetes with and without DPN or with or without neuropathic pain. Among individuals with normal thermal thresholds at baseline, those with PHS had a significantly higher risk of thermal sensory loss at follow-up (OR 3.6, p=0.026). PHS was overall associated with thermal sensory loss, but no predictive association was observed between PHS and incident DPN.

Conclusions: PHS is associated with impaired thermal sensation and may represent an early functional marker of small fiber dysfunction. It appears independent of neuropathic pain and is not predictive of DPN onset but may have value in identifying subclinical sensory impairment.

Comments: This is the first longitudinal study to examine the prognostic value of PHS in a well-characterized cohort with diabetes. The findings confirm cross-sectional observations that PHS is linked to thermal sensory loss and extend this by demonstrating its association with progressive thermal dysfunction over time. Notably, PHS was independent of neuropathic pain and did not differentiate between painful and painless DPN phenotypes, reinforcing its interpretation as a marker of altered sensory processing rather than of pain generation.

The study is methodologically robust, leveraging a large, well-phenotyped cohort with standardized protocols. Its longitudinal design provides novel insights into the temporal dynamics of sensory loss in diabetes, and the identification of PHS as a potential early indicator of future thermal dysfunction justifies its continued use in QST protocols.

However, the lack of association between baseline PHS and the future development of DPN limits its prognostic utility. Furthermore, the moderate follow-up participation rate and lack of cold/warm pain thresholds may restrict the interpretability of certain sensory dimensions. Nonetheless, these limitations are balanced by the comprehensive sensory profiling and rigorous statistical approach.

Overall, this study strengthens the evidence that PHS reflects early small fiber dysfunction and highlights its potential role in detecting subclinical sensory changes in diabetes. Further studies are warranted to explore its utility in other at-risk populations, especially amongst individuals without DPN at baseline.

Johan Røikjer

Reference: Schaldemose EL, Brask-Thomsen PK, Itani M, Fardo F, Karlsson P, Kristensen AG, Tankisi H, Jensen TS, Baron R, Finnerup NB, Gylfadottir SS. A longitudinal study of paradoxical heat sensation in 420 individuals. Pain. 2025 May 20. doi: 10.1097/j.pain.0000000000003652. Epub ahead of print. PMID: 40408231.

🔗https://journals.lww.com/pain/abstract/9900/a_longitudinal_study_of_paradoxical_heat_sensation.917.aspx