Tracking pain over time in diabetic neuropathy: who develops pain—and who recovers?

Aims: To examine the development of Painful-Diabetic Peripheral Neuropathy (Painful-DPN) over time, as well as identify factors associated with the development and relief of neuropathic pain in people with DPN.

Methods: This 5-year follow-up study of 102 people with at least probable DPN at baseline (Toronto criteria) (Tesfaye S et al Diabetes Care. 2010;33:2285–93), recruited from a nationwide Danish cohort of people with newly diagnosed type 2 diabetes. All participants underwent clinical assessment (history and examination), Quantitative Sensory Testing (QST) according to German Pain Research Network Protocol (Rolke R et al Pain. 2006;123:231–43), nerve conduction studies (NCS) at baseline and follow-up. Participants also underwent sensory mapping of lower limbs into five distal-to-proximal regions to determine spread of DPN with time. Participants were grouped according to presence of painful symptoms (P-DPN), symptoms which were non-painful but unpleasant dysaesthesia (D-DPN), or no sensations (N-DPN).

Results: The estimated prevalence of Painful-DPN increased from 11.5% to 14.8% at follow-up, with a higher proportion of those with dysesthesia symptoms (D-DPN) developing neuropathic pain (42.9%) compared to those without symptoms (27.9%, Chi-Square test p<0.01). Predictors of developing neuropathic pain included being female (47.6% vs. 18.6%), and a lower warm sensitivity on QST and lower baseline sural nerve amplitude on NCS. Those who had developed pain had higher HbA1c levels at follow-up versus baseline. For those who had P-DPN at baseline, 28.9% had relief of pain, which was associated with lower baseline BMI and total cholesterol, and better cold, mechanical and vibration detection thresholds. LDL fell in the group who had relief of pain and was lower at follow-up compared to those with persistent pain. Generally, spread of hyposensitivity was greater from baseline to follow-up, but was greater (and increased more) in those who developed pain.

Conclusions: Painful-DPN is a dynamic condition, with both progression and regression observed over time. Dysesthesia may represent a precursor state to neuropathic pain, and greater neuropathic severity appears to be associated with pain development, whereas more preserved sensory function and favourable metabolic profiles are associated with pain relief.

Comments: Despite decades of research, there is an incomplete understanding of the mechanisms underlying Painful-DPN. This is the main reason that newer therapies for the condition have either failed or led to modest improvements in pain at best. Notably, longitudinal data on the natural history of Painful-DPN has been sparse. This well-phenotyped prospective study is therefore a welcome addition to the literature, which confirms female sex as a key biological risk factor for Painful-DPN, consistent with other publications examining risk factors of the condition (Elliott J et al Diabetologia. 2024;67:190–8). Moreover, the study highlights that greater neuropathic impairment may be associated with Painful-DPN. The study also observed that nearly one-third of people with Painful-DPN have regression of neuropathic pain, suggesting the condition may be potentially reversible in some, possibly linked to metabolic factors, although larger studies would be needed to confirm this observation. Now larger studies which incorporate multimodal mechanistic approaches (including genetics, neuroimaging, serum biomarkers, psychometric measures, and small-fibre functional assessment) are urgently required to give further insight into the aetiology of Painful-DPN and factors leading to progression and regression of the disorder.

Gordon Sloan

Reference. Brask-Thomsen PK, Itani M, Karlsson P, Kristensen AG, Krøigård T, Jensen TS, Tankisi H, Sindrup SH, Finnerup NB, Gylfadottir SS. Neuropathic pain in diabetic polyneuropathy: a 5-year prospective study. PAIN. 2025 Nov;166(11):e527–e542. doi: 10.1097/j.pain.0000000000003649. Epub 2025 May 13. PMID: 40359373.

🔗 https://journals.lww.com/pain/abstract/2025/11000/neuropathic_pain_in_diabetic_polyneuropathy__a.34.aspx