The Pain in Neuropathy Study (PiNS): a cross-sectional observational study determining the somatosensory phenotype of painful and painless diabetic neuropathy

Abstract

Disabling neuropathic pain (NeuP) is a common sequel of diabetic peripheral neuropathy (DPN). We aimed to characterise the sensory phenotype of patients with and without NeuP, assess screening tools for NeuP, and relate DPN severity to NeuP. The Pain in Neuropathy Study (PiNS) is an observational cross-sectional multicentre study. A total of 191 patients with DPN underwent neurological examination, quantitative sensory testing, nerve conduction studies, and skin biopsy for intraepidermal nerve fibre density assessment. A set of questionnaires assessed the presence of pain, pain intensity, pain distribution, and the psychological and functional impact of pain. Patients were divided according to the presence of DPN, and thereafter according to the presence and severity of NeuP. The DN4 questionnaire demonstrated excellent sensitivity (88%) and specificity (93%) in screening for NeuP. There was a positive correlation between greater neuropathy severity (r = 0.39, P < 0.01), higher HbA1c (r = 0.21, P < 0.01), and the presence (and severity) of NeuP. Diabetic peripheral neuropathy sensory phenotype is characterised by hyposensitivity to applied stimuli that was more marked in the moderate/severe NeuP group than in the mild NeuP or no NeuP groups. Brush-evoked allodynia was present in only those with NeuP (15%); the paradoxical heat sensation did not discriminate between those with (40%) and without (41.3%) NeuP. The "irritable nociceptor" subgroup could only be applied to a minority of patients (6.3%) with NeuP. This study provides a firm basis to rationalise further phenotyping of painful DPN, for instance, stratification of patients with DPN for analgesic drug trials.

Figure 1

Flow diagram of study participant recruitment and the criteria used to subdivide the study participants into the different subgroups.

Figure 2

Scatter plot of (A) DN4 scores, (B) painDETECT scores, against 7-day pain intensity diary mean. All screening scores were highly correlated with the 7-day pain dairy mean (Spearman correlation).

Figure 3

(A) Scatter plot and median (interquartile range [IQR]) of Toronto Clinical Scoring System (TCSS) scores for study participants with no peripheral diabetic neuropathy, and diabetic neuropathy with no neuropathic pain (NeuP), mild NeuP, moderate/severe NeuP. Kruskal–Wallis, Dunn multiple comparison test: **P < 0.01. (B) Scatter plot and median (IQR) of intraepidermal nerve fibre density (IENFD) from the distal leg for study participants with no peripheral diabetic neuropathy, and diabetic neuropathy with no NeuP, mild NeuP, moderate/severe NeuP. Intraepidermal nerve fibre densities were determined for 182 (87%) study participants. Kruskal–Wallis, Dunn multiple comparison test: **P < 0.01. (C) Heat maps obtained from the 7-day pain diary demonstrating the areas of NeuP (in red) and non-NeuP (in blue) within the study participants with diabetic neuropathy and no NeuP, mild NeuP, and moderate/severe NeuP.

Figure 4

Scatter plot of (A) Toronto Clinical Scoring System (TCSS), and (B) MRC sensory sum score scores, against the 7-day pain intensity diary mean showing a correlation of clinical neuropathy severity and neuropathic pain intensity (Spearman correlations).

Figure 5

(A) Scatter plot and mean ± 95% CI of z-scores for thermal quantitative sensory testing (QST) parameters in study participants with no neuropathic pain (NeuP), mild NeuP, and moderate/severe NeuP. One-way analysis of variance (ANOVA), least significant difference (LSD) post hoc test: *P < 0.05; **P < 0.01. (B) Scatter plot and mean ± 95% confidence interval of z-scores for mechanical QST parameters in study participants with no NeuP, mild NeuP, and moderate/severe NeuP. One-way ANOVA, LSD post hoc test: **P < 0.01. (C) Loss and gain of sensory function. Comparison of study participants with no NeuP, mild NeuP, and moderate/severe NeuP who have QST values outside the 95% confidence interval of the German research network of neuropathic pain reference database. The y-axis shows the percentage of patients in each group with ‘gain’ of sensory function plotted upwards and “loss” of sensory function plotted downwards. Data analysed with χ² test of association: †P < 0.05, ††P < 0.01 between no NeuP and moderate/severe NeuP, ##P < 0.01 between no NeuP and mild NeuP, ‡P < 0.05 between mild NeuP and moderate/severe NeuP. CDT, cold detection threshold; CPT, cold pain threshold; HPT, heat pain threshold; MDT, mechanical detection threshold; MPS, mechanical pain sensitivity; MPT, mechanical pain threshold; PPT, pressure pain threshold; TSL, thermal sensory limen; VDT, vibration detection threshold; WDT, warm detection threshold; WUR, wind-up ratio.

Figure 6

Venn diagram demonstrating the number of participants with brush-evoked allodynia reported only on questionnaires, dynamic mechanical allodynia only on examination, participants with both reported allodynia and allodynia on examination.