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

Andreas C Themistocleous,Solomon Tesfaye,Dinesh Selvarajah,David L.H Bennett,Juan D Ramirez,Christine Orengo,Andrew S.C Rice,Pallai R Shillo,Jonathan G Lees

doi:10.1097/j.pain.0000000000000491

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.

Highlights

We have undertaken detailed sensory phenotyping using patientreported pain descriptors, sensory examination, and quantitative sensory testing (QST) in a large cohort of patients with diabetic neuropathy, predominantly in those with type 2 diabetes mellitus. This sensory phenotype has been compared in patients with and without neuropathic pain (NeuP) and related to detailed assessment of neuropathy severity
Key findings are that the Douleur Neuropathique en 4 Questions (DN4) questionnaire performed extremely well as a screening instrument for NeuP in this population, the presence of NeuP was associated with more advanced Diabetic peripheral neuropathy (DPN) and higher HbA1c, and QST revealed hyposensitivity across a range of smallfibre and large-fibre mediated sensory modalities, and this sensory loss was most marked in patients with moderate/severe NeuP compared with patients with mild or no NeuP
A minority of patients had sensory gain signs, and very few patients with NeuP would be classified in the “irritable nociceptor” group

Summary

Introduction

Diabetic peripheral neuropathy (DPN) is one of the most frequent complications of diabetes mellitus[46] and affects between 28% and 49% of patients.[1,53] Between 25% and 50% of patients with DPN develop neuropathic pain (NeuP)1,8,50—defined as pain arising as a consequence of a lesion or disease of the a Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom, b Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom, c Structural & Molecular Biology, Division of Biosciences, University College London, London, United Kingdom, d Pain Research Group, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital Campus, London, United Kingdom, e Pain Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom

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