A biomarker of spinally-driven pain in diabetes
Research type
Research Study
Full title
A biomarker of spinally-driven pain in diabetes
IRAS ID
220627
Contact name
Andrew Marshall
Contact email
Sponsor organisation
University of Manchester
Duration of Study in the UK
2 years, 9 months, 31 days
Research summary
Research Summary
The most common complication of Type 1 and Type 2 diabetes is nerve damage (diabetic neuropathy). Over half of all patients developing nerve dysfunction in their lifetime, approximately 30% of which also report pain that can severely disrupt quality of life. There is no consistently effective treatment for this neuropathic pain and the underlying mechanisms are unclear. Current treatment options for pain in diabetes are effective in no better than 20-25% of patients and often involve a trial and error approach. Evidence is emerging that abnormalities in the way the spinal cord processes nerve signals occurs in diabetic neuropathy in both rodents and humans and, at least in rodents, that these abnormalities along with the associated neuropathic pain can be corrected.
Here we aim to study whether abnormalities in these spinal cord processes occur diabetic neuropathy and whether any such abnormality associates with particular clinical symptoms and signs. It is anticipated that the findings will help to define the mechanisms of pain generation in diabetic neuropathy and, by providing a marker of abnormalities in spinal cord processing, may lead to means of personalising treatment of neuropathic pain.
We propose to perform a cross-sectional study of 120 patients with diabetic neuropathy, 60 with and 60 without pain and 60 age-matched healthy controls. Studies will be performed in the Clinical Neurophysiology department at the Manchester Royal Infirmary. Patients and controls will attend for a single 3 hour visit. Participants will undergo detailed assessment of their neuropathy including standardised questionnaires, nerve conduction studies and corneal confocal microscopy. Neuropathic pain symptoms and signs will be carefully evaluated using standard testing of sensation. Spinal cord processing will be assessed using electrical tests on lower limb nerves. All tests are non-invasive with no side effects and are routinely performed in clinical practice.
Summary of Results
Damage to the nerves because of diabetes is called diabetic neuropathy and is the most common complication of diabetes. It affects the feet and can cause severe pain and distressing sensations which are difficult to treat. There are gaps in the understanding of the processes involved in the development of pain in diabetic neuropathy which has led to inadequate treatment. Diabetes causes damage to the ends of the nerve fibres, which leads to an increase of pain signals to the spinal cord. Normally the nerve circuits in the spinal cord would attempt to suppress these pain signals. However, in animal studies of diabetes, changes within the spinal cord inappropriately amplify these pain signals rather than suppress them – a process called spinal disinhibition. A biomarker (measure) of spinal disinhibition is a physiological measure called H-reflex rate dependent depression (HRDD), which can be tested non-invasively in humans.
We have demonstrated that HRDD is impaired in people with painful diabetic neuropathy. We have provided evidence of impaired and enhanced HRDD in patients with and without painful diabetic neuropathy, respectively which was not associated with the presence or severity of diabetic neuropathy. Additionally, the study details analysis to distinguish patients with painful diabetic neuropathy, specifically those whose pain is likely driven by spinal disinhibition. We have demonstrated HRDD to have excellent predictive ability and provided a detailed summary of its clinical utility.
Furthermore, detailed pain profiling using a method called quantitative sensory testing has revealed that greater impairment of HRDD is associated with higher patient ratings for burning pain and a ‘hyperpathia’ type profile, characterised by difficulty in detecting mechanical and thermal stimuli but once felt, an increased sensitivity to pain.
Finally, we assessed the transferability of HRDD into a clinic setting, in a time and cost-effective manner. We establish the use of the Neuropathy Disability Score as a predictor of H-reflex amplitude, to identify patients who may benefit from HRDD assessment.REC name
East Midlands - Leicester South Research Ethics Committee
REC reference
17/EM/0076
Date of REC Opinion
28 Feb 2017
REC opinion
Further Information Favourable Opinion