Painful and Painless Diabetic Neuropathies: What Is the Difference?

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Abstract

Purpose of Review

The prevalence of diabetes mellitus and its chronic complications are increasing to epidemic proportions. This will unfortunately result in massive increases in diabetic distal symmetrical polyneuropathy (DPN) and its troublesome sequelae, including disabling neuropathic pain (painful-DPN), which affects around 25% of patients with diabetes. Why these patients develop neuropathic pain, while others with a similar degree of neuropathy do not, is not clearly understood. This review will look at recent advances that may shed some light on the differences between painful and painless-DPN.

Recent Findings

Gender, clinical pain phenotyping, serum biomarkers, brain imaging, genetics, and skin biopsy findings have been reported to differentiate painful- from painless-DPN.

Summary

Painful-DPN seems to be associated with female gender and small fiber dysfunction. Moreover, recent brain imaging studies have found neuropathic pain signatures within the central nervous system; however, whether this is the cause or effect of the pain is yet to be determined. Further research is urgently required to develop our understanding of the pathogenesis of pain in DPN in order to develop new and effective mechanistic treatments for painful-DPN.

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Most cited references 120

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New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain.

Eva Feldman, David Bennett, Klaus-Armin Nave … (2017)

Pre-diabetes and diabetes are a global epidemic, and the associated neuropathic complications create a substantial burden on both the afflicted patients and society as a whole. Given the enormity of the problem and the lack of effective therapies, there is a pressing need to understand the mechanisms underlying diabetic neuropathy (DN). In this review, we present the structural components of the peripheral nervous system that underlie its susceptibility to metabolic insults and then discuss the pathways that contribute to peripheral nerve injury in DN. We also discuss systems biology insights gleaned from the recent advances in biotechnology and bioinformatics, emerging ideas centered on the axon-Schwann cell relationship and associated bioenergetic crosstalk, and the rapid expansion of our knowledge of the mechanisms contributing to neuropathic pain in diabetes. These recent advances in our understanding of DN pathogenesis are paving the way for critical mechanism-based therapy development.

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The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study.

P J Dyck, K. M. Kratz, J L Karnes … (1993)

The magnitude of the health problem from diabetic neuropathies remains inadequately estimated due to the lack of prospective population-based studies employing standardized and validated assessments of the type and stage of neuropathy as compared with background frequency. All Rochester, Minnesota, residents with diabetes mellitus on January 1, 1986, were invited to participate in a cross-sectional and longitudinal study of diabetic neuropathies (and also of other microvascular and macrovascular complications). Of 64,573 inhabitants on January 1, 1986 in Rochester, 870 (1.3%) had clinically recognized diabetes mellitus (National Diabetes Data Group criteria), of whom 380 were enrolled in the Rochester Diabetic Neuropathy Study. Of these, 102 (26.8%) had insulin-dependent diabetes mellitus (IDDM), and 278 (73.2%) had non-insulin-dependent diabetes mellitus (NIDDM). Approximately 10% of diabetic patients had neurologic deficits attributable to nondiabetic causes. Sixty-six percent of IDDM patients had some form of neuropathy; the frequencies of individual types were as follows: polyneuropathy, 54%; carpal tunnel syndrome, asymptomatic, 22%, and symptomatic, 11%; visceral autonomic neuropathy, 7%, and other varieties, 3%. Among NIDDM patients, 59% had various neuropathies; the individual percentages were 45%, 29%, 6%, 5%, and 3%. Symptomatic degrees of polyneuropathy occurred in only 15% of IDDM and 13% of NIDDM patients. The more severe stage of polyneuropathy, to the point that patients were unable to walk on their heels and also had distal sensory and autonomic deficits (stage 2b) occurred even less frequently--6% of IDDM and 1% of NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

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Descending pain modulation and chronification of pain.

Michael Ossipov, Frank Porreca, K Morimura (2014)

Chronic pain is an important public health problem that negatively impacts quality of life of affected individuals and exacts an enormous socio-economic cost. Currently available therapeutics provide inadequate management of pain in many patients. Acute pain states generally resolve in most patients. However, for reasons that are poorly understood, in some individuals, acute pain can transform to a chronic state. Our understanding of the risk factors that underlie the development of chronic pain is limited. Recent studies have suggested an important contribution of dysfunction in descending pain modulatory circuits to pain 'chronification'. Human studies provide insights into possible endogenous and exogenous factors that may promote the conversion of pain into a chronic condition. Descending pain modulatory systems have been studied and characterized in animal models. Human brain imaging techniques, deep brain stimulation and the mechanisms of action of drugs that are effective in the treatment of pain confirm the clinical relevance of top-down pain modulatory circuits. Growing evidence supports the concept that chronic pain is associated with a dysregulation in descending pain modulation. Disruption of the balance of descending modulatory circuits to favour facilitation may promote and maintain chronic pain. Recent findings suggest that diminished descending inhibition is likely to be an important element in determining whether pain may become chronic. This view is consistent with the clinical success of drugs that enhance spinal noradrenergic activity, such as serotonin/norepinephrine reuptake inhibitors (SNRIs), in the treatment of chronic pain states. Consistent with this concept, a robust descending inhibitory system may be normally engaged to protect against the development of chronic pain. Imaging studies show that higher cortical and subcortical centres that govern emotional, motivational and cognitive processes communicate directly with descending pain modulatory circuits providing a mechanistic basis to explain how exogenous factors can influence the expression of chronic pain in a susceptible individual. Preclinical studies coupled with clinical pharmacologic and neuroimaging investigations have advanced our understanding of brain circuits that modulate pain. Descending pain facilitatory and inhibitory circuits arising ultimately in the brainstem provide mechanisms that can be engaged to promote or protect against pain 'chronification'. These systems interact with higher centres, thus providing a means through which exogenous factors can influence the risk of pain chronification. A greater understanding of the role of descending pain modulation can lead to novel therapeutic directions aimed at normalizing aberrant processes that can lead to chronic pain.

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Author and article information

Contributors

Pallai Shillo: shillopr@yahoo.com

Gordon Sloan: Gordon.sloan@nhs.net

Marni Greig: Marni.Greig@sth.nhs.uk

Leanne Hunt: Leanne.Hunt@sth.nhs.uk

Dinesh Selvarajah: Dinesh.Selvarajah@sth.nhs.uk

Jackie Elliott: Jackie.Elliott@sth.nhs.uk

Rajiv Gandhi: Rajiv.Gandhi@sth.nhs.uk

Iain D. Wilkinson: i.d.wilkinson@sheffield.ac.uk

Solomon Tesfaye: solomon.tesfaye@sth.nhs.uk , s.tesfaye@sheffiedl.ac.uk

Journal

Journal ID (nlm-ta): Curr Diab Rep

Journal ID (iso-abbrev): Curr. Diab. Rep

Title: Current Diabetes Reports

Publisher: Springer US (New York )

ISSN (Print): 1534-4827

ISSN (Electronic): 1539-0829

Publication date (Electronic): 7 May 2019

Publication date PMC-release: 7 May 2019

Publication date (Print): 2019

Volume: 19

Issue: 6

Electronic Location Identifier: 32

Affiliations

[1 ]ISNI 0000 0000 9422 8284, GRID grid.31410.37, Diabetes Research Unit, Royal Hallamshire Hospital, , Sheffield Teaching Hospitals NHS Foundation Trust, ; Glossop Road, Sheffield, S10 2JF UK

[2 ]ISNI 0000 0004 1936 9262, GRID grid.11835.3e, Department of Oncology and Human Metabolism, , University of Sheffield, ; Sheffield, UK

[3 ]ISNI 0000 0004 1936 9262, GRID grid.11835.3e, Academic Unit of Radiology, , University of Sheffield, ; Sheffield, UK

Article

Publisher ID: 1150

DOI: 10.1007/s11892-019-1150-5

PMC ID: 6505492

PubMed ID: 31065863

SO-VID: 50c8b478-46d6-42bc-9dfe-86630dac9571

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Funding

Funded by: University of Sheffield

Custom metadata

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: diabetes,peripheral neuropathy,neuropathic pain,small fiber neuropathy,painful diabetic neuropathy,diabetic neuropathy

Data availability:

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: diabetes, peripheral neuropathy, neuropathic pain, small fiber neuropathy, painful diabetic neuropathy, diabetic neuropathy

Painful and Painless Diabetic Neuropathies: What Is the Difference?

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Abstract

Purpose of Review

Recent Findings

Summary

Related collections

Bioscientifica Open Endocrinology

Most cited references 120

New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain.

The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study.

Descending pain modulation and chronification of pain.

Author and article information

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Affiliations

Article

History

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