Why Is Diabetic Neuropathy Painful?

Pain is universally disliked, so why does it exist? Pain is a great teacher. It’s how we learn not to touch a hot stove, not to stand on a broken leg, and not to fly economy if you’re over 6 feet tall. But as parents will attest, you really, really don’t want the teaching system to go wrong - though it often does. With diabetic peripheral neuropathy (DPN), the system can crash hard and leave painful reminders in its wake. In this article, we’ll cover what pain is, how diabetes can ruin the system, and what we can do about it. On the way, we’ll discuss what we know and don’t know about DPN, and how we can find out what we don’t know.

First, let’s cover what we know about pain. Pain is part of the somatosensory nervous system. This system includes nerves that tell the brain about touch, temperature, pressure, movement, and the like. Pain information is carried by special nerves. These require a high threshold to activate (so a feather on the skin doesn’t feel painful) and send an unignorable signal to the brain to teach us a lesson. This threshold can change under different conditions, becoming amplified or subdued - think about the sensitivity of a sunburn or the anesthetic effect of adrenaline. Unfortunately, some conditions like diabetes can amplify our perception of pain to a debilitating degree.

Diabetes is a condition where the body can’t process sugar correctly, leading to excess sugar in the blood. Over time, this can be detrimental to the body, causing damage to the blood vessels, heart, kidneys, and more. Large studies have found that up to 50% of people with diabetes may have damage to the nerves (neuropathy) in the body (peripheral nerves) that causes pain, a condition called painful diabetic peripheral neuropathy (PDPN).

What we know about PDPN is that it’s caused by damage, injury, or disease to the somatosensory nervous system. We know that normal pain responses are amplified. We also know a few of the ways in which this may start, but we don’t know exactly how this all works, so this is a “best guess.” With diabetes, blood sugar (glucose) can be excessively high. These sugars can glycate, or bond, to different proteins, changing them slightly. These changes allow them to hold onto metallic atoms within the blood vessels. These metals inhibit nitrous oxide production. From here, we know a little less. It seems that when the metals disrupt nitrous oxide production, blood vessels are less able to relax, making them constricted and unable to bring fresh blood to the feet and hands. Further, dangerous forms of oxygen can cause damage. We don’t know all of the pathways that diabetes disrupts, but the general path is clear. Diabetes leads to myriad metabolic problems within our cells, causing functional abnormalities where cells can’t perform well. Finally, the affected tissues are damaged. With PDPN, the neurons are the cells that are damaged or performing incorrectly.

Adding a wrinkle to what we don’t know about PDPN is that it doesn’t affect everyone in the same way. Genetics likely play a role in this. Studies in mice have shown that some genes are critical to the progression of PDPN. Another reason people have different responses to diabetes is that our bodies have to try to walk a tightrope when damage occurs. The body compensates for nerve damage by trying to restore any nerve signals that were lost. It cleans up debris, makes new nerve connections, readjusts the sensitivity settings, and more. Hopefully, the body gets this all just right and we can still feel and learn from our ability to touch and feel pain. When it overcompensates, however, we can get wonky signals that do more harm than good.

Painful diabetic peripheral neuropathy is just that - painful. It is characterized by chronic (long-lasting) pain. This pain can take three major forms. Hyperalgesia is increased pain signals; an ant bite may become unbearable. Allodynia is pain from things that usually aren’t painful; the feeling of a sock on your foot might send pain signals to the brain. Spontaneous pain is pain that arises from no apparent stimulus. On top of this, some nerves may not function at all, giving pain signals without giving normal sensory information that might be useful.

Finally, we get to what we really don’t know; how to solve PDPN. There are a few different classes of medication available. These include antidepressants such as tricyclic antidepressants and Serotonin-norepinephrine reuptake inhibitors (SNRIs). Anticonvulsants like gabapentinoids and pregabalin may also be prescribed. Opioids can also be prescribed for PDPN. Unfortunately, these medications are only associated with around a 50% reduction in pain severity, and there is a lot of room for improvement. This unfilled room is often filled with anecdotal and untested ideas. I’ve seen recommendations for changes in diet, abandoning medicines, vitamins, ice, and illegal and unregulated drugs. In an uncontrolled environment, some of these can be dangerous, and we don’t know which (if any) give repeatable relief to patients.

How do we find out what will help? Clinical trials! Clinical trials to research specific pathways and genes are underway and results are on the horizon. These trials use the power of statistics to find out which treatments are effective enough to become the medicines of tomorrow. With clinical trials, we don’t just learn the lessons pain teaches us, but the lessons on how to keep the teacher from going rogue.

Staff Writer / Editor Benton Lowey-Ball, BS, BFA

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References:

Chang, W., & Li, P. (2023). Copper and diabetes: current research and prospect. Molecular Nutrition & Food Research, 67(23), 2300468. https://doi.org/10.1002/mnfr.202300468

Costigan, M., Scholz, J., & Woolf, C. J. (2009). Neuropathic pain: a maladaptive response of the nervous system to damage. Annual review of neuroscience, 32(1), 1-32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768555/

Kostich, W., Hamman, B. D., Li, Y. W., Naidu, S., Dandapani, K., Feng, J., ... & Albright, C. F. (2016). Inhibition of AAK1 kinase as a novel therapeutic approach to treat neuropathic pain. Journal of Pharmacology and Experimental Therapeutics, 358(3), 371-386. https://jpet.aspetjournals.org/content/358/3/371

Malik, R. A. (2005). Diabetic peripheral neuropathy: linking microvascular etiology to potential treatments. Adv Stud Med, 5(3A), 144-9.

Qian, M., & Eaton, J. W. (2000). Glycochelates and the etiology of diabetic peripheral neuropathy. Free Radical Biology and Medicine, 28(4), 652-656. https://doi.org/10.1016/S0891-5849(99)00262-2

Singh, R., Kishore, L., & Kaur, N. (2014). Diabetic peripheral neuropathy: current perspective and future directions. Pharmacological research, 80, 21-35. http://dx.doi.org/10.1016/j.phrs.2013.12.005

Snedecor, S. J., Sudharshan, L., Cappelleri, J. C., Sadosky, A., Desai, P., Jalundhwala, Y., & Botteman, M. (2014). Systematic review and meta‐analysis of pharmacological therapies for pain associated with postherpetic neuralgia and less common neuropathic conditions. International Journal of Clinical Practice, 68(7), 900-918. https://onlinelibrary.wiley.com/doi/full/10.1111/ijcp.12411

Tesfaye, S., & Selvarajah, D. (2012). Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes/metabolism research and reviews, 28, 8-14. https://doi.org/10.1002/dmrr.2239

Watterworth, B., & Wright, T. B. (2019). Diabetic peripheral neuropathy. Pain: A Review Guide, 3-8, 911-913.