neck pain

Metabolic syndrome and chronic pain

We are currently experiencing a metabolic syndrome epidemic in modern societies, mostly driven by the development of wide spread insulin resistance. Metabolic syndrome is not only associated with arthritis and pain in one's joints, but many other areas in the body as well. A common complication of diabetes and metabolic syndrome is the loss of small nerve fibers in the skin and is associated increased pain sensation [1, 2]. Some have proposed that a loss in the regenerative capacity of nerves is driving this phenomena [2, 3]. Fibromyalgia, a complicated multi-factorial chronic pain condition is also highly associated with metabolic syndrome and is becoming increasingly common paralleling rising rates of all other chronic diseases of modern society [4].

In the context of arthritis, the pain that is experienced is THE most important part of the disease. It is the pain that reduces one's quality of life the most. It is the pain that reduces one's propensity to get up and move more throughout the day, thereby increasing sedentary behavior and contributing to the development of obesity, diabetes, high blood pressure, and heart disease.

It is also important to understand that not all arthritic joints are painful! I frequently see knee X-Rays that look terrible, yet the patient is doing just fine with only mild discomfort. I see others with mild arthritis on imaging, yet experiencing crippling pain. Studies have shown that the severity of osteoarthritis seen on X-Rays do not necessarily correlate with the person's degree of pain and dysfunction [5].

Further...chronic pain is THE driver of the current opioid epidemic in the United States. The CDC recently reported exponential increases in overdose deaths from synthetic opioids in the last year, with estimates of over 2 million Americans with opioid use disorders. This is a HUGE problem and we need as many tools as possible to manage pain and reduce opioid dependence. Especially non-opioid options.

opioids increase overdose
Carbohydrate Restriction and Ketosis may be one such tool in the toolbox...

Pain and Anticonvulsants Medications
Like seizures, chronic pain is thought to involve increased excitability of neurons of both the peripheral and central nervous systems [6, 7]. Anti-seizure medications work to blunt this excitability and are therefore also effective in treating neuropathic pain. A common example is gabapentin, which was originally developed for treating seizures and is now more commonly used to treat neuropathic pain.

Like anticonvulsant medications, it is well established that the ketogenic diet is effective at reducing seizures. Also similar to anticonvulsants, the ketogenic diet partly works by decreasing neuron excitability [8, 9]. Since there are some similarities in their mechanism-of-action, it is reasonable to hypothesize that the ketogenic diet may also be effective at reducing pain; especially neuropathic pain.

Fasting/Caloric restriction has been shown to decrease sensitivity to pain
Fasting and caloric restriction have been shown in animal studies to result in significant reduction in pain sensitivity regardless of the pain source (thermal, chemical, cutaneous, or visceral). This appears to act via activation of endogenous K-Opioid pathways which block pain signals centrally in the spinal cord [10, 11]. Fasting is a well-established method to induce ketosis, and this could be contributing to the effects on pain observed in these studies.

The neuromodulator, adenosine, has been shown to decrease pain levels [12, 13] and appears to be involved in acupuncture's beneficial effects [14, 15]. High-intensity exercise in an animal model has been shown to significantly reduce neuropathic pain by activating the adenosine pathways [16]. Fasting and the ketogenic diet both increase adenosine levels, presenting another potential pathway for improved pain control with these tools [17-21].

cell diagram
NLRP3 Inflammasome (nucleotide-binding and oligomerization domain-like receptor containing protein 3)
The NLRP3 inflammasome is an important part of our innate immune system which functions as the body's immediate defense against external and internal threats. Once activated, the NLRP3 inflammasome releases caspase-1 which activates pro-inflammatory cytokines IL-1B and IL-18 leading to a strong inflammatory response. The innate immune system is crucial for us to be able to mount a rapid defense against threats and is enormously advantageous to our survival [22]. It appears that this inflammasome (as well as several others) is involved in the body's pain pathways, in particular neuropathic pain and central nervous system (brain and spinal cord) mediated pain [23-27]. There is also evidence that it plays an important role in fibromyalgia, a common chronic pain disorder [24].

Fortunately for us, we have the capability for inhibiting this pathway without any medications!

The ketone body, beta-hydroxybutyrate (BHB), strongly inhibits the NLRP3 infammasome pathway [28]! BHB was shown to reduce NLRP3 mediated inflammatory cytokine (IL-1B and IL-18) production in HUMAN monocytes [29]. This has been demonstrated in multiple mouse models of other NLRP3-mediated diseases across the board with therapeutic benefits [30]. In a rodent model for gout, rats fed a ketogenic diet were significantly protected from IL-1B elevation, knee swelling, synovial inflammation, and joint necrosis when compared to the control group, and this was by direct NLRP3 and IL-1B inhibition [31].

For more detail on this pathway and its relationship to arthritis and the ketogenic diet, please see my prior blog post...

Research studies examining the ketogenic diet's influence on pain...

Reduced pain and inflammation in juvenile and adult rats fed a ketogenic diet (2009) [32]
In this study, rats were given a ketogenic diet for 3 weeks demonstrated significantly reduced pain response to heat compared to a control group. The ketogenic group also experienced significantly less of an inflammatory response compared to the control diet group.

BHB promotes functional recovery and relieves pain hypersensitivity in mice with spinal cord injury (2017) [33] Here, infused with BHB were significantly protected from a pain hypersensitivity phenomena that is commonly seen following a SCI. This was for both mechanical and thermal stimulation. They also noted inhibition of the NLRP3 inflammasome which likely played a role in these effects. AN IMPORTANT SIDE NOTE, is that the mice in the ketosis group also experienced less severe motor deficits from the spinal cord injury.

A ketogenic diet reduces metabolic syndrome-induced allodynia and promotes peripheral nerve growth in mice (2018) [34] In this study, a mouse model of metabolic syndrome was used, and the group that was fed a ketogenic diet experienced reversal of the increased pain sensitivity (allodynia) typically seen. In other words, it was able to reduce the hypersensitivity. Also, both a KD or ketone supplementation increased growth of the axons (hyperlink) of sensory nerves. This may be important in the pathogenesis of many chronic pain conditioning, and supports the idea that ketosis may be a useful tool in the management of peripheral neuropathy.

Ketogenic diets and thermal pain: dissociation of hypoalgesia, elevated ketones, and lowered glucose in rats (2013) [35]
This rat study demonstrated reduced thermal pain in the ketogenic diet group compared to the control diet group, and this appeared to be secondary to central nervous system adaptations. Interestingly, the onset of improved pain control did not correlate with the timing of lowered blood glucose or the elevation of ketone bodies.

Ketones and pain: unexplored role of HCAR2 in the pathophysiology of neuropathic pain (2018) [36]
This mouse study found that the ketone, BHB, reduced neuropathic pain, which appeared to have been mediated by an up-regulation in HCAR (hydroxyl carboxylic acid receptor type 2) in the sciatic nerve and dorsal root ganglion of neuropathic mice.

In closing...

There is currently an epidemic of opioid addiction and overdose deaths in the United states, and these medications are typically prescribed for chronic pain. This epidemic parallels an exponential increase in metabolic syndrome (with insulin resistance as the driver) which is highly associated with many chronic pain syndromes, including joint arthritic pain, peripheral neuropathy, and fibromyalgia. We need to develop more tools to combat this problem. Carbohydrate restriction and appropriate ketogenic diets can not only reduce metabolic syndrome and associated chronic disease, but may also be able to inhibit pain pathways directly. There are many anecdotal stories of reduced pain while on a ketogenic diet, or when fasting. There are also multiple animal studies demonstrating this phenomena. More research studies involving humans are needed to better characterize this effect.

  1. Callaghan, B. and E. Feldman, The metabolic syndrome and neuropathy: therapeutic challenges and opportunities. Ann Neurol, 2013. 74(3): p. 397-403.
  2. Smith, A.G. and J.R. Singleton, Obesity and hyperlipidemia are risk factors for early diabetic neuropathy. J Diabetes Complications, 2013. 27(5): p. 436-42.
  3. Singleton, J.R., et al., Supervised exercise improves cutaneous reinnervation capacity in metabolic syndrome patients. Ann Neurol, 2015. 77(1): p. 146-53.
  4. Loevinger, B.L., et al., Metabolic syndrome in women with chronic pain. Metabolism, 2007. 56(1): p. 87-93.
  5. Bedson, J. and P.R. Croft, The discordance between clinical and radiographic knee osteoarthritis: a systematic search and summary of the literature. BMC Musculoskelet Disord, 2008. 9: p. 116.
  6. Woolf, C.J., Evidence for a central component of post-injury pain hypersensitivity. Nature, 1983. 306(5944): p. 686-8.
  7. Raja, S.N., R.A. Meyer, and J.N. Campbell, Peripheral mechanisms of somatic pain. Anesthesiology, 1988. 68(4): p. 571-90.
  8. Bough, K.J., P.A. Schwartzkroin, and J.M. Rho, Calorie restriction and ketogenic diet diminish neuronal excitability in rat dentate gyrus in vivo. Epilepsia, 2003. 44(6): p. 752-60.
  9. Cantello, R., et al., Ketogenic diet: electrophysiological effects on the normal human cortex. Epilepsia, 2007. 48(9): p. 1756-1763.
  10. de los Santos-Arteaga, M., et al., Analgesia induced by dietary restriction is mediated by the kappa-opioid system. J Neurosci, 2003. 23(35): p. 11120-6.
  11. Hargraves, W.A. and I.D. Hentall, Analgesic effects of dietary caloric restriction in adult mice. Pain, 2005. 114(3): p. 455-61.
  12. Yarbrough, G.G. and J.C. McGuffin-Clineschmidt, In vivo behavioral assessment of central nervous system purinergic receptors. Eur J Pharmacol, 1981. 76(2-3): p. 137-44.
  13. Schmidt, A.P., et al., Anti-nociceptive properties of the xanthine oxidase inhibitor allopurinol in mice: role of A1 adenosine receptors. Br J Pharmacol, 2009. 156(1): p. 163-72.
  14. Goldman, N., et al., Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture. Nat Neurosci, 2010. 13(7): p. 883-8.
  15. Takano, T., et al., Traditional acupuncture triggers a local increase in adenosine in human subjects. J Pain, 2012. 13(12): p. 1215-23.
  16. Martins, D.F., et al., High-intensity swimming exercise reduces neuropathic pain in an animal model of complex regional pain syndrome type I: evidence for a role of the adenosinergic system. Neuroscience, 2013. 234: p. 69-76.
  17. Zhao, Y.T., S. Tekkok, and K. Krnjevic, 2-Deoxy-D-glucose-induced changes in membrane potential, input resistance, and excitatory postsynaptic potentials of CA1 hippocampal neurons. Can J Physiol Pharmacol, 1997. 75(5): p. 368-74.
  18. Minor, T.R., et al., Escape deficits induced by inescapable shock and metabolic stress are reversed by adenosine receptor antagonists. Behav Brain Res, 2001. 120(2): p. 203-12.
  19. Kawamura, M., Jr., D.N. Ruskin, and S.A. Masino, Metabolic autocrine regulation of neurons involves cooperation among pannexin hemichannels, adenosine receptors, and KATP channels. J Neurosci, 2010. 30(11): p. 3886-95.
  20. Jinka, T.R., et al., Altered thermoregulation via sensitization of A1 adenosine receptors in dietary-restricted rats. Psychopharmacology (Berl), 2010. 209(3): p. 217-24.
  21. Masino, S.A., et al., A ketogenic diet suppresses seizures in mice through adenosine A(1) receptors. J Clin Invest, 2011. 121(7): p. 2679-83.
  22. McAllister, M.J., et al., NLRP3 as a potentially novel biomarker for the management of osteoarthritis. Osteoarthritis and Cartilage, 2018. 26(5): p. 612-619.
  23. Jia, M., et al., Activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain. Mol Pain, 2017. 13: p. 1744806917719804.
  24. Bullon, P., et al., AMPK Phosphorylation Modulates Pain by Activation of NLRP3 Inflammasome. Antioxid Redox Signal, 2016. 24(3): p. 157-70.
  25. Pan, Z., et al., miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis. J Neuroinflammation, 2018. 15(1): p. 29.
  26. Khan, N., et al., Pharmacological inhibition of the NLRP3 inflammasome as a potential target for multiple sclerosis induced central neuropathic pain. Inflammopharmacology, 2018. 26(1): p. 77-86.
  27. Zhang, H., et al., The inflammasome as a target for pain therapy. Br J Anaesth, 2016. 117(6): p. 693-707.
  28. Yamanashi, T., et al., Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses. Sci Rep, 2017. 7(1): p. 7677.
  29. Youm, Y.H., et al., The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med, 2015. 21(3): p. 263-9.
  30. Coll, R.C., et al., A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med, 2015. 21(3): p. 248-55.
  31. Goldberg, E.L., et al., beta-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares. Cell Rep, 2017. 18(9): p. 2077-2087.
  32. Ruskin, D.N., M. Kawamura, and S.A. Masino, Reduced pain and inflammation in juvenile and adult rats fed a ketogenic diet. PLoS One, 2009. 4(12): p. e8349.
  33. Qian, J., et al., D-beta-hydroxybutyrate promotes functional recovery and relieves pain hypersensitivity in mice with spinal cord injury. Br J Pharmacol, 2017. 174(13): p. 1961-1971.
  34. Cooper, M.A., et al., A ketogenic diet reduces metabolic syndrome-induced allodynia and promotes peripheral nerve growth in mice. Exp Neurol, 2018. 306: p. 149-157.
  35. Ruskin, D.N., et al., Ketogenic diets and thermal pain: dissociation of hypoalgesia, elevated ketones, and lowered glucose in rats. J Pain, 2013. 14(5): p. 467-74.
  36. Boccella, S., et al., Ketones and pain: unexplored role of hydroxyl carboxylic acid receptor type 2 in the pathophysiology of neuropathic pain. Faseb j, 2018: p. fj201801033R.
  37. Ziegler, D.R., et al., Nociception and locomotor activity are increased in ketogenic diet fed rats. Physiol Behav, 2005. 84(3): p. 421-7.