Understanding of the gut microbiome is leading to new strategies for treating neuropathic pain, including trigeminal neuralgia, postherpetic neuralgia, and radiculopathy. Plus, IASP’s new classifications for peripheral neuropathic pain.
Research presented at the American Academy of Neurology (AAN) annual meeting over a decade ago first showed that individuals with inflammatory bowel disease (IBD) were about four times more likely to develop neuromuscular conditions, including carpal tunnel syndrome and small fiber neuropathy, and six times more likely to have sensorimotor polyneuropathy.¹ Since then, investigations have confirmed that the bidirectional communication between the gut and brain involves immune, neural, endocrine, and metabolic routes, and that the microbiota-gut-brain axis is the nexus of interactions among them.
Peripheral neuropathic pain is categorized by IASP as including trigeminal neuralgia, peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, and painful radiculopathy (Image: iStock).
Dysregulated communication causing imbalances in the microbiota-gut-brain axis may be a factor in overall gastrointestinal (GI) functional disorders and recently has been implicated in Alzheimer’s disease, Parkinson’s disease, depression, and chronic pain.
Neuropathic Pain and The Gut Microbiota
A key thread through many of these disorders is the central nervous system (CNS) and neuropathic pain. Neuropathic pain is the abnormal perception of pain caused by a lesion or disease of the somatosensory nervous system. It has a worldwide prevalence of 6.9% to 10%. Despite its clinical significance, neuropathic pain is not adequately represented in the current version of the International Classification of Diseases and Related Health Problems (ICD-10). However, the International Association for the Study of Pain (IASP) recently proposed a classification for ICD-11 that differentiates neuropathic pain of peripheral and central origin.
New IASP Neuropathic Pain Categories
In this reclassification – to take effect January 2022, peripheral neuropathic pain is categorized as including:
trigeminal neuralgia
peripheral nerve injury
painful polyneuropathy
postherpetic neuralgia
painful radiculopathy
Central neuropathic pain includes pain caused by a spinal cord or brain injury, poststroke pain, or pain associated with multiple sclerosis (MS).
As the intersection of immune, neural, endocrine, and metabolic signaling pathways, the gut microbiota has become an intense focus of research, wrote Binbin Lin, MD, of Zhejiang University in Hangzhou, China, in a recently published review of the role of gut microbiota in neuropathic pain. Emerging research shows the microbiota facilitates the formation of complex networks and thus is a pivotal modulator in the occurrence and development of neuropathic pain.
From the Gut to the CNS: Mechanisms & Pathways
The mechanisms underlying neuropathic pain remain unclear, and pharmacologic agents recommended as first-line treatments are often unsatisfactory because the underlying causes of the pain cannot always be established. An understanding of pathophysiology is needed to develop more effective therapeutic strategies. Gut microbiota has been shown to play a crucial role in abdominal pain, opioid tolerance, headache, inflammatory pain, chemotherapy-induced peripheral neuropathy (CIPN), and neuropathic pain. Research shows that bacteria can activate nociceptors directly, and viral and fungal pathogens can alter pain sensitivity by activating immune cells.
The gut microbiota regulates several metabolic and neurological signaling pathways between the gut and the CNS that are associated with neuropathic pain.² In an animal study using a classic chronic constriction injury (CCI) model of peripheral nerve injury-induced NP and 165 rDNA and metabolomics sequencing, Peng Chen, MD, of Guizhou University of Traditional Chinese Medicine, Guiyang, China, and his team investigated a possible mechanism through which the gut microbiota mediates neuropathic pain. They found that:
CCI-induced neuropathic pain results in obvious hyperalgesia.
CCI significantly alters the gut microbiota composition and Firmicutes/Bacteroidetes (F/B) ratio to levels indicative of dysbiosis and neuropathic pain. Increases in the F/B ratio were previously found to be associated with nervous system diseases such as stroke, cognitive impairments, and sleep deprivation, and other bacteria within the Firmicutes phylum have been implicated in other neurological and psychiatric disorders.
CCI alters metabolism in the serum and spinal cord. Differentially expressed metabolites that regulate lipid metabolism, inflammation, amino acid metabolism, and energy production were identified in serum and spinal cord samples.
The function and specific mechanisms of the gut microbiota are extremely sophisticated, concluded Dr. Chen. “These results, which provide new information on the potential roles of the gut microbiota and related metabolites in neuropathic pain, are important, though preliminary, and must be confirmed in patient studies,” he wrote.
Gut-Based Therapeutic Strategies for Neuropathic Pain
In his review, Dr. Lin noted that current therapies for neuropathic pain can be complex and provide inadequate pain relief for certain patients. He provided a potential therapeutic strategy for alleviating neuropathic problems that may be simpler and result in fewer complications. Targeting the gut microbiota as a therapeutic strategy for neuropathic pain encompasses several components²:
Probiotics and antibiotics. As living bacteria, probiotics can help improve digestion, enhance immunity, and alleviate pain associated with intestinal dysfunction. They may also inhibit immune signaling transmission associated with neuropathic pain. Probiotics and antibiotics may change the activity of gut microbiota via different mechanisms, but some antibiotics may lead to hyperalgesia. More preclinical and clinical work is needed to investigate the role of probiotics and antibiotics in neuropathic pain treatment based on gut microbiota.
Low FODMAPs diet. A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) – short-chain carbohydrates that are resistant to digestion – may protect the intestinal barrier and reduce gut mucosal inflammation by regulating the level of lipopolysaccharides (LPS) and decreasing the production of short-chain fatty acids (SCFAs) in the gut. Studies have shown the effectiveness of a low-FODMAP diet on alleviating the visceral pain of IBS through potential gut microbiota-related pathways, and this is likely to be an emerging approach for the treatment of neuropathic pain.
Vitamin D Supplementation. Vitamin D deficiency results in decreased calcium absorption and induces gastric statis leading to increased gut permeability. The resulting release of endotoxins such as LPS into the bloodstream stimulates the production of inflammatory cytokines within the CNS, increasing the risk for diabetic neuropathy progression and possibly multiple sclerosis initiation. In addition to impacting the gut barrier, vitamin D may change the composition of gut microbiota communities. Supplementation of vitamin D3 was shown to reduce pathogenic microbes while increasing the volume of bacteria in the gut. Animal studies have shown that vitamin D can attenuate neuropathic pain, but the mechanism remains uncertain.
Emotional management. Depression and anxiety play a role in the occurrence and development of neuropathic pain, and gut microbiota are closely correlated with brain function. Studies have shown that depression induced by early life stress can alter the gut microbiota and that modulation of the microbiota affects behaviors related to depression as well as anxiety. The gut microbiota, therefore, may be a therapeutic target for psychiatry, as manipulating the microbiota may help relieve neuropathic pain by controlling its comorbidities.
Fecal microbiota transplantation (FMT). FMT involves transferring the gut microbiota from healthy individuals to patients to reconstruct their intestinal microflora, and it has been effective for the treatment of ulcerative colitis and recurrent Clostridium difficile infection, although some abdominal discomfort and illness may occur. The transplanted healthy flora may induce the growth of anti-inflammatory mediators, thereby counteracting pro-inflammatory mediators.
Of note, one published case on FMT, included a woman with type 2 diabetes and diabetic neuropathy. After two rounds of FMT, the patient experienced reduced limb pain and paresthesia along with improvements in her fasting blood glucose and glycosylated hemoglobin levels.
In Summary
Most of the research conducted on gut microbiota and neuropathic diseases thus far has been preclinical. However, targeting gut microbiota has become a rapidly growing therapeutic approach for a wide range of diseases including neuropathic pain. Given how far the data connecting the gut to the CNS have progressed since the AAN pointed to IBD over a decade ago, the pain management community is hopeful that solid new strategies for treating neuropathic pain will be here soon.
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