International Pain Awareness Day | Research Progress on Traditional Chinese Medicine and Herbal Treatments for Neuropathic Pain

October 11th is the International Day Against Drug Abuse and Illicit Trafficking. In 2011, the International Association for the Study of Pain (IASP) updated the definition of neuropathic pain (NPP) as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. The pathogenesis of NPP is complex, and compared to other types of chronic pain, NPP patients often experience varying degrees of anxiety and depression, significantly impacting their daily lives.

Currently, the primary treatment for NPP relies on western medicine, primarily antidepressants and antiepileptic drugs, which offer definite efficacy and faster results. However, given that NPP is a chronic condition often accompanied by a lengthy course, the corresponding treatment duration is also prolonged. Prolonged medication use can lead to drug dependence and adverse reactions, and disease relapse is common after discontinuation, resulting in ongoing debates about overall safety and effectiveness. These factors limit the application of western medicine in NPP treatment.

Increasingly, neurologists are turning to traditional Chinese medicine (TCM) for NPP management. TCM boasts a long history of treating NPP, encompassing a diverse range of treatments such as plant-based, animal-derived, and mineral medicines, as well as traditional Chinese medicine compound prescriptions and other non-pharmacological therapies.

Plant-based medications primarily encompass flavonoids, alkaloids, glycosides, organic acids, and phenols. Among flavonoid medications, plant-derived traditional chinese medicinal materials such as quercetin, dragon's blood (Sanguis Draconis), and puerarin are prominent. Quercetin, widely distributed in the plant kingdom, possesses various biological activities, including resistance to the onset and progression of inflammation, and the alleviation of pain. Literature reports indicate that quercetin can elevate pain thresholds in rats, reduce levels of certain pain and inflammatory factors in their bodies, and inhibit the activation of the Wnt/β-catenin pathway, ultimately achieving the goal of analgesia.

The primary component of dragon's blood is dracorhodin B, which promotes blood circulation to dissipate blood stasis, relieves pain, and exhibits excellent hemostatic effects. The analgesic mechanism of dragon's blood involves blocking neural transmission in the body, affecting the transmission of pain sensations, and regulating voltage-gated sodium channels and capsaicin receptors involved in pain signal transmission, thereby exerting an analgesic effect.

Puerarin, an isoflavonoid derivative, has the effects of promoting blood circulation to remove blood stasis and improving microcirculation. By increasing the peripheral nerve blood flow in NPP patients, puerarin alleviates nerve ischemia and hypoxia, promotes nerve conduction, and thereby reduces pain.

Alkaloid medications primarily consist of plant-based traditional chinese medicinal materials such as ligustrazine, sophocarpine, oxymatrine, lappaconitine, and sinomenine. Ligustrazine promotes blood circulation, activates qi (vital energy), dispels wind, and alleviates pain. Research has found that administering ligustrazine can inhibit the expression of nerve growth factor in the extracellular fluid of the ventromedial prefrontal cortex and central nucleus of the amygdala in NPP model rats, stabilize the dynamic balance of neurofactors, and reduce the degree of nerve damage.

Sophocarpine exerts an inhibitory effect on the central nervous system, achieving the purposes of analgesia and anti-inflammation. Meanwhile, oxymatrine demonstrates effective analgesia against neuropathic pain, inflammatory pain, and irritant pain.

Glycoside medications primarily encompass plant-based traditional chinese medicinal materials such as gastrodin, white peony root (Paeonia lactiflora), and baicalin. Gastrodin, an organic compound, possesses sedative and analgesic properties. Literature reports indicate that gastrodin exerts an analgesic effect by inhibiting the activation of spinal microglia in NPP rats.

White peony root soothes the liver and alleviates pain. Research has shown that paeoniflorin, the primary monoterpenoid glycoside component of white peony root, can reduce intracellular calcium levels in NPP model mice, thereby decreasing their pain sensitivity.

Baicalin possesses anti-inflammatory and analgesic effects. It reduces nitric oxide and cyclooxygenase-2 levels in diabetic NPP rats, and by inhibiting microglial activation, it decreases the levels of interleukin-6 and tumor necrosis factor-alpha in the body, ultimately lowering pain sensitivity and alleviating pain.

Organic acids and phenolic medications primarily include plant-based traditional chinese medicinal materials such as curcumin and resveratrol. Among them, curcumin exhibits pharmacological activities such as inhibiting inflammation progression and effectively alleviating pain. Research has found that curcumin can effectively inhibit the activation of nuclear factor-κB in trigeminal neuralgia rats, reduce inflammation in their bodies, and exhibit good analgesic effects. Additionally, curcumin significantly downregulates the level of Toll-like receptor 4, inhibits the expression of proinflammatory factors, and thereby reduces the severity of NPP pain.

Resveratrol, a non-flavonoid polyphenolic organic compound, is an antitoxin produced by various plants in response to stimuli. It possesses biological activities such as antioxidation and anti-inflammation.  

Animal-derived medications for treating NPP primarily include cinobufagin, cobra venom, and bezoar. Cinobufagin, as one of the traditional chinese medicinal materials, possesses the effects of detoxifying, reducing swelling, and alleviating pain. Its analgesic effect is related to increasing the level of β-endorphin (a pain-relieving substance) at the site of the body's pathology, and it can also produce analgesia by blocking opioid receptors.Contrary to being a typical analgesic drug, cobra venom can significantly block the neuromuscular blockade caused by curare-like substances. At the same time, it can significantly elevate the levels of messenger RNA (mRNA) for glutamate-aspartate transporter and glutamate transporter subtype 1 mRNA, as well as related proteins within the spinal cord, thereby producing spinal analgesia.Bezoar has sedative, heat-clearing, and detoxifying effects. The bilirubin and bile acid components it contains both exhibit significant analgesic effects.

The primary mineral medication used in the treatment of NPP is gypsum, which belongs to the monoclinic crystal system and possesses the effects of antipyretic and analgesic. Gypsum can significantly elevate the level of calcium ions in the body, stimulating the secretion of large amounts of analgesic substances such as endogenous opioids and β-endorphin, thereby producing a good analgesic effect on the central nervous system. Additionally, gypsum-based analgesic ointments can markedly increase the levels of cellular fatty acid synthase-related death domain-like interleukin-1β-converting enzyme inhibitory protein in patients with herpes zoster associated neuralgia, facilitating the differentiation and proliferation of T-cells, reducing the degree of neural stress response in the body, and enhancing the analgesic effect. Further research has confirmed that gypsum injections can not only significantly inhibit the exudation of inflammatory factors caused by acetic acid but also effectively alleviate the degree of foot pad swelling.

Currently, the commonly used traditional chinese medicinal compound prescriptions for analgesia in clinical practice primarily include Yuanhu Zhitong Formula, Shaoyao Gancao Formula, Huangqi Guizhi Wuwutang, and Wutou Tang. Yuanhu Zhitong Formula possesses the effects of regulating qi, promoting blood circulation, and alleviating pain, and can be used in the treatment of NPP. Its main ingredients include Corydalis Yanhusuo and Angelica dahurica, with Corydalis Yanhusuo serving as the principal herb that promotes blood circulation to remove blood stasis and regulates qi to stop pain. Angelica dahurica, as the assistant herb, has the functions of dispersing and warming, dispelling wind and cold, drying dampness, and alleviating pain, while also enhancing the efficacy of Corydalis Yanhusuo in promoting blood circulation and alleviating pain.Shaoyao Gancao Formula, which originates from "Treatise on Febrile Diseases," consists of peony root and licorice root. It has the effects of transforming sour and sweet flavors into yin, harmonizing the liver and spleen, and soothing tendons to alleviate pain. Huangqi Guizhi Wuwutang can nourish qi, warm meridians, harmonize blood, and dispel obstruction, comprising astragalus, cassia twig, peony root, ginger, and red dates. Astragalus can tonify qi, strengthen the exterior, promote urination, drain toxins, and promote tissue regeneration. Cassia twig belongs to the category of pungent and warm exterior-releasing herbs, able to induce diaphoresis, relieve muscle tension, and disperse cold. Ginger can disperse cold and relieve exterior symptoms, stop nausea and vomiting, resolve phlegm and suppress coughs, and neutralize the toxicity of fish and crabs. Red dates nourish blood and calm the spirit. When combined, these herbs can promote blood circulation and alleviate pain, achieving the goal of treating NPP.Wutou Tang is composed of ephedra, peony root, astragalus, licorice root, and Sichuan aconite. Ephedra can induce sweating to disperse cold, disperse lung qi to relieve asthma, and promote urination to reduce swelling. Peony root nourishes yin and enriches blood. Sichuan aconite dispels wind-dampness and warms meridians to alleviate pain. When combined, these herbs can warm meridians to disperse cold, eliminate dampness, and relieve obstruction.

Furthermore, non-pharmacological therapies in traditional Chinese medicine (TCM) primarily encompass acupuncture and acupoint application. Acupuncture, which includes techniques such as electroacupuncture, filiform needle acupuncture, and scalp acupuncture, can effectively enhance blood and lymphatic circulation in muscle tissues, accelerate metabolism, and improve muscle function, ultimately achieving the goals of improving muscle tone and alleviating pain. Research has confirmed that acupuncture can significantly inhibit the activation of glial cells in NPP patients, influence synaptic plasticity, and suppress the secretion of excitatory neurotransmitters, thereby achieving a dynamic balance between proinflammatory and anti-inflammatory factors. Subsequently, it produces an analgesic effect by modulating the expression of pain-related substances.

Acupoint application, based on the meridian theory of TCM, is a non-invasive acupoint therapy. It involves applying a paste, made by mixing crushed medicinal herbs with medicinal liquid or mentholatum, onto acupoints associated with the disease condition, in this case NPP, for therapeutic purposes.

The pathogenesis of NPP is complex, making it difficult to treat, and it is prone to recurrence after treatment. With the recent development of clinical Chinese medicine applications, an increasing number of NPP patients are opting for traditional Chinese medicine (TCM) therapy. As TCM clinical research progresses, numerous TCM treatment methods have been utilized in the management of NPP, providing research directions for its treatment with relatively ideal outcomes. Additionally, TCM clinical treatment boasts high safety, low treatment costs, and ease of administration, making it increasingly prominent in enhancing the therapeutic effects of NPP. The combined use of TCM and Western medicine has also gradually been implemented in clinical practice, offering benefits in alleviating patient pain, delaying disease progression, and improving treatment outcomes. This combined approach may become a primary direction for future research and treatment of NPP.

References:

[1] Liao Yue, Zhang Yu, Wu Baoxian, Liu Jisheng, Lan Caihong, Zhou Mei. "Research Progress on Traditional Chinese Medicine Treatment of Neuropathic Pain." Medical Recapitulation, 2021, 27(12): 2457-2461.

[2] Wang Haina, Fu Yongqing, Zhang Juan. "Research Progress on Neuropathic Pain and Its Treatment with Traditional Chinese Medicine." Inner Mongolia Journal of Traditional Chinese Medicine, 2011, 30(11): 126-128.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.