How Effective Is Capsaicin for Diabetes?

The etiology and pathogenesis of diabetic neuropathy is not completely clear, and scholars believe that it is multifactorial. Recent studies have suggested that the occurrence of diabetic neuropathy is related to the following factors.

Yang Lijuan

(Chief physician)

Department of Endocrinology, PLA General Hospital

Diabetic neuropathy is one of the most common chronic complications of diabetes. Lesions can affect the central and peripheral nerves, the latter being particularly common. Among them, distal sensory neuropathy is the most common lesion, accounting for more than 50% of all diabetic neuropathy.

Western Medicine Name: Diabetic neuropathy
English name: diabetic neuropathy

Affiliated Department: Internal Medicine-Endocrinology
Main cause: unknown
Multiple groups: Diabetics

Causes and pathogenesis of diabetic neuropathy

(A) genetic factors

(Two) ischemia and hypoxic factors

(3) Oxidative stress:

(D) the polyol pathway is too active

(5) Advanced glycosylation end product (AGE) -AGE receptor-nuclear factor (AGE-RAGE-NF-KB)

(6) Activation of protein kinase C (PKC):

(7) Abnormal metabolism of essential fatty acids

(8) Neurogenic trophic factors: including nerve growth factor (NGF), IGF-1, etc.

(IX) Comprehensive pathogenesis hypothesis: The pathogenesis model of diabetic neuropathy after the above information is synthesized. Hyperglycemia reduces nerve blood flow and increases blood viscosity by affecting the relaxation of nerve microvessels. The contractility of the microvessels increases, and the diastole decreases. Coupled with reduced microvascular blood flow, it can enhance the expression of adhesion molecules, damage the blood-nerve barrier, generate peroxide roots, and activate PKC and NF-KB. This was followed by endometrial ischemia and hypoxia. As a result, increased lipolysis, hyperglycemia-induced r-linolenic acid deficiency, AGE production (AGE-RAGE-NF-KB), hyperactive metabolism in the polyol pathway, PKC and auto-oxidation, and lack of growth factors have led to excessive lipid oxidation. The state of diabetes exacerbates the inflammatory response to ischemia. HNE is particularly important because it can cause apoptosis of neurons, neuron appendages, and support cells. This figure is simplified. The pathogenesis of neuropathy is intricate. Most of the possible pathogenesis are staggered, and there are important interactions and synergies between different mechanisms.

Pathological changes in diabetic neuropathy

Diabetic neuropathy has extensive pathological changes, mainly involving peripheral nerves, autonomic nerves, cranial nerves, and brain and spinal cord. Early manifestations of nerve fiber demyelination and axonal mutation. Schwann cell proliferation, with the course of the disease, manifested as axonal mutation and disappearance of myelin fibers, while myelin fibers degenerate, regeneration plexuses are produced. As the disease progresses, the density of the regeneration plexus decreases, suggesting an inappropriate Repair, this phenomenon is especially common in T2 diabetes. Sometimes, clinical data and electrophysiological examinations of diabetic neuropathy suggest chronic inflammatory demyelinating polyneuropathy (CIDP). The main changes are inflammatory infiltration, demyelination and axonal loss, and Idiopathic CIDP is difficult to identify. When autonomic nerve is involved, it mainly manifests as degeneration of visceral autonomic nerve and sympathetic ganglion cells. Microvascular involvement is mainly manifested by endothelial cell proliferation and hypertrophy, thickening of blood vessel walls, narrowing of the lumen, and hyaline degeneration, reducing the number of capillaries, and in severe cases, small vessel occlusion may occur. Brain lesions mainly involve cerebral blood vessels and are prone to stroke, especially cerebral infarction, and some can cause brain atrophy and sclerosis. Spinal cord lesions are mainly posterior cord damage, mainly degenerative changes.

Classification of diabetic neuropathy diseases

There are many types of diabetic neuropathy, and there are many classification methods. At present, the most widely used and simplest classification method was first proposed by Thomas. The revised classification method is as follows:

A. Symmetric neuropathy

Distal symmetrical sensorimotor polyneuropathy

Autonomic neuropathy

Acute painful neuropathy

Hyperglycemic neuropathy

Treatment-induced neuropathy

Proximal lower limb neuropathy

B. Focal and multifocal neuropathy

1. Brain neuropathy

2. Thoracoabdominal neuropathy

3 Local limb neuropathy

4 Diabetic muscular atrophy

Clinical manifestations of diabetic neuropathy

(A) distal symmetrical sensorimotor polyneuropathy : This is the most common type of diabetic peripheral neuropathy. Symptoms start from the distal end of the limb and gradually progress toward the proximal end. They appear in a glove-sock-like distribution, generally starting from the lower limbs. It is predominantly sensory disorders with varying degrees of autonomic symptoms, while motor disorders are relatively mild. Most cases are hidden.

The manifestation of sensory symptoms is related to the size of the affected nerve fibers. In the case of small fibers, pain and paresthesia are the main symptoms. Pain can be a variety of pain manifestations such as dull pain, burning pain, tingling pain, stabbing pain, and most are exacerbated at night. Paresthesia can manifest as numbness, chills, ant movements, insect crawling, fever, burning, and electric shock. Deep sensations (joint position and vibration) are usually mild. There may also be a decrease or loss of temperature and pain. With the exacerbation of symptoms, it may happen that the distal part of the limb suffers from various accidental injuries and is completely unknown, such as burns, hot water burns, ulcers caused by foot trauma, etc. Autonomic neuropathy does not cause sweating in the feet, causing dry and cracked skin, which is more likely to promote ulcers. Secondary infections of foot ulcers and arterial thrombosis can cause necrosis and gangrene, leading to eventual amputation. If the affected fiber is thick, it mainly affects joint position and vibration. Symptoms of gait and standing instability are more obvious when eyes are closed, that is, sensory ataxia. Patients often complain of feeling cotton on the floor or feeling strange on the floor. It is easy to cause falls, trauma and even fractures due to unstable movement. Clinically, small fiber damage is more common, but the most common is a mixed type of disease in which both small and large fibers are affected. Dyskinesias, such as distal weakness, atrophy of small muscles of the hands and feet, generally occur later in the disease. ^[1]

(Two) autonomic neuropathy:

Autonomic neuropathy rarely occurs alone, and is often accompanied by somatic neuropathy. Conversely, in cases of diabetes with somatic neuropathy, through functional tests, it is found that the incidence of some degree of autonomic dysfunction can be as high as 40%. However, once the clinical symptoms of autonomic dysfunction appear, the prognosis may be poor.

Cardiovascular system

(1) Orthostatic hypotension: When the patient stands up from the supine position, if the systolic blood pressure of the standing position drops more than 30mmHg compared with the supine position, it is called orthostatic hypotension.

(2) Tachycardia at rest: The heart rate is 90 to 100 beats / min at rest, and some 130 beats / min.

(3) Painless myocardial infarction: the most severe manifestation of cardiac autonomic dysfunction.

(4) Sudden death: In diabetic patients with severe autonomic neuropathy, there are respiratory and cardiac arrest events.

2. Gastrointestinal system: Diabetic gastroparesis can be manifested as nausea, abdominal distension after eating, early satiety, and vomiting. Most people with diabetes have constipation, but there are also a small number of patients with diarrhea, or alternating diarrhea and constipation.

3. Urogenital system and diabetic bladder disease: Bladder dysfunction can be seen in 37-50% of diabetic patients. Symptoms of bladder associated with autonomic neuropathy include poor urination, reduced urine flow, excessive residual urine, endless urine, urinary retention, and sometimes urinary incontinence, prone to urinary tract infections. Reproductive system manifests as male libido and impotence. The reported incidence is 30-75%. Impotence may be the earliest symptom of diabetic autonomic neuropathy. .

4. Sweating abnormalities: Sweating glands dominate nerve dysfunction is a common symptom of diabetic autonomic neuropathy. Mainly manifested as less sweat at the extremities, but often accompanied by excessive sweating in the trunk.

(Three) acute painful neuropathy

This type is rare and occurs mainly in diabetic patients with poor disease control. Acute onset of severe pain and hyperalgesia is most pronounced at the distal end of the lower extremity, and can also affect the entire lower extremity, trunk or hands. It is often accompanied by muscle weakness, atrophy, weight loss and depression, and some patients have neuropathic cachexia. This type has a better effect on insulin treatment, but the recovery time is often longer.

(D) Cerebral neuropathy

Among diabetic mononeuropathy, the most common is oculomotor nerve palsy. At first, it appears as diplopia, and within a few days it progresses to complete ophthalmoplegia, and ptosis and dilated pupils also appear. Diabetic oculomotor nerve palsy usually recovers spontaneously within 6-12 weeks, but there may be relapses or bilateral lesions. ^[2]

Laboratory tests and special tests for diabetic neuropathy

(A) nerve electromyography

Neuromyography is of certain value in the diagnosis of diabetic peripheral neuropathy. It can find subclinical neurological damage, which has changed significantly in the early stages of diabetes and even before clinical symptoms, so it has early diagnostic value.

(2) Relevant examination of cardiovascular autonomic nerve injury:

1. Heart rate at rest: Cardiovascular neuropathy is more than 90 beats / min at rest.

2. Heart rate difference per minute during deep breathing. The patient is supine, first training deep breathing six times per minute, recording the maximum and minimum heartbeat interval (R-R interval) during a single deep aspiration and deep exhalation on lead ECG, and calculating the deep and deep aspiration The difference in heart rate per minute (respiratory difference), normal people under 50 years old has a respiratory difference of more than 15 breaths per minute, 50 to 60 years old is more than 10 to 15 breaths per minute, and if less than 10 breaths per minute is abnormal.

3 Fragile Action Response Index. After instructing the patient to inhale deeply, cover his nose and close his mouth for a forced expiratory action, that is, 15 seconds of exhaustion, and then relax and exhale naturally for 10 seconds. At the same time, record the ECG to determine the maximum R-R interval after the exhaustion and exhaustion The ratio of the smallest R-R interval is the fatigue action response index. Normal people should be greater than or equal to 1.21, and less than or equal to 1.10 is abnormal.

4 Heart rate difference per minute in the upright position. After recording the ECG of the supine position II, it quickly stood up within 5 seconds and continued to record the ECG. Measure the R-R interval between the standing position and the lying position, and calculate the difference in heart rate per minute between the standing position and the lying position. Normally greater than 15 times / minute, if less than 15 times / minute is abnormal.

5. R-R interval ratio (30/15 ratio) between the 30th and 15th heartbeats after standing. A normal person's 30/15 ratio is greater than or equal to 1.03, and less than 1.03 is abnormal.

6. Orthostatic hypotension test. If the systolic blood pressure in the standing position drops more than 30mmHg compared with the lying position, it is called orthostatic hypotension.

7. SPECT: Cosson et al. Reported that single-photon emission computed tomography using m-iodobenzoguanide (MIBG) can reflect cardiac sympathetic neuropathy. This method can reflect cardiac autonomic neuropathy earlier and more sensitively than the above method. The disadvantage is that it is expensive and radioactive.

Among the above indicators, respiratory difference, standing and lying difference, fatigue's action response index and 30/15 ratio are more sensitive.

(3) Gastrointestinal autonomic nerve function test : Gastric emptying measurement: At present, the scintillation diagram of gastric emptying is the most sensitive and can be used in clinical methods. The manometry can find that the motility of the proximal stomach and antrum is reduced, the low-amplitude gastric antrum movement and the high-pyloric pyloric contraction are found. electrogastrogram.

(4) Bladder function test: Bladder ultrasound measured residual urine volume, diabetic autonomic neuropathy increased residual urine volume. Urodynamic tests. Using urethral flow meters, bladder manometry, nerve conduction velocity, and International Prostate Symptom Score (IPSS) to evaluate urethral-bladder autonomic nerve function can reveal abnormalities.

Differential diagnosis of diabetic neuropathy

(A) clinical diagnosis of diabetic neuropathy

It includes three steps: 1. Diagnosis of diabetes. 2. Diagnosis of neuropathy. 3. Determination of the relationship between neuropathy and diabetes. Clinically, regardless of the duration of diabetes, the possibility of diabetic neuropathy should be considered. According to the medical history and typical clinical manifestations, the diagnosis of typical cases is relatively easy, and nerve function measurement can be performed when necessary. The neuropathy that occurs in diabetic patients cannot be easily considered to be diabetic neuropathy. Neuropathy caused by other causes can also coexist in diabetic patients. Due to the clinical manifestations of diabetic neuropathy, laboratory tests and special tests lack specificity. Therefore, the diagnosis of diabetic neuropathy must have evidence of diabetes; the clinical manifestations and relevant laboratory tests have evidence of diabetic neuropathy; the diagnosis can be confirmed only after the neuropathy caused by other reasons, and according to the type and location of the nerve involved in the disease type. ^[3]

(B) Differential diagnosis:

1. Symmetric peripheral nerve damage: Attention should be paid to the identification of toxic peripheral neuropathy and infectious polyradiculitis. The former often has a history of drug poisoning or pesticide exposure, and the pain symptoms are more prominent. The latter often have acute or subacute onset. They usually have a history of respiratory or intestinal infections before the disease. They show symmetrical flaccid paralysis of the extremities, severe dyskinesias, and light sensory disturbances, and obvious muscle atrophy after 1 to 2 weeks. Cerebrospinal fluid protein increased quantitatively, the number of cells was normal or slightly increased.

2. Asymmetric peripheral nerve injury: should be distinguished from spinal cord tumors, spinal bone hyperplasia and compression nerves and other pathological changes, the corresponding segment of the spine photos or CT, MRI can help diagnosis.

3 Diarrhea should be distinguished from gastrointestinal inflammation and tumors: diabetic diarrhea is more common with watery stools, no mucus pus and blood, spastic abdominal pain with increased bowel sounds before diarrhea, symptoms can be improved after defecation, routine stool and culture without inflammation Sexual ingredients and bacterial growth. If necessary, colonoscopy and other tests can help identify.

4 Cardiac autonomic dysfunction should be distinguished from other cardiac organic lesions, but the latter has no history of diabetes, normal blood sugar and often the symptoms and signs of the corresponding disease. ^[4]

Treatment and prevention of diabetic neuropathy

(1) Diabetes control: DCCT and UKPDS studies have confirmed that strict control of blood glucose can prevent and delay the occurrence of diabetic neuropathy and prevent its further progress. At the same time when controlling blood sugar, attention should be paid to blood lipid, blood pressure and other standards, and smoking should be controlled.

(II) Treatment for the pathogenesis of diabetic neuropathy:

1. Antioxidants These drugs improve the symptoms of diabetic peripheral neuropathy by suppressing the state of oxidative stress in the nerves, increasing the blood flow of nutritional nerve blood vessels, increasing the speed of nerve conduction, and increasing the activity of nerve Na +-K +-ATPase. Alpha-lipoic acid is a co-factor of pyruvate dehydrogenase system, and it is also an antioxidant commonly used in clinic.

2. The neurotrophic drug mecobalamin is a methionine synthase coenzyme, which promotes the synthesis of lecithin, the main component of myelin sheath, and is related to the functions of myelin sheath, ribosome membrane, mitochondrial membrane, synapses and receptors, etc. It can promote the synthesis of nucleic acids and proteins, improve the metabolism and synthesis of neurons and Schwann cells, promote the axonal transport and axonal regeneration, and restore the delayed transmission of neural bonds.

3. The drugs that improve the nerve microcirculation mainly include vasodilators, such as angiotensin-converting enzyme inhibitors, pentoxifylline; Dilate blood vessels, reduce blood viscosity, 10 ~ 20g / d drop-in, 2 weeks as a course of treatment, it can alleviate numbness and pain of diabetic neuropathy.

4 Aldose reductase inhibitors (ARIs) In principle, aldose reductase inhibitors can restore Na +-K + -ATPase activity by inhibiting aldose reductase activity and reduce the deposition of sorbitol and fructose in peripheral nerve tissue, which can improve Diabetic neuropathy. In the past 20 years, such drugs have been gradually researched and applied, but some of them have been discontinued or are still in clinical research due to doubts about their efficacy and safety.

5. Gamma-linolenic acid neuropathy has a disorder of essential fatty acid metabolism. Supplementation of -linolenic acid can increase blood flow in the nerve and improve nerve conduction speed.

6. Others include inhibitors of the formation of advanced glycation end products: aminoguanidine, C peptide, protein kinase C inhibitors, etc., which have not yet entered the stage of clinical use.

(Three) the treatment of autonomic neuropathy

1. Orthostatic hypotension: First, remove the underlying cause of orthostatic hypotension. Diuretics, antihypertensives, antiangina, and antidepressants are the most common causes. Attention should be paid to raising the head of the bed properly, standing slowly and wearing elastic socks. In severe cases, drug treatment may be required. The preferred drug is 9--hydrocortisone 0.1-0.3 mg / d. The drug restricts its application due to difficulties caused by supine hypertension.

2. Gastroparesis: Less food and more meals combined with medication is the standard method for diabetic gastroparesis. Domperidone (Doxorline): Dopamine Receptor Blocker, 10mg, 3 times a day, taken 30 minutes before a meal. Can cause adverse reactions such as lactation. Cisapride: It is a gastrointestinal prokinetic drug for the whole digestive tract, which works by stimulating the intestinal muscular plexus and increasing the release of acetylcholine, 5 mg, 3 to 4 times per day. Occlopramide (Metoprolol): 5 ~ 10mg, 3 times / d. This medicine has both cholinergic and anti-dopaminergic effects. It is easy to cross the blood-brain barrier and cause extrapyramidal reactions. It should not be used for a long time. Erythromycin: Stimulate the release of motilin and directly stimulate the motilin receptor to promote gastric emptying. The dose is 200 ~ 250mg, 3 times / d.

3 Diabetic neurogenic bladder: For the weak bladder, lower abdominal massage can be used to help the bladder empty, and more severe urinary retention can be catheterized or detained. A bladder fistula if necessary. Can be used to promote bladder contraction drugs, such as carbamylcholine, orally, 10-30mg / times, 2-3 times / d.

4 Erectile Dysfunction: Patients with impotence can take the following measures: Yohimbine, due to its high price and low efficiency, can be selectively used. Androgens are only considered when blood testosterone levels are reduced. Vasoactive drugs can be injected into the cavernous body, vacuum negative pressure erectile system, vascular surgery, and penile prosthesis insertion. And should cooperate with psychotherapy.

(D) Treatment of painful neuropathy: Patients with painful neuropathy severely affect the quality of life due to pain, and the pain is characterized by exacerbation at night, so effective pain relief is one of the keys to treatment. At present, the treatment for the mechanism of pain is still considered as the main treatment to relieve the pain symptoms of painful neuropathy.

1. Tricyclic antidepressants are still the most studied first-line drugs for neuropathic pain. Amitriptyline and Berkomine are the most widely used.

2. Antidepressants: Carbamazepine and phenytoin sodium tests have proven to be effective in alleviating the pain symptoms of painful neuropathy, but they have large side effects and are currently rarely used in clinical practice. Gabapentin is currently the first-line drug for pain caused by diabetic peripheral neuropathy.

3. Opioids: The principle of opioid analgesics and analgesics is mainly to act on opioid receptors in the central pain sensory pathway, increase the pain threshold, and relieve pain. The most common side effects are sedation, constipation, nausea and vomiting, and addiction.

4 Local treatment drugs: Some patients have relatively limited pain areas, and can be used locally. Topical medicine has the advantages of small systemic side effects and less interaction with other drugs, so it is also the research direction of analgesics in the future. For example, lidocaine patches that have been approved by the FDA for marketing, as well as ketamine gel, capsaicin ointment, Xiaoxintong spray, nitroglycerin patch can alleviate pain. ^[5]