Rheumatic diseases are a generalized group of diseases that affect bones, joints, and their surrounding soft tissues, such as muscles, tendons, bursae, and nerves. Many rheumatic diseases are characterized by pain. In the West, the word “rheuma” was first used to mean catarrhos (catarrh-inflammation), which means pain. As an unpleasant subjective sensory and emotional experience associated with tissue damage or potential damage, pain is also an important cause of dysfunction in many rheumatic diseases. I. Clinical characteristics of pain in rheumatic diseases (a) Arthralgia Arthralgia is common in rheumatic diseases. Differential diagnosis of arthralgia is a common problem faced by rheumatologists. Due to the different diseases, the pain site, nature, characteristics of joint pain and its relationship with activities are also different. Common diseases include rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, crystalline arthritis and infectious arthritis. 1, rheumatoid arthritis The cause of rheumatoid arthritis is unclear. The basic pathological changes of the joints are synovitis, including thickening of synovial lining cells, synovial microvascular hyperplasia, inflammatory cell infiltration, and the formation of vascular cataracts, etc. The above changes are also the cause of joint pain. The main clinical features of RA arthralgia are: (1) It occurs in young women and has a slow onset. (2) It is accompanied by morning stiffness, which can be relieved after activities. (3) Pain in three or more joints. (4) It is easy to invade the small joints of both hands, such as wrist joints, metacarpophalangeal joints, proximal interphalangeal joints and so on. (5) Joint pain is symmetrical. (6) Good response to NSAIDS. 2.Osteoarthritis Osteoarthritis is a kind of chronic joint inflammation with progressive reduction of articular cartilage and overgrowth of bone. Arthropathologic changes can be seen as focal, erosive cartilage destruction, cartilage sclerosis, cystic degeneration and compensatory osteoid formation. The characteristics of arthralgia are: (1) it is mostly seen in elderly patients; (2) the affected joints are mostly weight-bearing joints such as knees, hips, lumbar vertebrae, etc., and there can be joint friction and popping sound. (3) Most of the pain is after activity and can be relieved after rest. (4) Joint stiffness is usually less than 30 minutes. (5) Heberden’s nodes are often found in the distal interphalangeal joints. Crystalline arthritis Crystalline arthritis is a group of diseases associated with metabolic abnormalities in the body. The presence of sodium urate crystals or CPPD crystals can be found on synovial pathology. In the acute stage, the villi may be congested and swollen. Arthralgia is characterized by: (1) The first attack is mostly monoarthritis and is asymmetric. (2) Acute attack of joint pain, mostly in 24-48 hours to reach the peak, redness and swelling around the joint is obvious. (3) The joints of the lower limbs, such as the first metatarsophalangeal joints, ankle joints, knee joints, etc., are easily invaded. (4) Mostly subside within 2 weeks, and may recur. (5) X-ray can be seen in the subchondral bone and bone marrow with puncture-like or worm-eaten defects. (B) Skin pain The skin is one of the target organs involved in rheumatic diseases, especially diffuse connective tissue disease. Common rheumatic diseases include seborrhea, erythema nodosum, systemic lupus erythematosus, and vasculitis. 1.Recurrent nodular non-suppurative lipomatitis Recurrent nodular non-suppurative lipomatitis is a kind of inflammation originating in the subcutaneous fat layer. Pathologic examination of the early stage of adipocyte degeneration, necrosis and inflammatory cell infiltration. The second stage is characterized by foam cells and lipophagocytic cells that have engulfed fat particles. The final stage is characterized by fibroblast hyperplasia and proliferation of collagen fibers. Its skin pain is characterized by (1) prevalence in young and middle-aged women (2) mostly accompanied by subcutaneous nodules and plaques with tenderness. (3) Nodules often occur in batches, symmetrically distributed to the buttocks and lower limbs, nodules subside at the local skin depressions, and hyperpigmentation. (4) It may be accompanied by fever, which is of variable type. (5) Diagnosis depends on pathological biopsy. 2.Erythema nodosum Erythema nodosum is an inflammatory disease of dermal vasculature and lipid membrane mediated by immune complexes or immune cells. The main pathologic changes are located in the lower middle part of the dermis and the upper part of the subcutaneous tissues, with nonspecific acute inflammatory changes; various types of blood vessels are involved to varying degrees; and there are inflammatory changes in the peripheral zone of the fat lobules. The pain is characterized by (1) prevalence in adolescents. (2) Mostly accompanied by red or purplish-red subcutaneous nodules on the extensor side of the calf, which may gradually subside after a few days~weeks, leaving temporary hyperpigmentation without scarring or ulcer formation. (3) Self-limiting, may recur. （Visceral pain Visceral pain caused by rheumatic disease is rare. It is characterized by low sensitivity, diffuse location and unclear localization. It is characterized by low sensitivity, diffuse location and unclear localization. It is mostly manifested as discomfort in the innervated area of the affected organs, and is easily confused with muscle pain originating from the spine and trunk. The occurrence of visceral pain is mainly related to the vascular inflammatory changes in the related organs. Common diseases include systemic lupus erythematosus, leukemia, anaphylactic purpura, polyarteritis nodosa, rheumatoid arthritis and so on. 1.Systemic lupus erythematosus Systemic lupus erythematosus is a typical autoimmune disease. The basic pathological manifestation is vasculitis, and the characteristic pathological changes include hematoxylin vesicles, splenic vascular “onion skin”-like lesions, and warty endocarditis, etc. In addition to zygomatic erythema, SLE may also be characterized by erythema of the zygomatic region. In addition to zygomatic erythema, discoid erythema, photosensitivity and other clinical manifestations, the patient due to the involvement of organs and their different degrees of severity, the visceral pain is also different. For example, vasculitis involving pericardium and pleura can have chest pain and corresponding symptoms. And mesenteric vasculitis can have abdominal pain, vomiting, diarrhea and other different degrees of clinical manifestations. 2.Allergic purpura Allergic purpura is a kind of atypical allergic vasculitis. Pathological manifestations of capillaries, micro-arteries and micro-veins of vascular inflammatory changes, with neutrophils as the main; vascular wall was fibrinoid necrosis, there may be erythrocyte exudation. Its abdominal pain is characterized by (1) the first age is below 20 years old, and it is more common in males. (2) Diffuse abdominal pain, aggravated after meals. (3) Accompanied by skin purpura, especially on the extensor side of both lower limbs, symmetrically distributed. (4) There may be manifestations of joint and kidney involvement, such as arthralgia, proteinuria, hematuria, and so on. (d) Peripheral neuralgia Peripheral neuralgia caused by rheumatic diseases is mostly related to the occlusion of nerve trophoblastic vessels or direct compression of peripheral nerves caused by vasculitis. The former common diseases are nodular polyarteritis, rheumatoid arthritis, SLE, etc., and the latter can be seen in carpal tunnel syndrome, lumbar intervertebral disc herniation. Peripheral neuralgia is often accompanied by sensory abnormalities and motor deficits in the innervated area of the affected nerve. Polyarteritis nodosa is a necrotizing vasculitis that mainly involves small and medium-sized muscular arteries throughout the body. Early stage of the disease is characterized by swelling, fibrinoid necrosis and cellular infiltration of the arterial endothelium and middle layer of muscle fibers; when the whole layer of the artery is involved, aneurysmal dilatation, rupture, and thrombosis may be observed, leading to ischemia or infarction of the tissues. Late stage manifests as fibrous tissue proliferation at the lesion site. The characteristics of peripheral neuralgia are (1) early manifestation of deep pain in the lesion area, which may then evolve into burning pain. Sensory abnormalities and motor disorders may be present in the innervated area of the affected nerves. (2) It may be accompanied by manifestations of other systemic involvement, such as generalized weight loss, reticular cyanosis, myalgia, muscle weakness, myalgia, testicular pain or tenderness and elevated diastolic blood pressure. (3) There may be elevated BUN, Cr, and HBV (+). (4) Arteriographic abnormalities. (E) Central pain The clinical manifestations of central neuropathy caused by rheumatic diseases are varied, among which, headache is one of the most common neuropsychiatric manifestations. The underlying pathologic changes are mostly related to inflammatory lesions in the intracranial vasculature. The main features of central pain are (1) persistent pain of recent onset. (2) It may fluctuate with subsequent onset, is not easily self-healed, and may or may not be accompanied by other localized neurological signs. Common rheumatic diseases include leukemia, polyarteritis nodosa, systemic lupus erythematosus, and dry syndrome. Leukoaraiosis The pathologic basis of leukoaraiosis is vasculitis. There is infiltration of inflammatory cells around blood vessels, and in severe cases, there is necrosis of the vessel wall. Large, medium and small vessels can be involved, with luminal narrowing and aneurysm-like changes. The central pain of leukoencephalopathy is characterized by (1) Meningoencephalitis-induced headache may be accompanied by fever and cervical rigidity. (2) Increased intracranial pressure in intracranial dural venous sinus to thrombosis, manifested as chronic headache, blurred vision, and in severe cases, optic papillary edema. (3) It may be accompanied by recurrent oral or genital ulcers, ophthalmia, and skin lesions. (4) Positive reaction to acupuncture. (VI) Muscle pain Muscle pain is one of the common clinical manifestations of rheumatic diseases, especially diffuse connective tissue disease. Common diseases include polymyositis, dermatomyositis, rheumatic polymyalgia, fibromyalgia syndrome and so on. 1, polymyositis and dermatomyositis The main pathological changes of myositis are inflammatory cell infiltration of the affected muscle tissue and myofibrillar degeneration and necrosis, regeneration, and myofibrillar bundles of unequal size. Myalgia is characterized by (1) symmetrical muscle weakness, myalgia, and muscle tenderness in the proximal extremities. (2) Patients with dermatomyositis may be accompanied by purplish spots on the upper eyelids, edematous purplish spots centered on the periorbital area, or Gottron’s rash. (3) There may be elevated muscle enzymes and electromyography showing myogenic damage. 2.Rheumatic polymyalgia The etiology and pathogenesis of rheumatic polymyalgia are unclear. Myalgia is the most prominent localized pain in rheumatic polymyalgia. It is characterized by: (1) The age of onset is more than 50 years old. (2) Mostly pain in the temporal region, neck, scapular girdle, pelvic girdle, and proximal muscle and tendon attachment sites of the extremities. (3) It is accompanied by muscle stiffness, which gradually disappears after 1-2 hours of activity and worsens after rest. (4) There is no redness, swelling, or heat in the affected muscles, and there is no loss of muscle strength or muscle atrophy. (4) Good response to small doses of hormones. 3.Fibromyalgia syndrome Fibromyalgia syndrome is a common disease causing low back and neck and shoulder pain and periarticular joints. It is characterized by: (1) widespread pain throughout the body, especially in the central axis of the skeleton and the scapular and pelvic bands. (2) It is often a stabbing pain, which is distracting. (3) Accompanied by symmetrically distributed pressure points in the musculature, muscles and other tissues. (VII) Bone pain The incidence of simple bone pain in rheumatic diseases is low, and it is more common in some metabolic bone diseases, osteonecrosis and bone tumors. Ischemic osteonecrosis The occurrence of osteonecrosis is related to trauma, hormone, alcoholism and many other factors. It is generally believed that, under the action of internal and external pathogenic factors, it can cause the reduction of nutritive blood flow in bone tissue, the pressure of intraosseous vascular network or the obstruction of outflow veins, resulting in the obstruction of blood supply, and in severe cases, it can cause ischemic necrosis of bone tissue. Bone pain is characterized by (1) sudden severe pain, aggravated by active activities, and 2/3 of the patients also have pain when resting. Activity limitation and pain level are closely related. (2) Pain level and X-ray are not parallel. (3) MRI is helpful for early diagnosis. Osteoporosis is a systemic skeletal disease with low bone mass and small destruction of bone tissue. Pathologic changes include thinning of the bone cortex, enlargement of the canal of Hart’s disease, scarcity of banded and lamellar bone, and erosion of the inner cortical bone and subendosteal bone. Bone pain often occurs as a result of spinal curvature, vertebral compression fractures and posterior vertebral herniation. Definitive diagnosis is based on clinical presentation, radiographic changes, and bone densitometry. (viii) Affective pain Rheumatic diseases are mostly chronic. In the organic lesions, psychosocial factors, drug factors and other factors of long-term joint action, rheumatic disease patients are often prone to psychogenic symptoms. Common diseases include systemic lupus erythematosus, rheumatoid arthritis, and polyarteritis nodosa. The pain of such patients, in addition to the characteristics of the original disease, is also accompanied by manifestations of mental disorders, such as anxiety and depression. Second, the mechanism of rheumatic disease pain Each rheumatic disease pain will involve a variety of pain causes and pain mechanisms, from this point of view rheumatic disease pain is a composite mechanism. But the main cause is non-infectious, immune inflammatory pain. (A) chronic inflammatory pain involved in a variety of arthritis, myositis, dermatitis, visceral inflammation, vasculitis, neuritis pain. 1, immune complex chronic inflammation, inflammation and pain connected. 2, lymphocyte-mediated chronic inflammation 3, acute exacerbation of chronic inflammation (ii) Crystalloid deposition Crystalloid deposition is associated with systemic metabolic abnormalities. Some diseases are associated with localized metabolic abnormalities at the site of the lesion. Crystallites have a certain hardness, volume, direct stimulation of the deposition site of the peripheral nerves to produce pain, activity pain aggravation or even stop moving. Crystallites directly or indirectly activate the pathogenesis of chronic inflammation. 1, inorganic salt crystals: a variety of calcium salts, resulting in joint calcification, ligament calcification, pleural calcification. 2, organic salt crystals: sodium urate, calcium pyrophosphate dihydrate, cholesterol, ferritin, globulin. (C) tendon, ligament, joint capsule pulling pain Inflammation and edema state of the tendon, ligament, joint capsule on the pulling force to bear the decline, resulting in pulling pain. The tendons, ligaments and joint capsules with scar contracture after inflammation are less flexible and cannot make large movements, so they are easy to be torn and strained, resulting in pulling pain. (D) Force line misalignment strain After joint deformity, the misalignment of adjacent bone force lines will produce transverse, phasic and rotational force, resulting in cartilage wear and tear, ligament and tendon chronic injury. (v) Cartilage and bone injury Abnormal cartilage metabolism is the main cause of osteoarthritis, and osteoporosis can lead to painful periosteal irritation. The mechanism is unclear. (VI) Emotional pain Patients with chronic diseases, who are treated repeatedly, tend to fear pain or have a decreased pain threshold. If the pain threshold is high, the loss of protective response, triggering greater damage and pain. Second, rheumatic disease pain (a) anti-inflammatory pain Almost every rheumatic disease has a different degree of non-infectious inflammation. Inflammation produces a variety of inflammatory substances, pain must be anti-inflammatory. However, anti-inflammatory drugs do not necessarily have a pain-relieving effect, non-steroidal anti-inflammatory drugs at the same time with anti-inflammatory and pain-relieving effect. Other anti-inflammatory drugs are glucocorticoids, slow-acting antirheumatic drugs, immunosuppressants, biochemical drugs, traditional Chinese medicine and so on. (ii) Stopping movement to reduce pain For patients in the acute stage, severe patients need to rest. Absolute bedridden and absolute immobilization for too long will cause joint stiffness, muscle atrophy, impaired function of limbs, and decreased function of internal organs. Chronic patients can only take proper rest and avoid strenuous exercise or heavy physical labor. (C) Psychological pain relief: To ease the psychological barriers, let the patients understand the condition and treatment plan, keep optimistic mood, do not overly rely on pain relief methods, describe the pain level truthfully, and reduce the drug dose in a timely manner. (D) Comprehensive pain relief Adopt comprehensive pain relief methods of Chinese medicine and Western medicine (E) Treatment principles Treatment objectives: reduce symptoms, alleviate the condition, reduce disability, and improve survival. Treatment principles: early diagnosis and treatment, comprehensive treatment, segmental changes, long-term treatment. Principles of medication: early and adequate amount, comprehensive medication, segmental adjustment, and avoidance of toxic side effects. Fourth, non-steroidal anti-inflammatory drugs (NSAID) (a) pharmacological mechanism In 1853 from the willow bark extracted sodium acetylsalicylate. 1899 Germany Bayer synthesized Asprin, used to this day. 1964 U.S. Shick launched ibuprofen. 1971 France Vane found the cyclo-oxygenase enzyme and its cognate function COX-1 and COX-2. In 1989 Niedermann discovered the mechanism of action of COX and lipoxygenase in analgesia. In the past 30 years, NSAIDs have evolved from three parent drugs: aspirin, ibuprofen, and anti-inflammatory pain into 10 categories and more than 150 varieties, but their pharmacological mechanism is still through the inhibition of oxidative enzymes, reducing the concentration of PG and leukotrienes and thus blocking the pain-sensitizing link. Nowadays, the annual prescription of NSAID is 500 million, and 30 million people take NSAID every day, and the development of new pharmacological mechanism of anti-inflammatory and analgesic drugs is an important research direction. (B), NSAID clinical drug characteristics 1, NSAID difference Existing NSAID pharmacological mechanism is the same, to distinguish these drugs rely on the following points: 1, relative acidity. 2, the degree of inhibition of COX-1 and COX-2. 3, dosage form. 4, synovial and tissue penetration. 5, chemical structure. 6, protein binding rate. 7, half-life. 8, medicinal chemistry. 9, pharmacokinetics. 10, Pharmacodynamics. 11, Drug side effects. 2, NSAID characteristics Now the common characteristics of drugs are: (1) the same pharmacological mechanism, so do not advocate the use of two drugs at the same time in sufficient quantities, because it will make the drug toxicity superimposed. 2, bioavailability are high, oral can be effective, the general situation does not advocate the intramuscular or intravenous drip. 3, most of the drugs have to go through the hepatic detoxification, and some of the drugs have hepatic and intestinal circulation, which can cause hepatic and renal injury. 4, oral are There are gastrointestinal reactions, gastric mucous membrane damage of 20-51% in one year, gastric ulcer perforation incidence of 5%, for A-type adverse drug reactions. Occurrence of leukopenia, allergic skin rash, mostly sensitive individuals. 5, on chronic non-infectious inflammation eat pain, do not eat pain, not improve the condition of the drug, no immunosuppressive effect, in the treatment program can increase the efficacy of the drug, reduce the dosage. In addition to anti-inflammatory and analgesic, all have different degrees of antipyretic effect. Some drugs have an anticoagulant effect. Recently, it has been found that these drugs can increase apoptosis of cancer cells and inhibit DNA synthesis of lymphocytes.6. There are complete dosage forms of drugs, including oral tablets, gelatin pills, slow-release agents, enterosolvents, injections, intravenous injections, suppositories, creams and so on. Cream, etc. 3, drug selection characteristics of foreign literature is summarized as follows: 1, the individual is sensitive to that kind of drug, can continue to use. Initial use of the drug, analgesic effect 15 to 150 species, anti-inflammatory effect 1 to 14 days, even one month of ineffective use of the drug, considered insensitive. Continuous use of 6 to 9 months, the analgesic effect declined, the need to increase the amount of drugs, but there are also maintained for 18 months or even longer still analgesic effect is very good. Blunted varieties need to choose new varieties to be replaced. 2, individual tolerance of the best kind of drug, choose that kind of drug. Mainly refers to the gastrointestinal adverse drug reactions. This reaction has little to do with the drug dosage form, individuals can be asymptomatic gastric mucosal lesions, and even small doses can occur. Drug tolerance is closely related to the patient’s adherence to medication.3. Adequate supply of medication so that the patient can reduce the frequency of medication changes (the patient can conveniently purchase the medication).4. The price of the medication is affordable to the patient. In order to maintain a longer period of medication. The author believes that attention should be paid to the following items: 1, the choice of drug varieties, as far as possible, the first patients to choose the inhibition of cyclooxygenase and lipoxygenase are drugs. Select COX-2 inhibitory specificity of drugs and drugs with long half-life. Relapsed patients or refractory patients should choose drugs with new pharmacological effects or new chemical structures as much as possible.2. Dosage selection: The initial patients are advocated to be given sufficient amount of drugs in the treatment program. However, severe cases should not be completely analgesic before the inflammation is controlled, in order to prevent too much activity to damage the tissues. Chronic patients should be completely analgesic and appropriate activities. Patients in complete remission should have their NSAIDs completely removed from their treatment regimen.3. Course of treatment: patients with initial disease should have their pain resolved in 3 to 6 months. Those with a long history of the disease need to take the minimum dose of NSAID for life.4. Principle of compounding: In the comprehensive treatment program, NSAID is an indispensable component. Comprehensive use of drugs can reduce the dose, increase the efficacy. Do not advocate the full amount of two NSAID. 5, dose selection: injection for gastrointestinal mucosal lesions; gastrointestinal absorption disorders; the need for immediate relief of pain; a variety of oral agents have a high degree of bioavailability, the same species of different dosage forms are allowed to be used in conjunction with the same species. 6, the principle of individualization: through the treatment of the patient’s pain relief and can tolerate, happy, can take care of themselves and engage in light physical labor. Advocate to do blood drug concentration test. The lower the PH value of the drug, the greater the concentration of intracellular aggregation, the easier it is to affect the blood and urine PH value. 7, the principle of reduction and potentiation. In addition to the joint use of drugs, the same night with the sedative, the same day with the muscle relaxant. At the same time with acupuncture, massage, Chinese medicine, will achieve the reduction and increase the effect. 4, the adverse drug reaction to most patients gastrointestinal adverse drug reaction is A-type adverse drug reaction, a few patients are B-type adverse drug reaction. Common gastrointestinal symptoms include poor appetite, nausea, vomiting, epigastric discomfort, stomach pain, heartburn and so on. Serious gastrointestinal reactions include upper gastrointestinal bleeding, pyloric obstruction, and ulceration. Risk factors that increase the risk of gastrointestinal bleeding are 1. history of ulcers. 2. concomitant use of glucocorticoids. 3. age >60 years. 4. drug dosage form. 5. alcoholism. 6. Helicobacter pylori infection. 7. combination of multiple organ injuries. 8. failure to implement prophylactic measures. Other type A adverse drug reactions are mild hepatic abnormalities, transient bilirubin elevation, renal interstitial injury, increased bleeding tendency, headache and migraine.Type B adverse drug reactions are drug rash, asthma, leukopenia, and secondary reentry. NSAID should be used with caution in patients who are >60 years old, have atherosclerosis, elevated blood muscle liver, and use diuretics, low perfusion status and uterine contraction dysfunction. (C) NSAID classification 1, according to the enzyme selective classification According to the inhibition of cyclo-oxygenase and lipoxygenase activity, it can be divided into: 1, cyclo-oxygenase and lipoxygenase double inhibition of the drug can be anti-inflammatory and analgesic. 2, inhibit the enzyme cyclo-oxygenase drug, analgesic and anti-inflammatory weak. 3, inhibition of cyclo-oxygenase, anti-inflammatory and strong. Inhibitors of cyclooxygenase activate lipoxygenase. Inhibit cyclooxygenase and activate lipoxygenase, analgesic but not anti-inflammatory. 2, inhibit cyclooxygenase, activate lipoxygenase drugs, analgesic but not anti-inflammatory. According to the inhibition of COX1 and COX2 activity, can be divided into: 1, inhibition of COX2 selective high drugs. 2, inhibition of COX-1 selective high drugs. 2, inhibition of COX-1 selective high drugs. 3, inhibition of COX-1 selective high drugs.