bubble_chart Overview

Fibromyalgia syndrome (FMS) is a non-articular Bi disease, clinically manifested as widespread pain and stiffness in the musculoskeletal system, with tender points at specific locations. Fibromyalgia syndrome can occur secondary to trauma, various Bi diseases such as osteoarthritis (OA), rheumatoid arthritis (RA), and various non-Bi diseases (e.g., hypothyroidism, malignant tumors). This type of fibromyalgia syndrome is referred to as secondary fibromyalgia syndrome. If it is not associated with other disorders, it is called primary fibromyalgia syndrome.

bubble_chart Epidemiology

Regarding the epidemiological status of fibromyalgia syndrome, there have been no domestic reports, and there is also a lack of precise statistical data abroad. However, preliminary data suggest that this disease is not uncommon. A survey from the UK indicates that among people unable to work due to illness, 10.9% are caused by wind-dampness disorders, with fibromyalgia syndrome accounting for approximately half of these cases. The American Bi Disease Association points out that primary fibromyalgia syndrome is one of the most common Bi diseases, ranking third only after RA and OA. Yunus et al. treated a total of 285 patients with musculoskeletal diseases within one year, among which 29% had OA, 20% had primary fibromyalgia syndrome, and 16% had RA. Among Asian countries, a report from Japan states that over two years in a connective tissue disease outpatient clinic, they treated 182 Bi disease patients, among whom 11 cases were fibromyalgia syndrome, accounting for 6% of the total. This ranks seventh after rheumatoid arthritis (27.5%), systemic lupus erythematosus (16%), systemic sclerosis (10.4%), and Sjögren's syndrome (7.7%).

bubble_chart Pathogenesis

The mechanism of this disease remains unclear. Literature reports suggest associations with sleep disorders, abnormal neurotransmitter secretion, and immune dysregulation.

1. Sleep Disorders

Sleep disorders affect 60–90% of patients, manifesting as easy awakening, dreamfulness, lack of energy in the morning, fatigue, generalized pain, and morning stiffness. Nocturnal EEG recordings reveal the intrusion of alpha waves into stage IV delta sleep waves. Similar EEG patterns and clinical symptoms can be induced by disrupting non-rapid eye movement (NREM) sleep in volunteers using auditory stimuli. Other factors affecting sleep, such as mental stress and environmental noise, can exacerbate fibromyalgia symptoms. It is thus hypothesized that this stage IV sleep abnormality plays a significant role in the onset of fibromyalgia syndrome.

2. Abnormal Neurotransmitter Secretion

Literature reports indicate that neurotransmitters such as serotonin (5-HT) and substance P play crucial roles in the pathogenesis of this condition.

The precursor of serotonin is tryptophan. After dietary tryptophan is absorbed in the intestines, most of it binds to plasma proteins, while a small portion remains free. Free tryptophan can cross the blood-brain barrier via carriers and enter brain tissue, where it is hydroxylated and decarboxylated in 5-HTergic neurons to form 5-HT. The 5-HT released into the synaptic cleft is partly reabsorbed by presynaptic nerve terminals and partly metabolized by mitochondrial monoamine oxidase into inactive 5-hydroxyindole acetic acid (5-HIAA). 5-HT is also present in the gastrointestinal mucosa, platelets, and mammary cells. However, since it poorly crosses the blood-brain barrier, the 5-HT in the central nervous system and peripheral blood constitutes two separate systems. Research has found: ① Fibromyalgia patients exhibit reduced plasma levels of free tryptophan and its transport ratio, with the degree of reduction correlating with musculoskeletal pain—the lower the plasma concentration and transport ratio, the more severe the pain. ② High-affinity 5-HT receptors on platelet membranes can competitively bind with imipramine and 5-HT. Using tritium-labeled imipramine to measure 5-HT receptor density on platelet membranes, fibromyalgia patients show altered receptor function compared to healthy individuals. ③ The 5-HT levels in the brain tissue of fibromyalgia patients are significantly lower than in healthy individuals. Experiments demonstrate that 5-HT regulates NREM sleep, reduces pain sensitivity, alleviates depressive states, and enhances the analgesic effects of anesthesia. Amitriptyline and cyclobenzaprine inhibit the conversion of 5-HT to 5-HIAA, thereby increasing 5-HT concentration, which explains their therapeutic efficacy in fibromyalgia syndrome. Conversely, administering the tryptophan hydroxylase inhibitor parachlorophenylalanine (PCPA) can induce fibromyalgia-like pain, which resolves upon discontinuation of the drug.

Another neurotransmitter associated with fibromyalgia syndrome is substance P. Littlejohn found that physical or chemical stimuli could induce significant skin hyperemia in fibromyalgia patients, and this excessive reaction may be related to persistent peripheral nociceptive stimulation. Due to these stimuli, polymodal cutaneous nociceptors reflexively release pathological amounts of substance P from nerve endings, which in turn can cause local vasodilation, increased vascular permeability, and a neurogenic inflammation. After the release of substance P from nerve endings, the primary sensory neurons in the dorsal root ganglia will synthesize more substance P to maintain a constant level. The synthesized substance P is transmitted bidirectionally to both the peripheral and central nervous systems, leading to elevated levels of substance P in the central nervous system. Given its slow but persistent and potent excitatory effects, the central nervous system is inevitably affected to some extent.

Additionally, it was found that under normal or high levels of 5-HT, substance P has a damping effect on the firing of sensory nerve impulses. In the absence of 5-HT, it loses this regulatory function, leading to hyperalgesia.

3. Immune Dysregulation

Some authors have reported the deposition of immune reactants at the dermal-epidermal junction in patients with fibromyalgia syndrome. Electron microscopy observations revealed swelling of the capillary endothelial cells in the muscles of fibromyalgia patients, suggesting acute vascular injury, tissue hypoxia, and increased permeability. Patients often report unexplained weight gain, diffuse hand swelling, and increased nocturia, which may be related to enhanced permeability.

Furthermore, preliminary studies have found elevated levels of interleukin-2 (IL-2) in fibromyalgia syndrome. Patients receiving IL-2 therapy for tumor diseases develop fibromyalgia-like symptoms, including widespread pain, sleep disturbances, morning stiffness, and the appearance of tender points. It has also been observed that alpha-interferon can cause fatigue. These phenomena suggest immune dysregulation. Abnormal levels of cytokines in the body may be directly related to the onset of fibromyalgia syndrome.

bubble_chart Clinical Manifestations

Fibromyalgia syndrome is more common in women, with the most frequent onset age between 25 and 45 years. Its clinical manifestations are diverse, but mainly include the following four groups of symptoms:

1. **Primary symptoms**: Widespread pain throughout the body is a symptom present in all fibromyalgia syndrome patients. Although some patients only report pain in one or a few areas, a quarter of patients may experience pain in more than 24 locations. The pain is distributed across the entire body, particularly in the axial skeleton (neck, thoracic spine, lower back) and areas like the shoulder girdle and pelvic girdle. Other common sites include the knees, head, elbows, ankles, feet, upper back, mid-back, wrists, hips, thighs, and calves. Most patients describe this pain as a **stabbing pain**, which is deeply distressing.

Another symptom present in all patients is widespread tender points, which are found in tendons, muscles, and other tissues, often symmetrically distributed. At these tender points, patients react differently to pressure compared to healthy individuals, but no difference is observed in other areas.

2. **Characteristic symptoms**: This group includes sleep disturbances, fatigue, and morning stiffness. About 90% of patients experience sleep disturbances, manifesting as **insomnia**, frequent awakenings, **dreamfulness**, and low energy. Nighttime EEG shows alpha waves intruding into non-REM sleep, indicating a lack of deep sleep. Fatigue is reported by 50–90% of patients, with about half describing it as severe enough to feel "too exhausted to work." Morning stiffness occurs in 76–91% of patients, and its severity correlates with sleep quality and disease activity.

3. **Common symptoms**: The most frequent in this group are numbness and swelling. Patients often complain of joint or periarticular swelling, though no objective **signs** are observed. Other common symptoms include **headache** and irritable bowel syndrome. Headaches may be **migraine** or non-migraine types, the latter presenting as a dull, pressing pain in the occipital region or the entire head. Psychological abnormalities, such as depression and anxiety, are also relatively common. Additionally, patients often experience reduced work capacity, with about one-third needing to change jobs and a small fraction unable to continue regular work. These symptoms often worsen with damp and cold weather, stress, or overexertion, while local heat, relaxation, good sleep, and moderate activity may alleviate them.

4. **Mixed symptoms**: Primary fibromyalgia syndrome is rare; most patients with fibromyalgia syndrome also suffer from some form of **Bi** disease. In such cases, the clinical symptoms are a combination and overlap of both conditions. Fibromyalgia syndrome often exacerbates the symptoms of the coexisting **Bi** disease, and failure to recognize this may lead to excessive treatment and testing for the latter.

bubble_chart Auxiliary Examination

Unless combined with other diseases, fibromyalgia syndrome generally shows no laboratory abnormalities. However, there have been reports of increased IL-1 levels, decreased natural killer cell and serotonin activity, and elevated substance P concentrations in the cerebrospinal fluid of fibromyalgia patients. About one-third of patients exhibit Raynaud's phenomenon, and in this group, positive antinuclear antibodies and reduced C₃ levels may be observed.

Since Smythe first proposed the diagnostic criteria for fibromyalgia syndrome in the 1970s, many diagnostic criteria have emerged. However, these criteria vary in methodology and content, posing challenges for epidemiological and clinical research. To address this, international scholars conducted multicenter collaborations, analyzing clinical symptoms and tender points from a large number of patients based on previous criteria. They identified the most discriminative clinical symptom and 18 tender points (Figure 1), leading to the 1990 classification criteria for fibromyalgia syndrome, as follows:

Figure 1 Locations of tender points in the 1990 classification criteria for fibromyalgia syndrome

1. Widespread pain lasting more than three months: Pain must be present on both sides of the body, in the upper and lower back, and in the axial skeleton (cervical spine, anterior chest, thoracic spine, or lower back) to be considered widespread.

2. Pain in at least 11 of 18 tender points upon thumb palpation (with a pressure of approximately 4 kg). These 18 (9 pairs) tender points are located at: the muscle attachments at the base of the occipital bone; the midpoint of the upper trapezius; the anterior aspect of the intertransverse spaces of C5–C7; the origin of the supraspinatus muscle, near the medial border of the scapular spine; 2 cm distal to the lateral epicondyle of the humerus; the second costochondral junction, just lateral to the upper border; the upper outer quadrant of the buttocks, at the anterior gluteal fold; posterior to the greater trochanter; and the medial fat pad of the knee, proximal to the joint line. A diagnosis of fibromyalgia syndrome requires meeting both criteria.

This standard helps unify the definition of fibromyalgia syndrome. It emphasizes distinguishing fibromyalgia from similar conditions and thus does not include characteristic syndrome features such as fatigue, sleep disturbances, or morning stiffness. Considering these features when applying the criteria improves diagnostic reliability and accuracy. However, this standard does not differentiate between primary and secondary fibromyalgia syndrome. Therefore, after diagnosing fibromyalgia, additional evaluations are necessary to identify any underlying conditions and distinguish primary from secondary fibromyalgia syndrome. This distinction is essential for clinical research and treatment evaluation.

bubble_chart Treatment Measures

Fibromyalgia syndrome is an idiopathic disease with an unclear pathophysiology to date, resulting in limited treatment options. Its primary clinical manifestation is diffuse chronic pain, with no objective signs other than "tender points." Consequently, not only is treatment selection challenging, but efficacy evaluation is also quite difficult. Current treatments primarily focus on improving sleep quality, reducing the sensitivity of pain receptors, and enhancing muscle blood flow, as these aspects are believed to be related to the etiology of fibromyalgia syndrome. Treatment efficacy is mainly assessed based on changes in the number of tender points and symptom severity before and after treatment.

A crucial aspect of treatment is providing reassurance and explanation to patients. Informing them that it is not a life-threatening condition nor does it cause lifelong disability can alleviate their anxiety and depression.

Regarding pharmacological treatment, most authors report that tricyclic antidepressants such as amitriptyline and cyclobenzaprine are currently the ideal drugs for treating this condition. They work through: ① antidepressant effects; ② increasing non-rapid eye movement (NREM) sleep and reducing rapid eye movement (REM) sleep; ③ increasing serotonin levels; and ④ relieving muscle spasms, thereby improving sleep and reducing stiffness and pain. Amitriptyline is initially prescribed at 10mg and may be gradually increased to 20–30mg, or cyclobenzaprine at 10–40mg, both taken once before bedtime. Side effects include dry mouth, sore throat, and constipation, but due to the low dosage, most patients can tolerate them.

In recent years, S-adenosylmethionine (SAMe) has been found to have some efficacy in treating fibromyalgia syndrome. It serves as a methyl donor for many methylation reactions in brain tissue and also exhibits antidepressant effects.

For non-pharmacological treatments, literature reports that cardiovascular fitness training and electromyographic (EMG) biofeedback training have shown some efficacy. McCain et al. divided 42 patients with primary fibromyalgia into a cardiovascular fitness training group and a flexibility exercises group. Each group trained three times a week for 60 minutes per session. The cardiovascular fitness training group used a bicycle ergometer, aiming for a heart rate exceeding 150 beats per minute, with the duration gradually extended. The flexibility exercise group performed various activities, rarely reaching a heart rate of 115 beats per minute. After 20 weeks, the cardiovascular fitness training group showed significant improvements in tender point pain intensity, as well as overall assessments by both patients and physicians. Furaccioli et al. conducted 15 sessions of EMG biofeedback training over five weeks for 15 patients with primary fibromyalgia, among whom nine showed improvements in morning stiffness, the number of tender points, and pain intensity. These improvements persisted for six months after treatment ended, and subsequent controlled studies yielded similar results.

Other treatments, such as local sympathetic nerve block, tender point injections, transcutaneous electrical nerve stimulation (TENS), interferential current therapy, acupuncture, and massage, may also be tried. However, the efficacy and mechanisms of these treatments require further research.

bubble_chart Differentiation

The symptoms of fibromyalgia syndrome, such as fatigue and pain, are common clinical manifestations. It needs to be differentiated from the following diseases.

1. Psychogenic wind-dampness pain: Fibromyalgia syndrome is easily confused with psychogenic Bi disease, but the two are significantly different. Psychogenic wind-dampness has emotionally charged symptoms, such as describing the pain as knife-like or burning severe pain, or as numbness, tightness, needle-like, or compressive pain. These symptoms are often vaguely localized, highly variable, lack an anatomical basis, and are unaffected by weather or activity. Patients often have mental or emotional disorders, such as psychoneurosis, depression, schizophrenia, or other psychiatric conditions. Distinguishing between the two is important because the former is more difficult to manage and often requires psychiatric treatment.

2. Chronic fatigue syndrome: Chronic fatigue syndrome includes chronic active EB virus infection and idiopathic chronic fatigue syndrome. It manifests as fatigue and lack of strength but lacks an underlying disease cause. Examining the patient for low-grade fever, pharyngitis, or swollen cervical or axillary lymph nodes, and testing for IgM antibodies against EB virus membrane antigens can help differentiate the two.

3. Wind-dampness polymyalgia: Wind-dampness polymyalgia presents as widespread pain in the neck, shoulder girdle, back, and pelvic girdle. However, it can be distinguished from fibromyalgia syndrome based on characteristics such as elevated erythrocyte sedimentation rate (ESR), prevalence in individuals over 60 years old, synovial membrane biopsy showing inflammatory changes, and sensitivity to hormones.

4. Rheumatoid arthritis (RA): Both RA and fibromyalgia syndrome patients experience widespread pain, stiffness, and a sensation of joint swelling. However, fibromyalgia syndrome lacks objective evidence of joint swelling, its morning stiffness is shorter in duration than RA, and laboratory tests, including rheumatoid factor, ESR, and joint X-rays, are normal. The pain distribution in fibromyalgia syndrome is more widespread, less confined to joints, and often located in the lower back, thighs, abdomen, head, and hips, whereas RA pain is more commonly distributed in the wrists, fingers, and toes.

5. Myofascial pain syndrome: Myofascial pain syndrome, also known as localized fibrositis, also has tender points and can easily be confused with fibromyalgia syndrome. However, the two differ in diagnosis, treatment, and prognosis.

Table 104-1 Comparison of Fibromyalgia Syndrome and Myofascial Pain Syndrome

Gender	More common in women	No gender difference
Pain distribution	Whole body	Localized
Stiffness	Whole body	Localized
Fatigue	Common	Uncommon
Tender areas	Widespread	Localized
Morning fatigue	Present	Sometimes secondary to pain
Treatment	Multiple treatments	Myofascial treatment
Prognosis	Prone to recurrence	Curable

The tender points in myofascial pain syndrome are usually called trigger points. Pressing on these points can cause pain to radiate to other areas. Although patients feel the pain, they may not know where the trigger points are located.

Myofascial syndrome usually has only one or a few localized trigger points. The trigger points originate in the muscles, and the affected muscles have limited movement. Pain can be elicited by either passive stretching or active contraction of the muscle. Local injection of 1% procaine into the trigger points can temporarily relieve the pain. It differs from fibrositis in that it does not involve widespread pain, stiffness, or fatigue. However, if persistent pain leads to stage IV sleep disturbances, myofascial syndrome may evolve into fibromyalgia syndrome.

Myofascial syndrome is usually caused by trauma or overuse. The prognosis is generally favorable.