The etiology of fibromyalgia (FM) is unknown, and some patients may have a history of prior physical or psychological trauma. The most prominent symptom is a diffuse generalized pain that lasts for more than 3 months, combined with other clinical manifestations, including mood disorders, anxiety disorders, migraines, tension headaches, irritable bowel syndrome, chronic fatigue syndrome, temporomandibular joint disorder syndrome, and chemical sensitivities. It is also currently a chronic pain disorder that cannot be cured. The global prevalence is estimated at 2.7%, with a male to female ratio of 1:3. The origin of pain appears to be neurological, often producing nociceptive hypersensitivity (increased response to painful stimuli) and nociceptive hypersensitivity (pain produced by stimuli that do not normally cause pain).
A high percentage of patients with rheumatic diseases have FM, ranging from 12.6 to 30.4% in ankylosing spondylitis, 13.4 to 16.2% in SLE, and 6.6 to 15.4% in RA. For those with RA only, those with both RA and FM presented with more severe rheumatoid arthritis symptoms, higher disease activity, and poorer quality of life.
In those with inflammatory arthritis, moderate to severe pain and poorer mental health were associated with a clinical diagnosis of FM. Recent studies have found that inflammatory rheumatic disease is a relatively common co-morbidity in patients with FM, with an incidence of 7% in the studied population. Patients with FM with inflammatory rheumatic disease were worse than those without in terms of physical functioning and pain indices, but there were no significant differences in quality of life or mental health between the two groups.
Based on the available evidence, pregabalin, duloxetine and milnacipran should be the drugs of choice for the treatment of this disease, followed by amitriptyline and cyclobenzaprine. Other drugs (with at least one positive clinical trial result) include some selective 5-hydroxytryptamine reuptake inhibitors: morclobemide, pyridostigmine, gabapentin, tramadol, toltestrone, sodium oxybutynate and cannabisolone.
None of the currently known drugs are effective for all symptoms of fibromyalgia, i.e. pain, fatigue, sleep disturbances and depression, and combination therapy in the most relevant symptoms is an option, but more thorough clinical trial studies are needed.
The numerous symptoms in patients with fibromyalgia are accompanied by a high proportion of co-morbidities, making fibromyalgia a highly disabling syndrome that increases health care costs and impairs quality of life. This complex syndrome is difficult to treat, so multidisciplinary crossover treatment is recommended, with combined pharmacologic and nonpharmacologic treatments often recommended. In addition, combining two or more non-pharmacologic treatments (also called polytherapy) is also recommended by most evidence-based guidelines for the treatment of fibromyalgia.
I. Pharmacologic treatment.
Only three drugs, pregabalin, duloxetine and milnacipran, are approved by the US FDA for the treatment of fibromyalgia and must be considered as first-line agents. Health Canada has approved pregabalin and duloxetine, but the European Medicines Agency has not approved any drugs.
1. Antidepressants
Antidepressants are often used to treat different types of chronic pain, including fibromyalgia, although its effectiveness varies with the type of drug and mechanism of action.
Although different tricyclic antidepressants TCAs have been used to treat chronic pain, amitriptyline has been most thoroughly studied in the treatment of fibromyalgia and is recommended by all published clinical practice guidelines.
A systematic review study evaluating the efficacy and acceptability of amitriptyline (10 studies), duloxetine (4 studies), and milnacipran (5 studies) found that amitriptyline improved pain, fatigue, sleep, and health-related quality of life by small to moderate effect sizes, and all outcomes were superior to duloxetine and milnacipran. However, due to methodological limitations, amitriptyline cannot be used as a gold standard. Another meta-analysis showed that amitriptyline was similar to duloxetine, milnacipran, and pregabalin in relieving pain and fatigue.
2. 5-Hydroxytryptamine and norepinephrine reuptake inhibitors
Two 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRIs), duloxetine and milnacipran, have been approved by the FDA for the treatment of fibromyalgia and are currently recommended in all published clinical practice guidelines for the treatment of this disorder.
Duloxetine has been shown to significantly improve the symptoms and effects of fibromyalgia, with the results of placebo-controlled trials suggesting a daily dose of 60 mg , as the 120 mg/d dose does not produce better results and is more poorly tolerated by patients. On the other hand, a 30 mg/d dose was not effective in improving pain.
According to the results of a meta-analysis, duloxetine (5 studies) and milnacipran (5 studies) improved pain and patient-perceived clinical symptoms: fatigue, depressed mood, and health-related quality of life. However, these two drugs had small effect values for pain and patient-perceived clinical symptoms, while the other three had no realistic effect values.
3. Selective 5-hydroxytryptamine reuptake inhibitors
Among the selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), citalopram, escitalopram, fluoxetine, paroxetine, and sertraline have been studied for the treatment of fibromyalgia. All practice guidelines recommend the use of SSRIs.
Based on the results of the meta-analysis, SSRIs (2 studies of paroxetine, 2 studies of citalopram, and 3 studies of fluoxetine) improved pain, depression, sleep, and health-related quality of life. However, effect values for pain, depression and HRQL were small, while sleep effect values were not practically meaningful, and SSRIs are non-interchangeable, so a question remains about the usefulness of these drugs.
4.Monoamine oxidase inhibitors
Two monoamine oxidase inhibitors MAOIs, both reversible with selective monoamine oxidase subtype A, called morclobemide and pyridoxine, have been investigated for the treatment of fibromyalgia.
Moclobemide (150 mg bid) has been shown to improve depression, sleep disturbance, and fatigue significantly more than placebo, but effectiveness did not differ from placebo in terms of pain. Pyrindole (75 mg bid) has been reported to be superior to placebo in improving pain, but does not improve psychological symptoms, fatigue and sleep disturbances, and their use is only recommended by the European League Against Rheumatism (EULAR) practice guidelines.
5.Gabapentin analogues
Pregabalin and gabapentin are drugs that bind to the α2-delta subunit of voltage-gated calcium channels in the central nervous system. Although they were originally licensed as antiepileptic drugs, they are currently used primarily for the treatment of chronic pain. Pregabalin is approved by the FDA for the treatment of fibromyalgia and is recommended in all published guidelines.
In all six short-term placebo-controlled clinical trials, pregabalin was shown to improve pain and sleep disturbances. And the results of a long-term placebo replacement study showed that it significantly maintained, long-term improvements in all outcomes, including quality of life.
A meta-analysis showed that pregabalin (5 studies) and gabapentin (1 study) improved pain, fatigue, sleep, and HRQL, but had small effect values and did not improve depression; in addition, it significantly improved fatigue and anxiety, but the effect values were not realistic.
6.Other drugs
(1) Cyclobenzaprine
Cyclobenzaprine is an “old drug” like tricyclic antidepressants, similar in structure, but approved as a muscle relaxant, and recommended by the European League Against Rheumatism and practice guidelines in Germany and Spain.
It was found that the combination of cyclobenzaprine with ibuprofen (600 mg/d) was not superior to cyclobenzaprine alone (10 mg/d) in relieving pain and improving sleep, while the combination of cyclobenzaprine (10 mg/d) with fluoxetine (20 mg/d) resulted in more significant pain relief.
In a meta-analysis of five clinical trials on cyclobenzaprine, the authors concluded that the drug improved patients’ systemic function and provided moderate improvement in sleep quality.
(2) Tramadol
Tramadol is an atypical analgesic because it is a weak agonist of μ-opioid receptors, as well as a 5-hydroxytryptamine, norepinephrine reuptake inhibitor. A single dose of intravenous tramadol relieves pain in patients with fibromyalgia.
The efficacy of oral tramadol alone versus combined with acetaminophen has been evaluated in the treatment of fibromyalgia for pain relief and improved physical function when combined with acetaminophen. The use of tramadol for the treatment of fibromyalgia is recommended by the European League Against Rheumatism and by practice guidelines in Germany, Spain, and Canada.
(3) 5-HT3 antagonists
Among the drugs used as 5-HT3 receptor antagonists, oral and intravenous toltesetron and intravenous administration of dolasetron have been studied for the treatment of fibromyalgia. 5 mg intravenous toltesetron and 5 mg/10 mg oral toltesetron were more effective in relieving pain than placebo. Intravenous 5mg toltesetron combined with physical therapy was more effective in reducing pain than physical therapy alone. Similarly, intravenous dolasetron provided more effective pain relief, but had no effect on depression, overall symptoms, or quality of life. Practice guidelines from the European League Against Rheumatism and Germany recommend the use of toltestrone.
(4) Dopaminergic agonists
Pramipexole has been found to improve pain, fatigue, and overall symptoms, while two clinical trials evaluating ropinirole failed to demonstrate effectiveness in this regard. The European League Against Rheumatism and Spanish practice guidelines recommend pramipexole for the treatment of fibromyalgia.
(5) Sodium hydroxybutyrate
Sodium hydroxybutyrate is the sodium salt of gamma-hydroxybutyrate, a GABA metabolite. It is licensed for the treatment of narcolepsy and was reported for approval in the United States for the treatment of fibromyalgia. However, in 2010, the FDA denied the request due to concerns about potential abuse risks.
In five clinical trials, the drug was found to improve the symptoms of fibromyalgia. Spanish practice guidelines recommend the use of sodium oxybate for the treatment of fibromyalgia, with the caveat that its use is complex and subject to potential abuse.
Chinese medicine treatment
Fibromyalgia syndrome belongs to the category of paralysis in Chinese medicine. Traditional Chinese medicine treatment can be applied to calm the mind and nourish the blood. The treatment is aimed at relieving the pain and sleep disorders of the patients.