Patients with fibromyalgia (FM) demonstrate dysregulation of pain neurotransmitter function and experience a neurohormone-mediated association with sleep irregularities.
There are currently no specific instrumental tests or diagnostic markers for FM, and many of the existing indicators are only meaningful for research purposes.
Antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, sedatives, muscle relaxants, and antiepileptics have been used to treat FM with variable results.
Interdisciplinary treatment programs have been shown to lead to greater improvements in subjective pain and function than monotherapies. Physical exercise and multimodal cognitive-behavioral therapy are the most accepted and beneficial forms of non-pharmacological therapy.
| Diagnosis |
FM is usually diagnosed in clinical and observational research studies based on the American College of Rheumatology (ACR) criteria: pain must have been present for at least three months in all four quadrants of the body and there must be >11/ 18 positive tender points (TP) revealed by applying pressure (4 kg/cm2) to predefined body sites.
However, these criteria do not take into account the wide range of symptoms commonly associated with FM and reflected by the term “syndrome ,” including sleep disorders, depression, anxiety, fatigue, cognitive dysfunction, morning stiffness, irritable bowel syndrome. , headache and migraine.
Some recently proposed diagnostic criteria that assess widespread pain, as well as the severity of fatigue, sleep disturbances and cognitive dysfunction, and the extent of somatic symptoms, may improve diagnosis and treatment.
Wolfe et al. have proposed simple clinical criteria that do not require the use of TP and expand the definition of FM to include symptoms other than pain and provide a means to assess their severity. Additionally, the diagnosis is made by combining the patient’s history with a physical examination and laboratory tests, and excluding or taking into account other causes of symptoms attributed to FM.
As FM overlaps with a number of other medical conditions, ranging from rheumatoid arthritis and lupus to hepatitis C infection, treating physicians must be carefully analytical in the overall evaluation of all patients with suspected FM.
| Interdisciplinary treatment |
The goal of FM treatment is to reduce pain and increase function through a multimodal therapeutic strategy that, in most cases, includes pharmacological and non-pharmacological interventions and has as its main objective the treatment of symptoms.
Because patients with FM often present with complex symptoms and comorbidities, they cannot realistically be managed by primary care physicians alone but require the assistance of multidisciplinary teams with expertise in a variety of physical, cognitive, behavioral, and educational strategies. .
Most directors of multidisciplinary treatment programs are rheumatologists or rehabilitation specialists, but there is no reason to exclude other health professionals. Some of the programs that are primarily based on promoting cognitive-behavioral changes only involve rheumatologists and psychologists or psychiatrists, which are often considered essential because most FM patients have difficulty dealing with stress and interpersonal problems, and They are at higher risk of developing depression or anxiety.
Since exercise is a critical part of FM treatment and a key element to the success of cognitive behavioral therapy, most programs would benefit from the addition of an exercise physiologist or physical therapist with prescribing experience. of stretching exercises, aerobic conditioning and strength training. Other potential team member consultants include social workers, occupational therapists, sleep or headache specialists, or massage therapists.
| Pharmacological treatments |
Once a diagnosis of FM is made, patients typically begin drug treatment. Boomershine and Crofford suggest that the three drugs currently approved by the US Food and Drug Administration (FDA) should now be used as "anchor drugs" and, while still important, could later be complemented by older approaches. Unfortunately, no direct comparative studies have yet been published and there is still no consensus on where to start.
Patients with FM experience amplified ascending sensory input; mediated by excessive amounts of neurotransmitters such as glutamate and substance P, which can be reduced by medications such as pregabalin.
In parallel, deficiencies in the diffuse noxious inhibitory control (DNIC) system, descending pain regulatory pathways that play an inhibitory role in pain perception and are mediated in part by the neurotransmitters serotonin and norepinephrine, can be treated with inhibitors. serotonin and norepinephrine reuptake (SNRI). This may be an oversimplification, but it shows that there are at least two complementary symptom management strategies.
Pregabalin is an a2-d ligand that has analgesic, anxiolytic-like, and anticonvulsant activity in animal models, and biochemical studies have found that the major binding site for pregabalin and the related gabapentin is a2-d (type 1).
Alpha2-delta is an auxiliary protein associated with voltage-gated calcium channels, and the potent binding of pregabalin at the a2-d site reduces calcium entry into nerve terminals, reducing the release of several neurochemicals, including glutamate, norepinephrine and substance P, which may explain the analgesic, anticonvulsant and anxiolytic activity of pregabalin in animal models. It has also been suggested that reducing the release of neurotransmitters from neurons in the spinal cord and brain may be clinically beneficial for patients with FM.
Pregabalin is approved for the treatment of FM and neuropathic pain and, in some countries, also for the treatment of generalized anxiety disorder and as an adjuvant medication for seizures. The indicated dose for the treatment of FM is 300 to 450 mg/day divided into two administrations, although many doctors start with smaller nighttime doses as it appears to have a specific beneficial effect on sleep.
Anxiety is also very common in patients with FM, and since patients with comorbid sleep and anxiety disorders almost always experience initial insomnia, pregabalin is a rational choice. The dose may subsequently be increased to the recommended dose, but the increase may be limited by side effects such as weight gain, edema, and dizziness that may resolve over time.
Although not approved by the FDA, the use of gabapentin has also been studied in patients with FM, and daily doses ranging from 1200 mg to 2400 mg have been found to have some effect. Although the gabapentin trial involved many fewer patients than the pregabalin trials, the effect sizes appeared to be similar, so gabapentin may be considered an option, especially when pregabalin is not available.
The other two medications approved by the FDA for the treatment of FM are duloxetine and milnacipran.
Duloxetine is also approved by the FDA for depression, generalized anxiety disorder, painful diabetic neuropathy, and, more recently, chronic musculoskeletal pain.
Milnacipran is also approved for the treatment of major depression in Europe and Japan. Both are SSRIs, and it has been hypothesized that pain, anxiety, chronic stress and depression have overlapping pathogenic backgrounds (neurotransmitters and immune responses), and depression can be considered a systemic disease related to unbalanced neurotransmission also to other neurotrophic drugs, neurosteroids, central nerves, hormonal modifications of the central nervous system (CNS) and generalized somatic autonomic, immunological and metabolic changes.
According to this hypothesis, antidepressants restore neurotransmitter levels and modulate receptor expression in the hypothalamus, normalizing hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. Disturbances of the autonomic system, such as sympathetic overactivity, are found in both depression and FM.
Finally, proinflammatory cytokines within the CNS play a role in the pathophysiology of mood and pain disorders, and their modulation by chronic administration of antidepressants contributes to improving both.
Trials of duloxetine have shown that 70% of its effect on pain is due to its analgesic action rather than its antidepressant action, although it remains a good option for patients with FM, depression and anxiety. The dosage for FM is 60 mg once a day, but usually starts with a daily dose of 30 mg. Duloxetine appears to have a neutral effect on sleep.
Recommended doses of milnacipran range from 50 mg twice daily to 100 mg twice daily. It has been found to significantly improve fatigue and cognitive dysfunction, possibly due to its greater adrenergic effect.
| Analgesic treatment |
Tramadol has been found to be beneficial in patients with FM. It is an atypical analgesic that has a different action on the CNS (the reuptake of serotonin and norepinephrine) from that of other narcotics. Its most common side effects are drowsiness, dizziness, constipation and nausea, and it should not be administered in combination with tricyclic antidepressants (TCAs).
Alone or in combination with acetaminophen, it is commonly prescribed at a dose of 200-300 mg/day to relieve FM-related pain. Fortunately, its potential for drug abuse is negligible, but there is a theoretical risk of seizures and serotonin syndrome when combined with selective serotonin reuptake inhibitors (SSRIs), SSRIs, monoamine oxidase inhibitors (MAOIs), and triptans, although only a few, some cases have been described.
There is no scientific evidence that NSAIDs alone are effective in patients with FM, although they may be useful for analgesia when combined with TCAs. However, the results obtained when NSAIDs are combined with benzodiazepines have not been consistent. The CNS mechanisms of FM (central sensitization and disinhibition and a dysfunctional HPA axis) may explain the relatively reduced effectiveness of NSAIDs and opioids, particularly because the latter are more effective for peripheral pain.
However, NSAIDs may be useful in reducing pain flares induced by excessive physical activity, tendinitis, or bursitis, although they should only be used as necessary to avoid side effects. COX2 inhibitors have far fewer side effects, but are less effective against pain. A recent study has found that transdermal buprenorphine, a potent opioid, has beneficial effects on severe generalized pain (VAS > 6/10), but is less effective on the other typical symptoms of FM.
A subset of FM patients do not respond to opioids, but other patients who may have overlapping conditions such as diabetes, chronic myofascial pain, temporomandibular joint disorder, arthritis, degenerative disc disease, etc., may receive significant benefit. Doses of immediate-release opioids should be increased slowly until pain is reduced, and then patients should be switched to controlled-release opioids.
Opioids may be useful in treating FM-related pain, but they can also be tolerance-inducing and habit-forming, and are also associated with adverse effects such as constipation, sedation, and nausea. Doctors should obtain a detailed medical and psychological profile of the patient before prescribing opioids.
| Combination therapy |
Overall, approximately half of all patients treated with medication appear to experience a 30% reduction in symptoms, suggesting that many FM patients will require additional therapies.
The number of randomized controlled trials of exercise or behavioral interventions in the FM literature has increased dramatically over the past decade. Progressive walking, simple strength training movements, stretching activities, aerobic exercise improve functional status and self-efficacy in women with FM receiving active medication treatment.
Therefore, other forms of treatment, including exercise, cognitive-behavioral therapies, and self-management strategies, may be necessary to achieve satisfactory treatment results. Surprisingly, no randomized controlled data emerge from the literature to explain how many improvements can be obtained by combining pharmacological treatment with a structured rehabilitation or psychological program.
Several medications are commonly used, often in combination. However, it is important to be aware of potential adverse drug interactions, for example, concomitant use of SNRIs and SNRIs or two SNRIs may result in serotonin syndrome that may be difficult to detect and toxic. If a patient prefers to keep medication use to a minimum, it would make sense to choose one or two medications that can affect multiple symptom domains effectively rather than just one.
| Conclusions |
It is clear that, as with other disorders, the most effective treatment of FM must combine the main elements of pharmacotherapy, exercise, physical therapy and CBT. Various medical treatments have been used to treat the different symptoms of FM (pain, sleep disturbances, anxiety and depression) with the ultimate goal of improving patients’ quality of life.
Psychological and physical therapy can sometimes be more effective than drug treatment. Several studies have also evaluated the effect of moderate-intensity exercise, the most appropriate level for FM patients who are generally unfit and unfit.
Highlights for practice
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